[Federal Register Volume 68, Number 49 (Thursday, March 13, 2003)]
[Proposed Rules]
[Pages 12158-12263]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-5401]
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Part II
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Parts 111 and 112
Current Good Manufacturing Practice in Manufacturing, Packing, or
Holding Dietary Ingredients and Dietary Supplements; Proposed Rule
Federal Register / Vol. 68, No. 49 / Thursday, March 13, 2003 /
Proposed Rules
[[Page 12158]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 111 and 112
[Docket No. 96N-0417]
RIN 0910-AB88
Current Good Manufacturing Practice in Manufacturing, Packing, or
Holding Dietary Ingredients and Dietary Supplements
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing current
good manufacturing practice (CGMP) regulations for dietary ingredients
and dietary supplements. The proposed rule would establish the minimum
CGMPs necessary to ensure that, if you engage in activities related to
manufacturing, packaging, or holding dietary ingredients or dietary
supplements, you do so in a manner that will not adulterate and
misbrand such dietary ingredients or dietary supplements. The
provisions would require manufacturers to evaluate the identity,
purity, quality, strength, and composition of their dietary ingredients
and dietary supplements. The proposed rule is one of many actions
related to dietary supplements that we (FDA) are taking to promote and
protect the public health.
DATES: Submit written or electronic comments by June 11, 2003. Submit
written or electronic comments on the collection of information by
April 14, 2003.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments.
Fax written comments on the information collection to the Office of
Information and Regulatory Affairs, Office of Management and Budget
(OMB), Attn: Stuart Shapiro, Desk Officer for FDA, Fax (202) 395-6974,
or electronically mail comments to [email protected].
FOR FURTHER INFORMATION CONTACT: Karen Strauss, Center for Food Safety
and Applied Nutrition (HFS-821), Food and Drug Administration, 5100
Paint Branch Pkwy., College Park, MD 20740, 301-436-2375.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Background
A. Dietary Supplement Health and Education Act (DSHEA)
B. The Advance Notice of Proposed Rulemaking
C. Industry and Consumer Outreach
1. Dietary Supplement Strategic Plan Meetings
2. Small Business Outreach Meetings
3. Site Visits to Dietary Supplement Manufacturing Firms
D. Food Advisory Committee Report
E. FDA's Decision To Propose a Rule
1. Why Are CGMPs Needed?
a. CGMPs help protect the public health
b. CGMPs benefit consumers
2. How Will CGMP Regulations Take Into Account Technical
Feasibility?
3. How Can FDA Help Industry Achieve Compliance With CGMPs?
F. Proposal Highlights and Requests for Comments
II. General Issues
A. Legal Authority
B. Issues From the ANPRM
III. Description of the Proposed Rule
A. General Provisions (Proposed Subpart A)
1. Who Is Subject to These Part III Regulations? (Proposed Sec.
111.1)
2. What Are These Regulations Intended to Accomplish? (Proposed
Sec. 111.2)
3. What Definitions Apply to this Part? (Proposed Sec. 111.3)
4. Do Other Statutory Provisions and Regulations Apply?
(Proposed Sec. 111.5)
5. Exclusions (Proposed Sec. 111.6)
B. Personnel (Proposed Subpart B)
1. What Microbial Contamination and Hygiene Requirements Apply?
(Proposed Sec. 111.10)
2. What Personnel Qualification Requirements Apply? (Proposed
Sec. 111.12)
3. What Supervisor Requirements Apply? (Proposed Sec. 111.13)
C. Physical Plant (Proposed Subpart C)
1. What Sanitation Requirements Apply to Your Physical Plant?
(Proposed Sec. 111.15)
2. What Design and Construction Requirements Apply to Your
Physical Plant? (Proposed Sec. 111.20)
D. Equipment and Utensils (Proposed Subpart D)
1. What Requirements Apply to the Equipment and Utensils You
Use? (Proposed Sec. 111.25)
2. What Requirements Apply to Automatic, Mechanical, or
Electronic Equipment? (Proposed Sec. 111.30)
E. Production and Process Controls (Proposed Subpart E)
1. What Production and Process Controls Must You Use? (Proposed
Sec. 111.35)
2. What Requirements Apply to Quality Control? (Proposed Sec.
111.37)
3. What Requirements Apply to Components, Dietary Ingredients,
Dietary Supplements, Packaging, and Labels You Receive? (Proposed
Sec. 111.40)
4. What Requirements Apply to Establishing a Master
Manufacturing Record? (Proposed Sec. 111.45)
5. What Requirements Apply to Establishing a Batch Production
Record? (Proposed Sec. 111.50)
6. What Requirements Apply to Laboratory Operations? (Proposed
Sec. 111.60)
7. What Requirements Apply to Manufacturing Operations?
(Proposed Sec. 111.65)
8. What Requirements Apply to Packaging and Label Operations?
(Proposed Sec. 111.70)
9. What Requirements Apply to Rejected Components, Dietary
Ingredients, Dietary Supplements, Packaging, and Labels? (Proposed
Sec. 111.74)
F. Holding and Distributing (Proposed Subpart F)
1. What Requirements Apply to Holding Components, Dietary
Ingredients, Dietary Supplements, Packaging, and Labels? (Proposed
Sec. 111.80).
2. What Requirements Apply to Holding In-Process Material?
(Proposed Sec. 111.82)
3. What Requirements Apply to Holding Reserve Samples of
Components, Dietary Ingredients, and Dietary Supplements? (Proposed
Sec. 111.83)
4. What Requirements Apply to Returned Dietary Ingredients or
Dietary Supplements? (Proposed Sec. 111.85)
5. What Requirements Apply to Distributing Dietary Ingredients
or Dietary Supplements? (Proposed Sec. 111.90)
G. Consumer Complaints--What Requirements Apply to Consumer
Complaints? (Proposed Subpart G, Sec. 111.95)
H. Records and Recordkeeping--What Requirements Apply to
Recordkeeping? (Proposed Subpart H, Sec. 111.125)
IV. Statement Concerning the Use of Plain Language
V. Paperwork Reduction Act of 1995
VI. Environmental Impact Considerations
VII. Analysis of Impacts
A. Introduction
B. Preliminary Regulatory Impact Analysis
1. The Need for the Proposed CGMP Regulations
2. Regulatory Options
a. No new regulatory action
b. Fewer requirements for vitamins and minerals
c. More restrictive CGMP regulations than the proposed
regulations
d. HACCP without the other elements of CGMP regulations
e. Require final product testing only
f. Regulate only high-risk products
3. Coverage of the Proposed Rule
4. Baseline Practices
5. Baseline Risk
6. Benefits and Costs
a. Reduced illnesses
b. Fewer products recalled
c. Reduced hypothetical search costs as a measure of the benefit
from increased assurance of quality
d. Other benefits
e. Total measured benefits
7. Costs
a. Description of the costs
b. Costs of general activity
c. Major costs by type of activities
d. Estimating costs
8. Summary of Benefits and Costs
C. Initial Regulatory Flexibility Analysis
1. Introduction
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2. Economic Effects on Small Entities
a. Number of small entities affected
b. Costs to small entities
3. Regulatory Options
a. Exemptions for small entities
b. Longer compliance periods
4. Description of Recordkeeping and Reporting
5. Summary
VIII. Federalism
IX. Request for Comments
X. References
I. Background
A. Dietary Supplement Health and Education Act (DSHEA)
DSHEA (Pub. L. 103-417) was signed into law on October 25, 1994.
DSHEA, among other things, amended the Federal Food, Drug, and Cosmetic
Act (the act) by adding section 402(g) (21 U.S.C. 342(g)). Section
402(g)(2) of the act provides, in part, that the Secretary of Health
and Human Services (the Secretary) may by regulation prescribe good
manufacturing practices for dietary supplements. Such regulations shall
be modeled after CGMP regulations for food and may not impose standards
for which there is no current and generally available analytical
methodology. No standard of CGMP may be imposed unless such standard is
included in a regulation issued after notice and opportunity for
comment in accordance with 5 CFR chapter V.
Congress enacted DSHEA to ensure consumers' access to safe dietary
supplements. In the findings accompanying DSHEA, Congress stated that
improving the health status of U.S. citizens is a national priority and
that the use of dietary supplements may help prevent chronic diseases
and maintain good health (Ref. 1). If dietary supplements are
adulterated because they contain contaminants (such as filth), because
they do not contain the dietary ingredient they are represented to
contain (for example, a product labeled as vitamin C that actually
contains niacin), or because the amount of the dietary ingredient
thought to provide a health benefit (for example, folic acid to reduce
the risk of neural tube defects or calcium in an amount to reduce the
risk of osteoporosis) is not actually present in the supplement, then
the consumer may suffer harm or may not obtain the purported health
benefit from their consumption. CGMP regulations for dietary
ingredients and dietary supplements will help to ensure that the
potential health benefits that Congress identified as the basis for
DSHEA are obtained and that consumers receive the dietary ingredients
that are stated on the product label.
DSHEA directed the President to appoint a Commission on Dietary
Supplement Labels (the Commission) to consider several issues under
DSHEA needing clarification. The Commission was to conduct a study on,
and provide recommendations for, the regulation of label claims and
statements for dietary supplements, including the use of literature in
connection with the sale of dietary supplements and procedures for the
evaluation of such claims. In making its recommendations, the
Commission was to evaluate how best to provide truthful, scientifically
valid, and nonmisleading information to consumers so that such
consumers could make informed and appropriate health care choices for
themselves and their families. The Commission's report (Ref. 80) states
that the Commission supports the efforts of industry and FDA to develop
appropriate CGMPs for dietary supplements. Guidance on the type of
information that a responsible manufacturer should have to substantiate
statements of nutritional support and safety is also included in the
Commission's report. The Commission's report states that the
substantiation files should include assurance that CGMPs were followed
in the manufacture of the product.
B. The Advance Notice of Proposed Rulemaking
On November 20, 1995, representatives of the dietary supplement
industry submitted to FDA an outline for CGMP regulations for dietary
supplements and dietary supplement ingredients. We evaluated the
outline and determined that it provided a useful starting point for
developing CGMP regulations. Nonetheless, we believed that the industry
outline did not address certain issues that should be considered when
developing a proposed rule on CGMPs for dietary ingredients and dietary
supplements. For example, the industry outline did not address the need
for specific controls for automatic, computer-controlled or assisted
systems.
In addition to identifying a number of issues that were not
included in the industry outline but on which we wanted public comment,
we also recognized that other interested parties, such as consumers,
other industry segments who had not participated in developing the
outline, and the health care community should have an opportunity to
provide comments on CGMPs for dietary supplements before we developed a
proposal. Therefore, in the Federal Register of February 6, 1997 (62 FR
5700), we issued an advance notice of proposed rulemaking (ANPRM)
asking for comments on whether to institute rulemaking to develop CGMP
regulations for dietary ingredients and dietary supplements and what
would constitute CGMP regulations for these products.
The ANPRM contained the entire text of the industry outline. We
also asked nine questions (which we discuss later in section II.B of
this document) in the ANPRM. The questions focused on issues that the
industry outline did not address such as those issues noted above. We
received approximately 100 letters in response to the ANPRM. Each of
those letters contained one or more comments. The comments came from
consumers, consumer advocacy groups, health care professionals, health
care professional organizations, industry, and industry trade
associations. The majority of comments responded both to the nine
questions we asked in the ANPRM and on certain provisions in the
industry outline. We also address the comments on the nine questions in
section II.B of this document. We discuss significant comments about
certain provisions in the industry outline in our discussion of related
proposed requirements.
Included with its comments to the ANPRM, the United States
Pharmacopeia (USP) submitted a copy of its general chapter,
``Manufacturing Practices for Nutritional Supplements,'' (Ref. 2) and
in March/April 2002, USP proposed revisions to this general chapter to
introduce provisions pertaining to botanical preparations (Ref. 82). In
February 2000, we received a copy of the National Nutritional Foods
Association's (NNFA) ``NNFA Good Manufacturing Practice in
Manufacturing, Packing, or Holding Dietary Supplements'' (Ref. 3). We
found that the industry outlines published in the ANPRM, the USP
manufacturing practices, and the NNFA standards were useful in
developing this proposed rule. We included certain provisions found in
these outlines in this CGMP proposed rule. These three outlines
indicate that dietary ingredient and dietary supplement manufacturers
already recognize that there are basic, common steps needed to
manufacture a dietary ingredient or dietary supplement that is not
adulterated although, as established in the regulatory impact analysis,
a large percentage of manufacturers do not follow a good manufacturing
model. For example, these practices include requirements for:
[sbull] Designing and constructing physical plants that facilitate
maintenance, cleaning, and proper
[[Page 12160]]
manufacturing operations or to prevent mixup between different raw
materials and products;
[sbull] Establishing a quality control unit;
[sbull] Establishing and following written procedures for:
1. Maintaining and cleaning equipment and utensils;
2. Receiving, testing, or examining materials received and testing
of finished product;
3. Using master and batch control records;
4. Handling consumer complaints; and
5. Maintaining records for laboratory tests, production control,
distribution, and consumer complaints.
Based on the ANPRM, the comments that we received in response to
the ANPRM, our outreach activities (which we discuss below), and our
own knowledge and expertise about CGMPs for foods, drugs, cosmetics,
devices, and biologics, we are proposing to establish these CGMP
regulations for dietary ingredients and dietary supplements. The
proposed regulations would impose requirements for: (1) Personnel, (2)
physical plants, (3) equipment and utensils, (4) production and process
controls, (5) holding and distributing, (6) consumer complaints related
to good manufacturing practices, and (7) records and recordkeeping.
C. Industry and Consumer Outreach
During 1999, we conducted a number of outreach activities related
to dietary supplements. We held several public meetings to obtain input
from the public on developing our overall strategy for achieving
effective regulation of dietary supplements, which could include
establishing CGMP regulations. We also held public meetings focused
specifically on CGMPs and the economic impact that any CGMP rule for
dietary ingredients and dietary supplements may have on small
businesses. Additionally, FDA staff toured several dietary supplement
manufacturing firms to better understand the manufacturing processes
and practices that potentially would be subject to a CGMP regulation
for dietary ingredients and dietary supplements. Each of these
activities contributed to our knowledge about the industry.
1. Dietary Supplement Strategic Plan Meetings
We held public meetings on June 8 and July 20, 1999, to collect
stakeholder comments on the development of our overall strategy for
achieving effective regulation of dietary supplements. We designed the
meetings to provide an opportunity for public comment on both the
activities we should undertake as part of an overall strategy and the
prioritization of those activities. In the notices for these meetings,
we identified the development of CGMPs for dietary supplements as one
activity that should be considered in an overall strategy.
During and after the strategic meetings, we received comments from
consumers, consumer advocacy groups, health care professionals, health
care professional organizations, industry, and industry trade
associations. The comments addressed a wide range of activities related
to regulating dietary supplements. (These comments can be seen at our
Dockets Management Branch (see ADDRESSES) in docket number 99N-1174.)
The comments generally identified the development of CGMP regulations
as a high priority activity that should be included in any FDA
strategic plan for regulating dietary supplements. Some comments that
addressed the development of CGMPs are summarized as follows:
[sbull] It would be useful to industry to have FDA establish CGMPs
especially for small and intermediate-size firms that are not clear on
what they should be doing;
[sbull] CGMPs would establish a level playing field for industry,
which would help prevent irresponsible firms from making and selling
adulterated products;
[sbull] CGMPs should be able to accommodate a wide variety of
firms, that is, small and large firms that manufacture a wide array of
different types of products and ingredients;
[sbull] CGMPs should ensure that consumers get dietary supplements
with the strength and the purity that consumers expect;
[sbull] CGMPs should ensure that every dietary supplement on the
market has the safety, identity, purity, quality, and strength it
purports in the label to possess;
[sbull] CGMPs should include ingredient identity testing and other
testing;
[sbull] CGMPs should ensure that dietary supplements are produced
using a master formula procedure and produced in a sanitary facility;
[sbull] CGMPs should require that manufacturers have documented
evidence that their manufacturing process is under control on a
consistent basis;
[sbull] CGMPs should require manufacturers to test dietary
ingredients, particularly imported botanicals, for heavy metals,
pesticides, and industrial contaminants;
[sbull] CGMPs should require expiration dating and testing for
dissolution and bioequivalence;
[sbull] CGMPs should require that companies report adverse
reactions; and
[sbull] CGMPs should include guidance on testing for ingredient
identity and adulteration with toxic substances.
2. Small Business Outreach Meetings
We held public meetings on July 12, September 28, and October 21,
1999, to collect information from industry and others that would help
us to understand the economic impact on small businesses of CGMP
regulations for dietary supplements. Transcripts of these public
meetings (docket number 96N-0417, ``Development of Strategy for Dietary
Supplements'') are available at our Dockets Management Branch or
electronically at http://www.fda.gov/ohrms/dockets/dockets/96n0417/tr00001.pdf. Public comments from small businesses included both
support of and concern for CGMP regulations. Small businesses expressed
concerns about the cost and the time involved in complying with any
rule that contains the following requirements:
[sbull] Conducting tests to determine identity, purity, quality,
strength, and composition of dietary ingredients and dietary
supplements;
[sbull] Maintaining written procedures and records documenting that
procedures are followed; and
[sbull] Providing data that support expiration dating.
Public comments from small business expressed support for dietary
supplement CGMP regulation. Some small businesses (1 with 15 employees)
commented that they have CGMPs in place with written procedures
tailored to the size of their operations. One small business with sales
under $1 million commented that their plant materials received in fresh
form are identified onsite by a botanist, and when the onsite botanist
is not able to confirm identity, the plant material is sent to an
outside laboratory that conducts chemical analysis to confirm identity.
3. Site Visits to Dietary Supplement Manufacturing Firms
During the summer and fall of 1999, we visited eight dietary
supplement manufacturing firms. These visits included firms that: (1)
Manufacture a vitamin using a fermentation process; (2) grind, sift,
blend, and otherwise treat raw agricultural commodities (e.g.,
botanicals); (3) manufacture dietary ingredients for use in
manufacturing dietary supplement tablets, capsules, softgels, and
powders; (4) manufacture dietary supplements for packaging and labeling
by others; and (5) manufacture, package, and label dietary supplements
under their own and others' labels. The
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firms varied in size and were located in several parts of the country.
We found an array of manufacturing, packaging, and holding
practices in the firms. The practices included the following:
[sbull] Using CGMPs similar to those included in the ANPRM;
[sbull] Using automatic systems to quarantine, segregate, approve,
and release inventory;
[sbull] Following written procedures;
[sbull] Having quality control units with the responsibility and
authority outlined in the ANPRM;
[sbull] Performing one or more tests on dietary ingredients and
dietary supplements to determine the identity, purity, quality,
strength, and composition;
[sbull] Verifying the reliability of suppliers' certifications; and
[sbull] Documenting and maintaining records for certain procedures,
such as master and batch production, quality control and laboratory
operations, distribution, and processing consumer complaints.
D. Food Advisory Committee Report
In February 1998, the Food Advisory Committee (FAC) established a
Dietary Supplement Working Group to consider what constitutes adequate
testing for identity of different dietary ingredients and what records
are necessary to demonstrate that CGMPs are maintained throughout the
manufacturing and distribution process. The working group issued a
report that discussed the selection of the most appropriate and
reliable identity test and the general principles for consideration in
setting performance standards for such tests (Ref. 4). The report also
identified the types of records that would be necessary to demonstrate
that CGMPs are maintained throughout the manufacturing and distribution
process. On June 25, 1999, the working group presented its report, in
draft form, during an FAC public meeting. We received public comments
during and after the June 25, 1999, public meeting.
Although this proposal does not address dietary ingredient identity
testing in the same detail as the working group's report, we considered
the report in developing requirements for identity testing and CGMP
records requirements in this proposal. The working group's report may
be useful in developing industry guidance to supplement a CGMP
regulation for dietary ingredients and dietary supplements. We discuss
dietary ingredient and dietary supplement identity testing and
recordkeeping for CGMP proposed requirements in more detail later in
this document.
E. FDA's Decision To Propose a Rule
This proposed regulation, which sets forth proposed CGMPs for
dietary ingredients and dietary supplements, is part of our overall
strategy for regulating dietary supplements in a manner that promotes
and protects the public health. Before drafting the proposal, FDA
considered public comment in response to the ANPRM and to public
meetings, observations at site visits to dietary supplement
manufacturers, and advisory group reports. In drafting this proposal,
FDA used, in part, the industry coalition outline that was published as
an ANPRM (62 FR 5700) in which the industry adopted broad provisions
beyond those found in part 110 (21 CFR part 110). FDA's purpose at this
proposed rule stage is to present a broad enough scope so that it may
receive comment on the depth and breadth of what should be considered
by the agency in developing a final rule. Our intent is to provide the
proper balance of regulation so that dietary ingredients and dietary
supplements are manufactured in a manner to prevent adulteration using
recognized scientific principles and both industry and consumer
expectations that are reasonable and appropriate. Therefore, FDA seeks
comment on whether each of the proposed provisions are necessary to
ensure the safety and quality of dietary ingredients and dietary
supplements and whether they are adequate to protect the public health.
In addition, we seek comment on whether there are certain provisions
that are not proposed but that may be necessary. Comments should
include justification for why provisions may or may not be necessary,
including supporting data where appropriate. If comments assert that
certain provisions are not necessary, comments should include an
explanation on how, in the absence of the requirement, one can ensure
that there would be adequate protection of the public health when there
is risk of adulteration. Comments also should address whether the gains
to consumers in product safety and quality are warranted. Moreover,
assuming that this proposal does advance the public health, comments
should address whether there is any reason to apply different
requirements, including greater or lesser requirements on small firms
as compared to larger firms and the rationale for doing so. Finally,
comments should address the agency's legal authority to issue these
regulations.
In deciding whether to propose CGMP regulations for dietary
supplements, we asked ourselves:
[sbull] Why Are CGMP regulations needed?
[sbull] How will CGMP regulations take into account technical
feasibility? and
[sbull] How can FDA help industry achieve compliance with CGMPs?
1. Why Are CGMPs Needed?
CGMP regulations for dietary ingredients and dietary supplements
are necessary to promote and protect the public health. In addition,
CGMP regulations would benefit consumers economically and would benefit
industry.
a. CGMPs help protect the public health. The dietary supplement
industry is one of the fastest growing product areas that FDA
regulates. In 1999, Prevention magazine conducted a survey entitled
``Consumer Use of Dietary Supplements'' (Ref. 5). The survey used data
from telephone interviews with a nationally-representative sample of
2,000 adults living in households with telephones in the continental
United States. The telephone interviews were done in April and May,
1999. Using population estimates based on the Census Bureau's March
1998 Current Population Survey Estimates, the survey stated that
approximately 186,014,712 adults live in the households with telephones
in the United States and that an estimated 158.1 million of these
Americans in households with telephones use dietary supplement
products. These consumers spend approximately $8.5 billion a year on
dietary supplements. The survey also found that:
[sbull] Only 41 percent of the surveyed consumers who use vitamins
and minerals think they are very safe and only 50 percent think they
are somewhat safe;
[sbull] Only 24 percent of the surveyed consumers who use herbal
products think they are very safe; and only 53 percent think they are
somewhat safe; and
[sbull] Twelve percent of the surveyed consumers who have used
dietary supplements say they have experienced side effects or adverse
reactions from their use of dietary supplements.
The survey also found strong public support for increased
Government regulation of dietary supplements; 74 percent of the
surveyed consumers reported that they think that the Government should
be more involved in ensuring that these products are safe and do what
they claim to do.
However, unlike other major product areas, there are no FDA
regulations that
[[Page 12162]]
are specific to dietary ingredients and dietary supplements that
establish a minimum standard of practice for manufacturing, packaging,
or holding. The absence of minimum standards has contributed to the
adulteration and misbranding of dietary ingredients and dietary
supplements by contaminants or because manufacturers do not set and
meet specifications for their products, including specifications for
identity, purity, quality, strength, and composition. Thus, CGMP
regulations are necessary to protect the public health because a CGMP
rule would establish a minimum standard of practice for manufacturing,
packaging, and holding dietary ingredients and dietary supplements.
The following examples illustrate the wide range of dietary
ingredient and dietary supplement adulteration caused by manufacturing,
packaging, or holding practices. The examples, although not exhaustive,
demonstrate why CGMPs are necessary to protect public health:
[sbull] In 1997, we received an adverse event report (AER)
regarding a young woman who had taken a dietary supplement and
experienced a life-threatening abnormal heart function (Ref. 6). We
investigated the AER and determined that the dietary supplement the
woman consumed contained Digitalis lanata, a plant that can cause life-
threatening heart reactions (Refs. 6 through 10). We found D. lanata in
samples of raw material labeled ``plantain'' that was a dietary
ingredient in one of the dietary supplement products used by this woman
(Ref. 6). A nationwide listing of manufacturers indicated that 183
firms may have used the contaminated dietary ingredient in dietary
supplements. The proposed CGMP regulations, had they been in effect,
would have required identity and purity tests of dietary ingredients
and dietary supplements and would likely have prevented the use of the
D. lanata in these dietary supplements.
[sbull] In 1998, the American Herbal Products Association (AHPA)
surveyed its members about commonly adulterated botanicals and methods
useful in detecting adulteration in botanicals (Ref. 11). AHPA members
identified 43 botanicals, including D. lanata contaminated plantain,
that are commonly adulterated with contaminants, the common adulterant
for each botanical, and a method for identifying the adulterant. For
example, aflatoxin and mycotoxin (toxic compounds produced by certain
molds) are known to contaminate certain herbal and botanical dietary
supplements (Refs. 11 through 14). Under this proposed rule, a
manufacturer would have to establish specifications for botanicals that
may contain toxic compounds and conduct testing to ensure that there
are not toxic compounds present that may adulterate the dietary
ingredient or dietary supplement.
[sbull] We have found manufacturers using nonfood-grade chemicals
to manufacture dietary supplements (Ref. 15). The proposed rule would
require that manufacturers establish specifications for components used
in manufacturing and also would require manufacturers to establish and
follow laboratory control procedures that include criteria for
establishing appropriate specifications. The proposal would further
require manufacturers to conduct testing to confirm that their
specifications are met. These requirements, if finalized, would ensure
that manufacturers establish and use appropriate criteria, such as
using food-grade rather than industrial-grade chemicals, and would
ensure that manufacturers conduct testing to confirm that food-grade
chemicals were received from the supplier.
[sbull] Also during inspections, we have found insanitary
conditions in physical plants where dietary ingredients or dietary
supplements were manufactured, packaged, or held (Ref. 16). Pest
infestation, building and equipment defects, and leaking pipes that
drip onto dietary supplements are examples of insanitary conditions
that we have found that may lead to product adulteration and could
cause consumer illnesses and injuries. The proposed rule would require
a manufacturer, packager, or holder to maintain its physical plant used
for these activities in a sanitary condition.
[sbull] In the past, we have been involved in the recall of dietary
supplements contaminated with lead (Ref. 17), salmonella (Ref. 18),
Klebsiella pneumonia (Ref. 19), botulism (Ref. 20), and glass (Ref.
21). These contaminants can cause serious illness or injury and, in the
case of lead, may result in chronic irreversible cognitive defects in
children and progressive renal failure in adults. The proposed rule
would require dietary ingredients and dietary supplements to be
manufactured, packaged, and held in a manner that prevents
adulteration, including adulteration by the contaminants such as those
described.
[sbull] We also have been involved in recalls for super- and
subpotent dietary supplements. Recalls of superpotent dietary
supplements have included the following dietary ingredients: Vitamin A
(Ref. 22), vitamin D (Ref. 23), vitamin B6 (Ref. 24), and selenium
(Ref. 25). Each of these dietary supplements contained dietary
ingredient levels that could have caused serious illness or injury.
Illnesses or injuries such as nausea, vomiting, liver damage, and heart
attack were reported from superpotent niacin at an average level of 452
milligrams (mg) niacin, well above the upper limit for adults of 45 mg
daily (Ref. 26). Recalls for subpotent dietary supplements have
included a recall of folic acid because the dietary supplement
contained 34 percent of the declared level (Ref. 27). Such a product
would be misbranded under section 403 of the act (21 U.S.C. 343).
Folate plays a well-documented and important role in reducing the risk
of neural tube defects. Neural tube birth defects, primarily spina
bifida and anencephaly, cause serious lifetime debilitating injuries
and disabilities, and even death. Thus, use of subpotent folic acid by
women who are or may become pregnant may result in increased risk of
having a child with a neural tube defect. The proposed rule would
require manufacturers to establish specifications for the dietary
supplement the manufacturer makes and then meet those specifications.
Therefore, if the proposed rule is finalized, if the label for a folic
acid supplement declares that the dietary supplement contains a certain
level of folic acid, the folic acid supplement must actually contain
that level, or we would consider the folic acid supplement to be
adulterated under section 402(g) of the act.
[sbull] Other recalls have been necessary because of undeclared
ingredients, including color additives (Refs. 28 and 29), lactose (Ref.
30), and sulfites (Ref. 31). Undeclared ingredients, such as color
additives, lactose, and sulfites, may cause potentially dangerous
reactions in susceptible persons (Ref. 32). The proposed rule would
require manufacturers to verify that the correct labels have been
applied to dietary ingredients and dietary supplements produced. The
master manufacturing record would have to identify each ingredient
required to be declared on the ingredient list under section 403 of the
act.
[sbull] A study found that dietary ingredient content varied
considerably from the declared content (Ref. 33). The study examined
ephedra alkaloids in 20 herbal dietary supplements containing ephedra
(Ma Huang) to determine their ephedra alkaloid content. This study
found that norpseudoephedrine was often present in the ephedra dietary
supplements. The study also observed significant lot-to-lot variations
in alkaloid content for four products,
[[Page 12163]]
including one product that had lot-to-lot variations of ephedrine,
pseudoephedrine, and methylephedride that exceeded 180 percent, 250
percent, and 1,000 percent, respectively. Half of the products tested
differed in their label claims for ephedra alkaloid content and their
actual alkaloid content. In some cases, the discrepancy exceeded 20
percent. One product did not have any ephedra alkaloids. Lot-to-lot
variation in dietary ingredients is a public health problem
particularly because conditions of use recommended or suggested in the
labeling of dietary supplements are presumably based on the dietary
supplement containing a certain amount of the dietary ingredient. If
the dietary supplement contains more or less than the amount that the
manufacturer represents, then the consumer does not receive the
potential health benefit from the dietary supplement or is exposed to
an amount that could present risk of injury or illness. The proposed
rule would require manufacturers to establish controls, including
master manufacturing and batch production records to ensure that they
use the correct amount of the dietary ingredient to produce the dietary
supplement, and that they apply the correct label to the dietary
supplement.
[sbull] A private company analyzed a sample of dietary supplements
and found that some dietary supplements did not contain the dietary
ingredients claimed on the label (Ref. 34). The study found that 25
percent of gingko biloba products, 20 percent of saw palmetto, 33
percent of glucosamine, chrondroitin and combined glucosamine/
chondroitin, and 50 percent of SAMe did not contain the dietary
ingredients claimed in their product labels. The proposed rule would
require manufacturers to establish and meet specifications for the
identity, purity, quality, strength, and composition of dietary
supplements.
Given the wide range of public health concerns presented by the
manufacturing, packaging, and holding practices for dietary ingredients
and dietary supplements, a comprehensive system of controls is
necessary to prevent adulteration and misbranding. CGMPs are intended
to establish such a comprehensive system. Manufacturers who operate in
accordance with CGMPs would be less likely to distribute adulterated
and misbranded dietary ingredients or dietary supplements than those
who do not meet the requirements. Quality assurance will maximize the
probability that unadulterated dietary supplements will reach the
marketplace.
Establishing CGMP regulations for dietary supplements is only part
of our broad science-based regulatory program for dietary supplements
that is necessary to give consumers a high degree of confidence in the
safety, composition, and labeling of dietary supplements. Aside from
our CGMP efforts, we have taken other steps to protect the public
health, such as:
[sbull] Reviewing claim notifications under section 403(r)(6) of
the act to identify unlawful claims;
[sbull] Reviewing new dietary ingredient notifications to ensure
that new dietary ingredients are reasonably expected to be safe under
section 413 of the act (21 U.S.C. 350b);
[sbull] Evaluating the nutrition labeling of dietary supplements;
[sbull] Monitoring, through AERs voluntarily submitted to FDA, the
occurrence of adverse events to identify potentially unsafe products;
and
[sbull] Taking compliance actions against products that are
adulterated or misbranded.
The CGMP regulation, if finalized, would, along with our other
dietary ingredient and dietary supplement initiatives, contribute
further to the protection of public health.
b. CGMPs benefit consumers. In addition to the public health
benefits for consumers, CGMP regulations for dietary ingredients and
dietary supplements will benefit consumers in other ways. Consumers
should not have to wonder whether the dietary supplements they buy are
adulterated or whether they contain the correct dietary ingredients or
contain the dietary ingredients in the amount stated on the product's
label. Consumers who purchase a product that does not contain the
amount or strength listed on the label experience an economic loss
because they are paying for something that they did not receive. CGMPs
would require manufacturers to establish and meet specifications for
identity, purity, quality, strength and composition of dietary
supplements to help ensure that consumers buy dietary supplements that
are not adulterated, contain the dietary ingredients declared on the
product's label, and contain the amount or strength listed on the
label. Therefore, CGMPs would benefit consumers.
2. How Will CGMP Regulations Take Into Account Technical Feasibility?
In developing this proposed rule, we were careful not to propose
requirements that are not technically feasible to meet. In some areas
where there has been scientific study but where the science is still
evolving, the proposal recognizes the evolving state of the science,
but would give you maximum flexibility in meeting the requirement. For
example, there are tests available for identity, purity, quality,
strength, and composition of certain dietary ingredients or dietary
supplements. Because many tests for identity, purity, quality,
strength, and composition of dietary ingredient or dietary supplements
have not been officially validated, the proposal would permit tests
using methods other than those that are officially validated. By using
the term ``officially validated,'' we mean that the method is validated
using an interlaboratory collaborative study by which a proposed method
is validated by independent testing in separate laboratories under
identical conditions (Ref. 35). An AOAC International (formerly the
Association of Official Analytical Chemists) Official Method is an
example of an officially validated method. We discuss test methods
validation in more detail later in this document.
In areas where scientific study is still evolving, we did not
propose specific requirements. For example, we did not propose
requirements for dissolution, disintegration, bioavailability, or
expiration dating. In those areas, it may be premature to propose a
requirement at this time. In the preamble to this rule, we identify
those areas where additional scientific study is necessary before we
can propose a dietary supplement CGMP requirement. For example, we did
not identify defect action levels (DALs) for dietary ingredients
because there are not enough data available to identify an appropriate
DAL for most dietary ingredients. Likewise, further study is needed for
some dietary ingredients before dissolution, disintegration,
bioavailability, expiration dating, or other quality standard
requirements can be proposed.
3. How Can FDA Help Industry Achieve Compliance With CGMPs?
During small business outreach public meetings and in comments to
the ANPRM, members of the dietary supplement industry told us that they
would like our help in determining how to implement CGMP regulations
for dietary ingredients and supplements. We have heard that issuing
guidance documents and education and training would be helpful. We
invite comment on the use of guidance documents, education, training,
or other approaches and potential sources of education and training
that you believe would assist industry efforts to implement the
proposed CGMP regulations, if finalized as proposed.
[[Page 12164]]
F. Proposal Highlights and Requests for Comments
This proposed rule is intended to ensure that manufacturing
practices will not result in an adulterated dietary supplement and that
supplements are properly labeled. This proposed rule, if finalized as
proposed, will give consumers greater confidence that the dietary
supplements they choose to use will have the identity, strength,
purity, quality, or composition claimed on the label. A manufacturer of
a dietary ingredient or a dietary supplement cannot make claims that
state or imply that the dietary ingredient or dietary supplement is
safe and/or effective simply because it has been manufactured in
compliance with current good manufacturing practice (CGMP)
requirements. However, we believe that a voluntary labeling statement
about the fact that a dietary ingredient or dietary supplement has been
made in compliance with CGMP requirements might be made lawfully under
the act, provided that such a statement is made in an appropriate
context and with adequate disclaimers so that consumers fully
understand it and are not misled by it. The proposed rule governing
CGMP requirements for dietary supplements address manufacturing
controls to ensure that dietary ingredients and dietary supplements are
produced in a manner that will not adulterate or misbrand such
products. Compliance with any final rule, based on the proposal, will
not ensure that the dietary ingredient or dietary supplement itself is
safe or effective. Thus, the agency believes that an unqualified
statement saying simply ``produced in compliance with dietary
supplement current good manufacturing practice requirements,'' without
more, could well suggest that a product may be safe and effective or
somehow superior to other dietary ingredient and dietary supplement
products that are subject to the same CGMP requirements. Such a
statement would likely be considered misleading by FDA under sections
403(a)(1) and 201(n) of the act. We believe however, that it might be
possible to cure an unqualified statement by including language
clarifying to consumers that all dietary ingredients and dietary
supplements must be manufactured in compliance with CGMP requirements
and that such compliance does not mean that the dietary ingredient or
dietary supplement is safe or effective. As usual, the manufacturer
would be responsible for ensuring that any such voluntary labeling
statements on its dietary ingredient and dietary supplement products
are truthful and not misleading. The agency would review the lawfulness
of such statements under sections 403(a)(1) and 201(n) of the act.
We propose requirements for: (1) Personnel, (2) the physical plant
environment, (3) equipment and utensils, (4) production and process
controls, (5) holding and distributing, (6) consumer complaints related
to CGMPs, and (7) records and recordkeeping. Key provisions of the
proposed rule are highlighted below. We also seek comment on whether
certain additional provisions should be included as requirements in a
final rule.
Proposed ``personnel'' requirements would require that you have
qualified employees and supervisors, to take measures to exclude any
person from your operations who might be a source of microbial
contamination, and to use hygienic practices to the extent necessary to
protect against contamination.
Proposed ``physical plant'' requirements are intended to help
prevent contamination from your physical plant environment. You would
be required to design and construct your physical plant in a manner to
protect dietary ingredients and dietary supplements from becoming
adulterated during manufacturing, packaging, and holding. You would be
required to keep your physical plant in a clean and sanitary condition
and in sufficient repair to prevent contamination of components,
dietary ingredients, dietary supplements, or contact surfaces.
Proposed ``equipment and utensils'' provisions would require that
you use equipment and utensils that are of appropriate design,
construction, and workmanship for their intended use and that you
provide for adequate cleaning and maintenance. You would be required to
maintain and calibrate your instruments and controls for accuracy and
precision and to ensure that automatic, mechanical, and electronic
equipment works as intended. You would also be required to maintain,
clean, and sanitize, as necessary, all equipment utensils and contact
surfaces that are used to manufacture, package, or hold dietary
ingredients or dietary supplements.
Under the proposed ``production and process controls''
requirements, you would be required to establish and use a quality
control unit in your manufacturing, packaging, and label operations. We
propose requirements for establishing and using master manufacturing
records and batch control records to ensure batch-to-batch consistency.
Specifications would be required for any point, step, or stage in the
manufacturing process where control is necessary to ensure that the
dietary supplement contains the identity, purity, quality, strength,
and composition claimed on the label. We propose flexible testing
requirements: You would be required to test final products for
adherence to specifications, unless a scientifically valid analytical
method does not exist; in the latter case, you would be required to
test incoming shipment lots of components, dietary ingredients, or
dietary supplements for any such specification, and to test in-process
for any such specification in accordance with the master manufacturing
record where you determine control is necessary to ensure the identity,
purity, quality, strength, and composition of the product.
Proposed ``holding and distributing'' requirements would protect
components, dietary ingredients, dietary supplements, packaging, and
labels against contamination and deterioration. You would be required
to hold components, dietary ingredients, dietary supplements,
packaging, and labels under appropriate conditions of temperature,
humidity, and light so that their quality is not affected; and under
conditions that do not lead to the mixup, contamination, or
deterioration.
Proposed ``consumer complaints'' requirements would require that
you keep a written record of each consumer complaint related to good
manufacturing practices; review such complaints to determine whether
the consumer complaint involves a possible failure of a dietary
ingredient or dietary supplement to meet any of its specifications, or
any other requirements of this part, including those that may result in
a possible risk of illness or injury (i.e., an adverse event); and
investigate a consumer complaint when there is a reasonable possibility
of a relationship between the consumption of a dietary supplement and
an adverse event. For the purposes of this regulation, a consumer
complaint about product quality may or may not include concerns about a
possible hazard to health. However, a consumer complaint does not
include an adverse event, illness, or injury related to the safety of a
particular dietary ingredient independent of whether the product is
produced under good manufacturing practices.
Proposed ``records and recordkeeping'' requirements would tell you
how long you must keep certain records to show how you complied with
the CGMP requirements. We would require that you keep written records
for 3 years beyond the date of manufacture of the last batch of dietary
ingredients
[[Page 12165]]
or dietary supplements associated with those records and have all
required records, or copies of such records, readily available during
the retention period for authorized inspection and copying by FDA when
requested.
CGMP records document the manufacturer's operation throughout time
and are essential to an enforceable regulation. Because FDA does not
observe the manufacturer's operation fulltime, records can ensure that
the FDA has the information needed to identify noncompliance and to
bring a non-compliant manufacturer into compliance. Records can show
that appropriate monitoring is performed, pinpoint with confidence when
a deviation began and ended, and prove that required quality control
measures and practices were performed as often as necessary to ensure
control. Review of manufacturing records with sufficient frequency can
ensure that any problems are uncovered promptly and can facilitate
prompt modification, have an impact on the production of subsequent
batches of the product, and prevent introduction of potentially
hazardous dietary supplements into the market place. Review of consumer
complaint records can facilitate the identification of trends in
reports of illness or injury, identify related batch records to
identify previously undetected manufacturing deviation, and have an
impact on the prompt recall of any potentially hazardous dietary
supplement.
We seek comment on whether the proposed recordkeeping requirements
are not necessary to prevent adulteration; to ensure the identity,
purity, quality, strength, and composition of the dietary ingredient or
dietary supplement; to an enforceable regulation; and for the other
reasons cited. If comments assert that recordkeeping provisions are not
necessary, comments should include an explanation of why recordkeeping
requirements are not necessary including how, in the absence of the
requirements, one can prevent adulteration, ensure the identity,
purity, quality, strength, and composition of the dietary ingredient or
dietary supplement, ensure an enforceable regulation, and the other
reasons cited. If comments agree that the recordkeeping requirements
are necessary for reasons other than those we have provided, the
comments should so state and provide an explanation.
Although records are not required in 21 CFR Part 110, CGMPs in
manufacturing, packing, or holding human food, records are required in
the other commodity-driven food CGMPs (i.e., 21 CFR Part 129,
Processing and bottling of bottled drinking water; 21 Part CFR 120,
Hazard Analysis and Critical Control Point (HAACP) Procedures for the
Safe and Sanitary Processing and Importing of Juice; 21 CFR Part 123,
Fish and fishery products; 21 CFR Part 106 Infant formula quality
control procedures; and 21 CFR Part 113, Thermally processed low-acid
foods packaged in hermetically sealed containers). Further, records are
included in the CGMPs submitted to FDA by industry, the National
Nutritional Foods Association Standards, the NSF International draft
standards (Ref. 83), and the USP draft Manufacturing Practices for
Dietary Supplements.
We seek comment on whether certain additional provisions should be
included as requirements in a final rule. For example, we invite
comment on whether a final rule should include a requirement for
certain personnel records; for written procedures in a number of areas;
for equipment verification; and for expiration dating and related
testing. Written procedures are included in the dietary supplement CGMP
outline submitted to FDA by industry, National Nutritional Foods
Association standards, the NSF International draft standards, and the
USP draft Manufacturing Practices. In order to limit the burden to
manufacturers, FDA is not proposing to require written procedures.
However, FDA is proposing that manufacturers maintain appropriate
records to ensure the identity, purity, quality, strength, and
composition of a given product and records that are necessary for
efficient enforcement and to permit trace back. Although we have not
proposed requirements for written procedures as did these other groups,
we seek comment on whether such practices should be included in a final
rule. Later in this document, we request comments on specific written
procedures and describe FDA's current thinking concerning what could be
included in such a written procedure.
We also seek comment on whether this rule should include specific
requirements for the use of animal-derived dietary ingredients, and
requirements for persons who handle raw agricultural commodities.
Specific requests for comment of this type are contained below in
relevant sections of this preamble.
II. General Issues
A. Legal Authority
We are proposing these regulations under sections 201, 393, 409,
701(a), 704, and 801 of the act (21 U.S.C. 321, 903, 348, 371(a), 374,
and 381) and sections 402 and 403 of the act and section 361 of the
Public Health Service Act (the PHS Act) (42 U.S.C. 264).
Section 402(g) of the act gives us explicit authority to issue a
rule regulating conditions for manufacturing, packaging, and holding
dietary supplements. Section 402(g)(1) of the act states that a dietary
supplement is adulterated if ``it has been prepared, packed, or held
under conditions that do not meet current good manufacturing practice
regulations.'' Section 402(g)(2) of the act authorizes us to, by
regulation, ``prescribe good manufacturing practices for dietary
supplements.'' In addition, section 402(g)(2) of the act states that
any such regulations ``shall be modeled after current good
manufacturing practice regulations for food and may not impose
standards for which there is no current and generally available
analytical methodology.''
In section 402(g)(2) of the act, which describes the general
parameters of CGMPs for dietary supplements, Congress stated that the
regulations were to be ``modeled after current good manufacturing
practice regulations for food.'' To determine what Congress meant, we
look to the plain meaning of the phrase. Webster's II New Riverside
University Dictionary defines ``model'' as ``[a] preliminary pattern
serving as the plan from which an item not yet constructed will be
produced'' (Ref. 81). Thus, when Congress used the term ``modeled
after'' Congress intended that we use the food CGMPs as a ``preliminary
pattern'' for the dietary supplement CGMPs. If Congress had intended
for the agency to adopt food CGMPs as the CGMPs for dietary
supplements, Congress could have explicitly stated that dietary
supplements were subject to food CGMPs.
The provisions in the dietary supplement CGMP proposal are modeled
after food CGMPs. The general CGMP provisions for food in part 110
relate not only to insanitary production practices, but other
practices, such as having appropriate quality control operations, to
ensure that a food is manufactured in a manner that will not adulterate
the food. Further, the CGMPs in part 110 describe the minimally
acceptable practices for all food handling operations. They are not
intended to cover specific issues that may relate to a particular
product type, rather, are general provisions concerned with practices
relating to the receiving, inspecting, quality control operations,
packaging, segregating, processing, storing, and transporting of food.
The specific provisions of the food CGMPs
[[Page 12166]]
are linked to hazards that are inherent to foods (e.g., microbial
contamination and contamination with macroscopic filth).
The proposed dietary supplement CGMPs are modeled after the food
CGMPs in part 110 in that they cover the scope of practices related to
the receiving, inspecting, quality control operations, packaging,
segregating, processing, storing, and distribution of dietary
ingredients and dietary supplements. Dietary supplements require many
of the same types of sanitary practices and other practices as
conventional food production in order to produce a product that is not
adulterated; dietary supplements are subject to many of the same
hazards as are conventional foods. However, dietary supplements have
their own set of unique requirements as a result of the characteristics
and hazards due to their ``hybrid'' nature, e.g., dietary supplements
can be considered as falling somewhere along the continuum between
conventional foods on the one hand and drugs on the other. Thus, the
CGMPs for dietary supplements need to address the characteristics and
hazards of dietary supplements, the operations and processes used to
manufacture dietary supplements, particularly those necessary to ensure
the identity, purity, quality, strength, and composition claimed on the
label.
Dietary supplements, unlike conventional foods, contain ingredients
that are consumed in very small quantities, for example, in a tablet or
capsule. Such ingredients may be intended to have an anticipated,
specific physiological response. Such ingredients are more ``drug-
like'' than ``food-like,'' in part, because very small changes in the
strength, purity, or quality of the ingredient can have significant,
and possibly adverse, health consequences to those who ingest it. Thus,
the dietary supplement CGMPs, by necessity, need to include provisions
related to identity, purity, strength, quality, and composition of the
product so that the dietary supplement ``food'' product will be
manufactured in a manner that will not result in adulteration.
Further, plant products that are used to produce dietary
supplements may be ground or in a powder and not easily recognized
compared to conventional food that is readily identifiable (e.g., one
can readily distinguish between white flour and white sugar, but not
between ground plaintain and ground D. lanata). Thus, for the
manufacturer to be sure that the dietary supplement contains the
correct ingredient and the amount of the ingredient that is intended,
the manufacturer must test or examine the ingredient using appropriate
methods. The ``modeled after'' language in section 402(g) of the act
provides the agency with the flexibility to devise CGMPs that make
sense for dietary supplements, and that are based on the same
principles as food CGMPs in part 110, i.e., to prevent adulteration
related to insanitary conditions or other conditions that may be
necessary to prevent adulteration, given the nature of the specific
food product and the characteristics of, and hazards inherent in, that
food.
The scope of the legal authority for the proposed dietary
supplement CGMPs includes the legal authorities upon which the food
CGMPs are based. For example, section 402(a)(3) of the act states that
a food is deemed adulterated if ``it consists in whole or in part of
any filthy, putrid, or decomposed substance, or if it is otherwise
unfit for food.'' Section 402(a)(4) of the act states that a food is
deemed adulterated if ``it has been prepared, packed, or held under
insanitary conditions whereby it may have become contaminated with
filth, or whereby it may have been rendered injurious to health.''
While section 402(a)(3) of the act focuses on the food itself, section
402(a)(4) of the act focuses on the conditions under which the food is
prepared, packed, or held. Courts have adopted a broad reading of
section 402(a)(4) of the act when we have taken actions to advance the
public health (see U.S. v. Nova Scotia Food Products Corp., 568 F. 2d
240, 248 (2d Cir. 1977)). The agency tentatively concludes that the
authorities that it relied on for its umbrella CGMPs in part 110 for
food are relevant to the authorities that it needs for this proposed
rule for dietary supplement CGMPs. In addition, section 409 of the act
is another provision that is relevant to dietary supplement CGMPs.
Section 409 of the act addresses circumstances under which a food may
be deemed adulterated based on the use of a food additive. Section 409
of the act is relevant to good manufacturing practices for foods,
including dietary supplements, because a food would be deemed
adulterated if it contained a food additive that was not used in a
manner consistent with the statutory and regulatory requirements under
section 409 of the act (see sections 402(a)(2)(C) and 409 of the act).
Although Congress explicitly excluded ``dietary ingredients,'' as
defined in section 201(ff) of the act, from the definition of food
additive, (see section 201(s)(6) of the act), ingredients other than
dietary ingredients in a dietary supplement are subject to regulation
as a food additive under section 409 of the act, unless they are
subject to an exception to the definition of ``food additive'' under
section 201(s) of the act.
Moreover, dietary ingredients and dietary supplements may contain
pathogenic bacteria or viruses that pose serious public health and
safety concerns (Ref. 36). Botanical dietary ingredients are living
plants that may contain different microorganisms. These include
Lactobacillus, Leuconostoc, Pseudomonas, and Xanthomonas species and
molds. Potential pathogens such as Listeria monocytogens, Pseudomonas
aeruginosa and Enterobacteriacae may also be present. Secondary
microbial contamination from soil (Bacillus cereus, Clostridium
perfringens and mycotoxin-producing molds, etc.), animal feces
(Salmonella and Shigella spp., Escherichia coli) and handling
(Staphylococcus aureus) can also occur during harvesting, processing,
and transportation (Ref. 36). Animal-derived dietary ingredients or
dietary supplements may also pose a risk. For example, bovine
colostrum, the lacteal secretion which precedes milk after a cow gives
birth, is a substance that is used in dietary supplements and likely
presents the same potential health risks as does milk. Bovine milk may
contain pathogenic organisms capable of causing diseases in man such as
tuberculosis or undulant fever. Glands and other animal tissues may
contain the infective agent that causes transmissible spongiform
encephalopathy (TSE) if they originate from an animal infected with the
disease (Ref. 37).
We have authority to issue regulations under section 361 of the PHS
Act. The Secretary delegated authority to the Commissioner of FDA (the
Commissioner) to exercise the functions vested in the Secretary under
section 361 of the PHS Act (see 21 CFR 5.10(a)(3)). This authority
authorizes the Commissioner to issue and enforce regulations that, in
the Commissioner's judgment, are necessary to prevent the introduction,
transmission, or spread of communicable diseases from one State to
another. Because this authority is designed to eliminate the
introduction of diseases from one State to another, the Commissioner
may exercise the authority over the disease-causing substance within
the State where the food is manufactured, packaged, or held. The
Commissioner, therefore, assumes the authority to issue regulations
under the PHS Act to assure that foods are manufactured, packaged, and
held under conditions that will prevent the introduction, transmission,
[[Page 12167]]
or spread of communicable diseases between States. Thus, the agency is
invoking its authority under the PHS Act in this proposed rule to
prevent the spread of communicable disease from dietary ingredients or
dietary supplements in intrastate and interstate commerce.
In developing proposed CGMPs for dietary supplements, we relied on
the basic concept underlying the food CGMPs and upheld by the courts.
As a result, the basic concept for the food CGMPs and the proposed
dietary supplement CGMPs is the same: To establish regulations that
will help ensure that your practices for preparing, packaging, and
holding dietary ingredients and dietary supplements do not result in an
adulterated food entering interstate commerce.
In addition to relying on the broad authority in relevant sections
of the act that we used to issue the food CGMP regulations, we look to
the other relevant statutory language in section 402(g) of the act and
the act as a whole in deciding the basis for our legal authority in
proposing regulations related to the manufacture, packaging, and
holding of dietary ingredients and dietary supplements. We note that
certain terms Congress used in section 402(g)(2) of the act, i.e.,
``standards'' and ``current and generally available analytical
methodology,'' show that Congress intended to give us the authority to
establish regulations in this rule that do not have parallel provisions
in other food CGMPs. Specifically, the second phrase of the second
sentence in section 402(g)(2) of the act states that we ``may not
impose standards for which there is no current and generally available
analytical methodology.'' ``Standards'' and ``current and generally
available analytical methodology'' are terms of art in the scientific
field, and we are relying on the meaning of these terms in the field of
science in these proposed CGMPs regulations, which implement that
provision. This statutory language does not limit CGMPs for dietary
supplements solely to the food CGMP regulations at the time DSHEA was
enacted. If Congress had intended for the CGMPs for dietary supplements
to be identical to the CGMPs for food, the language in section
402(g)(2) of the act relating to ``standards'' and ``current and
generally available analytical methodolog[ies]'' would be meaningless.
Thus, CGMP regulations for dietary ingredients and dietary supplements
may include provisions relevant to dietary ingredients and dietary
supplements that were not in current food regulations at the time DSHEA
was enacted.
In addition to the broad authority in section 402(g) of the act, we
look to the statutory scheme of DSHEA as a whole in proposing
regulations related to the manufacture, packaging and holding of
dietary ingredients and dietary supplements. Section 403(q)(5)(F) of
the act (section 7(b) of DSHEA) requires that a dietary supplement
product provide nutrition information. To comply with section
403(q)(5)(F) of the act, you must be able to identify the dietary
ingredient or ingredients in a dietary supplement and the quantity of
each. Moreover, the provisions in section 403(s) of the act relate to
identity, purity, quality, strength, and compositional specifications
of a dietary supplement. Thus, Congress sought to ensure in DSHEA that
dietary supplements would provide accurate information to the consumer
on the identity of the dietary ingredient and, if an herb or botanical,
the source from which it is derived. Moreover, Congress sought to
ensure that the dietary supplement would have the strength or meet the
quality, purity, and compositional specifications that the dietary
supplement is represented to meet. Because Congress established section
403(s) of the act--a provision that requires that a dietary supplement
that bears representations about identity, purity, quality, strength,
and compositional specifications meet those representations--it is
reasonable for us to establish regulations for manufacturing,
packaging, and holding addressing those same features. These
representations relate to characteristics and hazards to which dietary
supplements are subject. Further, in section 402(f) of the act,
Congress identified circumstances under which a dietary supplement or a
dietary ingredient would be deemed adulterated because it may present a
significant or unreasonable risk of illness or injury. Congress
expected that a dietary supplement would be manufactured in a way that
ensures that the dietary supplement contains dietary ingredients that
do not present an unreasonable risk of illness or injury and for which
the conditions of use are based. Because one must be able to measure or
analyze a dietary ingredient in order to determine whether a supplement
in fact contains that dietary ingredient, it is reasonable for a
proposed rule on CGMPs to include provisions related to identity,
purity, quality, strength, and composition of a dietary ingredient or a
dietary supplement. Moreover, it is reasonable to propose a requirement
that records of complaints be kept and investigations be done, as
necessary, so that the manufacturer and FDA can be aware of any
potential problems relating to a particular dietary ingredient and
these CGMPs, and so that a manufacturer can take appropriate action
when necessary. The proposed CGMPs would reflect the act's regulatory
scheme generally and, more specifically, DSHEA's provisions that
contemplate consistent, controlled manufacture of dietary supplements
(see sections 402(f) and 403(q)(5)(F) and (s) of the act). We
tentatively conclude that, therefore, section 402(g)(2) of the act
gives us the authority to develop dietary supplement CGMPs that are not
identical to our food CGMPs and that are appropriately tailored to the
manufacturing, packaging, and holding of dietary ingredients and
dietary supplements.
Sections 701(a) and 704 of the act also give us authority to
establish regulations related to CGMPs for dietary ingredients and
dietary supplements. Under section 701(a) of the act, we have the
authority to issue regulations for the efficient enforcement of the
act, and such regulations have been held to have the force and effect
of law (see National Nutritional Foods Ass'n v. Weinberger, 512 F.2d
688, 697-98 (2d Cir. 1975)). Section 704 of the act gives us the
authority to inspect factories, warehouses, and other establishments in
which foods, including dietary ingredients and dietary supplements, are
manufactured, processed, packed, or held and to inspect their
facilities, equipment, finished and unfinished materials, containers,
and labeling.
In addition to having the authority to establish broad regulations
for manufacturing, packaging, and holding dietary ingredients and
dietary supplements, we also have the authority to require
recordkeeping as part of these regulations. Two questions that we
considered in deciding whether to propose requirements for
recordkeeping included whether the statutory scheme as a whole
justified the proposed regulation and whether the proposed
recordkeeping requirements would be limited, would clearly assist in
the efficient enforcement of the act, and would not create an
unreasonable recordkeeping burden. In the other relevant sections of
this document, we explain in more detail the recordkeeping provisions
that we believe are limited to what are necessary for the efficient
enforcement of the act, and because the requests are limited, would
therefore not create an unreasonable recordkeeping burden.
For this proposed CGMP rule for dietary ingredients and dietary
supplements, recordkeeping is necessary to provide the type of
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documentation that would demonstrate that dietary ingredients and
dietary supplements are manufactured, packaged, and held under the
conditions that would be required under the proposed CGMP regulations.
Further, FDA is using its authority under sections 801 and 701(a) of
the act in proposing recordkeeping requirements for dietary ingredients
and dietary supplements that may not be marketed or sold in the United
States and that are exported under section 801(e) of the act.
In addition to having the authority under the act to require
recordkeeping, we also have authority to require access to the records.
Because the practices set forth in the proposed CGMP rule are necessary
to providing consumers with dietary supplements that are not
adulterated, access to records that demonstrate that firms follow CGMPs
is essential to confirming systematic compliance with CGMPs. We also
have the authority to copy the records when necessary. We may consider
it necessary to copy records when, for example, our investigator may
need assistance in reviewing a certain record from relevant experts in
headquarters. If we were unable to copy the records, we would have to
rely solely on our inspector's notes and reports when drawing
conclusions. A failure to have a required record would mean that a food
is adulterated under section 402(g) of the act.
Recordkeeping will not only help the agency to determine whether
dietary ingredients or dietary supplements were manufactured, packaged,
and held consistent with CGMP regulations, but also will provide a
public health benefit to consumers. When manufacturers keep records,
for example, of lot or batch numbers, the records facilitate a
manufacturer's recall of suspect products in case a recall becomes
necessary. This benefits consumers because the manufacturer can recall
its products that may be adulterated or misbranded more quickly.
B. Issues From the ANPRM
As stated previously, in addition to inviting comment on the
industry-drafted CGMP outline, we asked nine questions in the ANPRM on
CGMP issues for dietary supplements that the industry outline did not
address. In this section, we summarize each question and the principal
comments we received, and we respond to the comments. We address other
significant comments about the ANPRM, other than the nine questions we
asked, elsewhere in this document.
The nine questions in the ANPRM, comments, and our responses are as
follows:
Question 1. Is there a need to develop specific defect action
levels (DALs) for dietary ingredients?
The ANPRM stated that the use of a botanical in a dietary
supplement may result in a much greater exposure to the botanical
ingredient for consumers because the dietary supplement will be
consumed in greater amounts than if the ingredient was in a food as a
spice or flavoring agent.
Several comments stated that establishing DALs for dietary
ingredients that are different than DALs for food is not necessary. The
comments disagreed with our statement that dietary ingredients in
dietary supplements and conventional foods are consumed in different
quantities. For example, the comments stated that generally botanical
ingredients are present in dietary supplements in approximately the
same amounts normally consumed in conventional foods.
Other comments generally opposed applying the current DALs for
foods to dietary ingredients and instead supported the development of
DALs for dietary ingredients, especially for botanicals and herbals.
Many comments recommended that we cooperate with industry, outside the
rulemaking process, to develop DALs for dietary ingredients.
We disagree with the comments that state that establishing DALs for
dietary ingredients that are different than DALs for food is not
necessary because an ingredient in food and in a dietary supplement
would be consumed in the same amounts. The comment did not provide
evidence or examples to support the comment. Some food ingredients for
which DALs have been established also are dietary ingredients used in
dietary supplements. For example, a DAL has been established for whole
ginger used in a conventional food. Ginger is also a dietary ingredient
used in dietary supplements. We have found dietary supplements that
recommend a daily intake of ginger of 4,815 mg, 1,260 mg, and 2,200 mg
(Ref. 38). One teaspoon of raw ginger root is equal to 2,000 mg (2
grams (g)) and one teaspoon of ground ginger is equal to 1,800 mg of
ginger (1.8 g) (Ref. 39). A recipe for gingersnaps yielding 18 cookies
specifies 1 teaspoon ginger (Ref. 40). Thus, ginger would be consumed
in greater amounts as a dietary supplement than as an ingredient in a
conventional food. However, we have tentatively concluded that we do
not have sufficient information to determine whether a DAL for a
dietary ingredient should be established at a different level than what
has been established for the same ingredient used in conventional food.
DALs are established for a food ingredient on a per weight basis.
The DALs for whole ginger for ``insect filth and/or mold'' is an
``average of 3 percent or more pieces by weight are insect-infected
and/or moldy'' and for ``mammalian excreta'' is an ``average of 3 mg or
more of mammalian excreta per pound'' (Ref. 41). Because the DAL is
established by weight of the whole ginger, the DAL for ginger would
apply whether it is used as an ingredient in a conventional food or a
dietary ingredient in a dietary supplement. Therefore, if we have
established a DAL in the industry compliance document for a
conventional food ingredient, that DAL also would apply to that
ingredient when used as a dietary ingredient in a dietary supplement
until such time that we would establish a different DAL for its use as
a dietary ingredient (Ref. 41). However, we do not have many dietary
ingredients that are included in the DAL compliance guide. We agree
that DALs may be needed for some dietary ingredients, especially
ingredients like botanicals that are subject to the same type of
defects (such as mold and insect parts) as other food for which DALs
have been established. We base DALs on scientific information such as
literature surveys, scientific market surveys, and laboratory analyses
and also on information gained through physical plant inspections. If
and when we determine that we have sufficient information to develop
DALs for dietary ingredients, we will consider whether to do so.
Question 2. We requested comments on appropriate testing
requirements to provide positive identification of dietary ingredients,
particularly plant materials, used in dietary supplements.
The ANPRM explained that the misidentification of dietary
ingredients, particularly plant materials, used in dietary supplements
may present a significant public health and economic concern. The ANPRM
also noted that the analytical methodology available for identifying
many dietary ingredients is limited. We invited comments on the
technical and scientific feasibility of identifying different types of
dietary ingredients. We also solicited information on what constitutes
``adequate testing'' for identity of different types of dietary
ingredients, and, in the absence of testing, what types of practices
would be effective alternatives to testing to ensure the
[[Page 12169]]
identity of different types of dietary ingredients.
Comments generally supported requiring tests of some kind to
positively identify dietary ingredients and to verify dietary
ingredient identity. The comments put forth different reasons, which
ranged from ensuring public safety to preventing economic adulteration.
Some comments suggested that suppliers should be responsible for
identifying the dietary ingredients they supply to manufacturers and
that manufacturers should be responsible for only verifying the
identity of the finished product. Other comments stated that the
manufacturer should be responsible for identification and should not
rely on a supplier's certification.
Some comments raised issues relating to the actual identity tests
that should be recommended or required and discussed analytical method
selection and method options, use of and availability of official
validated analytical methods, and certification of testing facilities
that conduct identity tests on natural products. Some comments
suggested that identity test method options should include organoleptic
and microscopic methods and chemical analytical methods. The comments
noted that selecting the appropriate method is dependent on the type
and form of the ingredient. Other comments said that manufacturers
should be responsible for selecting the appropriate method to confirm
ingredient identity. Most comments recommended that we provide guidance
to industry in defining what comprises adequate testing for different
types of ingredients, but did not support regulations prescribing the
test method or methods for specific ingredients.
Comments generally supported the use of a standard compendial
method, such as those published by the USP or AOAC International. Where
no published method exists, the comments suggested that manufacturers
should be responsible for developing adequate and effective
identification testing procedures, requirements, or practices to ensure
the identity of the dietary ingredients they use. One comment from a
vitamin manufacturer noted that most of its products have recognized
and established identity tests as part of their compendial status.
Other comments from botanical dietary supplement manufacturers noted
that their current methods for identifying plant material are adequate,
but that they will, over time, be enhanced by the availability of more
widely recognized methods and techniques as a result of current work in
this field. The comments noted that test methods that are presently
available and used for identifying botanicals are not officially
validated. If an officially validated method is not available for a
dietary ingredient, several comments suggested working towards AOAC
International validation and, in the interim, instituting peer review
of less formal test methods. Other comments noted that the dietary
supplement industry has begun an effort to develop validated test
methods for several botanical ingredients. One comment suggested that
it is important to develop methods that are subject to peer review and
to institute a certification program for testing facilities because the
analysis of natural products requires specialized training in natural
product chemistry. The comment did not indicate who (e.g., FDA or
another organization) should develop a certification program.
Some comments only addressed identity testing of unprocessed
botanicals. These comments said that for unprocessed botanicals in
whole or in part (e.g., flowers, roots, leaves, etc.), organoleptic
techniques are sufficient provided that accurate records are maintained
and that the manufacturing process provides a paper trail of positive
identification. One comment suggested that a ``voucher specimen'' (a
sample of the plant material) from the supplier along with a
certificate of botanical identity would be an adequate record. The
certificate of botanical identity would follow the material through the
manufacturing process, thus creating a paper trail. The voucher
specimen would be held for a specific period of time or, if necessary,
serve as a permanent record.
Dietary ingredient identification is an important part of CGMPs. We
agree with the comments that identity testing requirements are needed
but that no single approach or test method may be appropriate for every
dietary ingredient. For example, microscopic or organoleptic tests
might be appropriate for herbs or plant parts (because you can see,
taste, or smell them), but not appropriate for amino acids (which
cannot be identified by the naked eye or identified by using your
senses). A microscopic test might be appropriate for herbs that still
have their leaves or other distinguishing marks or characteristics, but
not for ground-up herbs. Thus, we agree with the comments stating that
the key principle in dietary ingredient identification testing is to
establish an appropriate procedure that will identify, with certainty,
the dietary ingredients used in making a dietary supplement. We agree
that a guidance document on ingredient identity testing may be useful,
and we will consider future development of ingredient identity testing
guidance documents.
Manufacturers should be responsible for identifying the ingredients
that they use in their products and, in addition, for verifying that
the dietary ingredients or dietary supplements they make contain the
identity, purity, quality, strength, and composition that the
manufacturer intends the product to have. As discussed previously in
this document, we have found serious adverse events to be related to
dietary ingredient misidentification. The manufacturer must conduct
identity tests to ensure that they used the correct ingredient to
prevent potential serious adverse events. We discuss identity testing
for dietary ingredients and dietary supplements later in this document.
We agree with the comments that certification of testing facilities
could be an important step in ensuring analytical quality. However,
certification of testing facilities is outside the scope of this rule.
Question 3. FDA requested comments on standards that should be met
in certifying that a dietary ingredient or dietary supplement is not
contaminated with filth; that it is free of harmful contaminants,
pesticide residues, or other impurities; that it is microbiologically
safe; and that it meets specified quality and identity standards.
The ANPRM noted that, under Sec. 110.80, a food manufacturer may
accept a supplier's certification that its products do not contain
microorganisms, filth, or other foreign material that would adulterate
the product instead of testing or evaluating the supplier's products
itself. As a result, we asked for comments on whether a certification
will provide assurance that dietary ingredients are not contaminated or
whether specific testing requirements are necessary.
Comments generally supported relying on a supplier's certification
that a dietary ingredient is what it purports to be and is not
contaminated. The comments stated that reliance on the supplier's
certification should be an alternative to testing raw materials to
detect microorganisms, filth, or foreign material so long as the
reliability of the supplier's certification is confirmed. Most comments
stated that manufacturers are responsible for determining, on a case-
by-case basis, whether a supplier's certification provides adequate
assurance that a dietary ingredient is what it purports to be and is
not adulterated. Some comments based their support for
[[Page 12170]]
relying on a supplier's certification on Sec. 110.80(a)(2) through
(a)(4); these provisions allow food manufacturers to rely on a
supplier's guarantee or certification that raw materials or other
ingredients do not contain levels of microorganisms or toxins that may
produce illness or are otherwise contaminated. The comments suggested
various means for determining the reliability of a supplier's
certification, including independent analysis, in-house testing, and
review of protocols.
Other comments stated that, because the CGMP regulations in part
110 permit reliance on a supplier's certification and because section
402(g)(2) of the act specifies that the CGMP regulations for dietary
supplements should be modeled after the CGMP regulations for food, a
supplier's certification for dietary supplements must be acceptable.
We have considered the comments on whether a supplier's
certification could provide adequate assurance that a dietary
ingredient is what it purports to be and is not adulterated. We
disagree that manufacturers may rely on such certifications to
determine that an ingredient is not contaminated, for example, with
filth or microorganisms. Using a supplier certification, guarantee, or
certification in lieu of performing testing on each shipment lot of
components, dietary ingredients, or dietary supplements is not
appropriate because a supplier's certification or guarantee would not
necessarily ensure that the identity, purity, quality, strength, or
composition of a component, dietary ingredient or dietary supplement is
met. We discuss testing requirements and why we believe that the use of
supplier's guarantee or certification is not sufficient in lieu of a
manufacturer's own testing in more detail later in this document.
Question 4. We asked for comments on whether a CGMP rule should
require manufacturers to establish procedures to document, on a
continuing or daily basis, that they followed preestablished procedures
for making dietary supplements.
The ANPRM noted that the food CGMP regulations under part 110 do
not require manufacturers to document that they are following
established procedures prescribed for manufacturing a food. However,
the ANPRM also noted that section 402(g) of the act does not preclude
us from adopting CGMP requirements for dietary ingredients and dietary
supplements that have no counterpart in part 110 if we have an
appropriate basis for doing so.
Most comments generally supported requiring manufacturers to
develop and follow written procedures and noted that the industry
outline in the ANPRM would require written procedures for many
processes and functions. Some comments noted that written procedures
and day-to-day records documenting that the procedures were followed
will ensure that products are safely and properly manufactured on a
day-to-day basis and that this can be confirmed by periodic independent
internal audits. One comment stated that the manufacturer should be
responsible for ensuring, through employee training, self-audit
programs, and batch records, that quality control and other procedures
prescribed for the manufacture of a dietary supplement are properly and
diligently executed. Other comments stated that it is good business
practice to ensure product quality through periodic review of records
and quality control audits and that failure to establish procedures
will result in product recalls, potential injury, and litigation for
damages for defective goods.
Some comments objected to any requirement for written procedures or
documentation that the procedures were followed. The comments stated
that section 402(g)(2) of the act states that dietary supplement CGMPs
must be modeled after the food CGMP regulations and the food CGMP
regulations do not require written procedures or documentation that
procedures were followed.
We agree with those comments that support the development and use
of written procedures by manufacturers and are considering whether we
should require written procedures in a final rule. We are proposing
requirements for documenting certain operations and processes while not
requiring written procedures to remove underlying costs for
establishing and updating such written procedures while preserving the
records necessary to permit trace back. When manufacturers develop and
follow written procedures such procedures help to ensure that
manufacturers produce a consistent dietary ingredient or dietary
supplement that is of a predictable quality and that is not
adulterated. Following written procedures and documenting compliance
with those procedures will ensure regular performance of a firm's
established programs and procedures and will provide additional
assurance of effective communication of appropriate information from
the firm management to the line personnel. We invite comment on whether
written procedures should be required in a final rule, and whether
there are other procedures, that we should include in a final rule. We
discuss written procedures for various stages of manufacturing,
packaging, labeling, holding, and for handling consumer complaints
later in this document.
We disagree, however, that records are not necessary to show that
certain operations and processes are being performed. Records document
that quality control operations and processes such as calibrating
instruments and controls; manufacturing a dietary ingredient or dietary
supplement batch; and handling consumer complaints were performed. We
further discuss the basis for the proposed recordkeeping requirement
for certain operations and processes later in this document. We believe
that section 402(g) of the act allows us to require written procedures
and documentation that the procedures were followed. As explained
previously, such records may be necessary for ensuring that dietary
ingredients and dietary supplements are manufactured, packaged, and
held consistent with these regulations. Moreover, we believe that the
fact that the food CGMPs in part 110 do not have recordkeeping
requirements does not preclude us from proposing recordkeeping
requirements in this proposed rule, although we seek further comment on
the issue.
Question 5. We invited comment on whether dietary supplement CGMP
regulations should require that firms have competent medical
authorities evaluate reports of injuries or illnesses and to determine
if followup action is necessary to protect the public health.
The ANPRM explained that many dietary supplements contain
pharmacologically active substances, which distinguish dietary
supplements from many foods, and some dietary supplements may contain
potential allergens. Because the characteristics may result in adverse
events in certain consumers, we asked whether we should consider
requiring firms to take certain actions with respect to reviewing AERs.
We also sought comments on whether a CGMP rule should require firms to
establish procedures for determining whether a reported injury
constitutes a serious problem, and what actions are to be taken when
serious problems are identified.
Comments generally opposed requiring manufacturers to establish a
procedure for evaluation and followup of reports of illness and
injuries. Comments also opposed requiring that a competent medical
authority evaluate all reports of illness or injuries to determine if
followup action is necessary to protect the public health. Some
comments, opposing requiring written procedures and evaluation,
[[Page 12171]]
suggested alternatives to requirements, such as using the Centers for
Disease Control and Prevention, poison control centers, FDA's MedWatch
program, and consumer complaint files to monitor and record injuries
and illnesses attributed to marketed products.
In contrast, several comments supported a requirement for written
procedures or medical evaluation of serious adverse events. Some
comments stated that an evaluation procedure is necessary and that
manufacturers are and should be responsible for establishing procedures
to respond appropriately to reports of serious illness and injury that
may have resulted from using a dietary supplement. Other comments
stated that medical evaluations are not necessary because manufacturers
should be using appropriate internal quality control procedures within
their quality control units or elsewhere to identify the cause of
adverse events and respond appropriately.
We agree with those comments stating that manufacturers are and
should be responsible for evaluating consumer complaints. Manufacturers
have an obligation to ensure that the dietary supplements that they put
on the market are not adulterated or misbranded. Consumer complaints
about a dietary supplement might indicate a CGMP-related problem
associated with a dietary supplement. For example, a consumer complaint
might identify a previously unknown manufacturing deviation that caused
a batch of dietary supplements to be adulterated. Thus, a procedure for
reviewing and investigating consumer complaints is recommended. Records
of consumer complaints related to CGMPs, and the review and
investigation of such records, are necessary and we discuss such a
record requirement later in this document. In that discussion, we
address what we mean by a consumer complaint and we address the
comments on the type of evaluation that would be necessary for consumer
complaints and whether the comments' suggested alternatives to written
procedures and medical evaluations are sufficient to identify potential
concerns.
Some comments objected to written procedures and medical evaluation
arguing that such requirements go beyond the CGMP regulations for food
and, therefore, would be contrary to section 402(g)(2) of the act.
Other comments claimed that written procedures would present
unwarranted potential criminal liability, that there are many
unsubstantiated injuries and illness inherent in the food industry, and
that dietary supplement safety problems are rare. These comments also
stated that a costly and burdensome safety surveillance system is not
warranted for these products, that the term ``serious adverse event''
is ambiguous, and that most manufacturers lack trained medical
personnel to serve this function.
Because we have found dietary supplement problems that could have
been prevented by CGMPs and that resulted in product recalls, we find
that manufacturers must be able to identify these types of problems
with their products. It is a manufacturer's responsibility to do so. We
disagree with those comments stating that we do not have legal
authority to require a manufacturer to evaluate consumer complaints as
we propose to define that term in this proposed rule.
We also disagree that written procedures would present unwarranted
potential criminal liability. Persons subject to regulation under the
act and its implementing regulations may face civil or criminal action
if they fail to comply with the act or our regulations (see, e.g.,
sections 301, 302, and 303 (21 U.S.C. 331, 332, and 333) of the act).
The fact that such an outcome is possible under the statutory scheme
does not mean that a provision that would require written procedures
and evaluation of consumer complaints is ``unwarranted.'' If we were to
accept such a claim, then we would find it difficult to issue any
regulation to implement the act, and that result would conflict with
our obligation to protect the public health. Therefore, we reject the
comments' argument regarding potential criminal liability and its
effect on rulemaking.
We also disagree with the claim that there is no basis for
requiring an evaluation of adverse events because there are many
unsubstantiated reports of injuries or illness and because dietary
supplement safety problems are rare. In the past, voluntary reports of
injury or illness have identified adulterated dietary supplements.
Consumer complaint reports associated with the use of marketed dietary
supplements, such as D. lanata contaminated plantain, identified the
need for further investigation and led to recalls or warnings to
protect the public health (Ref. 6). Evaluation of consumer complaint
reports can reveal patterns of adverse events that assist us and
manufacturers in identifying the need for further investigation to
determine what public health actions are needed.
For example, assume that, after you investigate an AER, you find
that the product contained an ingredient that should not have been used
and that the ingredient caused the adverse event. The fact that the
wrong ingredient appeared in your product would indicate that some type
of problem occurred in your manufacturing process of that product. Once
you identify the ingredient as the cause of the problem, you would be
able to take steps to remove any such product from the market and
prevent the problem from recurring, helping to ensure product quality
and purity, and restore consumer confidence that your products contain
the correct ingredients. In short, investigations of consumer
complaints benefit both manufacturers and consumers and these benefits
will exist regardless of whether there are many or few injuries or
illnesses believed to be associated with your product.
Question 6. We invited comment on whether a CGMP regulation for
dietary supplements should require manufacturers to establish
procedures to identify, evaluate, and respond to potential safety
concerns with dietary ingredients. We asked whether such an evaluation
is necessary, and, if so, what elements need to be included in such an
evaluation and their relative importance (e.g., the presence and
potency of pharmacologically active substances, the presence of
different microorganisms, the presence of different contaminants and
impurities). We also asked whether we should require that these
evaluations be documented in a firm's records, and, if so, what type of
records would be adequate to document that such an evaluation had
occurred.
In general, the comments opposed requiring manufacturers to
establish procedures to identify, evaluate, and respond to potential
safety concerns with dietary ingredients. Most comments claimed that
such procedures are unnecessary because dietary ingredients have a
history of safe use in food and that DSHEA is based on this history of
prior use in food. Other comments argued that, because DSHEA is based
on a history of prior use of existing dietary supplements and
established a notification procedure for new dietary ingredients, a
requirement concerning potential safety concerns for dietary
ingredients would be beyond the scope of this rulemaking.
Several comments noted that for those dietary ingredients that do
not have a history of safe use in food and are considered ``new dietary
ingredients,'' as defined in section 413(c) of the act, DSHEA
established procedures for evaluating safety concerns. Section
413(a)(2) of the act requires a manufacturer to submit a ``new dietary
ingredient'' notification to FDA 75 days
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before introducing or delivering a dietary supplement containing a new
dietary ingredient into interstate commerce. The notification must
provide the basis upon which the petitioner has concluded that the
dietary supplement containing the new dietary ingredient is reasonably
expected to be safe. Therefore, the comments argued that procedures to
identify, evaluate, and respond to potential safety concerns are not
necessary in a CGMP rule.
Other comments stated that FDA should not require procedures to
identify, evaluate, and consider potential safety concerns with dietary
ingredients because manufacturers already have an essential and
critical responsibility to substantiate the safety of the dietary
ingredients they use in manufacturing a product. The comments suggested
that FDA does not need to require written procedures because
manufacturers must consult the generally known and generally available
scientific literature to determine that a dietary ingredient is safe.
Some comments suggested that, instead of FDA requiring safety
evaluations, a third-party could evaluate safety concerns. Several
comments suggested that manufacturers who use dietary ingredients that
have little history of use in food in the United States should retain
documentation concerning the dietary ingredient's safety. One comment
suggested that we issue a guidance document to identify the types of
acceptable ``history of use'' standards for dietary ingredients having
little history of use in food in the United States and to describe the
documentation that would be needed regarding a dietary ingredient's
safety.
Although the comments focused on the safety of using particular
dietary ingredients, the safety concerns described in question 6
actually consist of two concepts: (1) Is the product formulated using
safe dietary ingredients; and (2) is the product manufactured,
packaged, and held in a manner that would not adulterate or misbrand
the product? The proposed rule focuses on safety concerns related to
the latter concept. Specifically, the proposed rule focuses on the
steps and processes used in the manufacturing, packaging, and holding
of the product to ensure, for example, that the product has the
identity, purity, quality, strength, and composition claimed and does
not become adulterated or misbranded. The agency notes that no comments
appeared to argue that safety issues relating to potential
contamination or adulteration related to manufacturing processes are
outside CGMPs. As the comments recognize, manufacturers have an
essential and critical responsibility to substantiate the safety of the
dietary ingredients they use in manufacturing a product.
Section 402(g) of the act is not the only provision relevant to
whether a dietary ingredient or dietary supplement may be deemed to be
adulterated. Section 402(f)(1) of the act, in part, declares a dietary
supplement to be adulterated if it:
[sbull] Presents a significant or unreasonable risk of illness or
injury under conditions of use described in the labeling or, if no
conditions of use are suggested or recommended in the labeling, under
ordinary conditions of use;
[sbull] Is a new dietary ingredient for which there is inadequate
information to provide reasonable assurance that the dietary ingredient
does not present a significant or unreasonable risk of illness or
injury; or
[sbull] Is or contains a dietary ingredient that renders it
adulterated under section 402(a)(1) of the act under the conditions of
use recommended or suggested in the labeling. (Section 402(a)(1) of the
act declares a food to be adulterated if it contains substances that
are poisonous or deleterious substance that may render it injurious to
health.)
Additionally, section 301(a) of the act prohibits the introduction
of adulterated food into interstate commerce.
So, for a dietary ingredient or dietary supplement manufacturer to
comply with sections 301(a) and 402(f)(1) of the act, it must take
steps regarding potential safety concerns before it markets the
product. Otherwise, if the manufacturer had no obligation to evaluate
possible safety concerns before marketing a product, sections 301(a)
and 402(f)(1) of the act would not make sense and the manufacturer
would be acting contrary to the basic congressional intent behind
DSHEA, which was to ensure that safe dietary supplements are available
to consumers. For example, assume that a manufacturer wanted to market
a new dietary ingredient but lacked evidence to show that it is safe.
Under section 402(f)(1)(B) of the act, the manufacturer must have
adequate information to provide reasonable assurance of the dietary
ingredient's safety before it markets the dietary ingredient;
otherwise, the dietary ingredient is adulterated under section
402(f)(1)(B) of the act, and section 301(a) of the act would prohibit
its sale in interstate commerce. Thus, the manufacturer has a statutory
obligation to examine safety concerns relating to the dietary
ingredients it uses before it markets the product.
The proposed CGMP rule focuses on ensuring that the manufacturer
knows what it is putting in its product and is manufacturing,
packaging, and holding the product in a manner that will not adulterate
or misbrand the product. For example, assume that you use a particular
herb as your dietary ingredient. However, there are different species
of that herb. Some species are poisonous; others are not. Additionally,
there are variations within the same species of herb depending on where
the herbs were grown. Some variants may contain higher levels of a
particular dietary ingredient or marker compound than other variants.
So, how do you know whether you have the right herb (nonpoisonous
species of herb intended for use) and whether it meets your
specifications? CGMPs would require that you check the identity of the
herbs you receive; by doing so, you would be able to tell whether you
have the correct herbs, whether your herbs are poisonous, or whether
they meet your specifications. In this example, the potential safety
concerns involve the dietary ingredient itself rather than any issue
concerning contamination which would adulterate or may lead to
adulteration of the dietary ingredient, and thus, the dietary
supplement which contains the dietary ingredient.
As for the comments' arguments concerning a dietary ingredient's
history of use, we do not need to address history of use as part of
this CGMP proposal. CGMPs focus on how a product is made under current
manufacturing processes. A dietary ingredient's history of use does not
provide any assurance that a particular product has the identity,
purity, quality, strength, and composition that it purports to have.
Further, history of use does not necessarily provide any assurance that
a particular product would not pose a significant or unreasonable risk
of illness or injury under conditions of use recommended or suggested
in the labeling or under ordinary conditions of use.
As for those comments discussing whether manufacturers or other
parties should evaluate potential safety concerns, the proposed rule
would require a manufacturer to evaluate a consumer complaint to
determine whether the complaint relates to good manufacturing
practices. Such an evaluation would include possible hazards to health
resulting from the manufacturing, packaging, or holding of a product.
Nevertheless, you should note that, insofar as compliance with the act
and any CGMP regulations are
[[Page 12173]]
concerned, persons who market dietary ingredients and dietary
supplements always remain responsible for their products. If the
manufacturer markets the product, it would have to meet all proposed
CGMP requirements, if the agency finalizes the rule as proposed. If
another person buys a product (such as bulk dietary ingredients) from a
manufacturer and distributes the product under its own name, that
person must meet all applicable CGMP requirements.
Question 7. We invited comment on whether specific controls are
necessary for computer-controlled or assisted operations and how best
to ensure that the software programs and equipment used to direct and
monitor the manufacturing process are properly designed, tested,
validated, and monitored.
Comments generally supported specific controls for computer-
controlled or computer-assisted operations. One comment suggested
requiring manufacturers to confirm, by adequate and documented testing,
that their computer software programs perform their intended functions
when computers are used as part of an automated production system
having a significant and direct impact on product safety. Another
comment suggested requiring that software programs and equipment used
to direct and monitor manufacturing processes are properly designed,
tested, evaluated, and monitored. The comment added that, if we
consider imposing specific requirements on how firms document the
adequacy of their computer-controlled or assisted operations, we should
address those recommendations through a guidance document instead of
issuing regulations.
We agree that computer-controlled or computer-assisted operations
need to be properly designed, tested, evaluated, and monitored to
ensure that the computers do what they are supposed to do.
Manufacturers should confirm, by adequate and documented testing, that
their computer software programs perform their intended functions
because computer use as part of an automated production system has a
significant and direct impact on product safety. Computers are an
important controlling piece of equipment in the manufacture of dietary
supplements because they often direct and control key steps or
processes in the manufacture of dietary supplements. If computers do
not operate correctly, the dietary supplements manufactured using those
computers may be adulterated.
Several comments supported requirements for specific controls, but
opposed using validation-of-operation mandates like those in the CGMP
regulations for drugs. One comment suggested that we regulate computer-
controlled and computer-assisted operations for dietary supplements in
the same way that we regulate such operations in the pharmaceutical
industry, but only where an operation is directly related to the
product's concentration or purity. One comment suggested that we
consider adopting the computer-controlled and computer-assisted
procedures specified in the proposed infant formula CGMP.
We propose general requirements to ensure that equipment is
suitable for its intended use. However, we seek comment, in the
proposed rule, about whether we should include requirements, written
procedures, and records for equipment verification and re-verification.
We request comment on what verification manufacturers should be using
in their computer-controlled or computer-assisted operations to ensure
that a dietary ingredient or a dietary supplement that is produced is
not adulterated during manufacturing. In addition, we request comment
on whether we should issue guidance documents on verification
procedures for use with computer-controlled or computer-assisted
operations. Guidance documents generally represent FDA's advice or
current thinking on a particular matter and are not binding on any
person. In contrast, regulations create enforceable requirements that
apply to all persons engaged in the same action or who make the same
product.
As discussed in greater detail later in this document, certain
processes are necessary to ensure that computer-controlled or computer-
assisted equipment functions properly. This is because of the important
role of such equipment in manufacturing. For example, if computer-
controlled or computer-assisted equipment is used to control
components, inprocess materials, and rejected materials unsuitable for
use, the operation must function as expected to ensure that components
suitable for use in manufacturing dietary ingredients and dietary
supplements are not mixed up with components held under quarantine such
as those components that have been rejected as unsuitable for use. If
computer-controlled or computer-assisted operations are used for the
addition and mixing of components, they must function properly to
ensure that the correct components are added and appropriately mixed to
avoid producing a dietary ingredient or dietary supplement that is
adulterated. Computer-controlled or computer-assisted operations are
not perfect; computers are subject to malfunctions and ``bugs''
(errors) in the software they use. Problems with data entered into the
computer may produce unreliable results. For these reasons, specific
controls for computer-controlled or computer-assisted operations are
necessary to prevent the manufacture of an adulterated dietary
ingredient or dietary supplement.
A few comments stated that no specific requirements for computer-
controlled or computer-assisted operations are needed because computer
hardware and software are simply specialized plant equipment so that no
special regulations are needed.
We agree that computers are specialized pieces of plant equipment
and, therefore, should be subject to additional requirements beyond
those which would apply to plant equipment. Computers are specialized
pieces of equipment because they are subject to malfunctions and
``bugs'' (errors) in the software, they are reliant upon data entered
into a computer, and they may be used to perform important roles such
as component or dietary ingredient identification, measuring components
and dietary ingredients, and quarantining materials. Consequently,
proposed Sec. 111.30 would establish requirements for automatic,
mechanical, or electronic equipment. The proposed requirements would
cover, among other things, automatic equipment design, and routine
calibration, inspection, and checks to ensure proper performance. As
stated previously, we are seeking comment on whether we should include
requirements for verification and re-verification of automatic,
mechanical, or electronic equipment and processes and whether we should
include requirements for computerized systems that are separate from
requirements for other mechanical or automatic equipment. We discuss
proposed Sec. 111.30 in greater detail later in this document.
Question 8. We asked for comments on whether certain, or all, of
the requirements for manufacturing and handling dietary ingredients and
dietary supplements may be more effectively addressed by a regulation
based on the principles of Hazard Analysis and Critical Control Point
(HACCP), rather than the system outlined in the industry submission.
In the ANPRM, we noted that, because of the wide variety of dietary
ingredients and dietary supplements and because of the heterogenous
composition of the dietary supplement
[[Page 12174]]
industry, CGMPs based on HACCP principles may provide a more flexible
and less burdensome regulatory framework for manufacturers and
distributors than the approach set out in the industry submission.
Most comments opposed basing a CGMP regulation for dietary
ingredients and dietary supplements on HACCP principles. Most comments
supported applying traditional CGMP requirements on manufacturing,
packaging, and holding to dietary ingredients and dietary supplements.
In general, the comments that opposed requiring HACCP for dietary
ingredients and dietary supplements asserted that: (1) A HACCP program
would not be appropriate because HACCP focuses on microbial
contamination of products that provide a favorable environment for
growth of microbes that may be present, and these hazards are not a
major concern for dietary supplements; (2) CGMPs are the best means of
assuring the safety, quality, and composition of dietary ingredients
and dietary supplements; (3) HACCP is not required for the food
industry as a whole; and (4) HACCP would provide minimal incremental
value at significant additional costs.
Other comments opposed mandatory HACCP regulations for dietary
ingredients and dietary supplements, but said manufacturers could
implement voluntarily HACCP instead. One comment, which supported
voluntary implementation of HACCP, wanted manufacturers to be exempt
from having to disclose HACCP records to any Federal agency.
HACCP principles can be applied to a broad range of manufacturing
practices and HACCP principles are not solely focused on microbial
contamination, but instead, are intended to identify and appropriately
control steps in manufacturing where any type of adulteration can
occur. Nevertheless, after considering the comments, we have decided to
propose a CGMP approach for dietary ingredients and dietary
supplements. We believe that CGMPs would establish a system of controls
that, given the variations in size, technological sophistication, and
regulatory experience among dietary ingredient and dietary supplement
firms, would create a strong regulatory foundation throughout the
industry.
You may voluntarily choose to implement a HACCP plan that meets the
requirements of the National Advisory Committee on Microbiological
Criteria for Foods, however, proposed part 111 would still apply to you
(Ref. 42). Any HACCP plans that also are intended to meet the records
requirements under proposed part 111 would be treated as records under
this proposal.
Question 9. We invited comment on whether broad CGMP regulations
will be adequate, or whether it will be necessary to address the
operations of particular segments of the dietary supplement industry.
Most comments supported broad CGMP regulations covering all
segments of the dietary supplement industry instead of specific
regulations tailored to distinct segments of the industry. One comment
stated that the differences between distinct segments of the dietary
supplement industry, such as manufacturers of raw materials or
distributors of finished products, are no more pronounced than similar
segments in the food industry. Another comment stated that having
numerous CGMPs could subject raw materials and dietary ingredients to
multiple CGMPs, thus making manufacturing operations more complex. This
comment also questioned whether issuing multiple regulations is
necessary or economically justified in an era of limited corporate and
government regulatory resources. Other comments emphasized the
importance of ensuring that all dietary supplement manufacturers (i.e.,
both small and large manufacturers, and foreign manufacturers planning
to import dietary supplements into the United States) follow the same
CGMP requirements.
In contrast, some comments supported drafting regulations for
particular segments of the dietary supplement industry. One comment
stated that certain stages of the manufacturing process, such as the
distribution of raw dietary ingredients, should be more strictly and
comprehensively regulated than other stages because potential hazards
are more prevalent during these manufacturing stages. The comment
stated that conversely, the holding, distribution, and sale of a
finished dietary supplement may require less comprehensive regulations
because they are subject to fewer potential hazards. Other comments
supported different levels of safety testing for different types of
dietary supplement products. For example, some comments said that
products such as melatonin and dehydroepiandrosterone resemble drugs,
so we should require safety testing in animals and humans and impose
druglike CGMP requirements for manufacturing. Another comment stated
that less stringent CGMPs would be appropriate for herbal dietary
supplements because they have long histories of food use and safety.
We agree that some manufacturing operations are subject to greater
hazards than others, and have drafted the proposed rule accordingly.
For example, there are microbial hazards associated with raw
botanicals. To address these hazards, the proposal would require that
you perform tests on the botanicals. On the other hand, there are fewer
hazards associated with holding and distributing finished dietary
supplements, so the proposal would impose less comprehensive
requirements for holding and distributing operations.
We are persuaded by the comments that support a broad CGMP
regulation as preferable to multiple regulations focused on particular
segments of the industry. We agree with the comments that multiple
regulations might be confusing and burdensome, especially to firms that
manufacture products that fall into multiple categories. For instance,
it would be easier for regulated firms and for us if firms were
required to adhere to one set of CGMP requirements rather than follow,
for example, one set of CGMP requirements for vitamins and a different
set of CGMP requirements for minerals.
We also recognize, though, that there may be some reasons to treat
different types of dietary ingredients or dietary supplements
differently in specific instances. For example, it may be appropriate
to require one type of test for confirming the identity of amino acids
and another type of test for confirming the identity of herbals.
However, for the reasons discussed previously, we are proposing to
establish one set of broad CGMP regulations for all types of products.
Because we recognize that one set of specific requirements may not be
appropriate for all types of dietary ingredients and dietary
supplements, we have proposed regulations that allow manufacturers to
develop practices to meet CGMP requirements. Depending on our
experience with this proposed rule, we will consider whether we need to
reevaluate our decision to establish one set of requirements for all
dietary ingredients and dietary supplements.
We agree with the comments that the proposed rule should not make
any distinction between dietary ingredients or dietary supplements made
in the United States and those made in a foreign country. The proposed
rule would require that foreign firms that want to export dietary
ingredients and dietary supplements to the United States manufacture,
package, and hold dietary ingredients and dietary supplements
consistent with proposed part 111. Moreover, under this proposed rule,
if a U.S. firm contracts with a
[[Page 12175]]
foreign firm to package dietary supplements for sale in the United
States, the imported product would have to comply with the requirements
in proposed part 111. In addition, the U.S. firm would be required to
meet all applicable CGMP regulations under this proposed CGMP rule
related to those activities in which it engages under the proposed
rule. We invite comment on how best to ensure that dietary ingredients
and dietary supplements exported to the United States have been
manufactured, packaged, and held consistent with part 111.
This proposal does not include requirements for safety testing in
animals and humans for certain types of dietary ingredients and dietary
supplements. As discussed in several parts of this preamble, you are
responsible for ensuring that the dietary ingredients or dietary
supplements that you make are safe prior to marketing such products.
Although we are focusing on the manufacturing steps in actual
production and distribution of dietary ingredients and dietary
supplements, there may be the need for specific regulations related to
the use of animal tissue. We invite comment on whether there is a need
for such specific regulations.
III. Description of the Proposed Rule
This proposal will supercede what the agency said about the
placement in Title 21 of the Code of Federal Regulations for any
regulations resulting from the proposed rule for dietary supplements
containing ephedrine alkaloids (62 FR 30678, June 4, 1997). That
proposal included proposed revisions of part 111 and the table of
contents for part 111 and we are now proposing those for 21 CFR part
112 (as explained below).
This proposal for dietary supplement CGMPs amends part 111 (21 CFR
part 111), revising the heading from ``Current Good Manufacturing
Practice for Dietary Supplements'' to ``Current Good Manufacturing
Practice in Manufacturing, Packing, or Holding Dietary Ingredients and
Dietary Supplements.'' Proposed part 111, with the heading ``Current
Good Manufacturing Practice in Manufacturing, Packing, or Holding
Dietary Ingredients and Dietary Supplements,'' includes only the CGMP
for dietary supplements and the table of contents contains categorical
CGMP practices in subparts A through H.
Further, we propose the heading and table of contents for part 112.
Proposed part 112 has the heading ``Restrictions for Substances Used in
Dietary Supplements.'' The table of contents for proposed part 112
includes: Subpart A ``General Provisions'' [Reserved]; Subpart B ``New
Dietary Ingredients'' [Reserved]; and Subpart C ``Restricted Dietary
Ingredients'' [Reserved]. Proposed subpart C would include restrictions
for substances used in dietary supplements, such as the proposed rule
for dietary supplements containing ephedrine alkaloids, if finalized.
These proposed changes are made for ease of use and clarity. CGMP
regulations will be found more easily if located in one part, part 111,
and clarity will be enhanced by using subparts to organize categorical
CGMP practices. Similarly, restrictions for substances used in dietary
supplements will be found more easily if located in one part, part 112,
and clarity will be enhanced if the restrictions for substances used in
dietary supplements are located in one subpart, subpart C.
The proposed part 111 consists of eight subparts. Several of the
proposed provisions in the CGMP regulations for dietary ingredients and
dietary supplements are similar to the CGMP regulations for food
products at part 110. However, we edited the text in many cases to make
the proposed rule easier to read and to understand consistent with
plain language principles under the presidential memorandum of June 1,
1998 (Ref. 43). Some provisions are derived from the industry outline
that we included in the ANPRM; others are derived from comments we
received on the ANPRM or from our outreach efforts described
previously. We also developed provisions based on our knowledge and
expertise in the areas of dietary supplements, manufacturing, and
contamination.
We tentatively decided to exclude certain CGMP requirements in part
110 for food products because they do not appear to be appropriate for
dietary ingredients and dietary supplements. There are differences in
the nature of the product (i.e., conventional food versus dietary
ingredients or dietary supplements) and in the manufacturing practices
used to produce the product that require specific practices appropriate
for dietary ingredients and dietary supplements. We invite comment on
whether any provision from part 110 that we have not included should be
included in this proposed CGMP for dietary ingredients and dietary
supplements.
A. General Provisions (Proposed Subpart A)
Proposed subpart A contains five provisions that would provide
basic information to the reader.
1. Who Is Subject to These Part III Regulations? (Proposed Sec. 111.1)
Proposed Sec. 111.1 entitled ``Who is subject to these
regulations?'' describes the scope of the rule. Proposed Sec. 111.1
states that you are subject to the requirements in part 111 if you
manufacture, package, or hold a dietary ingredient or dietary
supplement. As stated previously in this document, in our response to
question 9 of the ANPRM, this proposed CGMP rule would apply to a wide
variety of activities associated with the manufacture, packaging, and
holding of dietary ingredients and dietary supplement products. These
activities include labeling, testing, quality control, holding, and
distribution. For example, if you contract with a manufacturer to
perform an operation subject to proposed part 111, you will need to
comply with those regulations directly applicable to the operation that
you perform. For example, if you are a firm that has contracted with a
dietary supplement manufacturer to package a dietary supplement, you
are responsible for complying with all the regulations, including
recordkeeping, that would otherwise be required of a manufacturer who
does its own onsite packaging. Further, if you are a manufacturer and
you contract with a firm to perform a particular manufacturing step,
you would remain responsible for ensuring that such step is done in a
manner that complies with the requirements in proposed part 111. As in
the previous example, a manufacturer who contracts with a firm to
package a product is still responsible for the actions of its
contractor for the packaging activities and must ensure that its
contractor complies with the applicable CGMP regulations.
Proposed part 111 also would apply to foreign firms that
manufacture, package, or hold dietary ingredients and dietary
supplements that are imported or offered for import into the United
States, unless imported for further processing and export under section
801(d)(3) of the act, to persons who distribute such imported dietary
ingredients and dietary supplements, and to persons who export dietary
ingredients and dietary supplements from the United States, unless
exported in compliance with section 801(e).
One comment to the ANPRM, relating to the scope of the CGMPs,
requested an exemption from the CGMP for ``herbalist'' practitioners
who individually manufacture dietary supplements for their clients.
We decline to exempt herbalist practitioners from the proposed
rule. If
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an herbalist practitioner introduces or delivers for introduction into
interstate commerce, a dietary ingredient or dietary supplement, that
practitioner must use the same good manufacturing practices as other
manufacturers to ensure that their clients receive dietary supplements
that are not adulterated. The risks of adulteration are not eliminated
just because the practitioner is an herbalist. Therefore, we decline to
exempt ``herbalist'' practitioners who manufacture dietary ingredients
and dietary supplements. Herbalist practitioners who introduce or
deliver for introduction into interstate commerce, a dietary ingredient
or dietary supplement, are manufacturers who must meet CGMPs.
2. What Are These Regulations Intended To Accomplish? (Proposed Sec.
111.2)
Proposed Sec. 111.2, entitled ``What are these regulations
intended to accomplish?'' discusses the purpose of the CGMP
regulations. The proposal states that the regulations establish the
minimum CGMPs that you must use to the extent that you manufacture,
package, or hold a dietary ingredient or dietary supplement. By using
the phrase ``to the extent,'' we mean that you must comply with the
provisions that are applicable to you or to the operations that you
perform and that, depending on the type of operations you perform, some
provisions may not apply to you. For example, some provisions discuss
requirements for automatic, mechanical, and electronic equipment; if
you do not use such equipment, you would not have to comply with those
provisions.
Our primary purpose in proposing these regulations is to protect
consumers from adulterated and misbranded dietary supplements due to
improper manufacturing, packaging, or holding practices. By observing
CGMP regulations that require that dietary ingredients and dietary
supplements are manufactured, packaged, or held in a controlled
environment, manufacturers can ensure that dietary ingredients and
dietary supplements are not adulterated or misbranded during
manufacturing, packaging, and holding operations. Manufacturing,
packaging, and holding dietary ingredients and dietary supplements
under CGMPs will provide consumers with greater confidence that dietary
supplements contain the dietary ingredients that they are supposed to
contain and that these dietary ingredients were evaluated for their
identity, purity, quality, strength, or composition. The CGMP
regulations, if finalized as proposed, would require a manufacturer to
establish specifications for the dietary ingredients and dietary
supplements that it makes. Thus, under the proposed CGMPs, a dietary
supplement with a particular dietary ingredient listed on its label
must contain that particular dietary ingredient. Moreover, that dietary
ingredient must meet certain specifications that the manufacturer
establishes as to the purity, quality, strength, and composition. CGMPs
are intended to ensure that a dietary supplement contains what the
label says it contains. If it does not, the dietary supplement would
not only be misbranded under section 403 of the act, but also would be
adulterated under section 402(g) of the act.
3. What Definitions Apply to This Part? (Proposed Sec. 111.3)
Proposed Sec. 111.3 defines various terms used in proposed part
111. In general, we have used definitions that are similar to
definitions in part 110 for food and other CGMP regulations. However,
we have modified some definitions for ``plain language'' purposes under
the presidential ``plain language'' memorandum (Ref. 43) and to make
other definitions more appropriate for dietary ingredients and dietary
supplements.
In some cases, we based a definition on provisions in the industry
outline published in the ANPRM. However, we did not adopt all of the
definitions in the industry outline. For example, the industry outline
defined terms such as, ``adequate,'' ``composition,'' ``raw material,''
``representable sample,'' and ``rework.'' We omitted those definitions
from this proposal because the terms are generally understood, or
because definitions for those terms are unnecessary for purposes of
understanding the proposed rule.
Proposed Sec. 111.3 states that the definitions and
interpretations of terms in section 201 of the act apply to such terms
when used in these regulations. Section 201 of the act defines various
terms that appear throughout the act, including ``dietary supplement''
(see section 201(ff) of the act). Other terms in section 201 of the
act, such as ``label'' (section 201(k) of the act) and ``pesticide
chemical'' (section 201(q)(1) of the act), have a long history of use.
The definitions and interpretations of such terms apply when we use
those terms in this rule.
Proposed Sec. 111.3 defines specific terms used in the proposal.
Proposed Sec. 111.3 defines ``batch'' as ``a specific quantity of
a dietary ingredient or dietary supplement that is intended to meet
specifications for identity, purity, quality, strength, and
composition, and is produced during a specified time period according
to a single manufacturing record during the same cycle of
manufacture.''
The phrase ``identity, purity, quality, strength, and
composition,'' means that the production on a batch-by-batch basis is
consistent with the master manufacturing record and is what it is
represented on the label to be (identity); is without impurities and is
the desired product (purity); is the identity, purity, and strength for
its intended purpose (quality); is the concentration, that is, the
amount per unit of use intended (strength); and is the intended mix of
product and product-related substances (composition).
Proposed Sec. 111.3 defines ``batch number, lot number, or control
number'' as ``any distinctive group of letters, numbers, or symbols, or
any combination of them, from which the complete history of the
manufacturing, packaging, or holding of a batch or lot of dietary
ingredients or dietary supplements can be determined.'' You should note
that the proposed definition would have the batch, lot, or control
number be ``distinctive,'' which means, for the purposes of this
proposal, that it is unique in some fashion, and is not a reused
number. Numbers must be distinctive because, if a problem involving a
marketed dietary ingredient or dietary supplement later results, a
distinctive batch number will make it possible for you to investigate
the source of the problem and the manufacturing history for the batch.
This would help you to take appropriate actions concerning that batch
more quickly.
Proposed Sec. 111.3 defines ``component'' as ``any substance
intended for use in the manufacture of a dietary ingredient or dietary
supplement including those that may not appear in the finished dietary
ingredient or dietary supplement.'' Proposed Sec. 111.3 states that
``component'' includes ingredients and dietary ingredients as described
in section 201(ff) of the act. Under proposed Sec. 111.3, components
would include ingredients, dietary ingredients, manufacturing aids
(such as solvents that are removed during manufacturing), and reagents
that are used to synthesize a product.
Under the proposed definition of ``component,'' a component may or
may not appear in the finished product. For example, solvents that are
used to produce herbal extracts do not necessarily appear in a finished
dietary supplement, but the proposed rule still would consider the
solvents to be ``components.'' As another example, ingredients, such as
cellulose (which is
[[Page 12177]]
used to make tablets) or gelatin (which is used to make capsules),
might be used to produce dietary supplements; these ingredients remain
in the finished product, but would be ``components'' under the proposed
rule.
Proposed Sec. 111.3 defines ``consumer complaint'' as:
* * * communication that contains any allegation, written or
oral, expressing dissatisfaction with the quality of a dietary
ingredient or a dietary supplement related to good manufacturing
practices. Examples of product quality related to good manufacturing
practices are: Foul odor, off taste, superpotent, subpotent, wrong
ingredient, drug contaminant, other contaminant (e.g., bacteria,
pesticide, mycotoxin, glass, lead), disintegration time, color
variation, tablet size or size variation, under-filled container,
foreign material in a dietary supplement container, improper
packaging, or mislabeling. For the purposes of this regulation, a
consumer complaint about product quality may or may not include
concerns about a possible hazard to health, which would include a
consumer complaint. However, a consumer complaint does not include
an adverse event, illness, or injury related to the safety of a
particular dietary ingredient independent of whether the product is
produced under good manufacturing practices.
Communication about prices, package size or shape, or other matters
that could not possibly reveal the existence of a hazard to health or
do not concern the appearance, taste, odor, or quality of a dietary
ingredient or a dietary supplement are not considered ``consumer
complaints'' under the proposed rule. Consumer complaints related to an
illness or injury related to a pharmacologically active substance of a
dietary ingredient such as aristolochic acid would not be related to
good manufacturing practices. The use of products containing
aristolochic acid has resulted in several life-threatening adverse
incidents. Aristolochic acids are potent carcinogens and nephrotoxins
that are present, primarily, in plants of the family Aristolochiaceae.
A product that contains a large amount of it may result in the rapid
onset of acute toxicity symptoms in a consumer using the product. A
product containing a small amount could be used for years with no
apparent adverse effects, until serious, irreversible effects, such as
renal failure, has occurred. Such adverse effects are related to a
pharmacologically active substance of a particular dietary ingredient,
aristolochic acid. Thus, for the purpose of this regulation, a
communication from a consumer that contains any allegation, written or
oral, related to the safety of the use of a product because it
contained a particular dietary ingredient, e.g., aristolochic acid
would not be considered a ``consumer complaint.'' We consider that a
dietary supplement containing a dietary ingredient such as aristolochic
acid, a substance that is nephrotoxic and carcinogenic, is adulterated
under section 402(a)(1), (f)(1)(A), and (f)(1)(D) of the act.
Proposed Sec. 111.3 defines ``contact surface'' as:
* * * any surface that contacts a component, dietary ingredient, or
dietary supplement, and those surfaces from which drainage onto the
component, dietary ingredient, or dietary supplement, or onto
surfaces that contact the component, dietary ingredient, or dietary
supplement ordinarily occurs during the normal course of operations.
Proposed Sec. 111.3 gives some examples of contact surfaces, such as
containers, utensils, tables, contact surfaces of equipment, and
packaging. Under the proposed definition the term drainage includes
both liquid and dry materials.
The proposed definition of ``contact surface'' is similar to the
definition of ``food-contact surface'' in Sec. 110.3(g), except we
have used the terms ``component, dietary ingredient, or dietary
supplement'' instead of food, and we have added several examples of
contact surfaces. The proposed definition would include the inside of
containers.
Proposed Sec. 111.3 defines ``ingredient'' as ``any substance that
is used in the manufacture of a dietary ingredient or a dietary
supplement that is intended to be present in the finished dietary
ingredient or dietary supplement.'' The proposed definition would
explain that an ingredient ``includes, but is not necessarily limited
to, a dietary ingredient as described in section 201(ff) of the act.''
Thus, under proposed Sec. 111.3, an ``ingredient'' may be a substance
that is present in the finished dietary ingredient or dietary
supplement that is intended to have some activity (such as a vitamin,
mineral, or amino acid), but could also be a substance that is not
intended to have any activity (such as the gelatin used to make the
capsule holding the dietary ingredients). This proposed definition and
the proposed definition for ``component'' in proposed Sec. 111.3
differ in that ``component'' includes the various materials used to
manufacture a dietary supplement that may not appear in the final
product. Because an ingredient is defined as a substance that is
intended to be present in the finished dietary ingredient or dietary
supplement and a component is defined as a substance that may or may
not be included in the finished dietary ingredient or dietary
supplement, all ingredients are components but not all components are
ingredients.
Proposed Sec. 111.3 defines ``in-process material'' as ``any
material that is fabricated, compounded, blended, ground, extracted,
sifted, sterilized, derived by chemical reaction, or processed in any
other way for use in the manufacture of a dietary ingredient or dietary
supplement.'' In-process material differs from a component because in-
process material is created and used during manufacturing. For example,
assume you manufacture a dietary supplement in hard tablet form. During
the manufacturing process, you mix various ingredients, and you add
binding agents and water to mix the ingredients thoroughly before
making individual tablets. The mixture would be an ``in-process
material'' because it is a blend or processed material that you will
use to make your dietary supplement.
Proposed Sec. 111.3 defines ``lot'' to mean:
* * * a batch, or a specific identified portion of a batch intended
to have uniform identity, purity, quality, strength, and
composition; or, in the case of dietary ingredient or dietary
supplement produced by continuous process, a specific identified
amount produced in a specified unit of time or quantity in a manner
that is intended to have uniform identity, purity, quality,
strength, and composition.
The proposed definition for ``lot'' is similar to the definition for
``lot'' in the proposed CGMP regulations for infant formula (61 FR
36154 at 36209, July 9, 1996), but would refer to ``identity, purity,
quality, strength, and composition'' instead of ``character and
quality'' to reflect the different characteristics of dietary
ingredients and dietary supplements.
Proposed Sec. 111.3 defines ``microorganisms'' as ``yeasts, molds,
bacteria, viruses, and other similar microscopic organisms having
public health or sanitary concern.'' The proposed definition would
include, but would not be limited to, species that:
[sbull] Have public health significance;
[sbull] Could cause a component, dietary ingredient, or dietary
supplement to decompose;
[sbull] Indicate that the component, dietary ingredient, or dietary
supplement is contaminated with filth; or
[sbull] Otherwise may cause the component, dietary ingredient, or
dietary supplement to be adulterated.
The definition of ``microorganisms'' includes microorganisms of
public health concern and microorganisms that are of sanitary concern.
Proposed Sec. 111.3 is similar to the definition of microorganism in
Sec. 110.3 but we added
[[Page 12178]]
``sanitary concern'' to the definition of microorganism. We added
``sanitary'' to clarify that we intend to include microorganisms of
public health and sanitary concern. Although the term ``sanitary'' is
not included in part 110, this change does not alter the generally
recognized and scientific and legal meaning of the definition of
``microorganism'' in part 110, because part 110 is similarly concerned
with sanitation. Under proposed Sec. 111.3, E. coli O157:H7 would be a
``microorganism'' because it is a species that has public health
significance. Other forms of E. coli, however, might not be of public
health significance because not all forms of E. coli are pathogenic and
present a public health risk. However, the presence of other forms of
E. coli would be of sanitary concern.
One comment to the ANPRM objected to including viruses in a
definition of ``microorganisms'' because it might imply that a
manufacturer is able to demonstrate the absence of viral contamination
in its dietary supplement.
We recognize that there are few effective virus detection methods
and that the industry may be incapable of showing the presence or
absence of specific viruses in its products. However, we have included
viruses in the definition for ``microorganisms'' because animal tissues
are used in the manufacture of dietary supplements, and the use of
virus-containing tissue would adulterate the product. In order to
ensure that animal tissue that may be used in or as a dietary
ingredient does not contain viruses of public health significance,
certain precautions may be needed to be taken in procuring and handling
such tissue. We discuss in section III.A.4 of this document what
precautions we are seeking comment on that manufacturers take to
prevent the use of tissue that may contain viruses of public health
significance for dietary ingredient or dietary supplement manufacture
or to prevent the introduction of such viruses into a dietary
ingredient or a dietary supplement.
Proposed Sec. 111.3 defines ``must'' to indicate that you have to
comply with a particular requirement. ``Must'' is the plain language
term that replaces ``shall.''
Proposed Sec. 111.3 defines ``pest'' as ``any objectionable
insects or other animals including, but not limited to, birds, rodents,
flies, mites, and larvae.'' Proposed Sec. 111.3 is similar to Sec.
110.3(j), although the proposed definition would add ``mites'' to the
list of pests. We added mites to the definition of ``pest'' in this
proposed rule because mites are capable of causing allergic reactions
in persons who consume mite-contaminated foods (Ref. 44).
Proposed Sec. 111.3 defines ``physical plant'' as ``all or parts
of a building or facility used for or in connection with manufacturing,
packaging, or holding a dietary ingredient or a dietary supplement.''
The proposed definition is similar to the definition of ``plant'' at
Sec. 110.3(k), except that we added the word ``physical'' before
``plant'' to distinguish between plants that are herbs, vegetables, and
growing organisms, and buildings or facilities that are used in
manufacturing, packaging, and holding a dietary ingredient or a dietary
supplement. We also expanded the definition to cover the types of
activities that would be subject to a CGMP rule for dietary ingredients
and dietary supplements.
Proposed Sec. 111.3 defines ``quality control'' as ``a planned and
systematic operation or procedure for preventing a dietary ingredient
or dietary supplement from being adulterated.'' A planned and
systematic operation or procedure provides a framework of current and
effective methods and procedures for each dietary ingredient or dietary
supplement you manufacture that will prevent dietary ingredients and
dietary supplements from being adulterated. We discuss quality control
in more detail later in this document.
Proposed Sec. 111.3 defines ``quality control unit'' as ``any
person or group that you designate to be responsible for quality
control operations.'' The quality control unit should consist of as
many people as necessary to perform the quality control operations.
Other provisions in this proposed rule address the quality control
unit's authority and responsibilities, and we discuss those provisions
later in this document.
Proposed Sec. 111.3 defines ``representative sample'' as ``a
sample that consists of a number of units that are drawn based on
rational criteria, such as random sampling, and intended to ensure that
the sample accurately portrays the material being sampled.'' By stating
that the ``sample accurately portrays the material being sampled,'' we
mean that it correctly represents and is typical of the material being
sampled. It is important that the sample drawn accurately portrays the
material being sampled because your analysis of the representative
sample will be used to determine whether the material received is
suitable for use in manufacturing or to determine that the dietary
ingredient or dietary supplement is not adulterated and may be released
for distribution. If the sample is not representative, you risk using a
contaminated component or dietary ingredient in manufacturing and you
may distribute an adulterated dietary ingredient or dietary supplement.
Proposed Sec. 111.3 defines ``reprocessing'' as:
* * * using, in the manufacture of a dietary ingredient or a dietary
supplement, clean, unadulterated components, dietary ingredients, or
dietary supplements that have been previously removed from
manufacturing for reasons other than insanitary conditions and that
have been made suitable for use in the manufacture of a dietary
ingredient or dietary supplement.
The phrase ``for reasons other than insanitary conditions'' means that
the component, dietary ingredient, or dietary supplement was removed
from manufacturing because the incorrect amount of a component was
added or other reason not due to insanitary conditions. However, the
component, dietary ingredient, or dietary supplement that was removed
from manufacturing because it became contaminated because of insanitary
conditions, that is, it became contaminated with a microorganism of
public health concern or a microorganism of sanitary concern, must not
be reprocessed.
Proposed Sec. 111.3 defines ``sanitize'' as:
* * * to adequately treat equipment containers, utensils, or any
other dietary product contact surface by applying cumulative heat or
chemicals on cleaned food contact surfaces that when evaluated for
efficacy, yield a reduction of 5 logs, which is equal to 99.999
percent reduction, of representative disease microorganisms of
public health significance and substantially reduce the numbers of
other undesirable microorganisms, but without adversely affecting
the product or its safety for the consumer.
One comment to the ANPRM pointed out that the industry-drafted
outline's definition of sanitize differed from FDA's Food Code
definition of sanitization (Ref. 45).
The FDA ``Food Code'' is a reference that guides retail outlets,
such as restaurants and grocery stores and institutions such as nursing
homes in how to prevent foodborne illnesses from food that is consumed
without further processing by the consumer. Because dietary supplements
also are consumed without further processing by the consumer, the FDA
``Food Code'' definition also is appropriate for use in sanitizing
contact surfaces used in the manufacture of dietary ingredients and
dietary supplements. The FDA ``Food Code'' definition of sanitization
is to apply cumulative heat or chemicals on
[[Page 12179]]
cleaned food contact surfaces that when evaluated for efficacy, yield a
reduction of 5 logs, which is equal to 99.999 percent reduction of
representative disease microorganisms of public health significance.
Because dietary supplements are consumed without further processing,
and for consistency with other agency definitions and standards, we are
persuaded to propose the FDA ``Food Code'' definition of ``sanitize.''
The agency believes that there may be a number of agents that can
reduce the number of microorganisms present on contact surfaces. A
tolerable level of risk may be achieved by interventions that have been
validated to achieve a cumulative 5-log reduction in the target
pathogens. However, we do not specify the manner in which the risk is
reduced. The proposed requirement mandates that you validate that the
control measures are both appropriate to their operation and
scientifically sound. In many cases, processors may rely on a written
certification from the equipment manufacturer or may obtain a written
scientific evaluation of a process, especially in cases where two or
more control measures are used to accomplish the 5-log reduction in the
target pathogen, to ensure that the process is adequate to destroy
microorganisms of public health significance or to prevent their
growth. The agency requests comments on its approach to pathogen
reduction. In particular, the agency requests comments on whether all
contact surfaces should be subject to proposed Sec. 111.3
``sanitize.''
Proposed Sec. 111.3 defines ``theoretical yield'' as ``the
quantity that would be produced at any appropriate step of manufacture
or packaging of a particular dietary ingredient or dietary supplement,
based upon the quantity of components or packaging to be used, in the
absence of any loss or error in actual production.'' We would
complement this definition by defining ``actual yield'' in proposed
Sec. 111.3 as ``the quantity that is actually produced at any
appropriate step of manufacture or packaging of a particular dietary
ingredient or dietary supplement.'' Comparing theoretical yields to
actual yields may help identify deviations or problems in the
manufacturing or packaging process. To illustrate this point, you
should understand that the theoretical yield is the quantity or amount
that you expect to see at a particular step, while the actual yield is
the quantity or amount that you actually obtain at a particular step.
Proposed Sec. 111.3 defines ``water activity'' as ``a measure of
the free moisture in a component, dietary ingredient, or dietary
supplement and is the quotient of the water vapor pressure of the
substance divided by the vapor pressure of pure water at the same
temperature.'' The proposed definition is consistent with the
definition at Sec. 110.3(r) and 21 CFR 113.5(w) and 114.5(h). Water
activity can play an important role in promoting microbial growth, and
that, in turn, can play a part in the contamination of your components,
dietary ingredients, and dietary supplements.
Proposed Sec. 111.3 defines ``we'' as meaning the U.S. Food and
Drug Administration.
Proposed Sec. 111.3 defines ``you'' as ``a person who
manufactures, packages, or holds dietary ingredients or dietary
supplements.'' ``You'' is the recommended ``plain language'' term
designed to make regulations easier to understand. In this proposed
rule, ``you'' refers to any person, within the meaning of section
201(e) of the act, who engages in any activity covered by this proposed
rule. You should note that ``you'' includes, but is not limited to, the
owner of the manufacturing firm as well as supervisors responsible for
ensuring that these CGMPs are followed. In other words, ``you'' can be
the person who owns the dietary ingredient or dietary supplement
company as well as persons who work for the company.
4. Do Other Statutory Provisions and Regulations Apply? (Proposed Sec.
111.5)
Proposed Sec. 111.5 would require that you comply with the
regulations in proposed part 111, and with other applicable statutory
provisions, and regulations under the act, related to manufacturing,
packaging, or holding dietary ingredients or dietary supplements. Other
statutory provisions or regulations that may apply to the manufacture,
packaging, or holding of dietary ingredients or dietary supplements
include, but are not limited to: (1) The PHS Act to prevent the
introduction, transmission, or spread of communicable diseases; (2)
part 110 (``Current Good Manufacturing Practice in Manufacturing,
Packing, or Holding Human Food''); (3) part 113 (21 CFR part 113)
(``Thermally Processed Low-Acid Foods Packaged in Hermetically Sealed
Containers''); (4) part 123 (21 CFR part 123) (``Fish and Fishery
Products''); (5) parts 70 through 82 (21 CFR parts 70 through 82) (for
color additives); and (6) parts 170 through 189 (21 CFR parts 170
through 189) (for food additives). For example, a manufacturer who
produces a dietary supplement that includes fish and fishery products,
such as fish oil, would have to comply with HACCP regulations as
required by part 123 as well as these CGMP provisions, if this rule is
finalized, that apply to the dietary supplement. These other statutory
provisions and regulations may apply because of the type of
manufacturing process used or the type of ingredient in the dietary
supplement.
Certain dietary ingredients, e.g., an animal-derived ingredient,
may require certain manufacturing, packaging, and holding practices
because, without such practices, they may pose serious public health
and safety concerns related to the transmission of communicable
disease. For purposes of this discussion, the term ``animal-derived
dietary ingredient'' refers to materials, substances, tissues, body
fluids, or body secretions from animals, birds, reptiles, insects, and
other living creatures and substances that may be derived from them. We
do not consider human tissues and other parts of humans, other than
human milk, to be eligible to be a dietary ingredient under section
201(ff) of the act because such products have not been used as a
``dietary substance for use by man to supplement the diet by increasing
the total dietary intake'' (21 U.S.C. 321(ff)(1)(E)).
Certain animal-derived dietary ingredients, as well as the handling
practices associated with such ingredients, may pose serious public
health and safety risks, and therefore, may require regulations.
Animal-derived materials, substances, and tissues have the potential to
cause serious illnesses or injuries when ingested. For example, bovine
colostrum is a substance that is used in dietary supplements (Ref. 46).
Bovine colostrum which is the lacteal secretion which precedes milk
after a cow gives birth, likely presents the same potential health
risks as does milk. Bovine milk may contain pathogenic organisms
capable of causing diseases in man such as tuberculosis, undulant
fever, and gastrointestinal disease (Ref. 47). Such milk must be
pasteurized in accordance with 21 CFR 1240.61. We have proposed a
specific requirement at Sec. 111.65(c)(5) that would require that you
sterilize, pasteurize, freeze, refrigerate, control hydrogen-ion
concentration (pH), control humidity, control water activity, or use
any other effective means to remove, destroy, or prevent the growth of
microorganisms and to prevent decomposition. This requirement, which
would apply to bovine colostrum for use in a dietary supplement, is
necessary to remove certain potential health risks. Milk also may
contain contaminants, such as drug residues if the cow has been treated
with such substances prior to beginning lactation,
[[Page 12180]]
that can cause serious adverse health effects in humans consuming the
colostrum (Ref. 48). For example, if the colostrum contains drug
residues, a dietary supplement containing colostrum could cause an
adverse effect in a person who is allergic to the drug residue. In
addition, some dietary supplements contain raw brain tissue or glands
(Ref. 49) that have a high risk of containing the infective agent that
causes bovine spongiform encephalopathy (BSE) if they originate from an
animal infected with the disease (Ref. 37). In fact, dietary
ingredients derived from different wild and domesticated animals may
present microbiological and contaminant hazards that are unique to
animal-derived dietary ingredients simply because the ingredient may
not be amenable to physical treatments (for example, sterilization to
eliminate pathogens) or there may not be appropriate methods to
identify or correct a potential risk (as in the case of BSE or other
transmissible spongiform encephalopathies (TSEs)).
The PHS Act is intended to prevent the introduction, transmission,
or spread of communicable diseases (42 U.S.C. 264). Dietary supplements
may be regulated under the PHS Act to the extent necessary to prevent
the introduction, transmission, or spread of communicable diseases in
intrastate and interstate commerce. Dietary supplements that contain
animal-derived ingredients may carry infective agents that may not be
able to be identified or that may be resistant to inactivation, as
described previously. We are not aware of dietary supplement
manufacturers' current procurement and handling practices of such
dietary ingredients, nor the extent to which such dietary ingredients
may be used. However, because the animal-derived dietary ingredients
present important public health and safety issues, we are seeking
comment on whether we should include in the final rule specific
requirements for manufacturing, packaging, or holding animal-derived
dietary ingredients. The U.S. Department of Agriculture (USDA) has
imposed certain restrictions (see 9 CFR 94.18) on importation from
certain regions of meat and edible products from certain animals. The
USDA has determined that these regions present an undue risk of
introducing BSE into the United States because BSE exists in the
regions, because the regions have import requirements less restrictive
than those that would be acceptable for import into the United States,
and/or because of inadequate surveillance. Because there is no broadly
applicable or validated diagnostic test available to manufacturers to
identify BSE agent infected ruminant animals or BSE agent infected
materials, the agency is considering whether to require, in our final
rule, specific requirements under proposed Sec. 111.35 that are
designed to prevent the use of materials derived from certain animals
from regions (``BSE Countries'') identified in 9 CFR 94.18. Such
requirements would likely include manufacturer procedures and records
and supplier certifications to ensure that a component, dietary
ingredient, or dietary supplement is free of the agent of BSE. To
prevent use of BSE agent-contaminated components, dietary ingredients,
or dietary supplements, requirements for supplier certifications would
likely include certification:
[sbull] Of the species of animal,
[sbull] Of the geographic origin of the animal,
[sbull] That no BSE was present in any of the animals in the herd
from which the animal came and that none of the animals from the herd
consumed mammalian-derived protein prohibited from use in ruminant
feed,
[sbull] That any foreign manufacturer from which the material
derived from animals was obtained:
1. Did not co-mingle material derived from animals from BSE
countries with material derived from animals from non-BSE countries,
2. Established, validated, and followed plans or procedures to
identify, track, and segregate material derived from animals from BSE
countries from material derived from animals from non-BSE countries,
and
3. Used dedicated manufacturing operations to prevent co-mingling
of materials derived from animals from BSE countries with materials
derived from animals from non-BSE countries.
Manufacturers that rely on supplier certifications to ensure that
materials derived from animals are BSE-free would likely need to verify
the reliability of supplier certifications by conducting supplier
audits at appropriate intervals. We invite comment on whether there are
other requirements that should be considered by FDA for supplier
certification or other manufacturing requirements to prevent the use of
BSE agent-contaminated components, dietary ingredients, or dietary
supplements. These specific requirements may be issued under the
authority of the act or may need to be issued under PHS Act authority
and may need to include relevant remedies available under the PHS Act.
In addition, we invite comment on whether there are animal-derived
materials from BSE countries that do not present a safety concern and,
if so, whether FDA should consider exempting such materials from a
possible requirement that would prevent the use of animal-derived
materials from BSE countries in dietary supplements and why. The agency
will consider whether to include, in the final rule, provisions
specifically related to the manufacture, packaging, and holding of
animal-derived dietary ingredients or dietary supplements. One of the
more obvious and serious hazards is the transmission of TSE (Ref. 37).
We have communicated with the public and manufacturers of FDA-regulated
products about appropriate steps to increase product safety and
minimize the risk of products contaminated with the BSE agent. We
published a notice in the Federal Register of August 29, 1994 (59 FR
44592), entitled ``Bovine-Derived Materials; Agency Letters to
Manufacturers of FDA-Regulated Products'' (Ref. 50). The notice, in
part, published the November 1992 and December 1993 letters to
manufacturers. In November 1992, we wrote to manufacturers of dietary
supplements to alert them to the developing concern about TSEs in
animals and Creutzfeldt-Jakob Disease in humans and recommended that
they investigate the geographic source of any bovine and ovine material
used in their products. We suggested that manufacturers develop plans
to ensure, with a high degree of certainty, that bovine and ovine
materials used in their products were not from BSE countries or from
sheep flocks (foreign or domestic) infected with scrapie. In December
1993, we issued a letter recommending against the use of bovine-derived
materials from cattle that resided in, or originated from, BSE
countries in FDA-regulated products. In this letter, we recommended
that manufacturers: (1) Identify bovine-derived materials in their
products and identify all countries where the animals used to produce
the materials had lived, (2) maintain traceable records for each lot of
bovine materials and for each lot of FDA-regulated product using these
materials, (3) document the country of origin of the live animal source
of any bovine-derived materials used in the manufacture of the
regulated products, and (4) maintain copies of the records identified
above for FDA-regulated products manufactured using bovine-derived
materials at foreign sites or by foreign manufacturers. To assure the
safety and suitability for human use of animal-derived biologics, our
Center for
[[Page 12181]]
Biologics Evaluation and Research (CBER) has developed guidances for
industry that describe steps that manufacturers should take. For
example, CBER guidances have recommendations that address viral safety,
infections, disease risks, and BSE-risk reduction of biologic products
that are animal-derived (see 63 FR 51074, September 24, 1998, and 63 FR
50244, September 21, 1998) (Refs. 51 and 52). Because we believe that
the use of an animal-derived material, substance, or tissue in a
dietary supplement may raise many of the same serious public health and
safety issues as animal-derived materials, substances, or tissues, in a
biologic, we are considering whether the procedures that CBER
recommends for a product with animal-derived materials, substances, or
tissues would be appropriate for dietary ingredients and dietary
supplements that contain animal-derived materials, substances, or
tissues. We, therefore, invite comment on whether there should be
specific CGMP requirements for the use of animal-derived materials,
substances, or tissues in dietary ingredients and dietary supplements.
We invite comment on these issues and specifically on whether there is
a scientific basis for FDA to treat animal-derived dietary ingredients
in a manner that is different from, or that would offer less protection
than, what is recommended for animal-derived biologics when the same
public health and safety risks may be present. We also invite comment
on our legal authority with respect to these issues.
5. Exclusions (Proposed Sec. 111.6)
Proposed Sec. 111.6 would state that these CGMP regulations do not
apply to a person engaged solely in activities related to the
harvesting, storage, or distribution of raw agricultural commodities
that will be incorporated into a dietary ingredient or dietary
supplement by other persons. This proposed exclusion is similar to the
exclusion in Sec. 110.19 for raw agricultural commodities.
Accordingly, persons who engage in such activities related to raw
agricultural commodities (which are defined in section 201(r) of the
act), although not subject to these proposed CGMP regulations under
section 402(g) of the act, would continue to be subject to other
adulteration provisions in section 402 of the act.
We recognize that including in the proposed rule persons who engage
in the activities related to the harvesting, storage, or distribution
of such commodities, as described previously, could reduce the risk of
microbial contamination in dietary ingredients and dietary supplements.
Nevertheless, the proposal does not contain requirements for persons
handling such commodities before distribution to a dietary ingredient
or dietary supplement manufacturer because the scientific basis for
reducing or eliminating pathogens in various settings is evolving. We
invite comments on whether we should include provisions in the CGMP
proposal that would include persons who handle raw agricultural
commodities.
Even though the proposed rule would not cover persons who harvest
or otherwise handle raw agricultural commodities before distribution of
these commodities to a dietary ingredient or dietary supplement
manufacturer, we recommend some practices to help you minimize
microbial food safety hazards in such commodities that you may use in a
dietary ingredient or dietary supplement. We recommend that you adapt,
to your practices, the good agricultural practices (GAPs) and good
manufacturing practices for fruits and vegetables that we issued as a
guidance document: ``Guide to Minimize Microbial Food Safety Hazards
for Fresh Fruits and Vegetables'' (Ref. 53). This guidance document
includes recommended GAPs for water, worker health and hygiene,
sanitary facilities, field sanitation, packing, and transportation.
Those who harvest, store, or distribute raw agricultural commodities
for incorporation into dietary ingredients or dietary supplements
should adapt these practices to their specific operations.
B. Personnel (Proposed Subpart B)
Proposed subpart B contains three provisions dealing with personnel
matters. In general, the proposed provisions are similar to the current
CGMP requirements for food personnel in Sec. 110.10.
1. What Microbial Contamination and Hygiene Requirements Apply?
(Proposed Sec. 111.10)
Individuals who handle components or dietary supplements may affect
the purity or quality of those components or dietary supplements if
they fail to take precautions to guard against microbial contamination
or other types of contamination. For example, an employee who has an
illness could unintentionally transfer bacteria or viruses causing such
illness to a dietary supplement by simply handling the dietary
supplement.
Proposed Sec. 111.10(a), therefore, would require that you take
measures to exclude from any operations any person who might be a
source of microbial contamination of any material including components,
dietary ingredients, dietary supplements, or contact surfaces used in
the manufacture, packaging, or holding of a dietary ingredient or a
dietary supplement. We based proposed Sec. 111.10(a) on similar
requirements in Sec. 110.10.
Proposed Sec. 111.10(a)(1) would require that you exclude any
person who, by medical examination or supervisory observation, is shown
to have, or appears to have an illness, open lesion (such as a boil,
sore, or an infected wound), or any other abnormal source of microbial
contamination from any operations, which may be expected to result in
microbial contamination of components, dietary ingredients, dietary
supplements, or contact surfaces, from working in any operations until
the condition is corrected. For example, if an employee tells you that
his or her physician has diagnosed that the employee has a fever, and
the employee normally handles your dietary supplements, you must take
steps to ensure that the employee does not come into contact with your
dietary supplements because the fever may suggest that the employee has
an infection and there is a reasonable possibility of contamination.
Likewise, if your supervisors see that an employee has an open wound or
sore, and the employee normally handles dietary ingredients, you must
take steps to ensure that he or she is excluded from handling dietary
ingredients because the open wound or sore could be a source of
microbial contamination and because there is a reasonable possibility
of contamination.
Proposed Sec. 111.10(a)(2) would require that you instruct your
employees to notify their supervisor(s) if they have, or if there is a
reasonable possibility that they have, a health condition that could
contaminate any components, dietary ingredients, dietary supplements,
or any contact surface.
Proposed Sec. 111.10(b) would apply if you work in operations
where adulteration of components, dietary ingredients, dietary
supplements, or contact surfaces may occur. The proposal would require
that you use hygienic practices to the extent necessary to protect
against contamination of those components, dietary ingredients, dietary
supplements, or contact surfaces.
These hygienic practices would include, but would not be limited
to:
[sbull] Wearing outer garments in a manner that protects against
contamination of components, dietary ingredients, dietary supplements,
or any
[[Page 12182]]
contact surface. Outer garments may include gowns or aprons;
[sbull] Maintaining adequate personal cleanliness;
[sbull] Washing hands thoroughly (and sanitizing if necessary to
protect against contamination with microorganisms) in an adequate hand-
washing facility:
1. Before starting work; and
2. At any time when hands may become soiled or contaminated. Hands
may become soiled or contaminated after meals or after using the
bathroom;
[sbull] Removing all unsecured jewelry and other objects that might
fall into components, dietary ingredients, dietary supplements,
equipment, or packaging, and removing hand jewelry that cannot be
adequately sanitized during periods when you manipulate components,
dietary ingredients, or dietary supplements by hand. If the hand
jewelry cannot be removed, the proposal would require that it be
covered by material that is intact, clean, and in sanitary condition
that effectively protects against contamination of your components,
dietary ingredients, or dietary supplements, or contact surfaces.
[sbull] Maintaining gloves used in handling components, dietary
ingredients, or dietary supplements in an intact, clean, and sanitary
condition;
[sbull] Wearing, where appropriate, in an effective manner, hair
nets, caps, beard covers, or other hair restraints;
[sbull] Not storing clothing or other personal belongings in areas
where components, dietary ingredients, dietary supplements, or any
contact surfaces are exposed or where contact surfaces are washed;
[sbull] Not eating food, chewing gum, drinking beverages, and using
tobacco products in areas where components, dietary ingredients,
dietary supplements, or any contact surfaces are exposed or where
contact surfaces are washed; and
[sbull] Taking any other necessary precautions to protect against
contamination of components, dietary ingredients, dietary supplements,
or contact surfaces by microorganisms, filth, or other extraneous
materials, including, but not limited to, perspiration, hair,
cosmetics, tobacco, chemicals, and medicines applied to the skin.
Each of these procedures is necessary because good personal hygiene
should help prevent contamination from microbial sources (such as
bacteria) as well as from nonmicrobial sources (such as dirt and hair).
We seek comment on whether we should require, in a final rule, that
you establish and follow written procedures to ensure that you comply
with the requirements of that section. As stated previously, we invite
comment on whether such written procedures should be required in a
final rule, and whether there are other procedures, that we should
include in a final rule. If comments assert that written procedures are
necessary, comments should include an explanation of why the
requirement is necessary to prevent adulteration including how such a
requirement would ensure the identity, purity, quality, strength, and
composition of the dietary ingredient or dietary supplement.
Conversely, if comments assert that written procedures are not
necessary, comments should include an explanation of why the
requirement is not necessary including how, in the absence of the
requirement, one can prevent adulteration and ensure the identity,
purity, quality, strength, and composition of the dietary ingredient or
dietary supplement. Further, we seek comment on whether any of the
proposed requirements in this section are not necessary to prevent
adulteration and to ensure the identity, purity, quality, strength, and
composition of the dietary ingredient or dietary supplement. If
comments assert that certain provisions are not necessary, comments
should include an explanation of why the requirement is not necessary
including how, in the absence of the requirement, one can prevent
adulteration and ensure the identity, purity, quality, strength, and
composition of the dietary ingredient or dietary supplement. If
comments agree that the proposed requirements are necessary for reasons
other than those we have provided, the comments should so state and
provide an explanation.
A comment to the ANPRM stated that any requirements on disease
control should be limited to manufacturing, processing, and handling of
raw agricultural material and are not appropriate for manufacturing
dietary supplements derived from chemicals. The comment stated that
chemical processes are carried out in closed pipes and vessels, so the
risk for human contamination is very low. The comment, therefore, said
that FDA should allow workers who have wounds to continue working in
manufacturing operations.
We disagree that the regulations on disease control should be
limited to manufacturing, processing, and handling raw agricultural
material. Because contamination may occur at any time during
manufacturing, packaging, or holding operations, requirements
concerning disease control must apply to all operations where a person
may contaminate a component, dietary ingredient, dietary supplement, or
contact surface. For example, an employee could contaminate a dietary
supplement (of agricultural origin or synthetic origin) or contact
surface during packaging operations. However, if we adopted the
comment's suggested limitation, contamination of a synthetic dietary
supplement could occur, and there would be no regulatory requirement to
guard against such contamination.
As for employees with open wounds, proposed Sec. 111.10(a) would
require that you exclude a person with an open lesion or any other
abnormal source of microbial contamination from any operation which may
adulterate the component, dietary ingredient, dietary supplement, or
contact surface. Whether the proposed rule would require that you
exclude a person with an open lesion or another abnormal source of
microbial contamination from working in a closed system area, such as
when the product is contained completely in closed pipes or vessels,
would depend on whether, as a result of exposure, there would be a
reasonable possibility of the component, dietary ingredient, dietary
supplement, or contact surface becoming contaminated. Thus, when a
dietary ingredient or dietary supplement is manufactured in a
completely closed system, this proposed requirement on open lesions
might not apply if there is no reasonable possibility of contamination.
However, you must take the measures that would be required by Sec.
111.10(a) if there is a reasonable possibility that any person might
cause contamination of components, dietary ingredient, dietary
supplements, or contact surfaces.
Comments to the personnel provisions, and other provisions, stated
that the industry-drafted outline used phrases such as ``includes, but
are not limited to,'' when giving examples of how to comply with
various requirements. The comments suggested that this phrase be
changed to ``may include'' to clarify that items that follow the phrase
are simply examples of how to comply with a particular requirement and
are not binding or do not represent an exhaustive list of examples.
We decline to draft the proposal as suggested by the comments
because we do not agree that when we state ``includes, but are not
limited to,'' we are providing examples of how to comply with the
regulations. When we state that a regulation requires a manufacturer,
packager, or holder to establish certain practices which ``includes,
but is not limited to'' a list
[[Page 12183]]
of procedures or activities, we are stating that compliance with the
regulation requires that you adopt, at the minimum, the procedures or
activities listed in the regulation. Therefore, when we state
``includes, but is not limited to,'' we mean that the list of
procedures or activities following the ``includes'' statement is a list
of requirements.
2. What Personnel Qualification Requirements Apply? (Proposed Sec.
111.12)
Proposed Sec. 111.12 would establish basic qualification
requirements for employees. Proposed Sec. 111.12(a)(1) would require
that you have qualified employees to manufacture, package, or hold
dietary ingredients or dietary supplements. We are not proposing a
general standard for determining how many employees are necessary, but
there should be enough to manufacture, package, or hold dietary
ingredients or dietary supplements consistent with these proposed
CGMPs. A one-person operation is not precluded provided that one person
is sufficient to achieve, maintain, and document CGMPs. However,
general manufacturing practice suggests the need for a minimum of two
persons, the first to perform the work and a second person to check the
work performed to ensure that a manufacturing deviation or an
unanticipated occurrence is not overlooked. However, we leave the
determination of the actual number of employees necessary to your
discretion. As stated previously, we invite comment on whether there is
a minimum number of employees needed to manufacture dietary ingredients
or dietary supplements.
Proposed Sec. 111.12(a)(2) would require that each person engaged
in manufacturing, packaging, or holding must have the training and
experience to perform the person's duties. Training is necessary to
ensure that employees know how to correctly and fully perform the
operations in question and to ensure that the employees are competent
to produce an unadulterated product. The extent and frequency of the
training is left to the manufacturer's discretion. The extent and
frequency of training needed for your employees will depend on the
scope of the employee's activities and experience. For example,
training may be necessary when you hire new employees, when employees
engage in new activities, when your physical plant implements new
manufacturing practices, or when you add new equipment or new processes
to manufacturing. For example, an employee responsible for measuring
ingredients during batch production should have sufficient training or
expertise to perform those functions. If that employee does not know
how to measure correctly, the employee may add too much of an active
ingredient, which may cause the product to be adulterated. Thus,
proposed Sec. 111.12 would establish requirements for your employees.
We invite comment on whether we should require, in a final rule, a
requirement that you document and keep records regarding each
employee's training. We believe that the records, if required, should
show the content and date of the training. Such records may be useful
in determining whether an employee has received the training necessary
to perform his or her duties. We invite comment on not only whether
such records should be required in a final rule, but also what types of
information such records should contain.
You may use consultants to advise you on any aspect of the
manufacture, packaging, or holding of dietary ingredients or dietary
supplements. Any consultant you use should be qualified by training and
experience to provide the advice they give to you. We invite comment on
whether we should require, in a final rule, that you document each
consultant's name, address, and qualifications and include a
description of the services that the consultant provided. Such records
may assist you in knowing who to contact and where to contact him or
her if questions arise concerning the advice given.
A comment to the ANPRM suggested that the employee qualification
requirements in the industry outline should, in part, state that
``proper education, training, or experience'' is required instead of
``proper education, training, and experience'' is required (emphasis
added).
We disagree with the use of ``or'' instead of ``and.'' We omitted
the term ``proper education'' because ``training'' may be considered a
form of ``education.'' However, the proposed rule uses the conjunction
``and'' because, while some might consider ``experience'' to be a form
of ``training,'' most consider ``experience'' to be knowledge that a
person gains over time as he or she becomes increasingly familiar with
a particular action or piece of equipment.
Training, however, may not just include on-the-job training, but
may include some type of educational experience derived from attending
classes or lectures or some other formal instruction on a particular
subject. Some positions not only require the employee to have
experience or training on the job, but also require that the employee
have the appropriate educational background, for example, to understand
the significance of using a particular test method or understanding the
significance of a processing deviation and how to respond to such
deviation. The word ``and'' includes situations where on-the-job
training may be adequate and also situations where educational training
may be required. Therefore, proposed Sec. 111.12(a)(2) refers to
``training and experience.''
3. What Supervisor Requirements Apply? (Proposed Sec. 111.13)
Proposed Sec. 111.13 would establish general supervision
requirements and is similar to a provision that appeared in the
industry-drafted outline. Proposed Sec. 111.13(a) would require that
you clearly assign to qualified supervisory personnel the
responsibility for ensuring that all CGMP requirements in part 111 are
met. You should assign an adequate number of qualified personnel to
supervise the manufacturing, packaging, or holding of dietary
ingredients and dietary supplements. We are not proposing a general
standard for determining how many supervisors are necessary and a one-
person operation is not precluded provided that one person is
sufficient to supervise CGMPs. As stated previously, we invite comment
on whether there is a minimum number of qualified personnel to
supervise the manufacturing, packaging, or holding of dietary
ingredients or dietary supplements. Proposed Sec. 111.13(b) would
require you and your supervisors to be qualified by training and
experience to supervise.
Making supervisors responsible for compliance with the regulations
would be an important step in manufacturing, packaging, and holding
dietary ingredients and dietary supplements under conditions that will
not cause adulteration and misbranding. We believe that clearly
designating compliance responsibilities to individuals increases the
likelihood of compliance with the regulations.
One comment to the ANPRM questioned why supervisory personnel must
be ``qualified'' when the food CGMP regulations require supervisory
personnel to be ``competent'' (see Sec. 110.10(d)).
We consider the terms to be equivalent in this case. The Webster's
II New Riverside University Dictionary defines competent as ``able to
perform as required: competent'' and further defines ``qualified'' as
``having met the requirements for a specific position or
[[Page 12184]]
task'' (Ref. 54). Therefore, we consider the words ``qualified'' and
``competent'' in proposed Sec. 111.13 and Sec. 110.10(d),
respectively, should be considered synonymous.
Another comment to the ANPRM questioned making supervisors
responsible for ensuring compliance by all personnel with all CGMP
requirements. The comment stated that absolute compliance with each and
every CGMP requirement cannot be ensured, but that requiring a
supervisor to be responsible may make the supervisor personally liable
in the event of noncompliance.
Proposed Sec. 111.13(a) would require that manufacturers assign
responsibility to qualified supervisory personnel. Doing so will help
ensure that the CGMPs are followed. In general, if the proposed rule is
finalized, manufacturers, packagers, and holders would be responsible
for complying with these CGMP requirements and for ensuring that they
assign responsibility to qualified supervisors. We consider many
factors when we take enforcement action, and so the facts surrounding a
CGMP violation will influence the type of enforcement action we take.
The manufacturer is responsible under Sec. 111.13(a) for ensuring that
qualified supervisory personnel are assigned to oversee the
implementation of these CGMPs.
C. Physical Plant (Proposed Subpart C)
Proposed subpart C consists of provisions intended to help prevent
contamination from your physical plant. These provisions are similar to
the food CGMP requirements found in Sec. Sec. 110.20, 110.35, and
110.37 which pertain to buildings and facilities.
We have not proposed requirements similar to the food CGMP
requirements found in Sec. 110.20(a) for keeping the grounds bordering
your physical plant in a condition that protects against contamination
of components, dietary ingredients, or dietary supplements. In order to
limit the burden to manufacturers, FDA is not proposing such
requirements. However, we invite comment on whether such requirements
should be included in a final rule. Section Sec. 110.20(a), identifies
several methods necessary for adequate ground maintenance, such as:
[sbull] Properly storing equipment, removing litter and waste, and
cutting weeds or grass within the immediate vicinity of your physical
plant so that it does not attract pests, harbor pests, or be used by
pests for breeding;
[sbull] Maintaining roads, yards, and parking lots so that they do
not constitute a source of contamination in areas where food is
exposed;
[sbull] Adequately draining areas that may contribute to the
contamination to food by seepage, filth, other extraneous materials, or
by providing a breeding place for pests; and
[sbull] Adequately operating systems for waste treatment and
disposal in an adequate manner so that they do not constitute a source
of contamination in areas where food is exposed.
For example, rodents, insects, and other pests may be attracted to
garbage, and if you do not take adequate steps to remove or dispose of
garbage, you may be risking contamination from those rodents, insects,
or other pests. Rodents, insects, and other pests are sources of feces,
hair, and other potential contaminants (Refs. 55 and 56). We invite
comment on whether we should require, in a final rule, that you take
these steps and/or other steps to protect against contamination.
1. What Sanitation Requirements Apply to Your Physical Plant? (Proposed
Sec. 111.15)
Proposed Sec. 111.15(a), like Sec. 110.35(a), would require that
you keep your physical plant in a clean and sanitary condition and in
sufficient repair to prevent contamination of components, dietary
ingredients, dietary supplements, or contact surfaces. For example,
holes in your physical plant's walls or windows could allow pests or
contaminants to enter, so proposed Sec. 111.15(a) would require that
you repair those holes.
Proposed Sec. 111.15(b) pertains to cleaning compounds, sanitizing
agents, and pesticides you use. The proposal is similar to Sec.
110.35(b) and, in essence, would require that you use cleaning
compounds and sanitizing agents that are free from microorganisms of
public health significance and are safe and adequate under the
conditions of use. By saying that the cleaning compounds and sanitizing
agents should be ``free from microorganisms,'' we mean that your use of
those cleaning compounds and sanitizing agents should not contaminate
your components, dietary ingredients, dietary supplements, or contact
surfaces with microorganisms. We are proposing this requirement because
microorganisms, if present in your cleaning compounds or sanitizing
agents, can contaminate your contact surfaces or deactivate the
sanitizing agent and, as a result, adulterate your components, dietary
ingredients, dietary supplements, or contact surfaces. We advise that
you should verify that cleaning compounds and sanitizing agents are
free from contamination by microorganisms of public health significance
and are safe and adequate under their conditions of use. Such
verification may include buying these substances under a supplier's
guarantee or certification or you may examine them for contamination.
Several comments on the industry outline published in the ANPRM
objected to the idea that compliance ``may be verified by any effective
means including purchase of these substances under a supplier's
guarantee or certification, or examination of these substances for
contamination.'' The comments stated that such language is unnecessary
and may be interpreted as too restrictive and that manufacturers should
be able to determine the appropriate means of assuring compliance.
We agree with the comments that you may determine the appropriate
means of assuring compliance with this regulation. The proposed rule
would not require that you follow any particular method for assuring
compliance; instead, the proposal would give you the flexibility to
decide how to ensure that your cleaning compounds and sanitizing agents
are free from contamination and are safe and adequate under the
conditions of use.
Proposed Sec. 111.15(b)(2) would require that you not use or hold
toxic materials in a physical plant in which contact surfaces,
components, dietary ingredients or dietary supplements are manufactured
or exposed, unless those toxic materials are necessary:
[sbull] To maintain clean and sanitary conditions,
[sbull] For use in laboratory testing procedures,
[sbull] For maintaining or operating the physical plant or
equipment, or
[sbull] For use in the physical plant's operations.
If at least one of the listed conditions is not met, you must not use
or hold the toxic material because there would be no reason to risk
contamination from exposure to such material if it is not necessary to
your operations.
Proposed Sec. 111.15(b)(3) would require that you identify and
hold toxic cleaning compounds, sanitizing agents, pesticides, and
pesticide chemicals in a manner that protects against contamination of
components, dietary ingredients, dietary supplements, and contact
surfaces. You must take steps to store your toxic materials in a way
that prevents them from contaminating your dietary ingredients and
dietary supplements. If such products were stored in manufacturing
areas or where dietary ingredients or dietary
[[Page 12185]]
supplements may be otherwise exposed to such products, those toxic
materials may come in contact with the dietary ingredients or dietary
supplements and thereby contaminate them. In addition, clearly
identifying the containers in which such toxic materials are held will
prevent accidental use.
One comment to the ANPRM objected to the provision in the industry
outline that would require manufacturers to register and use
rodenticides, insecticides, and fungicides in accordance with the
Federal Insecticide, Fungicide, and Rodenticide Act and to follow all
relevant Federal, State, and local government requirements. The comment
said the requirement would be redundant with other regulations.
Although this CGMP proposed rule does not propose a requirement
that you follow all relevant Federal, State, and local government
requirements when applying, using, or holding toxic cleaning compounds,
sanitizing agents, and pesticides, the proposed rule does not relieve
you from such obligations.
Proposed Sec. 111.15(c) pertains to pests. Proposed Sec.
111.15(c)(1) would require that you exclude animals or pests from all
areas of your physical plant, while proposed Sec. 111.15(c)(2) would
require that you take effective measures to exclude pests from your
physical plant and to protect against the contamination of components,
dietary ingredients, dietary supplements, or contact surfaces.
Therefore, if you have pests in your physical plant, you must take
immediate action to get rid of them. In addition, you must take
measures to prevent those and any other type of pests from entering
your physical plant.
You should note that, like Sec. 110.35(d), proposed Sec.
111.15(c)(1) would allow guard dogs and guide dogs in your physical
plant if their presence will not result in the contamination of
components, dietary ingredients, dietary supplements, or contact
surfaces.
Proposed Sec. 111.15(c)(3) would require that you not use
insecticides, fumigants, fungicides, or rodenticides unless you take
precautions to protect against contamination of your components,
dietary ingredients, dietary supplements, or contact surfaces. For
example, some pesticides may cause adverse effects in humans, so you
must take precautions to ensure that any pesticides you use will not
contaminate your components, dietary ingredients, dietary supplements,
or contact surfaces.
Proposed Sec. 111.15(d) would apply to water supplies and is
patterned after the food CGMP requirement at Sec. 110.37(a). Proposed
Sec. 111.15(d)(1) would require that you provide water that is ``safe
and of adequate sanitary quality,'' at suitable temperatures and under
pressure as needed in all areas where water is necessary for:
[sbull] Manufacturing dietary ingredients or dietary supplements;
[sbull] Making ice that comes into contact with components, dietary
ingredients, dietary supplements, or contact surfaces;
[sbull] Cleaning surfaces; and
[sbull] Employee bathrooms and hand washing facilities.
Proposed Sec. 111.15(d)(2) would require that water that contacts
components, dietary ingredients, dietary supplements, or any contact
surfaces, at a minimum, comply with the National Primary Drinking Water
(NPDW) regulations prescribed by the Environmental Protection Agency
(EPA) and any State and local government requirements. (EPA's NPDW
regulations can be found at 40 CFR part 141.)
Proposed Sec. 111.15(d) would require that you use water that is
of safe and sanitary quality in all aspects of your operation where, if
such water was not used, could result in contamination and adulteration
of your dietary ingredients and dietary supplements. Further, under
proposed Sec. 111.15(d)(2), in any operation where water contacts
components, dietary ingredients, dietary supplements or any contact
surfaces, the water must comply with the EPA's NPDW regulations. We
believe that the EPA's NPDW water regulations are necessary because
contaminated water can contaminate dietary ingredients and dietary
supplements both when used as an ingredient in the dietary ingredient
or dietary supplement and when contaminated water is allowed to enter
the product indirectly, as can occur, for example, when water is used
to cool a product or to clean a contact surface.
We recognize that, for some operations, you may want to use water
that is more pure or of higher quality than that required under the
NPDW regulations. For example, to ensure the purity of your dietary
supplements, you might use water that has gone through water
purification and filtering equipment to ensure that the water is clean
and sterile. In contrast, to clean contact surfaces and other surfaces,
sterilized water may be unnecessary because a contact surface that is
exposed to the environment will not remain sterile; airborne
microorganisms and microorganisms on your employees will find their way
onto the contact surface, thereby rendering it nonsterile. Proposed
Sec. 111.15(d) would not prevent you from using water that is more
pure than that required under the NPDW regulations. Proposed Sec.
111.15(d) provides you with the flexibility to raise your water quality
above the minimum criteria to meet your particular manufacturing needs.
We acknowledge that foreign firms may not be subject to EPA water
requirements or adhere to EPA requirements. Nevertheless, water quality
is an important part of CGMPs, so we invite comment on our proposed
requirement that does not distinguish between foreign or domestic
requirements, and, therefore, would require foreign firms to meet the
NPDW regulations.
A number of comments to the ANPRM suggested that we should require
the use of potable water (water that is fit to drink) or a higher
quality water or establish potable water as the minimum quality water
standard. One comment stated that the industry outline, by referring to
potable water, prevents the use of water whose quality exceeded a
potable water standard because a higher quality water would not be in
compliance.
We agree that potable water should be a minimum water quality
standard, and proposed Sec. 111.15(d) would reflect that standard.
Proposed Sec. 111.15(d)(1) would require water to be ``safe and of
adequate sanitary quality.'' Water that is ``safe and of adequate
sanitary quality'' is or should be potable. Proposed Sec. 111.15(d)(2)
would require water that contacts components, dietary ingredients,
dietary supplements, or contact surfaces to meet, at a minimum, EPA's
NPDW regulations and State and local requirements. Water meeting these
requirements is potable.
Please note that proposed Sec. 111.15(d) does not prevent you from
using water that is more pure or of higher quality than that required
under EPA's NPDW regulations. We reiterate that proposed Sec.
111.15(d) would establish minimum water quality standards.
Proposed Sec. 111.15(d) does not make any distinctions between
water from public sources and water from private sources. Consequently,
if you use water from private sources, you would need to ensure that
the water meets the minimum water quality standards in proposed Sec.
111.15(d). For example, if you use a well as your water source, you
would need to ensure that the well design meets government water
quality standards and you may need to perform appropriate water
treatment procedures, including filtration, sedimentation, and
chlorination. These actions are necessary because private water
sources, such as surface waters or water from shallow wells, may be
subject to microbiological, chemical, or radiological contamination.
For
[[Page 12186]]
example, fertilizer runoff can enter streams and contaminate surface
water. Contaminants in the ground may enter a well and contaminate well
water. Therefore, it is important that water from any source comply
with the requirements set out in proposed Sec. 111.15(d).
Another comment to the ANPRM suggested that a potable water
standard is inappropriate for use in manufacturing dietary ingredients
and dietary supplements from chemicals. The comment would limit the use
of potable water to manufacturing, processing, and handling of
vegetables, ready-cooked dishes, etc.
We disagree with the comment. If water is not suitable for drinking
(nonpotable), the water may contain microorganisms or contaminants that
will contaminate your dietary ingredients or dietary supplements. For
example, water from private sources may be untreated, so it may be
contaminated by pesticides due to water runoff from fields or may
contain microorganisms, algae, particulates, etc. Therefore, proposed
Sec. 111.15(d) would require that you use water that is of safe and
sanitary quality, regardless of whether you use natural or synthetic
components to make dietary ingredients and dietary supplements.
Proposed Sec. 111.15(d)(3) would require that you have
documentation or otherwise be able to show that the water that contacts
components, dietary ingredients, dietary supplements, or any contact
surface meets the water quality standard in proposed Sec.
111.15(d)(2). The proposal would not prescribe any particular type of
documentation or method for showing water quality, but you should
remember that water is used as a component in manufacturing dietary
ingredients and dietary supplements would fall within the definition of
``component,'' so it should meet whatever specifications you establish
for component identity, purity, quality, strength, and composition. We
discuss requirements for the identity, purity, quality, strength, and
composition of components later in this section when we describe
proposed Sec. 111.35, ``What production and process controls must you
use?''. Proposed Sec. 111.15(d)(3) would be similar to a provision in
the drug CGMP regulation at 21 CFR 211.48(a) and the proposed
requirement in the infant formula proposed rule (61 FR 36154 at 36211),
which requires that water meet EPA's drinking water requirements in 40
CFR part 141.
Proposed Sec. 111.15(e) is similar to the plumbing requirements in
the food CGMPs at Sec. 110.37(b). Proposed Sec. 111.15(e) would
require your physical plant's plumbing to be adequate size and design
and to be adequately installed and maintained to:
[sbull] Carry sufficient amounts of water to required locations
throughout the physical plant;
[sbull] Properly convey sewage and liquid disposable waste from
your physical plant;
[sbull] Avoid being a source of contamination to components,
dietary ingredients, dietary supplements, water supplies, or any
contact surface, or creating an unsanitary condition;
[sbull] Provide adequate floor drainage in all areas where floors
are subject to flooding-cleaning or where normal operations release or
discharge water or other liquid waste on the floor; and
[sbull] Not allow backflow from, or cross-connection between,
piping system that discharge waste water or sewage and piping systems
that carry water used for manufacturing dietary ingredients or dietary
supplements, or cleaning contact surfaces, or for use in bathrooms and
hand washing facilities.
This provision is intended to ensure that your plumbing system does
not adversely effect the water in your physical plant. If the plumbing
system is not adequately installed and maintained, it may contaminate
your water supply and, in turn, contaminate your components, dietary
ingredients, and dietary supplements through direct contact, such as
when you use water to make the products, or indirect contact, such as
when the contaminated water is used on a contact surface.
In addition to the water directly contaminating your components,
dietary ingredients, dietary supplements, or contact surfaces, standing
water can cause contamination by attracting pests or becoming a
breeding ground for microorganisms. Therefore, the proposal would
require your plumbing system to have adequate drainage and would not
allow backflows or cross-connections in your plumbing system because
backflows from a nonpotable water system to a potable water system
under negative pressure conditions could contaminate your water system
(Ref. 57).
A comment to the ANPRM stated that requiring a physical plant's
plumbing to carry sufficient amounts of water to required locations
throughout the plant was too vague. The comment stated the water is not
needed in many operations in the plant, and so firms should be able to
decide the location and availability of water throughout their own
physical plants.
The comment may have misinterpreted the ANPRM. Proposed Sec.
111.15(d) would not require water to be available in all parts of a
physical plant. In areas where water is unnecessary, we would not
expect you to make water available or to have any particular quantity
of volume of water available. However, there are areas where water is
necessary to ensure that any unadulterated dietary ingredient or
dietary supplement is manufactured, packaged or held. In those areas
where water is necessary, your plumbing must carry sufficient amounts
to those locations.
Proposed Sec. 111.15(f) would require that you dispose your
physical plant's sewage into an adequate sewage system or through other
adequate means. This proposed provision is similar to the sewage
provisions at Sec. 110.37(c). Proper sewage disposal is essential to
ensure that you maintain your manufacturing facility in a sanitary
condition, and this would include protecting the processing environment
against pathogenic microorganisms shed in fecal material. For example,
bathroom floors can become contaminated with pathogens if your sewage
disposal system fails to remove fecal material. Employees using those
bathrooms, in turn, can transport those pathogens into your processing
areas and contaminate components, dietary ingredients, dietary
supplements, or contact surfaces.
Proposed Sec. 111.15(g) would apply to bathrooms. Proposed Sec.
111.15(g) would require that you have adequate, readily accessible
bathrooms for your employees and require that the bathrooms be kept
clean and not become a potential source of contamination to your
components, dietary ingredients, dietary supplements, or contact
surfaces. The proposal would require that you keep your bathrooms from
becoming potential sources of contamination. You would be required to
keep the bathrooms in good repair at all times, provide self-closing
doors, and provide doors that do not open into areas where components,
dietary ingredients, dietary supplements, or contact surfaces are
exposed to airborne contamination, except where you have taken other
means (such as double doors or positive airflow systems) to protect
against airborne contamination.
Proposed Sec. 111.15(h) applies to hand washing facilities. The
proposal would require that you provide adequate and convenient hand
washing facilities that furnish running water at a suitable
temperature. Proposed Sec. 111.15(h)(1) would require that you have
hand washing facilities and, where appropriate, hand sanitizing
facilities at each location in your physical plant
[[Page 12187]]
where good hygienic practices require your employees to wash or
sanitize (or to both wash and sanitize) their hands.
One comment to the ANPRM suggested that, instead of requiring
employees to wash ``and/or'' sanitize their hands, we should require
employees to wash ``or'' sanitize their hands.
We disagree with the comments. In some cases, it is necessary to
both wash and sanitize the hands. Sanitizing which generally refers to
the removal or elimination of living microorganisms, may be more
effective if the hands are washed before they are sanitized, and
washing, alone, will not sanitize the hands. Therefore, the proposed
rule would address situations where good hygienic practices require
employees to wash or sanitize their hands or to wash and sanitize their
hands.
Proposed Sec. 111.15(h)(2) and (h)(3) would require that you
provide effective hand-cleaning and sanitizing preparations and air
driers, sanitary towel service, or other suitable drying devices.
Disposable paper towels would be an example of sanitary towel service.
One comment to the ANPRM suggested replacing ``effective hand-
cleaning and sanitizing preparation'' with ``commonly available'' hand-
washing and sanitizing preparations.
We disagree with the comment. The purpose behind proposed Sec.
111.15(h)(2) is to ensure that hand-cleaning and sanitizing
preparations are effective. While we have objection to the use of
``commonly available'' hand-washing and sanitizing preparations if they
are ``effective,'' the effectiveness of the hand-washing and sanitizing
preparation is essential to ensuring that the hand-washing and
sanitizing preparation will prevent adulteration of the product.
Another comment to the ANPRM suggested that a dietary supplement
CGMP rule mention paper towels as a hand drying device.
We have drafted proposed Sec. 111.15(h)(3) to identity disposable
paper towels as an example of sanitary towel service. However, under
proposed Sec. 111.15(h)(3), the paper towels must be both sanitary and
disposable.
Another comment to the ANPRM suggested that paper towels used in
hand-washing facilities should be made from recycled paper.
We take no position regarding the use of paper towels made from
recycled paper. The proposal neither requires nor prohibits the use of
paper towels made from recycled paper.
Proposed Sec. 111.15(h)(4) would require that you provide devices
or fixtures that are constructed to prevent recontamination of clean,
sanitized hands. For example, if sanitized hands are necessary at a
particular location, you might install hand sanitizing facilities that
can be activated by foot pedals or by motion so that your employees do
not have to use their hands--and, by doing so, risk contaminating their
hands--to turn on the hand sanitizing equipment.
Proposed Sec. 111.15(h)(5) would require that you have easily-
understood signs and to post them throughout your physical plant to
direct your employees who handle components, dietary ingredients,
dietary supplements, or contact surfaces to wash and, where
appropriate, sanitize their hands:
[sbull] Before they start work,
[sbull] After each absence from their duty station, and
[sbull] When their hands may have become soiled or contaminated.
Proposed Sec. 111.15(h)(6) would require that you have trash bins
that are constructed and maintained in a manner to protect against
recontamination of hands and contamination of components, dietary
ingredients, dietary supplements, or any contact surface. The proposal
would not specify any particular type of trash bin to use.
Proposed Sec. 111.15(i) applies to trash disposal. The proposal
would require that you convey, store, and dispose of trash to minimize
the development of odors; to minimize the potential for trash to
attract, harbor, or become a breeding place for pests; to protect
against contamination of components, dietary ingredients, dietary
supplements, any contact surface, water supplies, and grounds
surrounding your physical plant and to control hazardous waste to
prevent contamination of components, dietary supplements, and contact
surfaces.
Proposed Sec. 111.15(j) would require that you assign one or more
employees to supervise overall sanitation. Under the proposal, the
employee or employees would have to be qualified by training and
experience to develop and supervise sanitation procedures. The proposal
would give you discretion in deciding how many employees you need to
assign to supervise overall sanitation of your physical plant. As
previously discussed, the proposed requirement does not preclude the
possibility of a one-person operation. If you are a one-person
operation, you would need to be qualified by training and experience to
develop and perform all sanitation procedures.
We invite comment on whether written procedures for maintenance,
cleaning, and sanitation should be required in a final rule. If
comments assert that written procedures are necessary, comments should
include an explanation of why the requirement is necessary to prevent
adulteration including how such a requirement would ensure the
identity, purity, quality, strength, and composition of the dietary
ingredient or dietary supplement. Conversely, if comments assert that
written procedures are not necessary, comments should include an
explanation of why the requirement is not necessary including how, in
the absence of the requirement, one can prevent adulteration and ensure
the identity, purity, quality, strength, and composition of the dietary
ingredient or dietary supplement.
We invite comment on whether documentation at the time of
performance of equipment, utensil, and contact surface maintenance,
cleaning, and sanitation and keeping such records should be required in
a final rule. This would give you a record that you would be able to
consult if any questions regarding maintenance, cleaning, and
sanitation of equipment used in producing the batch arise. We seek
comment on whether any of the proposed requirements in this section are
not necessary to prevent adulteration and to ensure the identity,
purity, quality, strength, and composition of the dietary ingredient or
dietary supplement. If comments assert that certain provisions are not
necessary, comments should include an explanation of why the
requirement is not necessary including how, in the absence of the
requirement, one can prevent adulteration and ensure the identity,
purity, quality, strength, and composition of the dietary ingredient or
dietary supplement. If comments agree that the proposed requirements
are necessary for reasons other than those we have provided, the
comments should so state and provide an explanation.
2. What Design and Construction Requirements Apply to Your Physical
Plant? (Proposed Sec. 111.20)
Proposed Sec. 111.20 would describe the general requirements for
physical plant construction and design that are necessary to protect
dietary ingredients and dietary supplements from becoming adulterated
during manufacturing, packaging, and holding.
Proposed Sec. 111.20(a) would require any physical plant you use
in the manufacturing, packaging, or holding of dietary ingredients or
dietary supplements to be suitable in size, construction, and design to
facilitate maintenance, cleaning, and sanitizing operations. You should
note that proposed Sec. 111.20(a) refers to cleaning
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operations and to sanitizing operations. Although these terms appear to
be similar, they are distinct in the sense that a sanitizing operation
usually produces a sterile (free of living microorganisms) environment
whereas a cleaning operation may not. To illustrate the difference, if
you wipe a contact surface with a wet cloth to remove any components or
dietary ingredients, you would have engaged in a cleaning operation.
The contact surface is free of noticeable debris, but it might still
contain microorganisms. In contrast, if you used a disinfectant on the
contact surface in order to eliminate any possible microorganisms on
that surface, you would have engaged in a sanitizing operation.
Size, construction, and design of a physical plant are important to
manufacturing, packaging, and holding dietary ingredients and dietary
supplements that are not adulterated because they can help you identify
and eliminate possible sources of contamination that result in or may
lead to adulteration. For example, condensation can occur on water
pipes. If these pipes are exposed and run above a contact surface,
condensation from those pipes may fall onto the contact surface and
adulterate your dietary ingredients or dietary supplements. So, if you
design your physical plant to eliminate exposed pipes or to shield your
contact surfaces from condensation, you would eliminate a possible
source of adulteration.
As another example, you might find it more practical to clean
certain floors in your physical plant by spraying them with water.
Obviously, a floor design that uses floor drains would facilitate the
cleaning of those floors.
Proposed Sec. 111.20(b) would require your physical plant to have
adequate space for the orderly placement of equipment and holding of
materials as is necessary for maintenance, cleaning, and sanitizing
operations and to prevent contamination and mixups of components,
dietary ingredients, and dietary supplements during manufacturing,
packaging, or holding. Adequate space for the orderly placement of
equipment and holding of materials is important because it can directly
affect your ability to maintain, clean, or sanitize your equipment or
physical plant effectively. For example, assume that your manufacturing
operation involves the use of a large mixer. However, the mixer is
installed in a small room which makes it difficult to open the mixer
fully. This may make it difficult for you to maintain and clean the
mixer properly and, as a result, may increase the possibility that
residues in the mixer will contaminate the next batch of ingredients
that go into the mixer.
Proposed Sec. 111.20(c) would require your physical plant to
permit the use of proper precautions to reduce the potential for mixups
or contamination of components, dietary ingredients, dietary
supplements, or contact surfaces, with microorganisms, chemicals,
filth, or other extraneous material. The proposal would require the
physical plant to have, and require that you use, separate or defined
areas of adequate size or other control systems, such as computerized
inventory controls or automated systems of separation, to prevent
contamination and mixups of components, dietary ingredients, and
dietary supplements during specific operations. The specific operations
would be listed at proposed Sec. 111.20(c)(1) through (c)(7) and are
as follows:
[sbull] Receiving, identifying, holding, and withholding from use,
components, dietary ingredients, dietary supplements, packaging, and
labels that will be used in or during the manufacturing, packaging, or
holding of dietary ingredients and dietary supplements;
[sbull] Separating, as necessary, components, dietary ingredients,
dietary supplements, packaging, and labels that are to be used from
components, dietary ingredients, dietary supplements, packaging, or
labels that are awaiting material review and disposition decision,
reprocessing, or are awaiting disposal after rejection;
[sbull] Separating the manufacturing, packaging, and holding of
different product types, including, but not limited to, different types
of dietary ingredients, dietary supplements, and other foods,
cosmetics, and pharmaceutical products;
[sbull] Performing laboratory analyses and holding laboratory
supplies and samples;
[sbull] Cleaning and sanitizing contact surfaces;
[sbull] Packaging and label operations; and
[sbull] Holding dietary ingredients or dietary supplements.
The proposal would not specify the types of precautions your
physical plant must have to reduce the potential for mixups or
contamination. The precautions may depend on your physical plant and
the products you make. For example, depending on your physical plant's
size and layout, you may be able to receive components and dietary
ingredients at one location, hold them in another location and store
rejected components and dietary ingredients in yet another location.
However, if your physical plant does not allow for physically separate
areas, you would have to develop an alternative approach for
segregating components, dietary ingredients, and dietary supplements at
points when they are received, stored, and rejected.
Proposed Sec. 111.20(d) would require that your physical plant be
designed and constructed in a manner that prevents contamination of
components, dietary ingredients, dietary supplements, or contact
surfaces. The proposal would require that the design and construction
include floors, walls, and ceilings that are of smooth and hard
surfaces that may be adequately cleaned and kept clean and in good
repair. Smooth, hard surfaces are necessary because they are easier to
clean and sanitize than those surfaces that are not smooth and hard.
The proposal also would require that you use fixtures, ducts, and pipes
that do not contaminate components, dietary ingredients, dietary
supplements, or contact surfaces by dripping or condensate.
Condensation may contain microorganisms or contaminants that can
contaminate your components, dietary ingredients, dietary supplements,
or contact surfaces.
Proposed Sec. 111.20(d) also would require your physical plant's
design and construction to:
[sbull] Use adequate ventilation or environmental control
equipment, such as air flow systems, including filters, fans, and other
air-blowing equipment, that minimize odors and vapors (including steam
and noxious fumes) in areas where they may contaminate components,
dietary ingredients, dietary supplements or contact surfaces. Adequate
ventilation or environmental control equipment is a necessary part of
your physical plant's design and construction because some contaminants
and microorganisms may be airborne, so a failure to provide adequate
ventilation will increase your chances of airborne contamination. In
addition, some potentially harmful gases (such as carbon monoxide and
carbon dioxide) are colorless and odorless, so it is important to have
a ventilation or environmental control system that minimizes odors and
vapors;
[sbull] Use fans and other air-blowing equipment located and
operated in a manner that minimizes the potential for microorganisms
and particulate matter to contaminate components, dietary ingredients,
dietary supplements, or contact surfaces;
[sbull] Use equipment to control temperature and humidity. For
example, high temperatures may stimulate
[[Page 12189]]
reproduction of microorganisms and pests, and these microorganisms and
pests may, in turn, contaminate your components, dietary ingredients,
dietary supplements, and contact surfaces; and
[sbull] Include aisles or working spaces between equipment and
walls that are adequately unobstructed and of adequate width to permit
all persons to perform their duties and to protect against
contamination of components, dietary ingredients, dietary supplements,
or contact surfaces with clothing or personal contact. For example,
your employees will perform their duties more efficiently and more
effectively if they have sufficient space to perform those duties. The
clothing worn by your employees will be less likely to be a source of
contamination if there is sufficient space between your employees and
your components, dietary ingredients, dietary supplements, or contact
surfaces.
Proposed Sec. 111.20(e) would require your physical plant to
provide adequate light in all areas where components, dietary
ingredients, or dietary supplements are examined, processed, or held
and in all areas where contact surfaces are cleaned. Proposed Sec.
111.20(e) also would require that you provide adequate lighting in hand
washing areas, dressing and locker rooms, and bathrooms. Inadequate
lighting in areas where components, dietary ingredients, or dietary
supplements are examined, processed, or held may make it difficult to
examine a component or read a label; as a result, incorrect ingredients
may be used in a dietary supplement. Adequate lighting also is
important in areas where contact surfaces are cleaned to ensure that
the contact surfaces have been cleaned properly. Adequate lighting is
important in hand-washing areas, dressing and locker rooms to ensure
that personal cleanliness is maintained in accordance with proposed
Sec. 111.10(b).
Proposed Sec. 111.20(f) would require your physical plant to use
safety-type light bulbs, fixtures, skylights, or other glass that is
suspended over exposed components, dietary ingredients, or dietary
supplements in any step of preparation, unless otherwise constructed in
a manner that will protect against contamination in case of glass
breakage. These precautions are necessary because glass shards can be
very small and difficult to see, and some lights may spread their
contents if they burst or explode. So, to protect your components,
dietary ingredients, and dietary supplements, the proposal would
require your physical plant to take precautions concerning your
lighting and other suspended glass.
Proposed Sec. 111.20(g) would require that your physical plant
provide protection by any effective means against contamination of
components, dietary ingredients, and dietary supplements in bulk
fermentation vessels. The proposal describes some means to consider,
such as using protective coverings, placement in areas where you can
eliminate harborages for pests over and around vessels, placing bulk
fermentation vessels in areas where you can check regularly for pests,
pest infestation, filth, or other extraneous material, and using
skimming equipment. You must protect components, dietary ingredients,
and dietary supplements held in bulk fermentation vessels because, if
the contents of a bulk fermentation vessel are contaminated, those
contaminated contents may be used to make many dietary ingredients or
dietary supplements that, as a result, would be adulterated.
Proposed Sec. 111.20(h) would require your physical plant to
include adequate screening or other protection against pests, where
necessary. This provision would be one measure to exclude certain pests
from the physical plant that also may assist you in complying with
proposed Sec. 111.15(c). As we explained earlier in the discussion of
proposed Sec. 111.15(c), pests are a potential source of contamination
because they may carry microorganisms, shed hair or feathers, leave
droppings, or carry filth or dirt into your physical plant.
D. Equipment and Utensils (Proposed Subpart D)
Proposed subpart D consists of two provisions. These proposed
provisions consist of general requirements for equipment and utensils
and for automatic equipment, including computerized systems, hardware,
and software.
1. What Requirements Apply to the Equipment and Utensils You Use?
(Proposed Sec. 111.25)
Proposed Sec. 111.25 would establish general requirements
pertaining to equipment design, construction, and sanitation. For
example, proposed Sec. 111.25(a)(1) would require that you use
equipment and utensils of appropriate design, construction, and
workmanship that would enable them to be suitable for their intended
use, adequately cleaned, and properly maintained. The equipment and
utensils covered under the proposal would include, but not be limited
to:
[sbull] Equipment used to hold or convey;
[sbull] Equipment used to measure;
[sbull] Equipment using compressed air or gas;
[sbull] Equipment used to carry out processes in closed pipes and
vessels; and
[sbull] Equipment used in automatic, mechanical, or electronic
systems.
To show how proposed Sec. 111.25(a)(1) might apply, assume that
you use a mixer to blend powdered ingredients. If the mixer blade is
too small, it might not mix the ingredients properly or thoroughly, and
the resulting batches might be adulterated if the ingredients are not
provided at the required levels throughout the batch. In this example,
the mixer was not suited for its intended use. As another example, if
your manufacturing equipment is so complex or designed in a way that
makes cleaning difficult, any unclean surfaces on that equipment could
become a source of contamination in the future. In this case, the
equipment was not adequately cleaned and properly maintained or,
alternatively, was not of appropriate design for its intended uses.
Proposed Sec. 111.25(a)(2) would require that you use equipment
and utensils of appropriate design and construction whose use will not
result in the contamination of your components, dietary ingredients, or
dietary supplements with lubricants, fuel, coolants, metal or glass
fragments, filth or other extraneous material, contaminated water, or
any other contaminants.
Proposed Sec. 111.25(a)(3) would require your equipment and
utensils to be:
[sbull] Installed and maintained to facilitate cleaning the
equipment, utensils, and all adjacent spaces;
[sbull] Corrosion-resistant if the equipment or utensils contact
components, dietary ingredients, or dietary supplements;
[sbull] Made of nontoxic materials;
[sbull] Designed and constructed to withstand the environment of
their intended use, the action of components, dietary ingredients, or
dietary supplements, and, if applicable, cleaning compounds and
sanitizing agents; and
[sbull] Maintained to protect components, dietary ingredients, and
dietary supplements from being contaminated by any source.
Deteriorating equipment can be a source of contamination. For
example, repeated contact between metal surfaces in a grinding or
tableting machine can result in metal fragments that can contaminate
your dietary ingredients or dietary supplements. So, your equipment and
utensils must be designed and constructed to withstand the environment
of their intended use and you must maintain your equipment
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and utensils to guard against contamination.
Proposed Sec. 111.25(a)(4) would require your equipment and
utensils to have seams that are smoothly bonded or maintained to
minimize accumulation of component, dietary ingredient, or dietary
supplement particles, dirt, filth, organic material, or any other
extraneous material or contaminants. We are proposing this requirement
because equipment and utensils containing breaks, pits, cuts, or
grooves can be difficult to clean, and the pores or crevices in those
breaks, pits, cuts, or grooves can become a breeding ground for
microorganisms and insulate them from cleaning and sanitizing agents.
Proposed Sec. 111.25(a)(5) would require freezers and cold storage
compartments that hold components, dietary ingredients, or dietary
supplements to be fitted with accurate thermometers or other
temperature-measuring or temperature-recording devices and would
recommend automatic devices for regulating temperature or for sounding
an alarm to indicate significant temperature changes in a manual
operation. These devices are necessary to ensure that you are able to
monitor the temperatures where you hold your components, dietary
ingredients, or dietary supplements and to indicate whether they were
held at appropriate temperatures to minimize the growth of pathogens
and to prevent deterioration.
While we patterned proposed Sec. 111.25(a)(5) after a provision in
the food CGMPs (Sec. 110.40(e)), we invite comment on whether we
should require specific target temperatures for dietary ingredients or
dietary supplements held in freezers or cold storage, and if so, what
those temperatures should be and why.
Proposed Sec. 111.25(a)(6) would require instruments or controls
used in the manufacturing, packaging, or holding of a dietary
ingredient or dietary supplement to be accurate and precise, adequately
maintained, and adequate in number for their designated uses. By using
the words, ``accurate and precise,'' we mean that the instruments or
controls must be accurate--the recorded measurements are equal to the
true value of the thing being measured--and precise--individual
measurements should be close to each other when made under the same
conditions. For example, if the temperature inside a particular piece
of equipment is 100 [deg]F, and your thermometer for that piece of
equipment reads a temperature of 100 [deg]F, the thermometer is
accurate. If multiple temperature readings for that thermometer ranged
from 99.7 [deg]F to 100.4 [deg]F, and the variation in temperature was
not significant statistically, you could say the thermometer is
precise. The proposed requirement identifies examples of such
instruments and controls, such as instruments or controls you use to
measure, regulate, or record:
[sbull] Temperatures;
[sbull] pH;
[sbull] Water activity; or
[sbull] Other conditions that control or prevent the growth of
microorganisms or other contamination.
Instruments or controls that affect the environment, such as
instruments that regulate temperature, pH, and water activity, are
important because environmental factors can influence microorganism
growth and deterioration. For example, changes in water activity
(aw) can have a dramatic impact on microorganism growth. A
population of Salmonella typhimurium is reduced tenfold in 0.18 minutes
at 60 [deg]C if the aw for the suspending medium is 0.995.
If the aw is 0.94, it takes 4.3 minutes (or nearly 24 times
as long) at 60 [deg]C to achieve the same tenfold reduction (Ref. 58).
Adequate maintenance is an important part of proposed Sec.
111.25(a)(6). If you fail to properly maintain your instruments and
controls, they may produce unreliable readings and contribute towards
the contamination and adulteration of your dietary ingredients and
dietary supplements. For example, assume that you refrigerate a
particular dietary ingredient to prevent microorganism growth. If your
refrigerator gives you the wrong temperature readings so that the
actual temperature inside your refrigerator is too high, you may be
unaware of microorganism growth that has occurred on your dietary
ingredient. Similarly, if the actual temperature inside your
refrigerator is too low so that you unintentionally froze the dietary
ingredient, the freezing process may have produced a chemical change in
your dietary ingredient that will cause it to be out of specification.
Note, too, that the proposal also would require that your
instruments and controls be adequate in number for their designated
uses. For example, if the temperature of a large piece of equipment
needs to be monitored, several temperature-indicating devices may be
needed to accurately monitor the temperature in all parts of the
equipment.
A comment to the ANPRM objected to requiring all instruments and
controls used in all aspects of dietary supplement manufacturing be
accurate. The comment said such a requirement would imply strongly a
need for validation, but that validation is a standard applicable to
drug CGMPs, but not to food CGMPs. The comment said that a dietary
supplement CGMP rule should not require validation of instruments and
controls.
We disagree with the comment's objection to requiring all
instrument and controls be accurate because, as we stated earlier,
inaccurate instruments and controls may generate inaccurate readings,
and those readings may adulterate your dietary ingredients and dietary
supplements. We believe that all instruments and controls used in the
manufacture, packaging, and holding of dietary ingredients and dietary
supplements be accurate and precise, adequately maintained, and
adequate in number for their designated uses.
We further disagree that the principles of validation are
applicable to drugs, but not to foods. We stated in a previous FDA
publication (Ref. 59) that the ``computerized system used to control
critical functions in food processing should be validated in its
entirety.'' We have no basis to conclude that validation of instruments
and controls is a standard applicable to drugs and not to foods, nor
did the comment provide a reason for its assertion that validation does
not apply to foods. We invite comment in this proposal on whether we
should include requirements in a final rule, that would address the
same or similar concerns that the principles of validation would
address. We also invite comment on whether there are other procedures
that we should include in a final rule.
Proposed Sec. 111.25(a)(7) would require compressed air and other
gases that are introduced into or onto a component, dietary ingredient,
dietary supplement, or contact surface or that are used to clean
contact surfaces to be treated in a way so that they do not contaminate
the component, dietary ingredient, dietary supplement or contact
surface. Air or other gases that are not properly treated and filtered,
or air that is not of the proper purity, can introduce contaminants
into the dietary supplement product and adulterate it. Also, compressed
gases can be contaminated with oil from the equipment (such as an air
compressor) or with filth or microbiological contaminants from the
compression, storage, or distribution equipment. So, if left untreated,
the compressed air can deposit those contaminants onto your components,
dietary ingredients, dietary supplements, and contact surfaces.
Filtration at the air intake and after compression, storage, and
distribution may be an effective means of reducing
[[Page 12191]]
the risk that such contaminants will enter the compressed air or other
gases.
Proposed Sec. 111.25(b)(1) would require that you calibrate your
instruments and controls that you use in manufacturing or testing
components, dietary ingredients, or dietary supplements. Proposed Sec.
111.25(b)(2) would require that you calibrate before you first use the
instruments and controls and either as specified in writing by the
manufacturer of the instrument and control or at routine intervals or
as otherwise necessary to ensure their accuracy and precision.
Calibrating instruments and controls will ensure that they are accurate
and precise and that the instrument or control readings are ``true
values.'' We invite comment on whether we should require, in a final
rule, that you establish and follow a written procedure for calibrating
instruments and controls, and whether there are other procedures, that
we should consider including in a final rule. If comments assert that
written procedures are necessary, comments should include an
explanation of why the requirement is necessary to prevent adulteration
including how such a requirement would ensure the identity, purity,
quality, strength, and composition of the dietary ingredient or dietary
supplement. Conversely, if comments assert that written procedures are
not necessary, comments should include an explanation of why the
requirement is not necessary including how, in the absence of the
requirement, one can prevent adulteration and ensure the identity,
purity, quality, strength and composition of the dietary ingredient or
dietary supplement. Further, we seek comment on whether any of the
proposed requirements in this section are not necessary to prevent
adulteration and to ensure the identity, purity, quality, strength, and
composition of the dietary ingredient or dietary supplement. If
comments assert that certain provisions are not necessary, comments
should include an explanation of why the requirement is not necessary
including how, in the absence of the requirement, one can prevent
adulteration and ensure the identity, purity, quality, strength, and
composition of the dietary ingredient or dietary supplement. If
comments agree that the proposed requirements are necessary for reasons
other than those we have provided, the comments should so state and
provide an explanation.
Proposed Sec. 111.25(c) would require that you must establish a
written procedure for calibrating instruments and controls you use in
manufacturing or testing a component, dietary ingredient, or dietary
supplement and document that the written procedure was followed each
time a calibration was performed or that you must document, at the time
of performance, that the instrument and control calibration established
in accordance with this section was performed. The proposed calibration
requirement gives you discretion in deciding whether to establish and
follow a written calibration procedure. If you establish a written
procedure for calibrating instruments and controls, you must document,
at the time of calibration performance, that the written procedure was
performed. If you do not establish a written calibration procedure then
you must document, at the time of performance, that the calibration
established accordance with this section was performed. You must
identify the following for calibrating instruments and controls in any
written procedure or at the time of performance:
[sbull] The instrument or control calibrated;
[sbull] The date of calibration;
[sbull] The reference standard used including the certification of
accuracy of the known reference standard and a history of
recertification of accuracy. A certification of accuracy usually
accompanies a standard reference material and often is valid for a
specific period of time, but the supplier of the reference standard may
recertify the standard's accuracy. The recertification typically
involves testing by the supplier to verify that the material maintains
accuracy as a testing reference. This information also may help you
trace the source of a problem, if one arises, in your dietary
ingredients or dietary supplements. For example, if consumers report an
adverse event with a batch of dietary supplements, records containing a
certification of accuracy of the reference standards used and a history
of their recertification would help you determine if the problem
resulted from using an inaccurate reference standard to calibrate your
instruments;
[sbull] The calibration method used including appropriate limits
for accuracy and precision of instruments and controls when
calibrating;
[sbull] The calibration reading or readings found;
[sbull] The recalibration method used if accuracy or precision or
both accuracy and precision limits for instruments and controls were
not met; and
[sbull] The initials of the person who performed the calibration.
These records will enable you to determine whether the calibration
schedule can maintain the accuracy of your instruments and controls,
and will also provide information on when and how the instruments and
controls were calibrated in case a problem arises with a batch of
dietary ingredients or dietary supplements. If you examine these
records over time, you also will be able to see how precise your
instruments and controls are and to make any necessary adjustments or
repairs. For example, if your records show that a scale gives a
particular reading for a standard reference weight in January, but then
shows a different reading in June for the same standard reference
weight, you may need to adjust, repair, or even replace your scale.
In fact, proposed Sec. 111.25(d) would require that you repair or
replace instruments and controls that cannot be adjusted to agree with
the reference standard. You should not trust any instrument or control
that cannot be adjusted to agree with a reference standard because an
inaccurate measurement or reading may result in an adulterated dietary
ingredient or dietary supplement. Again, to use a scale as an example,
if you have a scale that you cannot adjust to read the correct weight,
using that scale to weigh a dietary ingredient to be added to a
particular mix would cause you to add either too much or too little of
the dietary ingredient into your mix, thus throwing your mix out of
specification. So, proposed Sec. 111.25(d) would require that you
repair or replace that scale.
Proposed Sec. 111.25(e) applies to maintenance and sanitation. The
word ``maintenance,'' in this provision, means the act of keeping your
equipment and utensils in working order as recommended by their
manufacturer. Proposed Sec. 111.25(e)(1) would require that you
maintain, clean, and sanitize, as necessary, all equipment, utensils,
and any other contact surfaces that are used to manufacture, package,
or hold components, dietary ingredients, or dietary supplements and to
take apart your equipment and utensils as necessary for thorough
maintenance, cleaning, and sanitizing. Obviously, if you fail to keep
your equipment, utensils, and contact surfaces clean, you risk
contaminating them with microorganisms and other contaminants and risk
transferring those microorganisms or other contaminants to anything
that touches the equipment, utensils, and contact surfaces.
Proposed Sec. 111.25(e)(2) would require that you ensure that all
contact surfaces used for manufacturing or holding low-moisture
components, dietary ingredients, or dietary supplements are in a dry
and sanitary condition at the time of their use. If the surfaces are
wet-cleaned, you must sanitize them, when
[[Page 12192]]
necessary, and allow them to dry thoroughly before you use them again.
Thoroughly drying equipment before it is used for manufacturing or
holding dry dietary products is essential to ensure that the equipment
will not change the composition of the dry product. For example, if
moisture is left on equipment, the moisture will become a part of the
product and may change the composition of the product. Moist surfaces
can also promote microorganism growth, and microorganisms can
adulterate your components, dietary ingredients, or dietary
supplements.
Proposed Sec. 111.25(e)(3) would apply if you use wet processing
during manufacturing. Under the proposal, you would have to clean and
sanitize all contact surfaces as necessary to protect against the
introduction of microorganisms into components, dietary ingredients, or
dietary supplements. Proposed Sec. 111.25(e)(3) also would require
that, when cleaning and sanitizing is necessary, you must clean and
sanitize all contact surfaces before use and after any interruption
during which the contact surface may become contaminated. If you use
contact surfaces in a continuous production operation or in back-to-
back operations involving different batches of the same dietary
ingredient or dietary supplement, the proposal would require that you
clean and sanitize the contact surfaces as necessary.
Proposed Sec. 111.25(e)(4) would complement proposed Sec.
111.25(e)(2) and (e)(3) by requiring that you clean, as frequently as
necessary, surfaces that do not touch components, dietary ingredients,
or dietary supplements to protect against contamination. For example,
you would not have to clean your ceilings as often as you clean your
contact surfaces because your ceilings normally do not touch
components, dietary ingredients, or dietary supplements. However, you
would have to clean your ceilings as frequently as necessary to prevent
dust or other contaminants from falling onto your components, dietary
ingredients, dietary supplements, and contact surfaces.
Proposed Sec. 111.25(e)(5) would establish requirements for
single-service articles, such as utensils intended for one-time use,
paper cups, and paper towels. Proposed Sec. 111.25(e)(5) would require
these articles to be stored in appropriate containers and handled,
dispensed, used, and disposed of in a manner that protects against
contamination of components, dietary ingredients, dietary supplements,
or any contact surface. For example, you would not place a paper towel
dispenser over a contact surface because persons reaching for those
paper towels might drip contaminated water or other fluids onto the
contact surface. Inadvertent reuse of a single-service article also
could lead to contamination, so disposing of single-service articles is
an important element in proposed Sec. 111.25(e)(5).
Proposed Sec. 111.25(e)(6) would require your cleaning compounds
and sanitizing agents to be adequate for their intended uses and safe
under their conditions of use. An adequate cleaning compound is one
that will lower the surface tension of water so that spills can be
lifted and flushed away (Ref. 60). Ordinary soap has a limited ability
to solubilize fats, oils, and proteins. Inorganic alkaline detergents
can dissolve food solids, such as fats and proteins, but mineral
deposits will frequently require the use of acid cleaners (Ref. 60).
Proposed Sec. 111.25(e)(6) would not prescribe any particular cleaning
compound. Instead, you may select cleaning compounds that are suited to
your particular needs. An adequate sanitizing agent is one that has a
bactericidal effect on the types of microorganisms normally present in
the physical plant environment and is safe, chemically stable, and
convenient for use. However, sanitizing agents can achieve their
intended effect only after they are applied to a surface that has been
thoroughly cleaned, and if they are applied at a proper concentration
(Ref. 61).
Proposed Sec. 111.25(e)(7) would require that you store cleaned
and sanitized portable equipment and utensils that have a contact
surface in locations and in a manner that protect them from
contamination. This requirement is necessary to ensure that your
portable equipment remains clean and sanitized until used; otherwise,
if the contact surfaces on the portable equipment or utensils become
contaminated, they could lead to adulteration of your dietary
ingredients or dietary supplements.
We invite comment on whether we should require, in a final rule,
that you establish and follow a written procedure for maintenance,
cleaning, and sanitizing. Further, we invite comment on whether we
should require that the person who performs the maintenance, cleaning,
and sanitizing described in this section document, at the time of
performance that the maintenance, cleaning, and sanitizing were
performed. Those procedures may be helpful to inform you that equipment
is being maintained, cleaned, and sanitized regularly and as frequently
as is necessary based on the actual use, as opposed to the planned use,
of the equipment. If comments assert that written procedures are
necessary, comments should include an explanation of why the
requirement is necessary to prevent adulteration including how such a
requirement would ensure the identity, purity, quality, strength, and
composition of the dietary ingredient or dietary supplement.
Conversely, if comments assert that written procedures are not
necessary, comments should include an explanation of why the
requirement is not necessary including how, in the absence of the
requirement, one can prevent adulteration and ensure the identity,
purity, quality, strength, and composition of the dietary ingredient or
dietary supplement.
As discussed later, proposed Sec. 111.50(c)(4) would require that
you document, in the batch production record, the date and time of the
maintenance, cleaning, and sanitizing of the equipment and processing
lines used to producing the batch. Records that document the batch or
lot number of each batch or lot of dietary ingredients or dietary
supplements processed using a particular piece of equipment or a
particular utensil between equipment startup and shutdown for
maintenance, cleaning, and sanitizing will allow you to identify all
dietary ingredients or dietary supplements that may have been
manufactured or packaged with a specific piece of equipment or utensil
if you later discover that the equipment or utensil was improperly
maintained, cleaned, or sanitized.
Proposed Sec. 111.25(f) would require that you keep calibration
records as required by this section in accordance with the
recordkeeping requirements in proposed Sec. 111.125. Such records will
verify for you and the agency that calibrations are performed. More
importantly, these records will help you ensure that all calibrations
are performed. If problems do occur with the production of a product,
these records will help you determine whether those problems are
associated with faulty calibrations. These records will help you
determine which batches were produced under these conditions. Further,
these records will help you train employees or adjust the calibration
schedule as needed to avoid further problems.
2. What Requirements Apply to Automatic, Mechanical, or Electronic
Equipment? (Proposed Sec. 111.30)
Manufacturers of dietary ingredients and dietary supplements often
rely on automatic, mechanical, and electronic
[[Page 12193]]
equipment in production. Automated equipment is often used to ensure
proper formulation, mixing, and processing or to test a batch of
dietary ingredient or dietary supplement. Such automated equipment
frequently consists of a computer or system of computers that control
many or all stages of production, inprocess sampling, and testing. It
is important that such systems and equipment function as expected to
ensure that the dietary ingredient or dietary supplement contains the
correct ingredients in the appropriate amounts and is manufactured
according to these CGMP proposed requirements, and thus, is not
adulterated under section 402(g) of the act.
Proposed Sec. 111.30 sets forth requirements for automatic,
mechanical, or electronic equipment. These types of equipment include,
for example, mechanical equipment such as a scale used to weigh bulk
components and electronic equipment such as a computerized blending
machine.
Proposed Sec. 111.30(a) would allow you to use automatic,
mechanical or electronic equipment to manufacture, package, label, and
hold a dietary ingredient or dietary supplement. Thus, the proposal
would let you decide what type of equipment meets your needs. Proposed
Sec. 111.30(a)(1) would require that you must design or select
equipment to ensure that dietary ingredient or dietary supplement
specifications are consistently achieved. Equipment used in dietary
ingredient or dietary supplement manufacturing, packaging, and label
operations must be, for example, of an appropriate size and installed
properly in order to produce an unadulterated product. If not designed
or installed properly, the equipment can lead to a variety of problems.
For example, a mixer for the blending of powdered ingredients will not
properly perform its function if the blade is too small relative to the
size of the mixer or not properly placed inside of the mixer. Such a
mixer may produce an adulterated product because the dietary
supplement, for example, is not of uniform composition and therefore
would not be able to meet the specifications for purity, quality,
strength, or composition in the final product. Thus, equipment design
and selection is critical to ensure that you manufacture an
unadulterated dietary ingredient or dietary supplement.
Proposed Sec. 111.30(a)(2) would require that you determine the
suitability of your equipment. The equipment that you use must be
capable of operating satisfactorily within the operating limits
required by the process. The equipment must function as intended. Some
systems may work properly only within a narrow range of environmental
conditions, such as temperature and humidity, and some might be
particularly sensitive to electromagnetic interference. The actual
conditions of use of a system should be considered as early as possible
in its design and development. Systems need to be installed in a manner
that takes into account the inherent limitations of the system, tested
under conditions that reflect actual conditions of use, and properly
maintained to ensure that they continue to function as expected during
their lifetime.
Moreover, the incorporation of software into the operation of
automatic equipment has not only increased the complexity of such
equipment but also has resulted in a process that may operate
differently for each execution because a software-based control system
can be configured at will by the operator or by the system itself.
Therefore, proposed Sec. 111.30(a) would require that you exercise
appropriate controls over systems and, in particular, over the software
used in the systems.
Proposed Sec. 111.30(b) would require, for any automatic,
mechanical, or electronic equipment that you use, that you must:
[sbull] Routinely calibrate, inspect, or check to ensure proper
performance.
[sbull] Make and keep written records of equipment calibrations,
inspections, or checks;
[sbull] Establish and use appropriate controls to ensure that your
quality control unit approves changes in master manufacturing record,
batch control records, packaging operations and label operations, or
changes related to the equipment that you use and that only authorized
personnel institute the changes;
[sbull] Establish and use appropriate controls to ensure that the
equipment functions in accordance with its intended use and have your
quality control unit approve these controls; and
[sbull] Make and keep backup file(s) of software programs and of
data entered into your computer system. Your backup file may be a hard
copy of data you have entered, diskettes, tapes, microfilm, or compact
disks but must be an exact and complete record of the data you entered.
We also propose to require that you keep your backup software programs
and data secure from alterations, inadvertent erasures, or loss. In
this way, you have a record of changes to your software program and of
your current software program used in manufacturing. This information
is important to both identify any production errors or discrepancies
and to make necessary corrections. Such records will allow you to
troubleshoot and to operate these systems with a minimum of
interruption when problems occur because the records will include a
copy of all software used and a backup file of data entered into the
computer or related system which can be used to reload the system. The
records also will provide information that you can use in trying to
determine why a problem with the system is occurring or why the system
is not producing a dietary ingredient or dietary supplement that
complies with your specifications for the product.
Appropriate controls that you establish and use for automated
measuring, regulating, or recording temperatures, pH, acidity, water
activity, or other conditions will minimize the potential for growth of
microorganisms, for contamination, or for adding too much or too little
of a dietary ingredient. Observations, inspections, and checks of the
equipment will help you to determine if critical factors such as
revolutions per minute, temperatures, pressures, process times, and
automatic documentation are being controlled by the system. Under
proposed Sec. 111.30(b), examples of controls to ensure that the
equipment functions in accordance with its intended use include:
[sbull] Determining the extent and frequency of calibration,
inspections and checks to ensure proper performance;
[sbull] Determining and using predetermined action plans when an
alarm sounds indicating an out-of-limits situation or malfunction;
[sbull] Checking in-put and out-put on a sufficient basis to
provide a high degree of assurance that input and output is accurate;
[sbull] Comparing manual calculations of data with the automated
calculations on a sufficient basis to provide a high degree of
assurance that the automated calculations are accurate; and
[sbull] Determining the adequacy of automated cleaning and residue
elimination.
We invite comment on whether we should require, in a final rule,
that you establish and follow written procedures for the calibration,
inspection, and checking of automatic equipment. In addition, we invite
comment on whether there are procedures, other than those mentioned,
that we should include in a final rule. If comments assert that written
procedures are necessary, comments should include an explanation of why
the requirement is necessary to prevent adulteration
[[Page 12194]]
including how such a requirement would ensure the identity, purity,
quality, strength, and composition of the dietary ingredient or dietary
supplement. Conversely, if comments assert that written procedures are
not necessary, comments should include an explanation of why the
requirement is not necessary including how, in the absence of the
requirement, one can prevent adulteration and ensure the identity,
purity, quality, strength, and composition of the dietary ingredient or
dietary supplement. Further, we seek comment on whether any of the
proposed requirements in this section are not necessary to prevent
adulteration and to ensure the identity, purity, quality, strength, and
composition of the dietary ingredient or dietary supplement. If
comments assert that certain provisions are not necessary, comments
should include an explanation of why the requirement is not necessary
including how, in the absence of the requirement, one can prevent
adulteration and ensure the identity, purity, quality, strength, and
composition of the dietary ingredient or dietary supplement. If
comments agree that the proposed requirements are necessary for reasons
other than those we have provided, the comments should so state and
provide an explanation.
For computerized equipment, you should note that we already have
issued guidance documents that may give you some helpful information.
The guidance documents are: ``FDA Guide to Inspections of Computerized
Systems in the Food Processing Industry'' (Ref. 59), and a ``Guide to
Inspections of Computerized Systems in Drug Processing'' (Ref. 62).
Although we did not draft these guidance documents for dietary
ingredient and dietary supplement firms, they still provide important
advice on establishing and using computerized systems in dietary
supplement manufacturing operations. Given the broad range in
sophistication, complexity, and computerization in manufacturing
equipment, we invite comments on whether we should regulate
computerized systems separately from other automatic equipment.
Although we are not proposing verification requirements in this
proposed rule, we are seeking comment on whether such verification
should be included in a final rule. Verification would be intended to
ensure that the processes using automatic, mechanical, and electronic
equipment consistently produce an outcome that meets a predetermined
specification and any predetermined quality characteristics.
Verification would be intended to show you whether your automatic,
mechanical, or electronic processes will consistently operate as they
should.
We believe, in general, that scientific knowledge and industry
experience have defined the basic elements of a sound verification
system to include; determining whether the capacity of the hardware
matches its assigned function; identifying and considering operational
limits in establishing production procedures; determining whether the
software matches the assigned operational function; testing simulated
production conditions including ``worst case'' conditions; repeating
tests enough times to assure a reasonable measure of consistent
reproducible results; documenting the verification program; and
initiating reverification when significant changes are made to the
system or when errors are noted.
Although verification steps would vary according to the nature of
the dietary supplement and the complexity of the process, the basic
elements of a verification system would be generally applicable to all
dietary ingredients and dietary supplements. The primary benefit of a
verification system would be to provide a foundation for building a
comprehensive approach to ensure that the equipment performs in a
predetermined way, but verification could impose additional costs on
manufacturers.
We invite comment on whether automatic, mechanical, and electronic
equipment verification and reverification elements that we have
discussed should be done, should be included in the final rule as
requirements, which would include requirements to document the
verification steps. We invite comment on whether we should regulate
computerized systems separately from other automatic equipment. We seek
comment on whether any of the proposed requirements in this section are
not necessary to prevent adulteration and to ensure the identity,
purity, quality, strength, and composition of the dietary ingredient or
dietary supplement. If comments assert that certain provisions are not
necessary, comments should include an explanation of why the
requirement is not necessary including how, in the absence of the
requirement, one can prevent adulteration and ensure the identity,
purity, quality, strength, and composition of the dietary ingredient or
dietary supplement. If comments agree that the proposed requirements
are necessary for reasons other than those we have provided, the
comments should so state and provide an explanation.
E. Production and Process Controls (Proposed Subpart E)
Proposed subpart E contains production and process controls to help
ensure that you have controls covering all manufacturing, packaging,
label, and holding operations, and that those controls will prevent
adulteration of your dietary ingredient or dietary supplement. We
propose to establish a framework in which decisions about producing a
dietary ingredient or dietary supplement are left to you, but that
charges you with incorporating into your production process, measures
that are designed to ensure that the dietary ingredient or dietary
supplement is manufactured in a manner that will prevent adulteration
and misbranding.
Dietary ingredient and dietary supplement manufacturing requires
technical knowledge and skill (e.g., in research and development,
production equipment and procedures, and analytical equipment and
methodology) that a vast majority of companies in the food processing
industry do not have. A dietary ingredient or dietary supplement
manufacturer must maintain constant control because a seemingly
innocuous change in the formulation or preparation method or in
exposure to an unanticipated environmental condition could create a
health hazard. Earlier, in section I.E of this document in our
discussion of ``FDA's Decision to Propose a Rule,'' we cite several
examples of problems arising from poorly controlled manufacturing
practices. For example, we cite problems of dietary ingredient
misidentification; super- and subpotent dietary supplements; and
contamination including toxic substances, microorganisms of public
health significance, and heavy metals. Thus, we believe that using a
production and inprocess control system covering all stages of
processing is necessary to insure that the dietary ingredient or
dietary supplement is manufactured in a manner that will prevent
adulteration.
1. What Production and Process Controls Must You Use? (Proposed Sec.
111.35)
Proposed Sec. 111.35(a) would require that you implement a system
of production and inprocess controls that covers all stages of
manufacturing, packaging, labeling, and holding of the dietary
ingredients and dietary supplements.
Proposed Sec. 111.35(b) would require that your production and
inprocess control system must be designed to ensure that you
manufacture, package, or hold dietary ingredients or dietary
[[Page 12195]]
supplements in a manner that will prevent their adulteration. The
proposal would require that your production and inprocess control
system must include all requirements of this subpart and also would
require your quality control unit to review and approve the production
and inprocess control system. We believe that requiring a production
and inprocess control system is necessary to provide consistency in
producing different batches of dietary ingredients or dietary
supplements and to facilitate preparing each batch.
Proposed Sec. 111.35(c) would require that you use your quality
control unit in your manufacturing, packaging, and label operations to
ensure that these operations are performed in a manner that prevents
adulteration and to ensure that the dietary ingredient or dietary
supplement meets specifications for identity, purity, quality,
strength, and composition.
Proposed Sec. 111.35(d) establishes requirements for any substance
that may be used in a dietary ingredient or a dietary supplement. This
section would require that any substance that is used be a ``dietary
ingredient'' within the meaning of that term in section 201(ff) of the
act, or, if not included with the meaning of that term, must meet the
applicable statutory and regulatory requirements under section 409 of
the act, or section 721 of the act (21 U.S.C. 379e) if a color
additive, to ensure that the substance is safe and lawful for use in a
dietary ingredient or a dietary supplement.
A ``dietary ingredient'' within the meaning of section 201(ff) of
the act that is in, or intended for use in, a dietary supplement is
exempt from the definition of ``food additive'' in section 201(s). Such
``dietary ingredients'' are not subject to the premarket approval
standard for food additives under section 409 of the act. However,
under section 402(f)(1) of the act, in order for a dietary ingredient
or a dietary supplement not to be deemed adulterated, substances that
are ``dietary ingredients'' that are used in the manufacture of a
dietary ingredient or a dietary supplement must not present a
significant or unreasonable risk of illness or injury under the
conditions of use recommended or suggested in labeling or, if no such
labeling, under ordinary conditions of use. In addition, there must be
adequate information to provide reasonable assurance that a new dietary
ingredient does not present a significant or unreasonable risk of
illness or injury. Further, under section 402(f)(1) of the act, dietary
ingredients must not be poisonous or deleterious substances within the
meaning of section 402(a)(1) of the act. Thus, manufacturers have a
responsibility to ensure that the dietary ingredients and dietary
supplements that they produce are not adulterated under section 402(f)
of the act.
However, certain substances are not ``dietary ingredients'' within
the meaning of section 201(ff) of the act, and thus, are not exempt
under section 201(s) from regulation as a food additive under section
409 of the act. Such substances include components that are added to
provide certain technical effects to the dietary supplement, such as
disintegration, lubrication, or binding. In addition, such substances
may include color additives that are used or intended for use to impart
color to the dietary ingredient or dietary supplement. Color additives
are exempt from the definition of ``food additive'' under section
201(s)(3) of the act and subject to approval and listing under section
721 of the act.
Proposed Sec. 111.35(d) would require that any substance, other
than a ``dietary ingredient,'' the intended use of which results or may
reasonably be expected to result, directly or indirectly, in its
becoming a component or otherwise affecting the characteristics of the
dietary ingredient or dietary supplement, must be:
[sbull] Authorized for use as a food additive under section 409 of
the act, or
[sbull] Authorized by a prior sanction consistent with 21 CFR
170.3(l), or
[sbull] If used as a color additive, subject to a listing that, by
the terms of that listing, includes the use in a dietary supplement, or
[sbull] Generally recognized as safe (GRAS) for use in a dietary
ingredient or dietary supplement. Any claim that a substance is GRAS,
other than a dietary ingredient within the meaning of section 201(ff)
of the act, must be supported by a citation to the agency's regulations
or by an explanation for why there is general recognition of safety of
the use of the substance in a dietary ingredient or dietary supplement,
and
[sbull] Must comply with all other applicable statutory and
regulatory requirements under the act.
Thus, if a color additive is used in a dietary ingredient or
dietary supplement, it must be listed in Title 21 of the Code of
Federal Regulations (CFR) for use in food and the listing must, by its
terms, include such use in a dietary supplement. If the substance is
not a color additive, it must be safe under other relevant sections of
the act. Relevant considerations about the safety of a substance that
may be used as an ingredient (other than a ``dietary ingredient'' under
section 201(ff) of the act) in a dietary ingredient or a dietary
supplement would include the amounts of the substance that likely would
be ingested, based on the amounts recommended or suggested in the
label, or under ordinary conditions of use. Such a use may present
concerns about the safety of exposure to such ingredient, based on the
chronic use suggested or reasonably expected. Therefore, it is
incumbent on the manufacturer to use ``non-dietary ingredients,'' that
are safe and lawful under applicable sections of the act for such use.
As stated previously, ingredients used in dietary ingredients or
dietary supplements, other than color additives, are required to be
approved for use as a food additive unless excepted from the definition
of a food additive under section 201(s) of the act. For example, we
approved the use of sucralose as a general purpose sweetener in food,
which would include its use in a dietary ingredient or dietary
supplement (64 FR 43908, August 12, 1999). Some other current food
additive listings that would include uses in certain types of dietary
supplements include, ethyl cellulose (21 CFR 172.868) as a component of
protective coatings for vitamin and mineral tablets, and hydroxypropyl
cellulose (21 CFR 172.870) as a binder and disintegrator in dietary
supplement vitamin or mineral tablets or wafers. If you have questions
about the regulatory status of any substances that you want to use in a
dietary ingredient or a dietary supplement, you are encouraged to
contact CFSAN's Office of Food Additive Safety.
We recognize that some ingredients may not be subject to section
409 of the act, food additive approval, because they are GRAS
substances. For those substances that are GRAS, proposed Sec.
111.35(d)(4) would require the manufacturer to have documentation for
the basis for why such a substance, that is not a ``dietary
ingredient'' within the meaning of section 201(ff) of the act, is
approved for use or is GRAS for use in a dietary ingredient or dietary
supplement.
The statute, under section 402(g)(2) of the act, provides that the
Secretary may by regulation prescribe good manufacturing practices for
dietary supplements. If the good manufacturing practices are not met,
the dietary ingredient or dietary supplement would be adulterated under
section 402(g) of the act. Under proposed Sec. 111.35(d), substances
that are not ``dietary ingredients'' that are used in dietary
ingredients and dietary supplements must be safe and lawful to comply
with CGMPs for such products. Thus, these
[[Page 12196]]
nondietary ingredient substances must be subject to a food additive
listing, authorized by a prior sanction, included with the terms of a
color additive listing, or listed as GRAS for such use in 21 CFR part
182 or affirmed as GRAS for such use in 21 CFR part 184. Alternatively,
you can meet the requirements of Sec. 111.35(d) by a showing that the
substance is GRAS within the meaning of Sec. 170.30 (21 CFR 170.30).
Proposed Sec. 111.35(d)(4) would require that you have information
in your files that would substantiate the GRAS status of any nondietary
ingredient substance that is not otherwise the subject of a food
additive approval, prior sanction, or color additive listing. We
believe that, to implement the act in a way to ensure that the
statutory goals are achieved; that is, to ensure that the manufacturer
has the relevant information to ensure that any asserted GRAS
ingredient is, in fact, GRAS, it is appropriate to require that you
maintain, in your files, the basis for why the nondietary substance you
assert is GRAS that you use in a dietary ingredient or dietary
supplement is, in fact, GRAS. You must not use unsafe ingredients in
your products. Therefore, you must have information on ingredients that
you intend to use in a dietary ingredient or dietary supplement to
demonstrate that such ingredient is safe. Otherwise, as a responsible
manufacturer, you would not use the ingredient in your product.
Therefore, under proposed Sec. 111.35(d)(4), for any claim that a
nondietary ingredient in a dietary supplement is GRAS, you must support
such claim with a cite to a FDA regulation or an explanation for why
there is general recognition of the safety of the use of the substance
in a dietary ingredient or dietary supplement. If such claim is based
on general recognition of safety based on scientific procedures, the
explanation would be based on evidence that demonstrates that there is
common knowledge about the safety of the substance throughout the
scientific community knowledgeable about the safety of such substance.
Under Sec. 170.30(c)(1), if a substance is GRAS based on common use in
food prior to January 1, 1958, this determination must be based solely
on food use of the substance before January 1, 1958, and ordinarily
must be based upon generally available data and information. Thus, GRAS
based on common use in food prior to January 1, 1958, may be determined
without the quantity or quality of scientific procedures required for
approval of a food additive regulation. If you wish to use an
ingredient based solely on food use of the substance prior to January
1, 1958, you would need to support a claim that the ingredient is GRAS
with an explanation of the basis for why the ingredient was in common
use in a dietary ingredient or a dietary supplement prior to January 1,
1958, and why that use provides the basis for general recognition of
the safety of the substance.
We will view any ingredient, that cannot meet the standard of Sec.
170.30 for a GRAS determination, as a food additive, and any dietary
ingredient or dietary supplement that contains a food additive that we
have not approved for use in the dietary ingredient or dietary
supplement is subject to regulatory action. If the safety of such
ingredient is not recognized expressly in an FDA regulation, you have
the burden to explain why the ingredient is GRAS under Sec. 170.30.
In the Federal Register of April 17, 1997, we issued a proposed
rule on GRAS notification (62 FR 18938). We are currently accepting
GRAS notifications under this proposed rule. However, we recognized in
the GRAS notification proposal (62 FR 18938 at 18951) that a failure by
us to object to a GRAS notification is not equivalent to a GRAS
affirmation of GRAS status and we, as a matter of discretion, may not
advise a notifier of a problem that we have identified that raises no
important public health issues. Therefore, if you submit a GRAS
notification to us under the April 17, 1997, proposed rule, our failure
to object to your determination that an ingredient is GRAS in a dietary
ingredient or dietary supplement will not constitute a GRAS affirmation
by us. Further, if we know of no reason to question the safety and
lawfulness of the ingredient that is the subject of a GRAS notification
and that is used in the manufacture of a dietary ingredient or dietary
supplement, we would not object to your reliance on your determination
that the use of the substance is GRAS. You could not use our response
to your GRAS notification as your basis for asserting compliance with
the requirements under proposed Sec. 111.35(d) because an FDA response
letter to a GRAS notification is not the same as your explanation,
e.g., a response letter does not provide an explanation for why an
ingredient is GRAS. We encourage any dietary ingredient or dietary
supplement manufacturer to consult with us on any ``nondietary
ingredient'' substance that it intends to use in such product to
ascertain whether the use of such ingredient may be more appropriately
submitted for review by us in a food additive petition.
Proposed Sec. 111.35(e) would require that you establish a
specification for any point, step, or stage in the manufacturing
process where control is necessary to prevent adulteration. These
points, steps, or stages may include heating steps, cooling steps,
points where specific sanitation procedures are needed, product
formulation control steps, points where cross contamination may occur,
and steps where employee and environmental hygiene are necessary to
prevent adulteration of the dietary ingredient or dietary supplement.
These specifications are regulatory specifications and you would be
required to perform testing or examination to confirm such regulatory
specifications are met. We discuss performing testing or examination to
confirm that a regulatory specification is met later in this document.
A deviation from such specification would signify that the dietary
ingredient or dietary supplement could be adulterated. Such deviation
would require investigation and a disposition decision approved by the
quality control unit under proposed Sec. 111.35(i) (which we also
discuss later in this document).
The proposed rule would not prevent you from establishing
additional specifications that are not at points, steps, or stages
where control is necessary to prevent adulteration if those additional
specifications will help you meet your quality control demands, but a
failure to meet those nonregulatory specifications will not require
that you make a material review and disposition decision. In other
words, you may establish additional specifications beyond those that
the proposed rule would require, and a material review and disposition
decision would be needed only for those specifications if not met, that
are required under the proposed rule. For example, if you determine
that a specific heat temperature is needed at a point, step, or stage
in the manufacturing process to prevent adulteration, that heat
temperature specification is a general regulatory specification. If not
met, you would need to make a material review and disposition decision.
In addition, proposed Sec. 111.35(e) identifies certain points,
steps, or stages where a regulatory specification is required.
Regulatory specifications are required for materials that you receive,
at the inprocess stage, and that you manufacture, e.g., at the finished
product stage. Specifically, we are proposing to require that you
establish specifications at these control points for the identity,
purity, quality, strength,
[[Page 12197]]
and composition of the components (upon receipt only) and for dietary
ingredients or dietary supplements (at all of these control points).
You may establish additional specifications (i.e., those in
addition to identity, purity, quality, strength, and composition) at
these same control points. For example, you may determine that an
inprocess specification is necessary during the manufacturing process
to prevent adulteration. That inprocess specification would be a
regulatory specification. Specifications also are needed for the
inprocess materials to ensure that inprocess materials are not
adulterated by the manufacturing process and are in compliance with the
master manufacturing record. Additional specifications also may be
needed for the finished product stage. Specifications are needed for
dietary ingredients and dietary supplements you manufacture to ensure
that the manufacturing process produces the correct dietary ingredient
or dietary supplement and that adulterated and misbranded dietary
supplements do not reach the marketplace.
Containers and closures are a form of packaging. The containers and
closure or other packaging, such as blister pack, that comes in contact
with dietary ingredients or dietary supplements must not be reactive or
absorptive so as to affect the safety of the dietary ingredient or
dietary supplement and must be composed of substances that are
authorized by the agency for use as a food additive, the subject of a
valid notification under section 409 of the act, authorized by a prior
sanction issued by the agency, or GRAS for such use.
Thus, under this proposed requirement, you would be required to
establish specifications for any point, step, or stage in the
manufacturing process where control is necessary to prevent
adulteration. Specific specifications that would be required for you to
establish include:
[sbull] The identity, purity, quality, strength, and composition of
components, dietary ingredients, or dietary supplements that you
receive;
[sbull] The inprocess controls in the master manufacturing record
where control is necessary to ensure the identity, purity, quality,
strength, and composition of dietary ingredients or dietary
supplements;
[sbull] The identity, purity, quality, strength, and composition of
the dietary ingredient or dietary supplement that you manufacture; and
[sbull] The packaging that may come in contact with dietary
ingredients and dietary supplements. The packaging must be safe and
suitable for its intended use and comply with all other applicable
statutory and regulatory requirements under the act and must not be
reactive or absorptive so as to affect the safety of the dietary
ingredient and dietary supplement.
Proposed Sec. 111.35(f) would require that, for each point, step,
or stage, for which a specification is established under proposed Sec.
111.35(e), you must monitor the production and inprocess control
points, steps, or stages to ensure that they meet specifications and to
detect any unanticipated occurrence that may result in adulteration.
Regular monitoring of these points is necessary to ensure that the
product meets the specifications under proposed Sec. 111.35(e) and to
ensure that any trend toward loss of control is quickly identified.
Quick identification of any trends that may lead to a deviation from a
specification could mean that adjustments may be made to prevent a
deviation from occurring. In the event that a deviation or unexpected
occurrence (such as leakage from a pipe onto a component) occurs,
effective corrective actions can be taken to remove the adulterated
product from the system.
Under proposed Sec. 111.35(g) you must ensure through testing or
examination that each specification that you establish under Sec.
111.35(e) is met. Under Sec. 111.35(e), you would have to determine
the points, steps, or stages where control is necessary to prevent
adulteration. However, there are certain points, steps, or stages in
proposed Sec. 111.35(e) that we tentatively have determined to be
those where control is necessary to prevent adulteration. Specifically,
we tentatively have determined that such control points include the
receipt of components, dietary ingredients, or dietary supplements, the
inprocess stage of manufacturing, and the finished product batch stage.
Further, we tentatively have determined that at each of those control
points, there need to be specifications for the identity, purity,
quality, strength, and composition of components (only at receipt stage
for components), dietary ingredients and dietary supplements (at all of
these control points). In addition, we tentatively have determined that
specifications are necessary for dietary ingredient and dietary
supplement labels and packaging.
The testing and examination requirements in proposed Sec.
111.35(g) would require that you conduct a test or examination to
ensure that specifications that you established are met; i.e., that you
conduct a test or examination at those points, steps, or stages in the
manufacturing process where you determined that a specification is
needed to ensure that the specification, in fact, is met. For certain
specifications that we would require, i.e., the identity, purity,
quality, strength, and composition upon receipt, inprocess, and at the
finished product batch stage, we are providing some flexibility for
testing. To illustrate, testing or examination requirements for
specifications that you establish (e.g., those other than the identity,
purity, quality, strength, and composition of the dietary ingredients
or dietary supplements received; inprocess, or finished product), such
as for a botanical extraction process that uses a specific heat
temperature for spray drying, you would be required to ensure by
testing or examination that the specified temperature was used. You
would be required to perform such a test or examination at the
inprocess point, step, or stages where control is necessary. As another
example, if a specific temperature is used on a finished batch of
dietary ingredient or dietary supplement as a heat treatment to
inactivate or remove objectionable microorganisms that pose a health
hazard, and thus, the heat treatment temperature is a critical control
point specification, then you must perform testing or examination to
determine that the specific temperature was used. You would be required
to perform such a test on each finished batch of dietary ingredient or
dietary supplement that is manufactured.
For those specifications that we tentatively have determined are
necessary (identity, purity, quality, strength, and composition) at
receipt, inprocess, and finished product stage, we are proposing
specific testing requirements that provide some flexibility. Under
Sec. 111.35(g)(1), we would require that you test each finished batch
of the dietary ingredient or dietary supplement produced before
releasing for distribution to confirm that specifications are met for
the identity, purity, quality, strength, and composition intended,
provided that there are scientifically valid analytical methods
available to perform such testing. We recognize that certain tests for
identity, purity, quality, strength, or composition for certain
finished product may not be available due to complex finished matrices
that would make such testing impracticable. Further, even though there
may not be a scientifically valid analytical method that you could use
to provide you with the information to evaluate, for example, the
identity and composition of the finished
[[Page 12198]]
product, there may be methods available for testing at the finished
product stage for other required specifications of purity, quality, and
strength. Under proposed Sec. 111.35(g)(3), your quality control must
document that a scientifically valid analytical method is not available
to perform finished product testing for any one of the required
specifications for identity, purity, quality, strength or composition.
If your quality control unit documents that a scientifically valid
analytical method for testing each batch of dietary ingredient or
dietary supplement is not available for any one of those required
specifications, then you would be required, under Sec. 111.35(g)(2)(i)
and (g)(2)(ii) to test incoming shipment lots of components, dietary
ingredients, or dietary supplements for any such specification to
determine whether it is met and to test inprocess for any such
specification in accordance with the master manufacturing record where
control is necessary to ensure the identity, purity, quality, strength,
and composition of dietary ingredients or dietary supplements.
Using a supplier certification, guarantee, or certification in lieu
of performing testing on each shipment lot of components, dietary
ingredients, or dietary supplements required in accordance with this
section is not appropriate because it is possible that a supplier's
certification or guarantee may not ensure the identity, purity,
quality, strength, or composition of a component, dietary ingredient or
dietary supplement. For example, a supplier of the dietary ingredient
plantain provided a ``certificate of analysis'' indicating that the
plant material was plantain powder, with a description of certain of
its physical characteristics (Ref. 6). The plantain was contaminated
with D. lanata (a plant that contains powerful heart stimulants that
can cause life-threatening reactions including cardiac arrest, if
ingested) and was distributed to at least 150 manufacturers,
distributors, and retailers. Thus, if you do not perform finished
product testing under Sec. 111.35(g)(1) for identity, purity, quality,
strength, or composition, then you would need to test for that
nontested finished product specification upon receipt and inprocess as
specified in the master manufacturing record to ensure that adulterated
dietary ingredients or dietary supplements are not distributed to the
marketplace.
If you are able to perform testing on each finished batch of
dietary ingredient or dietary supplement to confirm that specifications
are met for the identity, purity, quality, strength, and composition
intended, then we would recommend, but would not require, that you also
test materials received for these same specifications to ensure that
they are the right ingredients and so that you do not end up having to
destroy an entire batch of finished product after using an erroneous
ingredient that could have otherwise been identified earlier before
being added to a batch.
For example, if you manufacture a batch of dietary supplements that
contains only one single dietary ingredient, St. John's Wort extract
(Hypericum perforatum), and there are scientifically valid analytical
methods available to test the finished dietary ingredient or supplement
to confirm that the specifications are met for the identity, purity,
quality, strength, and composition intended, then you must test each
batch using such methods. In this example, you would not be required to
perform testing of incoming shipment lots of St. John's Wort to confirm
identity, purity, quality, strength, and composition to confirm that
specifications are met nor would you be required to perform testing of
inprocess for these same specifications in accordance with the master
manufacturing record. As discussed later under proposed Sec.
111.40(b)(2), although testing would not be needed at receipt stage for
identity, purity, quality, strength, and composition, you would be
required under that section, to visually compare the label, supplier's
invoice, guarantee, or certification with your purchase order for
consistency. In another example, if you manufacture a dietary
supplement that contains multiple dietary ingredients (e.g., Ginkgo
Biloba, vitamin C, and folic acid) and you do not perform testing on
the finished dietary supplement because there are not scientifically
valid analytical methods available to confirm that the specifications
for identity, purity, quality, strength, and composition are met for
each dietary ingredient in the finished batch mixture, then you would
be required to perform testing of incoming shipment lots of each
dietary ingredient to confirm that such specifications are met and
perform inprocess testing in accordance with the master manufacturing
record to ensure that such specifications are met. Thus, the proposed
testing requirements provide flexibility for testing for identity,
purity, quality, strength, and composition, based on the availability
of scientifically valid testing methods to perform testing on each
batch of dietary ingredients or dietary supplements.
Proposed Sec. 111.35(h) would require that you use an appropriate
test or examination to determine whether your specifications are met.
An appropriate test is one that is a scientifically valid analytical
method. If there is an AOAC or FDA method available that is appropriate
for your purpose, you should use that test method. For example, if your
dietary supplement claims to contain vitamin C, there is a specific
test for identifying vitamin C, and so proposed Sec. 111.35(h) would
require that you use that test (Ref. 68). If an AOAC or FDA method is
not available, a scientifically valid analytical method is one that is
based on scientific data or results published in, for example,
scientific journals, references, text books, or proprietary research.
While there may not be an AOAC or FDA method available, we are not
aware of a situation where an appropriate scientifically valid
analytical method is not available. You could perform the tests
yourself or have someone perform these tests for you.
Proposed Sec. 111.35(i) would require that you must:
[sbull] Establish corrective action plans for use when an
established specification is not met. We believe that this requirement
is necessary because you may need to take corrective action quickly,
and the best way to ensure that a corrective action is appropriate is
to determine the action in advance. For example, if, during the
production of a specific batch, the temperature specified for tablet
coating drying is not met, you would be able to consult the corrective
action plan to see whom you should contact, what correction to make,
and when to make the correction. Having corrective action plans in
place before a problem occurs can help you deal with those problems
quickly and efficiently. As another example, if during production an
operator notes that too low a temperature is used during a tablet
coating drying operation, it would be best for the operator to have an
action plan for immediate implementation, rather than having to stop
the drying process to wait for instructions on what to do. Quick action
may reduce the possibility of diminished changes in tablet dissolution
or an adulterated product and enable you to avoid having to destroy
incorrect tablets that are too moist or clump together or to avoid
recalling a product because it settled into a clump or became moldy in
the container;
[sbull] Review the results of the monitoring required by this
section and conduct a material review of any component, dietary
ingredient, dietary supplement, packaging or label for which you
establish a specification that is not met, or any unanticipated
occurrence that adulterates or could result in adulteration of the
component,
[[Page 12199]]
dietary ingredient, dietary supplement, packaging, or label. This
review will reveal whether the monitoring is actually being done and
being done correctly, and whether the specifications are being met; and
[sbull] Make a material disposition decision for any component,
dietary ingredient, dietary supplement, packaging, or label if:
1. A component, dietary ingredient, dietary supplement, packaging,
or label fails to meet specifications;
2. Any step established in the master manufacturing record is not
completed;
3. There is any unanticipated occurrence during the manufacturing
operations that adulterates or may lead to adulteration of the
component, dietary ingredient, dietary supplement, packaging, or label;
or
4. Calibration of an instrument or control suggests a problem that
may have caused batches of a dietary ingredient or dietary supplement
to become adulterated; and
5. A dietary ingredient or dietary supplement is returned.
[sbull] Have your quality control unit approve any material review
and disposition decision.
You should review the public health significance of any deviations
from specifications or of any unexpected occurrences to ensure that
dietary ingredients and dietary supplements that may have been affected
adversely by a deviation do not enter the marketplace. A material
review and disposition decision would ensure that the disruption of a
manufacturer's business is minimized when a deviation does occur. For
example, if review of a dietary supplement formulation does not contain
the required identity, purity, quality, strength, or composition, you
can take steps to dispose of the formulation before it is packaged and
labeled. If the monitoring records are not reviewed, a dietary
supplement made with a deficient formulation may be placed on the
market, and a costly and embarrassing recall may be necessary.
Proposed Sec. 111.35(i)(4) would require that for any deviation or
unanticipated occurrence which resulted in or could lead to
adulteration of the component, dietary ingredient, dietary supplement,
packaging, or label, the proposal would require that you reject the
component, dietary ingredient, dietary supplement, packaging, or label,
unless the quality control unit determines that inprocess adjustments
are possible to correct the deviation or occurrence. You would be able
to reprocess a rejected component, dietary ingredient, or dietary
supplement if the quality control unit approves such reprocessing.
However, the proposal states that you must not reprocess any component,
dietary ingredient or dietary supplement if it is rejected because of
contamination with microorganisms or other contaminants, such as heavy
metals. We propose to prohibit reprocessing in such cases because it is
unlikely that reprocessing will eliminate such forms of contamination
or will eliminate such contamination without adversely affecting the
component, dietary ingredient, or dietary supplement.
Proposed Sec. 111.35(i)(5) would require that this review be
conducted by an individual from the quality control unit. This is
necessary to ensure that the review is conducted by a person who is
qualified by training and experience to conduct such reviews and who
understands the production and inprocess control system, understands
the significance of a processing deviation, and knows how to respond to
a deviation. This will ensure that the review that is conducted and the
response to any deviation is appropriate. The requirements of this
section do not mean that the manufacturer needs a large number of
employees.
Proposed Sec. 111.35(j) would require the person who conducts the
material review and makes the disposition decision to document, at the
time of performance, every material review and disposition decision in
proposed Sec. 111.35(i). The documentation must be included in the
batch production record. Proposed Sec. 111.35(j) would require this
documentation to:
[sbull] Identify the specific deviation from the specification or
the unanticipated occurrence;
[sbull] Describe your investigation into the cause of the deviation
from the specification or the unanticipated occurrence;
[sbull] Evaluate whether or not the deviation from the
specification or unanticipated occurrence has resulted in or could lead
to adulteration;
[sbull] Identify the action(s) taken to correct and prevent a
recurrence of the deviation or the unanticipated occurrence; and
[sbull] Discuss what you did with the component, dietary
ingredient, dietary supplement, packaging, or label. For example, did
you segregate the component? Did you quarantine it until the quality
control unit decided whether it should be returned to its supplier,
reprocessed, or destroyed?
Proposed Sec. 111.35(k) would require that you test or examine
components, dietary ingredients, and dietary supplements for those
types of contamination that may adulterate or may lead to adulteration.
The proposal also would require that you use an appropriate
scientifically valid methodology for the test or examination. We
discuss analytical methods in more detail elsewhere in this document in
our discussion of laboratory operations, proposed Sec. 111.60. The
types of contamination covered by proposed Sec. 111.35(k) include, but
are not limited to, the following:
[sbull] Filth, insects, or other extraneous material;
[sbull] Microorganisms; and
[sbull] Toxic substances.
Under this proposed requirement, you must test or examine for those
types of contamination that may adulterate or may lead to adulteration.
The words, ``for those types of contamination that may adulterate or
may lead to adulteration,'' at least in part, mean that you must test a
botanical for filth and microorganisms of public health significance.
For example, it is highly likely or certain that botanical components
would be contaminated with filth and undesirable microorganisms of
public health significance based on the areas in which they are
harvested. Therefore, it would be inappropriate if you did not test
botanical components for filth and microorganisms. The types of tests
and when to test would be left to your discretion. The proposed rule
would not specify any particular test or examination, so you would be
able to decide on the appropriate methods for testing or examination
that are suited to your components, dietary ingredients, and dietary
supplements.
Contamination also can create conditions that promote further
contamination by other organisms. For example, contamination resulting
from possible fungal growth on a botanical component can provide the
environment for mycotoxin production, especially aflatoxin (Refs. 63
and 64). Therefore, if a toxic substance is a type of contamination
that may adulterate or lead to adulteration of the dietary ingredient
or dietary supplement, you must perform an appropriate test to detect
the toxic substance.
In other cases, a certain amount of micro flora on a botanical may
be unavoidable. For example, some botanical components always will
contain a certain number of microorganisms that live on the plant or
come from other organisms (micro flora) on the plant. Processing these
components may destroy a substantial number of the microorganisms, but
some may survive processing (Ref. 65).
[[Page 12200]]
Therefore, for natural products it may be appropriate to perform tests
of finished product to confirm that, of the microorganisms present,
those of public health significance did not survive processing and
those that remain that are not of public health significance do not
contaminate the dietary ingredient or dietary supplement.
Although the proposal does not specify microbial limits for
undesirable microorganisms, other non-FDA sources have established
acceptable, general limits of microbial levels for dietary ingredients
and dietary supplements (Refs. 66 and 67). These often include limits
for total aerobic microbial count, which ranges from 104 to
107 per g, depending on source and nature of components; a
total combined yeast and molds count, which can range from
103 to 105 per g, again depending on source and
nature of components; and the absence of Salmonella species, E. coli
and Staphylococcus aureus. We establish microbial limits for
undesirable microorganisms based on scientific information such as
literature surveys and laboratory analyses. At this time, however, we
do not have sufficient information to support establishing microbial
limits for undesirable microorganisms for dietary ingredients.
Therefore, the proposed rule does not establish microbial limits for
dietary ingredients. However, you must be aware of potential
contamination, regardless of whether it is due to filth, insects,
microorganisms, or toxins, and you must test or examine as appropriate
components, dietary ingredients, or dietary supplements for those types
of contamination that may adulterate or may lead to adulteration.
Proposed Sec. 111.35(l) would explain that the tests you use to
determine whether your components, dietary ingredients, and dietary
supplements meet specifications must include at least one of the
following tests: Gross organoleptic analysis, microscopic analysis,
chemical analysis, or other appropriate test. These tests may vary in
detail or complexity depending on the purposes of the test and the
material being tested. For example, if your component is raw
cranberries, and you are trying to verify that a shipment of red
berries consists of raw cranberries, an organoleptic (visual test) may
be sufficient (assuming that you recognize cranberries). However, if
your component is a chemical substance, and you are trying to verify
that a shipment of bulk powder is that chemical substance, chemical
analysis may be more appropriate than an organoleptic analysis.
Proposed Sec. 111.35(m) would require that you must record the
results of all testing and examinations performed in accordance with
this section. If a test or examination is performed on a production
batch, you must record the test or examination result in the batch
production record in accordance with Sec. 111.50(c)(10). Your records
must document whether the testing and examination demonstrates that
specifications are met.
Proposed Sec. 111.35(n) would require for any specification that
is not met, that you must conduct a material review and disposition
decision under Sec. 111.35(i).
Proposed Sec. 111.35(o) would require that you make and retain
records, in accordance with proposed Sec. 111.125, to ensure that you
follow the requirements of this section. The proposal would require
these records to include, but would not limit them to:
[sbull] The specifications established;
[sbull] The actual results obtained during the monitoring
operation;
[sbull] Any deviation from specifications and any unanticipated
occurrences;
[sbull] Any corrective actions taken;
[sbull] The disposition decisions and followup; and
[sbull] The identity of the individual qualified by training and
experience who investigated any deviation from specifications or
unanticipated occurrence and the identity of the individual from the
quality control unit who reviewed the results of that investigation.
These records would enable you to show, and for us to determine,
your compliance with proposed Sec. 111.35. We generally determine CGMP
compliance by conducting inspections, so records play an important role
during those inspections in determining CGMP compliance.
2. What Requirements Apply to Quality Control? (Proposed Sec. 111.37)
Proposed Sec. 111.37(a) would require that you use a quality
control unit to ensure that your manufacturing, packaging, label, and
holding operations in the production of dietary ingredients and dietary
supplements are performed in a manner that prevents adulteration and
misbranding, including ensuring that dietary ingredients and dietary
supplements meet specifications for identity, purity, quality,
strength, and composition. This requirement does not mean that the
manufacturer needs a large number of employees. The manufacturing
process for an ingredient or a dietary supplement can be a
sophisticated process, and all organizational units that are involved
in critical formulation and manufacturing steps, such as production,
engineering, research, and regulatory affairs, may be included in
quality control functions.
Proposed Sec. 111.37(b) would require that your quality control
unit must do the following:
[sbull] Approve or reject all process, procedures, specifications,
controls, tests, and examinations, and deviations from or modifications
to them that may affect the identity, purity, quality, strength, and
composition of a dietary ingredient or dietary supplement;
[sbull] Determine whether all components, dietary ingredients,
dietary supplements, packaging, and labels conform to their
specifications;
[sbull] Approve or reject all components, dietary ingredients,
dietary supplements, packaging, and labels;
[sbull] Review and approve all master manufacturing records and all
modifications to the master manufacturing records;
[sbull] Review and approve all batch production-related records
which include, but are not limited to, cross-referencing receiving and
batch production records, approval of a material review and disposition
decision, approval for reprocessing, and approval for releasing for
distribution. Cross-referencing receiving and batch production records
means that the quality control unit must verify that the batch record
includes certain documentation of the receiving records for the
components and dietary ingredients such as the unique identifier
assigned to the shipment lot of components, testing results, a material
review and disposition decision, if conducted, and approval for use by
the quality control unit.
[sbull] Review and approve all processes for calibrating
instruments or controls;
[sbull] Review all records for calibration of instruments,
apparatus, gauges, and recording devices;
[sbull] Review all records for equipment calibrations, inspections,
and checks;
[sbull] Review and approve all laboratory control processes and
testing results;
[sbull] Review and approve all packaging and label records which
include, but are not limited to, cross-referencing receiving and batch
production records, approval for repackaging and relabeling, and
approval for releasing for distribution;
[sbull] Collect representative samples of:
1. Each shipment lot of components, dietary ingredients, dietary
supplements, packaging, and labels received for testing or examination,
as needed, to determine whether the component, dietary ingredient,
dietary supplement, packaging, or labels meet specifications before use
or for testing,
[[Page 12201]]
as needed, in consumer complaint investigations;
2. Inprocess materials at points, steps, or stages, in the
manufacturing process as specified in the master manufacturing record
where control is necessary to ensure the identity, purity, quality,
strength, and composition of dietary ingredients or dietary
supplements;
3. Each batch of dietary ingredient or dietary supplement that is
manufactured to determine, before you release it for distribution,
whether it meets its specifications for identity, purity, quality,
strength, and composition; and
4. Each batch of packaged and labeled dietary ingredients or
dietary supplements to determine that you used the packaging specified
in the master manufacturing record and applied the label specified in
the master manufacturing record;
[sbull] Review and approve all material review and dispostion
decisions; and
[sbull] Collect representative reserve samples of each shipment lot
of components, dietary ingredients, and dietary supplements and each
batch of dietary ingredient or dietary supplement. The proposal would
require that you keep the reserve samples for 3 years from the date of
manufacture for use in appropriate investigations, such as, consumer
complaint investigations to determine, for example, whether the dietary
ingredient or dietary supplement associated with a consumer complaint
failed to meet any of its specifications for identity, purity, quality,
strength, and composition. We tentatively decide to require that you
keep reserve samples for 3 years because we believe that 3 years would
be a reasonable time period beyond the date of manufacture for
appropriate followup of consumer complaints received during the
marketing period. Because we have not proposed requirements for
expiration dating of dietary supplements, we tentatively conclude that
the date of manufacture is an appropriate starting time for the
retention period. This requirement in proposed Sec. 111.37(b)(11) also
would require that the reserve samples be identified with the batch or
lot number and consist of at least twice the quantity necessary for
tests;
[sbull] Perform appropriate tests and/or examinations of:
1. Components, dietary ingredients, dietary supplements, packaging,
and labels received to ensure that they meet specifications;
2. Dietary ingredient and dietary supplement batch production at
points, steps, or stages identified in the master manufacturing record
where control is necessary to prevent adulteration;
3. Dietary ingredients and dietary supplements that you manufacture
to ensure that they meet specifications; and
4. Packaged and labeled dietary ingredients and dietary supplements
to ensure that you used the packaging specified in the master
manufacturing record and you applied the label specified in the master
manufacturing record;
[sbull] Review and approve all material review and disposition
decisions; and
[sbull] Approve the reprocessing or distribution of returned
dietary ingredients or dietary supplements.
Proposed Sec. 111.37 would impose duties on your quality control
unit that are necessary to the quality control unit. The duties
proposed in Sec. 111.37 are important in any CGMP standards to ensure
that the dietary ingredient or dietary supplement manufactured has the
identity, purity, quality, strength, and composition intended. If a
quality control unit did not do, that is, lacked the responsibility and
authority to do, the actions described in proposed Sec. 111.37,
coordination between various parts of your manufacturing, packaging, or
holding operation might become haphazard and the product could be
adulterated. For example, if your quality control unit did not make
decisions concerning use of components, dietary ingredients, and
dietary supplements you receive, you could use the wrong component, or
a contaminated component in manufacturing a dietary ingredient or
dietary supplement. If your quality control unit makes decisions
concerning releasing dietary ingredients and dietary supplements for
distribution, it will prevent you from releasing for distribution an
adulterated dietary ingredient or dietary supplement before the
necessary tests results confirm that the dietary ingredient or dietary
supplement meets specifications for identity, purity, quality,
strength, and composition.
Your quality control unit must document, at the time of
performance, that it performed the review, approval, or rejection
requirements established in accordance with proposed Sec. 111.37 by
recording the date when the review, approval, or rejection and
requirement was performed, and the signature of the person performing
the requirement. As we explained elsewhere in this document, one of the
ways we determine compliance with CGMP's is by conducting inspections,
so records enable you to show, and for us to determine, compliance with
CGMP's. We invite comment on whether we should require, in a final
rule, written procedures for the quality control unit duties required
in Sec. 111.37. If comments assert that written procedures are
necessary, comments should include an explanation of why the
requirement is necessary to prevent adulteration including how such a
requirement would ensure the identity, purity, quality, strength, and
composition of the dietary ingredient or dietary supplement.
Conversely, if comments assert that written procedures are not
necessary, comments should include an explanation of why the
requirement is not necessary including how, in the absence of the
requirement, one can prevent adulteration and ensure the identity,
purity, quality, strength, and composition of the dietary ingredient or
dietary supplement.
3. What Requirements Apply to Components, Dietary Ingredients, Dietary
Supplements, Packaging, and Labels You Receive? (Proposed Sec. 111.40)
Proposed Sec. 111.40 would establish requirements to ensure that
the components, dietary ingredients, dietary supplement, packaging, and
labels you receive are, in fact, what you ordered. We are proposing
these requirements because receiving the wrong materials can lead to
mixups or the use of wrong materials and this could result in the
manufacture of an adulterated and misbranded dietary ingredient or
dietary supplement.
Proposed Sec. 111.40(a)(1) and (a)(2) would apply to components,
dietary ingredients, or dietary supplements you receive, and would
require that you:
[sbull] Visually examine each container or grouping of containers
in a shipment for appropriate content label, container damage, or
broken seals to determine whether the container's condition has
resulted in contamination or deterioration of the components, dietary
ingredients, or dietary supplements;
[sbull] Visually examine the supplier's invoice, guarantee, or
certification to ensure that the components, dietary ingredients, or
dietary supplements are consistent with your purchase order and perform
testing, as needed, under proposed Sec. 111.35(g), to determine
whether specifications are met.
We state in proposed Sec. 111.40(a)(2) that you must perform
testing ``as needed.'' This flexibility is necessary, given the
proposed testing scheme in Sec. 111.35(g). As previously discussed in
proposed Sec. 111.35(e), you must establish specifications for any
points, steps, or stages in the manufacturing process where control is
necessary to prevent adulteration. In addition, we propose to require,
under Sec. 111.35(e), certain
[[Page 12202]]
specifications, i.e., identity, purity, quality, strength, and
composition, for components, dietary ingredients, and dietary
supplements upon receipt. However, in Sec. 111.35(g), we are proposing
to provide some flexibility for when testing is required for the
identity, purity, quality, strength, and composition specifications.
Specifically, if you perform finished product testing under Sec.
111.35(g)(1) for identity, purity, quality, strength, and composition,
then under Sec. 111.40(a)(2) we would require that you visually
compare the supplier's invoice, guarantee, or certification with your
purchase order to confirm consistency between your order and the
supplier's invoice, guarantee, or certification. You would not need to
do testing upon receipt. That is why we have added language to Sec.
111.40(a)(2) that states, ``and perform testing, as needed, to
determine whether specifications are met.'' Alternatively, for
specifications that you establish (e.g., other than the identity,
purity, quality, strength, and composition of the components, dietary
ingredients or dietary supplements received), such as for a holding
temperature necessary during transportation to your physical plant to
avoid adulteration, you would be required to ensure by testing or
examination that the specified temperature was used.
If you do not perform finished product testing under Sec.
111.35(g)(1) for identity, purity, quality, strength, or composition,
then you would need to test for that nontested finished product
specification upon receipt. In that case, testing would be needed under
both proposed Sec. Sec. 111.35(g)(2) and 111.40(a)(2). You still would
need to visually compare the supplier's invoice, guarantee, or
certification with your purchase order to confirm consistency between
your order and the supplier's invoice, guarantee, or certification.
Thus, for those specifications of identity, purity, quality,
strength, or composition for which your quality control unit determines
that you cannot test for at the finished product stage (because there
are no available scientifically valid methods), then you would be
required, under Sec. 111.35(g)(2)(i) to test incoming shipment lots of
components, dietary ingredients, or dietary supplements for any such
specification to determine whether it is met, and such a test also
would be considered to be necessary under Sec. 111.40(a)(2). As
discussed earlier, you may not rely on a supplier's certification or
guaranty in lieu of such testing, and in addition to such testing,
still would need to visually examine the supplier's invoice, guarantee,
or certification.
Under Sec. 111.40(b)(3) through (b)(5), we would require that you:
[sbull] Quarantine components, dietary ingredients, or dietary
supplements until your quality control unit reviews the supplier's
invoice, guarantee, or certification and performs testing, as needed
under proposed Sec. 111.35(g), of a representative sample to determine
that specifications are met. These are the specifications that you
would set in accordance with proposed Sec. 111.35(e) and appropriate
tests or examinations used in accordance with proposed Sec. 111.35(g)
for materials that you receive. If specifications are not met, proposed
Sec. 111.40(a)(3) would require that you conduct a material review and
make a disposition decision. Your quality control unit must approve and
release the components, dietary ingredients, and dietary supplements
from quarantine before you use them;
[sbull] Identify each lot of components, dietary ingredients, or
dietary supplements in a shipment in a manner that allows you to trace
the shipment to the supplier, the date received, the name of the
component or dietary supplement, and the status (e.g., quarantined,
approved, or rejected) and to trace the shipment lot to the dietary
ingredient or dietary supplement manufactured and distributed. You must
use this unique identifier whenever you record the disposition of each
shipment lot received. Using a unique identifier throughout the
manufacturing process will make it possible to track and account for
components, dietary ingredients, and dietary supplements you receive
and is necessary to conduct investigations of consumer complaints; and
[sbull] Hold components, dietary ingredients, or dietary
supplements under conditions that will protect against contamination,
deterioration, and avoid mixups. For example, you must segregate
components that your quality control unit has not released for use from
those components that have been released for use. This provision would
require that you refrigerate components that are subject to
contamination or deterioration without such refrigeration or that
otherwise require storage at a certain temperature.
Proposed Sec. 111.40(b) would apply to packaging and labels you
receive and would require that you:
[sbull] Visually examine each container or grouping of containers
in a shipment for appropriate content labels, container damage, or
broken seals to determine whether the container's condition has
resulted in contamination or deterioration of the packaging and labels;
[sbull] Quarantine packaging and labels until your quality control
unit tests or examines a representative sample to determine that
specifications are met. You must conduct at least a visual
identification on the containers and closures. If specifications are
not met, the proposal would require that you conduct a material review
and make a disposition decision and also require your quality control
unit to approve and release packaging and labels from quarantine before
you use them;
[sbull] Identify each shipment lot of packaging and labels in a
manner that allows you to trace the shipment lot to the supplier, the
date received, the name of the packaging and label, and the status
(e.g., quarantined, approved, or rejected) and to trace the shipment
lot to the dietary ingredient or dietary supplement manufactured and
distributed. Like proposed Sec. 111.40(a)(4), proposed Sec.
111.40(b)(3) would require that you use this unique identifier whenever
you record the disposition of each shipment lot received; and
[sbull] Hold packaging and labels under conditions that will
protect against contamination and deterioration and avoid mixups.
Proposed Sec. 111.40(c) deals with written documentation and
records. Proposed Sec. 111.40(c)(1) would require that the person who
performs the requirements established in accordance with this section
to document, at the time of performance, that he or she performed the
requirements. The documentation would have to include, but not be
limited to, the date that the requirement was performed; the signature
of the person performing the requirement; any test results; and any
material review and disposition decision conducted, and the disposition
of any rejected material.
Proposed Sec. 111.40(c)(2) would require that you keep component,
dietary supplement, packaging, and label receiving records in
accordance with proposed Sec. 111.125. These records are necessary to
be able to determine the source of the component, dietary ingredient,
dietary supplement, packaging, and labels, so that if adulteration of
dietary ingredient or dietary supplement occurs, the records will show
the source of the material so that its use can be stopped. In addition,
the records will show the basis on which each component, dietary
ingredient, dietary supplement, packaging, or label was released for
use in dietary ingredient or dietary supplement production. These
records
[[Page 12203]]
are necessary to demonstrate compliance with the CGMP and quality
control procedures.
We invite comment on whether we should require, in a final rule,
that you establish and follow written procedures that implement
proposed Sec. 111.40(a) and (b). If comments assert that written
procedures are necessary, comments should include an explanation of why
the requirement is necessary to prevent adulteration including how such
a requirement would ensure the identity, purity, quality, strength, and
composition of the dietary ingredient or dietary supplement.
Conversely, if comments assert that written procedures are not
necessary, comments should include an explanation of why the
requirement is not necessary including how, in the absence of the
requirement, one can prevent adulteration and ensure the identity,
purity, quality, strength, and composition of the dietary ingredient or
dietary supplement.
4. What Requirements Apply to Establishing a Master Manufacturing
Record? (Proposed Sec. 111.45)
Proposed Sec. 111.45 would require that you prepare and follow a
written master manufacturing record for each type of dietary ingredient
or dietary supplement that you manufacture and for each batch size to
ensure uniformity from batch to batch. A master manufacturing record is
analogous to a recipe that sets forth the ingredients to use, the
amounts of ingredients to use, the tests to perform, and the
instructions for preparing the amount the recipe calls for, e.g., 250
mg, 500 mg, vitamin C. This master manufacturing record helps ensure
that you manufacture each ingredient or dietary supplement in a
consistent and uniform manner. If you neglect to follow the master
manufacturing record, you would not add all of the necessary components
in the appropriate strength or amount, and this would result in an
adulterated ingredient or dietary supplement.
Therefore, proposed Sec. 111.45(a) is necessary to ensure that you
prepare and follow a written master manufacturing record for each type
of dietary ingredient or dietary supplement to ensure that all the
necessary components as specified, and in the amounts specified, are
used to manufacture each batch to ensure uniformity from batch to batch
and to ensure that the dietary ingredient or dietary supplement is not
adulterated. Proposed Sec. 111.45(a)(1) and (a)(2) describe the
proposed contents of the master manufacturing record. The master
manufacturing record would identify specifications for the points,
steps, or stages in the master manufacturing record where control is
necessary to prevent adulteration, and establish controls and
procedures to ensure that each batch of dietary ingredient or dietary
supplement manufactured meets those specifications. For example, assume
that your manufacturing process blends various ingredients in order to
make a dietary supplement. Under proposed Sec. 111.45(a), your master
manufacturing record would establish controls to look at specific steps
in the manufacturing process and evaluate the blends for specific
ingredients to ensure that you added the correct ingredients at the
correct amounts or concentrations that meet your specifications before
the blend proceeds to the next manufacturing step, in accordance with
the master production record. Throughout the manufacturing process, you
would evaluate, as necessary, any points, steps, or stages where
control is necessary to prevent adulteration to ensure that
specifications established for those points, steps, or stages are met.
Proposed Sec. 111.45(b) would establish additional requirements
for the master manufacturing record. These proposed requirements would
include:
[sbull] The name of the dietary ingredient or dietary supplement to
be manufactured and the strength, concentration, weight, or measure of
each dietary ingredient for each batch size. For example, assume you
have a million tablet batch size of a vitamin C product in 250 mg
tablets and that the only other ingredients in your product are starch,
microcrystalline cellulose, and dicalcium phosphate. Under proposed
Sec. 111.45(b)(1), your master manufacturing record would state,
``Vitamin C 250 mg, 1,000,000 tablets'';
[sbull] A complete list of components to be used. Again, to
continue using the example immediately above, for proposed Sec.
111.45(b)(2), the master manufacturing record also would show that you
used starch, microcrystalline cellulose, and dicalcium phosphate in the
product;
[sbull] An accurate statement of the weight or measure of each
component to be used. For example, under proposed Sec. 111.45(b)(3),
the master manufacturing record for our hypothetical vitamin C tablet
would state the amount of each component used, such as ``200 lbs. of
Vitamin C, 10 lbs. of microcrystalline cellulose'' and the amounts of
starch and dicalcium phosphate used. (We would not require that you
show the amount using an appropriate English or metric standard in a
particular way, but we would expect that you use the most appropriate
weight or measure for the component);
[sbull] The identity and weight or measure of each dietary
ingredient that will be declared on the Supplement Facts label and the
identity of each ingredient that will be declared on the ingredients
list of the dietary supplement in compliance with section 403(s) of the
act. For proposed Sec. 111.45(b)(4), therefore, the master
manufacturing record for our hypothetical product would state that the
dietary ingredient is Vitamin C at 250 mg (because Vitamin C would be
the dietary ingredient declared on the Supplement Facts label) and
identify starch, microcrystalline cellulose, and dicalcium phosphate
(because those ingredients would be in the product's ingredient list,
but not on the Supplement Facts label); and
[sbull] A statement that explains any intentional excess amount of
a dietary ingredient. We recognize that some manufacturers
intentionally add a specific amount of a dietary ingredient in excess
of the declared label amount so that the finished product can meet the
label declaration for that dietary ingredient throughout the product's
shelf life. For our hypothetical vitamin C tablet, if you added an
extra 25 mg of vitamin C to ensure that your product contains at least
250 mg of vitamin C throughout its shelf life, your master
manufacturing record would state the component and the actual amount of
the component as ``Vitamin C, 250 mg, (10 percent excess) 25 mg'' or
``275 mg of Vitamin C.'' So, proposed Sec. 111.45(b)(5) would require
the master manufacturing record to specify the controlled amount of the
excess dietary ingredient necessary to achieve the declared label
declaration. This provision is not intended to allow a manufacturer to
add excess dietary ingredients in unspecified amounts that would be in
excess of the amount actually needed to meet the label declaration.
The agency considered whether to propose requirements in this proposed
rule for expiration dating, shelf-life dating, or best if used by
dating (hereinafter referred to as expiration dating). Although we
recognize that there are current and generally available methods to
determine the expiration date of some dietary ingredients, for example
vitamin C, we are uncertain whether there are current and generally
available methods to determine the expiration dating of other dietary
ingredients, especially botanical dietary ingredients. We are not
proposing expiration dating at this time because we have insufficient
scientific information to determine the biological
[[Page 12204]]
activity of certain dietary ingredients used in dietary supplements,
and such information would be necessary to determine an expiration
date. Further, because official validated testing methods (i.e., AOAC
or FDA) for dietary supplements are evolving, especially for botanical
dietary ingredients, few official methods are available to assess the
strength of a dietary ingredient in a dietary supplement. Nevertheless,
if you use an expiration date on a product, you should have data to
support that date. You should have a written testing program designed
to assess the stability characteristics of the dietary supplement, and
you should use the results of the stability testing to determine
appropriate storage conditions and expiration dates.
We invite comment on whether any final dietary ingredient and
dietary supplement CGMP rule should contain provisions regarding
expiration dating and the feasibility of conducting tests needed to
support such dates. We also invite comments on whether to require
expiration dating on certain dietary ingredients and not others, for
example, require expiration dating of vitamin, mineral, and amino acid,
but not of botanical dietary ingredients.
Proposed Sec. 111.45(b) also would require your master
manufacturing record to contain:
[sbull] A statement of theoretical yield of a manufactured dietary
ingredient or dietary supplement expected at each point, step, or stage
of the manufacturing process where control is necessary to prevent
adulteration, and the expected yield when you finish manufacturing the
dietary ingredient or dietary supplement, including the maximum and
minimum percentages of theoretical yield beyond which a deviation
investigation of a batch is performed and material review is conducted
and disposition decision is made. In this particular instance, when we
refer to the manufacture of dietary ingredients, we mean to say that if
you use a master manufacturing record to make dietary ingredients (that
is, you make dietary ingredients rather than dietary supplements), the
proposal would require the master manufacturing record to contain a
theoretical yield at each point, step, or stage where control is
necessary to prevent adulteration. Likewise, if you manufacture dietary
supplements, the proposal would require your master manufacturing
record to contain a theoretical yield at each point, step, or stage
where control is necessary to prevent adulteration;
[sbull] A description of packaging and a copy of the label to be
used. We propose to require such information because, depending on the
type of material you use, packaging could adulterate your dietary
ingredients or dietary supplements. For example, the correct container
may protect the dietary ingredient or dietary supplement from the
deteriorating effects of light and if an incorrect container is used
that does not provide this protection, your dietary ingredient or
dietary supplement could deteriorate and could be adulterated. The
description might consist of information such as the type of bottle to
be used with your manufacturer's code number, if available; a
description of the cap to be used with the liner specified with a
manufacturer's code number, if applicable; additional materials needed
in packaging; and the control number, if applicable, of the label to be
used in packaging the dietary ingredient or dietary supplement. We are
not aware of evidence of that dietary supplement manufacturers are
using unlawful containers. Section 201(s) of the act defines ``food
additive'' to mean any substance the intended use of which results or
may reasonably be expected to result, directly or indirectly, in it's
becoming a component or otherwise affecting the characteristics of any
food (including any substance intended for use in producing,
manufacturing, packing, processing, preparing, treating, packaging,
transporting, or holding food; and including any source of radiation
intended for any such use). Materials used in packaging that come in
contact with food or that react chemically with food, may be considered
to be food contact substances or food additives. Foods and dietary
ingredients may contain active substances that can react with packaging
materials. Thus, FDA is proposing a CGMP requirement that
manufacturer's use containers that are lawful under the act and that do
not impose a risk such as leakage or the possibility of physical
contamination of dietary ingredients or dietary supplements.
Information on packaging and labels materials will also be helpful in
case an adverse event occurs; and
[sbull] Written instructions including, but not limited to:
1. Specifications for each point, step, or stage in manufacturing
the dietary ingredient or dietary supplement necessary to prevent
adulteration;
2. Sampling and testing procedures;
3. Specific actions necessary to perform and verify points, steps,
or stages, necessary to meet specifications and otherwise prevent
adulteration, including, but not limited to, one person weighing or
measuring a component and another person verifying the weight or
measure and one person adding the component and another person
verifying the addition;
4. Special notations and precautions to be followed; and
5. Corrective action plans for use when a specification is not met.
You should think of the written instructions as being similar to a
recipe; they should cover the important steps in your manufacturing,
packaging, or holding processes, but they also should tell the reader
about any special directions to follow, tests to perform, precautions
to be observed, and personnel to use.
Proposed Sec. 111.45(c) would require that you have your quality
control unit review and approve each master manufacturing record and
any modifications to a master manufacturing record. This provision
reiterates the quality control requirements in proposed Sec. 111.37.
This proposed requirement is necessary to prevent potential problems
that could result from changes to the master manufacturing record made
by persons who are not qualified to assess the impact of such changes.
By having your quality control unit review and approve the master
manufacturing record and changes to that record, you will reduce your
risk of not detecting the inclusion of an incorrect ingredient in the
batch production. The quality control unit review will ensure that
necessary inprocess verifications and testing instructions are included
in the master manufacturing record. Further, any changes to the master
manufacturing record will reduce your risk of adding the wrong
component, dietary ingredient or dietary supplement or the wrong amount
of a component, dietary ingredient or dietary supplement. For example,
in one case, a dietary supplement manufacturer made a product that had
10 times the labeled amount of vitamin D, but did not perform any tests
for vitamin D concentration as part of its review of its batch records
(Ref. 23). The manufacturer discovered the superpotent batches only
after State authorities had contacted them, and had to recall the
product. Had the manufacturer's quality control unit reviewed the
master manufacturing and batch production records earlier, the
superpotent batches that represented a change from the master
manufacturing record might have been detected before the product left
the manufacturer, and the recall could have been avoided. The
manufacturer later took steps to increase its audits of batch records,
to require approval of all changes to its master
[[Page 12205]]
formulas, and to perform tests for its manufacturing activities.
In another example, several consumers and employees at spas in
Massachusetts and Arizona complained of dizziness, vomiting, or
lightheadedness after consuming several dietary supplements. We did an
inspection and found that, in the case of two products, the
manufacturer's formula called for the use of a product having 0.2
percent selenium by weight, but the manufacturer's records showed that
it used a product that had 5 percent selenium by weight. This
difference meant that the supplements, instead of containing 200 [mu]g
of selenium, contained between 400 to 4,699 [mu]g of selenium. After
further investigation, we determined that the error occurred when the
quantity of selenium to be used was printed in kilograms (kg), instead
of g. The change in unit measurement represents a change from the
master manufacturing record. Had the manufacturer's quality control
unit reviewed the change in the master manufacturing record, it
probably would not have approved the change to include use of the
product containing the higher percent of selenium.
One comment to the ANPRM opposed a requirement that would have a
quality control unit review and approve the master manufacturing
record. The comment stated that this review and approval process is
overly restrictive because other units can perform this function and
only need be audited or periodically verified by the quality control
unit. The comment suggested that the quality control unit assure that a
master production and control record must be prepared for the
manufacture of each dietary ingredient and dietary supplement, rather
than review and approve such records.
We do not agree that the review and approval process is overly
restrictive and decline to adopt the comment's suggestion. The quality
control unit can be composed of individuals from various parts of the
organization. Removing this responsibility from the quality control
unit would diminish the quality control unit's responsibility and
authority. As stated earlier, the manufacturing process of a dietary
ingredient or a dietary supplement can be a sophisticated process, and
we understand that all organizational units that are involved in
critical formulation and manufacturing steps, such as production,
engineering, research, and regulatory affairs, should review and
approve a master production order and changes to it. However, the
responsibility for reviewing and approving the master manufacturing
record and modifications to that record properly rests with the quality
control unit because the individuals in the quality control unit would
have the expertise to make a decision whether the master manufacturing
record, if followed, will result in an unadulterated dietary ingredient
or dietary supplement and does not mean that the manufacturer needs a
large number of employees.
You should note that, while the quality control unit is responsible
for reviewing and approving the master manufacturing record and changes
to that record, this does not mean that the quality control unit must
prepare the master manufacturing record itself or act without any
involvement from other parts of your manufacturing operation. Other
individuals or groups may help prepare, review, and approve drafts of a
master manufacturing record and draft changes to an existing master
manufacturing record, but the quality control unit is responsible for
reviewing and approving the final master manufacturing record and
modifications to that record.
Proposed Sec. 111.45(d) would pertain to written documentation and
recordkeeping. Proposed Sec. 111.45(d) would require that you keep
your master manufacturing records in accordance with proposed Sec.
111.125. The master manufacturing record in addition to the batch
production records will ensure that a complete history of each batch of
dietary ingredient or dietary supplement is available for your review
in the event that a problem arises with a particular batch. These
records also are necessary to demonstrate compliance with the CGMP and
quality control procedures.
We invite comment on whether a written procedure for preparing the
master manufacturing record and making any modifications to the record,
consistent with the requirements in this section, should be required in
a final rule. If comments assert that written procedures are necessary,
comments should include an explanation of why the requirement is
necessary to prevent adulteration including how such a requirement
would ensure the identity, purity, quality, strength, and composition
of the dietary ingredient or dietary supplement. Conversely, if
comments assert that written procedures are not necessary, comments
should include an explanation of why the requirement is not necessary
including how, in the absence of the requirement, one can prevent
adulteration and ensure the identity, purity, quality, strength, and
composition of the dietary ingredient or dietary supplement. Further,
we seek comment on whether any of the proposed requirements in this
section are not necessary to prevent adulteration and to ensure the
identity, purity, quality, strength, and composition of the dietary
ingredient or dietary supplement. If comments assert that certain
provisions are not necessary, comments should include an explanation of
why the requirement is not necessary including how, in the absence of
the requirement, one can prevent adulteration and ensure the identity,
purity, quality, strength, and composition of the dietary ingredient or
dietary supplement. If comments agree that the proposed requirements
are necessary for reasons other than those we have provided, the
comments should so state and provide an explanation.
5. What Requirements Apply to Establishing a Batch Production Record?
(Proposed Sec. 111.50)
Proposed Sec. 111.50(a) would require that you prepare a batch
production record every time you manufacture a batch of dietary
ingredient or dietary supplement. This requirement would apply to any
batch, including a batch approved for reprocessing by the quality
control unit. The proposal also would require the batch production
record to include complete information relating to the production and
control of each batch. The batch production record is necessary to
document that you followed the master manufacturing record to make each
batch of dietary ingredients or dietary supplements. It is important to
document such information for each batch because it serves as a check
that the master manufacturing record was followed. If you later
discover problems with a particular batch of dietary ingredients or
dietary supplements, you could look at the batch production record for
that batch, compare it to the master manufacturing record, and see
whether the problems occurred because of a failure to follow the master
manufacturing record. These records, in conjunction with your master
manufacturing records, will create a written system which, when
followed, will result in a reproducible, high-quality, and uniform
dietary ingredient or dietary supplement.
Proposed Sec. 111.50(b) would require the batch production record
to accurately follow the appropriate master manufacturing record and
also require that you perform each step in producing the batch. Even if
you have someone else (such as a contractor) perform a particular step,
you would remain responsible for ensuring that each step is done that
complies with the
[[Page 12206]]
requirements in proposed part 111. The contractor, however, is also
considered a manufacturer and must comply with the regulations that
apply to the responsibilities that it has specifically contracted to
perform.
Proposed Sec. 111.50(c) would specify the batch production
record's contents. The proposal would require that certain information
be included in the batch production record including, but not be
limited to, the following information:
[sbull] The batch, lot, or control number;
[sbull] Documentation, at the time of performance, showing the date
on which each step of the master manufacturing record was performed,
and the initials of the persons performing each step including, but not
limited to, the person responsible for weighing or measuring each
component used in the batch and the person responsible for adding the
components to the batch;
[sbull] The identity of equipment and processing lines used in
producing the batch;
[sbull] The date and time of the maintenance, cleaning, and
sanitizing of the equipment and processing lines used in producing the
batch;
[sbull] The shipment lot unique identifier of each component,
dietary ingredient, dietary supplement, packaging, and label used;
[sbull] The identity and weight or measure of each component used;
[sbull] The initials at the time of performance or at the
completion of the batch of the person responsible for verifying the
weight or measure of each component used in the batch;
[sbull] The initials at the time of performance or at the
completion of the batch of the person responsible for verifying the
addition of components to the batch;
[sbull] A statement of the actual yield and a statement of the
percentage of theoretical yield at appropriate phases of processing;
[sbull] The actual test results for any testing performed during
the batch production in accordance with Sec. 111.35(m);
[sbull] Documentation that the dietary ingredient and dietary
supplement meets specifications;
[sbull] Copies of all container labels used and the results of
examinations conducted during the label operation to ensure that the
containers have the correct label;
[sbull] Any documented material review and disposition decision in
accordance with Sec. 111.35(j); and
[sbull] The signature of the quality control unit to document batch
production record review and any approval for reprocessing or
repackaging.
Proposed Sec. 111.50(b) and (c) are necessary to ensure that you
made your batches correctly under the master manufacturing record and
that you correctly performed each significant step in the manufacturing
process. If you did not create a batch production record for each batch
production that accurately followed the master manufacturing record,
you would not be sure that your dietary ingredient or dietary
supplement was not adulterated. The master manufacturing record is
intended to ensure batch to batch uniformity and to prevent
adulteration. Your batch production record also may be valuable in the
event of a product recall. We seek comment on whether any of the
proposed requirements in this section are not necessary to prevent
adulteration and to ensure the identity, purity, quality, strength, and
composition of the dietary ingredient or dietary supplement. If
comments assert that certain provisions are not necessary, comments
should include an explanation of why the requirement is not necessary
including how, in the absence of the requirement, one can prevent
adulteration and ensure the identity, purity, quality, strength, and
composition of the dietary ingredient or dietary supplement. If
comments agree that the proposed requirements are necessary for reasons
other than those we have provided, the comments should so state and
provide an explanation.
In one case (Ref. 27), we found that a manufacturer had produced a
subpotent folic acid product. When the manufacturer reviewed the batch
production records, it discovered that the bulk product was not mixed
properly, and this caused the folic acid to be distributed poorly
throughout the product. Thus, in this instance, the batch production
record helped identify the point in the manufacturing process when the
error occurred, and the reason why the error occurred and enabled the
manufacturer to correct the problem.
Review of batch production records might have prevented another
incident where several persons experienced dizziness, vomiting, or
lightheadedness after consuming vitamin and mineral products. As we
mentioned in our discussion of proposed Sec. 111.45, this incident
involved a mixup during the manufacturing process where the
manufacturer's master manufacturing record called for the use of a
product having 0.2 percent selenium by weight, but the manufacturer's
batch records showed that it used a product that had 5 percent selenium
by weight. This difference meant that the supplements, instead of
containing 200 [mu]g of selenium, contained between 400 to 4,699 [mu]g
of selenium. As discussed earlier, the quality control unit review and
approval of the master manufacturing record would have noted the change
in percent selenium by weight and the necessary changes to the master
manufacturing record could have been made. The quality control unit
review and approval of the batch production record provides another
check to ensure that a mixup has not occurred. Had the manufacturer's
quality control unit compared the master manufacturing record to the
batch production record, it would have noticed the mixup during the
manufacturing process and prevented the use of the higher percentage
selenium dietary ingredient. The information that would be required
under proposed Sec. 111.50(c) would help you determine what product
was manufactured, when it was manufactured, how it was manufactured,
and where it was manufactured. As another example, if your batch
production records identify the equipment and processing lines being
used, you would be able to go to that piece of equipment or to that
processing line and determine which dietary ingredient or dietary
supplement is being manufactured or processed. Further, if your batch
records reflect the initials of those persons who weighed a component,
added that specific component, and performed a particular step to
prevent adulteration of the product, you would be able to see who was
responsible for a particular action and, if necessary, to consult that
person in the event of a problem or to see how he or she performed a
particular task. In addition, if your batch production records contain
batch or lot numbers and if you later discover a problem with a
particular batch, that information will help you investigate the
problem by showing you the manufacturing history for that particular
batch.
A comment to the ANPRM stated that keeping written records of
equipment cleaning and use, including the date, product, and lot number
of each batch processed, would be burdensome compared to the benefits
it would provide, particularly when equipment is cleaned after each
use. The comment added that manufacturers can modify their production
records to note which machines they used.
We disagree with the comment. Written records will help you to
ensure that all cleaning operations are performed correctly and, if
problems do occur with the production of a product, will help you
determine whether those
[[Page 12207]]
problems are associated with maintenance, cleaning, or sanitizing
operations. Batch and lot information, as we stated earlier, will let
you identify batches or lots that may have been affected by any
equipment or utensil that was improperly maintained, cleaned, or
sanitized.
Proposed Sec. 111.50(d) and (e) would set forth your quality
control unit's responsibilities regarding batch production records.
These responsibilities relate to not only the review but the
documentation of their review and decisions about whether a batch could
be reprocessed. As we noted in our discussion of proposed Sec. 111.37,
the quality control unit has special knowledge and expertise to
determine if a batch is produced correctly, that those records are
complete, and that it is appropriate to reprocess a batch. The quality
control unit also serves as a quality control check that the batch
production record accurately follows the master manufacturing record. A
quality control unit review of batch production records could have
detected and corrected the previously discussed manufacturing error
caused by use of the dietary ingredient with the incorrect selenium.
Therefore, the review and documentation by the quality control unit of
batch production records provides the necessary quality assurance to
prevent the production of an adulterated dietary ingredient or dietary
supplement.
Specifically, proposed Sec. 111.50(d) would require your quality
control unit to review in accordance with Sec. 111.37(b)(5) the batch
production record. If a batch production record deviates from the
master manufacturing record, including any deviation from
specifications, proposed Sec. 111.50(d)(1) would require your quality
control unit to conduct a material review and make a disposition
decision and record any decision in the batch production record.
Proposed Sec. 111.50(d)(2) would instruct your quality control unit to
not approve and release for distribution any batch of dietary
ingredient or dietary supplement that does not meet all specifications.
Proposed Sec. 111.50(e) would require your quality control unit to
document in accordance with Sec. 111.37(c) the review performed in
accordance with proposed Sec. 111.50(d). The proposal would require
the quality control unit to document this review at the time it does
the review and would require the review and documentation to include,
but would not limit them to, the following:
[sbull] Review of component, dietary ingredient, and dietary
supplement receiving records including review of testing and
examination results;
[sbull] Identification of any deviation from the master
manufacturing record that may have caused a batch or any of its
components to fail to meet specifications identified in the master
manufacturing record;
[sbull] Records of investigations, conclusions, and corrective
actions performed in accordance with proposed Sec. 111.50(d); and
[sbull] The identity of the person qualified by training and
experience who performed the investigation in accordance with proposed
Sec. 111.50(d).
Proposed Sec. 111.50(f) would prohibit you from reprocessing a
batch that deviates from the master manufacturing record unless your
quality control unit approves it for reprocessing. Proposed Sec.
111.50(f) also would prohibit you from reprocessing a dietary
ingredient or dietary supplement if it is rejected because of
contamination with microorganisms of public health significance or
other contaminants, such as heavy metals because you cannot rely on
reprocessing to correct public health concerns that a product with
pathogens and/or heavy metals would present.
Proposed Sec. 111.50(g) would require that you meet all
specifications established in the master manufacturing record for any
batch of dietary ingredient or dietary supplement that is reprocessed
and would require your quality control unit to evaluate and approve the
batch before releasing for distribution. This requirement is intended
to ensure that a reprocessed batch is not subject to any lesser
specifications than are otherwise applicable to a nonreprocessed batch.
Proposed Sec. 111.50(g) also would require that you document the
results of the quality control unit's reevaluation in the batch
production record.
Proposed Sec. 111.50(h) would require that you collect
representative reserve samples of each batch of dietary ingredient or
dietary supplement and to keep the reserve samples for 3 years from the
date of manufacture for use in appropriate investigations including,
but not limited to, consumer complaint investigations to determine
whether, for example, the dietary ingredient or dietary supplement
associated with a consumer complaint failed to meet any of its
specifications for identity, purity, quality, strength, and
composition. Reserve samples also may prove helpful in investigating
possible tampering or counterfeiting of your products. We invite
comment on whether we should require, in a final rule, that you
identify each reserve sample with the batch number so that you can
readily identify the correct reserve sample in the event that there is
a problem with a particular batch.
Proposed Sec. 111.50(i) would require that you keep your batch
production records in accordance with proposed Sec. 111.125. The batch
production records in addition to the master manufacturing records will
ensure that a complete history of each batch of dietary ingredient or
dietary supplement is available for your review in the event that a
problem arises with a particular batch. These records also are
necessary to demonstrate compliance with the CGMP and quality control
procedures.
6. What Requirements Apply to Laboratory Operations? (Proposed Sec.
111.60)
Proposed Sec. 111.60 would establish various requirements for
laboratory operations. Proposed Sec. 111.60(a) would require that you
use adequate laboratory facilities to perform any necessary tests or
examinations to determine that components, dietary ingredients, and
dietary supplements you receive meet specifications; that
specifications are met during inprocess as specified in the master
manufacturing record; and that the dietary ingredients and dietary
supplements you manufacture meet their specifications.
One comment to the ANPRM recommended that the regulations related
to laboratory operations apply to laboratory facilities located and
operated within a company and those facilities that a company may
contract with that are located elsewhere. Proposed Sec. 111.60(a)
would apply to laboratory facilities generally and is not restricted to
laboratory facilities located and operated within a company. In other
words, even if you hire a private laboratory to perform various tests
for you, proposed Sec. 111.60(a) would require that you make sure that
the private laboratory's facilities are adequate to perform whatever
tests are necessary. The most important point in proposed Sec.
111.60(a), however, is not where the facility is located, but whether
the laboratory facility is adequate for the tests and examinations that
need to be done.
Proposed Sec. 111.60(b)(1) would require that you establish and
follow laboratory control processes that the quality control unit has
approved. For example, under proposed Sec. 111.60(b)(1)(i) and
(b)(1)(ii), the laboratory control processes would include use of
criteria for selecting appropriate testing and examination methods and
for establishing appropriate specifications. Specifications play an
important role in CGMP's because they may help
[[Page 12208]]
determine whether a dietary ingredient or dietary supplement is
adulterated.
Criteria for establishing appropriate specifications must be
specific to the component, dietary ingredient, or dietary supplement.
The specifications are the parameters that you must meet. For example,
for ascorbic acid, your specifications would include all the criteria
that you want your incoming dietary ingredient or for your finished
product to meet. For example, you might establish criteria for the
appearance, color, odor, identity using one or more tests, heavy metals
(e.g., lead, arsenic, mercury), and organic volatile impurities.
Similarly, criteria for selecting appropriate test and examination
methods include parameters such as type of tests and examinations
needed based on the component you receive. For example, you might use
morphological characters and organoleptic characteristics in some cases
to identify botanical dietary ingredients at the time of collection or
for unprocessed botanicals. When sufficient morphological characters
are present to separate the plant species from other plant species, an
accurate identification can be made since morphological characters are
the sole basis of distinguishing most of the world's plant species.
However, unprocessed botanicals that do not contain all the plant parts
necessary to include adequate morphological characters to assure the
correct species should have other identity aids or tests to assure the
identity of the botanical. It is possible to use only a picture as an
identity standard for whole fresh Ginkgo leaf from a cultivated field
because the Ginkgo leaf is not easily confused with the leaf shape,
venation, and color of other leaves that could be present in the field.
In contrast, powdered Ginkgo leaf is a different form of the dietary
ingredient and would require microscopic and/or chemical analysis.
Ginkgo extracts have no morphological or anatomical features, and it is
possible that extracts may include a number of chemical compounds at
different ratios and concentrations that would require a different
chemical test to assure the identity of the dietary ingredient.
Botanical dietary ingredients that come from wild rather than
cultivated sources may grow among and be unintentionally harvested with
``poisonous'' plants; therefore, an identity test also would need to
show whether a botanical dietary ingredient is adulterated with another
substance or a poisonous plant.
To illustrate this point, a specification may contain a simple
identity test, and these tests may show whether a dietary ingredient is
adulterated with another substance or is a poisonous plant that should
not be ingested. Misidentification or a mixup of botanical ingredients
can cause a product to be adulterated (Refs. 6 and 69 through 73).
Heavy metals may contaminate botanical and natural-occurring
ingredients if a plant is grown and harvested in an area contaminated
with heavy metals or even processed in a contaminated area (Refs. 74
and 75). Pesticides also may contaminate botanical ingredients; this
occurs in rural areas where the botanical plant grow alongside
commercial crops (Ref. 64). Therefore, you must consider what criteria
you need to include for the types of testing that are needed, for
example, for heavy metal or pesticide contamination, or identity
testing criteria for selecting appropriate test methods, for example,
whether to use organoleptic or chemical analyses for identity testing.
In addition, you must establish criteria for specifications for the
tests and examinations used. Establishing such criteria for
specifications and appropriate test and examination methods will
provide you with internal processes that will help prevent
misidentification and contamination.
Proposed Sec. 111.60(b)(1)(iii) would require your laboratory
control processes to include use of sampling plans for obtaining
representative samples of:
[sbull] Components, dietary ingredients, and dietary supplements
received;
[sbull] Inprocess materials during the batch manufacturing when
testing or examination is required in the master manufacturing record;
[sbull] Each batch of dietary ingredient or dietary supplement
manufactured to determine that the dietary ingredient or dietary
supplement meets specifications;
[sbull] Packaging and labels received to determine that the
materials meet specifications; and
[sbull] Each batch of packaged and labeled dietary ingredients or
dietary supplements to ensure that the label specified in the master
manufacturing record has been applied.
For example, a representative sample is important to being able to
have an adequate sample to detect contamination. Contamination may not
be distributed evenly throughout a product and may not be detected
without a representative number of units. Determining the size of a
representative sample is important because the sample size must be
large enough to meet your testing needs for specific types of
components, dietary ingredients, or dietary supplements, and packaging
and labels. Your sampling plans should include reserve samples, too,
because reserve samples will enable you to investigate and identify
possible manufacturing problems in the future. The proposal would not
specify any particular sampling plan; it would leave such details to
your discretion so that you can develop a sampling plan that suits your
products and your testing needs.
Proposed Sec. 111.60(b)(iv) through (b)(vi) would require the
laboratory control processes to include:
[sbull] Use of criteria for selecting standard reference materials
used in performing tests and examinations. An authenticated plant
reference material may be used as standard reference material in
performing certain organoleptic examinations. An authenticated plant
reference material is material that has been authenticated as the
correct plant species and correct plant part(s) by a qualified plant
taxonomist. As described earlier in this document, an organoleptic
examination may be an appropriate examination to confirm plant identity
when sufficient morphological characters are present to separate the
plant species from other plant species. For microscopic and chemical
tests, a reference material is a highly purified compound that is well
characterized, and you would use the reference material to perform
tests including calibration tests. In general, there are two types of
reference materials: (1) Compendial reference standards that do not
require characterization; and (2) noncompendial standards.
Noncompendial standards should be of the highest purity that can be
obtained by reasonable effort and should be thoroughly characterized to
assure their identity, purity, quality, and strength. Ideally, you
should use compendial reference standards whenever possible, but if no
compendial reference standard exists, you should establish
appropriately characterized inhouse materials prepared from
representative lots;
[sbull] Use of appropriate test method validations. Test method
validation determines whether a newly-developed or existing test method
is accurate, precise, and specific for its intended purpose. We have
discussed previously the terms ``accurate'' and ``precise.'' Validation
involves evaluating the test method on multiple occasions or in
multiple test facilities. Official methods, such as AOAC International
methods, are validated in collaborative studies using several
laboratories under identical conditions. The AOAC International methods
that are validated
[[Page 12209]]
in collaborative studies often are often cited as ``official validated
methods.'' If you modify an officially validated method, you should
document the reason for the modification and have data to show that the
modified method produced results that are at least as accurate and
reliable as the established method for material being tested. Further,
you should have complete records of any testing and standardization of
laboratory reference standards, reagents, and standard solutions that
you use in your laboratory operations. Proposed Sec. 111.25(b)(1)
would require calibration of laboratory instruments, apparatus, gauges,
and recording devices. Validated methods also exist in official
compendia for vitamins, minerals, and several botanicals, so you should
use validated methods whenever available. You may use validated methods
that can be found in official references, such as AOAC International,
USP and others. Other method validations are conducted using two or
three laboratories or in a single laboratory by repeating the same test
multiple times. Official and nonofficial method validations use similar
performance parameters in conducting method validations. If an official
validated method does not exist in an official reference, the method
you use may be validated by using multiple tests at your laboratory or
multiple laboratories performing the same test to document that the
intended use of the method is consistently fulfilled. You must validate
that the official or nonofficial method works under your conditions of
use in your setting. You also should conduct day-to-day validations of
the method that you use, whether it is an official validated method or
a less-formal validated method, under the conditions of use to ensure
that the method will provide the information you need to ensure that
your dietary ingredient or dietary supplement has the identity, purity,
quality, strength, and composition that it is supposed to have and is
thus not adulterated. Consistent, day-to-day test recoveries for the
reference material are one indicator that the analytical method is
working. There are at least two references that describe test method
validation performance parameters: (1) Performance parameters for
chromatographic methods are described in ``Reviewer Guidance,
Validation of Chromatographic Methods'' (Center for Drug Evaluation and
Research, FDA, November 1994) (Ref. 76); and (2) International
Conference on Harmonisation (ICH); Draft Guidance on Specifications:
Test Procedures and Acceptance Criteria for Biotechnological/Biological
Products (63 FR 31506, June 9, 1998); and
[sbull] Use of test methods in accordance with established
criteria. Your process for performing test methods criteria must
include sufficient detail, including the material you are testing, the
purpose of the test, and the test method. The description of the test
method criteria must include any reagents used and preparation
instructions, apparatus required, any instructions for preparing the
sample to be tested, and instructions for conducting the examination.
For example, if you receive components of plant origin from an outside
source, your specifications must indicate that you test those
components to verify that they are not contaminated with adulterants of
vegetable origin and to determine that the microscopic examination
method is appropriate for use. Further, you may decide that the AOAC
International Official Method 961.01 entitled ``Adulterants in Spices''
is the appropriate analytical method to detect the contaminant which is
a method to detect adulterants of vegetable origin in spices. Your test
methods criteria must specify the component, dietary ingredient, or
dietary supplement to be tested, and what specifically to test for,
e.g., the identity of the component, dietary ingredient, or dietary
supplement, or a specific contaminant. The method criteria must provide
detailed information about performing the analysis (i.e., the reagent
solutions needed and their preparation, the type of microscope and
other equipment required, preparing the sample, and examination
instructions). The proposed rule would not require that you test for
any specific substance and would not require a specific test for a
substance, so you would be able to evaluate what the most appropriate
test would be for the component, dietary ingredient, or dietary
supplement and to use the test methods that are suited to your products
and your manufacturing needs. Your test methodology must be specific
for the component, dietary ingredient, or dietary supplement and the
specifications you have established.
Proposed Sec. 111.60(b)(2) and (b)(3) would apply to documentation
and recordkeeping for your laboratory operations. Proposed Sec.
111.60(b)(2) would require the person who conducts the testing and
examination to document, at the time of performance, that they followed
the laboratory method and the testing and examination results. Proposed
Sec. 111.60(b)(3) would require that you keep laboratory testing and
examination records in accordance with proposed Sec. 111.125.
Laboratory records are necessary to ensure compliance with established
specifications and to demonstrate compliance with the CGMP and quality
control processes.
Proposed Sec. 111.60(c) would require that you verify that the
laboratory testing methodologies are appropriate for their intended
use.
Proposed Sec. 111.60(d) would require that you identify and use
the appropriate validated testing method to use for each established
specification for which testing is required to determine whether the
specification is met. In other words, the proposal would recognize that
requiring that you have testing methods is not sufficient alone; you
must also use those testing methods to prevent the adulteration of
dietary ingredients or dietary supplements.
We invite comment on whether we should require, in a final rule,
written procedures for your laboratory operations and should require
that the person who performs the laboratory processes document, at the
time of performance, that the laboratory processes were performed. If
comments assert that written procedures are necessary, comments should
include an explanation of why the requirement is necessary to prevent
adulteration including how such a requirement would ensure the
identity, purity, quality, strength, and composition of the dietary
ingredient or dietary supplement. Conversely, if comments assert that
written procedures are not necessary, comments should include an
explanation of why the requirement is not necessary including how, in
the absence of the requirement, one can prevent adulteration and ensure
the identity, purity, quality, strength, and composition of the dietary
ingredient or dietary supplement. Further, we seek comment on whether
any of the proposed requirements in this section are not necessary to
prevent adulteration and to ensure the identity, purity, quality,
strength, and composition of the dietary ingredient or dietary
supplement. If comments assert that certain provisions are not
necessary, comments should include an explanation of why the
requirement is not necessary including how, in the absence of the
requirement, one can prevent adulteration and ensure the identity,
purity, quality, strength, and composition of the dietary ingredient or
dietary supplement. If comments agree that the proposed requirements
are necessary for reasons other than those we have provided, the
comments should so state and provide an explanation.
[[Page 12210]]
7. What Requirements Apply to Manufacturing Operations? (Proposed Sec.
111.65)
Proposed Sec. 111.65 would require that you take all necessary
precautions to ensure that, during the manufacturing operations, you do
not create a source of possible contamination and that specifications
are consistently achieved.
Under proposed Sec. 111.65(a), you must design or select equipment
and processes to ensure that dietary ingredient or dietary supplement
specifications are consistently achieved. Frequently, a computer or
system of computers may control many or all stages of manufacturing
operations such as mixing, producing tablets, and packaging. It is
important that such systems and equipment function as expected to
ensure that the dietary ingredient or dietary supplement contains a
homogenous mixture, a tablet that is neither too hard or too friable,
and that the packaging contains the correct dietary ingredient or
dietary supplement. Equipment used in dietary ingredient or dietary
supplement manufacture, packaging, and label operations must be, for
example, of an appropriate size and installed properly in order to
produce an unadulterated product. If not designed or installed
properly, the equipment can result in a variety of problems. For
example, a mixer for the blending of powdered ingredients will not
properly perform its function if the blade is too small relative to the
size of the mixer or not properly placed inside of the mixer. Such a
mixer may produce an adulterated product because the dietary
supplement, for example, is not of uniform composition and therefore
would not be able to meet the specifications for purity, quality,
strength, or composition in the final product. Thus, equipment design
and selection is critical to ensure that you manufacture an
unadulterated dietary ingredient or dietary supplement.
Proposed Sec. 111.65(b) would require that you conduct all
manufacturing operations in accordance with adequate sanitation
principles. We discussed the importance of having adequate sanitation
earlier and related it to the use of sanitary practices for employees,
physical plant, and equipment.
Proposed Sec. 111.65(c)(1) through (c)(11) would require that you
take all the necessary precautions during the manufacture of dietary
ingredients and dietary supplements to prevent contamination of
components, dietary ingredients, and dietary supplements.
Proposed Sec. 111.65(c)(1) would require that you perform
manufacturing operations under conditions and controls that protect
against the potential for microorganism growth and the potential for
contamination. This would require that you conduct all operations in
receiving, inspecting, transporting, segregating, preparing,
manufacturing, packaging, sorting, and packing dietary ingredients and
dietary supplements in accordance with appropriate and established
sanitation procedures. Operations with poor sanitation in the
production and processing environment can significantly increase the
risk of contaminating components, dietary ingredients, or dietary
supplements. Pathogenic microorganisms may be found on the floors and
in the drains of the processing area and on all contact surfaces.
Without good sanitary practices, any surface that comes in contact with
components, dietary ingredients, and dietary supplements could be a
potential source of microbial contamination. Thus, using appropriate
sanitation procedures would provide conditions and controls to protect
against potential contamination and microbial growth.
Proposed Sec. 111.65(c)(2) would require that you wash or clean
components that contain soil or other contaminants. This is a basic
sanitation procedure to protect against contamination and microbial
growth. Raw agricultural materials and other components that contain
soil or other contaminants must be washed or cleaned as necessary.
Water quality used for washing, rinsing, or conveying raw agricultural
materials must be adequate for its intended use, both at the start and
at the end of the processing operation, and should not contribute to
the contamination of such materials.
Proposed Sec. 111.65(c)(3) would require that you use water that
meets the EPA's NPDW regulations or, where necessary, higher sanitary
quality and that complies with all applicable Federal, State, and local
regulations for water that is used in the manufacturing operation. If
you reuse water that was used to remove soil or contaminants from
components, the proposal would require that the reused water be safe
and of adequate sanitary quality so that it does not become a source of
contamination. Some manufacturing operations may require water of a
higher sanitary quality than water that meets the NPDW regulations. For
example, the fluoride or chloride levels in water meeting the NPDW
regulations may interfere with certain capsule or tablet operations and
a higher quality water such as distilled water may be necessary. This
proposed requirement allows the manufacturer discretion in determining
whether NPDW regulations or higher sanitary quality water is necessary
for a manufacturing operation.
Proposed Sec. 111.65(c)(4) would require that you perform
chemical, microbiological, or other testing, as necessary, to prevent
the use of contaminated components, dietary ingredients, and dietary
supplements. You should consider identifying those areas in the
processing and production areas where chemical, microbial, or other
forms of contamination are most likely to occur. Chemical, microbial,
or other testing is necessary to identify areas where sanitation
measures have not been adequate or where products may become
adulterated.
Proposed Sec. 111.65(c)(5) would require that you sterilize,
pasteurize, freeze, refrigerate, control hydrogen-ion concentration
(pH), control humidity, control water activity, or use any other
effective means to remove, destroy, or prevent the growth of
microorganisms and to prevent decomposition. The measures you decide to
use to remove, destroy or prevent the growth of microorganisms on or in
your components, dietary ingredients, or dietary supplements must be
appropriate under the conditions of manufacture, handling, and
distribution. Such measures are necessary to prevent their adulteration
and misbranding. Microorganisms include pathogenic bacteria that, if
present would adulterate the product. In addition, decomposition may
result in a change in the component, dietary ingredient, or dietary
supplement strength; the consequence of not using the appropriate
measure may be that the dietary ingredient or dietary supplement no
longer meets specifications, and thus, would be adulterated under
section 402(g) of the act and misbranded under section 403 of the act.
By including the phrase, ``any other effective means,'' we provide you
with discretion to decide which measures to use to destroy or prevent
the growth of microorganisms and to prevent decomposition.
Proposed Sec. 111.65(c)(6) would require that you hold components,
dietary ingredients, and dietary supplements that can support the rapid
growth of microorganisms of public health significance in a manner that
prevents them from becoming adulterated.
Proposed Sec. 111.65(c)(7) would require that you identify and
hold any components, dietary ingredients, and dietary supplements, that
require a material review and disposition decision, in a manner that
protects the components, dietary ingredients, and dietary supplements
against
[[Page 12211]]
contamination and mixups. A dietary ingredient or dietary supplement
under this proposed rule would require a material review and
disposition decision when the components, dietary ingredients, or
dietary supplements deviate from specifications. As previously
explained, the specifications established as production and process
controls under proposed subpart E of part 111, are regulatory
specifications. Thus, a deviation from such a specification means that
the components, dietary ingredients, or dietary supplements may be
adulterated. Any component, dietary ingredient, or dietary supplement
that may be adulterated must be segregated from such material that
meets specifications so that it does not become a source of
contamination. The proposal would require that you hold these
components, dietary ingredients, and dietary supplements in a manner
that protects against contamination and mixups.
Proposed Sec. 111.65(c)(8) would require that you perform
mechanical manufacturing steps (such as cutting, sorting, inspecting,
shredding, drying, grinding, blending, and sifting) by any effective
means to protect the dietary ingredients or dietary supplements against
contamination. Such steps must include consideration of cleaning and
sanitizing contact surfaces, using temperature controls, and using time
controls. For example, when blending components, if you use a mixer
that has not been cleaned and sanitized, your blended material may
become contaminated with microorganisms, including microbial pathogens.
Thus, it is important to clean and sanitize your mixer before use.
Proposed Sec. 111.65(c)(9) would require that you use effective
measures, such as filters, traps, magnets, or electronic metal
detectors, to protect against the inclusion of metal or other foreign
material in your components, dietary ingredients, or dietary
supplements. This proposed requirement is intended to exclude foreign
and extraneous matter that would contaminate components, dietary
ingredients, or dietary supplements. The purpose of this proposed
requirement is not to exclude dietary ingredients that are intended to
be used and that are of mineral origin.
One comment to the ANPRM suggested that we require the use of
effective measures to protect against the inclusion of metal or other
extraneous material in dietary products when there is reason to suspect
that the product is contaminated by metal or other extraneous material.
The comment stated that manufacturers typically are able to identify
the particular piece of equipment that is the source of the metal
contamination.
We disagree with the comment. The purpose behind proposed Sec.
111.65(c)(9) is to ensure that no metal or foreign material becomes a
source of possible contamination and not to establish mechanisms to be
used after contamination has or is suspected to have occurred. We
believe that the most practical way to protect against the inclusion of
metal and foreign material is to require that you use effective
measures during the manufacturing operations. The source of metal
contamination is not limited to equipment and we previously emphasize
the need to maintain equipment to prevent such contamination. Metal
contamination also may occur during harvesting of natural products and
use of utensils such as metal brushes. Therefore, because we believe
that it is not possible to identify and eliminate all possible sources
of metal contamination or to determine when measures would be necessary
to eliminate such contamination, proposed Sec. 111.65(c)(9) would
require that you use effective measures to protect against the
inclusion of metal and foreign material for all your manufacturing
operations.
Proposed Sec. 111.65(c)(10) would require that you segregate and
identify all containers for a specific batch of dietary ingredients or
dietary supplements to identify their contents and, where necessary,
the phase of manufacturing. This proposed requirement is intended to
protect ingredients or dietary supplements from potential contamination
or misuse during manufacturing or storage. Identifications of these
items will enable you to determine accurately the status of all batches
of dietary ingredients or dietary supplements during all stages of the
manufacturing process, will help to prevent mixups in the addition of
components or dietary ingredients to the dietary supplement and will
facilitate prompt action if any problems in processing are identified.
Proposed Sec. 111.65(c)(11) would require that you identify all
processing lines and major equipment used during manufacturing and to
indicate their contents, including the name of the dietary ingredient
or dietary supplement and the specific batch or lot number and, when
necessary, the phase of manufacturing. The same reasons given for
proposed Sec. 111.65(c)(10) apply to this proposed requirement.
Proposed Sec. 111.65(d) would require that you conduct a material
review and make a disposition decision in accordance with proposed
Sec. 111.35(i) for any component, dietary ingredient, or dietary
supplement that fails to meet specifications or that is, or may be,
adulterated. If the material review and disposition decision allows you
to reprocess the component, dietary ingredient, or dietary supplement,
proposed Sec. 111.65(d) would require that you retest or reexamine it
to ensure that it meets specifications and is approved by the quality
control unit.
The person who performs the material review and disposition review
required in accordance with this section would be required to document
at the time of performance the results of the material review and
disposition decision. In accordance with Sec. 111.50(d), such
documentation must be maintained with the batch production record.
We invite comment on whether we should require, in a final rule,
that you establish and follow written procedures to implement the
manufacturing operations required in proposed Sec. 111.65. If comments
assert that written procedures are necessary, comments should include
an explanation of why the requirement is necessary to prevent
adulteration including how such a requirement would ensure the
identity, purity, quality, strength, and composition of the dietary
ingredient or dietary supplement. Conversely, if comments assert that
written procedures are not necessary, comments should include an
explanation of why the requirement is not necessary including how, in
the absence of the requirement, one can prevent adulteration and ensure
the identity, purity, quality, strength, and composition of the dietary
ingredient or dietary supplement. Further, we seek comment on whether
any of the proposed requirements in this section are not necessary to
prevent adulteration and to ensure the identity, purity, quality,
strength, and composition of the dietary ingredient or dietary
supplement. If comments assert that certain provisions are not
necessary, comments should include an explanation of why the
requirement is not necessary including how, in the absence of the
requirement, one can prevent adulteration and ensure the identity,
purity, quality, strength, and composition of the dietary ingredient or
dietary supplement. If comments agree that the proposed requirements
are necessary for reasons other than those we have provided, the
comments should so state and provide an explanation.
[[Page 12212]]
8. What Requirements Apply to Packaging and Label Operations? (Proposed
Sec. 111.70)
Proposed Sec. 111.70 would establish requirements for your
packaging and label operations. The correct use of packaging and labels
can affect whether your product is adulterated. For example, if a
packaging material, intended only for use with a dry product, is used
to package a liquid, unsafe substances could migrate from the packaging
to the liquid, and adulterate your dietary ingredients or dietary
supplements. In addition, if you apply the wrong label, your product
would be adulterated under section 402(g) of the act because your label
must be that which is specified in the master manufacturing record. In
addition, your product would be misbranded under section 403 of the
act.
Proposed Sec. 111.70(a) would require that you take necessary
actions to ensure each packaging container for holding dietary
ingredients or dietary supplements meets its specifications so that the
packaging container's condition will not contaminate your dietary
ingredients or dietary supplements or cause them to deteriorate. As
previously stated in the discussion of proposed Sec. 111.35(e)(4), you
must establish specifications for packaging materials that may come in
contact with dietary ingredients or dietary supplements. Meeting such
specifications would ensure that the packaging that is used is safe and
suitable for the intended use and meets all of the statutory and
regulatory requirements under the act. In that way, the packaging
materials will not adulterate the dietary ingredient or dietary
supplement. This proposed requirement would give you the discretion to
establish the specifications for each packaging container, and would
require that these specifications are routinely met. For example, if
your product is sensitive to light, you would choose a container that
protects the product from the light so that it does not deteriorate.
Proposed Sec. 111.70(b) would require that you fill, assemble,
package, and perform other related operations in a way that protects
your dietary ingredients or dietary supplements against adulteration
and misbranding. The proposal would require that you use any effective
means to do this, which would include:
[sbull] Cleaning and sanitizing all filling and packaging
equipment, utensils, and dietary ingredient or dietary supplement
containers, as appropriate. This is important because cleaning and
sanitizing all filling and packaging equipment can help you avoid some
common mistakes that can adulterate your products. For example, in one
case, a consumer complained about receiving two different sized
capsules in a bottle labeled as containing acidophilus capsules. We
conducted an investigation and found that the manufacturer had received
a similar report from a different consumer (Ref. 77). We analyzed the
capsules and found that the smaller capsules were not acidophilus
capsules but contained levels of stannous fluoride that would cause
convulsions in certain persons and even exceeded the lethal dose in
small children. We also collected unopened bottles of the acidophilus
product and, after opening the product, found different sized capsules.
The presence of smaller capsules containing stannous fluoride mixed in
with the larger acidophilus capsules adulterated the product. The fact
that these small stannous fluroride capsules mixed in with the larger
acidophilus capsules indicated that the manufacturer had not cleaned
the filling equipment properly.
In another case, consumer complaints about a vitamin C product
prompted us and the product's manufacturer to investigate the product
(Ref. 78). We both discovered that the products contained niacin
instead of vitamin C, and the problem was the result of a failure to
clean out the packaging equipment so that niacin that had been left in
the packaging equipment was put into the capsules during the
manufacturing operation for the vitamin C product. The manufacturer
reviewed its packing operations and instructed its personnel at the
manufacturing plant to prevent this problem from reoccurring.
[sbull] Protecting manufactured dietary ingredients and dietary
supplements from contamination, particularly airborne particulates such
as dust, dirt, or microbes that may contaminate your product when your
product is exposed to the environment.
[sbull] Using sanitary handling procedures.
[sbull] Establishing physical or spatial separation of packaging
and labels from operations on other dietary ingredients and dietary
supplements to prevent mixups. It is important to keep inprocess
material separate from finished product that is ready to be packaged
and labeled so that inprocess material is not inadvertently packaged
and labeled as finished product. In addition, this proposed requirement
would prevent mixup of one type of dietary ingredient with another type
of dietary ingredient during packaging and label operations such as the
vitamin C and niacin mixup described earlier.
[sbull] Identifying, by any effective means, filled dietary
ingredient or dietary supplement containers that are set aside and held
in unlabeled condition for future label operations, to prevent mixups;
[sbull] Identifying the dietary ingredient or dietary supplement
with a batch, lot, or control number that can be used to determine the
manufacturing history and control of the batch. Using a unique
identifier for each batch or lot is necessary for you to trace the
manufacturing history for a particular batch, and thus help you
investigate and correct any safety problems for a batch or to recall a
dietary ingredient or dietary supplement batch. For example, if you
discovered a particular batch had a safety problem, you could recall
the batch by identifying the batch number for the problem product. If
you did not have a unique identifier, consumers would be unable to
determine which product was the subject of a recall, and they may not
stop using the product or you will have to recall more of the product.
[sbull] Examining a representative sample of the packaged and
labeled dietary ingredient or dietary supplement to ensure that it
meets specifications and that the label specified in the master
manufacturing record has been applied; and
[sbull] Suitably disposing of labels and other packaging for
dietary ingredients or dietary supplements that are obsolete or
incorrect to ensure that they are not used in any future packaging and
label operations. The use of any obsolete or incorrect label would
adulterate the product because it would not comply with the requirement
that the correct label as specified in the master manufacturing record
be used.
Proposed Sec. 111.70(c) would require that you conduct a material
review and make a disposition decision of any packaged and labeled
dietary ingredients or dietary supplements that do not meet
specifications. If packaged and labeled dietary ingredients or dietary
supplements do not meet specifications, it means that there is a
problem and that the dietary ingredient or dietary supplement may be or
is adulterated and this step is needed to determine what to do and how
to handle the product to ensure that it does not get distributed.
Sometimes problems arise because a manufacturer used the wrong
label on a particular ingredient. For example, in one case, an
ingredient manufacturer put the wrong label on its product so that a
product labeled as containing zinc picolinate actually contained zinc
polynicotinate (Ref. 79). The dietary
[[Page 12213]]
ingredient went to another manufacturer who, believing that the product
was zinc picolinate, used the dietary ingredient to make its dietary
supplement. The error was discovered after consumers who used the
product started complaining of adverse reactions that are associated
with niacin supplements, but the problem could have been avoided if the
dietary ingredient manufacturer had taken steps to ensure that the
correct labels were used.
Proposed Sec. 111.70(d) would require that you repackage or
relabel dietary ingredients or dietary supplements if approved and
appropriately documented by your quality control unit. The quality
control unit would need to decide whether the improperly packaged
product was adulterated by the incorrect package and could be
repackaged and relabeled without reprocessing of the dietary ingredient
or dietary supplement.
Proposed Sec. 111.70(e) would require that you retest or reexamine
any repackaged or relabeled dietary ingredients or dietary supplements.
They must meet all specifications and the quality control unit must
approve or reject their release for distribution. The reason this is
necessary is to ensure for example, by testing or examination, that the
repackaged or relabeled product meets specifications and that the
container in which the product is repackaged meets specifications.
Proposed Sec. 111.70(f)(1) would require that you control the
issuance and use of packaging and labels and reconcile the issuance and
use of discrepancies. It is important to control access to the storage
of packaging and labels; for example, only the labels that are required
for current label operations should be issued to prevent issuance of
any incorrect labels during the label operation. Using batch or lot
numbers on your labels may be one control method. Batch or lot numbers
also help you (and us) to identify a particular product and to trace
that product's manufacturing history through your CGMP records. They
can help identify which products are affected by a product recall, if a
recall is necessary, and this can help preserve consumer confidence in
your product.
For example, if a recall covers batch A123, and a particular
consumer has a product whose batch number is C456, he or she will know
that the product is not covered by the recall. In contrast, if no batch
numbers appear on the product label, the consumer would not be able to
tell whether his or her product is covered by the recall and may
continue to use it.
As another example, controlling access of labels can help identify
instances when mislabeling may have occurred. If you issue only the
necessary number of labels to cover a particular production run but use
fewer labels than expected even though you labeled the expected number
of containers for the production run, this discrepancy would suggest
that you used some wrong labels during the run and that you should
conduct an investigation to determine the cause of, or reconcile the
discrepancy.
Proposed Sec. 111.70(f)(2) would require that you must examine
carefully, before packaging operations, packaging and labels for each
batch of dietary ingredient or dietary supplement to ensure that the
label and packaging conform to the master manufacturing record.
Proposed Sec. 111.70(g) would require that the person who performs
the requirement established in accordance with this section document,
at the time of performance, that he or she performed the requirement.
This would include, but not be limited to, documentation in the batch
production record of:
[sbull] The identity and quantity of the packaging and labels used
and reconciliation of any discrepancies between issuance and use;
[sbull] The examination of a representative sample (as proposed
Sec. 111.70(b)(7) would require);
[sbull] The conclusions you reached from retests conducted under
proposed Sec. 111.70(e); and
[sbull] Any material reviews and disposition decisions for
packaging and labels.
Proposed Sec. 111.70(h) would require that you keep the packaging
and label operations records required under this section established in
accordance with proposed Sec. 111.125. These records are necessary to
ensure that the correct packaging and label, i.e., the packaging and
label specified by the master manufacturing record, were used in and
applied to the batch of dietary ingredient or dietary supplement. These
records together with the master manufacturing records and batch
production records will ensure that a complete history of each batch of
dietary ingredient or dietary supplement including use of the correct
packaging and label is available for your review in the event that a
problem arises with a particular batch. These records also are
necessary to demonstrate compliance with the CGMP and quality control
procedures. We invite comment on whether we should require, in a final
rule, that you establish and follow written procedures for packaging
and label operations that implement the requirements of this section.
If comments assert that written procedures are necessary, comments
should include an explanation of why the requirement is necessary to
prevent adulteration including how such a requirement would ensure the
identity, purity, quality, strength, and composition of the dietary
ingredient or dietary supplement. Conversely, if comments assert that
written procedures are not necessary, comments should include an
explanation of why the requirement is not necessary including how, in
the absence of the requirement, one can prevent adulteration and ensure
the identity, purity, quality, strength and composition of the dietary
ingredient or dietary supplement. Further, we seek comment on whether
any of the proposed requirements in this section are not necessary to
prevent adulteration and to ensure the identity, purity, quality,
strength, and composition of the dietary ingredient or dietary
supplement. If comments assert that certain provisions are not
necessary, comments should include an explanation of why the
requirement is not necessary including how, in the absence of the
requirement, one can prevent adulteration and ensure the identity,
purity, quality, strength, and composition of the dietary ingredient or
dietary supplement. If comments agree that the proposed requirements
are necessary for reasons other than those we have provided, the
comments should so state and provide an explanation.
9. What Requirements Apply to Rejected Components, Dietary Ingredients,
Dietary Supplements, Packaging, and Labels? (Proposed Sec. 111.74)
Proposed Sec. 111.74 is intended to ensure that you do not
mistakenly use rejected materials that are determined by the quality
control unit to be unsuitable for use to make a dietary ingredient or
dietary supplement.
Proposed Sec. 111.74(a) would require that you clearly identify,
hold, and control, under a quarantine system any component, dietary
ingredient, dietary supplement, packaging, and label that is rejected
and unsuitable for use in manufacturing, packaging, or label
operations. The term ``control under a quarantine system'' indicates
that you must prevent the use of any rejected component, dietary
ingredient, dietary supplement, packaging, or label because such
rejected product is unsuitable for use. For example, under this
proposed rule, if a component, dietary ingredient, or dietary
supplement is rejected and determined by the quality control unit
[[Page 12214]]
to be unsuitable for use, such material would be adulterated and not be
suitable for reprocessing. Therefore, to prevent contamination of
nonrejected material, you must quarantine the rejected material before
disposal. The proposed rule would not specify any particular mechanism
for how you quarantine the material, instead, you would have discretion
in deciding what actions to take or what process to use.
You also should note that, by referring to items that are rejected
and unsuitable for use, proposed Sec. 111.74(a) excludes items that
can be reprocessed and made suitable for use. Those items that can be
reprocessed and made suitable for use are dealt with in proposed Sec.
111.82.
F. Holding and Distributing (Proposed Subpart F)
1. What Requirements Apply to Holding Components, Dietary Ingredients,
Dietary Supplements, Packaging, and Labels? (Proposed Sec. 111.80)
Proposed Sec. 111.80 would require that you hold dietary
ingredients and dietary supplements under conditions that will protect
them against contamination and deterioration. Proposed Sec. 111.80(a)
would require that you hold components, dietary ingredients, and
dietary supplements under appropriate conditions of temperature,
humidity, and light so that the identity, purity, quality, strength,
and composition of the components, dietary ingredients, and dietary
supplements are not affected. This proposed provision includes the
holding of components, dietary ingredients, dietary supplements in your
physical plant and at any point in the distribution process, however,
we would not extend the holding requirements under this proposed CGMP
regulation to retail establishments, but would defer to State and local
governments for regulating operations that provide dietary supplements
to retail for sale to the consumer. However, if a retail holding area
is filthy, we would not be prevented from taking an enforcement action
under a legal authority other than section 402(g) of the act.
This requirement would ensure that products are not contaminated
while they are held by the manufacturer, the wholesaler, or while being
held at a warehouse. This would increase the likelihood that the
products consumers purchase have the same quality as when they left the
manufacturer. Note that proposed Sec. 111.80(a) uses the words ``not
affected;'' this means that the conditions under which you hold
components, dietary ingredients, and dietary supplements must not
adulterate the components, dietary ingredients, or dietary supplements.
For example, dried plants stored in a hot, humid warehouse may become
moldy. Mold contamination could adversely affect the purity of the
dietary ingredients and dietary supplements you manufacturer. You will
decrease the chances of mold contaminating your dried plants if you
control temperature and humidity.
Proposed Sec. 111.80(b) would require that you hold packaging and
labels under appropriate conditions of temperature, humidity, and light
so that the quality of the packaging and labels are not affected. For
example, some plastics become brittle when exposed to extreme
temperatures. If brittle plastic containers are used to hold dietary
ingredients or dietary supplements, they could crack or break, thereby
losing their protective qualities, and lead to contamination or
deterioration of the dietary ingredient or dietary supplement. You need
to know the conditions of temperature, humidity, and light that are
appropriate for your packaging and labels and you need to hold the
packaging and labels under such conditions.
Proposed Sec. 111.80(c) would require that you hold components,
dietary ingredients, dietary supplements, packaging, and labels under
conditions that do not lead to mixup, contamination, or deterioration
of the components, dietary ingredients, dietary supplements, packaging,
and labels. For example, your holding conditions must include a system
for identifying container contents and its status (e.g., segregated,
approved for use) in a manner that prevents mixup or use of unsuitable
materials in manufacturing. Further, the presence of rodents in your
holding area may cause contamination or deterioration of components,
dietary ingredients, dietary supplements, packaging, and labels.
Therefore, your holding conditions must be rodent-free. Moreover,
rodents in your holding area would adulterate your dietary ingredient
or dietary supplement under section 402(g) of the act. Holding
conditions that prevent mixup, contamination, or deterioration of
components, dietary ingredients, dietary supplements, packaging, or
labels are necessary to prevent the production of an adulterated
dietary ingredient or dietary supplement.
We invite comment on whether we should require, in a final rule,
that you establish and follow written procedures for holding
components, dietary ingredients, dietary supplements, packaging, and
labels. If comments assert that written procedures are necessary,
comments should include an explanation of why the requirement is
necessary to prevent adulteration including how such a requirement
would ensure the identity, purity, quality, strength, and composition
of the dietary ingredient or dietary supplement. Conversely, if
comments assert that written procedures are not necessary, comments
should include an explanation of why the requirement is not necessary
including how, in the absence of the requirement, one can prevent
adulteration and ensure the identity, purity, quality, strength, and
composition of the dietary ingredient or dietary supplement.
2. What Requirements Apply to Holding Inprocess Material? (Proposed
Sec. 111.82)
Proposed Sec. 111.82 discusses proposed requirements for holding
inprocess material. Proposed Sec. 111.82 would require that you
segregate any inprocess material that does not meet your
specifications, is awaiting further processing, or needs further
evaluation by the quality control unit (e.g., because the inprocess
material does not meet specifications, or because of an unexpected
occurrence) to determine if it is suitable for reprocessing.
Proposed Sec. 111.82(a), therefore, would require that you
identify and hold inprocess material under conditions that will protect
such material against mixup, contamination, and deterioration.
Proposed Sec. 111.82(b) would require that you hold inprocess
material under appropriate conditions of temperature, humidity, and
light. The intent here is to prevent any contamination or deterioration
of that inprocess material.
We invite comment on whether we should require, in a final rule,
that you establish and follow written procedures for holding inprocess
material. If comments assert that written procedures are necessary,
comments should include an explanation of why the requirement is
necessary to prevent adulteration including how such a requirement
would ensure the identity, purity, quality, strength, and composition
of the dietary ingredient or dietary supplement. Conversely, if
comments assert that written procedures are not necessary, comments
should include an explanation of why the requirement is not necessary
including how, in the absence of the requirement, one can prevent
adulteration and ensure the identity, purity, quality, strength, and
composition of the dietary ingredient or dietary supplement.
[[Page 12215]]
3. What Requirements Apply to Holding Reserve Samples of Components,
Dietary Ingredients, and Dietary Supplements? (Proposed Sec. 111.83)
Earlier, we discussed a provision concerning the collection of
reserve samples. Proposed Sec. 111.50(h) would require that you
collect representative reserve samples of each batch of dietary
ingredient or dietary supplement. Proposed Sec. 111.83 would set forth
requirements for holding any reserve samples collected.
Proposed Sec. 111.83(a) would require that you hold any reserve
samples of components or dietary ingredients collected in a manner that
protects against contamination and deterioration.
Proposed Sec. 111.83(b) would require that you hold such reserve
samples of dietary supplements in a manner that protects against
contamination and deterioration. Further, this provision would require
that you hold the reserve samples under conditions of use recommended
or suggested in the label of the dietary supplement and, if no
conditions of use are recommended or suggested in the label, then under
ordinary conditions of use. This proposed requirement also would
require that you use the same container-closure system in which the
dietary supplement is marketed or one that provides the same level of
protection against contamination or deterioration as the marketed
container-closure system. It is necessary to hold the reserve sample of
a dietary supplement under the same conditions and in the same
packaging as you would expect a consumer to hold that dietary
supplement so that, if you need to later test that reserve sample, the
testing would reflect current conditions under which the dietary
supplement is held by the consumer prior to being consumed.
4. What Requirements Apply to Returned Dietary Ingredients or Dietary
Supplements? (Proposed Sec. 111.85)
Proposed Sec. 111.85 would establish requirements for returned
dietary ingredients or dietary supplements. ``Returned'' dietary
ingredients or dietary supplements are those products that a
distributor, wholesaler, or retailer returns to a manufacturer.
Proposed Sec. 111.85(a) would require that you identify returned
dietary ingredients or dietary supplements and to quarantine them until
your quality control unit conducts a material review and makes a
disposition decision. (Your quality control unit would do this under
proposed Sec. 111.37.) For example, you could attach a tag or other
identifier on the returned dietary ingredient or dietary supplement to
show that it is ``returned.'' We would require that you identify and
quarantine (not just identify and segregate) returned dietary
ingredients or dietary supplements so that they cannot be used. We
propose to require that you quarantine returned products because you
must assume that the returned product is adulterated until tests show
otherwise. Thus, the product should not have physical closeness or
contact with nonreturned product to ensure that it will not be mixed up
mistakenly with nonreturned product, redistributed or reused in
manufacturing.
Proposed Sec. 111.85(b)(1) states that you may salvage returned
dietary ingredients and dietary supplements only if:
[sbull] Evidence from their packaging (or, if possible, an
inspection of the premises where the dietary ingredients and dietary
supplements were held) indicates that the dietary ingredients and
dietary supplements were not subjected to improper storage conditions.
This would require that you have personal knowledge of the exact
conditions under which the returned dietary ingredients or dietary
supplements were held. Normally, for most types of packaging, simply
examining the packaging will not tell you about the storage conditions
that existed. However, we are aware of some technologies that are being
used, such as temperature-sensitive materials that change colors, that
could provide some information about storage conditions; and
[sbull] Tests demonstrate that the dietary ingredients or dietary
supplements meet all specifications for identity, purity, quality,
strength, and composition. This requirement will ensure that you do not
return to distribution a dietary ingredient or dietary supplement that
does not meet specifications. Salvage is available for only those
products for which testing can be performed on finished product.
For purposes of this discussion, ``salvage'' means to return to
distribution without reprocessing the dietary ingredient or dietary
supplement.
Proposed Sec. 111.85(c) would require that you destroy or suitably
dispose of the returned dietary ingredients or dietary supplements if
they do not meet specifications for identity, purity, quality,
strength, and composition, unless the quality control unit conducts a
material review and makes a disposition decision to allow reprocessing.
Proposed Sec. 111.85(d) would require that you conduct an
investigation of your manufacturing processes and those other batches
if the reason for a dietary ingredient or a dietary supplement being
returned implicates other batches. The point of the investigation would
be to determine whether, for example, the other implicated batches may
have the same problem or have been subject to the same problematic
manufacturing process for which the dietary ingredient or dietary
supplement was returned. Other batches may be implicated if the
component or dietary ingredient used in the returned product also was
used in additional batches or if your investigation indicates that
there was a problem with a step in the manufacturing process that
affected additional batches. The proposal also would require that you
document the investigation and include your conclusions and followup.
Proposed Sec. 111.85(e) would require you to establish and keep
records for any material review and disposition decision and any
required testing to determine compliance with specifications done for
any returned dietary ingredient or dietary supplement. You should
include the following information in your records:
[sbull] The name of the person or company or both the name of the
person and company who returned the dietary ingredients or dietary
supplements;
[sbull] A description of the returned dietary ingredient or dietary
supplement;
[sbull] The batch or lot number of the returned dietary ingredient
or dietary supplement and any reprocessed batch or batch manufactured
using the returned dietary ingredient or dietary supplement;
[sbull] The reason for the return;
[sbull] The quantity returned;
[sbull] The disposition of the dietary ingredient or dietary
supplement; and
[sbull] The date of disposition.
Proposed Sec. 111.85(f) would require that you make and keep
records for returned dietary ingredients and dietary supplements in
accordance with Sec. 111.125. These records are necessary to ensure
that returned products that could be adulterated are not inadvertently
redistributed or inadvertently used in manufacturing. Further, records
of any reprocessed batch or batch manufactured using the returned
product will be useful in the event that a problem arises with a
particular batch that is manufactured with returned product. These
records also are necessary to demonstrate compliance with the CGMP and
quality control procedures. We invite comment on whether we should
require, in a final rule, that you establish and follow
[[Page 12216]]
written procedures for identifying, quarantining, and salvaging
returned dietary ingredients and dietary supplements. If comments
assert that written procedures are necessary, comments should include
an explanation of why the requirement is necessary to prevent
adulteration including how such a requirement would ensure the
identity, purity, quality, strength, and composition of the dietary
ingredient or dietary supplement. Conversely, if comments assert that
written procedures are not necessary, comments should include an
explanation of why the requirement is not necessary including how, in
the absence of the requirement, one can prevent adulteration and ensure
the identity, purity, quality, strength, and composition of the dietary
ingredient or dietary supplement.
5. What Requirements Apply to Distributing Dietary Ingredients or
Dietary Supplements? (Proposed Sec. 111.90)
Proposed Sec. 111.90 would establish requirements concerning the
distribution of dietary ingredients and dietary supplements. Proposed
Sec. 111.90(a) would require any distribution of dietary ingredients
or dietary supplements to be under conditions that will protect them
from contamination and deterioration. This is to protect dietary
ingredients and dietary supplements from distribution practices that
may adulterate them.
As discussed previously, proposed part 111 also would apply to
foreign firms that manufacture, package, or hold dietary ingredients
and dietary supplements that are imported or offered for import into
the United States, unless imported for further processing and export
under section 801(d)(3) of the act. It also would apply to persons who
distribute imported dietary ingredients and dietary supplements, and to
persons who export dietary ingredients and dietary supplements from the
United States unless exported in compliance with section 801(e) of the
act.
We recognize that the safety of dietary supplements cannot be
adequately ensured if the imports are not subject to the same controls
as domestic products. In addition, we believe that the importer who
distributes a foreign product should share responsibility with the
foreign manufacturer for safety. More often than not, it is a U.S.
importer, rather than the foreign manufacturer, who actually
distributes imported dietary supplements for sale in the United States.
Thus, we believe that importers of dietary ingredients or dietary
supplements should take steps to ensure that their shipments are
obtained from manufacturers that follow these proposed CGMP
requirements.
In addition, these proposed CGMPs would apply to manufacturers who
export their dietary ingredient or dietary supplement, unless exported
in compliance with section 801(e) of the act. Section 801(e)(1) of the
act states that a food intended for export must not be deemed to be
adulterated or misbranded under the act if it:
[sbull] Accords to the foreign purchaser's specifications;
[sbull] Is not in conflict with the laws of the country to which it
is intended for export;
[sbull] Is labeled on the outside of the shipping package that it
is intended for export; and
[sbull] Is not sold or offered for sale in domestic commerce.
Dietary ingredients and dietary supplements for export are subject
to section 801(e)(1) of the act and would be subject to the
notification and recordkeeping requirements of Sec. 1.101 (21 CFR
1.101) and you would be required to comply with the export requirements
of Sec. 1.101.
We invite comment on whether we should require, in a final rule,
that you make and keep records on the distribution of dietary
ingredients and dietary supplements that you manufacture, package, or
hold.
G. Consumer Complaints--What Requirements Apply to Consumer Complaints?
(Proposed Subpart G, Sec. 111.95)
Proposed Sec. 111.95 would establish requirements for receiving
and handling consumer complaints. Consumer complaints can be helpful in
alerting you to possible manufacturing and safety problems associated
with your dietary ingredients or dietary supplements.
As stated in Sec. 111.3, consumer complaint refers to a possible
failure of a dietary ingredient or dietary supplement to meet any of
the requirements of this part, including those that, if not met, may
result in a possible risk of illness or injury. Proposed Sec.
111.95(e) would require that you keep a written record of every
consumer complaint that is related to good manufacturing practices.
Thus, whether the complaint was sent by regular mail, electronic mail,
or any other form of written communication, or whether received orally,
you would be required to keep a written record of each consumer
complaint. You should include all information that would allow your
quality control unit to determine whether an investigation of the
complaint is necessary.
Proposed Sec. 111.95(a) would require that you have a qualified
person review all consumer complaints to determine whether the consumer
complaint involves a possible failure of a dietary ingredient or
dietary supplement to meet any of its specifications, or any other
requirements of this part, including those specifications and other
requirements that, if not met, may result in a possible risk of illness
or injury. A ``qualified person'' would be a person who has the
training and experience to determine whether a complaint represents a
possible failure of a dietary ingredient or dietary supplement to meet
any of the requirements in this part, or represents a possible risk of
illness or injury that is unrelated to such failure. The qualified
person's review is important for distinguishing between those consumer
complaints that your quality control unit must review and those
consumer complaints that represent a consumer's dissatisfaction with a
dietary ingredient or dietary supplement that is unrelated to a
possible failure to meet specifications that would be required by this
proposal, or any other requirement in this part. For example, some
consumer complaints about quality may simply express a personal dislike
of the taste, color, odor, or size of tablet, which would probably not
require your quality control unit to review them. As stated earlier,
consumer complaints related to an illness or injury related to a
pharmacologically active substance of a particular dietary ingredient,
such as aristolochic acid, would not be a consumer complaint within the
meaning of that term in this proposal and thus would not be of the type
that the quality control unit must review under this proposed rule.
Proposed Sec. 111.95(b) would require that your quality control
unit review all consumer complaints involving the possible failure of a
dietary ingredient or dietary supplement to meet any of its
specifications, or any of the other requirements in this part,
including those specifications and other requirements that, if not met,
may result in a possible risk of illness or injury, to determine
whether there is a need to investigate the consumer complaint. When
there is a reasonable possibility of a relationship between the quality
of a dietary supplement and an adverse event, such as a report of an
illness or injury that may be due to a wrong ingredient or wrong label,
then the manufacturer would be required to do an investigation that
includes both batch records associated with the
[[Page 12217]]
dietary ingredient or dietary supplement involved in the consumer
complaint. However, if the quality control unit determines that an
investigation is unnecessary, it would be helpful to you if your
quality control unit documents why an investigation was not necessary.
This information would be useful to you because it could save time if
you receive additional similar consumer complaints about a particular
product.
Proposed Sec. 111.95(c) would require that your quality control
unit investigate a consumer complaint when there is a reasonable
possibility of a relationship between the quality of a dietary
supplement and an adverse event. For example, if a manufacturer uses
too much of a dietary ingredient in a dietary supplement (e.g., 400 to
4,699 [mu]g of selenium instead of 200 [mu]g of selenium), it is a
manufacturing error that may result in an adverse event. Further, if a
communication alleges consumer dizziness, vomiting, or lightheadedness
after consuming several dietary supplements, it is a adverse event
report that is worthy of quality control unit investigation.
Proposed Sec. 111.95(d) would describe what the quality control
unit's investigation must include. In brief, the quality control unit's
investigation of a consumer complaint must include the batch records
associated with the dietary ingredient or dietary supplement involved
in the consumer complaint. The quality control unit must extend the
investigation to other batches of dietary ingredients or dietary
supplements that may have been associated with a failure to meet a
specification or any other requirements of this part. When there is a
possible product defect or failure, we recommend that the investigation
include laboratory testing of the dietary ingredient or dietary
supplement because you will need the test results to determine if
specifications or requirements for the dietary ingredient or dietary
supplement were not met. Complaints such as those that involve serious
adverse events should include followup by a health care provider. For
other types of complaints, neither laboratory nor medical investigation
may be necessary because the product defect or failure may be
identified by reviewing batch documents or the consumer complaint may
not involve a serious adverse event.
Proposed Sec. 111.95(e) would require that you make and keep a
written record of every consumer complaint that is related to good
manufacturing practices. For the purposes of this regulation, a
consumer complaint about product quality may or may not include
concerns about a possible hazard to health. However, a consumer
complaint does not include an adverse event, illness, or injury related
to the safety of a particular dietary ingredient independent of whether
the product is produced under good manufacturing practices. The
consumer complaint written record must include, but is not limited to,
the following:
[sbull] The name and description of the dietary ingredient or
dietary supplement;
[sbull] The batch or lot number of the dietary supplement, if
available;
[sbull] The complainant's name, if available;
[sbull] The nature of the complaint, including how the consumer
used the product;
[sbull] The reply to the complainant, if any; and
[sbull] Findings of the investigation and followup action taken
when an investigation is performed.
We suggest that you report the consumer complaint and the
investigation results to us when there is a possibility of a
relationship between the consumption of a dietary supplement and a
serious adverse event. While the proposal would not require that you
submit these reports, we strongly suggest that you do so because we may
have additional expertise or data that may be helpful in investigating
the complaint or determining whether the problem applies to more than
one product. We suggest that you submit these reports within 15 days
after you receive such information to the FDA MedWatch program by
calling our ``MedWatch'' program (our database for reporting possible
adverse events) at 1-800-FDA-1088 (1-800-332-1088) to request that a
reporting form (one-page, return postage paid) and instructions on how
to complete the form be mailed to you, downloading a form and
instructions from the MedWatch Internet site at http://www.fda.gov, or
using the interactive form available on the MedWatch Internet site at
http://www.fda.gov.
Further, we suggest that you report a consumer complaint even if
you are not the manufacturer of a dietary ingredient or dietary
supplement and only package or distribute a dietary ingredient or
dietary supplement if you receive a consumer complaint that may be
related to the manufacture of the dietary ingredient or dietary
supplement. Sometimes consumers submit complaints to the person who
distributes a product or the person who is listed on the package label.
If this happens, you should notify the manufacturer of the dietary
ingredient or dietary supplement of the consumer complaint because the
manufacturer may not be aware of possible problems associated with its
products.
Proposed Sec. 111.95(f) addresses documentation and recordkeeping.
Consumer complaints can alert you (and us) to potential quality
problems with a product that is related to good manufacturing
practices, such as cases where the manufacturer used the wrong
ingredient or put the wrong label on a product. A prudent manufacturer,
therefore, must investigate any complaints regarding its products
because the results of its investigations might lead to solutions or
improvements that will make the product or manufacturing process better
and benefit the manufacturer and consumers.
Proposed Sec. 111.95(f)(1) would require the person who performs
the requirement established in accordance with this section to
document, at the time of performance, that he or she performed the
requirement.
Finally, proposed Sec. 111.95(f)(2) would require that you keep
consumer complaint records established in accordance with proposed
Sec. 111.125. These records are necessary for handling consumer
complaints in a manner that ensures that an unanticipated problem with
a dietary ingredient or dietary supplement is reviewed and
investigated. These records also are necessary to demonstrate
compliance with the CGMP.
We invite comment on whether we should require, in a final rule,
that you establish and follow a written procedure for receiving,
reviewing, and investigating consumer complaints. If comments assert
that written procedures are necessary, comments should include an
explanation of why the requirement is necessary to prevent adulteration
including how such a requirement would ensure the identity, purity,
quality, strength, and composition of the dietary ingredient or dietary
supplement. Conversely, if comments assert that written procedures are
not necessary, comments should include an explanation of why the
requirement is not necessary including how, in the absence of the
requirement, one can prevent adulteration and ensure the identity,
purity, quality, strength, and composition of the dietary ingredient or
dietary supplement.
H. Records and Recordkeeping--What Requirements Apply to Recordkeeping?
(Proposed Subpart H, Sec. 111.125)
Throughout this discussion of the proposed rule, some provisions
have included a paragraph that would require
[[Page 12218]]
that you keep records established in accordance with proposed Sec.
111.125. Proposed Sec. 111.125 would establish general recordkeeping
requirements and tell you how long you must keep certain records. As we
have stated several times in this document, we determine CGMP
compliance by conducting inspections. Records, therefore, enable you to
show, and for us to determine, how you complied with the CGMP
requirements.
Proposed Sec. 111.125(a) would apply to all records covered by the
proposed rule and would require that you keep those records for 3 years
beyond the date of manufacture of the last batch of dietary ingredients
or dietary supplements associated with those records. Retention for 3
years beyond the date of manufacture would be appropriate for followup
of consumer complaints received during the marketing period.
Proposed Sec. 111.125(b) would deal with the form in which you
keep records. The proposal would allow you to keep records required
under this part as original records, as true copies (such as
photocopies, microfilm, microfiche, or other accurate reproductions of
the original records), or as electronic records. If you use reduction
techniques, such as microfilming, the proposal would require that you
make suitable reader and photocopying equipment readily available to
us. If you use electronic records, the proposal would require that you
comply with part 11 (our requirements for electronic records).
Proposed Sec. 111.125(c) would require that you make your records
available for inspection and copying by us when requested. We sometimes
need to copy records when our field inspectors need guidance or
additional expertise from our headquarters staff; if we were unable to
copy records, our inspections would become more complicated and longer
in duration, particularly if the inspection involved a complex
scientific or technical issue that normally would be handled at FDA
headquarters.
IV. Statement Concerning the Use of Plain Language
In response to the June 1, 1998, White House Presidential
Memorandum on Plain Language, we drafted this proposed rule in plain
language. Plain language is intended to help readers find requirements
quickly and understand them easily. To do that, we have reorganized
sections modeled after existing regulations and reworded the paragraphs
using:
[sbull] Short sections, paragraphs, sentences, and words to speed
up reading and enhance understanding;
[sbull] Sections as questions and answers to focus sections better;
and
[sbull] Personal pronouns to reduce passive voice and draw readers
into the text.
In some cases, we modeled a proposed provision after an existing
regulation, but wrote the proposed rule using plain language
techniques. We invite the public to comment on the plain language
techniques used in this proposed rule. In developing your comments,
please consider addressing the following points:
[sbull] Do you like the proposed rule's appearance?
[sbull] Do plain language techniques make the document easier to
read and understand? and
[sbull] Do you have other suggestions to improve the format?
V. Paperwork Reduction Act of 1995
This proposed rule contains information collection requirements
that are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). A
description of these requirements is given below with an estimate of
the annual recordkeeping burden. Included in the estimate is the time
for reviewing instructions, searching existing data sources, gathering
and maintaining the data needed, and completing and reviewing each
collection of information.
We invite comments on: (1) Whether the proposed collection of
information is necessary for the proper performance of our functions,
including whether the information will have practical utility; (2) the
accuracy of our estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (3) ways to enhance the quality, utility, and clarity of the
information to be collected; and (4) ways to minimize the burden of the
collection of information on respondents, including the use of
automated collection techniques, when appropriate, and other forms of
information technology.
Title: Current Good Manufacturing Practice in Recordkeeping and
Reporting for Dietary Ingredients and Dietary Supplements.
Description: Section 402(g) of the act gives us explicit authority
to issue a rule regulating conditions for manufacturing, packaging, and
holding dietary supplements. Section 402(g)(1) of the act states that a
dietary supplement is adulterated if ``it has been prepared, packed, or
held under conditions that do not meet current good manufacturing
practice regulations.'' Section 402(g)(2) of the act authorizes us to,
by regulation, ``prescribe good manufacturing practices for dietary
supplements.'' Other relevant legal authority is discussed in section
II of this document.
For this proposed CGMP rule for dietary ingredients and dietary
supplements, recordkeeping is necessary to provide the type of
documentation that would demonstrate that dietary ingredients and
dietary supplements are manufactured, packaged, and held under the
conditions that would be required under the proposed CGMP regulations.
Under section 701(a) of the act, we may issue regulations necessary for
the efficient enforcement of the act. If you did not keep records, for
example, documenting practices performed during previous production
runs, it would be difficult for us to determine whether, as stated
under section 402(g)(1) of the act, the dietary supplement had been
manufactured, packaged, and held under CGMPs. By requiring records, we
will be able to ensure that you follow CGMPs and that your dietary
supplements are not adulterated and misbranded during manufacturing,
packaging, or holding operations.
The proposed rule would establish the minimum manufacturing
practices necessary to ensure that dietary supplements are
manufactured, packaged, or held in a manner that will not adulterate
and misbrand the dietary ingredients or dietary supplements.
The proposed regulations would impose requirements for: (1)
Personnel, (2) physical plants, (3) equipment and utensils, (4)
production and process controls, (5) holding and distributing, (6)
consumer complaints, and (7) records and recordkeeping.
We are proposing recordkeeping requirements that include records
pertaining to: (1) Calibration of instruments and controls; (2)
automatic, mechanical, or electronic equipment calibration, inspection,
or checks; (3) production and process controls; (4) quality control;
(5) receiving components, dietary supplements, packaging, and labels;
(6) master manufacturing and batch production; (7) packaging and label
operations; (8) returned dietary ingredients or dietary supplements;
and (9) consumer complaints.
Description of Respondents: Dietary ingredient manufacturers,
dietary supplement manufacturers, packagers and repackagers,
distributors, warehousers, exporters, importers, large businesses, and
small businesses.
We estimate the burden of this collection of information as
follows:
[[Page 12219]]
Table 1.--Estimated Annual Recordkeeping Burden \1\
----------------------------------------------------------------------------------------------------------------
Annual
21 CFR Section Number of frequency of Total annual Hours per Total hours
recordkeepers recordkeeping records record
----------------------------------------------------------------------------------------------------------------
111.15(b)(3).................... 231 12 2,772 0.1 277
111.15(d)(3).................... 231 260 60,060 0.25 15,015
111.25(d)....................... 213 365 77,745 0.5 38,873
111.30(b)(2) and (b)(5)......... 707 260 183,820 0.5 91,910
111.35(d)....................... 10 1 10 10 100
111.35(e)....................... 367 260 95,420 0.25 23,855
111.35(f)....................... 367 260 95,420 0.1 9,542
111.35(i)(1).................... 367 10 3,670 0.25 918
111.35(j)....................... 367 260 95,420 .25 23,855
111.35(m)....................... 367 365 133,955 0.1 13,396
111.37(b)(1), (b)(3) through 286 260 74,360 0.5 37,180
(b)(5), (b)(7) through (b)(10),
and (b)(12)(i).................
111.37(c)....................... 286 365 104,390 0.5 52,195
111.40(a)(3), (a)(4), (b)(2), 449 365 163,885 0.1 16,389
and (b)(3).....................
111.40(c)(1).................... 218 365 79,570 0.5 39,785
111.45(a) \2\ and (b) \2\....... 200 1 200 30 6,000
111.50(a) through (c), (d)(1), 68 260 17,680 1 17,680
and (e)........................
111.50(g)....................... 68 260 17,680 0.5 8,840
111.60(b)(2).................... 133 365 48,545 1 48,545
111.60(d) \2\................... 133 1 133 3 399
111.65(c)(7), (c)(10), and 133 365 48,545 0.1 4,855
(c)(11)........................
111.70(b)(5) through (b)(6), 245 260 63,700 0.1 6,370
(d), and (e)...................
111.70(g)....................... 245 260 63,700 0.50 31,850
111.74(a)....................... 200 12 2,400 0.1 240
111.82(a)....................... 53 52 2,756 0.1 276
111.85(a)....................... 53 260 13,780 0.1 1,378
111.85(d) and (e)............... 53 260 13,780 0.5 6,890
111.95(e)....................... 53 75 3,975 0.1 398
111.95(f)(1).................... 93 75 6,975 0.5 3,488
111.125......................... 220 4 880 0.1 88
---------------
Total....................... .............. .............. .............. .............. 500,587
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
\2\ One time burden.
The burden estimates above are based on our institutional
experience with CGMP requirements for drugs and on data provided by
Research Triangle Institute (RTI) in the ``Survey of Manufacturing
Practices in the Dietary Supplement Industry'' (Refs. E1 and E2). We
tentatively conclude that there are no capital costs or operating costs
associated with this proposed rule. However, we invite comments on
information provided in table 1 of this document or on any anticipated
costs.
The estimates for number of firms affected by each provision of the
rule are based on the percentage of manufacturers, ingredient
suppliers, repacker/relabelers, distributors, and warehousers that
reported to RTI that they have not established or do not maintain
records that would be required or recommended under the proposed rule.
The RTI survey estimated that 1,566 firms would be covered by this rule
including manufacturers, dietary ingredient suppliers, repacker/
relabelers, distributors, and warehousers. The time estimates include
the burden involved in documenting that certain requirements are
performed and in recordkeeping. We used an estimated annual batch
production of 260 batches per year to estimate the burden of
requirements that are related to the number of batches produced
annually, e.g., proposed Sec. 111.50, ``What requirements apply to
establishing a batch production record?'' The estimate of 260 batches
per year is near the midpoint of the number of annual batches reported
by RTI survey firms.
Proposed Sec. 111.125 prescribes the length of time for which CGMP
records must be maintained. The burden chart reflects the estimated
annual burden for record maintenance, for periodically reviewing
records to determine if they may be discarded, and for any associated
documentation for that activity for records that would be required
under part 111. To avoid double-counting, we have not included a
separate estimate of burden for those sections that would require
maintaining records in accordance with proposed Sec. 111.125, but have
included a single burden estimate for all such records maintenance
under proposed Sec. 111.125. For example, proposed Sec. 111.50(a)
would require that the batch production records be prepared every time
a batch is manufactured and Sec. 111.50(i) would require that batch
production records be kept in accordance with proposed Sec. 111.125.
The estimated burden for establishing the batch production records is
counted in proposed Sec. 111.50(a) and the estimated burden for
keeping the batch production records as would be required in accordance
with Sec. 111.50(i) is counted in proposed Sec. 111.125.
In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C.
3507(d)), the agency has submitted a copy of this proposed rule to OMB
for its review. Interested persons are requested to send comments
regarding information collection to the Office of Information and
Regulatory Affairs, OMB (see ADDRESSES).
VI. Environmental Impact Considerations
The agency has determined under 21 CFR 25.30(j) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore,
[[Page 12220]]
neither an environmental assessment nor an environmental impact
statement is required.
VII. Analysis of Impacts
A. Introduction
FDA has examined the economic implications of this proposed rule as
required by Executive Order 12866. Executive Order 12866 directs
agencies to assess all costs and benefits of available regulatory
alternatives and, when regulation is necessary, to select regulatory
approaches that maximize net benefits (including potential economic,
environmental, public health and safety, and other advantages;
distributive impacts; and equity). Executive Order 12866 classifies a
rule as significant if it meets anyone of a number of specified
conditions, including: Having an annual effect on the economy of $100
million, adversely affecting a sector of the economy in a material way,
adversely affecting competition, or adversely affecting jobs. A
regulation is also considered a significant regulatory action if it
raises novel legal or policy issues. FDA has determined that this
proposed rule, if it were to become a final rule, would be a
significant regulatory action as defined by Executive Order 12866.
The Small Business Regulatory Enforcement Fairness Act of 1996
(Pub. L. 104-121) defines a major rule for the purpose of congressional
review as being likely to cause one or more of the following: an annual
effect on the economy of $100 million; a major increase in costs or
prices; significant adverse effects on competition, employment,
productivity, or innovation; or significant adverse effects on the
ability of U. S.-based enterprises to compete with foreign-based
enterprises in domestic or export markets. In accordance with the Small
Business Regulatory Enforcement Fairness Act, OMB has determined that
this proposed rule, when final, will be a major rule for the purpose of
congressional review.
FDA has examined the economic implications of this proposed rule as
required by the Regulatory Flexibility Act (5 U.S.C. 601-612). If a
rule has a significant economic impact on a substantial number of small
entities, the Regulatory Flexibility Act requires agencies to analyze
regulatory options that would lessen the economic effect of the rule on
small entities. FDA finds that this proposed rule would have a
significant economic impact on a substantial number of small entities.
We carry out the cost-benefit analyses required for significant
rules in the Preliminary Regulatory Impact Analysis, in section VII.B
of this document. We perform the Initial Regulatory Flexibility
Analysis of the effects on the proposed rule on small businesses in
section VII.C of this document.
B. Preliminary Regulatory Impact Analysis
1. The Need for the Proposed CGMP Regulations
The proposed CGMP regulations are needed because establishments
that manufacture, package, and hold dietary ingredients and dietary
supplements may not have sufficient market incentives to use controls
to prevent the adulteration and misbranding of dietary ingredients or
dietary supplements, including incentives to ensure their identity,
purity, quality, strength, and composition (product quality).
Manufacturing, packaging, and holding practices that ensure product
quality can be costly, so establishments may not adopt them unless
required to do so by regulation. Without the proposed regulations
consumers of dietary supplements cannot be assured that all
establishments are manufacturing dietary supplements in a way that
ensures that these products are not adulterated or misbranded.
Manufacturing, packaging, and holding practices can compromise
safety if they fail to prevent biological, chemical, and physical
contamination, or if the wrong dietary ingredients are used that
present an unreasonable risk of illness or injury. Strength (which is
the amount of a specific dietary supplement or dietary ingredient in
each tablet or capsule) that differs from label statements, missing or
extra ingredients, and inconsistency across units of the product are
other problems caused by poor manufacturing practices. Products may
also be held in insanitary or environmentally inappropriate conditions,
or may be physically damaged if stored improperly. Some poor
manufacturing practices, such as the use of ingredients that are
undeclared, of incorrect strength, or missing altogether result in a
misbranded product. The proposed CGMP regulations would establish
minimum requirements to ensure that manufacturing, packaging, and
holding practices ensure the identity and quality of components,
dietary ingredients, and dietary supplements.
Consumers today rely on manufacturer's assurances, existing
regulations and statutes (for example, section 402(a)(3) and (a)(4) of
the act), and recourse to the legal system to ensure that products are
not defective. Brand names convey some information to consumers about a
firm's manufacturing practices. Some private organizations, such as the
National Nutritional Foods Association and the USP design minimum
product standards or manufacturing requirements. The current act
contains some provisions that prevent using putrid substances and
insanitary manufacturing practices. In addition, either the threat of
litigation or consumers seeking compensation for defective products and
adverse health events may create incentives for establishments to adopt
good manufacturing practices.
Actions by manufacturers, primarily voluntary quality controls, do
not provide sufficiently protective industry-wide minimum requirements
for manufacturing, packaging, and holding of dietary ingredients and
dietary supplements. Without the proposed regulations, survey evidence
shows that products in the dietary supplement market are sorted
somewhere between two types:
[sbull] Higher-priced products with brand names or industry
certification that follow several of the good manufacturing practices
proposed here;
[sbull] Lower-priced products that contain no private certification
or respected brand name and that follow few of the good manufacturing
practices that are proposed here.
Without the proposed rule, the current practices do not provide all
consumers with safe manufacturing practices or reliable product quality
throughout the industry.
The market for dietary supplements is full of information;
consumers of dietary supplements must sort through information and
misinformation about the properties of these products from magazines,
brochures, popular books, television, and a host of other sources.
However, the information from these sources deals most often with the
claims for the products themselves, not with the steps taken by
establishments to protect against contamination or to ensure quality.
Private quality control fails to provide industry-wide minimum good
manufacturing practices for the following reasons:
[sbull] Establishments do not have incentives to disclose
information about their own practices, because disclosure that some
consumers may perceive to be harmful or undesirable would reduce the
demand for their products. Establishments therefore have incentives to
withhold information from consumers.
[sbull] Businesses normally do not advertise differences in
manufacturing
[[Page 12221]]
practices. They seldom have access to competitors' proprietary
information, and they may fear that advertising based on differences in
practices would discredit the entire industry.
[sbull] Without public disclosure of product quality and adverse
health events, the link between manufacturing practice and health
hazard is difficult to establish. The link is probabilistic, requires
data pooling across products and establishments (in order to establish
cross sectional variation), and can be interpreted in a variety of
ways.
[sbull] Because many consumers already mistakenly believe that the
Federal Government guarantees safety, businesses have weak incentives
to adopt good manufacturing practices, which are costly. In one recent
survey of the nation's consumers, 34 percent report that they believe
that the government regulates dietary supplements to ensure safety and
that products do what they claim to do. (For details of the survey, see
Ref. E3.) If people believe that good manufacturing practices are
already followed, manufacturers may believe they gain little from
voluntarily adopting them.
Information about manufacturing practices for dietary supplements
is imperfect and costly to produce, so well-informed people should be
willing to pay for improvements in the quality of information. An
important benefit of the proposed regulations will be to reduce
variation in manufacturing practices and ensure minimum quality for
dietary supplement products. Reducing the variation in product quality
by creating industry-wide minimum requirements reduces the information
consumers now attempt to get through costly and uncertain sources in
order to make purchasing decisions.
2. Regulatory Options
FDA considered several regulatory options for dealing with current
manufacturing, packaging, and holding practices that may not ensure
product quality. The options considered include: (a) No new regulatory
action, (b) fewer requirements for vitamins and minerals, (c) more
restrictive regulations than the proposed CGMP regulations, (d) HACCP
without the other elements of CGMP regulations, (e) final product
testing only, (f) regulations for high-risk products or hazards only,
and (g) the proposed rule.
a. No new regulatory action. Under this option, consumers would
probably rely on the following as protection against defective
products:
[sbull] Possible enforcement action by FDA under, for example,
section 402(a)(3) and (a)(4) of the act, regarding adulterated foods
that consist of filthy, putrid, or decomposed substances or foods that
have been prepared, packed, or held under insanitary conditions so that
they may become contaminated or may be rendered injurious to health;
[sbull] Publicity from private consumer groups or health agencies
on the risks from products not manufactured using CGMP regulations,
manufacturers assurances, and the voluntary adoption of some or all
provisions of the proposed regulations;
[sbull] Current or enhanced State and local enforcement activity to
bring about a reduction of potential harm from contaminated or poor
quality dietary supplements; or
[sbull] Litigation or the threat of litigation by consumers who
allege harm from consumption of the dietary supplement.
We believe that there are compelling reasons not to rely on these
alternatives alone.
If public and private health agencies, consumer groups,
competitors, trade organizations or other third parties publicized the
risks from products not manufactured using private good manufacturing
practices, then consumers would decide for themselves on the risks of
contaminated or poor quality products. The weakness of this alternative
is that third-party organizations cannot easily discover many of the
problems caused by poor manufacturing practices because manufacturers
are reluctant to voluntarily share information to third parties about
their manufacturing practices.
Actions by manufacturers, such as by voluntarily introducing good
manufacturing practices, occur when the expected private economic
benefits of the actions exceed the private costs. Voluntary adoption of
good manufacturing practices will occur when it is profitable to do so.
Many establishments appear to be adopting some publicly available good
manufacturing practice models in order to meet the demand for safer and
more uniform products. NNFA is implementing a good manufacturing
practice certification program. The USP sets standards for strength,
purity, disintegration, and dissolution for individual and combination
vitamins and minerals. Also, Consumerlab.com is introducing a
certification label, CL, to show when ingredients meet their minimum
requirements. However, 36 percent of recently surveyed dietary
supplement establishments do not follow any good manufacturing practice
models for their products (Ref. E2). The breakdown of survey results
shows that 48 percent of very small firms, 27 percent of small firms
and 11 percent of large firms do not follow a good manufacturing
practice model. The survey results also show that 32 percent of
vitamins and mineral establishments, 39 percent of amino acid/protein/
animal extract establishments, 41 percent of herbal and botanical
establishments, and 59 percent of establishments not already
classified, do not follow a good manufacturing practice model.
Without industry-wide uniform requirements, some establishments may
follow different practices but convey the message that they follow good
manufacturing practices. In short, people who want to discriminate
between establishments that use good practices and those that do not
would not have sufficient information to do so. Another reason for our
skepticism about universal voluntary adoption of good manufacturing
practices is that good practices appear to be taken for granted by many
consumers. Indeed, some consumers already believe that the Federal
Government regulates the manufacturing practices of the industry, so
firms lack an incentive to provide additional assurance (Ref. E3).
Current or enhanced State and local regulations could bring about a
reduction of potential harm from contaminated supplements. This
alternative has the advantage that State and local governments can
exercise more discretion when responding to local manufacturing
conditions or consumer health practices than the Federal Government.
Because most of the industry engages in interstate commerce, however,
Federal regulations are appropriate. Also, Federal regulations would
apply uniformly across the country, whereas State and local regulations
might impose different standards on establishments that supply
supplements across State and local boundaries.
Litigation or the threat of litigation may help to bring about the
goals of the proposed rule. The potential of costly litigation from the
harm caused by deficient manufacturing practices creates an incentive
for manufacturers to reduce the risks from defective products. However,
we do not believe that litigation or the threat of litigation has
created the incentives for all manufacturers to implement the
manufacturing practices that we believe are necessary to avoid
adulterated or misbranded products. As discussed earlier, not all
surveyed dietary supplement manufacturers reported that they followed
good manufacturing practices. Furthermore, in some cases it is
difficult and costly to demonstrate to the courts that the harm to
plaintiffs was
[[Page 12222]]
actually the result of poor manufacturing practices, making recourse to
the courts sometimes impractical.
In the absence of the proposed CGMP regulations, the burden of
monitoring manufacturing practices would fall more heavily on
consumers, despite the difficulties consumers face in monitoring
manufacturers. Moreover, the proposed CGMP regulations are preventative
and should ensure that problems are identified and dealt with during
manufacturing, packaging, and holding, rather than after someone has
consumed an unsafe product and experienced an adverse effect.
b. Fewer requirements for vitamins and minerals. FDA could require
more controls from establishments that manufacture, package, or hold
plant or animal derived dietary ingredients such as amino acids,
proteins, herbals, botanicals and other products not classified as
vitamin and mineral manufacturers, packagers, or holders. The plant or
animal derived dietary ingredients are probably characterized by
greater variation in product quality than synthetically derived dietary
ingredients. Under this option, the segment of the industry that
manufacture, package, or hold products that are the most likely to have
difficulty manufacturing or maintaining uniform product quality dietary
ingredients would be required to follow the proposed testing and other
production and process control requirements. Manufacturers of vitamins
and minerals would be required to follow the sanitation, holding, and
consumer complaint provisions only, they would not have to adopt
manufacturing controls to ensure that products did not contain too much
or too little of a vitamin or mineral.
Plant or animal ingredients are likely to experience greater
natural variation in product quality than synthetic compounds, so they
may require the higher minimum standard of regulation contained in the
proposed regulation. The advantage of this option is that fewer
establishments will be affected as much; approximately 723
establishments classified as manufacturers, packagers or holders of
products other than vitamins and minerals, rather than the 1,566
establishments estimated to be covered by the proposed regulation (see
table 2 of this document). The compliance costs would therefore be
lower. The disadvantage is that vitamin and mineral manufacturers also
potentially manufacture products of variable quality, so the expected
benefits from more consistent product quality would be reduced.
Moreover, if dietary supplements contain too little of a vitamin or
mineral consumers may not receive the intended health benefits, and if
the dietary supplements contain too much of a vitamin or mineral they
may experience illness or injury.
We estimate that the benefits of this option would be approximately
proportional to the ratio of recalled products that were classified as
vitamins and minerals to all recalled dietary supplements products.
Approximately 50 percent of the recalled products were vitamins and
minerals so we estimate that this option would generate no more than
$109 million in benefits. We assumed that the costs of this option
would be proportional to the fraction of establishments that would be
required to follow all of the proposed provisions and those that follow
the reduced requirements with the total costs estimated for this
proposal as shown in table 17 of this document. The estimated mean cost
of the proposed regulation is $86 million (see table 19 of this
document). The fraction of establishments required to follow all the
provisions is .46 (= 723/1566). The fraction of establishments that
would have reduced testing is .54 (= 843/1566). Testing is
approximately 36 percent of the total costs. We estimate the total
costs from this option to be $69 million ($86 million x .46 + $86
million x .54 x (1-.36)).
c. More restrictive CGMP regulations than the proposed regulations.
One option is to propose (or finalize) more restrictive rules than the
proposed CGMP regulations. Under this option, CGMP regulations could
provide consumers with additional safeguards. Several of the largest
manufacturers of dietary supplements now voluntarily comply with some
of these additional safeguards (Ref. E2). The most significant
additional provisions that would be required under this option are
product quality testing for each incoming shipment lot of components
and dietary ingredients, inprocess testing for contaminates at critical
control points and mandatory written procedures for all of the various
provisions of the proposed regulation.
The advantage of this option is that the additional requirements
provide safeguards that the essential safety and quality provisions are
being followed. The disadvantage of this option is that it is more
costly than the proposed rule, and we are not aware of any information
that would show any additional verifiable health benefits.
d. HACCP without the other elements of CGMP regulations. The agency
could propose a requirement that manufacturers implement a HACCP (or
HACCP like) system for the manufacturing of dietary supplements without
the other elements of the proposed CGMP regulations. A critical control
point is where production controls can be applied to reduce or
eliminate hazards (including biological, chemical, or physical
contamination) that may make dietary supplements unsafe.
The advantage of an industry-wide HACCP program is that HACCP does
not require manufacturers to follow detailed uniform requirements in
order to achieve desirable outcomes. Manufacturers themselves determine
for their specific products and processes how they will best eliminate,
reduce, or control hazards in the manufacturing of dietary supplements.
We have not designed a hypothetical HACCP system for the dietary
supplement industry. For the purpose of generating estimates of costs
and benefits, we assumed that a HACCP regulation for a dietary
supplement manufacturer would be likely to encompass sanitation
prerequisites that are met, writing a HACCP plan, and monitoring
critical control points. The benefits and costs of the HACCP plan would
be generated by controls for a narrower set of hazards in the
manufacturing, packaging, and holding processes than those covered by
this proposal, and would not include the other benefits and costs
generated by the proposed rule especially the reduced consumer search
costs, because uniform product quality would not necessarily be
assured. The advantage of HACCP as an option to prevent product
contamination is that it does not specify detailed manufacturing
requirements. The disadvantage is that in the absence of uniform
controls there would not be uniform minimum product quality across the
industry and consumers would not derive the same benefits from lower
search costs.
e. Require final product testing only. FDA could propose that
manufacturers test their finished products for identity, purity,
quality, strength, and composition but not include any of the other
mandatory provisions of the proposed regulation. The advantage of this
option is that it would be the least costly option of those considered.
Many firms already test some of their finished products, reducing the
impact of this option. Approximately 69 percent of manufacturing plants
conduct finished product testing and almost 65 percent of all finished
batches in the industry are already tested using physical, chemical,
microbiological, visual or organoleptic
[[Page 12223]]
testing techniques (Ref. E2). The problem with this option is that
finished product testing alone cannot ensure product quality for some
types of products. Not every finished product currently has a test that
confirms identity, purity, quality, strength, or composition,
especially for multiingredient products. Tests may not have been
developed, or they may not be completely reliable, or they may not be
capable of evaluating every type of product defect. Also, potentially
lower cost alternatives to finished product testing--such as incoming
component lot testing, inprocess testing, or both--might be available
and desirable to firms as a means to protect the public. Moreover,
finished product testing alone is not sufficient to prevent products
with microbiological or chemical contamination from being discovered
because it is possible that false negatives might occur, as when there
is ``hotspot'' contamination within a batch. Preventative controls must
be imposed to achieve that goal. Finally, finished product testing
alone also will not facilitate trace backs when defective products are
discovered in the marketplace, nor will it facilitate responsible
investigations of consumer complaints. The estimated cost of this
option is lower than that of the other options, but it does not
generate the full range of benefits provided by the proposed rule.
f. Regulate only high-risk products. FDA could propose CGMP
regulations that would cover only high-risk products. The advantage of
this option is that it would impose lower costs than the proposed rule,
but (if all risky products could be identified and regulated) generate
the same level of benefits. Only those establishments that manufacture
high-risk products or have high-risk hazards would incur the costs of
adopting CGMP regulations. High-risk might be defined as those products
most likely to be contaminated, or suffer other product defects. There
are two problems with this option. Adverse event reporting is not
mandatory, so significant underreporting is expected. Also, it is
possible that the confirmed illnesses and other problems linked to
particular dietary supplements may be those most easily traced, rather
than those with the highest risk. High levels of identified problems
may not be closely correlated with high levels of risk. In other words,
problems associated with the known defective products may or may not be
correlated with the highest risk. Without more data and risk
assessments, it would be difficult to distinguish what risks may be
associated with particular dietary supplements. We therefore have no
basis upon which to begin a full evaluation of what the high-risk
products are or may be.
3. Coverage of the Proposed Rule
The proposed rule would cover establishments that manufacture,
package, hold dietary ingredients or dietary supplements. Tables 2, 3,
and 4 of this document list the estimated number of covered
manufacturers, packagers, dietary ingredient suppliers, holders, and
other establishments. Table 2 of this document shows the number of
covered establishments by product type and size. A small business,
based on the Small Business Administration definition, is any firm with
500 or fewer employees. For purposes of analysis, we defined very small
establishments as having fewer than 20 employees. Table 3 of this
document shows the number of establishments categorized as
manufacturers, ingredient suppliers, repackers or relabelers, holders
whose primary business is dietary ingredients or dietary supplements,
and other (although not including other holders and distributors).
Table 4 of this document shows our estimate of the number of general
warehouses and wholesalers that hold dietary supplements.
Table 2.--Covered Establishments by Product Type and Size From Dietary Supplement Enhanced Establishment Database (DS-EED)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Very
Product type small % Small % Large % Unknown % Total
--------------------------------------------------------------------------------------------------------------------------------------------------------
Vitamins and Minerals......................................... 252 29.8 223 26.5 78 9.2 290 34.5 843
Amino Acids, Proteins......................................... 21 31.0 16 23.0 6 6.9 27 39.1 69
Herbals and botanicals........................................ 148 42.6 46 13.2 5 1.1 150 43.1 348
Supplements not already classified............................ 93 30.4 66 21.6 20 6.5 127 41.6 306
----------
Total..................................................... 514 32.8 351 22.4 106 6.8 594 38.0 1,566
--------------------------------------------------------------------------------------------------------------------------------------------------------
Table 3.--Covered Establishments by Type of Operation From DS-EED
------------------------------------------------------------------------
Number of Percent of
Establishment type establishments establishments
------------------------------------------------------------------------
Manufacturer............................ 1,228 78.4
Dietary ingredient supplier............. 106 6.7
Repacker; relabeler..................... 26 1.7
Holder.................................. 114 7.3
Establishments not already classified... 92 5.9
-----------------
Total............................... 1,566 100.0
------------------------------------------------------------------------
Table 4.--Covered Establishments That Hold Dietary Supplements
------------------------------------------------------------------------
Number of
Type of holders Source and SIC code establishments
------------------------------------------------------------------------
Grocery Wholesalers or Drug Dunn and Bradstreet: 25,527
Wholesalers. 5122, 5141.
Food or Drug Warehouse......... Dunn and Bradstreet: N/ 738
A.
Miscellaneous Food or Drug Dunn and Bradstreet: 238
Warehouse. 4225, 4226, 5912,
5499, 5411, 5122,
5141, 5149, 5399,
5311, and 5331.
[[Page 12224]]
Dietary Supplement............. DS-EED................. 114
--------------------------
Total...................... ....................... 26,617
------------------------------------------------------------------------
We consulted several sources to estimate the number of
establishments reported in tables 2, 3, and 4 of this document. The
number shown in tables 2 and 3 of this document, 1,566, is the
estimated number of establishments in the DS-EED that manufacture,
repackage, supply dietary ingredients, or hold dietary supplement
products in the United States. RTI developed the DS-EED using FDA's
Official Establishment Inventory (OEI) and supplemented that source
with information from trade organizations, trade shows, and electronic
databases (Refs. E1 and E2).
The number of establishments in the DS-EED that hold dietary
supplements is not the total number of holders covered by the proposed
regulation. The holding establishments in the DS-EED identified holding
dietary supplements as their primary business. To estimate the total
number of establishments that could hold dietary ingredients or dietary
supplements but do not consider dietary supplements as their primary
business, we performed three searches of firms that are listed with Dun
and Bradstreet's Dialog database. We first looked for a count of firms
that had standard industrial classification (SIC) codes for wholesalers
of groceries or drugs. Next we looked for a count of firms that met the
description of warehouses of groceries or drugs (no SIC codes were
used). Finally, we looked for a count of any firms that had both
warehouse SIC codes and miscellaneous drug stores, food stores,
sundries, and general merchandise (SIC 4225, 4226, 5912, 5499, 5411,
5122, 5141, 5149, 5399, 5311, and 5331). The results are shown in table
4 of this document. We concluded that the total number of
establishments in this category that could hold dietary ingredients or
dietary supplements and would be covered by the regulation was
approximately the sum of the numbers counted in the three searches, or
26,617.
The number of establishments that hold dietary ingredients or
dietary supplements includes retailers that sell dietary supplements to
consumers, and transporters of dietary ingredients and dietary
supplements. We made no effort to determine the number of such holders,
because the proposed requirements do not apply to retailers and
transporters. We believe that retailers and transporters may
voluntarily adopt provisions related to the holding of these products
and thus there may be changes in the marketplace with accompanying
costs and benefits. However, we expect that the only retailers and
transporters that will voluntarily adopt the proposed requirements are
those that expect the private benefits of adoption will exceed the
private costs.
4. Baseline Practices
a. Consumer baseline practices. Baseline consumer and manufacturer
practices, governed by current market forces and existing government
regulations, give rise to the current risks associated with the
manufacturing of dietary supplements. When determining baseline
manufacturing practices, it is necessary to estimate both the practices
that are used now, as well as the likely changes in manufacturing
practices that will occur even in the absence of new regulations. The
risks to consumers from these products can be associated with a
combination of consumption habits, the contamination of the products,
or both. Contamination may be caused by current manufacturing
practices. Consumption is influenced by the price and quality of
dietary supplements, set by the interaction of market participants.
Finally, changes in practices of either consumers or manufacturers
caused by new regulatory requirements will give rise to changes in
risks, as estimated by changes in costs and benefits.
The consumption of dietary supplements has grown in recent years.
Consumers report that they are using a wider range of product types,
and that they are using dietary supplements for more reasons than they
were in the past.
Table 5 of this document illustrates the rapid sales growth of the
dietary supplement industry from 1994 to 2000. Panel A of table 5 of
this document shows annual sales of three general categories of dietary
supplements, a measure of the market size of the supplement industry.
Annual increases in sales of herbals and botanicals were the greatest,
averaging 18 percent per year, while annual increases in sales of
supplements that were neither vitamins and minerals nor herbals and
botanicals increased less, averaging 11 percent per year. The lowest
annual sales increases were for vitamins and minerals, averaging 8
percent per year. For all dietary supplements combined, sales increased
an average of 12 percent a year since 1994 (not shown on the table).
While the sales growth shown in table 5 of this document, Panel A,
is impressive, only part of this apparent growth represents increased
use. Population growth and rising prices also contributed to the
apparent growth. The real (growth inflation-adjusted) increase in
dietary supplement prices is estimated by subtracting the inflation
rate from the rate of price increases of dietary supplements (Ref. E4).
As shown in table 5 of this document, Panel B, between 1995 and 1997
the real price of vitamins and minerals and supplements other than
vitamins and minerals all increased. Rising real price indicates that
demand is growing rapidly.
Table 5 of this document, Panel C, shows estimated annual increases
in per capita consumption of dietary supplements.\1\ As shown in table
5 of this document, Panel C, the estimated per capita consumption of
the different categories of dietary supplements has increased since
1994.
---------------------------------------------------------------------------
\1\ An index measuring per capita consumption of dietary
supplements can be derived using the following equation:
PCCt = [1,000 x Salest]/[POP x Pt
], where, t = year index; PCCt = per capita consumption
( of unit sales); Sales = millions of dollars of sales;
POPt = thousands of U.S. residents; Pt =
average price of supplement. In the formula, we measure consumption
as the number of dietary supplement units (bottles, packages, etc.)
sold per U.S. resident for a given year.
---------------------------------------------------------------------------
For the consumption estimates in table 5 of this document, we
averaged dietary supplement use over the entire U.S. population, 275
million. In table 6 of this document, we included estimated average
supplement use for the population of supplement users, 160 million
(Ref. E13). The three panels in table 6 of this document show the
annual consumption per supplement user and the annual change in
consumption per supplement user for
[[Page 12225]]
vitamins and minerals, herbals and botanicals, and supplements other
than vitamins and minerals and herbals and botanicals. Table 6 of this
document also shows that during this period the proportion of consumers
using supplements increased faster than the average consumption for the
total population. The surprising implication of this result is that
consumption per user has apparently declined since 1994.
One limitation of the estimates in table 6 of this document is that
prevalence of supplement use is based on the proportion of U.S. adults
consuming supplements, while the per capita consumption figures are
based on the entire U.S. population. Nonetheless, we do not have any
reason to believe that the estimated trend in consumption per user is
biased. This trend, expressed as the percentage change in consumption
per user, is negative for all segments of the dietary supplement
industry since 1994. The large and rising number of consumers accounts
for the growing size of the dietary supplement industry.
Table 5.--Growth in Market Size and per Capita Consumption of Dietary Supplements, 1994-2000
--------------------------------------------------------------------------------------------------------------------------------------------------------
1994 1995 1996 1997 1998 1999 2000
--------------------------------------------------------------------------------------------------------------------------------------------------------
Panel A--Nominal Market (Millions of Current Dollars)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Vitamins..................................................... 3,960 4,220 4,780 5,190 5,550 5,940 6,360
Growth rate (percent)........................................ ........... 6.57 13.27 8.58 6.94 7.03 7.07
Minerals..................................................... 700 800 900 1,070 1,160 1,250 1,350
Growth rate (percent)........................................ ........... 14.0 13.0 19.0 8.0 8.0 8.0
Herbals and Botanicals....................................... 2,070 2,530 2,990 3,530 4,170 4,840 5,520
Growth rate (percent)........................................ ........... 22.22 18.18 18.06 18.13 16.07 14.05
Supplements other than vitamins/minerals and botanicals...... 2,070 2,290 2,620 2,890 3,180 3,490 3,840
Growth rate (percent)........................................ ........... 10.63 14.41 10.31 10.03 9.75 10.03
Total.................................................... 8,080 9,840 11,290 12,680 14,060 15,520 17,070
Growth rate (percent)........................................ ........... 12.0 15.0 12.0 11.0 10.0 10.0
--------------------------------------------------------------
Panel B--Prices
--------------------------------------------------------------------------------------------------------------------------------------------------------
Consumer price index-units (percent)......................... 148.5 152.5 157.0 160.5 163.2 166.7 ...........
Inflation rate (percent)..................................... 2.56 2.76 2.957 2.23 1.68 2.14 2.39
Vitamins and minerals........................................ ........... ........... ........... ........... ........... ........... ...........
Average nominal price (IRI).................................. $6.20 $6.50 $6.87 $7.34 $7.54 $7.78 $8.05
Nominal price increase (percent)............................. 2.69 4.84 5.69 6.84 2.72 3.18 3.43
Real price increase (percent)................................ 5.25 2.08 2.74 4.61 1.04 1.04 1.04
Supplements other than vitamins and minerals:
Average nominal price.................................... $6.20 $6.50 $6.87 $7.34 $7.70 $8.11 $8.56
Nominal price increase (percent)......................... 5.80 4.84 5.69 6.84 4.85 5.31 5.56
Real price increase (percent)............................ 3.24 2.08 2.74 4.61 3.17 3.17 3.17
--------------------------------------------------------------
Panel C--Per Capita Consumption (Number of Units Sold Per U.S. Resident)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Vitamin/mineral sales........................................ 2.45 2.47 2.62 2.64 2.72 2.80 2.87
Growth (percent)............................................. ........... 0.69 6.19 0.66 3.12 2.74 2.55
Herbals sales................................................ 1.28 1.48 1.64 1.80 2.00 2.19 2.34
Growth (percent)............................................. ........... 15.48 10.79 9.45 11.60 9.17 7.03
Supplements other than vitamins and minerals and herbals 1.28 1.34 1.44 1.47 1.53 1.58 1.63
sales.......................................................
Growth (percent)............................................. ........... 4.53 7.26 2.26 3.95 3.23 3.25
--------------------------------------------------------------------------------------------------------------------------------------------------------
Table 6.--Comparison of Consumption per Person With Consumption per User: Evidence That the Dietary Supplement Market Is Becoming Broader Not Deeper
--------------------------------------------------------------------------------------------------------------------------------------------------------
Average Growth 1994 1995 1996 1997 1998 1999 1994-2000
--------------------------------------------------------------------------------------------------------------------------------------------------------
A. Vitamins and Minerals
--------------------------------------------------------------------------------------------------------------------------------------------------------
Per capita consumption (units per U.S. resident)............. 2.45 2.47 2.62 2.64 2.72 2.80 ...........
% Growth..................................................... ........... 0.69 6.19 0.66 3.12 2.74% 2.68%
Consumption prevalence (percent)............................. ........... 47.70 54.0 61.0 70.0 79.0 ...........
Reference.................................................... ........... Ref. E6 Ref. E6 Ref. E6 Ref. E6 Ref. E7 ...........
% Growth..................................................... ........... ........... 13.44 13.44 13.44 13.44 13.44
Consumption per user (units)................................. ........... 5.18 4.85 4.30 3.91 3.54 ...........
% Growth..................................................... ........... ........... -6.39 -11.27 -9.10 -9.43 -9.05
--------------------------------------------------------------
1994 1995 1996 1997 1998 1999 1994-1999
--------------------------------------------------------------
B. Herbals and Botanicals
--------------------------------------------------------------------------------------------------------------------------------------------------------
Per capita consumption (units per U.S. resident)............. 1.28 1.48 1.64 1.80 2.00 2.19 ...........
[[Page 12226]]
% Growth..................................................... ........... 15.48 10.79 9.45 11.60 9.17 11.30
Consumption prevalence (percent)............................. 8.20 12.10 12.10 12.10 28 49 ...........
Reference.................................................... Ref. E8 Ref. E8 Ref. E8 Ref. E9 Ref. E10 Ref. E7 ...........
% Growth..................................................... ........... 47.56 0.00 0.00 131.40 75.00 50.79
Consumption per user (units)................................. 15.64 12.24 13.56 14.84 7.16 4.47 ...........
% Growth..................................................... ........... -21.74 10.79 9.45 -51.77 -37.62 -18.18%
--------------------------------------------------------------
C. Supplements Other than Vitamins and Minerals and Herbals and Botanicals
--------------------------------------------------------------------------------------------------------------------------------------------------------
Per capita consumption (units per U.S. resident)............. 1.28 1.34 1.44 1.47 1.53 1.58 ...........
% Growth..................................................... ........... 4.53 7.26 2.26 3.95 3.23 4.24
Consumption prevalence (percent)............................. 5.1 8.8 11.2 14.2 18.1 23.0 ...........
Reference.................................................... Ref. E8 Ref. E8 Ref. E8 Ref. E8 Ref. E8 Ref. E7 ...........
% Growth..................................................... ........... 72.55 27.15 27.15 27.15 27.14 36.23
Consumption per user (units)................................. 25.15 15.24 12.85 10.34 8.45 6.86 ...........
% Growth..................................................... ........... -39.42 -15.64 -19.58 -18.25 -18.81 -22.34
--------------------------------------------------------------------------------------------------------------------------------------------------------
b. Manufacturer's baseline practices. FDA contracted with RTI to
conduct a survey of the dietary supplement industry to learn about both
baseline (existing) manufacturing practices and the existing standards
used for manufacturing dietary ingredients and dietary supplements
(Ref. E2). A sample of 966 dietary supplement establishments from the
DS-EED database was selected from an estimated eligible population of
1,566 firms in the industry. The sample was stratified by
manufacturer's product type and the size of firm in the industry.
Stratification helps ensure that estimates of the subpopulations are
more precise. Establishments that were stratified by manufacturer's
product type were classified as primarily: (1) Vitamins and minerals;
(2) amino acids, proteins, or animal extracts; (3) herbals and
botanicals; or (4) all other product types not already classified. The
product type strata were further stratified by four size categories:
(1) Very small, (2) small, (3) large, and (4) unknown. This
categorization generated 16 sampling strata.
The contractor, RTI, sent each of the 966 firms in the sample a
lead letter on FDA letterhead and a one-page brochure to explain the
purpose of the survey, the value of the establishment's participation,
and the agency's confidentiality procedures. Following the mailing, RTI
placed telephone calls to each establishment to screen for eligibility
and to recruit eligible establishments for the mail survey. To be
eligible for the survey, establishments had to currently manufacture,
repackage, supply dietary ingredients, hold, import or export dietary
supplements for human consumption. Almost 50 percent of the
establishments sampled were not eligible for the survey because they
were no longer in operation at the listed address or did not handle any
dietary supplements or ingredients for human consumption.
To achieve the highest possible response rate, RTI operated a toll-
free help line and attempted to contact each establishment up to eight
times before assigning a disposition of nonresponse. RTI also attempted
up to two refusals conversions, which are attempts to persuade firms
that declined to answer the survey to respond. The survey was conducted
over a 10-week period, November 29, 1999, to February 4, 2000. There
were a total of 238 completed surveys, resulting in a final disposition
of: (1) An overall eligibility rate of close to 50 percent, and (2) a
response rate of 50 percent.
Determining baseline practices is necessary in order to determine
the new activities that are likely to take place as a result of
implementation of this proposed rule. Each of the new activities
potentially brought about by the proposed rule has both a marginal (or
incremental) cost and a marginal (or incremental) benefit. These
incremental costs and benefits of likely new activities form the basis
of our economic analysis of the proposed rule.
The survey asked establishments a series of questions about
existing practices; we used the responses to estimate how many
establishments in the industry already operated in accordance with the
requirements of the proposed regulation. One key assumption in this
analysis is that no firms are expected to stop CGMPs and no firms are
expected to start good manufacturing practices in the absence of this
rule. The universe for the survey includes the establishments discussed
in section VII.B.3 of this document. If firms start good manufacturing
practices in the absence of this rule, both the costs and benefits of
the rule would be less than we estimate. If firms were to stop in the
absence of the rule, both the costs and benefits would be more than we
estimate. We lack information about the trend in the industry, so we
assumed that the survey reflects both the current and future practices
in the industry. We request comment or information about the industry
trend in adopting good manufacturing practices.
i. Stratification. The survey was stratified by product type and
establishment size. Stratification ensures that samples are
representative of the industry population.\2\ The subdivisions of the
population of interest here were establishment size (by the number of
employees) and product type, because these characteristics are likely
to influence whether an establishment already has adopted the practices
that would be required by the regulation. The DS-EED includes nine
product types: (1) Vitamins and minerals; (2) herbals and botanicals;
(3) herbal and botanical extracts; (4) amino acids; (5) proteins; (6)
animal extracts; (7) tea like products; (8) concentrates, metabolites,
or constituents; and (9) supplements not already classified (all other
supplements). Establishments may produce more than one product type;
establishments with multiple product types were, however, only
classified in one category. For stratification and reporting purposes,
we defined the
[[Page 12227]]
following four mutually exclusive categories of dietary supplements:
---------------------------------------------------------------------------
\2\ Stratification is a subdivision of the population of
establishments in the dietary supplement industry by a unique
characteristic such as product type or number of employees.
---------------------------------------------------------------------------
1. Vitamins and minerals (includes establishments that may also
manufacture, package, or hold herbals and botanicals, amino acids,
proteins, or animal extracts but predominately manufacture vitamins and
minerals);
2. Amino acids, proteins, and animal extracts (includes
establishments that also manufacture, package or hold herbals and
botanicals, including extracts; excludes establishments already
classified as vitamins and minerals);
3. Herbals and botanicals, including extracts (excludes
establishments already classified as ``vitamins and minerals'' or
``amino acids, proteins, or animal extracts''); and
4. Supplements not already classified (all other product types).
We further stratified each of the four product categories into four
size categories, very small, small, large, and unknown--resulting in 16
sampling strata. We classified each establishment into one mutually
exclusive industry category (manufacturer, dietary ingredient supplier,
repacker/relabeler, holder, or establishment not already classified).
Establishments that manufacture supplements and also supply, repack, or
hold dietary supplements or ingredients were classified as
manufacturers.
ii. Size stratification. The Small Business Administration
classifies companies as ``small'' based on the size of the entire
company, including both parent and subsidiaries. If firms that
manufacture dietary supplements have 500 or fewer employees, they are
classified as small. Because the DS-EED data on size are only for
specific establishments and not parent firms, we had to obtain parent
company information on employment or revenue to correctly classify each
establishment as part of a small or large company. To obtain parent
company data for establishments in the survey universe, we sent InfoUSA
\3\ the DS-EED data records (N = 2,004) and requested the name,
address, primary SIC, employment size (in ranges), and revenue (in
ranges) of parent company firms with establishments in the survey
universe. InfoUSA matched 1,219 of the 2,004 records in the DS-EED to
their U.S. database of 10.3 million businesses. Of the 1,219 matched
records, 31 records were found to be duplicates of another record and
were removed, leaving 1,188 matched records and 1,566 total records in
the sampling frame. The nonmatched records did not match because: (1)
They were recently established businesses, (2) they were out of
business, or (3) they had recently changed their names or addresses.
Because data on revenue or employment size were not available for the
nonmatched records, we created an ``unknown'' stratum for these
establishments. The survey of practices collected information on
employment that allowed us to classify some of these establishments by
size for the analysis.
---------------------------------------------------------------------------
\3\ InfoUSA is a publicly held company that creates proprietary
business databases. Their database includes such information as:
Company name, address, phone number, fax number, estimated sales,
volume, number of employees, type of business (SIC code or yellow
page heading), key contact names, and titles.
---------------------------------------------------------------------------
Of the 1,188 matched records, 180 were linked to parents. The
parent company data for these 180 establishments were merged with the
survey universe. The remaining 1,008 records did not link to an
ultimate parent company. For these records, the establishment and
parent company were the same entity, so we used establishment level
data to classify size. We classified each of the establishments in the
survey universe as part of very small, small, or large businesses based
on the employment size or annual revenues of each establishment's
parent company. If an establishment or its parent company had 500 or
fewer employees or sales less than $20 million (if data on employment
were not available), then the establishment was classified as small. An
establishment was classified as very small if the number of employees
was less than 20.
iii. Survey response. Table 7 of this document presents the number
of establishments surveyed, stratified by the four product types and by
size. Although the sample allocation was designed to yield 400
completed surveys, we received only 238 completed mail surveys. The
number of respondents was fewer than expected because the number of
establishments that were ineligible was greater than we expected and
because some establishments did not respond to the survey after
agreeing to participate. Ineligible establishments are those that no
longer produce dietary supplements because they have gone out of
business or changed product lines, or they have moved and could not be
located. Despite receiving fewer responses than planned, the confidence
level for the final results allowed us to make meaningful inferences
regarding the industry. For example, 65 percent of the establishments
surveyed responded that they followed published good manufacturing
practice models; the 95 percent confidence interval was 56 to 72
percent. By size category, 52 percent of very small, 73 percent of
small, and 89 percent of large establishments responded that they
followed published good manufacturing practice models (Ref. E2).
Although we do not suggest that these percentages are precise, they do
tell a plausible story of the current use of good manufacturing
practice models in the supplement industry: The use of good
manufacturing practice models appears to be widespread but far from
universal, with use more likely the larger the establishment.
Table 7.--Number of Completed Surveys by Sampling Strata
----------------------------------------------------------------------------------------------------------------
Size
-------------------------------------------------
Product type Very
small Small Large Unknown Total
----------------------------------------------------------------------------------------------------------------
Vitamins and minerals......................................... 19 39 13 1 72
Amino acids, proteins......................................... 8 7 0 5 20
Herbals and botanicals, including extracts.................... 58 25 0 30 113
Supplements not already classified............................ 14 13 2 4 33
-----------
Total..................................................... 99 84 15 40 238
----------------------------------------------------------------------------------------------------------------
The mean survey results reflect the degree of uncertainty
associated with each practice. The use of a survey for this economic
analysis often required the use of the survey answers from more than
one question to assess the impact
[[Page 12228]]
of each proposed provision. For example, answers to questions about
testing herbals might have been combined with questions about whether
the firms manufactured herbals. Some highlights of the survey are:
[sbull] Plant characteristics: Manufacturers account for 62 percent
of the total firms and 36 percent of manufacturers produce vitamins and
minerals as their primary product.
[sbull] Use of published good manufacturing practice model: 65
percent of all firms follow some type of good manufacturing practice
model, primarily food good manufacturing practices; 28 percent follow
the NNFA good manufacturing practices and 31 percent follow FDA's drug
good manufacturing practice requirements.
[sbull] Personnel: 67 percent of all establishments maintain
records of personnel education, training, or experience.
[sbull] Quality control: 85 percent of all establishments have a
unit or person responsible for quality control. Almost 80 percent of
all manufacturers conduct at least some type of identity tests on
incoming components and dietary ingredients and 96 percent of these
firms also conduct some type of contamination test; 63 percent conduct
some type of potency test. Nearly 70 percent conduct tests on inprocess
materials or finished products. Of these firms, 97 percent conduct
identity tests, 94 percent conduct contamination tests and 72 percent
conduct potency tests. Asked whether firms hold reserve samples of each
finished batch, 75 percent answered yes. Of the plants that have
production processes, 70 percent use production and process controls
that identify the points, steps, or stages in the manufacturing process
to prevent adulteration. Almost 68 percent of all incoming ingredient
or component lots are tested now and almost 70 percent of inprocess or
finished product batches are tested in some manner.
[sbull] Warehousing: 70 percent of warehouses have temperature
controls and 22 percent have humidity controls.
[sbull] Consumer complaints: Only 19 percent report incidents to
FDA.
5. Baseline Risk
The current number of illnesses caused by poor manufacturing
practices requires data linking illnesses directly to poor practices.
Without direct evidence on the number of illnesses caused by poor
manufacturing practices, we had to use an indirect approach. There are
two indirect ways to estimate the number of illnesses caused by
defective products:
[sbull] We could take the number of reported cases and multiply by
a factor to account for underreporting.
[sbull] We could take the number of defective products and multiply
by the probability of illness for the given defect.
In an ideal analysis, we would estimate the baseline both ways and
then compare them. For the analysis of illnesses from poor
manufacturing practices, however, we did not have sufficient data to
perform either type of baseline estimate.
We looked at many sources for information, including medical and
other literature on adverse events, information from poison control
centers, reports to the agency, popular newspaper and magazine
articles, and surveys of users. The literature review was conducted
using Medline, Healthstar, Aidsline, Cancerlit, and OldMedline (Ref.
E12). We found evidence of many adverse events associated with dietary
supplements. For example, one recent survey found that 12 percent of
consumers (about 11.9 million) who have used an herbal remedy claim to
have suffered from side effects or other adverse reactions (Ref. E13).
The American Association of Poison Control Centers received 6,914
reports on dietary supplements in 1998 (Ref. E14). In a recent survey,
46 percent of respondents answered that people get sick from dietary
supplements ``often'' or ``sometimes'' (Ref. E3). In addition, the
agency has received many voluntary reports of illnesses caused by
dietary supplements (Ref. E15). The vast majority of the illnesses
described in the sources we consulted, however, are reported as
associated with the ingredients used in the products themselves, not
with poor manufacturing processes. We have no direct evidence on what
fraction of illnesses can be attributed to manufacturing processes. The
anecdotal evidence implies that many illnesses could have been caused
by poor manufacturing processes, but with a few exceptions, no evidence
explicitly links illnesses to these manufacturing processes.
The agency's recall records are more useful than the reports on
illnesses, because the class 1 and class 2 recalls all involve
defective products that could have caused illness if ingested. The
major public health events that have been linked to poor manufacturing
processes show up in the list of dietary supplements recalled. Although
the recall data cannot be linked directly to illness data, we have
found anecdotes, surveys, and some medical literature on illnesses that
could be caused by avoidable manufacturing mistakes. We have recall
data that show that manufacturing mistakes exist, so we can construct a
possible link between manufacturing mistakes and potential illnesses or
injuries. The number of illnesses associated with a recall is both
variable and uncertain, and could be anything from zero to quite large.
We concluded that one illness would not be an implausibly high average
for a recall, so we assumed that a recalled product could be a proxy
for a single reported illness associated with a defective product. We
ask for comments on this assumption.
Because there are no well established systems for the notification
of adverse health events related to dietary supplements, and some
significant barriers to reporting, we assume that unreported illnesses
caused by poor manufacturing practices are substantially greater than
reported illnesses. We relied on Ref. E16 to estimate a more precise
relationship between reported and unreported rates. Based on empirical
data for drug and vaccine reporting rates among other studies, the
author of Ref. E16 determined that for dietary supplements, reported
illnesses represent at best approximately 1 percent of total illnesses
(Ref. E16). A similar multiplier of 100 linking known cases of
foodborne illness to total incidence is often used. We assume that
reporting adverse health events due to poorly manufactured dietary
supplements would occur at the same proportion as adverse health events
caused for other reasons by dietary supplements. We show the
sensitivity of benefits to the choice of multiplier below, in the
uncertainty and sensitivity analysis of our results.
The outbreak of eosinophilia-myalgia syndrome (EMS) resulting from
contaminated L-Tryptophan resulted in the recall of the contaminated
products. In part based on this example, we assume that product recalls
can indicate when there are adverse health events. We also assume that
the reported class 1 and class 2 recalls that have occurred over the
last 10 years represent the number and type of recalls that will occur
in the future but for the implementation of this regulation. From 1990
through 1999, the agency received reports on an annual average of 13
class 1 and class 2 recalls of dietary supplements. If each recall is a
proxy for a reported illness, then the total number of unreported
illnesses per year is approximately 1,300. Obviously, to the extent
that products are successfully recalled, illnesses will be avoided. Our
assumption is that the recall occurs
[[Page 12229]]
because at best one person on average has been made ill. We recognize
that our procedure generated highly uncertain estimates of the number
of illnesses. The use of recalls to estimate reported and unreported
illnesses probably generated a distribution of illnesses below the
``true'' distribution, because many illnesses occur that are not linked
to recalls and are never reported. We were not able to determine even
the approximate size of the underestimation from this procedure.
We estimated the monetary value of the health benefits from CGMP
regulations by multiplying the number of illnesses prevented by the
health costs associated with an illness. The health benefits associated
with preventing an illness come from: (1) Preventing the loss of
productivity, (2) the reduction in pain and suffering, and (3) the
reduction in expenditures on medical treatment. We measured lost
productivity indirectly with measures of functional state, which
includes measures of physical function. We estimated the losses caused
by pain and suffering with a symptom-problem index. We used direct
measures of medical costs, such as payments to physicians and
hospitals.\4\
---------------------------------------------------------------------------
\4\ The cost of a hospital day is from the Health Care Financing
Agency's Indicator Tables. It is the amount per patient day in 1997,
adjusted to 1999 dollars. See Ref. E17.
---------------------------------------------------------------------------
Table 8 of this document contains summaries of our measures of the
health effects potentially caused by known instances of defective
products associated with poor manufacturing processes. We estimated the
health loss per day for the different levels of illness severity by
summing the lost productivity (as measured by functional state) and the
loss from pain and suffering (as measured by the symptom-problem index
\5\). These losses per day can be interpreted as the difference between
a day of normal health, where normal is defined as the population's
health not affected by these products, and a day of suffering from the
health conditions caused by these defective products. The numerical
scale is a relative baseline that rests on the notion of a quality-
adjusted life day (QALD). The QALD for a day of normal health equals 1;
the QALD for death equals 0. The loss of QALDs per illness equals the
daily loss multiplied by the number of days the illness lasts. We
converted QALDs to dollars by multiplying the index numbers by the
value of a statistical life day and adding the direct medical costs.
---------------------------------------------------------------------------
\5\ Functional Status Code is a measure of lost mobility (MOB),
physical activity (PAC) and social activity (SOC). Lost MOB might
mean an inability to drive a car. Lost PAC might mean walking with
physical limitations. Lost SOC might mean self-care is not possible.
Symptom-problem health utility index is a weighted measure of the
cost of each symptom. For example, a sick or upset stomach has a
utility weight of .290.
Table 8.--Summary of Health Effects Based on Potential Illness Associated With Recalls Between 1990 and 1999
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number Frequency of Quality Duration of Medical Health cost
Problem Class of of Outcomes illness adjusted illness cost ($) ($) per
recall recalls (percent) life day (days) per event event
--------------------------------------------------------------------------------------------------------------------------------------------------------
Hypervitaminosis A.................... 1 2 ......................... 100 0.472 3 84 936
Salmonella............................ 1 4 Mild..................... 93.8 0.473 2 0 534
........ ........ Moderate................. 5 0.473 5 800 2,223
........ ........ Severe................... 1.2 0.563 17 9,100 14,859
........ ........ Reactive arthritis (short 2 0.42 25 100 6,438
term).
........ ........ Reactive arthritis (long 1 0.42 5,223 400 1,320,252
term).
2 4 Death.................... 0.04 ............ ........... 9,100 5,009,100
Klebsiella pneumonia.................. 1 1 Severe................... 85 ............ ........... 6,235 10,650
........ ........ Death.................... 15 ............ ........... 6,235 5,006,325
Selenium poisoning.................... 1 1 Low doses................ 50 0.482 3 84 954
........ ........ Severe................... 35 0.482 3 2,578 4,448
........ ........ Death.................... 15 ............ ........... 2,578 5,002,578
Stannous fluoride..................... 1 1 Acute.................... 100 0.473 3 84 938
2 1 ......................... ............ 0.473 3 84 938
Eosinophilia-myalgia syndrome......... 1 7 Mild..................... 47 0.482 5,223 1,176 1,515,863
........ ........ Moderate................. 50 0.482 60 84 17,484
2 41 Severe................... 10 ............ ........... 14,964 27,394
Glass fragments....................... 2 1 Dental injury, simple.... 50 0.231 1 139 ...........
........ ........ Dental injury, 12 ............ ........... 3,741 ...........
complicated.
........ ........ Oral emergency........... 12 ............ ........... 3,741 6,428
........ ........ Tracheo-esophageal 25 ............ ........... ........... 290
obstruction.
........ ........ Esophageal performation.. 1 ............ ........... 14,964 23,343
Hypervitaminosis D.................... 2 1 ......................... 100 0.473 3 168 1,022
Pyridoxine (vitamin B6)............... 2 2 ......................... 100 0.482 30 168 8,868
Super-potent zinc..................... 2 1 Mild..................... 50 ............ ........... ........... 285
........ ........ Moderate................. 40 ............ ........... ........... 596
........ ........ Severe................... 10 ............ ........... 1,247 3,347
Niacin................................ 2 1 ......................... 100 ............ ........... 84 4,258
Yellow 5 (undeclared)........ 2 5 Mild allergic reaction... 90 0.44 2 0 529
........ ........ Severe allergic reaction. 10 ............ ........... 2,494 3,346
[[Page 12230]]
........ ........ Contact dermatitis....... 50 ............ ........... 84 1,205
Yellow 6, red 40, 2 1 Abdominal cramps......... 10 0.473 3 84 938
blue 2 (undeclared).
........ ........ Contact dermatitis....... 90 ............ ........... 84 1,205
Copper salts.......................... 2 1 ......................... 100 0.473 1 84 369
Digitalis............................. 1 33 Mild..................... 94.9 0.473 3 84 938
........ ........ Severe (heart block)..... 5 ............ ........... 1,247 455,883
........ ........ Death.................... 0.1 ............ ........... ........... 5,000,000
Ephedra (undeclared).................. 1 1 Cardiovascular........... 14 ............ ........... 1,415 3,530
........ ........ CVS w/chronic............ 2 ............ ........... 2,591 457,227
........ ........ Nervous system........... 14 0.47 2 1,331 1,900
........ ........ NS w/chronic............. 2 ............ ........... 2,507 455,597
........ ........ Liver impairment......... 4 ............ ........... 168 4,342
........ ........ Exfoliative dermatitis... 7 ............ ........... 84 1,206
........ ........ Other.................... 54 0.29 1 0 174
........ ........ Death.................... 3 ............ ........... 2,507 5,002,507
Lactose (undeclared) intolerance...... 2 1 Mild..................... 100 0.48 1 0 290
Iron poisoning........................ 2 1 Mild..................... 100 0.48 1 84 374
Sulfites (undeclared)................. 1 1 Mild allergic reaction... 100 0.44 2 0 529
--------------------------------------------------------------------------------------------------------------------------------------------------------
We used the transformed value of statistical life to estimate the
value of QALD. For the most likely value of a statistical life day, we
used $630. We derived this value from a widely-used estimate of the
value of a statistical life: $5 million. The $5 million estimate is
based on calculations matching labor market risks with wages for risky
jobs. Workers in risky jobs tend to receive increased wages to
compensate them for (usually) small increases in the probability of
death. The implicit value of a statistical life is the increased wage
divided by the increased probability of death. The advantage of valuing
statistical lives with this method is that it reflects the observed
willingness of workers, and by inference, of the whole population of
adults, to accept small risks to their lives in a real world risk-
dollar tradeoff.
We turn the estimated value of a statistical life into a value of a
statistical life day by first assuming that the workers have a
remaining life expectancy of 36 years (Ref. E18). Using a 3 percent
social rate of time preference, the present value of 36 years is 21.83
years. The social rate of time preference is the average long-term real
rate of interest, with no premiums for risk and other factors that
affect interest rates. Most analysts use the average real rate on long-
term treasury bonds (3 to 5 percent in recent years) to represent the
social rate of time preference. The discounted expected days lost for a
statistical death is 21.83 x 365 = 7,968. Therefore, the value of a
statistical day is $5 million/7,968, which is approximately $630. We
use this value to estimate the public health benefits from preventing
illness.
In addition to lost productivity and pain and suffering, illness
caused by supplement contamination leads to direct medical costs.
Direct medical costs include the cost of medicine, hospitalization, and
visits to physicians and other professionals. We included all estimated
medical costs, not just out-of-pocket expenses. These full medical
costs often are missed because most medical care is covered by health
insurance that separates the bearer of the medical cost (society) from
the bearer of the utility losses (the ill person).
The total costs of illnesses caused by the contamination of dietary
supplements from poor manufacturing practices would be the costs per
illness (classified by severity) multiplied by the number of illnesses
(classified by severity). For chronic illnesses, the utility losses and
medical costs stretch indefinitely into the future. We used a real
discount rate of 7 percent to calculate the present value of chronic
medical expenditures and utility losses. OMB suggests using a real
discount rate of 7 percent to analyze the costs and benefits of
regulations. This rate approximates the marginal rate of return on an
average investment in the private sector in recent years. We used a
different discount rate for the social rate of time preference (3
percent) and the discount rate of future medical costs (7 percent).
Medical costs, like all expenditures, reflect the foregone benefits
from alternative investments. The pure social rate of time preference
can differ from the return on private investments.
6. Benefits and Costs
Changes in current practices by manufacturers, or consumers, or
both, cause incremental (marginal) benefits and costs. There are
several possible reactions manufacturers might have to the proposed
regulatory requirements:
[sbull] Stop producing dietary supplements and possibly go out of
business.
[sbull] Move production to a foreign country where compliance with
these regulations is more difficult to enforce.
[sbull] Comply with part or all of the proposed regulation.
Consumers will likely be confronted with higher priced dietary
supplements but also products that are, on average, more uniform and
higher quality. To the extent that the latter is unknown to consumers,
they will probably reduce consumption of dietary supplements, perhaps
in some cases substituting them with alternative products such as
foods.
The benefits from the proposed regulation and the regulatory
options result from reducing contamination and adopting practices that
will result in consistently high quality dietary supplements. Creating
industry-wide minimum requirements for good manufacturing practices
should reduce the occurrence of product defects, which in turn should
reduce the number of illnesses and deaths.
[[Page 12231]]
Defective products can cause isolated cases of illnesses, but also rare
catastrophic events such as the outbreak of eosinophilia myalgia
syndrome (EMS) that resulted from the consumption of contaminated L-
Tryptophan. That outbreak caused 38 deaths and over 1,500 illnesses.
The provisions that require establishments to maintain consumer
complaint files related to manufacturing practices will generate
additional health benefits. The use of these files by manufacturers and
the agency will help identify dietary supplements that were
manufactured or contaminated in ways that could cause a significant or
unreasonable risk of illness or injury. These records may reduce the
likelihood of catastrophic events, because a cluster of illness
complaints could be identified, and preventive action taken before the
number of illnesses reached catastrophic levels.
Improved product quality will also reduce the number of products
recalled. Certain manufacturing practices, such as more frequent
finished product quality testing, help establishments to identify
problems before the products are released for consumption. If defective
products are caught before they are released, they will not be
recalled.
Creating minimum requirements should also generate benefits for
consumers by reducing the variation in product quality. Creating
verifiable minimum manufacturing requirements reduces the private
effort necessary to distinguish products manufactured, packaged, and
held using good practices from those using poor practices. Reducing the
effort needed to find products with the identity, purity, strength,
quality, and composition, among other characteristics, creates a
potentially substantial, though implicit, benefit for consumers.
The benefits from the proposed rule, then, are from:
[sbull] Reduced health costs caused by the reduced number of
illness;
[sbull] Fewer product recalls, and;
[sbull] Greater assurance of consistent and better quality
products.
a. Reduced illnesses. The proposed regulation would improve the
safety of dietary supplements, which would reduce the number of
illnesses and the probability of deaths caused by manufacturing
problems. The proposed rule would also improve product safety through
the provisions requiring records and investigations of consumer
complaints related to manufacturing practices. We assumed that the
proposed rule would reduce both sporadic illnesses and catastrophic
outbreaks. We estimated the reduction of sporadic or annual illnesses
by using the agency's recall records as evidence of possible illnesses;
class 1 and class 2 recalls of dietary supplements all involved
adulterated products that could have caused illness if ingested. We
estimated the reduction of illnesses from preventing catastrophic
events by using the public health effects of the outbreak of EMS that
resulted from consumption of contaminated L-Tryptophan.
i. Reduced illnesses estimated from recall data. For annual
illnesses, we used this formula for estimating the benefits from fewer
illnesses:
Marginal health benefits = baseline (or current) number of illnesses
caused by poor manufacturing practices x expected reduction in the
number of illnesses brought about by the proposed regulation x health
cost saved per prevented illness.
We estimated the annual expected health benefits for the proposed
rule by taking the values in table 8 of this document and weighing them
by their incidence in the table. We computed the expected health
benefits from preventing a single illness (of any type) associated with
a class 1 recall as a weighted average of all potential illnesses (see
table 8 of this document), with the potential illness divided by the
total number of class recalls.
The following formulas show how we calculated the average health
benefits of preventing a single illness associated with a class 1
recall.
$healthij = (QALD x days x $ per QALD)ij + $
medicalij
EBj = [Sgr]i (fij x
$healthij)
EB [c1] = [Sgr]j (wj x EBj)
wj = rj/([Sgr]j rj)
Where:
$healthij = health costs of severity level i of illness j;
QALD = quality adjusted life day;
$ per QALD = dollar value of a statistical day;
$ medical = direct medical costs;
Ebj = expected health benefit from preventing a single case
of illness j;
fij = frequency of severity i of illness j ([Sgr]
fij = 1);
m = number of levels severity for illness j;
EB [c1], EB [c2] = expected benefits from preventing an average illness
associated with a class 1 recall or a class 2 recall;
wj = weight of illness j;
rj = number of product recalls for hazard j;
n = number of hazards or potential types of illness.
We then repeated the procedure for class 2 recalls and the associated
illnesses in table 8 of this document. Table 9 of this document shows
the average value of preventing a single illness associated with class
1 and class 2 recalls.
We estimated the annual marginal health benefits as the health
benefits per illness for each class of recall multiplied by the
estimated number of recalls.
Health Benefits = (EB[c1] x estimated annual number of class 1
illnesses prevented) + (EB[c2] x estimated annual number of class 2
illnesses prevented).
To estimate the number of illnesses prevented, we started with the
average annual number of products recalled for the decade 1990 to
1999--six class 1 and seven class 2. As discussed above, we then
assumed that these recalled products represented proxies for about 1
percent of all illnesses caused by these problems leading to the
recalls. With that assumption, we get 600 illnesses from class 1
recalls and 700 illnesses from class 2 recalls (see table 9 of this
document).\6\
---------------------------------------------------------------------------
\6\ We used a probability distribution to represent the
uncertainty associated with the number of illnesses. We modeled the
number of illnesses prevented for each class as the average number
of recalled products plus a negative binomial distribution
representing unknown cases. The negative binomial distribution
estimates the number of failures (unknown cases) that will occur
before some number of successes (known cases) for a given
probability of success. In the negative binomial distribution, we
assumed that the number of recalled products were reported cases and
that the probability of reporting equaled 1 percent (Ref. E16). The
result is that the mean estimated number of illnesses is 100 times
the reported number of recalls.
---------------------------------------------------------------------------
Table 9 of this document shows the estimated value of the health
benefits from the proposed rule using class 1 and 2 recall data.
Table 9.--Health Benefits Using Recall Data
------------------------------------------------------------------------
------------------------------------------------------------------------
Total number of illnesses prevented, recall base............. 1,300
Total number of illnesses associated with class 1 recalls.... 600
Total number of illnesses associated with class 2 recalls.... 700
[[Page 12232]]
Dollar estimate of health benefit for preventing an illness $60,000
associated with a class 1 recall............................
Dollar estimate of health benefit for preventing an illness $5,000
associated with a class 2 recall............................
Dollar estimate of annual health benefits, recall base $39
(million)...................................................
------------------------------------------------------------------------
ii. Health benefits from preventing a rare catastrophic event. We
estimated the marginal health benefits from reducing the probability of
a catastrophic event as follows:
Marginal health benefits = Change in probability of rare catastrophic
event caused by poor manufacturing practices brought about by the
proposed regulation x the number of illnesses caused by the rare event
x health cost saved per illness.
In 1989, there was a widespread outbreak of EMS resulting from
consumption of contaminated L-Tryptophan. More than 1,500 cases (175
acute illnesses and 1,287 chronic illnesses) and 38 deaths were
identified in 50 states (Refs. E21 and E22). The outbreak prompted a
recall of all dietary supplements that contained more than 100 mg per
daily dose, which later was expanded to almost all products containing
L-Tryptophan. We used the public health cost of this event as an
estimate of the cost of a future rare catastrophic event associated
with dietary supplements.
EMS is characterized by severe myalgia and elevated eosinophils
counts. Some of the most common symptoms are fatigue, weakness, fever,
and arthralgia. Although a repeat of the EMS outbreak is not expected,
it is an example of the rare, catastrophic events that should be
prevented or mitigated by the proposed CGMP regulation. The testing
provisions of the proposed regulation should reduce the probability
that contaminated ingredients would be released to the public. The
provisions for keeping complaint files and investigating complaints
would allow more rapid identification of a major health event; the
defective products could be identified and withdrawn well before the
event claimed as many victims as L-Tryptophan.
To estimate the benefits from preventing reduction in the
probability of a rare catastrophic event occurring, we first estimated
the period between now and the last rare catastrophic event, 1989, and
we needed to make baseline assumptions about the likely time interval
between events. The last catastrophic event occurred over 13 years ago,
so we assumed that the lower bound would be 50 years. For lack of data,
we then assumed a uniform probability distribution between these two
bounds, which leads to a rough estimate of once in 30 years. We do not
know how likely rare events are, nor do we actually know the likelihood
of reducing these events by the proposed regulation. There can be no
conclusive empirical support for the likelihood of a future event
because the past may not predict the future in the absence of a stable
frequency distribution that reflects a statistically significant number
of similar events. All we know is that such an event occurred at least
once in the recent past, and remains a possibility. We recognize that
our lack of information about such events creates significant
uncertainty about the social costs of these events and the health
benefits from reducing their impact. Our estimate is meant to convey
the potential or hypothetical enormity of such an event, not the
certainty of such an event. We would like comments regarding our
estimate of such an event.
The health cost of the EMS outbreak was large because of the
number, severity, and duration of the cases. One followup study (Ref.
E21) found 88 percent of EMS patients were still symptomatic 21 to 64
months after onset. The symptoms associated with EMS also frequently
lead to activity limitations. Another study of victims (Ref. E22) found
that 74 percent of symptomatic EMS sufferers were limited in their
functions 12 months after the onset of illness.
To find the health cost of the outbreak, we estimated the cost of
the following health outcomes: Death, acute illness only, chronic
illness with no activity limitation, chronic illness with mild activity
limitation, chronic illness with moderate limitation, and chronic
illness with severe limitations. To determine the cost for each of
these health outcomes, we multiplied the lost quality-adjusted life
days over the duration of the illness by the value of a life day. For
medical costs, we estimated the cost of hospitalization for the EMS
patients who required hospitalization (32 percent of all victims), by
assuming 3 days per hospital stay. We used $1,284 as the cost per day
of time spent in a hospital (Ref. E17). We assumed that chronic
sufferers visited the doctor once a year at a cost of $84 per visit. We
estimated the total cost of the event to be about $2 billion. Most of
the cost of the outbreak comes from the deaths and severe chronic
illnesses. Table 10 of this document shows the values used in the
calculation. Note that the categories are not mutually exclusive. The
average age of victims was about 50, so the value of statistical life
was adjusted accordingly. If the event occurs about once in 30 years in
the absence of the proposed rule, then the expected average annual cost
would be about $66 million.
Table 10.--Health Benefits From Preventing Rare Catastrophic Event
------------------------------------------------------------------------
Costs per
Number case
------------------------------------------------------------------------
Hospitalization............................... 480 $3,741
Death......................................... 38 4,214,301
Acute Illness................................. 175 8,760
Chronic illness not limited................... 380 1,091,849
Mild chronic illness, limited................. 190 1,349,002
Moderate chronic illness, limited............. 307 1,601,539
Severe chronic illness, limited............... 409 1,602,844
Visits to physicians.......................... 1,287 1,539
------------------------------------------------------------------------
[[Page 12233]]
The benefits attributable to this proposed rule from preventing a
rare catastrophic event are highly uncertain. We do not know if such an
event would, in the absence of the proposed regulation, ever occur
again. The EMS outbreak may have been a unique event, although the
recent severe public health effects associated with aristolochic acid
in Europe show that such similar events remain possible (Ref. E23). We
also do not know that if another catastrophic event occurred, the
health effects would be as large as for L-Tryptophan. Some of the
smaller clusters associated with dietary supplements could represent
small events potentially prevented by the proposed CGMP regulations
(Ref. E15).
We included reducing the likelihood of a catastrophic public health
event as a benefit of the rule because the battery of checks and
controls that would be required under the proposed regulation would
reduce the likelihood of such an event occurring again. In particular,
the requirement that establishments keep records of consumer complaints
should lead to early identification and prevention of potential
catastrophic events related to manufacturing practices.
Our estimate of the health benefits associated with this proposal
is based on two models that estimate future illnesses and deaths
prevented by this proposed rule: Illnesses caused by sporadically
adulterated products and predicted by recall data; and rare
catastrophic outbreaks of illnesses, as predicted by one previous event
in the United States and corroborated by one in Europe. The frequency
and magnitude of a rare catastrophic event is largely hypothetical. In
contrast, sporadic illnesses are small but frequent events that happen
routinely. Small sporadic events are characterized by significant
underreporting primarily because of the difficulty linking an illness
with the cause of an illness. Determining the cause of an illness in
small sporadic events is made even more difficult because only the most
serious illnesses are likely to be reported and because of the
difficulty of linking the cause of an illness with poor manufacturing
practices. Catastrophes are large but infrequent events that create
hundreds of illnesses with reporting that is close to complete because
the public health system typically devotes considerable care in
identifying the origin and magnitude of the problem. Adding these two
models should not lead to double counting the health benefits. Double
counting would most likely occur if a recalled product caused both
sporadic illnesses and a catastrophic number of illnesses and the
public health system accurately recorded the full number of both
sporadic and catastrophic illnesses.
b. Fewer products recalled. Implementation of the proposed
regulation would reduce the number of adulterated products distributed
to the public, which would reduce the number of products recalled.
Manufacturing practices, such as testing of finished products and
better recordkeeping, will increase the ability of establishments to
identify problems before products are released for distribution. If
adulterated products are caught before they are distributed, they will
not be recalled.
To estimate the direct benefits from fewer recalled adulterated
dietary supplements, we estimated the baseline number of annual recalls
of dietary supplements due to contamination before the proposed
regulation. From 1990 to 1999, FDA received reports on an average of 20
recalls per year (Ref. E12). The average figure reported here includes
class 3 recalls. The number of units of dietary supplements for each
recalled product varied, so we used a distribution per recalled product
of 1,000 units to 34,000 units (Ref. E12). Product price also varied,
with most prices falling between $5 per unit and $9 per unit; we used a
most likely price of $7.70 per unit. We also included an adjustment for
the goodwill lost by the establishment as a result of the recall.
Studies of changes in market valuations of firms after recalls indicate
that the value of lost customer goodwill, based on the decline of the
share price of publicly traded stocks from recalls is often as large as
the cost of the recall itself (Ref. E24). We multiplied the direct cost
of the recall by two in order to include the lost goodwill. The result
is an estimated savings of about $3 million per year.
We based the estimated benefits from fewer recalled products on our
recall data. If there were private recalls due to contaminated
supplements that were not included in our data, the benefits from
reduced recalls may be understated.
c. Reduced hypothetical search costs as a measure of the benefit
from increased assurance of quality. Consumers incur a cost if they
purchase products but do not get the quality of product they
anticipated. Determining the cost they incur is difficult, because we
cannot look at the price of poor quality products and conclude that
consumers paid too much, even when they did not get the quality they
anticipated. We cannot disentangle the price consumers are paying, from
the price they should be paying, because we assume consumers expect
some unknown number of their products may not meet their expectations
but purchase them anyway. In other words, we cannot rule out the
possibility that the purchase price already incorporates the
expectations of consumers that some products will be ``lemons.''
Because we cannot look into the minds of consumers to determine their
expectations or their willingness to pay for these products, we can
only estimate the benefits from more uniform quality by estimating the
changes in behavior that would occur if consumers were aware of the
change in quality brought about by the proposed rule. In other words,
we assume that if the quality attributes of dietary supplements were
observable, then consumers would spend time searching for those
attributes, as they do for other goods. We measured this benefit as a
reduction in the hypothetical search costs for product quality, meaning
the identity, quality, purity, strength, and composition claimed on the
label.
The hypothetical measure of quality starts by assuming the
existence of a baseline amount of search necessitated by the existence
of poor manufacturing practices. Our hypothetical consumers must search
for products made with good manufacturing practices, because they
cannot take such practices for granted when purchasing dietary
supplements. Although the search we use as a measure of the benefits
from improved quality is hypothetical, the values we use in estimating
our search model are based on data and inferences about real searches
for other products.
To get the products they want, people search across the range of
market alternatives. Several recent articles have noted the large
variation in product quality for different goods and services (Refs.
E25, E26, and E27). Searching takes time and resources that could be
used for other purposes, so a regulation that reduces search provides
measurable benefits to consumers. To reduce the effort devoted to
searching, consumers of dietary supplements should therefore be willing
to pay some amount. We lack, however, a measure of what they would be
willing to pay, partly because some consumers may not know that dietary
supplements may contain more or less (or something not even expected)
of what they think they are buying. Indeed, if consumers of dietary
supplements could determine the quality of these products by merely
examining the product or the label, the market alone would be
sufficient to ensure that firms responded to consumer preferences for
product quality. Consumers would search for those brands that are more
[[Page 12234]]
likely to have the desired quality, and manufacturers would most likely
adopt sufficient quality controls to satisfy consumer preferences. The
market response is weak now because only some consumers know that
product quality problems exist, and even these consumers must rely on
imperfect information. If there were uniform quality control practices
throughout the industry that ensured against product quality defects,
consumers would not have to search for the products that they believe
are free from contamination or have the identity, purity, strength,
quality, and composition they want. Consumers could more reasonably
assume that all products are free from contamination and have the
identity, purity, strength, quality, and composition stated on the
label.
We faced the problem of trying to measure what people would pay for
more uniform products quality if they knew that manufacturing quality
requirements did not already exist. To estimate what people would pay,
we start with the hypothetical behavior of people aware of the lack of
uniform product quality; we call these hypothetical people the
``sophisticated consumers.''
Sophisticated consumers spend time searching for signals about the
quality of dietary supplements. The proposed CGMP regulations would
reduce the amount of search (by some uncertain amount) carried out by
these consumers. The benefits of the rule, however, would not be
confined to sophisticated consumers. We also expect ``naive consumers''
to enjoy the benefits. Naive consumers would incur the costs of
additional search once the correct or adverse information about quality
is available, suffer from worry or an illness from taking poor quality
products, or incur the cost of paying for products that do not meet
their needs (Ref. E28). Once good practices are in place they would
avoid these costs. Naive consumers are those who fail to search for
quality or search little not because they do not care but because they
do not know that quality varies as much as it does. In other words,
they lack the information that problems exist; if they know about the
problems, they would search or be willing to pay more to ensure that
supplements they consume meet minimum quality standards. Although these
naive consumers may not change their behavior in response to the
proposed CGMP regulation, they would nonetheless enjoy the benefits.
The naive consumers, of course, also represent real consumers of
dietary supplements. The total benefits of the quality standards part
of the proposed rule will be the implicit value of the gain in product
quality enjoyed by all consumers.
The problem is to measure that gain based on hypothetical searches.
We needed to use data from searches in other markets, because we found
no information on direct or indirect searching for minimum dietary
supplement quality standards. For the sophisticated consumer, we
assumed that the value of search time should be approximately the same
as the willingness to pay for an attribute of the good. Sophisticated
consumers will hypothetically search until the expected benefit of
continued searching is less than the expected cost of continued
searching. The total cost of search time will, on average, be no more
than the expected cost of the additional quality desired. Search time
includes the time spent: Reading product labels and other literature
about the product, comparing one product with other products, examining
the product itself (sometimes carefully), thinking about the product,
and second guessing final decisions. It might also include the time
actually shopping for the product: Finding the locations where the
product is sold, driving there and back, waiting in checkout lines, and
walking up and down the aisles.
We used information on shopping times for a range of products to
derive an estimate for the hypothetical search time for dietary
supplements. We assumed that some fraction of shopping time is pure
search time, although we also recognize that search time includes more
than the search for product quality. Some search time, for example, is
for price, efficacy, and other attributes. The reduction in search time
for the sophisticated consumer would therefore be at most a fraction of
total search time for dietary supplements. The measure of time saved
then is:
Reduced search time due to CGMP regulation = shopping time x fraction
of shopping time spent searching x fraction of search time associated
with searches for quality x fraction of search time associated with
searches for quality that would be eliminated if CGMP rule guaranteed
minimum quality.
We took the estimated reduction in hypothetical search time for the
sophisticated consumer and applied it to all consumers to get an
estimate of the implicit benefits of establishing minimum quality
standards. This estimated saving in hypothetical search time is not a
forecast of reduced shopping time; it is a proxy measure of the benefit
from reduced variance and improved mean product quality. We anticipate
little or no change in aggregate shopping time for dietary supplements.
We converted the time measure into a monetary measure by
multiplying the time reduction for sophisticated consumers by the
average wage rate. The benefits measure reduced search time associated
with improved quality assurance:
Quality assurance benefits = reduction in search time (in hours per
year) per sophisticated consumer x average wage rate per hour x total
number of consumers.
The shopping time model is an indirect approach to measuring benefits
in a market with asymmetric information; it is not a prediction about
how shopping behavior will change in that market. Indeed, we believe
that most of the beneficiaries of this part of the rule will never
recognize that they are beneficiaries.
Standardization imposes minimum requirements on manufacturing,
which in turn should reduce the variance of product quality. The
reduction in product quality variation should reduce the amount of
information sophisticated consumers need to acquire before purchasing
dietary supplements (Ref. E29). People need not rely as much on such
indicators as brand names, price, place of purchase, articles in
consumer magazines, or advertising to determine the likelihood that
dietary supplements meet minimum quality standards.
Although no studies deal with dietary supplements directly, the
literature on consumer search for other commodities provides insights
that increase our understanding of the search costs for supplements
(Refs. E30 and E31). Duncan and Olshavsky (Ref. E32) surveyed buyers of
television sets and found that 88 percent of respondents performed some
type of search activity before purchase. In a study (Ref. E33) of
consumer search for microwave ovens, the average buyer of a new
microwave oven was willing to search for four alternative products.
Search for groceries has been characterized as a two-stage process
(Ref. E34). First, people engage in prestore activities, such as
reading advertisements, writing shopping lists, clipping coupons, and
comparing stores. Second, people engage in search activities at the
store, including price and product comparison and search for items with
coupons. Most people devote time to search activities for all but the
most routine purchases.
To estimate the reduction in hypothetical search costs from the
proposed rule, we started with estimates
[[Page 12235]]
of the time consumers spend in search for groceries and other household
purchases (including durable goods). We assumed that the search time
for these products was related to shopping time. Because search costs
include the costs of evaluating magazine articles or brochures, the
costs of obtaining a friend's advice, and the costs of instore product
comparisons, our estimates will not correspond precisely to the actual
costs of search for these products (Ref. E35). We believe, however,
that the measure will be a reasonable approximation. Although search
time often takes place outside of measured shopping time, measuring
search time as some proportion of total shopping time should generate a
plausible if not a precise estimate.
We generated three models of search time for dietary supplements,
based on three separate studies of shopping time:
[sbull] Drug Store.
[sbull] Use of Time.
[sbull] Grocery Store.
We used three models based on different assumptions because using a
range of studies reduced the likelihood of systematic bias in our
analysis.
The drug store model. The drug store study recorded the amount of
time people spent looking at an item on the shelf before making a
purchase (Ref. E36). Customers, on average, spent 3.75 minutes studying
a product before purchasing it. Although there are quality standards in
place for over-the-counter drugs and not for dietary supplements, we
assumed that this represented a measure of the amount of time the
sophisticated consumer might spend searching for a product with the
desired quality.
The use of time model. The Americans' Use of Time Project (Ref.
E37) used time diaries to study how adults spent all of their time. The
study collected data from over 3,500 adults on use of time. Data from
these time diaries reveal that adult Americans spent about 364 minutes
per week shopping for personal consumption items, such as groceries and
other household products.
The grocery store model. In the grocery store study, hidden
observers tracked and recorded shopping time in the store (Ref. E38).
The study found that people on average spent about 21 minutes shopping
in the grocery store. By combining estimated time per trip with the
Food Marketing Institute's (Ref. E10) finding that consumers average
about 2.2 grocery shopping trips per week, we generated an estimate of
search time for all grocery store purchases of 46.2 (= 2.2 x 21)
minutes per week.
For each of the models, we needed to make assumptions to convert
shopping time for other commodities into search time for dietary
supplements. Table 11 of this document shows the assumptions and
information used in each model.
Table 11.--Three Models of Search Time: Assumptions Used in Simulations
------------------------------------------------------------------------
Value or
Variable distribution Source and notes
------------------------------------------------------------------------
Drug Store Model
------------------------------------------------------------------------
Search time in minutes per 3.75................ Ref. E30.
item.
Number of products per 6.57................ Ref. E4.
person per year.
Average wage rate........... $15.65 per hour, or Ref. E42.
$0.26 per minute.
Population.................. 273 million......... Ref. E19.
Fraction of search time 0.2 (based on Based on number of
devoted to searching for uniform attributes
quality. distribution, 0.1 consumers search
to 0.3). for.
-----------------------------
Use of Time Model
------------------------------------------------------------------------
Weekly shopping time for all 346................. Ref. E37.
items in minutes.
Fraction percent of budget $15.5 billion/$6,250 Ref. E4 and E19.
spent on supplements. billion.
Average wage rate........... $15.65 per hour, or Ref. E42.
$0.26 per minute.
Adult population............ 205 million......... Ref. E19.
Ratio of search time to 0.7 (based on Based on
shopping time. uniform descriptions of
distribution, 0.4 shopper behavior.
to 1.0).
Fraction of search time 0.2 (based on Based on number of
devoted to searching for uniform attributes
quality. distribution 0.1 to consumers search
3.0). for.
Potential reduction in 33% most likely Based on likelihood
search time attributable to (could be between of problem and
CGMP regulations. 15 and 50%). likelihood that
search will decline
proportionally, and
the expert opinion
of pharmacists.
-----------------------------
Grocery Store Model
------------------------------------------------------------------------
Weekly shopping time for 46.2................ Ref. E38.
groceries in minutes.
Ratio of supplement $15.5 billion/$710 Ref. E38.
expenditures to grocery billion.
expenditures.
Average wage rate........... $15.65 per hour, or Refs. E4 and E19.
$0.26 per minute.
Adult population............ 205 million......... Ref. E19.
Ratio of search time to 0.7 (based on Based on
shopping time. uniform descriptions of
distribution, 0.4 shopper behavior.
to 1.0).
Fraction of search time 0.2 (based on Based on the number
devoted to searching for uniform of attributes that
quality. distribution, 0.1 consumers search
to 0.3). for.
Potential reduction in 33% most likely Based on likelihood
search time attributable to (could be between of problem, the
CGMP regulations. 1% and 50%). likelihood that
search will decline
proportionally, and
the expert opinion
of pharmacists.
------------------------------------------------------------------------
The drug store data generated a direct estimate of search time. In
the drug store model we assumed that the time spent standing in front
of the drug product could be used to estimate the time searching for
dietary supplements. We then used data on the number of products
purchased per person and the total U.S. population to generate an
estimate of annual search time for dietary supplements.
[[Page 12236]]
To estimate the time spent searching for supplements from the use-
of-time study, we assumed that the share of all shopping time devoted
to supplements would be proportional to the share of a consumer's
budget spent on supplements. We recognize that it could well be higher
if supplements require more search than the average commodity.
According to an industry source and FDA projections, consumers spent
about $15.5 billion on dietary supplements in 1999 (see table 5 of this
document). Consumers spent about $6,250 billion on all personal
consumption in 1999, which means that dietary supplements accounted for
about 0.24 percent of those expenditures. Personal consumption
expenditures included in this estimate are food, alcoholic beverages,
housekeeping supplies (such as laundry and postage), household
furnishings and equipment (such as furniture and appliances), apparel
(includes footwear), personal care products and services, reading
materials, tobacco products, and smoking supplies. Annual shopping time
per person for dietary supplements would therefore be about 44.6
minutes per year (= ($15.5 billion/$6,250 billion) x 346 minutes per
week x 52 weeks). We converted shopping time to search time by assuming
that search time equaled 40 to 100 percent of shopping time. Total
search time equaled search time per adult multiplied by 205 million
adults. We assumed that all adults would perform search, although we
recognize that not all adults consume dietary supplements and not all
search is conducted by adults. Children might search for these products
also. The opportunity cost for children, as measured by their wage rate
is much less than for adults, so we assumed their search time could be
ignored. We used the total adult population rather than just the adult
consumers of dietary supplements, because the shopping time studies are
for all adults.
We estimated search time in the grocery store model with
assumptions similar to those in the use-of-time model. We assumed that
the ratio of search time for supplements to search time for groceries
would equal the ratio of expenditures on supplements to expenditures on
groceries. Estimates from the 1998 Consumer Expenditure Survey (Ref.
E39) (adjusted for changes in prices between 1998 and 1999) reveal that
consumers spent approximately $710 billion on grocery store purchases
in 1999. Grocery store purchases included food, alcoholic beverages,
housekeeping supplies, personal care products, tobacco products, and
smoking supplies. Annual shopping time per person for dietary
supplements would therefore be about 52.5 minutes per year (= ($15.5
billion/$710 billion) x 46.2 minutes per week x 52 weeks). We again
converted shopping time to search time by assuming that search time
equaled 40 to 100 percent of shopping time. Like the estimate from the
use of time model, this value was then multiplied by 205 million
adults.
We used these three models based on different assumptions because
we wanted to explore a range of studies to avoid systematic bias in our
analysis. We recognize that the three estimated annual search times for
dietary supplements do not represent the search for quality alone.
Consumers search for a variety of features; only part of every search
will be devoted to quality. We assumed that 10 to 30 percent of pure
search time involves quality searches. Estimating the impact of CGMP
regulations on consumers' search time is difficult, since no previous
studies have analyzed the changes in search time following the adoption
of CGMP regulations or from increases in product quality
standardization. However, a consistent finding from the literature is
that search time should decline following a decrease in the variation
in product quality (Refs. E35 and E40). In the absence of previous
empirical studies, we assumed that the proposed rule would reduce the
hypothetical search time for quality ``the search time of sophisticated
consumers'' by 1 to 50 percent, with 33 percent the most likely value.
A survey of pharmacists reported their belief that 30 percent of their
customers place manufacturing quality as a top priority in selecting
one herbal over another (Ref. E41). We also used evidence from product
tests that indicated that up to 33 percent of products were missing key
ingredients or contained unwanted ingredients (Refs. E25, E26, and
E27). If the proposed rule guarantees that products will contain what
the label claims, then perhaps search time for quality will decline by
that percentage.
To estimate the value of the possible reduction in searching for
quality, we multiplied our estimated time saving by the average wage
rate, which is an estimate of the value of time. The average hourly
wage rate for U.S. workers was $15.65.\7\ We ran computer simulations
of all three models. The results for the three models are shown in
table 11 of this document.
---------------------------------------------------------------------------
\7\ Personnel Employment, Hours, and Earnings. Series ID:
EES00510006 Seasonally Adjusted, Industry: Goods-producing Data
Type: Average hourly earnings of production workers, Employment Cost
Index, Bureau of Labor Statistics.
---------------------------------------------------------------------------
d. Other benefits. The proposed regulation could also reduce the
total time and effort that all covered establishments expend to monitor
ingredient suppliers and holders of their products. Because all
ingredients and holders would be subject to the same uniform minimum
requirements, variation in their practices would decline, so firm
monitoring of upstream and downstream vendors could decline.
The provision that requires establishments to maintain complaints
files would allow a manufacturer to more readily be able to identify a
product that causes a significant or unreasonable risk of illness or
injury. The manufacturer can then take necessary steps to prevent any
additional adverse health impact. We have attempted to quantify this
benefit for preventing catastrophic events, but not for reducing
smaller risks. FDA adverse event reports, however, imply that many such
small events occur, and the proposed rule could prevent some of them
(Ref. E15).
In addition, if the same adverse events show up in complaints
received by different firms selling products with the same or similar
manufacturing problems, no one firm selling such products may recognize
the need to investigate the complaints especially if the risk is
relatively low. Because we would have access to complaint files, our
review would be more likely than any individual firm's review to
identify the need to investigate the complaint because of a reasonable
possibility of a relationship between the manufacturing process of a
dietary supplement and the adverse event.
e. Total measured benefits. The total measured benefits from the
proposed rule are the sum of the value of health benefits, the value of
the reduced number of product recalls, and the reduction in
hypothetical search costs. Table 13 of this document shows the total
benefits.
Table 12.--Three Models to Estimated Search Cost Savings
------------------------------------------------------------------------
Cost savings
Baseline model (in millions)
------------------------------------------------------------------------
Drug store model....................................... $108
Use of time model...................................... 101
Grocery store model.................................... 119
Average of three baseline models....................... 109
------------------------------------------------------------------------
[[Page 12237]]
Table 13.--Summary of Annual Benefits
------------------------------------------------------------------------
Mean (in
Benefits millions)
------------------------------------------------------------------------
Fewer illnesses (from table 8)......................... $39
Fewer illnesses (from table 10)........................ 66
Fewer product recalls (from table 9)................... 3
Reduced consumer search (from table 12)................ 109
----------------
Total benefits..................................... 218
------------------------------------------------------------------------
7. Costs
The same changes in practices that produce benefits also have
costs, the opportunity costs of not doing what consumers and
manufacturers are now doing. The proposed regulation would require
dietary supplement establishments to adopt some new practices in order
to manufacture, package, and hold their products. The costs incurred
for those who choose to comply will be for personnel, grounds and
physical plant, equipment and instrumentation controls, quality control
and laboratory operations, production and process controls, handling
consumer complaints, and holding. In some cases, establishments would
need to make capital improvements to the physical plant, add or replace
equipment or controls, perform additional maintenance, keep records,
carry out tests, or execute a variety of additional tasks that they may
not have previously performed. We estimated the additional costs of
production associated with the proposed rule and the leading regulatory
options, using the survey (Ref. E2) to estimate baseline manufacturing
practices.
a. Description of the costs. To estimate costs for the dietary
supplement industry, we initially divided the industry into four
product categories and three size categories. Because the survey showed
that there were only a few establishments in some categories, we
consolidated the size and product into three size categories. The size
categories were:
[sbull] Very small (fewer than 20 employees).
[sbull] Small (20 to 499 employees).
[sbull] Large (500 or more).
Although this consolidation glosses over the important differences
across products, the purpose is to estimate the broad average costs of
the rule.
For each category, we constructed a cost model that included every
provision of the CGMP regulations that the proposed rule requires or
recommends. We then attached a cost to each provision that had an
activity associated with it. Most provisions did not have costs
attached to them, mainly because they were either descriptive or the
costs were included elsewhere. For the rule as a whole, we estimated
the marginal, or additional costs for over 70 provisions of the
proposed rule.
We expressed the cost as cost per unit, with the unit being either
the establishment, the number of employees, or the annual number of
batches produced. The costs of this proposed rule included the
following general activities: Sanitation, production and process
controls, holding and distributing, and consumer complaints.
b. Costs of general activities. i. Sanitation. Sanitation includes
both one-time capital improvements and ongoing efforts. Some provisions
of the proposed regulation may require establishments to perform one-
time capital improvements to their physical plant facilities.
The proposed regulation would also require, if not already in
place, physical plant owners to install new or additional plumbing
systems to carry additional water or sewage, additional toilet or hand
washing facilities, additional facilities for trash disposal, or new
signs to instruct employees. The proposed regulations might also
require establishments to add space in order to keep equipment and
materials farther apart, which will help to prevent contamination or
mixups. Other possible capital expenditures (among many other possible
requirements) include:
[sbull] Replacing floors, walls, or ceilings with smooth, hard
surfaces;
[sbull] Changing fixtures, ducts, or pipes that might be a source
of contamination by dripping or condensation;
[sbull] Adopting ventilation control systems including filters,
fans, or other air-blowing equipment to prevent odors or vapors;
[sbull] Additional lighting to ensure that equipment, contact
surfaces, or other areas where supplements are examined, processed, or
held can be adequately seen.
Sanitation also requires that equipment utensils must be of
suitable design, construction, and workmanship to enable them to be
adequately cleaned and maintained. To meet this requirement, some
establishments may need to provide additional maintenance or additional
cleaning and sanitation for their equipment and utensils. Also,
freezers and cold storage compartments used to slow or arrest the
growth of microorganisms must be fitted with thermometers to accurately
show the temperature within the compartments. Instruments and devices
used in manufacturing must be accurate, adequately maintained, and
adequate in number. To meet this requirement establishments might have
to purchase new equipment, replace old equipment, or provide additional
maintenance to existing equipment.
ii. Production and process controls. Production and process
controls are the main preventive mechanism to ensure the identity,
purity, quality, strength, and composition in the proposed rule.
Establishments must implement a system of production and process
controls that covers all stages of processing, from the receipt and
acceptance of components, dietary ingredients, dietary supplements,
packaging, and labels through the release for distribution and holding
of the dietary ingredients and dietary supplements. Establishments must
identify points, steps, or stages in the manufacturing process where
control is necessary to prevent adulteration. Establishments must also
establish specifications for the identity, quality, purity, strength,
and composition of components, dietary ingredients, or dietary
supplements. Establishments must monitor the points, steps, or stages
in the batch production, as specified in the master manufacturing
record, where control is necessary to prevent adulteration.
Establishments must establish specifications for packaging to ensure
that containers or closures that come into contact with dietary
ingredients or dietary supplements are not reactive or absorptive and
are composed of substances that are safe for use in or on food.
Establishments that have not already done so must establish a
quality control unit with one or more individuals that have with the
authority and responsibility to review the results of monitoring, make
decisions on the disposition of materials, and identify whether actions
taken to correct any deviations are appropriate. The quality control
operation must ensure that components, dietary ingredients, and dietary
supplements conform to specifications.
iii. Holding and distributing. Establishments must hold and
distribute dietary ingredients and dietary supplements under
appropriate conditions of temperature, humidity, and light so that the
identity, quality, purity, strength, and composition of the dietary
ingredients and dietary supplements are not affected. Establishments
must also identify and
[[Page 12238]]
hold components, in-process materials, and dietary supplements under
conditions that will protect them against mixups and physical,
chemical, and microbial contamination. Packaging materials must also be
protected against deterioration. Establishments that do not now perform
these requirements and the other provisions associated with holding
will incur a compliance cost.
iv. Consumer complaints. The quality control unit must review all
consumer complaints involving the failure of a dietary supplement to
meet any of its specifications, or the failure to meet any other
requirements under proposed part 111, including those specifications
and other requirements that, if not met, may result in possible illness
or injury. In addition, the quality control unit must investigate such
a consumer complaint where there is a reasonable possibility of a
relationship between the consumption of a dietary supplement and an
adverse event. The complaint and report of the investigation results
should be reported to FDA when there is a possibility of a serious
adverse event.
c. Major costs by type of activity. Within these four categories
(sanitation, production and process controls, holding and distributing,
consumer complaints), the major costs of the proposed rule are
recordkeeping (except for sanitation), capital costs for physical plant
and equipment, finished product quality testing (part of production and
process controls only), labor costs for certain required tasks, and
some other costs that were not easily classified.
i. Recordkeeping. We used a study of a medical device CGMP
regulation to estimate the costs of recordkeeping (Ref. E44). We
request comments on the applicability of a study of the medical device
CGMP's to dietary supplements.
The compliance cost of recordkeeping is the sum of both the initial
design and printing of the recordkeeping documents and the recurring
costs of maintaining the records. The cost of training personnel to use
mandatory records is a recurring cost that depends on how frequently
records are modified, the frequency of personnel turnover, and how
complicated the tasks are that are being recorded. The recurring costs
are measured by the workers' wage rate, which we assumed is $15.65 per
hour based on the average manufacturing wage, multiplied by the
expected labor hours necessary to perform a written or electronic
record and the time necessary for management to review the records to
see the actions are documented accurately. For electronic records, the
recurring time is the time necessary to ensure that the equipment is
serviced and maintained properly.
ii. Capital costs for physical plant and equipment. We estimated
capital costs for physical plant redesign at $50 per square foot (Ref.
E45). For establishments with inadequate facilities, we assumed that
between 0 and 20 percent of the physical plant would have to be
renovated, with 10 percent the most likely. For equipment costs, we
assumed that very small establishments would on average spend 0 to
$1,000, with $100 the most likely amount. Small establishments would
bear costs 3 times that of very small establishments, which is the
ratio of the size of the physical plants of small establishments to the
size of the physical plants of very small establishments. We assumed
that large establishments would bear (if necessary) costs 20 times that
of very small establishments, which is the ratio of the size of the
physical plants of large establishments to the size of the physical
plants of very small establishments. In other words, we assumed capital
costs for physical plant and equipment would be proportional to
facility size, as measured in square feet.
iii. Testing. Establishments that do not already conduct the
required product quality tests of each batch of dietary ingredients or
dietary supplement produced would incur the cost for those tests. Under
the option for more restrictive CGMP rules, each lot of components
would also be tested. The costs per establishment depend on both the
number of tests and the costs per test. We did not estimate the cost of
developing new, validated tests methods because we lacked information
about the costs for this requirement and the number of such tests that
need to be developed. We ask for comments on the costs to develop
tests, for the number of tests and the costs for performing each test
to comply with this requirement.
[sbull] Number of tests: Model. To estimate the costs of testing,
we first estimated the number and costs of individual tests, without
adjusting for the amount of testing already being done. In this section
we show how we estimated the likely number of required tests,
unadjusted for current voluntary testing. For a representative
manufacturer, the annual number of tests would be the number of new
tests per batch multiplied by the number of batches produced in a year.
The proposed rule requires only tests for identity, purity,
quality, strength, and composition of the final product. The option for
stricter CGMP regulations would also require tests of components.
Estimating the number of component tests per batch is complicated,
because component tests are made on the shipment lots, rather than on
the parts of the lots that actually go into the final product. For
example, if a lot of some ingredient is used in 6 batches of final
products, it would probably be tested only once.
The establishment itself may test the shipment lots, and during
inprocess stages for identity, purity, quality, strength, and
composition, unless final product testing is done.
The number of component tests per batch of final product would
equal the number of tests per component, multiplied by the number of
components per batch, divided by the batches per shipment lot (to
account for the production of multiple batches of dietary supplements
from single lots of components).
The option for stricter CGMP regulations options would also require
some inprocess tests upon receipt. The number of inprocess tests per
batch is the same as the number of potential inprocess product defects.
The estimated number of inprocess tests counts only tests for defects
that can occur during production, not tests for the defects of dietary
ingredients and components supplied to the producer.
We used the following formulas to estimate the number of tests:
[GRAPHIC][TIFF OMITTED]TP13MR03.000
Quality tests per batch of final product = max [m x (1/z), 1]
Where:
Ij = jth listed ingredient;
m = number of ingredients per batch;
Rj = required tests for ingredient j;
[[Page 12239]]
Uk = kth unlisted component (an inactive substance);
n = number of unlisted components per batch;
Rk = required tests for unlisted component k;
S = number of shipments (or lots) of ingredients and unlisted
components;
B = number of batches produced;
H1 = 1th inprocess potential defects;
R1 = required inprocess tests per batch for potential defect
H1;
o = number of potential inprocess defects per batch;
z = number of ingredients identified per quality test.
[sbull] Number of tests: Evidence and distributions. The quantity
and quality of evidence on the variables used to estimate the number of
required tests varies greatly. In this section, we explain the evidence
and assumptions we used to construct the formulas for the number of
tests.
[sbull] Number of ingredients. We based our measure of the number
of dietary ingredients per product on a sample of almost 3,000 dietary
supplement labels (Ref. E46). Although some dietary ingredients may be
missing from the labels and some listed dietary ingredients may be
missing from the products, the ingredient list represents the best
evidence we are likely to have on what dietary ingredients are used in
dietary supplements.
[sbull] Number of ingredients per batch. According to the sample of
listed ingredients (Ref. E46). Vitamin and mineral products contain
about 13 listed ingredients. Other dietary supplements, mainly herbals,
contain about four.
[sbull] Number of tests per ingredient lot. The option for more
restrictive CGMP regulations would require that virtually all dietary
ingredients be tested for identity and defects at some stage between
harvesting the raw product and the beginning of the production of the
final product. We assumed one identity test per ingredient lot. The
number of tests for defects depends on the number of possible defects,
which can include: Filth; Microbial pathogens; Chemical hazards,
including pesticides; Insects; Physical hazards, such as metals;
Natural toxins, such as aflatoxin; and Inadequate purity, quality,
strength, or composition.
The number of potential defects is potentially unlimited. As a
practical maximum, however, few products would have more than five
potential defects. In the calculation of ingredient testing costs (part
of the option for more restrictive CGMP regulations), we assumed that
the average number of tests per listed dietary ingredient would be
between one and six: One identity test for identity, purity, strength,
quality, and composition and zero to five tests for defects.
[sbull] Number of unlisted components. Dietary supplements are
manufactured using solvents, binders, and lubricants that may not show
up in the final product. An industry source (Ref. E47) says that four
to six unlisted components are typical per product, although fewer are
certainly possible. The minimum number is zero. We assumed that the
number of unlisted components would be zero to six, with four the most
likely.
[sbull] Number of tests per unlisted components. The unlisted
components tend to be manufactured products, such as solvents.
Therefore, one identity test would likely be sufficient.
[sbull] Number of shipments (or lots) of ingredients and unlisted
components. We have no direct evidence on the number of shipment lots
of dietary ingredients and components. We also have no evidence on the
number of shipments per lot or on the number of shipments per batch.
The increasing use of just-in-time inventory practices indicates that
one shipment lot of components per batch may be the rule for some
products and some producers. It is costly and difficult to store
ingredients for an extended time, so establishments tend to buy more
and smaller lots of components rather than a few large lots and storing
them in bulk over an extended period (Ref. E48). Crude botanical and
other ingredients are inherently unstable and may lose their quality in
even a short time unless costly temperature, humidity, and light
controls are in place (Ref. E49). We also know, however, that some
dietary ingredient suppliers produce large amounts and then ship out
smaller packages. For dietary supplements produced using part of a
large production run of a dietary ingredient, the number of batches per
lot could be large. Also, some producers buy a single shipment lot of a
raw material and use it in many batches. We assume that as many as 12
batches per shipment lot of dietary ingredient is a plausible maximum.
In the cost calculation, we assumed that 1 was minimum and 12 the
maximum number of batches produced per lot, with 6.5 the average.
[sbull] Number of batches produced. We have survey results (Ref.
E2) on the number of batches produced per establishment. According to
the survey, very small establishments produce an average of 223 batches
per year, small establishments produce an average of 554 batches per
year, and large establishments produce an average of 309 batches per
year.
[sbull] Inprocess potential defects. Inprocess defects involve many
of the same potential defects that can occur in components. The more
restrictive CGMP option requires inprocess tests at all points where
contamination or other defects can occur. Filth, chemicals, microbial
pathogens, physical objects, and insects can be introduced into the
product during manufacturing. In addition, purity, quality, strength,
and composition can be compromised.
[sbull] Number of potential inprocess defects. Some processes may
have no control points, steps, or stages that involve the potential for
defects. If certain manufacturing processes in the production of a
dietary supplement can be carried out without being subject to
potential defects, no inprocess tests would be required for those
processes. We therefore assumed that zero inprocess tests would be the
lower bound requirement. For the upper bound, we assumed that no
products would have more than five potential control points or steps
that could lead to defects. We believe that most production processes
will have fewer than 5 control points, so we assumed an average of 2.5
control points requiring inprocess tests for defects.
[sbull] Number of required inprocess tests per control point. We
assumed one test per defect per control point.
[sbull] Number of ingredients identified per quality test. We had
no direct evidence on the number of identity tests per final dietary
supplement. For the maximum, we assumed that the number of tests would
equal the number of ingredients. The number of ingredients identified
per test varies from less than one to a very large number. We assumed
that for vitamins and minerals, the minimum number of identity tests
would be one and the maximum would be 30, with 2 the most likely.
Botanical and herbals are less easily characterized than vitamins; so
identifying large numbers of ingredients with a single test would be
highly unlikely. We assumed that one to two ingredients would be
identified per test for herbal products.
[sbull] Number of final product tests per batch. We had no direct
evidence on the number of quality tests per final dietary supplement.
After adjusting for the possibility of multiple results from a single
test, multiple ingredients in single products, and the differing number
of ingredients in herbal and vitamin products, we estimated that the
proposed rule would require about three tests for identity, purity,
quality, strength, and composition for each batch of final product.
These are the
[[Page 12240]]
only required tests in the proposed rule, but establishments may choose
to perform inprocess tests and tests on ingredients in order to prevent
waiting until final product testing to discover defects.
iv. Costs per test. We estimated the costs per test partly with
published prices of independent laboratories as posted on the Internet
(Refs. E50 and E51), and partly from our conversations with FDA and
industry experts on testing. We found that testing costs vary according
to frequency and complexity. The more frequently technicians perform
tests, the lower are the costs per test. Many tests require
sophisticated equipment, such as gas chromatography, high pressure
liquid chromatography, distillation, extraction, various
spectrophotometers, and other types of equipment. Using sophisticated
equipment requires trained personnel. Even simple physical or
organoleptic testing requires training or experienced personnel. The
type of ingredient, compound, or product can also affect the cost
because some are easily identified using routine or single step
techniques and others require multiple steps or complex techniques,
especially if there are similar products that can be mistaken for the
products being identified. The type of defect tested for affects the
cost; some defects can be found visually if they are found on the
surface, but others are latent. Some tests require multiple samples or
multiple steps. In addition, tests require the taking and of samples,
whose cost can vary.
We assumed that $20 per test represented a plausible lower bound.
This cost represents the full cost of carrying out a test, including
collecting and storing the sample, the time for training the personnel
who carry out the test, and any associated records. Although some
Internet testing prices for tests were as high as $300, we assumed that
with frequent testing $150 would be a more plausible upper bound
average cost. The majority of listed prices fell into the $20 to $80
range, so we selected $50 (the midpoint) as most likely. The average
cost per test was about $60.\8\
---------------------------------------------------------------------------
\8\ The average cost is higher than the most likely cost because
we modeled costs with a Beta-Pert distribution that was skewed
rightward (toward higher costs). The Beta distribution is part of
the Bernoulli family of distributions and is closely related to the
Binomial. The Binomial gives the distribution of the number of
successes (s) in n trials if the probability of the success in each
trial is p. The Beta shows the distribution of the value of p when s
successes occur in n trials. The Beta-Pert distribution is a Beta
distribution that has been rescaled to run between values other than
0 and 1. The Beta-Pert uses a minimum, maximum, and most likely
value to generate a distribution running from the minimum to the
maximum, with a mean equal to (minimum + (4 x most likely) +
maximum)/6. We used the Beta-Pert distribution because we did not
have a representative sample to derive the distribution, but we did
have enough information to identify a plausible maximum, minimum,
and most likely value. The use of the Beta-Pert, then, indicates
that we do not know the shape of the probability distribution of
possible testing costs, but we do have limited data.
---------------------------------------------------------------------------
Changing our assumption about the midpoint of testing costs would
change our estimate of the cost of the rule. If the cost of testing
each batch is actually significantly higher, then the impact to those
firms that incur the cost and to society will have been understated.
v. The number and cost of tests: summary. We estimated the number
of tests required of the representative manufacturer as a weighted
average of the number of tests required for vitamins and minerals and
the number of tests required for all other supplements (which were
mainly herbal products). We used survey responses to a question about
the establishment's primary line of business for the weights used to
compute the average number of tests. We dealt with multiple responses
by treating all nonvitamin and nonmineral responses as other dietary
supplements. The following weights, as shown below, differed by size of
manufacturer:
[sbull] 24 percent of very small manufacturers produce vitamins and
minerals; 76 percent produce other dietary supplements.
[sbull] 42 percent of small manufacturers produce vitamins and
minerals; 58 percent produce other dietary supplements.
[sbull] 69 percent of large manufacturers produce vitamins and
minerals; 31 percent produce other dietary supplements.
The annual cost of testing differed by the size of the firm,
because the average number of batches produced differed. For the option
calling for more strict regulation, the total costs of testing would be
much higher than in the proposed rule. The unadjusted total cost of
testing under the more restrictive CGMP option would be:
$148,000 for very small establishments;
$415,000 for small establishments;
$263,000 for large establishments.
We estimate that the adjusted total cost for testing for the
proposed regulation will be:
$11,230 for very small establishments;
$19,907 for small establishments;
$7,626 for large establishments.
We found some corroboration for these estimates in a comment on the
Advance Notice of Proposed Rulemaking entitled ``Current Good
Manufacturing Practice in Manufacturing, Packing, or Holding Dietary
Supplements'' published in the Federal Register of February 6, 1997 (62
FR 5699 to 5709). According to the comment, the cost of testing
components and final products inhouse would be at least $650 per batch
plus microbiological tests. Testing costs could be more if
establishments sent samples to independent laboratories for testing or
if they conducted extensive identity tests of herbal and botanical
products. If we apply the $650 to the annual number of batches per
establishment, the comment implies that very small establishments would
perform $145,000 (223 x $650) worth of tests, small establishments
would perform $360,000 (554 x $650) worth of tests, and large
establishments would perform $200,000 (309 x $650) worth of tests.
These estimates are reasonably close to our simulation estimate.
The unadjusted testing costs represent the total requirements and
recommendations, not the additional costs that would be incurred in
response to the proposed rule. Tests on incoming components and
inprocess tests would not be required by the proposed rule. Most
establishments already conduct some tests, or send samples out for
testing. We, therefore, adjusted the estimated testing costs of the
proposed rule to include only required tests and to account for the
testing costs currently borne voluntarily by manufacturers. The survey
results showed how many respondents were conducting various types of
tests.
Table 14.--Values Used in Testing Cost Calculations
------------------------------------------------------------------------
Value or
Name distribution used Source
------------------------------------------------------------------------
Number of dietary Vitamins and Sample from 3,000
ingredients per product minerals--13; All dietary supplement
batch. other categories--4. labels (Ref. E46).
[[Page 12241]]
Number of identify tests per 1 Identity test per Assumption based on
ingredient lot. ingredient lot. discussions with
industry--FDA
requests comments.
Number of tests for defects 0 to 5 tests for Assumption based on
per ingredient lot. defects. discussions with
industry--FDA
request comments.
Number of unlisted 0 to 6 components; 4 Ref. E47.
components. most likely.
Number of tests per unlisted 1 identity test per Assumption based on
components. component. discusssions with
industry--FDA
requests comments.
Number of shipments (Lots) 1 to 12 batches per Assumption based on
of ingredients and unlisted shipment lot of discussions with
components. dietary ingredients. industry--FDA
requests comments
(Ref. E48).
Number of batches produced.. Very small Ref. E2.
establishments--223
; Small
establishments--554
; Large--309.
Number of inprocess 0 to 5 potential Assumption based on
potential defects. control points; 2.5 discussions with
average. industry--FDA
requests comments.
Number of inprocess tests 1 test per defect Assumption based on
per control point. per control point. discussions with
industry--FDA
requests comments.
Number of ingredients Vitamins and Assumption based on
identified per identity minerals--1 to 30; discussions with
test. 2 most likely; All industry--FDA
other categories--1 requests comments.
to 2.
Number of final product 3 tests batch....... Assumption based on
tests per batch. discussions with
industry--FDA
requests comments.
Costs per test.............. Beta per Refs. E50 and E51.
distribution skewed
rightward between
$20 to $150; $50
most likely; $60
average.
------------------------------------------------------------------------
vi. Labor costs. We used the average manufacturing wage of $15.65
per hour to estimate the cost of labor. We assumed that various tasks
required by the proposed rule would take some number of hours per year,
per batch of product, or per square foot of physical plant. For
example, we assumed that time spent on the sanitation of physical
plants is a function of the square footage. We assumed 1 hour per week
for very small establishments, 3 hours per week for small
establishments, and 20 hours per week for large establishments. We
request comment or data about costs, hours, and the other requirements
for these proposed required procedures.
vii. Other costs. The main costs in this category are for pest and
rodent control. We consulted a commercial supplier of these services
for the estimated monthly costs, which were $400 to $600 a month for
very small establishments, $480 to $720 for small establishments, and
$700 to $1,000 for large establishments (Ref. E52). For each size of
establishment, we selected the midpoint of the range as the most likely
value.
d. Estimating costs. We initially gathered information and made
assumptions about the full cost of a provision. We then adjusted these
estimates to account for the many activities already being carried out,
as well other activities that would not have to be carried out by all
establishments. We used the survey to estimate the likelihood that an
establishment would incur a cost. To get an estimate of the average
cost of provision (adjusted for baseline activities) for each category,
we multiplied the average cost per establishment by the probability
that the establishment would need to undertake the expense (one minus
the probability that the establishment was already doing it). For each
provision of the proposed rule, the simulation carried out the
following calculation:
Cost per unit of analysis for each provision = number of units of
analysis per establishment x probability that establishment incurs cost
x adjustment for requirement (yes or no) = cost per provision per
establishment
We estimated both a setup cost (a one-time fixed cost) of the
provision and an annual recurring cost. The first-year costs would be
the setup costs plus the annual costs. To get the total costs of the
rule, we multiplied the number of establishments in each size category
(from the survey) by the average costs per establishment in that
category. We then adjusted for the establishments that did not respond
to the survey but are believed to be in the industry. Two hundred
thirty eight establishments responded to the survey; we estimated that
1,566 firms are in the industry. We estimated costs with the following
calculation:
[Number of very small establishments x costs per very small
establishment) + (Number of small establishments x costs per small
establishment) + (number of large establishments x costs per large
establishment)] x adjustment for establishments not in survey
The rule is complex and the industry is made up of very different kinds
of firms, so cost estimates are averages with, in some cases, large
variances. The cost per unit, number of batches and employees, and
probability that the establishment would incur the cost all contain
uncertainty. The values in table 15 of this document are used in the
cost estimates, and are generated from multiple sources.
Table 15.--Values Used in Cost Calculations
------------------------------------------------------------------------
Value or
Name distribution used Source
------------------------------------------------------------------------
Average wage per hour....... $15.65.............. Employment Index,
Bureau of Labor
Statistics.
Average size of Very small = 24,674; Ref. E2.
establishments in square small = 71,354;
feet. large = 596,000.
Average number of employees. Very small = 7.6; Ref. E2.
small = 95; large =
1,005.
Average annual number of Very small = 223; Ref. E44.
batches. small = 554; large
= 309.
[[Page 12242]]
Annual time recordkeeping... 1/10 of setup time Ref. E44.
per provision.
Personnel sanitation........ 1 hour per week per Assumption, based on
worker. requirements of
proposed rule.
Sanitation time for physical 1 hour per week for Assumption, based on
plant. very small difference in
establishments; 3 average physical
hours per week for plant size.
small
establishments; 20
hours for physical
plant per week for
large
establishments.
Sanitation supervisor....... Very small and small Assumption, based on
establishments = 1 number of workers.
hour per week;
large
establishments = 1
hour per week.
Pest control setup costs.... $1,500 to $2,000 for Ref. E52.
very small
establishments;
$1,800 to $2,400
for small
establishments;
$2,600 to $3,400
for large
establishments.
Average for each
size establishment
was midpoint
($1,750, $2,100,
$3,000).
Pest control annual costs... $400 to $600 per Ref. E52.
month for very
small
establishments;
$480 to $720 for
small
establishments;
$700 to $1,000 for
large
establishments.
Average for each
size establishment
was the midpoint
($500, $600, $850).
Renovation cost............. $50 per square foot; Based on
with 0 to 20 construction costs
percent of physical and square feet.
plant to be
renovated, with 10
percent most likely.
Minimum quality control unit 1 person or 1 Assumption based on
percent of requirements of
establishment work proposed rule.
force.
Equipment replacement....... For very small Assumption, based on
establishments, 0 size of
to $1,000, with establishments.
$100 most likely;
small, 0 to
$10,000, with
$1,000 most likely;
large, 0 to
$100,000 with
$1,000 most likely.
Setup costs for automatic $500 for hardware, Software costs and
equipment. 16 hours. assumptions about
labor hours.
Annual costs for automatic 1 to 2 hours per Assumption based on
equipment. month for very average size of
small and small establishments.
establishments; 2
to 4 hours per
month for large
establishments.
Sanitation of equipment and 5 hours per week for Assumption based on
surfaces. very small average sizes of
establishments, 15 establishments.
hours per week for
small
establishments, 100
hours per week for
large
establishments.
Number of dietary 12.8; standard Ref. E46.
ingredients per batch, deviation = 15.6.
supplements other than
vitamins.
Number of dietary 3.6; standard Ref. E46.
ingredients per batch, deviation = 4.8.
supplements other than
vitamins.
Cost per test............... $20 to $150, with See text discussion.
$50 most likely.
Holding products and dietary Setup cost for very Based on average
ingredients: capital small 0 to $1,000, sizes of
requirements. with $100 most establishments.
likely. Multiply by
3 for small
establishments and
by 20 for large
establishments.
Default probabilities that For very small Based on results of
establishments are not establishments, survey for other
currently acting in 0.2; for small practices.
accordance with a provision. establishments,
0.1, for large
establishments,
0.01.
------------------------------------------------------------------------
We combined the costs per establishment with the number of
establishments and probabilities from the survey, and adjusted for
establishments not in the survey to estimate the total costs of the
proposed rule. Table 16 of this document summarizes the estimated total
costs for very small establishments, small establishments, large
establishments, and warehouses. Table 17 of this document shows the
total costs for the first year and annually after the first year,
assuming that the proposed rule is phased in over 3 years. Table 18 of
this document shows the total costs of the proposed rule compared to
the total costs of other options.
Table 16.--Summary of Costs by Size of Establishment
----------------------------------------------------------------------------------------------------------------
Total 1st Total
Number of 1st Year costs Annual costs year costs annual
establishments per per (in costs (in
establishments establishments millions) millions)
----------------------------------------------------------------------------------------------------------------
Very small establishments............. 740 $62,000 $38,000 $46 $28
Small establishments.................. 766 99,000 61,000 76 47
Large establishments.................. 60 83,000 47,000 5 3
Warehouses and other holders.......... 26,617 436 342 12 9
----------------------------------------------------------------------------------------------------------------
[[Page 12243]]
Table 17.--Estimated Total Costs
[In millions]
----------------------------------------------------------------------------------------------------------------
4th Year
1st Year 2nd Year 3rd Year and after
----------------------------------------------------------------------------------------------------------------
Very small establishments................................... 0 0 $46 $28
Small establishments........................................ 0 $76 47 47
Large establishments........................................ 5 3 3 3
Warehouses.................................................. 12 9 9 9
--------------
Total................................................... 17 88 105 87
----------------------------------------------------------------------------------------------------------------
8. Summary of Benefits and Costs
We estimated that, once it is fully implemented, the measured
annual benefits from the proposed rule would be $218 million; measured
annual costs would be about $86 million. Additional but unmeasured
benefits should also be recognized when comparing the total costs and
benefits. Table 18 of this document compares the benefits and costs of
the proposed rule to the benefits and costs of the leading regulatory
options. Because the phase in period, complicates the comparison for
the early years, we limit the comparison to annual benefits once all
establishments are covered.
Table 18.--Annual Benfits and Costs of Regulatory Options
[In millions]
------------------------------------------------------------------------
Annual Annual
Regulatory option benefits costs
------------------------------------------------------------------------
Proposed rule................................. $218 $86
Fewer requirements for vitamins and minerals.. 109 69
Stricter CGMP................................. 218 178
HACCP only.................................... 42 38
Testing only (unable to estimate)............. ........... 32
High risk products only (unable to estimate).. ........... (\1\)
------------------------------------------------------------------------
\1\ Less than $86 million.
Uncertainties in the analysis. In this section, we list all of the
significant assumptions in the analysis, which if varied, could
significantly change the estimates of costs and benefits. Such changes
could have importance for the construction of any potential final rule.
Therefore, we ask that comments address these aspects of the analysis
and, where possible, provide FDA with better data to reduce the
uncertainty. We estimated the benefits using indirect methods, which
required several key assumptions that are critical for our estimates.
With the exception of the recall benefit, which is based directly on
FDA recall records, each component of the estimated benefits involves
assumptions that reflect our uncertainty.
Our basic assumption is that manufacturers lack market-based
incentives to prevent hidden product quality defects. Our survey (Ref.
E2) indicated that many firms do not have reliable quality control
mechanisms in place. The survey was a one-time look at the
manufacturing practices during the time of the survey. If the trend in
the market is toward the adoption of the controls that we are proposing
here in the absence of regulation, then both the cost and benefits of
the rule will be less than we estimate. If the market-based trend is
toward fewer controls, then both the cost and benefits of the
regulation will be greater. Other key assumptions are listed below:
The assumptions for the health benefits from reducing the number of
sporadic illnesses model are:
1. The baseline health of consumers is normal, not perfect. To
estimate the change in health status from consuming defective products,
we assumed that the baseline health of consumers is normal, which does
not mean that we assumed that consumers have perfect health. We
recognize that consumers will already have ``background'' health
problems, by which we mean that many will have health problems
unrelated to the consumption of defective products. Our assumption is
that only the change in health status is relevant for our analysis. If
an immune-compromised consumer is made ill by a defective product,
e.g., gets lead poisoning, the consumer might in fact have more
difficulty recovering than an otherwise healthy person. However, we
assume that the change in productivity, functional state, pain and
suffering, and medical costs will be the same, regardless of prior
health status. Accounting for confounding factors would have the effect
of making health problems worse than we estimate, not better, so our
estimate may be understating the true health benefits.
2. The average value of a QALY is $630 per day. That value, $630
per day, is in turn based on: (1) The value of a statistical life of $5
million; (2) the expected remaining life of consumers of 21.84 years
(average), discounted from 36 years; and, (3) the social rate of time
preference of 3 percent. The estimate is derived from workers in
somewhat risky occupations who demand a wage premium for their
additional risk of fatality. If our estimate of the value of a
statistical life of workers does not represent the value of a
statistical life of consumers of dietary supplements, then our benefits
estimate will be different from the true health benefits of the rule.
If consumers value their life differently than workers or if consumers
place different values for different kinds of hazard-related deaths
than do workers for job-related safety hazards, then we will have
incorrect estimates for the true health benefits. If we discount life
expectancy by 7 percent instead of 3 percent, the benefits would be
much higher.
3. There is one illness for each recall. We assumed that for each
class 1 and 2 recalled product there was only one illness that was
reported to the public health authority. For instance, if a product was
recalled because the defective product contained lead, we assume that a
person was made ill from lead poisoning and that was how the recalled
product was discovered. If there were more illnesses per recall than
one, then our estimates of benefits will be low. If fewer than one
illness per recall occurred (or is likely to occur in the future), then
our estimate of health benefits will be more than the actual health
benefits.
4. The assumed frequency of actual illnesses is 100 times the
frequency of reported illnesses. This assumption is based on Ref. E16.
We recognize that the factor of 100, although it has empirical support,
might be wrong and that there is likely to be considerable uncertainty
about this point estimate. It is widely believed in the public health
community that most illnesses are underreported to public health
authorities, particularly in passive reporting systems, such as the
case with
[[Page 12244]]
dietary supplements. Mild cases are the most underreported. For
instance, victims rarely notify public health authorities when they
have minor gastrointestinal tract related illnesses. It is even more
rare to report the likely source of a mild illness. It is also widely
believed that severe illnesses and death are reported much more
frequently than milder illnesses, even when the cause of illness or
death is not included in the report. Although the number of deaths that
are reported probably approach 100 percent, the cause of death from a
contaminated dietary supplement product might not be reported. We
believe that using a single composite factor--100--to represent the
total number of all unreported cases, including mild, severe, and
death, does not invalidate our assumption. The factor of 100 represents
an estimate of the composite probability of the full range of
probabilities for each severity level of an illness being reported.
Increasing the factor multiplier from 100 to some number higher would
increase the health benefits, while lowering the multiplier would
decrease the health benefits. If we assume that all illnesses are
reported--there are no unreported illnesses and no factor of 100, then
the health benefits from fewer sporadic illnesses will be less than $1
million.
5. Introducing CGMP's will reduce the probability of a recall to
zero. We believe that the proposed CGMP's creates the most reliable
means for discovering product adulteration. Indeed, we believe that it
will, if strictly used, cause the discovery of all adulteration.
Therefore, we assume that once an establishment fully adopts the
requirements, there should be no more health risk from adulterated
dietary supplements and consequently, no more class 1 and 2 recalls.
This conclusion rests on the assumption that there will be 100 percent
compliance with this regulation. We recognize that human error is
inescapable. If recalls--or a health risk from adulteration--would
still exist, then we overstated the true health benefits of the
regulation.
The assumptions for the health benefits from lowering the
likelihood of rare catastrophic event model are:
1. We assume that a rare catastrophic event would occur every 30
years. We recognize that the occurrence of a single event provides
little evidence about what will happen in the future. If the event
reported in this analysis was in fact a one-time occurrence, then our
estimate of the benefits from the prevention of the catastrophic health
event would overstate the true benefits, which in fact should be zero.
There would have been no future event, and there would be no benefit
from adopting a rule to avoid it. If a rare event would have happened
more frequently than our estimate of once every 30 years, then our
estimate of the benefits would underestimate the true health benefits.
2. Number of illnesses per rare event. We based our estimate of the
health impact from contaminated L-Tryptophan. If the number of
illnesses from a future rare event differed--either more or less--then
the health benefits would differ from our estimated benefits. If a
future event would have had 10,000 cases, not 1,500 cases, then our
estimate would understate the true health benefits of avoiding such a
large catastrophe.
The assumptions for fewer products recalled are:
1. The reported class 1 and 2 recalls that have occurred over the
last 10 years represent the number and type of recalls that would have
occurred in the future but for the implementation of this regulation.
If the number or types of recalls are not representative, then we over
or under estimated the benefit of avoiding recalls. Avoiding one very
large recall could result in significantly higher benefits. Conversely,
merely avoiding fewer or smaller recalls would result in smaller
benefits.
2. A product recall causes sellers to lose both goodwill and the
value of the recalled product and lost goodwill equals the value of the
recalled product. These two embedded assumptions have empirical support
from Ref. E24. A product recall adversely affects the wealth of
sellers--a recall leads to lost goodwill--by signaling to consumers
that products are defective. From evaluating the declines in public
share prices after product recalls in various industries, the authors
in Ref. E24 determined that the loss in share price is twice the value
of the loss of the actual value of the product recalled. They attribute
the difference to lost firm goodwill.
3. Full compliance with the proposed CGMP's will reduce the
probability of a recall to zero. As in our earlier assumption about the
probability of recalls after the rule is adopted, consistency requires
that if we believe that the rule will reliably cause the discovery of
adulterated products before they are commercially available, there
should be no more health risk from adulterated dietary supplements.
Consequently, there should be no more recalls.
We developed the hypothetical search model to estimate the implicit
value to consumers of better product quality although we lacked a model
that could enable us to directly estimate consumer preferences for
dietary supplement quality. With the adoption of the proposed rule, the
standardization of manufacturing practices will reduce product
differentiation. In a perfect information market, the change in product
differentiation would be reflected in the change in the price
differences between low and high quality products. In the existing
market, price differences alone are an inadequate signal because the
differences in product quality are typically hidden from the view of
both consumers and (though less so) manufacturers. In this hypothetical
model, we assumed that if there were actually indicators of product
quality in the market now, consumers would spend a certain amount of
time attempting to find a reasonably high quality product. Time spent
searching is an economic cost. In fact, in markets where quality is
discernible prior to purchase, such search does take place and it is
from those markets that our estimates were derived. In such a world of
easily available product quality signals, this regulation, by
standardizing product quality at the high end, would reduce that search
time. Our assumption is that this is a reasonable indicator of
consumers' value for high quality products. Further, we assume that in
fact consumers of dietary supplements do wish to purchase high quality
products, as the absence of quality could mean either an ineffective
product or worse, illness or death. We used various assumptions at each
step in our model, and the benefits change when the assumptions change.
The assumptions that we used for the search model are:
1. Consumers will search until the expected benefits of the search
equal the expected cost of additional search. The expected cost is the
value of their time, which we estimated is the average wage rate for
manufacturing workers--$15.65/hour. If the true wage rate is different,
the benefits of the rule will be different.
2. The three models--drug store, use of time and grocery store
models--represent consumers of dietary supplements. If not, then we
will not have estimated the true preferences of consumers. If consumers
value dietary supplements more highly than either drugs, groceries or
other uses of time, and they search more for better quality, then we
understated the benefits of product standardization. If consumers value
dietary supplements less highly than either drugs, they search more for
better quality, then we overstated the benefits.
3. The quality controls will reduce consumer search time by
approximately
[[Page 12245]]
33 percent. If our estimate is not representative of the true average
reduction, then our estimate will be wrong.
4. The type and number of consumers represent the true value. If
children, the elderly or other consumers search for these products in
significantly greater amounts than average workers or the estimated
population, then we may have overstated the benefits, because their
foregone wages would be less than that of average workers.
In an ideal analysis, the benefits and costs of each provision
would be evaluated. We were not able to quantify the benefits for each
of the provisions in our analysis although we do have fairly detailed
estimates of the cost. We request comments on marginal costs and
benefits of specific provisions in the rule. Comments can be directed
either at how well a specific provision might work to make dietary
supplements either safer or of higher quality, or be directed at the
cost of the provision. An example of this type of provision follows for
recordkeeping:
Benefits of Recordkeeping
Mandatory recordkeeping is intended to help the discovery of
manufacturing practices that create defective products. Recordkeeping
ensures that preventative controls are carried out for each batch of
dietary supplements produced. Records serve as a checklist that quality
control personnel can consult to monitor that necessary controls are
implemented or corrective actions taken. Further, mandatory
recordkeeping provides an incentive for manufacturers to comply more
fully with the provisions of the rule where recordkeeping is required.
Knowing that FDA inspectors will examine records and that falsifying
them is a criminal offense provides strong incentives to keep thorough
and accurate records that the required safety functions have been
performed adequately and in a timely manner. Thus, the benefits of
recordkeeping are to permit detection of defective products and
increase compliance with the provisions for which recordkeeping is
required. If, for example: (1) The total benefits of the requirements
that have recordkeeping attached to them were $50 million (not the real
value); (2) only half of the requirements would be met without
recordkeeping; and, (3) recordkeeping raised the compliance rate to 100
percent, then the benefits of recordkeeping would be $25 million. We
were not able to quantify the marginal benefits of this requirement
with numbers like this. Comments are requested for how well records are
likely to perform this function. We estimate that the additional cost
to society for the proposed new recordkeeping requirement will be
approximately 10 percent of the total annual cost of the proposed
regulation, or a little less than $9 million per year.
Further, we request comments on all of the provisions that would be
of a similar nature to this example.
The costs of the rule depend on our assumptions about the amount
and cost of testing. The amount of testing is highly uncertain; we have
tried to model the number of tests based on number of ingredients and
types of tests.
We first characterized the uncertainty as a probability
distribution. We ran 1,000 computer simulations to estimate both
benefits and costs. The simulations used distributions and assumptions
from tables 8 through 13 of this document in place of single estimates.
Table 19.--Distribution of Simulation Results for Annual Benefits and Costs
[In millions]
----------------------------------------------------------------------------------------------------------------
5th 95th
Percentile Median Mean Percentile
----------------------------------------------------------------------------------------------------------------
Annual benefits............................................. $89 $198 $218 $405
Annual costs................................................ 62 80 86 128
----------------------------------------------------------------------------------------------------------------
The computer simulation gives the distribution of estimated
benefits and costs. If the underlying distributions capture the
uncertainty of the estimates, then the results in table 19 of this
document give a clear picture of the uncertainty. Another way to show
the uncertainty is to see how sensitive the results are to plausible
changes in individual variables. We start with benefits.
Table 20.--Sensitivity of Benefits
[In millions]
------------------------------------------------------------------------
Estimated
Description annual
benefits
------------------------------------------------------------------------
The proposed rule....................................... $218
If reporting rate of illness is 0.1 (baseline is 0.01).. 182
If reporting rate of illness is 0.005 (baseline is 0.01) 257
If the value of a statistical life is $3 million 175
(baseline is $5 million)...............................
If the value of a statistical life is $7 million 259
(baseline is $5 million)...............................
If consumer search time per item is 1 minute (baseline 137
is 3.75 minutes).......................................
If consumer search time per item is 5 minutes (baseline 250
is 3.75 minutes).......................................
If consumer search time equals 40 percent of shopping 166
time (baseline is 70 percent)..........................
If consumer search time is equal to shopping time 254
(baseline is 70 percent)...............................
If consumer search for quality accounts for 30 percent 278
of search time (baseline is 20 percent)................
If consumer search time for quality accounts for 10 158
percent of search time (baseline is 20 percent)........
If catastrophic events are not prevented (baseline is 152
$66 million annual benefit from prevention)............
------------------------------------------------------------------------
We mainly looked at the cost effects of changing assumptions about
testing and consumer complaints. As table 21 of this document shows,
annual costs are quite sensitive to the assumptions about the average
cost and number of tests.
[[Page 12246]]
Table 21.--Sensitivity of Costs
[In millions]
------------------------------------------------------------------------
Estimated
Description Annual Costs
------------------------------------------------------------------------
The proposed rule....................................... $86
6 tests per batch (baseline is 3)....................... 119
1 test per batch (baseline is 3)........................ 66
$100 per test (baseline is $60)......................... 101
1 consumer complaint per 20 batches (baseline is 1 per 77
10)....................................................
1 consumer complaint per 5 batches (baseline is 1 per 104
10)....................................................
------------------------------------------------------------------------
C. Initial Regulatory Flexibility Analysis
1. Introduction
FDA has examined the economic implications of this proposed rule as
required by the Regulatory Flexibility Act (5 U.S.C. 601-612). If a
rule has a significant economic impact on a substantial number of small
entities, the Regulatory Flexibility Act requires agencies to analyze
regulatory options that would lessen the economic effect of the rule on
small entities. We find that this proposed rule would have a
significant economic impact on a substantial number of small entities.
2. Economic Effects on Small Entities
a. Number of small entities affected. The proposed regulations
would affect many small entities. Our classification of establishment
size is based on the Small Business Administration's definition for
small, as discussed previously in this document. A small business by
this definition is any establishment with fewer than 500 employees. For
this analysis, we defined very small establishments as establishments
with fewer than 20 employees. Some small and very small establishments
produce very large revenues and would probably not incur a large
decline in profitability from the proposed CGMP regulations. We lack
precise information about those establishments. Based on the survey, we
estimated that 830 establishments, 53 percent of the total
establishments, could be classified as very small (under 20 employees)
and 564 as small (20 to 499 employees), which is 36 percent of the
total establishments.
We estimated that 95 percent of all holders (warehouses and
wholesalers) covered by this regulation are small using the Small
Business Administration definition. The total number of holders likely
to be affected by this regulation is 26,617 (see table 4 of this
document), so the total number of holders that are small would be
25,286 (= 0.95 x 26,617).
The small establishments that would be affected by the proposed
regulations are those establishments that would have to perform the
various required activities, and that would not have done so without
the regulations. As in the preliminary regulatory impact analysis
(section VII.B of this document), we determined our estimate of
baseline (pre-CGMP) manufacturing practices with the survey of the
industry (Ref. E2). The survey asked representative respondents to
answer a series of questions, including how many employees they had and
what their existing practices were. From the survey, we determined that
small establishments do not now follow all of the provisions of the
proposed CGMP regulations now. Those that do not follow the proposed
requirements will incur a cost to do so.
b. Costs to small entities. Implementation costs vary across
establishments based on current practices and the types of products
manufactured, packaged, or held. We estimated the range of current
practices using the survey of the industry. The cost model divided
establishments by size, which allowed us to estimate the distribution
of costs per establishment for each size and product class. Table 22 of
this document shows the cost per establishment for very small and small
establishments. For comparison, we include the estimated average cost
per large establishment and the median revenues for each size category.
As the table shows, costs per establishment are proportionally higher
for very small than for large establishments. The table's most striking
result is that costs are highest for small (20 to 499 employees)
establishments.
Table 22.--Cost Per Establishment
------------------------------------------------------------------------
1st year Annual
------------------------------------------------------------------------
Very small--fewer than 20 employees; $62,000 $38,000
median revenue under $1 million........
Small--20 to 499 employees; median 99,000 61,000
revenue $5 to 10 million...............
Large--500 or more employees; median 83,000 47,000
revenue $20 to $50 million.............
------------------------------------------------------------------------
Small establishments that do not perform a substantial number of
the actions required by the proposed CGMP regulations would bear
relatively high costs for compliance with the provisions of this
proposed rule. As shown in table 22 of this document, we estimated the
average annual compliance costs for a very small establishment to be
around $38,000. About one-third of those establishments or about 500
firms have annual sales revenues under $500,000. In addition, the
average annual compliance cost for a small establishment is around
$61,000. As the survey indicated, about 14 percent of establishments
with 20 to 499 employees or about 200 firms have annual sales revenues
under $500,000. For purposes of our analysis, we regard firms with
revenues of $500,000 or less to be low revenue firms. Although the
proposed rule would raise product prices, the price increase (which
would largely be determined by changes made by large establishments)
would be much smaller than the increase in the average costs of very
small producers. The average burden to very small low revenue firms,
then, would be at least 8 percent of their annual revenue. The average
burden to small low revenue firms would be at least 12 percent of
annual revenue. Establishments with above average costs, and even
establishments with average costs,
[[Page 12247]]
would be hard pressed to continue to operate. Therefore, some of these
establishments, for example, such as those that produce other products
(foods or pharmaceuticals) or are part of firms with more than one
establishment, may decide it is too costly and either change product
lines or go out of business. If we assume that one half of these firms
have sales revenues from other products and locations and remove them
from the at-risk group, we are left with approximately 350 very small
and small establishments with less than $500,000 in revenue. It is
possible that a large number of these 350 very small and small
establishments would be unable to absorb the compliance costs and will
close.
3. Regulatory Options
a. Exemptions for small entities. The burden on small
establishments would be reduced if they were exempt from some
provisions of the proposed rule. Most entities affected by this
proposed rule, however, are small. Exempting small establishments from
some or all of its provisions would be likely to reduce benefits.
b. Longer compliance periods. Lengthening the compliance period
would provide regulatory relief for small entities. A longer compliance
period for small entities would allow additional time for setting up
recordkeeping, making capital improvements to the physical plant,
purchasing new or replacement equipment, and other one-time
expenditures. It would also delay the impact of the annual costs of
compliance. We have given very small and small firms an additional 2
years for compliance. The proposed rule, then, would be phased-in over
3 years, with large firms complying after 1 year, and both very small
and small firms after 3 years. After 3 years, the annual costs would be
incurred. The cost savings of delay may well be larger than simply the
present value of the delay because very small and small firms may also
be able to reduce their compliance costs by taking advantage of
increases in industry knowledge and experience in implementing CGMP
regulations. A summary of the compliance costs is shown in table 22 of
this document.
Although lengthening the compliance period would provide some
regulatory relief to small entities, relief for these provisions would
also delay the full realization of the benefits of the proposed rule.
4. Description of Recordkeeping and Reporting
The Regulatory Flexibility Act requires a description of the
recordkeeping and recording required for compliance with this proposed
rule. This proposed rule would require the preparation of records. As
described in the Preliminary Regulatory Impact Analysis, records must
be written or electronic documents must be kept that demonstrate that
specific action or actions occurred in the manufacturing process in
compliance with the proposed regulations. Records that would be
required in this proposed rule would demonstrate, that corrective
actions were taken, that equipment, instruments, and controls used in
laboratory operations and quality control were installed properly, and
calibrated; that maintenance programs were followed; and that the
results of any testing meet the necessary specifications.
The compliance cost of recordkeeping is the sum of both the initial
design and printing of the recordkeeping documents and the recurring
costs of maintaining the records. The cost of training personnel to use
the new documents is a recurring cost depending on how frequently
documents are modified, how often personnel turn over, and how
complicated the tasks are that are being recorded. The recurring costs
are measured by the workers' wage rate multiplied by the expected labor
hours necessary to perform a written or electronic record and the time
necessary for management to review the records to see that actions are
documented accurately. In addition, electronic records necessitate
recurring time spent ensuring that the equipment is serviced and
maintained properly.
5. Summary
The proposed CGMP regulations would have a significant economic
impact on a substantial number of small entities.
D. Unfunded Mandates
The Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4) requires
cost-benefit and other analyses for rules that would cost more than
$100 million in a single year. The current inflation-adjusted statutory
threshold is $112 million. The proposed rule qualifies as a significant
rule under the statute because there is a significant possibility that
the cost of the rule will be above the threshold. Most of the
requirements of the Unfunded Mandates are fulfilled in the Executive
Order 12866 analysis. The requirements under the Unfunded Mandates Act
of 1995 include assessing the rule's effects on future costs;
productivity; particular regions, communities, or industrial sectors;
economic growth; full employment; job creation; and exports.
Future Costs
The future costs from the rule include the recurring costs, which
reach their long-term value in the third year after the proposed rule
would become final. These costs would be incurred by the establishments
that manufacture, process, pack, transport, distribute, receive, hold,
or import dietary ingredients or dietary products. Recurring costs from
the regulatory requirements would be incurred in each future year.
Table 18 of this document summarizes the annual future recurring costs.
Particular Regions, Communities, or Industrial Sectors
The costs of the rule will be shared among manufacturers,
processors, packagers, transporters, receivers, holders, and importers
of dietary ingredients or dietary products as well as domestic
consumers. The higher costs incurred by domestic suppliers of dietary
supplement products as a result of these regulations will mostly be
passed on to consumers in the form of higher prices. Since consumer
demand for dietary supplements is price elastic, most of the higher
costs incurred by suppliers will be passed on to consumers.
Consequently, higher dietary supplement prices will reduce real incomes
for many consumers. However, the reduction in real incomes is thought
to be more than offset by the benefits from these regulations. These
benefits are measured as an improved ability by the FDA to respond to
and contain threats of serious adverse health consequences from
accidental contamination of dietary supplements.
National Productivity, Economic Growth, Job Creation, and Full
Employment
Although this proposed regulation is significant, we do not expect
it to substantially affect national productivity, growth, jobs, or full
employment. The total costs will be small relative to the economy, and
will be offset by benefits. The improved ability to respond to, and
contain, serious adverse health consequences means less illness and
fewer sick days taken by employees, and lower adjustment costs by firms
that would otherwise need to hire replacement employees.
[[Page 12248]]
Exports
This proposed rule would require additional controls to be kept
throughout the production and distribution chain for the manufacture of
dietary ingredients and dietary supplements. The additional control
costs would increase the total costs of production and distribution for
all of the regulated products, including products sold within the U.S.
and across national borders. These increased costs will be largely
passed on to consumers in the form of higher prices, which will tend to
reduce the quantity demanded of the regulated products. The increased
prices of U.S. exports could reduce the quantity of U.S. exports
demanded, particularly in comparison with exports from countries that
do not implement similar regulations. We expect this effect to be
insignificant, because under the proposed rule the increases in the
price of United States exports (and resulting decreases in quantity
demanded) would be quite small.
VIII. Federalism
FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. We consulted with seven
State officials to make a tentative determination about whether this
proposed rule would have federalism implications. Based on this
consultation, it does not appear that this proposed rule has federalism
implications. In addition, we sent a letter on March 7, 2000, to
elected State officials and their representative organization to notify
them that our unified agenda was published on November 22, 1999, and
identified this proposed CGMP rule as a rule that would publish in the
year 2000. In that letter, we solicited comments on any federalism
implications that this proposed rule may have. To date, no responses
have been received to our solicitation. After publishing this proposed
rule, FDA will send a letter to elected State officials and their
representative organization requesting consultation about any
federalism implications. We invite comment on our tentative
determination that this proposed rule does not have federalism
implications, and therefore, does not contain policies that have
substantial direct effects on the States, or on the distribution of
power and responsibilities among the various levels of government.
IX. Request for Comments
Interested persons may submit to the Dockets Management Branch (see
ADDRESSES) written or electronic comments regarding this document.
Submit a single copy of electronic comments to http://www.fda.gov/dockets/ecomments or two hard copies of any written comments, except
that individuals may submit one hard copy. Comments are to be
identified with the docket number found in brackets in the heading of
this document. Received comments may be seen in the Dockets Management
Branch between 9 a.m. and 4 p.m., Monday through Friday.
X. References
We have placed the following references on display in the Dockets
Management Branch (see ADDRESSES). You may see them between 9 a.m. and
4 p.m., Monday through Friday.
1. Section 2, ``Findings,'' Dietary Supplement Health and Education
Act, Pub. L. 103-417, pp. 4325-4326, October 25, 1994.
2. ``Manufacturing Practices for Nutritional Supplements,'' United
States Pharmacopeia, 12601 Twinbrook Pkwy., Rockville, MD 20852,
General Chapter 2750, 2186-2192, and 2834, 1993.
3. ``NNFA Good Manufacturing Practice in Manufacturing, Packing, or
Holding Dietary Supplements,'' National Nutritional Foods Association,
3931 MacArthur Blvd., suite 101, Newport Beach, CA 92660, 1999.
4. ``Draft Report of the Food Advisory Committee Dietary Supplement
Working Group on Ingredient Identity Testing and Records and
Retention,'' FDA Food Advisory Committee Dietary Supplement Working
Group, Center for Food Safety and Applied Nutrition, FDA, June 25,
1999.
5. ``Consumer Use of Dietary Supplements,'' Rodale Press, 733 Third
Ave., New York, NY 10017, 2000.
6. Slifman, N. R., W. R. Obermeyer, B. K. Aloi, S. M. Musser, W. A.
Correll, S. M. Cichowicz, J. M. Betz, and L. A. Love, ``Contamination
of Botanical Dietary Supplements by Digitalis Lanata,'' New England
Journal of Medicine, 339:12, pp. 806-811, 1998.
7. ``Cardiac Glycoside Drugs,'' In: Wagner, H., and S. Bladt, Plant
Drug Analysis: A Thin Layer Chromatography Atlas, 2d ed., Berlin,
Germany: Springer-Verlag, pp. 99-123, 1996.
8. Bruneton, J., Pharmacognosy, Phytochemistry, Medicinal Plants,
Paris, Lavoisier Publishing, pp. 572-598, 1995.
9. Evans, W. C., Trease and Evans' Pharmacognosy. 14th ed.,
Philadelphia, W. B. Saunders, pp. 309-318, 1996.
10. Moe, G. K. and A. E. Farah, ``Digitalis and Allied Cardiac
Glycosides,'' In L. S. Goodman and A. Gilman, eds., The Pharmacological
Basis of Therapeutics, 5th ed., New York. Macmillan Publishing, pp.
653-682, 1975.
11. ``Survey on Botanical Adulteration,'' American Herbal Products
Association, 8484 Georgia Ave., suite 370, Silver Spring, MD 20910,
March 4, 1998.
12. Roy, A. K. and H. K. Chourasia, ``Mycotoxin Incidence in Root
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List of Subjects
21 CFR Part 111
Dietary foods, Drugs, Foods, Packaging and containers.
21 CFR Part 112
Drugs, Packaging and containers, Labeling.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, FDA proposes
to amend 21 CFR chapter I, parts 111 and 112 as set forth below:
PART 111--CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING,
PACKING, OR HOLDING DIETARY INGREDIENTS AND DIETARY SUPPLEMENTS
1. The authority citation for part 111 is revised to read as
follows:
Authority: 21 U.S.C. 321, 342, 343, 348, 371, 374, 381, 393; 42
U.S.C. 264.
2. The part heading for part 111 is revised as set forth above.
3. Add new subpart A to part 111 to read as follows:
Subpart A--General Provisions
Sec.
111.1 Who is subject to these regulations?
111.2 What are these regulations intended to accomplish?
111.3 What definitions apply to this part?
111.5 Do other statutory provisions and regulations apply?
111.6 Exclusions.
Subpart A--General Provisions
Sec. 111.1 Who is subject to these regulations?
You are subject to the regulations in this part if you manufacture,
package, or hold a dietary ingredient or dietary supplement.
Sec. 111.2 What are these regulations intended to accomplish?
The regulations in this part establish the minimum current good
manufacturing practices that you must use to the extent that you
manufacture, package, or hold a dietary ingredient or dietary
supplement.
Sec. 111.3 What definitions apply to this part?
The definitions and interpretations of terms in section 201 of the
Federal Food, Drug, and Cosmetic Act (the act) apply to such terms when
used in these regulations. For the purpose of these regulations, the
following definitions also apply:
Actual yield means the quantity that is actually produced at any
appropriate step of manufacture or packaging of a particular dietary
ingredient or dietary supplement.
Batch means a specific quantity of a dietary ingredient or dietary
supplement that is intended to meet specifications for identity,
purity, quality, strength,
[[Page 12252]]
and composition, and is produced during a specified time period
according to a single manufacturing record during the same cycle of
manufacture.
Batch number, lot number, or control number means any distinctive
group of letters, numbers, or symbols, or any combination of them, from
which the complete history of the manufacturing, packaging, or holding
of a batch or lot of dietary ingredients or dietary supplements can be
determined.
Component means any substance intended for use in the manufacture
of a dietary ingredient or dietary supplement including those that may
not appear in the finished dietary ingredient or dietary supplement.
Component includes ingredients and dietary ingredients as described in
section 201(ff) of the Act.
Consumer complaint means communication that contains any
allegation, written or oral, expressing dissatisfaction with the
quality of a dietary ingredient or a dietary supplement related to good
manufacturing practices. Examples of product quality related to good
manufacturing practices are: Foul odor, off taste, superpotent,
subpotent, wrong ingredient, drug contaminant, other contaminant (e.g.,
bacteria, pesticide, mycotoxin, glass, lead), disintegration time,
color variation, tablet size or size variation, under-filled container,
foreign material in a dietary supplement container, improper packaging,
or mislabeling. For the purposes of the regulations in this part, a
consumer complaint about product quality may or may not include
concerns about a possible hazard to health. However, a consumer
complaint does not include an adverse event, illness, or injury related
to the safety of a particular dietary ingredient independent of whether
the product is produced under good manufacturing practices.
Contact surface means any surface that contacts a component,
dietary ingredient, dietary supplement, and those surfaces from which
drainage onto the component, dietary ingredient, dietary supplement, or
onto surfaces that contact the component, dietary ingredient, or
dietary supplement ordinarily occurs during the normal course of
operations. Examples of contact surfaces include, but are not limited
to, containers, utensils, tables, contact surfaces of equipment, and
packaging.
Ingredient means any substance that is used in the manufacture of a
dietary ingredient or dietary supplement that is intended to be present
in the finished dietary ingredient or dietary supplement. An ingredient
includes, but is not necessarily limited to, a dietary ingredient as
described in section 201(ff) of the Act.
Inprocess material means any material that is fabricated,
compounded, blended, ground, extracted, sifted, sterilized, derived by
chemical reaction, or processed in any other way for use in the
manufacture of a dietary ingredient or dietary supplement.
Lot means a batch, or a specific identified portion of a batch
intended to have uniform identity, purity, quality, strength, and
composition; or, in the case of a dietary ingredient or dietary
supplement produced by continuous process, a specific identified amount
produced in a specified unit of time or quantity in a manner that is
intended to have uniform identity, purity, quality, strength, and
composition.
Microorganisms means yeasts, molds, bacteria, viruses, and other
similar microscopic organisms having public health or sanitary concern.
This definition includes, but is not limited to, species that:
(1) Have public health significance;
(2) Could cause a component, dietary ingredient, or dietary
supplement to decompose;
(3) Indicate that the component, dietary ingredient, or dietary
supplement is contaminated with filth; or
(4) Otherwise may cause the component, dietary ingredient, or
dietary supplement to be adulterated.
Must is used to state mandatory requirements.
Pest means any objectionable insects or other animals including,
but not limited to, birds, rodents, flies, mites, and larvae.
Physical plant means all or parts of a building or facility used
for or in connection with manufacturing, packaging, or holding a
dietary ingredient or dietary supplement.
Quality control means a planned and systematic operation or
procedure for preventing a dietary ingredient or dietary supplement
from being adulterated.
Quality control unit means any person or group that you designate
to be responsible for quality control operations.
Representative sample means a sample that consists of a number of
units that are drawn based on rational criteria, such as random
sampling, and intended to ensure that the sample accurately portrays
the material being sampled.
Reprocessing means using, in the manufacture of a dietary
ingredient or a dietary supplement, clean, unadulterated components,
dietary ingredients, or dietary supplements that have been previously
removed from manufacturing for reasons other than insanitary conditions
and that have been made suitable for use in the manufacture of a
dietary ingredient or dietary supplement.
Sanitize means to adequately treat equipment, containers, utensils,
or any other dietary product contact surface by applying cumulative
heat or chemicals on cleaned food contact surfaces that when evaluated
for efficacy, yield a reduction of 5 logs, which is equal to 99.999
percent reduction, of representative disease microorganisms of public
health significance and substantially reduce the numbers of other
undesirable microorganisms, but without adversely affecting the product
or its safety for the consumer.
Theoretical yield means the quantity that would be produced at any
appropriate step of manufacture or packaging of a particular dietary
ingredient or dietary supplement, based upon the quantity of components
or packaging to be used, in the absence of any loss or error in actual
production.
Water activity (aw) is a measure of the free moisture in
a component, dietary ingredient, or dietary supplement and is the
quotient of the water vapor pressure of the substance divided by the
vapor pressure of pure water at the same temperature.
We means the United States Food and Drug Administration (FDA).
You means a person who manufactures, packages, or holds dietary
ingredients or dietary supplements.
Sec. 111.5 Do other statutory provisions and regulations apply?
In addition to the regulations in this part, you must comply with
other applicable statutory provisions and regulations under the Act
related to the manufacturing, packaging, or holding of dietary
ingredients or dietary supplements.
Sec. 111.6 Exclusions.
The regulations in this part do not apply to a person engaged
solely in activities related to the harvesting, storage, or
distribution of raw agricultural commodities that will be incorporated
into a dietary ingredient or dietary supplement by other persons.
4. Add new subpart B to part 111 to read as follows:
Subpart B--Personnel
Sec.
111.10 What microbial contamination and hygiene requirements apply?
111.12 What personnel qualification requirements apply?
[[Page 12253]]
111.13 What supervisor requirements apply?
Subpart B--Personnel
Sec. 111.10 What microbial contamination and hygiene requirements
apply?
(a) Microbial contamination. You must take measures to exclude from
any operations any person who might be a source of microbial
contamination of any material including components, dietary
ingredients, dietary supplements, and contact surfaces used in the
manufacture, packaging, or holding of a dietary ingredient or a dietary
supplement. Such measures include, but are not limited to, the
following:
(1) Excluding any person who, by medical examination or supervisory
observation, is shown to have, or appears to have an illness, open
lesion, or any other abnormal source of microbial contamination, which
may be expected to result in microbial contamination of components,
dietary ingredients, dietary supplements, or contact surfaces, from
working in any operations until the condition is corrected; and
(2) Instructing your employees to notify their supervisor(s) if
they have or if there is a reasonable possibility that they have a
health condition described in paragraph (a)(1) of this section that
could contaminate any components, dietary ingredients, dietary
supplements, or any contact surface.
(b) Hygienic practices. If you work in operations during which
adulteration of the component, dietary ingredients, dietary supplement,
or contact surface may occur, you must use hygienic practices to the
extent necessary to protect against contamination of components,
dietary ingredients, dietary supplements, or contact surfaces. These
hygienic practices include, but are not limited to:
(1) Wearing outer garments in a manner that protects against the
contamination of components, dietary ingredients, dietary supplements,
or any contact surface;
(2) Maintaining adequate personal cleanliness;
(3) Washing hands thoroughly (and sanitizing if necessary to
protect against contamination with microorganisms) in an adequate hand-
washing facility:
(i) Before starting work; and
(ii) At any time when the hands may have become soiled or
contaminated;
(4) Removing all unsecured jewelry and other objects that might
fall into components, dietary ingredients, dietary supplements,
equipment, or packaging, and removing hand jewelry that cannot be
adequately sanitized during periods in which components, dietary
ingredients, or dietary supplements are manipulated by hand. If hand
jewelry cannot be removed, it must be covered by material that is
maintained in an intact, clean, and sanitary condition and that
effectively protects against contamination of components, dietary
ingredients, dietary supplements, or contact surfaces;
(5) Maintaining gloves used in handling components, dietary
ingredients, or dietary supplements in an intact, clean, and sanitary
condition. The gloves must be of an impermeable material;
(6) Wearing, where appropriate, in an effective manner, hair nets,
caps, beard covers, or other effective hair restraints;
(7) Not storing clothing or other personal belongings in areas
where components, dietary ingredients, or dietary supplements or any
contact surfaces are exposed or where contact surfaces are washed;
(8) Not eating food, chewing gum, drinking beverages and using
tobacco products in areas where components, dietary ingredients,
dietary supplements, or any contact surfaces are exposed, or where
contact surfaces are washed; and
(9) Taking any other precautions necessary to protect against the
contamination of components, dietary ingredients, dietary supplements,
or contact surfaces with microorganisms, filth, or any other extraneous
materials, including, but not limited to, perspiration, hair,
cosmetics, tobacco, chemicals, and medicines applied to the skin.
Sec. 111.12 What personnel qualification requirements apply?
(a) You must have qualified employees to manufacture, package, or
hold dietary ingredients or dietary supplements; and
(b) Each person engaged in manufacturing, packaging, or holding
must have the training and experience to perform the person's duties.
Sec. 111.13 What supervisor requirements apply?
(a) You must assign qualified personnel to supervise the
manufacturing, packaging, or holding of dietary ingredients and dietary
supplements.
(b) You and the supervisors you use must be qualified by training
and experience to supervise.
5. Add new subpart C to part 111 to read as follows:
Subpart C--Physical Plant
Sec.
111.15 What sanitation requirements apply to your physical plant?
111.20 What design and construction requirements apply to your
physical plant?
Subpart C--Physical Plant
Sec. 111.15 What sanitation requirements apply to your physical
plant?
(a) Physical plant facilities. (1) You must maintain your physical
plant in a clean and sanitary condition; and
(2) You must keep your physical plant in repair sufficient to
prevent components, dietary ingredients, dietary supplements, or
contact surfaces from becoming contaminated.
(b) Cleaning compounds, sanitizing agents, and pesticides. (1) You
must use cleaning compounds and sanitizing agents that are free from
microorganisms of public health significance and safe and adequate
under the conditions of use.
(2) You must not use or hold toxic materials in a physical plant in
which contact surfaces, components, dietary ingredients, or dietary
supplements are manufactured or exposed, unless those materials are
necessary:
(i) To maintain clean and sanitary conditions;
(ii) For use in laboratory testing procedures;
(iii) For maintaining or operating the physical plant or equipment;
or
(iv) For use in the plant's operations.
(3) You must identify and hold toxic cleaning compounds, sanitizing
agents, pesticides, and pesticide chemicals in a manner that protects
against contamination of components, dietary ingredients, dietary
supplements, or contact surfaces.
(c) Pest control. (1) You must not allow animals or pests in any
area of your physical plant. Guard or guide dogs are allowed in some
areas of your physical plant if the presence of the dogs will not
result in contamination of components, dietary ingredients, dietary
supplements, or contact surfaces;
(2) You must take effective measures to exclude pests from the
physical plant and to protect against contamination of components,
dietary ingredients, dietary supplements, and contact surfaces on the
premises by pests; and
(3) You must not use insecticides, fumigants, fungicides, or
rodenticides, unless you take precautions to protect against the
contamination of components, dietary ingredients, dietary supplements,
or contact surfaces.
(d) Water supply. (1) You must provide water that is safe and of
adequate sanitary quality, at suitable temperatures, and under pressure
as
[[Page 12254]]
needed, in all areas where water is necessary for:
(i) Manufacturing dietary ingredients or dietary supplements;
(ii) Making ice that comes in contact with components, dietary
ingredients, dietary supplements, or contact surfaces;
(iii) Cleaning any surface; and
(iv) Employee bathrooms and hand-washing facilities.
(2) Water that contacts components, dietary ingredients, dietary
supplements, or any contact surface must at a minimum comply with the
National Primary Drinking Water regulations prescribed by the
Environmental Protection Agency under 40 CFR part 141 and any state and
local government requirements;
(3) You must have documentation or otherwise be able to show that
water that contacts components, dietary ingredients, dietary
supplements, or any contact surface meets the requirements in paragraph
(d)(2) of this section.
(e) Plumbing. The plumbing in your physical plant must be of an
adequate size and design and be adequately installed and maintained to:
(1) Carry sufficient amounts of water to required locations
throughout the physical plant;
(2) Properly convey sewage and liquid disposable waste from your
physical plant;
(3) Avoid being a source of contamination to components, dietary
ingredients, dietary supplements, water supplies, or any contact
surface, or creating an unsanitary condition;
(4) Provide adequate floor drainage in all areas where floors are
subject to flooding-type cleaning or where normal operations release or
discharge water or other liquid waste on the floor; and
(5) Not allow backflow from, or cross connection between, piping
systems that discharge waste water or sewage and piping systems that
carry water used for manufacturing dietary ingredients or dietary
supplements, for cleaning contact surfaces, or for use in bathrooms or
hand-washing facilities.
(f) Sewage disposal. You must dispose of sewage into an adequate
sewage system or through other adequate means.
(g) Bathrooms. You must provide your employees with adequate,
readily accessible bathrooms. The bathrooms must be kept clean and must
not become a potential source of contamination to components, dietary
ingredients, dietary supplements, or contact surfaces. You must:
(1) Keep the bathrooms in good repair at all times;
(2) Provide self-closing doors; and
(3) Provide doors that do not open into areas where components,
dietary ingredients, dietary supplements, or contact surfaces are
exposed to airborne contamination except where alternate means have
been taken to protect against contamination (such as double doors or
positive airflow systems).
(h) Hand-washing facilities. You must provide hand-washing
facilities that are adequate, convenient, and furnish running water at
a suitable temperature. You must do this by providing:
(1) Hand-washing and, where appropriate, hand-sanitizing facilities
at each location in your physical plant where good hygienic practices
require employees to wash or to sanitize or both wash and sanitize
their hands;
(2) Effective hand-cleaning and sanitizing preparations;
(3) Air driers, sanitary towel service, such as disposable paper
towels, or other suitable drying devices;
(4) Devices or fixtures, such as water control valves, designed and
constructed to protect against recontamination of clean, sanitized
hands;
(5) Signs that are easy to understand and are posted throughout the
physical plant that direct employees handling components, dietary
ingredients, dietary supplements, or contact surfaces to wash and,
where appropriate, to sanitize their hands before they start work,
after each absence from their duty station, and when their hands may
have become soiled or contaminated; and
(6) Trash bins that are constructed and maintained in a manner to
protect against recontamination of hands and contamination of
components, dietary ingredients, dietary supplements, or any contact
surface.
(i) Trash disposal. You must convey, store, and dispose of trash
to:
(1) Minimize the development of odor;
(2) Minimize the potential for the trash to attract, harbor, or
become a breeding place for pests;
(3) Protect against contamination of components, dietary
ingredients, dietary supplements, any contact surface, water supplies,
and grounds surrounding your physical plant; and
(4) Control hazardous waste to prevent contamination of components,
dietary ingredients, dietary supplements, and contact surfaces.
(j) Sanitation supervisors. You must assign one or more employees
to supervise overall sanitation. These supervisors must be qualified by
training and experience to develop and supervise sanitation procedures.
Sec. 111.20 What design and construction requirements apply to your
physical plant?
Any physical plant you use in the manufacture, packaging, or
holding of dietary ingredients or dietary supplements must:
(a) Be suitable in size, construction, and design to facilitate
maintenance, cleaning, and sanitizing operations;
(b) Have adequate space for the orderly placement of equipment and
holding materials as is necessary for maintenance, cleaning, and
sanitizing operations and to prevent contamination and mixups of
components, dietary ingredients, and dietary supplements during
manufacturing, packaging, or holding;
(c) Permit the use of proper precautions to reduce the potential
for mixups or contamination of components, dietary ingredients, dietary
supplements, or contact surfaces, with microorganisms, chemicals,
filth, or other extraneous material. Your physical plant must have and
you must use separate or defined areas of adequate size or other
control systems, such as computerized inventory controls or automated
systems of separation, to prevent contamination and mixups of
components, dietary ingredients, and dietary supplements during the
following operations:
(1) Receiving, identifying, holding, and withholding from use,
components, dietary ingredients, dietary supplements, packaging, and
labels that will be used in or during the manufacturing, packaging, or
holding of dietary ingredients and dietary supplements;
(2) Separating, as necessary, components, dietary ingredients,
dietary supplements, packaging, and labels that are to be used from
components, dietary ingredients, dietary supplements, packaging, or
labels that are awaiting material review and disposition decision,
reprocessing, or are awaiting disposal after rejection;
(3) Separating the manufacturing, packaging, and holding of
different product types including, but not limited to, different types
of dietary ingredients, dietary supplements and other foods, cosmetics,
and pharmaceutical products;
(4) Performing laboratory analyses and holding laboratory supplies
and samples;
(5) Cleaning and sanitizing contact surfaces;
(6) Packaging and label operations; and
(7) Holding dietary ingredients or dietary supplements.
(d) Be designed and constructed in a manner that prevents
contamination of
[[Page 12255]]
components, dietary ingredients, dietary supplements, or contact
surfaces. The design and construction must include, but not be limited
to:
(1) Floors, walls, and ceilings that are of smooth and hard
surfaces that can be adequately cleaned and kept clean and in good
repair;
(2) Fixtures, ducts, and pipes that do not contaminate components,
dietary ingredients, dietary supplements, or contact surfaces by
dripping or condensate;
(3) Adequate ventilation or environmental control equipment such as
air flow systems, including filters, fans, and other air-blowing
equipment, that minimize odors and vapors (including steam and noxious
fumes) in areas where they may contaminate components, dietary
ingredients, dietary supplements, or contact surfaces;
(4) Fans and other air-blowing equipment located and operated in a
manner that minimizes the potential for microorganisms and particulate
matter to contaminate components, dietary ingredients, dietary
supplements, or contact surfaces;
(5) Equipment that controls temperature and humidity; and
(6) Aisles or working spaces between equipment and walls that are
adequately unobstructed and of adequate width to permit all persons to
perform their duties and to protect against contamination of
components, dietary ingredients, dietary supplements, or contact
surfaces with clothing or personal contact.
(e) Provide adequate light in:
(1) All areas where components, dietary ingredients, or dietary
supplements are examined, processed, or held;
(2) All areas where contact surfaces are cleaned; and
(3) Hand-washing areas, dressing and locker rooms, and bathrooms.
(f) Use safety-type light bulbs, fixtures, skylights, or other
glass that is suspended over exposed components, dietary ingredients,
or dietary supplements in any step of preparation, unless otherwise
constructed in a manner that will protect against contamination of
components, dietary ingredients, or dietary supplements in case of
glass breakage.
(g) Provide protection by any effective means against contamination
of components, dietary ingredients, and dietary supplements in bulk
fermentation vessels, including consideration of:
(1) Use of protective coverings;
(2) Placement in areas where you can eliminate harborages for pests
over and around the vessels;
(3) Placement in areas where you can check regularly for pests,
pest infestation, filth or any other extraneous materials; and
(4) Use of skimming equipment.
(h) Use adequate screening or other protection against pests, where
necessary.
6. Add new subpart D to part 111 to read as follows:
Subpart D--Equipment and Utensils
Sec.
111.25 What requirements apply to the equipment and utensils you
use?
111.30 What requirements apply to automatic, mechanical, or
electronic equipment?
Subpart D--Equipment and Utensils
Sec. 111.25 What requirements apply to the equipment and utensils you
use?
(a)(1) You must use equipment and utensils that are of appropriate
design, construction, and workmanship to enable them to be suitable for
their intended use and to be adequately cleaned and properly
maintained. Equipment and utensils include, but are not limited to, the
following:
(i) Equipment used to hold or convey;
(ii) Equipment used to measure;
(iii) Equipment using compressed air or gas;
(iv) Equipment used to carry out processes in closed pipes and
vessels; and
(v) Equipment used in automatic, mechanical, or electronic systems.
(2) You must use equipment and utensils of appropriate design and
construction so that use will not result in the contamination of
components, dietary ingredients, or dietary supplements with:
(i) Lubricants;
(ii) Fuel;
(iii) Coolants;
(iv) Metal or glass fragments;
(v) Filth or any other extraneous material;
(vi) Contaminated water; or
(vii) Any other contaminants.
(3) All equipment and utensils you use must be:
(i) Installed and maintained to facilitate cleaning the equipment,
utensils, and all adjacent spaces;
(ii) Corrosion-resistant if the equipment or utensils contact
components, dietary ingredients, or dietary supplements;
(iii) Made of nontoxic materials;
(iv) Designed and constructed to withstand the environment of their
intended use, the action of components, dietary ingredients, or dietary
supplements, and, if applicable, cleaning compounds and sanitizing
agents; and
(v) Maintained to protect components, dietary ingredients, and
dietary supplements from being contaminated by any source.
(4) Equipment and utensils you use must have seams that are
smoothly bonded or maintained to minimize accumulation of component,
dietary ingredient, or dietary supplement particles, dirt, filth,
organic material, or any other extraneous materials or contaminants to
minimize the opportunity for growth of microorganisms.
(5) Each freezer and cold storage compartment you use to hold
components, dietary ingredients, or dietary supplements:
(i) Must be fitted with an indicating thermometer, temperature-
measuring device, or temperature-recording device that shows the
temperature accurately within the compartment; and
(ii) Must have an automatic device for regulating temperature or an
automatic alarm system to indicate a significant temperature change in
a manual operation.
(6) Instruments or controls used in the manufacturing, packaging,
or holding of a dietary ingredient or dietary supplement, including but
not limited to, instruments or controls you use to measure, regulate,
or record temperatures, hydrogen ion concentration (pH), water
activity, or other conditions that control or prevent the growth of
microorganisms or other contamination must be:
(i) Accurate and precise;
(ii) Adequately maintained; and
(iii) Adequate in number for their designated uses.
(7) Compressed air or other gases you introduce mechanically into
or onto a component, dietary ingredient, dietary supplement, or contact
surface or that you use to clean any contact surface must be treated in
such a way that the component, dietary ingredient, dietary supplement,
or contact surface is not contaminated.
(b)(1) You must calibrate instruments and controls you use in
manufacturing or testing a component, dietary ingredient, or dietary
supplement.
(2) You must calibrate before first use; and
(i) As specified in writing by the manufacturer of the instrument
and control, or
(ii) At routine intervals or as otherwise necessary to ensure the
accuracy and precision of the instrument and control.
(c) You must:
(1) Establish a written procedure for calibrating instruments and
controls you use in manufacturing or testing a
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component, dietary ingredient, or dietary supplement and document that
the written procedure was followed each time a calibration is
performed, or
(2) Document at the time of performance that the instrument and
control calibration established in accordance with this section was
performed.
(d) You must identify the following for calibrating instruments and
controls in any written procedure or at the time of performance:
(1) The instrument or control calibrated;
(2) The date of calibration;
(3) The reference standard used including the certification of
accuracy of the known reference standard and a history of
recertification of accuracy;
(4) The calibration method used including appropriate limits for
accuracy and precision of instruments and controls when calibrating;
(5) The calibration reading or readings found; and
(6) The recalibration method used if accuracy or precision or both
accuracy and precision limits for instruments and controls were not
met; and
(7) The initials of the person who performed the calibration.
(d) You must repair or replace instruments or controls that cannot
be adjusted to agree with the reference standard.
(e)(1) You must maintain, clean, and sanitize as necessary, all
equipment, utensils, and any other contact surfaces that are used to
manufacture, package, or hold components, dietary ingredients, or
dietary supplements. Equipment and utensils must be taken apart as
necessary for thorough maintenance, cleaning, and sanitizing.
(2) You must ensure that all contact surfaces used for
manufacturing or holding of low-moisture components, dietary
ingredients, or dietary supplements are in a dry and sanitary condition
at the time of use. When the surfaces are wet-cleaned, they must be
sanitized, when necessary, and thoroughly dried before subsequent use.
(3) If you use wet processing during manufacturing, you must clean
and sanitize all contact surfaces, as necessary, to protect against the
introduction of microorganisms into components, dietary ingredients, or
dietary supplements. When cleaning and sanitizing is necessary, you
must clean and sanitize all contact surfaces before use and after any
interruption during which the contact surface may have become
contaminated. If you use contact surfaces in a continuous production
operation or in back-to-back operations involving different batches of
the same dietary ingredient or dietary supplement, you must clean and
sanitize the contact surfaces as necessary.
(4) You must clean surfaces that do not touch components, dietary
ingredients, or dietary supplements as frequently as necessary to
protect against contaminating components, dietary ingredients, or
dietary supplements.
(5) Single-service articles (such as utensils intended for one-time
use, paper cups, and paper towels) must be:
(i) Stored in appropriate containers; and
(ii) Handled, dispensed, used, and disposed of in a manner that
protects against contamination of components, dietary ingredients,
dietary supplements, or any contact surface.
(6) Cleaning compounds and sanitizing agents must be adequate for
intended use and safe under condition of use;
(7) You must store cleaned and sanitized portable equipment and
utensils that have contact surfaces in a location and manner that
protects them from contamination.
(f) You must keep calibration records as required by this section
in accordance with Sec. 111.125.
Sec. 111.30 What requirements apply to automatic, mechanical, or
electronic equipment?
(a) When you use automatic, mechanical, or electronic equipment to
manufacture, package, label, and hold a dietary ingredient or dietary
supplement, you must:
(1) Design or select equipment to ensure that dietary ingredient or
dietary supplement specifications are consistently achieved and
(2) Determine the suitability of your equipment by ensuring that
your equipment is capable of operating satisfactorily within the
operating limits required by the process.
(b) For any automatic, mechanical, or electronic equipment you use,
you must:
(1) Routinely calibrate, inspect, or check to ensure proper
performance. Your quality control unit must approve these calibrations,
inspections, or checks;
(2) Make and keep written records of equipment calibrations,
inspections, or checks;
(3) Establish and use appropriate controls, to ensure that your
quality control unit approves changes in the master manufacturing
record, batch control records, packaging operations and label
operations, or changes to other operations related to the equipment
that you use and that only authorized personnel institute the changes;
(4) Establish and use appropriate controls to ensure that the
equipment functions in accordance with its intended use. These controls
must be approved by your quality control unit; and
(5) Make and keep backup file(s) of software programs and of data
entered into your computer system. Your backup file (e.g., a hard copy
of data you have entered, diskettes, tapes, microfilm, or compact
disks) must be an exact and complete record of the data you entered.
You must keep your backup software programs and data secure from
alterations, inadvertent erasures, or loss.
(c) You must keep automatic, mechanical, or electronic equipment
records required by this section in accordance with Sec. 111.125.
Sec. 111.50 [Redesignated as Sec. 111.72 and Amended]
7. Redesignate Sec. 111.50 as Sec. 111.72 and transfer it to a
new subpart E, Production and Process Controls, and revise the section
heading to read as follows:
Sec. 111.72 What requirements apply to packaging of iron-containing
dietary supplements?
* * * * *
8. Add Sec. Sec. 111.35 through 111.70 and Sec. 111.74 to newly
added subpart E to read as follows:
Sec. 111.35 What production and process controls must you use?
(a) You must implement a system of production and process controls
that covers all stages of manufacturing, packaging, labeling, and
holding of the dietary ingredients and dietary supplements.
(b) Your production and in-process control system must be designed
to ensure that the dietary ingredient or dietary supplement is
manufactured, packaged, and held in a manner that will prevent
adulteration of the dietary ingredient or dietary supplement. The
production and in-process control system must include all requirements
of this subpart and must be reviewed and approved by the quality
control unit.
(c) You must use a quality control unit in your manufacturing,
packaging, and label operations for producing the dietary ingredient or
dietary supplement to ensure that these operations are performed in a
manner that prevents adulteration and ensures that the dietary
ingredient or dietary supplement meets specifications for identity,
purity, quality, strength, and composition.
[[Page 12257]]
(d) Any substance, other than a ``dietary ingredient'' within the
meaning of section 201(ff) of the Federal Food, Drug, and Cosmetic Act
(the Act), the intended use of which results or may reasonably be
expected to result, directly or indirectly, in its becoming a component
or otherwise affecting the characteristics of the dietary ingredient or
dietary supplement must be:
(1) Authorized for use as a food additive under section 409 of the
Act; or
(2) Authorized by a prior sanction consistent with Sec. 170.3(l)
of this chapter; or
(3) If used as a color additive, subject to a listing that, by the
terms of that listing, includes the use in a dietary supplement; or
(4) Generally recognized as safe (GRAS) for use in a dietary
ingredient or dietary supplement. Any claim that a substance is GRAS,
other than a dietary ingredient within the meaning of section 201(ff)
of the Act, must be supported by a citation to the agency's regulations
or by an explanation for why there is general recognition of safety of
the use of the substance in a dietary ingredient or dietary supplement;
and
(5) Must comply with all other applicable statutory and regulatory
requirements under the Act.
(e) You must establish a specification for any point, step, or
stage in the manufacturing process where control is necessary to
prevent adulteration. Specifications must be established for:
(1) The identity, purity, quality, strength, and composition of
components, dietary ingredients, or dietary supplements that you
receive;
(2) The in-process controls in the master manufacturing record
where control is necessary to ensure the identity, purity, quality,
strength, and composition of dietary ingredients or dietary
supplements;
(3) The identity, purity, quality, strength, and composition of the
dietary ingredient or dietary supplement that you manufacture; and
(4) The dietary ingredient or dietary supplement labels and the
packaging that may come in contact with dietary ingredients and dietary
supplements. The packaging must be safe and suitable for its intended
use and comply with all other applicable statutory and regulatory
requirements under the Act and must not be reactive or absorptive so as
to affect the safety of the dietary ingredient and dietary supplement.
(f) You must monitor the in-process control points, steps, or
stages to ensure that specifications established under paragraph (e) of
this section are met and to detect any unanticipated occurrence that
may result in adulteration;
(g) You must ensure, through testing or examination, that each
specification that you established under paragraph (e) of this section
is met. Specific testing requirements are as follows:
(1) You must test each finished batch of the dietary ingredient or
dietary supplement produced before releasing for distribution to
determine whether established specifications for identity, purity,
quality, strength, and composition are met, provided that there are
scientifically valid analytical methods available to conduct such
testing.
(2) For any specification for identity, purity, quality, strength,
or composition for which you document cannot be tested on the finished
batch of a dietary ingredient or dietary supplement, because there is
no scientifically valid analytical method available for such testing,
then you must:
(i) Perform testing on each shipment lot of components, dietary
ingredients or dietary supplements received to determine whether such
specification is met; and
(ii) Perform testing in-process in accordance with the master
manufacturing record where control is necessary to ensure the identity,
purity, quality, strength, and composition of dietary ingredients or
dietary supplements; and
(3) Your quality control unit must determine when finished batch
testing cannot be completed for any specification on the identity,
purity, quality, strength, and composition of dietary ingredients or
dietary supplements.
(h) You must use an appropriate test or examination to determine
whether your specifications are met. An appropriate test is one that is
a scientifically valid analytical method.
(i) You must:
(1) Establish corrective action plans for use when an established
specification is not met;
(2) Review the results of the monitoring required by this section
and conduct a material review of any component, dietary ingredient,
dietary supplement, packaging or label for which you establish a
specification that is not met, or any unanticipated occurrence that
adulterates or could result in adulteration of the component, dietary
ingredient, dietary supplement, packaging, or label; and
(3) Make a material disposition decision for any component, dietary
ingredient, dietary supplement, packaging, or label:
(i) If a component, dietary ingredient, dietary supplement,
packaging, or label fails to meet specifications;
(ii) If any step established in the master manufacturing record is
not completed;
(iii) If there is any unanticipated occurrence during the
manufacturing operations that adulterates or may lead to adulteration
of the component, dietary ingredient, dietary supplement, packaging, or
label;
(iv) If calibration of an instrument or control suggests a problem
that may have caused batches of a dietary ingredient or dietary
supplement to become adulterated; or
(v) If a dietary ingredient or dietary supplement is returned.
(4) For any deviation or unanticipated occurrence which resulted in
or could lead to adulteration of the component, dietary ingredient,
dietary supplement, packaging, or label:
(i) You must reject the component, dietary ingredient, dietary
supplement, packaging, or label, unless the quality control unit
determines that in-process adjustments are possible to correct the
deviation or occurrence;
(ii) You must not reprocess a rejected component, dietary
ingredient, or dietary supplement unless approved by the quality
control unit; and
(iii) You must not reprocess any component, dietary ingredient or
dietary supplement if it is rejected because of contamination with
microorganisms or other contaminants, such as heavy metals;
(5) Have your quality control unit review and approve any material
review and disposition decision described in paragraphs (i)(2) and
(i)(3) of this section.
(j) The person who conducts the material review and makes the
disposition decision must, at the time of performance, document every
material review and disposition decision in paragraph (i) of this
section. The documentation must be included in the appropriate batch
production record and must:
(1) Identify the specific deviation from the specification or the
unanticipated occurrence;
(2) Describe your investigation into the cause of the deviation
from the specification or the unanticipated occurrence;
(3) Evaluate whether or not the deviation from the specification or
unanticipated occurrence has resulted in or could lead to adulteration;
(4) Identify the action(s) taken to correct and prevent a
recurrence of the deviation or the unanticipated occurrence; and
(5) Discuss what you did with the component, dietary ingredient,
dietary supplement, packaging, or label.
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(k) You must test or examine components, dietary ingredients, and
dietary supplements for those types of contamination that may
adulterate or may lead to adulteration. You must use an appropriate
scientifically valid method for the test or examination. The types of
contamination include, but are not limited to, the following:
(1) Filth, insects, or other extraneous material;
(2) Microorganisms; and
(3) Toxic substances.
(l) Tests in accordance with this section must include at least one
of the following:
(1) Gross organoleptic analysis;
(2) Microscopic analysis;
(3) Chemical analysis; or
(4) Other appropriate test.
(m) You must record results of all testing and examinations
performed in accordance with this section. If a test or examination is
performed on a batch production you must record the test or examination
result in the batch production record in accordance with Sec.
111.50(c)(10). Your records must document whether the testing and
examination demonstrates that specifications are met.
(n) For any specification that is not met, you must conduct a
material review and disposition decision under paragraph (i) of this
section.
(o) You must make and retain records, in accordance with Sec.
111.125, to ensure that you follow the requirements of this section.
The records must include, but are not limited to:
(1) The specifications established;
(2) The actual results obtained during the monitoring operation;
(3) Any deviation from specifications and any unanticipated
occurrences;
(4) Any corrective actions taken;
(5) The disposition decisions and followup; and
(6) The identity of the individual qualified by training and
experience who investigated any deviation from specifications or
unanticipated occurrence and the identity of the individual from the
quality control unit who reviewed the results of that investigation.
Sec. 111.37 What requirements apply to quality control?
(a) You must use a quality control unit to ensure that your
manufacturing, packaging, label, and holding operations in the
production of dietary ingredients and dietary supplements are performed
in a manner that prevents adulteration and misbranding, including
ensuring that dietary ingredients and dietary supplements meet
specifications for identity, purity, quality, strength, and
composition.
(b) Your quality control unit must do the following:
(1) Approve or reject all processes, specifications, controls,
tests, and examinations, and deviations from or modifications to them,
that may affect the identity, purity, quality, strength, and
composition of a dietary ingredient or dietary supplement;
(2) Determine whether all components, dietary ingredients, dietary
supplements, packaging, and labels conform to specifications;
(3) Approve or reject all components, dietary ingredients, dietary
supplements, packaging, and labels;
(4) Review and approve all master manufacturing records and all
modifications to the master manufacturing records;
(5) Review and approve all batch production-related records which
include, but are not limited to, cross referencing receiving and batch
production records, approval of a material review and disposition
decision, approval for reprocessing, and approval for releasing for
distribution;
(6) Review and approve all processes for calibrating instruments or
controls;
(7) Review all records for calibration of instruments, apparatus,
gauges, and recording devices;
(8) Review all records for equipment calibrations, inspections, and
checks;
(9) Review and approve all laboratory control processes, and
testing results;
(10) Review and approve all packaging and label records which
include, but are not limited to, cross-referencing receiving and batch
production records, approval for repackaging and relabeling, and
approval for releasing for distribution;
(11) Collect representative samples of:
(i) Each shipment lot of components, dietary ingredients, dietary
supplements, packaging, and labels received to determine whether the
component, dietary ingredient, dietary supplement, packaging, or labels
meet specifications;
(ii) Inprocess materials at points, steps, or stages, in the
manufacturing process as specified in the master manufacturing record
where control is necessary to ensure the identity, purity, quality,
strength, and composition of dietary ingredients or dietary
supplements;
(iii) Each batch of dietary ingredient or dietary supplement
manufactured to determine, before releasing for distribution, whether
the dietary ingredient or dietary supplement meets its specifications
for identity, purity, quality, strength, and composition; and
(iv) Each batch of packaged and labeled dietary ingredients or
dietary supplements to determine that you used the packaging specified
in the master manufacturing record and applied the label specified in
the master manufacturing record.
(12) Keep the reserve samples for 3 years from the date of
manufacture for use in appropriate investigations including, but not
limited to, consumer complaint investigations to determine, for
example, whether the dietary ingredient or dietary supplement
associated with a consumer complaint failed to meet any of its
specifications for identity, purity, quality, strength, and
composition. The reserve samples must:
(i) Be identified with the batch or lot number; and
(ii) Consist of at least twice the quantity necessary for tests.
(13) Perform appropriate tests and examinations of:
(i) Components, dietary ingredients, dietary supplements,
packaging, and labels received to ensure that they meet specifications;
(ii) Dietary ingredient and dietary supplement batch production at
points, steps, or stages identified in the master manufacturing record
where control is necessary to prevent adulteration;
(iii) Dietary ingredients and dietary supplements that you
manufacture to ensure that they meet specifications; and
(iv) Packaged and labeled dietary ingredients and dietary
supplements to ensure that you used the packaging specified in the
master manufacturing record and you applied the label specified in the
master manufacturing record.
(14) Review and approve all material review and disposition
decisions; and
(15) Approve the reprocessing or distribution of returned dietary
ingredients or dietary supplements.
(c) Your quality control unit must establish and maintain written
documentation at the time of performance that it performed the review,
approval, or rejection requirements of this section by recording the
following:
(1) Date the required review, approval, or rejection was performed;
and
(2) Signature of the person performing the requirement.
(d) You must keep quality control records in accordance with Sec.
111.125.
Sec. 111.40 What requirements apply to components, dietary
ingredients, dietary supplements, packaging, and labels you receive?
(a) For components, dietary ingredients, or dietary supplements you
receive, you must:
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(1) Visually examine each container or grouping of containers in a
shipment for appropriate content label, container damage, or broken
seals to determine whether the container condition has resulted in
contamination or deterioration of the components, dietary ingredients,
or dietary supplement;
(2) Visually examine the suppliers invoice, guarantee, or
certification to ensure that the components, dietary ingredients, or
dietary supplements are consistent with your purchase order and perform
testing, as needed, to determine whether specifications are met.
(3) Quarantine components, dietary ingredients, or dietary
supplements until your quality control unit reviews the suppliers
invoice, guarantee, or certification and performs testing, as needed,
of a representative sample to determine that specifications are met. If
specifications are not met, you must conduct a material review and make
a disposition decision. Your quality control unit must approve and
release the components, dietary ingredients, and dietary supplements
from quarantine before you use them;
(4) Identify each lot of components, dietary ingredients, or
dietary supplements in a shipment in a manner that allows you to trace
the shipment to the supplier, the date received, the name of the
component or dietary supplement, and the status (e.g., quarantined,
approved, or rejected) and to trace the shipment lot to the dietary
ingredient or dietary supplement manufactured and distributed. You must
use this unique identifier whenever you record the disposition of each
shipment lot received; and
(5) Hold components, dietary ingredients, or dietary supplements
under conditions that will protect against contamination,
deterioration, and avoid mixups.
(b) For packaging and labels you receive, you must:
(1) Visually examine each container or grouping of containers in a
shipment for appropriate content label, container damage, or broken
seals to determine whether the container condition has resulted in
contamination or deterioration of the packaging and labels;
(2) Quarantine packaging and labels until your quality control unit
tests or examines a representative sample to determine that
specifications are met. You must conduct at least a visual
identification on the containers and closures. If specifications are
not met, you must conduct a material review and make a disposition
decision. Your quality control unit must approve and release packaging
and labels from quarantine before you use them;
(3) Identify each shipment lot of packaging and labels in a manner
that allows you to trace the shipment lot to the supplier, the date
received, the name of the packaging and label and the status (e.g.,
quarantined, approved, or rejected) and to trace the shipment lot to
the dietary ingredient or dietary supplement manufactured and
distributed. You must use this unique identifier whenever you record
the disposition of each shipment lot received; and
(4) Hold packaging and labels under conditions that will protect
against contamination, deterioration, and avoid mixups.
(c)(1) The person who performs the component, dietary ingredient,
dietary supplement, packaging, or label requirements of this section
must document, at the time of performance, that the requirements were
followed. The documentation must include, but not be limited to:
(i) The date that the components, dietary ingredients, dietary
supplements, packaging, or labels were received;
(ii) The signature of the person performing the requirement;
(iii) Any test results; and
(iv) Any material review and disposition decision you conducted in
accordance with Sec. 111.35(i) and disposition of any rejected
material under Sec. 111.74.
(2) You must keep component, dietary supplement, packaging, and
label receiving records in accordance with Sec. 111.125.
Sec. 111.45 What requirements apply to establishing a master
manufacturing record?
(a) You must prepare and follow a written master manufacturing
record for each type of dietary ingredient or dietary supplement that
you manufacture and for each batch size to ensure uniformity from batch
to batch. The master manufacturing record must:
(1) Identify specifications for the points, steps, or stages in the
manufacturing process where control is necessary to prevent
adulteration; and
(2) Establish controls and procedures to ensure that each batch of
dietary ingredient or dietary supplement manufactured meets those
specifications.
(b) The master manufacturing record must include the following
information:
(1) The name of the dietary ingredient or dietary supplement to be
manufactured and the strength, concentration, weight, or measure of
each dietary ingredient for each batch size;
(2) A complete list of components to be used;
(3) An accurate statement of the weight or measure of each
component to be used;
(4) The identity and weight or measure of each dietary ingredient
that will be declared on the Supplement Facts label and the identity of
each ingredient that will be declared on the ingredients list of the
dietary supplement in compliance with section 403(s) of the Federal
Food, Drug, and Cosmetic Act;
(5) A statement that explains any intentional excess amount of a
dietary ingredient;
(6) A statement of theoretical yield of a manufactured dietary
ingredient or dietary supplement expected at each point, step, or stage
of the manufacturing process where control is needed to prevent
adulteration, and the expected yield when you finish manufacturing the
dietary ingredient or dietary supplement, including the maximum and
minimum percentages of theoretical yield beyond which a deviation
investigation of a batch is performed and material review is conducted
and disposition decision is made;
(7) A description of packaging and a copy of the label to be used;
and
(8) Written instructions including, but not limited to, the
following:
(i) Specifications for each point, step, or stage in manufacturing
the dietary ingredient or dietary supplement necessary to prevent
adulteration;
(ii) Sampling and testing procedures;
(iii) Specific actions necessary to perform and verify points,
steps, or stages, necessary to meet specifications and otherwise
prevent adulteration, including, but not limited to, one person
weighing or measuring a component and another person verifying the
weight or measure and one person adding the component and another
person verifying the addition;
(iv) Special notations and precautions to be followed; and
(v) Corrective action plans for use when a specification is not
met.
(c) You must have the quality control unit review and approve each
master manufacturing record and any modifications to a master
manufacturing record.
(d) You must keep master manufacturing records in accordance with
Sec. 111.125.
Sec. 111.50 What requirements apply to establishing a batch
production record?
(a) You must prepare a batch production record every time you
[[Page 12260]]
manufacture a batch of a dietary ingredient or dietary supplement and
the batch production record must include complete information relating
to the production and control of each batch.
(b) Your batch production record must accurately follow the
appropriate master manufacturing record and you must perform each step
in producing the batch.
(c) The batch production record must include, but is not limited
to, the following information:
(1) The batch, lot, or control number;
(2) Documentation at the time of performance, showing the date on
which each step of the master manufacturing record was performed, and
the initials of the persons performing each step, including but not
limited to:
(i) The person responsible for weighing or measuring each component
used in the batch; and
(ii) The person responsible for adding the component to the batch.
(3) The identity of equipment and processing lines used in
producing the batch;
(4) The date and time of the maintenance, cleaning, and sanitizing
of the equipment and processing lines used in producing the batch;
(5) The shipment lot unique identifier of each component, dietary
ingredient, dietary supplement, packaging, and label used;
(6) The identity and weight or measure of each component used;
(7) The initials at the time of performance or at the completion of
the batch of the person responsible for verifying the weight or measure
of each component used in the batch;
(8) The initials at the time of performance or at the completion of
the batch of the person responsible for verifying the addition of
components to the batch;
(9) A statement of the actual yield and a statement of the
percentage of theoretical yield at appropriate phases of processing;
(10) The actual test results for any testing performed during the
batch production;
(11) Documentation that the dietary ingredient and dietary
supplement meets specifications;
(12) Copies of all container labels used and the results of
examinations conducted during the label operation to ensure that the
containers have the correct label;
(13) Any documented material review and disposition decision in
accordance with Sec. 111.35(j); and
(14) Signature of the quality control unit to document batch
production record review and any approval for reprocessing or
repackaging.
(d) The quality control unit must review in accordance with Sec.
111.37(b)(5) the batch production record established in paragraph (c)
of this section.
(1) If a batch deviates from the master manufacturing record,
including any deviation from specifications, the quality control unit
must conduct a material review and make a disposition decision and
record any decision in the batch production record.
(2) The quality control unit must not approve and release for
distribution any batch of dietary ingredient or dietary supplement that
does not meet all specifications.
(e) The quality control unit must document in accordance with Sec.
111.37(c) the review performed in accordance with paragraph (d) of this
section and it must be documented at the time of performance. The
review and documentation must include, but is not limited to, the
following:
(1) Review of component, dietary ingredient, and dietary supplement
receiving records including review of testing and examination results;
(2) Identification of any deviation from the master manufacturing
record that may have caused a batch or any of its components to fail to
meet specifications identified in the master production record;
(3) Records of investigations, conclusions, and corrective actions
performed in accordance with paragraph (d) of this section; and
(4) The identity of the person qualified by training and experience
who performed the investigation in accordance with paragraph (d) of
this section.
(f) You must not reprocess a batch that deviates from the master
manufacturing record unless approved by the quality control unit. You
must not reprocess a dietary ingredient or dietary supplement if it is
rejected because of contamination with microorganisms of public health
significance or other contaminants, such as heavy metals;
(g) Any batch of dietary ingredient or dietary supplement that is
reprocessed must meet all specifications for the batch of dietary
ingredient or dietary supplement and be evaluated and approved by the
quality control unit before releasing for distribution. The results of
the reevaluation by the quality control unit must be documented in the
batch production record;
(h) You must collect representative reserve samples of each batch
of dietary ingredient or dietary supplement and keep the reserve
samples for 3 years from the date of manufacture for use in appropriate
investigations including, but not limited to, consumer complaint
investigations to determine whether, for example, the dietary
ingredient or dietary supplement associated with a consumer complaint
failed to meet any of its specifications for identity, purity, quality,
strength, and composition; and
(i) You must keep batch production records in accordance with Sec.
111.125.
Sec. 111.60 What requirements apply to laboratory operations?
(a) You must use adequate laboratory facilities to perform whatever
testing and examinations are necessary to determine that components,
dietary ingredients, and dietary supplements received meet
specifications; that specifications are met during in-process, as
specified in the master manufacturing record; and that dietary
ingredients and dietary supplements manufactured meet specifications.
(b)(1) You must establish and follow laboratory control processes
that are approved by the quality control unit. Laboratory control
processes must include, but are not limited to, the following:
(i) Use of criteria for selecting appropriate examination and
testing methods;
(ii) Use of criteria for establishing appropriate specifications;
and
(iii) Use of sampling plans for obtaining representative samples
of:
(A) Components, dietary ingredients, and dietary supplements
received to determine whether specifications are met;
(B) In-process materials during the batch manufacturing when
testing or examination is required in the master manufacturing record;
(C) Each batch of dietary ingredient or dietary supplement
manufactured to determine that the dietary ingredient or dietary
supplement meets specifications;
(D) Packaging and labels received to determine that the materials
meet specifications; and
(E) Each batch of packaged and labeled dietary ingredients or
dietary supplements to ensure that the label specified in the master
manufacturing record has been applied.
(iv) Use of criteria for selecting standard reference materials
used in performing tests and examinations;
(v) Use of appropriate test method validations; and
(vi) Use of test methods and examinations in accordance with
established criteria.
(2) The person who conducts the testing and examination at the time
of
[[Page 12261]]
performance, must document that laboratory methodology established in
accordance with this section is followed. The documentation must
include the testing and examination results.
(3) You must keep laboratory examination and testing records in
accordance with Sec. 111.125.
(c) You must verify that the laboratory examination and testing
methodologies are appropriate for their intended use.
(d) You must identify and use the appropriate validated testing
method for each established specification for which testing is required
to determine whether the specification is met.
Sec. 111.65 What requirements apply to manufacturing operations?
(a) You must design or select manufacturing processes to ensure
that dietary ingredient or dietary supplement specifications are
consistently achieved.
(b) You must conduct all manufacturing operations in accordance
with adequate sanitation principles.
(c) You must take all the necessary precautions during the
manufacture of a dietary ingredient or dietary supplement to prevent
contamination of components, dietary ingredients, or dietary
supplements. These precautions include, but are not limited to:
(1) Performing manufacturing operations under conditions and
controls that protect against the potential for growth of
microorganisms and the potential for contamination;
(2) Washing or cleaning components that contain soil or other
contaminants;
(3) Using water that meets the National Primary Drinking Water
regulations or, where necessary, higher sanitary quality and that
complies with all applicable Federal, State, and local regulations for
water that is used in the manufacturing operation. If you reuse water
that was used to wash components to remove soil or contaminants, the
reused water must be safe and of adequate sanitary quality so that it
does not become a source of contamination;
(4) Performing chemical, microbiological, or other testing, as
necessary to prevent the use of contaminated components, dietary
ingredients, and dietary supplements;
(5) Sterilizing, pasteurizing, freezing, refrigerating, controlling
hydrogen-ion concentration (pH), controlling humidity, controlling
water activity (aw), or using any other effective means to
remove, destroy, or prevent the growth of microorganisms and prevent
decomposition;
(6) Holding components, dietary ingredients, and dietary
supplements that can support the rapid growth of microorganisms of
public health significance in a manner that prevents the components,
dietary ingredients, and dietary supplements from becoming adulterated;
(7) Identifying and holding any components, dietary ingredients, or
dietary supplements, for which a material review and disposition
decision is required, in a manner that protects the components, dietary
ingredients, or dietary supplements against contamination and mixups;
(8) Performing mechanical manufacturing steps (such as cutting,
sorting, inspecting, shredding, drying, grinding, blending, and
sifting) by any effective means to protect the dietary ingredients or
dietary supplements against contamination. Such steps must include
consideration of:
(i) Cleaning and sanitizing contact surfaces;
(ii) Using temperature controls; and
(iii) Using time controls.
(9) Using effective measures to protect against the inclusion of
metal or other foreign material in components, dietary ingredients, or
dietary supplements. Compliance with this requirement must include
consideration of the use of:
(i) Filters or strainers;
(ii) Traps;
(iii) Magnets; or
(iv) Electronic metal detectors.
(10) Segregating and identifying all containers for a specific
batch of dietary ingredients or dietary supplements to identify their
contents and, where necessary, the phase of manufacturing; and
(11) Identifying all processing lines and major equipment used
during manufacturing to indicate their contents including the name of
the dietary ingredient or dietary supplement and the specific batch or
lot number and, when necessary, the phase of manufacturing.
(d) You must conduct a material review and make a disposition
decision in accordance with Sec. 111.35(i) for any component, dietary
ingredient, or dietary supplement that fails to meet specifications or
that is or may be adulterated. If the material review and disposition
decision allows you to reprocess the component, dietary ingredient, or
dietary supplement, you must retest or reexamine the component, dietary
ingredient, or dietary supplement to ensure that it meets
specifications and is approved by the quality control unit.
Sec. 111.70 What requirements apply to packaging and label
operations?
(a) You must take necessary actions to ensure that each packaging
container for holding dietary ingredients or dietary supplements meets
specifications so that the condition of the packaging container will
not contaminate your dietary ingredients or dietary supplements nor
cause them to deteriorate;
(b) You must fill, assemble, package, and perform other related
operations in a way that protects your dietary ingredients or dietary
supplements against adulteration and misbranding. You must do this
using any effective means, including but not limited to, the following:
(1) Cleaning and sanitizing all filling and packaging equipment,
utensils, and dietary ingredient or dietary supplement containers, as
appropriate;
(2) Protecting manufactured dietary ingredients and dietary
supplements from contamination, particularly airborne contamination;
(3) Using sanitary handling procedures;
(4) Establishing physical or spatial separation of packaging and
labels from operations on other dietary ingredients and dietary
supplements to prevent mixups;
(5) Identifying, by any effective means, filled dietary ingredient
or dietary supplement containers that are set aside and held in
unlabeled condition for future label operations, to prevent mixups;
(6) Identifying the dietary ingredient or dietary supplement with a
batch, lot, or control number that can be used to determine the
manufacturing history and control of the batch;
(7) Examining a representative sample of each batch of the packaged
and labeled dietary ingredient or dietary supplement to ensure that the
dietary ingredient or dietary supplement meets specifications and that
the label specified in the master manufacturing record has been
applied; and
(8) Suitably disposing of labels and other packaging for dietary
ingredients or dietary supplements that are obsolete or incorrect to
ensure that they are not used in any future packaging and label
operations.
(c) You must conduct a material review and make a disposition
decision of any packaged and labeled dietary ingredients or dietary
supplements that do not meet specifications.
(d) You must only repackage or relabel dietary ingredients or
dietary supplements after the quality control unit has approved and
documented such repackaging or relabeling.
(e) You must retest or reexamine any repackaged or relabeled
dietary ingredients or dietary supplements. They must meet all
specifications and
[[Page 12262]]
the quality control unit must approve or reject their release for
distribution.
(f)(1) You must control the issuance and use of packaging and
labels and reconciliation of any issuance and use discrepancies; and
(2) You must examine, before packaging operations, packaging and
labels for each batch of dietary ingredient or dietary supplement to
ensure that the label and packaging conform to the master manufacturing
record.
(g) The person that performs the requirements of this section must
document at the time of performance that the requirements are performed
including, but not limited to, documentation in the batch production
record of:
(1) The identity and quantity of the packaging and labels used and
reconciliation of any discrepancies between issuance and use;
(2) The examination conducted in accordance with paragraph (b)(7)
of this section;
(3) The conclusions you reached from retests conducted in
accordance with paragraph (e) of this section; and
(4) Any material reviews and disposition decisions for packaging
and labels.
(h) You must keep packaging and label operations records required
under this section in accordance with Sec. 111.125.
Sec. 111.74 What requirements apply to rejected components, dietary
ingredients, dietary supplements, packaging, and labels?
You must clearly identify, hold, and control under a quarantine
system any component, dietary ingredient, dietary supplement,
packaging, and label that is rejected and unsuitable for use in
manufacturing, packaging, or label operations.
9. Add subpart F to part 111 to read as follows:
Subpart F--Holding and Distributing
Sec.
111.80 What requirements apply to holding components, dietary
ingredients, dietary supplements, packaging, and labels?
111.82 What requirements apply to holding in-process material?
111.83 What requirements apply to holding reserve samples of
components, dietary ingredients, and dietary supplements?
111.85 What requirements apply to returned dietary ingredients or
dietary supplements?
111.90 What requirements apply to distributing dietary ingredients
or dietary supplements?
Subpart F--Holding and Distributing
Sec. 111.80 What requirements apply to holding components, dietary
ingredients, dietary supplements, packaging, and labels?
(a) You must hold components, dietary ingredients, and dietary
supplements under appropriate conditions of temperature, humidity, and
light so that the identity, purity, quality, strength, and composition
of the components, dietary ingredients, and dietary supplements are not
affected.
(b) You must hold packaging and labels under appropriate conditions
of temperature, humidity, and light so that the quality of the
packaging and labels are not affected.
(c) You must hold components, dietary ingredients, dietary
supplements, packaging, and labels under conditions that do not lead to
the mixup, contamination, or deterioration of components, dietary
ingredients, dietary supplements, packaging, and labels.
Sec. 111.82 What requirements apply to holding in-process material?
(a) You must identify and hold in-process material under conditions
that will protect them against mixup, contamination, and deterioration.
(b) You must hold in-process material under appropriate conditions
of temperature, humidity, and light.
Sec. 111.83 What requirements apply to holding reserve samples of
components, dietary ingredients, and dietary supplements?
(a) For any reserve samples of components or dietary ingredients
you collect, you must hold such reserve samples in a manner that
protects against contamination and deterioration.
(b) You must hold reserve samples of dietary supplements in a
manner that protects against contamination and deterioration. This
includes, but is not limited to:
(1) Holding the reserve samples under conditions of use recommended
or suggested in the label of the dietary supplement and, if no
conditions of use are recommended or suggested in the label, then under
ordinary conditions of use; and
(2) Using the same container-closure system in which the dietary
supplement is marketed or in one that provides the same level of
protection against contamination or deterioration.
Sec. 111.85 What requirements apply to returned dietary ingredients
or dietary supplements?
(a) You must identify and quarantine returned dietary ingredients
or dietary supplements until the quality control unit conducts a
material review and makes a disposition decision.
(b) You must not salvage returned dietary ingredients and dietary
supplements, unless:
(1) Evidence from their packaging (or, if possible, an inspection
of the premises where the dietary ingredients and dietary supplements
were held) indicates that the dietary ingredients and dietary
supplements were not subjected to improper storage conditions; and
(2) Tests demonstrate that the dietary ingredients or dietary
supplements meet all specifications for identity, purity, quality,
strength, and composition.
(c) You must destroy or suitably dispose of the returned dietary
ingredients or dietary supplements if such dietary ingredients or
dietary supplements do not meet specifications for identity, purity,
quality, strength, and composition, unless the quality control unit
conducts a material review and makes a disposition decision to allow
reprocessing.
(d) If the reason for a dietary ingredient or a dietary supplement
being returned implicates associated batches, you must conduct an
investigation of your manufacturing processes and those other batches
to determine compliance with specifications.
(e) You must establish and keep records for this section on the
material review and disposition decision and any testing conducted to
determine compliance with established specifications in the master
manufacturing record for the type of dietary ingredient or dietary
supplement that was returned.
(f) You must keep returned dietary ingredient and dietary
supplement records in accordance with Sec. 111.125.
Sec. 111.90 What requirements apply to distributing dietary
ingredients or dietary supplements?
Distribution of dietary ingredients and dietary supplements must be
under conditions that will protect the dietary ingredients and dietary
supplements against contamination and deterioration.
10. Add subpart G to part 111 to read as follows:
Subpart G--Consumer Complaints
Sec. 111.95 What requirements apply to consumer complaints?
(a) A qualified person must review all consumer complaints to
determine whether the consumer complaint involves a possible failure of
a dietary ingredient or dietary supplement to meet any of its
specifications, or any
[[Page 12263]]
other requirements of this part, including those specifications and
other requirements that, if not met, may result in a possible risk of
illness or injury.
(b) Your quality control unit must review all consumer complaints
involving the possible failure of a dietary ingredient or dietary
supplement to meet any of its specifications, or any other requirements
of this part, including those specifications and other requirements
that, if not met, may result in a possible risk of illness or injury,
to determine whether there is a need to investigate the consumer
complaint.
(c) Your quality control unit must investigate a consumer complaint
when there is a reasonable possibility of a relationship between the
quality of a dietary supplement and an adverse event.
(d) Your quality control unit's investigation of a consumer
complaint must include the batch records associated with the dietary
ingredient or dietary supplement involved in the consumer complaint.
Your quality control unit must extend the investigation to other
batches of dietary ingredients or dietary supplements that may have
been associated with an adverse event.
(e) You must make and keep a written record of every consumer
complaint that is related to good manufacturing practices. For the
purposes of the regulations in this part, a consumer complaint about
product quality may or may not include concerns about a possible hazard
to health. However, a consumer complaint does not include an adverse
event, illness, or injury related to the safety of a particular dietary
ingredient independent of whether the product is produced under good
manufacturing practices. The consumer complaint written record must
include, but is not limited to, the following:
(1) The name and description of the dietary ingredient or dietary
supplement;
(2) The batch or lot number of the dietary supplement, if
available;
(3) The name of the complainant, if available;
(4) The nature of the complaint including how the consumer used the
product;
(5) The reply to the complainant, if any; and
(6) Findings of the investigation and followup action taken when an
investigation is performed.
(f)(1) The person who performs the requirements in accordance with
this section must document at the time of performance that the
requirement was performed.
(2) You must keep consumer complaint records in accordance with
Sec. 111.125.
11. Add subpart H to part 111 to read as follows:
Subpart H--Records and Recordkeeping
Sec. 111.125 What requirements apply to recordkeeping?
(a) You must keep written records required by this part for 3 years
beyond the date of manufacture of the last batch of dietary ingredients
or dietary supplements associated with those records.
(b) Records required under this part must be kept as original
records, as true copies (such as photocopies, microfilm, microfiche, or
other accurate reproductions of the original records), or as electronic
records. If you use reduction techniques, such as microfilming, you
must make suitable reader and photocopying equipment readily available
to FDA. All electronic records must comply with part 11 of this
chapter.
(c) You must have all records required under this part, or copies
of such records, readily available during the retention period for
authorized inspection and copying by FDA when requested.
12. Part 112 is added to read as follows:
PART 112--RESTRICTIONS FOR SUBSTANCES USED IN DIETARY SUPPLEMENTS
Subpart A--General Provisions [Reserved]
Subpart B--New Dietary Ingredients [Reserved]
Subpart C--Restricted Dietary Ingredients [Reserved]
Authority: 21 U.S.C. 321, 342, 343, 371.
Dated: January 29, 2003.
Mark B. McClellan,
Commissioner of Food and Drugs.
Dated: January 29, 2003.
Tommy G. Thompson,
Secretary of Health and Human Services.
[FR Doc. 03-5401 Filed 3-12-03; 11:30 am]
BILLING CODE 4160-01-P