[Federal Register Volume 68, Number 81 (Monday, April 28, 2003)]
[Proposed Rules]
[Pages 22341-22343]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-10301]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 106 and 107
[Docket No. 95N-0309]
RIN 0910-AA04
Current Good Manufacturing Practice, Quality Control Procedures,
Quality Factors, Notification Requirements, and Records and Reports for
the Production of Infant Formula; Reopening of the Comment Period
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule; reopening of the comment period.
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SUMMARY: The Food and Drug Administration (FDA) is reopening until June
27, 2003, the comment period for the proposed rule, published in the
Federal Register of July 9, 1996 (61 FR 36154), revising its infant
formula regulations in 21 CFR parts 106 and 107. The proposed rule
would establish requirements for current good manufacturing practice
(CGMP) and audits, establish requirements for quality factors, and
amend its quality control procedures, notification, and records and
reports requirements for infant formula. FDA is reopening the comment
period to update comments and to receive any new information.
DATES: Submit written or electronic comments by June 27, 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.
FOR FURTHER INFORMATION CONTACT: Shellee Anderson, Center for Food
Safety and Applied Nutrition (HFS-800), Food and Drug Administration,
5100 Paint Branch Pkwy., College Park, MD 20740, 301-436-1491, or e-
mail: [email protected].
SUPPLEMENTARY INFORMATION:
I. Reopening of Comment Period
In the Federal Register of July 9, 1996 (61 FR 36154), FDA proposed
regulations (the 1996 proposal) to revise its infant formula
regulations to establish requirements for quality factors and CGMP; to
amend its quality control procedure, notification, and records and
report requirements for infant formulas; to require that infant
formulas contain, and be tested for, required nutrients and for any
nutrient added by the manufacturer throughout their shelf life, and
that they be produced under strict microbiological controls; and to
require that manufacturers implement the CGMP and quality control
procedure requirements by establishing a production and in-process
control system of their own design. The agency proposed these
requirements to implement provisions of the Drug Enforcement, Education
and Control Act of 1986 (Public Law 99-570) that amended section 412 of
the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 350a).
Interested persons were originally given until October 7, 1996, to
comment on the 1996 proposal. However, at the request of a trade
organization, the comment period was extended to December 6, 1996 (61
FR 49714, September 23, 1996).
FDA's Food Advisory Committee (FAC) met on April 4 and 5, 2002, to
discuss general scientific principles related to quality factors for
infant formula. The committee was also asked to discuss the scientific
issues related to the generalization of findings from a clinical study
using preterm infant formula consumed by preterm infants to a term
infant formula intended for use by term infants. On November 18 and 19,
2002, the Infant Formula Subcommittee (IFS) of the FAC met to discuss
the scientific issues and principles involved in assessing and
evaluating whether a ``new'' infant formula supports normal physical
growth in infants when consumed as a sole source of nutrition. The
Contaminants and Natural Toxicants Subcommittee (CNTS) of the FAC met
on March 18 and 19, 2003, to discuss the scientific issues and
principles involved in assessing and evaluating Enterobacter sakazakii
contamination in powdered infant formula, risk reduction strategies
based on available data, and research questions and priorities.
Information on these three meetings, including the agenda, questions
asked, guest speakers, committee roster, briefing information, and
transcripts of the meetings can be found at http://www.fda.gov/ohrms/dockets/ac/cfsan02.htm.
II. Request for Comments
Because of the length of time that has elapsed since publication of
the 1996 proposal and the occurrence of the FAC, IFS, and CNTS
meetings, FDA is interested in updating comments and receiving any new
information before issuing a final rule. Accordingly, the agency is
requesting comments on all
[[Page 22342]]
issues in the proposed rule. Comments previously submitted to the
Dockets Management Branch do not need to be resubmitted because all
comments submitted to the docket number will be considered in any final
rule to the 1996 proposal. Since the 1996 proposal was published,
several issues within the scope of that proposal have come to the
agency's attention and are set forth in this document for comment.
(Issue 1) In April 2001, an outbreak of E. sakazakii occurred in 10
infants in the neonatal intensive care unit of a hospital in Tennessee
(Ref. 1). One of these infants died. The ill infants had consumed
formula that was made from sterile water and a specific batch of
powdered infant formula. Samples from both opened and unopened cans of
the implicated brand of powdered infant formula were cultured. E.
sakazakii was found in all samples from one particular batch of the
product. Because of its concerns with E. sakazakii, FDA requests
comment on whether there is a need to include a microbiological
requirement for E. sakazakii and, if so, what requirement the agency
should consider to ensure the safety of powdered infant formula and
prevent future outbreaks. The agency requests comment on what other
changes, if any, in the proposed microbiological requirements would be
appropriate to ensure the safety of powdered infant formula and to
prevent outbreaks of illness. FDA also requests comment on whether
powdered infant formula to be consumed by premature and newborn infants
should meet stricter microbiological requirements than formula intended
for older infants. The agency specifically requests comments on issues
discussed at the CNTS meeting that are relevant to this rulemaking.
(Issue 2) On March 19, 2002, FDA issued a letter (Ref. 2) in
response to a notice of a manufacturer's conclusion that
Bifidobacterium lactis strain Bb12 and Streptococcus thermophilus
strain Th4 are generally recognized as safe (GRAS) for their intended
use as ingredients in milk based infant formula that is intended for
consumption by infants 4 months and older, at levels not to exceed
CGMP. The agency has no questions about the manufacturer's conclusion
at this time. In the 1996 proposal, FDA provided controls in proposed
Sec. 106.55 for powdered infant formula to prevent adulteration from
microorganisms, including a proposed limit on the maximum allowable
number of microorganisms in the aerobic plate count. The agency
requests comment on what changes, if any, in the proposed
microbiological requirements would be appropriate to provide for
powdered infant formula and to ensure its safety if microorganisms are
intentionally added to infant formulas. Would infant formula containing
these added microorganisms exceed the maximum allowable number in the
aerobic plate count? How can manufacturers ensure that a high aerobic
plate count is due to the intentional addition of microorganisms and
not contamination?
(Issue 3) The agency requests comments on which provisions of the
proposed rule would require manufacturers to change their current
activities. What new activities would manufacturers have to undertake
to comply with the proposed regulations? What activities would
manufacturers have to discontinue to comply with the proposed
regulations? What are the costs of these changes? For example:
(Issue 3a) Proposed Sec. 106.20(a) requires that buildings used in
the manufacture of infant formula allot space for the separation of
incompatible operations, such as the handling of raw materials, the
manufacture of the product, and packaging and labeling operations. FDA
requests comment on the types of control systems that manufacturers use
to separate raw, in-process, and finished materials and the costs of
making changes.
(Issue 3b) Proposed Sec. 106.20(d) would require manufacturers to
use air filtration systems, including prefilters and particulate matter
air filters, on air supplies to production areas where ingredients or
infant formula are directly exposed to the atmosphere. FDA requests
comment on the types and costs of air filtration systems used by infant
formula manufacturers and the costs of making changes.
(Issue 4) One comment to the 1996 proposal stated that the
validation section in proposed Sec. 106.35 is so vague and the impact
so enormous that implementing it would be counterproductive. In
proposed Sec. 106.35(a)(4) the agency proposed that, for purposes of
the section, ``validation'' means establishing documented evidence that
provides a high degree of assurance that a system will consistently
produce a product meeting its predetermined specifications and quality
characteristics. In proposed Sec. 106.35(b)(1), FDA proposed that all
automatic systems be designed, installed, tested, and maintained in a
manner that will ensure that they are capable of performing their
intended function. The agency proposed in proposed Sec. 106.35(b)(4)
that automatic systems be validated before their first use to
manufacture commercial product. Proposed Sec. 106.35(b)(5) states that
the infant formula manufacturer shall ensure that any automatic system
that is modified be validated after the modification and before use of
the modified system to manufacture commercial product. FDA requests
comments on the proposed validation requirements. The agency
specifically requests comments on current validation activities of
infant formula facilities and how often manufacturers validate their
systems.
(Issue 5) Several provisions of the 1996 proposal (e.g., Sec. Sec.
106.30(d)(1) and 106.35(b)(2)) would require that manufacturers
calibrate instruments and controls. In these proposed provisions the
agency specifies that calibration occur at routine intervals. FDA
requests comments on how often and under what conditions manufacturers
now calibrate instruments and controls against a known standard and the
adequacy of current procedures.
(Issue 6) FDA proposed to establish two quality factor measures for
infant formula, protein quality and normal physical growth. Quality
factors are those factors necessary to demonstrate that the infant
formula, as prepared for market, provides nutrients in a form that is
bioavailable and safe as shown by evidence that demonstrates that the
formula supports healthy growth when fed as a sole source of nutrition.
The agency requests comments on the appropriateness of these quality
factors and any information on other quality factors that could be
implemented to be consistent with current scientific knowledge as
required under section 412(b)(1) of the act. FDA specifically requests
comments on issues relevant to this rulemaking that were discussed at
the two FAC meetings and on the following quality factor issues:
(Issue 6a) What requirements should the agency establish to
determine when manufacturers must conduct clinical growth studies for a
new or reformulated infant formula?
(Issue 6b) In proposed Sec. 106.97, FDA would require that
manufacturers compare their clinical study growth data with the
National Center for Health Statistics (NCHS) growth charts. The IFS of
the FAC considered other sources of reference data in addition to the
NCHS and recommended the Iowa reference data as the most appropriate
reference data for comparison because they are longitudinal, collected
over the time period of interest for clinical studies of infant growth,
and collected in a research setting. FDA requests comments on whether
the Iowa reference data should be the standard
[[Page 22343]]
for clinical study growth data rather than the NCHS growth charts.
(Issue 6c) In proposed Sec. 106.97(a)(1)(i)(A), the agency would
require that manufacturers conduct clinical studies that are no less
than 4 months in duration, enrolling infants no more than 1 month old
at time of entry into the study. The IFS of the FAC recommended that
infants be enrolled by 14 days of age. FDA requests comments on the
appropriate age for infants enrollment into clinical studies and on the
duration of the studies.
(Issue 7) In proposed Sec. 106.97(a)(1)(ii), the agency states
provisions that it recommends manufacturers include in a clinical study
protocol. Proposed Sec. 106.97(a)(1)(ii)(C) discusses review and
approval by an Institutional Review Board (IRB) in accordance with part
56 (21 CFR part 56), and the need for obtaining written informed
consent from parents or legal representatives of the infants in
accordance with part 50 (21 CFR part 50). Subsequent to the publication
of the 1996 proposal, the agency issued an interim final rule entitled
``Additional Safeguards for Children in Clinical Investigations of FDA-
Regulated Products'' (66 FR 20589, April 24, 2001), which amended parts
50 and 56 to include, within the scope of that rule, data and
information about a clinical study of an infant formula when submitted
as part of an infant formula notification under section 412(c) of the
act. Thus, requirements related to IRB review and informed consent for
such clinical studies are dealt with in that interim final rule, and
therefore, reference to IRB review and informed consent will be removed
from the 1996 proposal. With respect to the other clinical study
protocol provisions in proposed Sec. 106.97(a)(1)(ii), the agency
intends to remove them from the proposed rule and develop a guidance
document on what it recommends be included in a clinical study protocol
for infant formula that is submitted as part of an infant formula
notification under section 412(c) of the act.
III. How to Submit 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 paper copies of any mailed comments, except
that individuals may submit one paper 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 Docket Management
Branch between 9 a.m. and 4 p.m., Monday through Friday.
IV. References
FDA has placed the following references on display in the Dockets
Management Branch (see ADDRESSES) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
1. Centers for Disease Control and Prevention, ``Enterobacter
sakazakii Infections Associated With the Use of Powdered Infant
Formula-Tennessee, 2001,'' 51(14):297, Morbidity and Mortality
Weekly Report, April 12, 2002.
2. FDA, Agency response letter to GRAS notice number GRN 00049,
March 19, 2002.
Dated: April 15, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-10301 Filed 4-25-03; 8:45 am]
BILLING CODE 4160-01-S