FR Doc 07-3039

[Federal Register: June 25, 2007 (Volume 72, Number 121)]
[Rules and Regulations]
[Page 34751-34958]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr25jn07-17]

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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 Part 111

Current Good Manufacturing Practice in Manufacturing, Packaging,
Labeling, or Holding Operations for Dietary Supplements; Final Rule

Petition To Request an Exemption From 100 Percent Identity Testing of
Dietary Ingredients; Interim Final Rule

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 111

[Docket No. 1996N-0417] (formerly Docket No. 96N-0417)
RIN 0910-AB88

Current Good Manufacturing Practice in Manufacturing, Packaging,
Labeling, or Holding Operations for Dietary Supplements

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule
regarding current good manufacturing practice (CGMP) for dietary
supplements. The final rule establishes the minimum CGMPs necessary for
activities related to manufacturing, packaging, labeling, or holding
dietary supplements to ensure the quality of the dietary supplement.
The final rule is one of many actions related to dietary supplements
that we are taking to promote and protect the public health.

DATES: This rule is effective August 24, 2007.
Compliance Dates: The compliance date is June 25, 2008; except that
for businesses employing fewer than 500, but 20 or more full-time
equivalent employees, the compliance date is June 25, 2009; and except
that for businesses that employ fewer than 20 full-time equivalent
employees, the compliance date is June 25, 2010.

FOR FURTHER INFORMATION CONTACT: Vasilios H. Frankos, Center for Food
Safety and Applied Nutrition (HFS-810), Food and Drug Administration,
5100 Paint Branch Pkwy., College Park, MD 20740, 301-436-1696.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background and Related Information
II. How is the Final Rule Organized?
III. What Does the Final Rule Do?
A. Overview of CGMP
B. Highlights of the Final Rule
IV. What General Comments Did We Receive?
A. What Comments Did We Receive on the Structure and Organization
of the Rule?
B. What Comments Did We Receive on the Need for Dietary Supplement
CGMP Requirements?
C. What Comments Did We Receive on Written Procedures?
1. Overview
2. Written Procedures That Are Required by This Final Rule
3. Written Procedures That Are Not Required by This Final Rule
D. Other Comments on Written Procedures
E. What Other General Comments Did We Receive?
V. What Legal Authority Comments Did We Receive?
A. Modeled After CGMP for Food
B. Records Authority
C. Public Health Service Act Authority
1. The Communicable Disease Risk Posed by Dietary Supplements
2. Activities For Which We Are Asserting Legal Authority Under the
PHS Act
D. The Interstate Commerce Nexus for the Final Rule
1. The PHS Act
2. The Act
3. Commerce Clause
E. Fifth Amendment
F. Miscellaneous
VI. What Comments Did We Receive on the General Provisions? (Subpart A)
A. Organization of Final Subpart A
B. Who Is Subject to This Part? (Final Sec. 111.1)
C. What Definitions Apply to This Part? (Final Sec. 111.3)
1. Actual Yield
2. Batch
3. Batch Number, Lot Number, or Control Number
4. Component
5. Contact Surface
6. Ingredient
7. In-Process Material
8. Lot
9. Microorganisms
10. Must
11. Pest
12. Physical Plant
13. Product Complaint
14. Quality
15. Quality Control
16. Quality Control Personnel
17. Representative Sample
18. Reprocessing
19. Reserve Sample
20. Sanitize
21. Theoretical Yield
22. Water Activity
23. We
24. You
25. What Other Terms Did the Comments Want Defined?
26. What Definitions Did the Comments Want Us to Delete?
D. Do Other Statutory Provisions and Regulations Apply? (Final
Sec. 111.5)
E. What Sections Did We Remove From the Rule, and Why?
1. ``What Are These Regulations Intended to Accomplish?'' (Proposed
Sec. 111.2)
2. ``Exclusions'' (Proposed Sec. 111.6)
VII. Comments on Personnel (Final Subpart B)
A. Organization of Final Subpart B
B. Highlights of Changes to the Proposed Requirements for Personnel
1. Revisions
2. Changes After Considering Comments
C. General Comments on Proposed Subpart B
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.8)
E. What Requirements Apply for Preventing Microbial Contamination
From Sick or Infected Personnel and for Hygienic Practices? (Final
Sec. 111.10)
1. Final Sec. 111.10(a)
2. Final Sec. 111.10(b)
F. What Personnel Qualification Requirements Apply? (Final Sec.
111.12)
G. What Supervisor Requirements Apply? (Final Sec. 111.13)
H. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.14)
VIII. Comments on Physical Plant and Grounds (Final Subpart C)
A. Organization of Final Subpart C
B. Highlights of Changes to the Proposed Requirements for Physical
Plant and Grounds
1. Revisions
2. Changes After Considering Comments
C. General Comments on Proposed Subpart C
D. What Sanitation Requirements Apply to Your Physical Plant and
Grounds? (Final Sec. 111.15)
1. Final Sec. 111.15(a)
2. Final Sec. 111.15(b)(1)
3. Final Sec. 111.15(c)
4. Final Sec. 111.15(d)
5. Final Sec. 111.15(e)
6. Final Sec. 111.15(f)
7. Final Sec. 111.15(g)
8. Final Sec. 111.15(h)
9. Final Sec. 111.15(i)
10. Final Sec. 111.15(j)
11. Final Sec. 111.15(k)
E. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.16)
F. What Design and Construction Requirements Apply to Your Physical
Plant? (Final Sec. 111.20)
1. Final Sec. 111.20(a) and (b)
2. Final Sec. 111.20(c)
3. Final Sec. 111.20(d)
4. Final Sec. 111.20(e)
5. Final Sec. 111.20(f)
6. Final Sec. 111.20(g)
7. Final Sec. 111.20(h)

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G. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.23)
IX. Comments on Requirements Related to Equipment and Utensils (Subpart
D)
A. Organization of Final Subpart D
B. Highlights of Changes to the Proposed Requirements for Equipment
and Utensils
1. Revisions
2. Revisions Associated With the Reorganization
3. Changes After Considering Comments
C. General Comments on Proposed Subpart D
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.25)
E. What Requirements Apply to the Equipment and Utensils That You
Use? (Final Sec. 111.27)
1. Final 111.27(a)
2. Final Sec. 111.27(b)
3. Final Sec. 111.27(c)
4. Final Sec. 111.27(d)
F. Reorganization of Certain Paragraphs in Proposed Sec. 111.25
G. What Requirements Apply to Automated, Mechanical, or Electronic
Equipment? (Final Sec. 111.30)
1. Comments on the Organization and Framework of Proposed Sec.
111.30
2. Comments Specific to Proposed Sec. 111.30
3. Reorganization of Certain Paragraphs in Proposed Sec. 111.30
H. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.35)
1. Final Sec. 111.35(a)
2. Final Sec. 111.35(b)(1) and (b)(2)
3. Final Sec. 111.35(b)(3)
4. Final Sec. 111.35(b)(4)
5. Final Sec. 111.35(b)(5)
6. Final Sec. 111.35(b)(6)
X. Comments on Requirement to Establish a Production and Process
Control System (Final Subpart E)
A. Reorganization of Proposed Sec. 111.35 Into Final Subpart E
B. General Comments on Proposed Sec. 111.35
C. Final Subpart E and Highlights of Changes to the Proposed
Regulations
D. What Are the Requirements to Implement a Production and Process
Control System? (Final Sec. 111.55)
E. What Are the Design Requirements for the Production and Process
Control System? (Final Sec. 111.60)
F. What Are the Requirements for Quality Control Operations? (Final
Sec. 111.65)
G. What Specifications Must You Establish? (Final Sec. 111.70)
1. Final Sec. 111.70(a)
2. Final Sec. 111.70(b)
3. Final Sec. 111.70(c)
4. Final Sec. 111.70(d)
5. Final Sec. 111.70(e)
6. Final Sec. 111.70(f)
7. Final Sec. 111.70(g)
H. What is Your Responsibility for Determining Whether Established
Specifications Are Met? (Final Sec. 111.73)
I. What Must You Do to Determine Whether Specifications Are Met?
(Final Sec. 111.75)
1. Final Sec. 111.75(a)
2. Final Sec. 111.75(b)
3. Final Sec. 111.75(c) and (d)
4. Final Sec. 111.75(e)
5. Final Sec. 111.75(f)
6. Final Sec. 111.75(g)
7. Final Sec. 111.75(h)
8. Final Sec. 111.75(i)
J. What Must You Do if Established Specifications Are Not Met?
(Final Sec. 111.77)
1. Final Sec. 111.77
2. Final Sec. 111.77(a)
3. Final Sec. 111.77(b)
4. Final Sec. 111.77(c)
K. Comments on Shelf Life
L. What Representative Samples Must You Collect? (Final Sec.
111.80)
1. Final Sec. 111.80(a)
2. Final Sec. 111.80(b)
3. Final Sec. 111.80(c)
4. Final Sec. 111.80(d)
5. Final Sec. 111.80(e)
M. What Are the Requirements for Reserve Samples? (Final Sec.
111.83)
1. Final Sec. 111.83(a)
2. Final Sec. 111.83(b)(1)
3. Final Sec. 111.83(b)(2)
4. Final Sec. 111.83(b)(3)
5. Final Sec. 111.83(b)(4)
N. Who Conducts a Material Review and Makes a Disposition Decision?
(Final Sec. 111.87)
O. What Requirements Apply to Treatments, In-Process Adjustments,
and Reprocessing When There is a Deviation or Unanticipated Occurrence
or When a Specification Established in Accordance With Sec. 111.70 Is
Not Met? (Final Sec. 111.90)
1. Final Sec. 111.90
2. Final Sec. 111.90(a)
3. Final Sec. 111.90(b)
4. Final Sec. 111.90(c)
P. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.95)
1. Final Sec. 111.95(a)
2. Final Sec. 111.95(b)
XI. Comments on Requirements for Quality Control (Final Subpart F)
A. Organization of Final Subpart F
B. Highlights of Changes to the Proposed Requirements for Quality
Control Operations
1. Revisions
2. Changes Associated With the Reorganization
3. Changes After Considering Comments
C. General Comments on Proposed Sec. 111.37 (Final Subpart F)
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.103)
E. What Must Quality Control Personnel Do? (Final Sec. 111.105)
1. Final Sec. 111.105(a)
2. Final Sec. 111.105(b), (c), (d), and (e)
3. Final Sec. 111.105(f)
4. Final Sec. 111.105(g)
5. Final Sec. 111.105(h)
6. Final Sec. 111.105(i)
F. What Quality Control Operations Are Required for Laboratory
Operations Associated With the Production and Process Control System?
(Final Sec. 111.110)
1. Final Sec. 111.110(a)
2. Final Sec. 111.110(b)
3. Final Sec. 111.110(c)
G. What Quality Control Operations Are Required for a Material
Review and Disposition Decision? (Final Sec. 111.113)
1. Final Sec. 111.113(a)
2. Final Sec. 111.113(b)
3. Final Sec. 111.113(c)
H. What Quality Control Operations Are Required for Equipment,
Instruments, and Controls? (Final Sec. 111.117)
1. Final Sec. 111.117(a) through (c)
2. Final Sec. 111.117(d)
I. What Quality Control Operations Are Required for Components,
Packaging, and Labels Before Use in the Manufacture of a Dietary
Supplement? (Final Sec. 111.120)
1. Final Sec. 111.120(a)
2. Final Sec. 111.120(b)
3. Final Sec. 111.120(c)
4. Final Sec. 111.120(d)
5. Final Sec. 111.120(e)
J. What Quality Control Operations Are Required for the Master
Manufacturing Record, the Batch Production Record, and Manufacturing
Operations? (Final Sec. 111.123)
1. Final Sec. 111.123(a)(1)
2. Final Sec. 111.123(a)(2)
3. Final Sec. 111.123(a)(3)
4. Final Sec. 111.123(a)(4)
5. Final Sec. 111.123(a)(5)
6. Final Sec. 111.123(a)(6)
7. Final Sec. 111.123(a)(7)
8. Final Sec. 111.123(a)(8)
9. Final Sec. 111.123(b)
K. What Quality Control Operations Are Required for Packaging and
Labeling Operations? (Final Sec. 111.127)

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1. Final Sec. 111.127(a) and (b)
2. Final Sec. 111.127(c)
3. Final Sec. 111.127(d)
4. Final Sec. 111.127(e)
5. Final Sec. 111.127(f) and (g)
6. Final Sec. 111.127(h)
L. What Quality Control Operations Are Required for Returned
Dietary Supplements? (Final Sec. 111.130)
1. Final Sec. 111.130(a)
2. Final Sec. 111.130(a)(1) and (a)(2)
3. Final Sec. 111.130(b)
4. Final Sec. 111.130(c)
5. Final Sec. 111.130(d)
M. What Quality Control Operations Are Required for Product
Complaints? (Final Sec. 111.135)
N. What Records Must You Make and Keep? (Final Sec. 111.140)
1. Final Sec. 111.140(a)
2. Final Sec. 111.140(b)(1)
3. Final Sec. 111.140(b)(2)
4. Final Sec. 111.140(b)(3)
XII. Comments on the Production and Process Control System:
Requirements for Components, Packaging, and Labels, and for Product
That You Receive for Packaging or Labeling as a Dietary Supplement
(Final Subpart G)
A. Organization of Final Subpart G
B. Highlights of Changes to the Proposed Requirements for
Components, Packaging, and Labels, and Product That You Receive for
Packaging or Labeling as a Dietary Supplement
1. Revisions
2. Changes After Considering Comments
C. General Comments on Proposed Sec. 111.40 (Final Subpart G)
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.153)
E. What Requirements Apply to Components of Dietary Supplements?
(Final Sec. 111.155)
1. Proposed Sec. 111.35(d)
2. Final Sec. 111.155(a)
3. Final Sec. 111.155(b)
4. Final Sec. 111.155(c)
5. Final Sec. 111.155(d)
6. Final Sec. 111.155(e)
F. What Requirements Apply to Packaging and Labels Received? (Final
Sec. 111.160)
1. Final Sec. 111.160(a)
2. Final Sec. 111.160(b)
3. Final Sec. 111.160(c)
4. Final Sec. 111.160(d)
5. Final Sec. 111.160(e)
G. What Requirements Apply to a Product Received for Packaging or
Labeling as a Dietary Supplement (and for distribution rather than for
return to the supplier)? (Final Sec. 111.165)
1. Final Sec. 111.165(a)
2. Final Sec. 111.165(b)
3. Final Sec. 111.165(c)
4. Final Sec. 111.165(d)
5. Final Sec. 111.165(e)
H. What Requirements Apply to Rejected Components, Packaging, and
Labels, and to Rejected Products That Are Received for Packaging or
Labeling as a Dietary Supplement? (Final Sec. 111.170)
I. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.180)
1. Final Sec. 111.180(a)
2. Final Sec. 111.180(b)(1)
3. Final Sec. 111.180(b)(2)
4. Final Sec. 111.180(b)(3)
XIII. Comments on the Production and Process Control System:
Requirements for the Master Manufacturing Record (Final Subpart H)
A. Organization of Final Subpart H
B. Highlights of Changes to the Proposed Requirements for the
Master Manufacturing Record
1. Revisions
2. Changes Associated With the Reorganization
3. Changes After Considering Comments
C. General Comments on Proposed Sec. 111.45 (Final Subpart H)
1. Comments on Written Procedures
2. Comments That Support Proposed Sec. 111.45
D. What Is the Requirement to Establish a Master Manufacturing
Record? (Final Sec. 111.205)
1. Final Sec. 111.205(a)
2. Final Sec. 111.205(b)(1)
3. Final Sec. 111.205(b)(2)
4. Final Sec. 111.205(c)
E. What Must the Master Manufacturing Record Include? (Final Sec.
111.210)
1. Final Sec. 111.210(a)
2. Final Sec. 111.210(b)
3. Final Sec. 111.210(c)
4. Final Sec. 111.210(d)
5. Final Sec. 111.210(e)
6. Final Sec. 111.210(f)
7. Final Sec. 111.210(g)
8. Final Sec. 111.210(h)(1)
9. Final Sec. 111.210(h)(2)
10. Final Sec. 111.210(h)(3)
11. Final Sec. 111.210(h)(4)
12. Final Sec. 111.210(h)(5)
F. Quality Control Responsibility (Proposed Sec. 111.45(c))
XIV. Comments on the Production and Process Control System:
Requirements for the Batch Production Record (Final Subpart I)
A. Organization of Final Subpart I
B. Highlights of Changes to the Proposed Requirements for the Batch
Production Record
1. Revisions
2. Changes Associated With the Reorganization
3. Changes After Considering Comments
C. What Is the Requirement to Establish a Batch Production Record?
(Final Sec. 111.255)
D. What Must the Batch Record Include? (Final Sec. 111.260)
1. Final Sec. 111.260(a)
2. Final Sec. 111.260(b)
3. Final Sec. 111.260(c)
4. Final Sec. 111.260(d)
5. Final Sec. 111.260(e) and (f)
6. Final Sec. 111.260(g)
7. Final Sec. 111.260(h)
8. Final Sec. 111.260(i)
9. Final Sec. 111.260(j)
10. Final Sec. 111.260(k)
11. Final Sec. 111.260(l)
12. Final Sec. 111.260(m)
13. Final Sec. 111.260(n)
E. Review of Batch Production Record Deviations (Proposed Sec.
111.50(d)(1), (e)(2), (e)(3), and (e)(4))
XV. Comments on Production and Process Control System: Requirements for
Laboratory Operations (Final Subpart J)
A. Organization of Final Subpart J
B. Highlights of the Changes to the Proposed Requirements for
Laboratory Operations
1. Revisions
2. Changes Associated With the Reorganization
3. Changes After Considering Comments
C. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.303)
D. What Are the Requirements for the Laboratory Facilities That You
Use? (Final Sec. 111.310)
E. What Are the Requirements for Laboratory Control Processes?
(Final Sec. 111.315)
1. Final Sec. 111.315(a)
2. Final Sec. 111.315(b)
3. Final Sec. 111.315(c)
4. Final Sec. 111.315(d)
5. Final Sec. 111.315(e)
F. What Requirements Apply to Laboratory Methods for Testing and
Examination? (Final Sec. 111.320)
1. Final Sec. 111.320(a)
2. Final Sec. 111.320(b)
G. Appropriate Test Method Validation (Proposed Sec.
111.60(b)(1)(v))
H. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.325)
1. Final Sec. 111.325(a)
2. Final Sec. 111.325(b)(1)
3. Final Sec. 111.325(b)(2)
XVI. Comments on the Production and Process Control System:
Requirements for Manufacturing Operations (Final Subpart K)
A. Organization of Final Subpart K

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B. Highlights of Changes to the Proposed Requirements for
Manufacturing Operations
1. Revisions
2. Changes Made After Considering Comments
3. Revisions Associated With the Reorganization
C. General Comments on Manufacturing Operations
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.353)
E. What Are the Design Requirements for Manufacturing Operations?
(Final Sec. 111.355)
F. What Are the Requirements for Sanitation? (Final Sec. 111.360)
G. What Precautions Must You Take to Prevent Contamination? (Final
Sec. 111.365)
1. Final Sec. 111.365(a)
2. Final Sec. 111.365(b)
3. Final Sec. 111.365(c)
4. Final Sec. 111.365(d)
5. Final Sec. 111.365(e)
6. Final Sec. 111.365(f)
7. Final Sec. 111.365(g)
8. Final Sec. 111.365(h)
9. Final Sec. 111.365(i)
10. Final Sec. 111.365(j)
11. Final Sec. 111.365(k)
H. What Requirements Apply to Rejected Dietary Supplements? (Final
Sec. 111.370)
I. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.375)
XVII. Comments on the Production and Process Control System:
Requirements for Packaging and Labeling Operations (Final Subpart L)
A. Organization of Final Subpart L
B. Highlights of Changes to the Proposed Requirements for Packaging
and Labeling Operations
1. Revisions
2. Changes Associated With the Reorganization
3. Changes After Considering Comments
C. General Comments on Proposed Requirements for Packaging and
Labeling Operations
D. General Comments on Requirements for What Must Be on the Product
Label Rather Than for Labeling Operations
E. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.403)
F. What Requirements Apply to Packaging and Labels? (Final Sec.
111.410)
1. Final Sec. 111.410(a)
2. Final Sec. 111.410(b)
3. Final Sec. 111.410(c)
4. Final Sec. 111.410(d)
G. What Requirements Apply to Filling, Assembling, Packaging,
Labeling, and Related Operations? (Final Sec. 111.415)
H. What Requirements Apply to Repackaging and Relabeling? (Final
Sec. 111.420)
1. Final Sec. 111.420(a)
2. Final Sec. 111.420(b) and (c)
I. What Requirements Apply to a Packaged and Labeled Dietary
Supplement That Is Rejected for Distribution? (Final Sec. 111.425)
J. Under this Subpart, What Records Must You Make and Keep? (Final
Sec. 111.430)
1. Final Sec. 111.430(a)
2. Final Sec. 111.430(b)
XVIII. Comments on Holding and Distributing (Final Subpart M)
A. Organization of Final Subpart M
B. Highlights of Changes to the Proposed Requirements for Holding
and Distributing
1. Revisions
2. Changes Associated With the Reorganization
3. Changes After Considering Comments
C. General Comments on Proposed Sec. Sec. 111.80, 111.82, 111.83,
and 111.85
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.453)
E. What Requirements Apply to Holding Components, Dietary
Supplements, Packaging, and Labels? (Final Sec. 111.455)
1. Final Sec. 111.455(a)
2. Final Sec. 111.455(b)
3. Final Sec. 111.455(c)
F. What Requirements Apply to Holding In-Process Material? (Final
Sec. 111.460)
1. Final Sec. 111.460(a)
2. Final Sec. 111.460(b)
G. Proposed Requirement for Holding Reserve Samples of Components
(Proposed Sec. 111.83(a))
H. What Requirements Apply to Holding Reserve Samples of Dietary
Supplements? (Final Sec. 111.465)
1. Final Sec. 111.465(a)
2. Final Sec. 111.465(b)
I. What Requirements Apply to Distributing Dietary Supplements?
(Final Sec. 111.470)
J. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.475)
XIX. Comments on Returned Dietary Supplements (Final Subpart N)
A. Organization of Final Subpart N
B. Highlights of Changes to the Proposed Requirements for Returned
Dietary Supplements
1. Revisions
2. Changes After Considering Comments
C. General Comments on Proposed Sec. 111.85
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.503)
E. What Requirements Apply When a Returned Dietary Supplement is
Received? (Final Sec. 111.510)
F. When Must a Returned Dietary Supplement be Destroyed, or
Otherwise Suitably Disposed Of? (Final Sec. 111.515)
G. When May a Returned Dietary Supplement Be Salvaged? (Final Sec.
111.520)
H. What Requirements Apply to a Returned Dietary Supplement That
Quality Control Personnel Approve for Reprocessing? (Final Sec.
111.525)
I. When Must an Investigation Be Conducted of Your Manufacturing
Processes and Other Batches? (Final Sec. 111.530)
J. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.535)
1. Final Sec. 111.535(a)
2. Final Sec. 111.535(b)(1)
3. Final Sec. 111.535(b)(2)
4. Final Sec. 111.535(b)(3)
5. Final Sec. 111.535(b)(4)
XX. Comments on Product Complaints (Final Subpart O)
A. Organization of Final Subpart O
B. Highlights of Changes to the Proposed Requirements for Product
Complaints
1. Revisions
2. Changes After Considering Comments
C. General Comments on Proposed Sec. 111.95 (Final Subpart O)
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.553)
E. What Requirements Apply to the Review and Investigation of a
Product Complaint? (Final Sec. 111.560)
1. Final Sec. 111.560(a)(1)
2. Final Sec. 111.560(a)(2), (b), and (c)
F. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.570)
1. Final Sec. 111.570(a)
2. Final Sec. 111.570(b)(1)
3. Final Sec. 111.570(b)(2)
4. Final Sec. 111.570(b)(2)(i)
5. Final Sec. 111.570(b)(2)(ii)
XXI. Comments on Records and Recordkeeping (Final Subpart P)
A. Organization of Final Subpart P
B. Highlights of Changes to the Proposed Requirements for Records
and Recordkeeping
1. Revisions
2. Changes After Considering Comments
C. General Comments on Proposed

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Sec. 111.125
D. What Requirements Apply to the Records That You Make and Keep?
(Final Sec. 111.605)
1. Final Sec. 111.605(a)
2. Final Sec. 111.605(b)
3. Final Sec. 111.605(c)
E. What Records Must Be Made Available to FDA? (Final Sec.
111.610)
1. Final Sec. 111.610(a)
2. Final Sec. 111.610(b)
XXII. Other Comments and Miscellaneous
A. Comments on Guidance Documents To Be Used With the Final Rule
B. Comments on Consideration for Other CGMP Programs
C. Comments on Public Involvement
D. Comments on Implementation and Enforcement
E. Removal of References to Part 112
XXIII. Paperwork Reduction Act of 1995
XXIV. Analysis of Impacts
A. Introduction
1. Summary of the Economic Analysis
2. Summary of Comments on the Economic Analysis
B. Final Regulatory Impact Analysis
1. The Need for the Final Current Good Manufacturing Practice Rule
2. Regulatory Options
3. Coverage of the Final Rule
4. Baseline Practices
5. Baseline Risk
6. Benefits
7. Costs
8. Summary of Benefits and Costs
9. Benefits and Costs of Regulatory Options
10. Cost Effectiveness Analysis
11. Uncertainties in the Analysis
C. Final Regulatory Flexibility Analysis
1. Introduction
2. Economic Effects on Small Entities
3. Regulatory Options
4. Description of Recordkeeping and Reporting
5. Summary
D. Unfunded Mandates
XXV. Analysis of Environmental Impact
XXVI. Federalism
XXVII. References

I. Background and Related Information

On October 25, 1994, the Dietary Supplement Health and Education
Act (DSHEA) (Public Law 103-417) was signed into law. DSHEA, among
other things, amended the Federal Food, Drug, and Cosmetic Act (the
act) by adding section 402(g) of the act (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. Section 402(g) of the
act also stipulates that such regulations shall be modeled after CGMP
regulations for food and may not impose standards for which there are
no current and generally available analytical methodology. The final
rule establishes, in part 111 (21 CFR part 111), the minimum CGMPs
necessary for activities related to manufacturing, packaging, labeling,
or holding dietary supplements to ensure the quality of the dietary
supplement. The final rule is one of many actions related to dietary
supplements that we are taking to promote and protect the public
health.
In response to DSHEA, we issued an Advance Notice of Proposed
Rulemaking (the 1997 ANPRM) in the Federal Register of February 6, 1997
(62 FR 5700). The 1997 ANPRM contained a CGMP outline submitted to us
on November 20, 1995, by representatives of the dietary supplement
industry. The 1997 ANPRM also asked nine questions that addressed
issues that the industry outline did not. For example, we asked if
there is a need to develop specific defect action levels (DALs) for
dietary ingredients. We also asked whether a CGMP rule should require
manufacturers to establish procedures to document, on a continuing or
daily basis, that they followed pre-established procedures for making
dietary supplements.
We received more than 100 comments in response to the 1997 ANPRM.
We evaluated these comments before we drafted and ultimately issued a
proposed rule on CGMPs for dietary ingredients and dietary supplements
(which we discuss later in this section of this document).
Additionally, during 1999, we conducted a number of outreach
activities related to dietary supplements. We held several public
meetings to develop 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 might have on small businesses.
Further, we toured several dietary supplement manufacturing facilities
to better understand the manufacturing processes and practices that
potentially would be subject to CGMP requirements for dietary
ingredients and dietary supplements (Refs. 1 through 6). These
activities contributed to our knowledge about the industry.
In the Federal Register of March 13, 2003 (68 FR 12157), we
published a proposed rule to establish CGMP requirements for dietary
ingredients and dietary supplements (the 2003 CGMP Proposal). The
preamble to the 2003 CGMP Proposal addressed the comments we had
received regarding the nine questions in the 1997 ANPRM, discussed our
legal authority to issue a CGMP rule, and described the basis for each
proposed requirement.
The 2003 CGMP Proposal specifically requested comment on a variety
of areas, including the need for written procedures and recordkeeping
requirements. Although the proposed rule's comment period was scheduled
to end on June 11, 2003, in the Federal Register of May 19, 2003 (68 FR
27008), we extended the comment period to August 11, 2003.
After we published the proposed rule, we conducted and/or
participated in outreach activities related to dietary supplements and
dietary ingredients. We held public stakeholder meetings on April 29,
2003, in College Park, MD, and on May 6, 2003, in Oakland, CA. We also
held a public meeting, via satellite downlink, on May 9, 2003, with
viewing sites at our district and regional offices throughout the
country. These public meetings gave an overview of the proposed rule,
and clarified specific points in the proposed rule. Since the public
stakeholder meetings held as part of our outreach efforts, we also have
participated in several meetings with industry and other interested
parties which are reflected in the public docket.
We received approximately 400 comments in response to the proposal.
The comments came from trade associations, government organizations and
officials, manufacturers of dietary supplements and dietary
ingredients, health care practitioners, consumer groups, and
individuals. In general, the comments supported the idea of CGMPs,
although many comments disagreed with specific aspects of the proposal.
Published elsewhere in this issue of the Federal Register we are
also issuing an interim final rule that sets forth a procedure for
requesting an exception to a CGMP requirement in this final rule. The
interim final rule allows for submission to, and review by, FDA of an
alternative to the required 100-percent identity testing of components
that are dietary ingredients (as discussed in section X of this
document (subpart E)), provided certain conditions are met. The interim
final rule also includes a requirement for retention of records related
to the FDA grant of an exception request.

[[Page 34757]]

II. How is the Final Rule Organized?

The 2003 CGMP Proposal was divided into eight subparts, with each
subpart devoted to a particular topic. For example, proposed subpart A
was titled ``General Provisions'' and contained sections describing the
rule's scope, purpose, definitions, applicability of other statutory
and regulatory provisions, and exclusions. As another example, proposed
subpart B was titled ``Personnel'' and described microbial
contamination and hygiene requirements, personnel qualification
requirements, and supervisor requirements.
In response to comments seeking a simpler, more ``user-friendly''
final rule or seeking clarification of the rule's applicability to
certain persons, items, or activities, and to reduce redundant
provisions or combine similar provisions, we have reorganized the final
rule into 16 subparts, with new subparts focusing on specific aspects
of the manufacturing process or addressing specific issues. For
example, the proposed rule placed all production and process control
requirements for manufacturing, packaging, labeling, and laboratory
operations in a single subpart (proposed subpart E). The final rule
creates separate subparts for the specific operations to make it easier
to find the relevant production and process control requirements for a
particular activity.
Table 1 of this document summarizes how we reorganized the rule. We
are providing this information to help readers understand the
structural changes we made between the proposed and final rules.

Table 1.--Reorganization and Revisions: 2003 CGMP Proposal and Final
Rule
------------------------------------------------------------------------
Final Final
Proposed Subpart Proposed Sections in Subpart and Sections in
and Title the Subpart Title the Subpart
------------------------------------------------------------------------
A--General 111.1 A--General 111.1
Provisions 111.2 Provisions 111.3
111.3 111.5
111.5
111.6
------------------------------------------------------------------------
B--Personnel 111.10 B--Personnel 111.8 (new)
111.12 111.10
111.13 111.12
111.13
111.14 (new)
------------------------------------------------------------------------
C--Physical Plant 111.15 C--Physical 111.15
111.20 Plant and 111.16 (new)
Grounds 111.20
111.23
(formerly
proposed
Sec.
111.15(d)(3)
and (e)(2))
------------------------------------------------------------------------
D--Equipment and 111.25 D--Equipment 111.25
Utensils 111.30 and (formerly
Utensils proposed
Sec.
111.25(c)(1)
and (e)(1))
111.27
(formerly
proposed
Sec.
111.25 (a),
(b), (d)\1\,
and (e))
111.30
111.35
(formerly
proposed
Sec. Sec.
111.25
(c)(1),
(c)(2), (d),
(f),
111.30(b)(2)
, (b)(5),
and (c),
111.50(c)(4)
)
------------------------------------------------------------------------

[[Page 34758]]

E--Production and 111.35 E--Requireme 111.55
Process Controls 111.37 nt to (formerly
111.40 Establish a proposed
111.45 Production Sec.
111.50 and Process 111.35(a))
111.60 Control 111.60
111.65 System (formerly
111.70 proposed
111.74 Sec.
111.35(b))
111.65
(formerly
proposed
Sec.
111.35(c))
111.70
(formerly
proposed
Sec.
111.35(e),
(f), (g),
and (k))
111.73
(formerly
proposed
Sec.
111.35(f),
(g), and (h)
111.75
(formerly
proposed
Sec.
111.35(e)
through (i),
(k), and
(l)), Sec.
111.37(b)(11
(iv), and
Sec.
111.40(a)(2)
111.77 (new)
111.80
(formerly
proposed
Sec.
111.37(b)(11
))
111.83
(formerly
proposed
Sec. Sec.
111.37(b)(12
),
111.50(h),
and
111.83(b)(2)
)
111.87
(formerly
proposed
Sec. Sec.
111.35(i)
and (n),
111.37(b)(5)
and (b)(14),
111.40(a)(3)
,
111.50(d)(1)
, and
111.85(a)
and (c))
111.90
(formerly
proposed
Sec. Sec.
111.35(i)(4)
,
111.50(d)(1)
, (f), and
(g), and
111.65(d))
111.95
(formerly
proposed
Sec.
111.35(o))
------------------------------------------------------------------------

[[Page 34759]]

....................... F--Productio 111.103 (new)
n and 111.105
Process (formerly
Control proposed
System: Sec.
Requirement 111.37(a),
s for (b)(1),
Quality (b)(11), and
Control (b)(12))
111.110
(formerly
proposed
Sec.
111.37(b)(9)
and (b)(13))
111.113
(formerly
proposed
Sec. Sec.
111.35(i)(2)
, (i)(3),
(i)(4)(i),
(i)(4)(ii),
(j), and
(n),
111.37(b)(3)
and (c),
111.40(a)(3)
and (b)(2),
111.50(d)(1)
, 111.65(d),
and
111.70(c))
111.117
(formerly
proposed
Sec. Sec.
111.30(b)(4)
and
111.37(b)(6)
through
(b)(8))
111.120
(formerly
proposed
Sec. Sec.
111.35(i)(4)
(i) and
(i)(4)(ii),
111.37(b)(2)
and (b)(10),
111.40(a)(3)
and (b)(2),
and
111.50(e)(1)
)
111.123
(formerly
proposed
Sec. Sec.
111.35(e)(2)
, (f),
(i)(2), and
(o)(2)
111.37(a),
(b)(2),
(b)(4),
(b)(5), and
(b)(11),
111.45(c),
and
111.50(d)(1)
, (d)(2),
and (g))
111.127
(formerly
proposed
Sec. Sec.
111.37(b)(2)
, (b)(10),
and (b)(11),
111.40(a)(2)
and (a)(3),
and
111.70(c),
(d) and (e))
111.130
(formerly
proposed
Sec. Sec.
111.37(b)(2)
and (b)(15),
and
111.85(a))
111.135 (new)
111.140
(formerly
proposed
Sec. Sec.
111.35(j)
and
111.37(c)
and (d)
------------------------------------------------------------------------
....................... G--Productio 111.153 (new)
n and 111.155
Process (formerly
Control proposed
System: Sec. Sec.
Requirement 111.35(d)(1)
s for through
Components, (d)(5) and
Packaging, 111.40(a)(1)
and Labels through
and for (a)(5))
Product 111.160
That You (formerly
Receive for proposed
Packaging Sec. Sec.
or Labeling 111.35(e)(4)
a Dietary , and
Supplement 111.40(a)(2)
and (b)(1)
through
(b)(4))
111.165
(formerly
proposed
Sec.
111.40(a)(1)
through
(a)(5))
111.170
(formerly
proposed
Sec.
111.74)
111.180
(formerly
proposed
Sec. Sec.
111.35(d)(4)
, and
111.40(c)(1)
(i) through
(c)(1)(iv)
and (c)(2))
------------------------------------------------------------------------
....................... H--Productio 111.205
n and (formerly
Process proposed
Control Sec.
System: 111.45(a)(1)
Requirement , (a)(2),
s for the and (d))
Master 111.210
Manufacturi (formerly
ng Record proposed
Sec.
111.45(b))
------------------------------------------------------------------------

[[Page 34760]]

....................... I--Productio 111.255
n and (formerly
Process proposed
Control Sec.
System: 111.50(a),
Requirement (b), and
s for the (i))
Batch 111.260
Production (formerly
Record proposed
Sec. Sec.
111.35(i)(2)
, (j), (m),
and (o)(2),
111.37(b)(3)
, (b)(5),
(b)(9) and
111.50(c)(1)
through
(c)(11),
(c)(13),
(c)(14),
(d)(2), (e),
and (g), and
111.70(b)(6)
and (g))
------------------------------------------------------------------------
....................... J--Productio 111.303 (new)
n and 111.310
Process (formerly
Control proposed
System: Sec.
Requirement 111.60(a))
s for 111.315
Laboratory (formerly
Operations proposed
Sec.
111.60(b)(1)
)
111.320
(formerly
proposed
Sec.
111.60(c)
and (d))
111.325
(formerly
proposed
Sec.
111.60(b)(2)
and (b)(3))
------------------------------------------------------------------------
....................... K--Productio 111.353 (new)
n and 111.355
Process (formerly
Control proposed
System: Sec.
Requirement 111.65(a))
s for 111.360
Manufacturi (formerly
ng proposed
Operations Sec.
111.65(b))
111.365
(formerly
proposed
Sec.
111.65(c))
111.370
(formerly
proposed
Sec.
111.74)
111.375 (new)
------------------------------------------------------------------------
....................... L--Productio 111.403 (new)
n and 111.410
Process (formerly
Control proposed
System: Sec.
Requirement 111.70(a),
s for (b)(6), and
Packaging (f))
and 111.415
Labeling (formerly
Operations proposed
Sec.
111.70(b))
111.420
(formerly
proposed
Sec.
111.70(d)
and (e))
111.425
(formerly
proposed
Sec.
111.74)
111.430
(formerly
proposed
Sec.
111.70(g)
and (h))
------------------------------------------------------------------------
F--Holding and 111.80 M--Holding 111.453 (new)
Distributing 111.82 and 111.455
111.83 Distributin (formerly
111.85 g proposed
111.90 Sec.
111.80)
111.460
(formerly
proposed
Sec.
111.82)
111.465
(formerly
proposed
Sec.
111.83(b)(1)
and (b)(2))
111.470
(formerly
proposed
Sec.
111.90)
111.475 (new)
------------------------------------------------------------------------

[[Page 34761]]

....................... N--Returned 111.503 (new)
Dietary 111.510
Supplements (formerly
proposed
Sec.
111.85(a))
111.515
(formerly
proposed
Sec.
111.85(b)
and (c))
111.520
(formerly
proposed
Sec.
111.37(b)(15
))
111.525
(formerly
proposed
Sec.
111.50(g))
111.530
(formerly
proposed
Sec.
111.85(d))
111.535
(formerly
proposed
Sec. Sec.
111.50(g)
and
111.85(e)
and (f))
------------------------------------------------------------------------
G--Consumer 111.95 O--Product 111.553 (new)
Complaints Complaints 111.560
(formerly
proposed
Sec.
111.95(a)
through (d))
111.570
(formerly
proposed
Sec.
111.95(e)
and (f))
------------------------------------------------------------------------
H--Records and 111.125 P--Records 111.605
Recordkeeping and (formerly
Recordkeepi proposed
ng Sec.
111.125((a)
and (b))
111.610
(formerly
proposed
Sec.
111.125(b)
and (c))
------------------------------------------------------------------------
\1\The reference to (d) is the second (d) in the proposed rule in this
section due to a misnumbering in the proposed rule.

We discuss all subparts and sections, and our reasons for amending
or creating subparts and sections, in our discussion of the comments to
the proposal.

III. What Does the Final Rule Do?

A. Overview of CGMP

In considering the specific requirements necessary for dietary
supplement CGMPs, we considered information from a variety of sources.
We considered information from our outreach activities, as described in
section I of this document; comments to the 2003 CGMP Proposal; our own
knowledge and expertise about CGMP for foods, including dietary
supplements; and characteristics of CGMP that apply to manufacturing,
labeling, packaging, and holding operations.
The general food CGMPs in part 110 (21 CFR part 110) largely
address practices designed to ensure that food is manufactured,
processed, packed, and held under sanitary conditions and that the food
is safe, clean, and wholesome. Although the general food CGMPs in part
110 apply to a variety of food products, including dietary supplements,
they do not address the unique characteristics of certain specific
types of food products. The agency has implemented separate, and more
specific, CGMPs for various types of food products to provide for
process controls in manufacturing that are not captured by the more
general part 110 food CGMPs. (See discussion in section V of this
document (``Legal Authority'') on product specific CGMP requirements).
At the time DSHEA was enacted, there were four such additional,
specific food CGMP regulations: Those for infant formula (part 106 (21
CFR part 106)), thermally processed low-acid canned food (part 113 (21
CFR part 113)), acidified food (part 114 (21 CFR part 114)), and
bottled water (part 129 (21 CFR part 129)).
Dietary supplements are a type of food product for which specific
food CGMPs also are needed. Manufacturing process controls are needed
to ensure that a dietary supplement contains what the manufacturer
intends. Unlike most foods, the majority of dietary supplements are
packaged into tablets, gelcaps, and capsules. Some dietary supplements
may contain bioactive ingredients for which certain, controlled amounts
are intended to be in each tablet or capsule. The process controls that
must be in place to ensure the tablet or capsule contains what it
purports to contain are different than those that must be in place to
ensure a food is manufactured, processed, packed, and held under
sanitary conditions. Process controls for dietary supplement
manufacture include establishing and meeting specifications to ensure
the finished dietary supplement contains the correct ingredient,
purity, strength, and composition intended.
Vitamins can present a concentrated source of biologically active
components. A vitamin, for example, that contains too high a
concentration, such as vitamin D at levels that are many times greater
than intended, can lead to illness and hospitalization (Refs. 7 and 8).
A manufacturer must establish a process for manufacturing a dietary
supplement product in order to produce the product consistently and
reliably each time. In order to achieve consistency and reliability,
there must be process controls in place to ensure, for example, that
appropriate tests and examinations are conducted, a master
manufacturing record is prepared, each batch production follows the
master manufacturing record, and the finished tablet or capsule is
placed in the intended package with the intended label.
These same types of controls are needed for herbal and botanical
dietary supplements. Botanicals are often complex mixtures that can
vary in

[[Page 34762]]

composition depending on factors such as the part of the plant used,
the location of harvesting and growing conditions that can vary from
year to year even in the same location. It can be difficult to
distinguish between closely related species of botanicals, and the
biological activity of components of an incorrectly identified species
can lead to adverse consequences. In addition, different species may be
present in different ratios or blends in a particular product. Various
products might contain different parts of the plant--flower, leaf,
root, stem, extract--and the test methods for each can vary in the
nature, sensitivity, and specificity of the test.
Well-established principles of CGMP require process controls at
each step of the manufacturing process as early in the production
process as possible. Quality cannot be tested into the product only at
the end (Ref. 9). Instead, the quality of the dietary supplement must
be built into the product throughout the manufacturing process; quality
begins with the starting material and continues with the product being
manufactured in a reproducible manner according to established
specifications. It is not sufficient, nor effective, to rely solely on
end product testing to assure the quality of the individual dietary
supplement product sold to the consumer.
CGMPs are intended to establish a comprehensive system of process
controls, including documentation of each stage of the manufacturing
process, that can minimize the likelihood of, or detect, problems and
variances in manufacturing as they occur and before the product is in
its finished form. These process controls that are a part of CGMPs are
essential to ensure that the dietary supplement is manufactured,
packaged, held, and labeled in a consistent and reproducible manner.
Manufacturing according to CGMP means that the manufacturing
process incorporates a set of controls in the design and production
processes to assure a quality finished product. CGMPs specific to
dietary supplements are necessary to help ensure that these products
have the identity, purity, strength, and composition that meet
specifications established in the master manufacturing record and that
they are not adulterated.
Many comments stressed that the most critical aspect of a
successful CGMP system is effective process control. Comments asserted
that, with effective process control, quality is built into a product
throughout the entire production process. The term ``quality'' came up
repeatedly in comments as the desired outcome of the dietary supplement
manufacturing process.\1\ In fact, several comments asked us to define
``quality'' and suggested various definitions, each of which related to
a dietary supplement having the identity, purity, strength, and
composition intended (see comment 49 in section VI of this document).
Some comments distinguished the concept of quality from that of
preventing adulteration. These comments objected to our statement that
dietary supplement CGMP requirements are needed to prevent adulteration
and stated that CGMP is focused on assuring that finished products are
manufactured using quality procedures, but are not related to
preventing adulteration. Other comments asked us to define
``adulteration.''
---------------------------------------------------------------------------

\1\ Throughout this final rule, we refer to the ``manufacture''
or ``manufacturing process'' of dietary supplements. We use these
terms in the broad sense, i.e., the terms refer to those activities
that may be done from receipt of raw ingredients through the
distribution of a finished dietary supplement, including labeling,
packaging, and holding activities. We discuss the various roles and
responsibilities of those who ``manufacture'' dietary supplements in
the context of final Sec. 111.1 ``Who is subject to this part?'' We
also sometimes use the terms to apply to only part of the process,
i.e., those operations other than labeling, packaging, and holding.
---------------------------------------------------------------------------

We agree that a critical aspect of CGMP is achieving control over
manufacturing processes. Controls are necessary to ensure that you
manufacture what you intend so that the characteristics and/or
attributes desired in a final product will be consistently and reliably
achieved. We disagree with the comments to the extent that they were
suggesting that quality is not related to preventing contamination in
the manufacturing process that may adulterate the finished product.
However, we have reconsidered, as discussed in this section, what types
of adulteration and misbranding are necessary to control for in this
dietary supplement CGMP rule.
To clarify what dietary supplement CGMP requirements are intended
to achieve, we have added a definition of quality in the final rule. As
defined, quality means ``that the dietary supplement consistently meets
the established specifications for identity, purity, strength, and
composition and has been manufactured, packaged, labeled, and held
under conditions to prevent adulteration under section 402(a)(1),
(a)(2), (a)(3), and (a)(4) of the Federal Food, Drug, and Cosmetic
Act.'' Ensuring the quality of the dietary supplement means that you
consistently and reliably manufacture what you intend and that you
establish manufacturing controls to prevent the dietary supplement from
being adulterated under section 402(a)(1) of the act due to the
presence of contaminants, under section 402(a)(2) of the act, for
example, if it bears or contains any unintentionally added poisonous or
deleterious substance, under section 402(a)(3) of the act if the
dietary supplement consists in whole or in part of any filthy, putrid,
or decomposed substance, or if it is otherwise unfit for food, or under
section 402(a)(4) of the act if the dietary supplement 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. The definition of quality limits to
section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act the types of
adulteration that you must control for in this CGMP final rule. The
definition applies to the controls that are designed to prevent
contamination of the product that you intend to manufacture.
In the 2003 CGMP Proposal, we said that our purpose was to present
a broad enough scope to the proposed rule so that we could receive the
depth and breadth of comment needed to develop a final rule that would
provide the proper balance of regulation (68 FR 12157 at 12161). We
asked for comment on whether each of the provisions proposed was
necessary to ensure the safety and quality of the dietary supplement
and was adequate to protect the public health (id.). We stated that 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'' (68 FR 12157 at 12158). For example, we stated
that the proposed rule would require the manufacturer to test for toxic
compounds in botanicals that may likely be present to ensure that no
such compounds are present that may adulterate the dietary supplement
(68 12157 FR at 12162). Further, we included a requirement that the
ingredients, other than dietary ingredients under section 201(ff) of
the act, be lawful under the applicable food additive regulations or be
generally recognized as safe (GRAS) (proposed Sec. 111.35(d).
The approach that we set forth in the 2003 CGMP Proposal was
designed to prevent a manufacturer, under CGMP regulations, from using
an ingredient, whether a dietary ingredient or another

[[Page 34763]]

component, in the manufacture of a dietary supplement that would
adulterate the product under relevant provisions of the act, such as
section 402(a)(1) or (a)(2)(C). The manufacturer would have been
required to establish specifications at any point, step, or stage in
the manufacturing process where control is necessary to prevent
adulteration (proposed Sec. 111.35(e)). Thus, the manufacturer would
not have been able to establish a specification, consistent with
proposed Sec. 111.35(e), for the use of an unlawful ingredient because
such use would not prevent adulteration. In addition, the manufacturer
would have to establish specifications for contaminants that may
adulterate or that could lead to adulteration of the dietary
supplement. The manufacturer would have to take necessary precautions
to prevent the presence or level of contaminants, that would otherwise
adulterate the dietary supplement under another provision of the act,
from being present in the dietary supplement. The specifications were
intended to ensure that adulterated and misbranded dietary supplements
would not reach the marketplace (68 FR 12157 at 12197).
In addition to the general specifications established under
proposed Sec. 111.35(e), the proposed rule would have required the
manufacturer to establish specifications for the identity, purity,
quality, strength, and composition of the components received (proposed
Sec. 111.35(e)(1)) and for the finished batch of dietary supplement
(proposed Sec. 111.35(e)(3)). Although we stated that the proposed
rule did not address questions related to the safety of dietary
ingredients used (68 FR 12157 at 12172), if a dietary ingredient was
deemed to be unsafe under the act--under section 402(a)(1) or another
provision--a specification could not have been established for that
dietary ingredient, consistent with proposed Sec. 111.35(e). Thus, a
manufacturer would not be able to use, under dietary supplement CGMP, a
dietary ingredient, or other component, that would otherwise adulterate
the product under another provision of the act.
Further, the proposed rule was designed to ensure that the correct
label was applied during manufacture so that the dietary supplement
label would accurately identify the dietary supplement (proposed
Sec. Sec. 111.45(b)(7), 111.50(c)(12), and 111.70(b)(7)). The proposed
rule also would have required the master manufacturing record to
contain the identity of each ingredient that is required to be declared
on the ingredient list in section 403 of the act (21 U.S.C. 343)
(proposed Sec. 111.45(b)(4)).
Several comments seemed to question why the dietary supplement CGMP
rule would require that a manufacturer use lawful ingredients when
other provisions of the act would require such use. In fact, some
comments objected to the proposed requirement in the rule that required
that a component, other than a dietary ingredient, be approved for use
as a food additive or be GRAS. The comments stressed that such a
provision was not necessary because the statute already requires that
such an ingredient be approved as a food additive or be GRAS. In light
of these comments, we reconsidered our interpretation of the scope of
``prevent adulteration'' in the proposed rule and whether that
interpretation should be narrowed. We also considered whether to
require, as part of a CGMP requirement, that the label that accurately
reflects the ingredients in the product be applied or whether such a
requirement was not necessary, given our existing authority in section
403 of the act.
We determined that ensuring quality in dietary supplement CGMP, in
part, means that you produce what you intend to produce. As stated in
section V of this document, manufacturers must plan what they intend to
produce, institute adequate controls to achieve the desired outcome,
and ensure that the controls work so that the desired outcome is
consistently achieved. Thus, for example, the manufacturer decides on
the identity, purity, strength, and composition of the dietary
supplement it manufactures. The focus of CGMP is on process controls to
ensure that the desired outcome is consistently achieved, and not on
the inherent safety of the ingredients used (which is addressed by
other statutory prohibitions).
We agree with the comments that the safety of a particular
ingredient is governed by other provisions of the act. If you
manufacture a dietary supplement, you have a responsibility as a
manufacturer to evaluate the safety of the ingredients under, for
example, section 402(f) of the act.\2\ Dietary supplement CGMP would
require you to establish the identity, purity, strength, and
composition specifications for the product and ensure that such
specifications are met in the finished batch of dietary supplement.
Nothing in the dietary supplement CGMPs relieves manufacturers from
complying with any other substantive provisions of the act relating to
the safety of ingredients and other components.
---------------------------------------------------------------------------

\2\Under section 402(f) of the act, a dietary supplement is
deemed to be adulterated if it is or contains a dietary ingredient
that presents a significant or unreasonable risk of illness or
injury under conditions of use recommended or suggested in labeling
or, if no such conditions, under ordinary conditions of use.
---------------------------------------------------------------------------

Quality not only means that you produce what you intend, but that
you prevent contamination in your manufacturing process that could
adulterate your product. Food CGMP regulations, after which the dietary
supplement CGMP rule is modeled, require that the manufacturer take
precautions to ensure that the manufacturer does not adulterate the
product under section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act.
For example, under Sec. 110.5 (food CGMP), the criteria and
definitions apply in determining whether a food is adulterated under
section 402(a)(3) and (a)(4) of the act. Specifically, Sec.
110.80(a)(2) states that raw materials shall not contain levels of
microorganisms that may produce food poisoning or other disease in
humans, unless otherwise treated during manufacturing operations so
that they no longer contain levels that would adulterate the product
within the meaning of the act. In addition, Sec. 110.80(a)(3) states
that raw materials and other ingredients susceptible to contamination
with natural toxins must comply with current FDA regulations and action
levels for poisonous or deleterious substances before such materials
are incorporated into finished food. Under dietary supplement CGMP, we
believe it is appropriate to require you to establish specifications
that are designed to prevent adulteration under section 402(a)(1),
(a)(2), (a)(3), and (a)(4) of the act from contamination during the
manufacturing, packaging, labeling, and holding operations. For
example, if you are manufacturing a dietary supplement that you know is
likely to contain a contaminant, you would need to establish limits on
the contaminant in your supplement, and you must design these limits to
prevent the dietary supplement from being adulterated under section
402(a)(1), (a)(2), (a)(3), and (a)(4) of the act.
Quality, as the term is used for the purposes of this final rule,
relates both to producing what is intended (i.e., establishing and
ensuring that specifications for the identity, purity, strength, and
composition are met) and to ensuring that the dietary supplement that
you intend to produce has been manufactured, packaged, labeled, and
held under conditions to prevent adulteration within the meaning of
section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act. Thus, this
final rule is not designed to specifically prevent all

[[Page 34764]]

types of adulteration that may occur under the act. Rather, this final
rule is designed to prevent adulteration from those types of
contamination that are commonly controlled in other food CGMP
regulations. We do expect, however, that compliance with CGMP
requirements in the final rule will help to avoid other types of
adulteration. Also, nothing in this rule exempts a manufacturer from
compliance with other relevant adulteration provisions of the act.
We are replacing the phrase ``prevent adulteration'' in the
codified with words that relate to ensuring the quality of the dietary
supplement. Thus, for example, we have modified proposed Sec.
111.35(e) (now final Sec. 111.70(a)) to read, ``You must establish a
specification for any point, step, or stage in the manufacturing
process where control is necessary to ensure the quality of the
finished dietary supplement and that the dietary supplement is packaged
and labeled as specified in the master manufacturing record'' instead
of ``* * * necessary to prevent adulteration.'' This phrase is replaced
in several codified provisions and an explanation of this change is not
provided in the preamble of this document each time it is made.
Moreover, you have a responsibility under CGMP to ensure that the
label you specify in the master manufacturing record is applied to the
product. Under section 403 of the act, you are required to ensure that
your label accurately reflects the ingredients in the product. Because
section 403 of the act provides that food, including dietary
supplements, is misbranded if a label that does not contain accurate
statements is applied, we do not need to impose the same requirement in
this final rule. Thus, if the representative label in the master
manufacturing record for the product does not identify the correct
dietary ingredients and the label that lists inaccurate information is
applied, that dietary supplement would be misbranded under section 403
of the act. Such labeling would not be a violation of dietary
supplement CGMP unless there is a mixup in your process control and you
do not put the representative label specified in the master
manufacturing record on the product. Such a mixup would be a violation
of dietary supplement CGMP requirements (see e.g., final Sec. Sec.
111.127(d), 111.160(e), 111.410(c), 111.415).
Thus, in addition to stating ``ensure the quality of the dietary
supplement,'' in the codified instead of ``prevent adulteration,'' we
are adding the language ``and that the dietary supplement is packaged
and labeled as specified in the master manufacturing record.'' Such
change is intended to clarify that the use of the packaging and
labeling that is stated in the master manufacturing record is what is
required in this final rule.
A failure to follow the requirements in this final rule, including
a failure to establish required specifications, could result in an
enforcement action by the agency under section 402(g) of the act
because the dietary supplement is adulterated in that it was prepared,
packed, labeled, or held under conditions that do not meet CGMPs for
dietary supplements. The act establishes certain prohibited acts and
enforcement mechanisms to remove adulterated product from the market
and prevent manufacturers from continuing to manufacture adulterated
product. Enforcement mechanisms currently available to us under the act
are not affected by this final rule.
Finally, we have included in this final rule the existing
requirements in part 110 that we believe are common to dietary
supplement manufacturing. For example, the requirements in subpart C,
Physical Plant and Grounds, are similar to those in Sec. 110.20. We
recognize that there may be operations related to the manufacturing of
dietary supplements for which certain provisions in part 110 apply, but
that we did not determine to be common to most dietary supplement
manufacturing operations. For example, there may be some dietary
supplements that are dehydrated and rely on the control of moisture
consistent with Sec. 110.80(b)(14). A manufacturer would be expected
to comply with the regulations in part 110 in addition to the
regulations in part 111, unless the regulations conflict. To the extent
that the regulations conflict, the dietary supplement manufacturer must
comply with the regulation in part 111.

B. Highlights of the Final Rule

The final rule:
Applies to persons who manufacture, package, label, or
hold dietary supplements unless subject to an exclusion in Sec. 111.1;
Establishes minimum requirements for personnel, physical
plant and grounds, and equipment and utensils;
Requires the establishment and use of written procedures
for certain operations, including those related to equipment, physical
plant sanitation, certain manufacturing operations, quality control,
laboratory testing, packaging and labeling, and product complaints;
Requires the establishment of specifications in the
production and process control system that will ensure dietary
supplements meet the identity, purity, strength, and composition
established in specifications and are properly packaged and labeled as
specified in the master manufacturing record;
Provides for the option to use a certificate of analysis
(for specifications other than the identity of a dietary ingredient)
from a component supplier instead of having manufacturers conduct tests
or examinations on the components they receive;
Requires testing of a subset of finished batches of
dietary supplements based on a sound statistical sampling or,
alternatively, testing all finished batches;
Requires implementation of quality control operations to
ensure the quality of a dietary supplement;
Requires the preparation and use of a written master
manufacturing record for each unique formulation of manufactured
dietary supplement, and for each batch size, to ensure your
manufacturing process is performed consistently and to ensure
uniformity in the finished batch from batch to batch;
Requires the preparation of a batch production record
every time a dietary supplement batch is made. The batch production
record must accurately follow the appropriate master manufacturing
record;
Requires the establishment and use of laboratory control
processes related to establishing specifications and to the selection
and use of testing and examination methods;
Requires reserve samples of dietary supplements to be held
in a manner that protects against contamination and deterioration;
Requires identification and quarantine of returned dietary
supplements until quality control personnel conduct a material review
and make a disposition decision;
Requires quality control personnel to conduct a material
review and make a disposition decision under certain circumstances;
Requires a qualified person to investigate any ``product
complaint'' that involves a possible failure of a dietary supplement to
meet any CGMP requirement, with oversight by quality control personnel;
and
Requires records associated with the manufacture,
packaging, labeling, or holding of a dietary supplement to be kept for
1 year beyond the shelf life dating (when such dating is used, such as
expiration dating, shelf life dating, or ``best if used by'' dating),
or if shelf life dating is not used, for 2 years beyond the date of
distribution of the last batch

[[Page 34765]]

of dietary supplements associated with those records.

IV. What General Comments Did We Receive?

We received approximately 400 comments on the proposed rule.
Although most comments support CGMP requirements for dietary
supplements and dietary ingredients, others question the need for a
regulation and many sought changes to the rule. We describe, in this
section, comments on general aspects of the final rule. We include
comments related to the structure and organization of the final rule,
comments we received on why CGMP requirements are needed, and comments
on written procedures. In addition, we describe some general comments
we received on multiple sections of the proposed rule that we believe
are better addressed in one response.
To make it easier to identify comments and our responses, the word
``comment,'' in parentheses, will appear before each comment, and the
word ``response'' will appear before each response. We also have
numbered the comments to make it easier to distinguish between
comments; the numbers are for organizational purposes only and do not
reflect the order in which we received the comments or any value
associated with the comment.

A. What Comments Did We Receive on the Structure and Organization of
the Rule?

(Comment 1) Several comments seek to restructure or reorganize the
rule. For example, one comment states we should simplify the entire
section on production and process controls. The comment asserts it
would be more logical to list contaminants that may adulterate a
dietary supplement or lead to adulteration as part of the requirements
for specifications (proposed Sec. 111.35(e)) than to list such
contaminants as part of the testing requirements (proposed Sec.
111.35(k)). Other comments say it would be more logical to list the
tests that are considered appropriate as part of proposed Sec.
111.35(h) (concerning appropriate tests or examinations to determine
whether specifications are met) than to have a separate requirement for
appropriate tests in proposed Sec. 111.35(l) (which listed the types
of analyses that should be part of a test).
Another comment claims the rule is too complex, asserting it would
create chaos. Other comments say that the proposal's degree of detail
required is unrealistic for small dietary supplement firms, and we
should rewrite the rule to be more user friendly.
Yet another comment says that any final rule we issue must clearly
set forth CGMP requirements. This comment seems to suggest the
requirements need to be more detailed in describing what is required.
The comment asserts that ambiguities in interpretation could result in
economic disadvantage for small businesses because they typically do
not have in-house legal counsel and, thus, must be more conservative in
interpreting ambiguous regulatory provisions.
(Response) In response to these comments, as well as comments on
specific subparts and provisions, we have reorganized the final rule
and have re-phrased or introduced concepts in a ``user-friendly'' or
plain language format. We also have eliminated certain redundant
regulatory requirements and combined similar requirements. For example,
rather than put all production and process control system requirements
in a single subpart, we have reorganized the final rule to create a
series of subparts that first describe the requirements for the overall
design and implementation of the production and process control system
and then describe the requirements of the individual operations
associated with that system. We also present each requirement as a
question rather than as a paragraph within a section. This question
format will help readers focus on the subparts or sections that apply
to specific operations.
As another example, we reduced the redundancy associated with the
interrelated nature of the proposed rule by combining most similar
requirements. Both proposed Sec. Sec. 111.35(m) and 111.60(b)(2) would
require you to keep testing and examination results. The final rule
places this requirement in a single section (Sec. 111.325(b)(2)(ii)).
The final rule also shortens the construction ``includes, but is
not limited to'' to ``includes.'' We did this because the use of the
word ``includes'' indicates that the specified list that follows is not
exclusive. The phrase ``but is not limited to'' is unnecessary.
Finally, some changes we have made to one specific section have an
impact on other sections. For example, after considering the comments,
we revised subpart B to require you to establish and follow written
procedures to fulfill the requirements of subpart B. Those written
procedures are records you must make and keep in accordance with the
recordkeeping requirements of subpart P, thus we made changes to
include that requirement of making and keeping records.

B. What Comments Did We Receive on the Need for Dietary Supplement CGMP
Requirements?

(Comment 2) Some comments state that dietary supplement CGMP
requirements will protect consumers from supplements that contain
inherently unsafe dietary ingredients. Other comments request that we
take additional action to ensure the safety of dietary ingredients.
(Response) This final rule focuses on the manufacturing practices
of dietary supplements and not on whether certain dietary ingredients
are or are not safe. Therefore, comments related to whether certain
dietary ingredients are inherently unsafe and any request to take
actions related to the inherent safety of dietary ingredients are
outside the scope of this rule.
(Comment 3) Some comments support the rule, explaining that it will
address current problems with superpotent and subpotent dietary
supplements, undeclared ingredients, and varying levels of ingredients.
Others indicate the rule will better protect consumers and increase
consumer confidence. One comment states that CGMP requirements for
dietary supplements are not needed for responsible manufacturers
because they already manufacture safe dietary supplements. Some
comments state that dietary supplement CGMP requirements are not needed
because the dietary supplements have a track record of safety. Other
comments say there were more adverse events reported from drug use than
from dietary supplement use and that a large number of Americans take
dietary supplements, and on that basis suggested that dietary
supplements are safer than foods or drugs.
(Response) We agree the final rule will better protect consumers
and help address the types of manufacturing problems identified in the
preamble to the 2003 CGMP Proposal (see 68 FR 12157 at 12162 through
12163) through consistent use of established production processes and
controls.
However, we disagree with the comments asserting dietary
supplements have a track record of safety such that dietary supplement
CGMP requirements are unnecessary. Section 402(g) of the act does not
require us to establish a ``bad'' track record of safety in the
manufacture of dietary supplements before we may issue a dietary
supplement CGMP rule. Furthermore, we disagree with the comments
comparing dietary supplement safety to drug safety; there

[[Page 34766]]

are different statutory requirements, different regulatory
requirements, and different safety evaluations for dietary supplements
and drugs.
We also disagree that the final rule should apply only to
manufacturers who cannot manufacture dietary supplements responsibly.
Establishing who is or is not a responsible manufacturer is not a
threshold requirement in section 402(g) of the act, and it would be
impractical to regulate dietary supplement CGMP in such a manner,
because parties may differ as to whether a particular manufacturer
acted ``responsibly'' in a particular situation. All dietary supplement
manufacturers are subject to this final rule, just as all dietary
supplement manufacturers are subject to section 402(g) of the act. We
therefore are not persuaded that dietary supplement CGMP requirements
are not needed, or should only be applied to manufacturers who have not
acted ``responsibly.''
(Comment 4) Some comments state that our authority under the
current food CGMP regulation in part 110 and our authority to take
actions against adulterated and misbranded products generally are
sufficient. Other comments state that DSHEA gives us the necessary
legal authority to protect the public health and that additional
regulatory requirements are unnecessary. Several comments object to our
statement that dietary supplement CGMP requirements are needed to
prevent adulteration. These comments suggest dietary supplement CGMP is
focused on ensuring finished products are manufactured using quality
procedures, but are not related to preventing adulteration. Other
comments state we should enforce current food CGMP regulations rather
than adopt new regulations.
(Response) We disagree that dietary supplement CGMP requirements
are not related to preventing adulteration. In fact, under the
statutory scheme a dietary supplement is deemed to be adulterated under
section 402(g)(1) of the act if it fails to meet CGMP requirements we
promulgate by regulation. As we discussed in section III of this
document, dietary supplement CGMP requirements are necessary to ensure
the quality of the dietary supplement; ensuring quality includes
ensuring that the dietary supplement has been manufactured, packaged,
labeled, and held under conditions to prevent adulteration under
section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act.
We also disagree with those comments stating that the requirements
in part 110 are adequate and that no additional requirements are
necessary. The comments do not explain why the specific requirements
set forth in the proposed rule that are not also in part 110 are
unnecessary. As discussed in greater detail in response to comments on
our legal authority in section V of this document, the particular
characteristics and hazards of dietary supplements call for CGMP
requirements tailored to dietary supplements. Congress specifically
provided independent authority under section 402(g) of the act for us
to promulgate CGMP requirements for dietary supplements. That authority
would have been unnecessary if Congress had concluded that part 110 was
adequate.
We also disagree that enforcement of part 110 would eliminate a
need for dietary supplement CGMP requirements. The dietary supplement
CGMP requirements include practices specifically tailored to the
characteristics and hazards of dietary supplements and their
manufacturers. The comments asserting that current food CGMP
requirements in part 110 are sufficient provided no persuasive or
compelling reasons for that assertion, or for why we should not
implement dietary supplement CGMP requirements under section 402(g) of
the act. For these reasons, we are not persuaded by the comments that
these dietary supplement CGMP requirements are not needed.
(Comment 5) Some comments object to the examples of manufacturing
problems that we used to support the need for CGMP requirements.
Specifically, some comments object to the Prevention magazine citation
and also object to the nine examples we presented in the preamble to
the 2003 CGMP Proposal (see 68 FR 12157 at 12161 through 12163). We
cited the Prevention magazine survey on consumer use of dietary
supplements to show that only 41 percent of surveyed consumers who use
vitamins and minerals think those products are very safe, and only 50
percent think the products are somewhat safe; among those using herbal
products, only 24 percent thought the products were very safe, and only
53 percent thought the products were somewhat safe. We noted that 74
percent supported increased government regulation of dietary
supplements (see, id.). As one example of adulterated dietary
supplements caused by manufacturing practices, the preamble to the 2003
CGMP Proposal mentioned an instance where a young woman suffered a
life-threatening abnormal heart function that was traced to a
mislabeled or contaminated dietary ingredient (68 FR 12157 at 12162).
Another example involved recalls of super- and subpotent dietary
supplements (id.).
Comments objecting to the Prevention survey said it provided no
rationale for why CGMP requirements are needed. Other comments said the
nine examples we provided represent a failure to conform to an existing
regulation and do not demonstrate a need for a new CGMP regulation for
dietary supplements. One comment disagrees that the CGMP requirements
would prevent adverse reactions, as one example suggested in the
preamble to the 2003 CGMP Proposal (see 68 FR 12157 at 12162) because,
the comment claims, most adverse reactions are not the result of
manufacturing problems. Another comment states the example involving
plantain (68 FR 12157 at 12162), where a raw material was labeled as
``plantain'' when it was, in fact, Digitalis lanata (a plant that can
cause life-threatening heart reactions), shows that, had there been a
system in place to test finished product for purity and identity or to
perform identity testing upon receipt, the manufacturer could have
prevented that adulterated product from entering the market place. The
comment states identity testing is necessary in the final rule.
Another comment objects to the example of ``non-food grade
chemicals'' (id.) because the reference supporting the example involved
Gamma-Butyrolactone, a substance we have stated is an unapproved new
drug and not a dietary supplement. Some comments say the risks cited in
the justification for these regulations are hypothetical or theoretical
and current statutory or regulatory authority is adequate.
(Response) We disagree, in most part, with the comments. We cited
the Prevention survey to illustrate consumer perception and support for
increased government involvement in dietary supplement regulation. We
did not describe the survey as illustrating CGMP problems associated
with dietary supplements.
We also disagree that the risks cited in the preamble to the 2003
CGMP Proposal are merely hypothetical or theoretical. We provided
actual examples of failures in the manufacturing of products marketed
as dietary supplements. The comments may have misunderstood what the
CGMP requirements for dietary supplements are intended to accomplish. A
principal goal of the CGMP requirements is to have those who
manufacture, package, label, or hold dietary supplements do so in a
manner that ensures the quality of the

[[Page 34767]]

dietary supplement and that the dietary supplement is packaged and
labeled as specified in the master manufacturing record. It is the
manufacturer who needs to establish procedures for its manufacturing
operations to ensure, for example, the final product is produced
according to its specifications in the master manufacturing record,
meets limits on contaminants, and is a quality dietary supplement. If a
product does not meet its specifications, a manufacturer who observes
the CGMP requirements should know that and be able to take corrective
action before the dietary supplement enters the marketplace. The onus
is on the manufacturer, and not simply on us, to take action to prevent
the adulterated product from entering the market or, if the product has
already been released, to remove the product from the market. The
umbrella food CGMP requirements in part 110 do not contain specific
provisions establishing specifications, requiring identity testing, or
requiring in-process and/or finished product testing. Through this
final rule, we are establishing a new CFR part regarding CGMP
requirements specifically for dietary supplements.
The examples we used in the preamble to the 2003 CGMP Proposal
included adverse event reports associated with contamination with
Digitalis lanata, the possible contamination of botanical ingredients
with toxic compounds, the use of non-food grade chemicals, the
manufacture of super- and subpotent dietary supplements, the presence
of undeclared ingredients, and the variability of ingredients from what
is declared on the label (Refs. 7, 8, and 10; see, also, 68 FR 12157 at
12162 through 12163). These were all examples where products were
manufactured, labeled, and sold to the consumer as dietary supplements.
We disagree with the comments' assertions that all these problems can
be adequately dealt with by the food CGMP requirements in part 110, but
agree with the comment that, had there been a system in place ``to
perform identity testing upon receipt, the manufacturer could have
prevented that adulterated product from entering the market place.''
Most of these examples present situations in which the manufacturer
could have identified these problems through the dietary supplement
CGMP requirements for specifications and testing or examination, such
as identity verification, and could have prevented such products from
entering the market or at least provided a greater assurance that such
products would not make it into the marketplace. The dietary supplement
CGMP requirements ensure adequate controls are in place to identify
many of these types of manufacturing errors before the product is in
the marketplace and not through postmarketing adverse event reports or
consumers' illnesses.\3\
---------------------------------------------------------------------------

\3\Mandatory reporting to FDA of serious adverse events is now
required as a result of the enactment of the ``Dietary Supplement
and Non-Prescription Drug Consumer Protection Act'' (Public Law 109-
462) signed into law on December 22, 2006 (see discussion in section
XX of this document).
---------------------------------------------------------------------------

The dietary supplement industry is diverse, as are the number and
types of products marketed as dietary supplements. As we stated in the
preamble to the 2003 CGMP Proposal (68 FR 12157 at 12163), given the
wide range of public health concerns presented by the manufacturing
practices for dietary supplements, a comprehensive system of controls
is necessary. This final rule will set the standards for CGMP for
dietary supplements that, if followed, will help ensure the quality of
the dietary supplement and that the dietary supplement is packaged and
labeled as specified in the master manufacturing record. The
establishment of production and process controls and adherence to these
and other CGMP requirements of this final rule will help to prevent the
types of events (and others) we described in the nine examples
presented in the preamble to the 2003 CGMP Proposal.
(Comment 6) Several comments suggest that dietary supplements are
no different in safety or physiologic effect and require no different
requirements than conventional food with respect to CGMP. One comment
disagrees with us that dietary supplements require different
requirements than conventional food because dietary supplements are
ground up or in powder form and may not be easily recognized or
differentiated; the comment says the same is true of many food
ingredients as well.
(Response) We disagree with the suggestions by these comments that
dietary supplement CGMP requirements need not differ from those for
conventional foods. By definition, a dietary supplement is in a
category of food separate and distinct from the category of
conventional food. The definition of dietary supplement in section
201(ff) of the act, in part, essentially describes a dietary supplement
as a type of food that differs from conventional food. The definition
refers to section 411(c)(1)(B)(i) and (c)(1)(B)(ii) of the act (21
U.S.C. 350(c)(1)(B)(i) and (c)(1)(B)(ii)), which describes the forms
that dietary supplements intended to be ingested may take, i.e.,
tablet, capsule, powder, softgel, gelcap, or liquid form, and if not in
such a form, limitations on how dietary supplements can be represented,
i.e., not as conventional food or as a sole item of a meal or the diet.
Congress included separate additional provisions under section 402
of the act (see section 402(f) and (g) of the act) for when a dietary
supplement may be adulterated. Congress considered that dietary
supplements may warrant CGMP requirements that are different than those
for conventional food. Although dietary supplements may include
substances that are used as ingredients in conventional foods, the
amounts consumed as a dietary supplement and as a conventional food
product may not be the same and, in fact, may be more concentrated, and
in higher amounts, when taken as a dietary supplement. The forms in
which dietary supplements are consumed differ (e.g., capsule, tablet),
as may the frequency, when compared to conventional foods. The uses of
dietary supplements also differ from use as conventional food.
Consequently certain manufacturing practices considered to be a part of
CGMP for dietary supplement manufacturing may not be necessary for all
types of food.

C. What Comments Did We Receive on Written Procedures?

1. Overview
In the 2003 CGMP Proposal (68 FR 12157 at 12165), we stated that
written procedures were included in the dietary supplement CGMP outline
submitted to us by industry, namely, the National Nutritional Foods
Association standards (NNFA), the NSF International draft standards,
and the United States Pharmacopoeia (USP) draft manufacturing
practices. We also stated that, to limit the burden to manufacturers,
we were not proposing to require written procedures for all the
requirements. We invited comment on whether we should require written
procedures for a variety of operations; specifically, for complying
with the CGMP requirements, under proposed Sec. 111.10 for personnel
hygiene and for preventing microbial contamination due to personnel (68
FR 12157 at 12182); maintenance, cleaning, and sanitation for the
physical plant under proposed Sec. 111.15 (68 FR 12157 at 12187);
calibrating instruments and controls under proposed Sec. 111.25(b),
(c), and (d) (68 FR 12157 at 12191); maintaining, cleaning, and
sanitizing equipment and utensils under proposed Sec. 111.25(e) (68

[[Page 34768]]

FR 12157 at 12192); calibrating, inspecting, and checking automatic
equipment under proposed Sec. 111.30 (68 FR 12157 at 12193); the
duties of the quality control unit under proposed Sec. 111.37 (68 FR
12157 at 12201); implementing the proposed requirements for receipt of
components, dietary supplements, packaging, and labels under proposed
Sec. 111.40(a) and (b) (68 12157 at FR 12203); preparing the master
manufacturing record under proposed Sec. 111.45 (68 FR 12157 at
12205); laboratory operations under proposed Sec. 111.60 (68 FR 12157
at 12209); manufacturing operations under proposed Sec. 111.65 (68 FR
12157 at 12211); packaging and labeling operations under proposed Sec.
111.70 (68 FR 12157 at 12213); holding components, dietary supplements,
packaging, labels, and in-process materials under proposed Sec. Sec.
111.80 and 111.82 (68 FR 12157 at 12214); identifying, quarantining,
and salvaging returned dietary supplements under proposed Sec. 111.85
(68 FR 12157 at 12216); and receiving, reviewing, and investigating
consumer complaints under proposed Sec. 111.95 (68 FR 12157 at 12217).
We stated that 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 supplement. Conversely, if comments assert
that written procedures are not necessary, we asked for an explanation
of why and how, in the absence of the requirement, one can prevent
adulteration and ensure the identity, purity, quality, strength, and
composition of the dietary supplement.
(Comment 7) Many comments stress the most critical aspect of a
successful CGMP system is effective process control, which requires
conducting key operations using written procedures. Several comments
assert that written procedures are an important part of manufacturing
operations to ensure uniform practices in production operations, from
receiving through final operations. Several comments assert written
procedures provide a sound basis for employee training and supervision.
Several comments state that without a written training program, it is
very likely that some employees may not receive sufficient training, or
in some cases, any CGMP training at all. One comment specifically
suggests that companies develop written procedures for the minimum CGMP
training common to all departments.
One comment points out that all well-recognized quality systems
require establishment of written procedures to ensure consistent
process control, and cites examples such as the International
Organization for Standardization, the American National Standards
Institute (ANSI), and the Malcolm Baldridge National Quality Award
criteria. Other comments state that written procedures are necessary
for the definition, operation, and documentation of a process control
system, and that without such procedures it would be virtually
impossible for any company, regardless of size, to consistently
manufacture products that meet established requirements for identity,
purity, quality, strength, and composition. The comments note that
written procedures contain the necessary instructions for all employees
to successfully execute their respective functions. Another comment
supports a requirement for conducting key operations using written
procedures and states that records document that operations were
performed, but that written procedures show how the task is to be
performed and at what frequency it should be performed. One comment
states effective communication is essential to build quality into a
process, and written procedures provide that throughout all levels of
an organization. Another comment states it is difficult to imagine how
the quality control unit could carry out its obligations under proposed
Sec. 111.37(b)(1) to ``approve or reject all processes,
specifications, controls, tests, and examinations, and deviations from
or modifications to them * * *'' if these are not subject to written
procedures.
Many comments which present one or more of these general reasons
for requiring written procedures also list operations that they believe
should be conducted using written procedures. The operations that one
or more comments list as key operations are:
Employee training;
Cleaning the physical plant, including pest control;
Maintenance, cleaning, and sanitizing of equipment and
utensils;
Calibration of equipment used in manufacturing or testing;
All aspects of the production process, including a general
procedure to document the minimum investigation, review, and approval
requirements for failures in manufacturing or packaging operations;
All quality control operations;
Reprocessing of batches or start-up materials that do not
conform to specifications;
Receipt, identification, examination, handling, sampling,
testing, and approval or rejection of components, packaging, and
labels;
Laboratory operations, including the establishment of
specifications and descriptions of laboratory test methods used to
ensure that components, in-process materials, and finished product meet
established specifications;
Packaging and labeling operations, including issuance and
use of appropriate labels, labeling, and packaging materials;
Holding and distribution procedures, including procedures
for quarantine and parameters for storage;
Return and salvage operations;
Handling of consumer complaints; and
Procedures for product recall.
Many comments assert an effective process control system that
includes extensive written procedures would justify a decreased testing
burden with respect to the finished product. One comment suggests we
exempt manufacturers from the requirement to test each finished batch
of product if they have a qualified manufacturing process that meets
certain basic criteria, including a requirement for written procedures
for each stage of the process. One comment notes it would be clearer to
all parties if specific written procedures were listed as required and
stresses the importance of having all companies know exactly what is
procedurally expected of them.
In addition to these general reasons for requiring that key
operations be conducted using written procedures, several comments
provide specific reasons for requiring that specific operations be
conducted using written procedures. In response to our request for
comment on whether written procedures should be required for complying
with proposed Sec. 111.10 (personnel hygiene and for preventing
microbial contamination due to personnel), one comment states that
written procedures help to ensure compliance with the proposed hygiene
requirements by clearly listing the requirements and requiring the
employees to follow them on a consistent basis.
In response to our request for comment on whether written
procedures should be required for complying with the proposed
requirements for maintenance, cleaning, and sanitation for the physical
plant under proposed Sec. 111.15, one comment states that having
written procedures in place to clean the physical plant will ensure
that there is no cross-contamination. Another comment states utility
areas such as effluent treatment, boilers, cooling towers, and water

[[Page 34769]]

treatment plants also should have documented procedures for cleaning in
order to create a general awareness of cleanliness throughout the
plant. Other comments state that such written procedures should not be
required because they would not directly prevent contamination or
ensure the identity, purity, quality, strength, and composition of the
dietary supplement if, as the ``bottom line,'' a manufacturer maintains
the physical plant in a clean and sanitary condition.
Responding to our request for comment on whether written procedures
should be required for complying with the proposed requirements for
calibrating instruments and controls under proposed Sec. 111.25(b),
(c), and (d), several comments assert we should require manufacturers
to establish and follow written procedures for calibrating equipment
and controls. According to these comments, such procedures would
provide us with a written record that is sufficient to evaluate the
adequacy of the company's calibration procedures and would provide the
necessary controls to meet the underlying intent of the rule. These
comments assert that written procedures will lessen the risk that
adulterated products will be produced.
In response to our request for comment on whether written
procedures should be required for complying with the proposed
requirements for maintaining, cleaning, and sanitizing equipment and
utensils under proposed Sec. 111.25(e), several comments assert such
written procedures are crucial. These comments claim that written
procedures promote consistency, clearly lay out expectations for
employees, facilitate training, and provide a reference for individuals
in performing their job functions. One comment states that written
procedures for maintaining, cleaning, and sanitizing equipment are an
industry standard.
In response to our request for comment on whether written
procedures should be required for complying with the proposed
requirements for preparing the master manufacturing record under
proposed Sec. 111.45, one comment states that written procedures for
in-process control and quality checks should ensure the addition of the
proper ingredients in the proper amount, and proper blending and
control of other critical points. Another comment states written
procedures are a critical element for ensuring consistent
implementation of proper corrective action. Other comments state they
do not support a requirement for written procedures for preparing the
master manufacturing record; and one comment suggests such a written
procedure is not necessary because the proposed regulations for
preparing the master manufacturing record already delineate the
requirements for what information must be included in the master
manufacturing record.
In response to our request for comment on whether written
procedures should be required for complying with the proposed
requirements for laboratory operations under proposed Sec. 111.60,
some comments specifically note the need for written procedures for the
laboratory test methods used to ensure that components, in-process
materials, and finished product meet established specifications. Some
comments emphasize written procedures would create a standard for
testing of products or groups of products and establishing parameters
for passing or failing products.
In response to our request for comment on whether written
procedures should be required for complying with the proposed
requirements for manufacturing operations under proposed Sec. 111.65,
one comment asserts this is an effective way to train personnel and a
means to hold operators accountable to a quality standard. Another
comment states written procedures can improve quality and consistency
in a manufacturing operation.
In response to our request for comment on whether written
procedures should be required for complying with the proposed
requirements for packaging and labeling operations under proposed Sec.
111.70, one comment asserts this is an effective way to train personnel
and a means to hold operators accountable to a quality standard.
Responding to our request for comment on whether written procedures
should be required for complying with the proposed requirements for
holding components, dietary supplements, packaging, labels, and in-
process materials under proposed Sec. Sec. 111.80 and 111.82, one
comment asserts this is an effective way to train personnel and a means
to hold operators accountable to a quality standard. Another comment
states a company cannot be considered to be a CGMP operation without
having written procedures for every product manufacturing activity,
including holding and distributing. This comment states mixups and
adulterations will be more likely to occur if there are no written
procedures for control of storage locations, manner of storage, and
container and storage location identification codes.
In response to our request for comment on whether written
procedures should be required for complying with the proposed
requirements for returned dietary supplements, one comment states
written procedures should govern all return and salvage operations to
create a standard for quarantine and salvage and to establish
parameters for proper salvage conditions.
Responding to our request for comment on whether written procedures
should be required for complying with the proposed requirements for
handling consumer complaints, some comments state written procedures
will encourage companies to handle consumer complaints in a uniform
manner. One comment asserts written procedures should be required for
handling consumer complaints because some complaints could relate to
serious illness or injury. The comment states that written procedures
would set out exactly what steps need to be taken when complaints are
reviewed, and are the best way to ensure the essential information is
captured.
(Response) We agree with the comments that effective process
control, using written procedures, is an important aspect of a
successful CGMP program. We also agree requiring written procedures
will help to ensure consistent practices in operations i.e., help to
ensure the operation is conducted in the same manner regardless of who
conducts the operation or when the operation is conducted. We also
agree that written procedures provide a sound basis for employee
training and supervision, are an effective communication tool, and
enable quality control personnel to carry out the responsibility to
approve or reject all processes, specifications, controls, tests, and
examinations, and deviations from or modifications to them. In
addition, written procedures establish expectations for each covered
operation so the operation does not proceed in an ad-hoc manner.
Written procedures provide specific guidance if there is an
unanticipated occurrence and, thus, can play a key role in ensuring a
quality product, because actions to correct the unanticipated
occurrence can take place swiftly and with confidence in the outcome.
This final rule establishes the minimum CGMPs necessary for
activities related to manufacturing, packaging, labeling, and holding
dietary supplements to ensure a quality

[[Page 34770]]

product. The operations required by this final rule must be conducted
in a consistent manner, regardless of who is conducting an operation or
when the operation is conducted. As discussed in the following
paragraphs, with a few exceptions, we are requiring that you establish
and follow written procedures to fulfill the requirements for the
operations covered by this final rule. The exceptions include final
subpart A, which addresses the scope of the rule, rather than
operations covered by the rule; final subparts E, H, and I, in which we
conclude that a requirement for written procedures would be redundant
to other requirements; and final subpart P, which establishes
requirements for making and keeping records, rather than for conducting
operations.
We believe requiring you to establish and follow written procedures
to fulfill the requirements of subparts B through D, F, G, and J
through O, when combined with other requirements of this final rule,
justifies reduced requirements for testing finished batches of product
compared to the proposed requirements for such testing as found in
proposed Sec. 111.35. By establishing and following written
procedures, you will focus your production and process control system
on ensuring the quality of the finished product at each stage in the
production process, rather than relying entirely on testing at the end
of the process.
2. Written Procedures That Are Required by This Final Rule
a. Written procedures for personnel (final subpart B). We believe
that successful programs for process control are directly connected to
appropriate training programs. Employee training must be conducted in a
consistent manner, regardless of who conducts the training or when it
is conducted. Failure to conduct employee training in a consistent
manner could lead to a failure in ensuring product quality. For
example, an employee who has not received appropriate training on how
to conduct a specific physical examination to verify the identity of a
dietary ingredient may erroneously report that the correct ingredient
was received when, in fact, the received dietary ingredient is related
to, but different from, the ingredient that is specified in the master
manufacturing record.
We also believe the requirements that apply to preventing microbial
contamination due to sick or infected personnel and that apply to
proper hygienic practices must be conducted in a consistent manner. For
example, it is well known that foodborne illness can be transmitted by
workers who are sick. For example, volunteer food workers at an outdoor
music festival were found to be the source of contamination for an
outbreak of Shigellosis (Ref. 11).
We include in final subpart B a requirement (final Sec. 111.8)
that you establish and follow written procedures for fulfilling the
requirements of subpart B.
b. Written procedures for cleaning the physical plant, including
pest control (final subpart C). We agree with the comments that written
procedures for cleaning the physical plant would reduce the potential
for cross-contamination and that such written procedures must include
written procedures for pest control. Cleaning operations and pest
control must be conducted in a consistent manner, regardless of who
conducts the operation or when it is conducted. Failure to conduct
cleaning operations and pest control in a consistent manner could lead
to failure in ensuring product quality. For example, application of a
chemical such as a fumigating agent or rodenticide in a production area
must be performed correctly to avoid contaminating dietary supplements.
Therefore, we disagree that written procedures would not directly
prevent contamination or ensure the identity, purity, strength, and
composition of the dietary supplement even if a manufacturer maintains
the physical plant in a clean and sanitary condition.
We include in final subpart C a requirement that you establish and
follow written procedures for cleaning the physical plant and for pest
control (final Sec. 111.16).
c. Written procedures for calibrating instruments and controls and
for calibrating, inspecting, and checking automated, mechanical, or
electronic equipment (final subpart D). Calibrating instruments and
controls, and calibrating, inspecting, and checking automated,
mechanical, or electronic equipment must be conducted in a consistent
manner, regardless of who conducts the operation or when it is
conducted. Without a consistent approach, the performance of these
operations could lead to equipment that produces inaccurate results.
For example, if a scale is out of calibration, the wrong amounts of
components could be added to a mixer. We include in final subpart D a
requirement that you establish and follow written procedures for
calibrating instruments and controls that you use in manufacturing or
testing a component or dietary supplement (final Sec. 111.25(a)) and
for calibrating, inspecting, and checking automated, mechanical, and
electronic equipment (final Sec. 111.25(b)). We note that the
manufacturers of equipment often provide written procedures for
calibrating equipment. Depending on your circumstances and
applications, you may be able to rely on written procedures provided by
the manufacturer of the equipment with little or no modification.
Final Sec. 111.25(a), pertaining to establishing and following
written procedures for calibrating instruments and controls used in
manufacturing or testing components or dietary supplements, is similar
to proposed Sec. 111.25(c)(1) which would provide an option, in
relevant part, that you establish written procedures for calibrating
such instruments and controls in addition to requiring you to document
that the procedure was followed each time a calibration is performed.
d. Written procedures for maintaining, cleaning, and sanitizing
equipment and utensils (final subpart D). Maintaining, cleaning, and
sanitizing equipment and utensils must be conducted in a consistent and
appropriate manner, regardless of who conducts the operation or when it
is conducted. Failure to clean and sanitize equipment and utensils in a
consistent and appropriate manner could lead to a product that is
adulterated because, for example, equipment and utensils that are not
properly cleaned and sanitized could be a source of microorganisms, or
could lead to cross-contamination of products. In addition, failure to
maintain equipment in a consistent manner could lead to the failure to
ensure product quality. For example, equipment that is properly
maintained is less likely to malfunction than equipment that is not
maintained, and using equipment that malfunctions could lead to errors
in production, such as dispensing an incorrect amount of each
ingredient.
We include in final subpart D a requirement that you establish and
follow written procedures for maintaining, cleaning, and sanitizing
equipment and utensils (final Sec. 111.25(c)). Final Sec. 111.25(c)
applies to equipment, utensils, and any other contact surfaces used in
labeling operations as well as in manufacturing, packaging, and holding
operations. Although the factors you must consider for maintaining,
cleaning, and sanitizing equipment used for labeling operations likely
are different from those for equipment used in manufacturing or
packaging operations, you nevertheless must determine the appropriate
steps to take to ensure that labeling equipment is appropriately
maintained and does not become a source of contamination

[[Page 34771]]

for dietary supplements. For example, equipment used for labeling
operations has a greater potential to contaminate a dietary supplement
when labeling operations are carried out in concert with packaging
operations, because the dietary supplement could be exposed to one or
more contact surfaces during the packaging operations.
Final Sec. 111.25(c) requires you to establish and follow written
procedures for maintaining, cleaning, and sanitizing, as necessary, all
equipment, utensils, and any other contact surfaces used to
manufacture, package, label, or hold components or dietary supplements.
Final Sec. 111.25(c) relates to proposed Sec. 111.25(e)(1) which
would, in relevant part, require you to maintain, clean, and sanitize
as necessary, all equipment, utensils, and contact surfaces used to
manufacture, package, label, or hold components, dietary ingredients,
or dietary supplements.
(Comment 8) Some comments suggest that written procedures for
maintaining, cleaning, and sanitizing equipment require visual
inspection of equipment when more than one product is manufactured
using the same equipment, and that the presence of residual components
from one product in a different product could be harmful. The comments
also suggest the written procedures include residual limits of
components from different product lines to guarantee the safety of the
dietary supplement.
(Response) The final rule gives you flexibility to develop written
procedures appropriate to your products and equipment. Consequently,
final Sec. 111.25(c) neither requires nor prohibits any specific
procedure, such as the visual inspection suggested by the comment.
As for the residual limits, the comment provides no data or other
information that would provide a basis for setting residual limits for
any particular components. However, as we discuss more fully in the
discussion of final Sec. 111.70(e) in section X of this document, the
final rule requires you to establish and meet specifications for the
identity, purity, strength, and composition of dietary supplements and
for limits on contamination for dietary supplements that you
manufacture. When considering the specifications you must establish to
ensure the quality of the dietary supplements, you must take into
account the need to ensure that components or dietary supplements are
not contaminated as a result of using the same equipment. Such
equipment could be a source of contamination if more than one product
is manufactured using the equipment and it is not properly cleaned and/
or sanitized.
e. Written procedures for quality control operations, including
written procedures for conducting a material review and making a
disposition decision and written procedures for approving or rejecting
reprocessing (final subpart F). Quality control operations must be
conducted in a consistent manner. Failure to carry out quality control
operations in a consistent and appropriate way could lead to failure to
ensure product quality and to ensure the dietary supplement is packaged
and labeled as specified in the master manufacturing record. For
example, you could use a component that should not have been released
for use in manufacturing, or you could distribute a packaged and
labeled dietary supplement that should not have been released for
distribution.
We include in final subpart F a requirement that you establish and
follow written procedures for quality control operations (final Sec.
111.103). We agree with the comments that there should be written
procedures for investigating failures in manufacturing operations. In
the 2003 CGMP Proposal, we referred to the process of investigating
such failures as a ``material review'' and proposed a series of
requirements related to a material review and the disposition decision
that follows a material review. The review must be conducted in a
consistent manner, and the criteria for making a disposition decision
must be consistent, regardless of who is conducting the material review
or when it is conducted, and regardless of who makes the disposition
decision and when the decision is made. For example, if you do not have
written criteria for determining whether a deviation from
specifications has resulted in, or could lead to, adulteration,
different individuals who conduct a material review could reach
different decisions regarding the appropriate disposition of the
affected dietary supplement, including decisions that incorrectly
result in the release of an adulterated product. As discussed more
fully in sections X and XI of this document, the final rule requires
that quality control personnel conduct all required material reviews
and make all required disposition decisions. Therefore, we are
requiring that the written procedures for quality control operations
include written procedures for conducting a material review and making
a disposition decision (final Sec. 111.103).
We considered the comments that suggest that there should be a
requirement for you to establish and follow written procedures for
reprocessing from two perspectives: (1) Determining whether
reprocessing should be approved or rejected and (2) performing the
reprocessing. In general, reprocessing is performed when there is a
problem with the manufacturing process, such as when a specification is
not met or any step in the master manufacturing record is omitted.
Depending on the nature of the dietary supplement, the manufacturing
process, and the problem, reprocessing may or may not be able to
correct the problem. From the perspective of determining whether
reprocessing should be approved or rejected, under the final rule it is
quality control personnel who must approve or reject any reprocessing
(see final Sec. Sec. 111.90, 111.113, 111.120, 111.123, and 111.130).
The decision to approve reprocessing must be made in a consistent
manner, regardless of who conducts the operation or when it is
conducted. For example, if it is not possible to test the product at
the finished batch stage to determine whether the reprocessing
corrected the problem (because, for example, there is no scientifically
valid method available to test for a specification that is directly
related to the reason for reprocessing), you must have a clear basis to
decide that reprocessing will actually correct the problem or you will
not know if all required specifications can be met. Without written
procedures for approving reprocessing, different individuals who
approve or reject any reprocessing could make very different decisions
on when reprocessing can correct a problem and when it cannot.
Therefore, we are specifically requiring that the written procedures
for quality control operations include written procedures for approving
or rejecting any reprocessing.
From the perspective of performing the reprocessing, we agree that
any procedure for reprocessing must be written because, for example,
quality control personnel may need to rely on the procedure that you
followed to determine whether all specifications are met for the
reprocessed material. However, the final rule requires you to document
any reprocessing in the batch record (final Sec. 111.260(n)) rather
than establishing and following written procedures to conduct
reprocessing, because the actual procedure you follow to reprocess a
dietary supplement likely will be different depending on the
circumstances.
f. Written procedures for components, packaging, labels, and
product that is received for packaging and labeling as a dietary
supplement (final subpart G). We agree with the comments that the

[[Page 34772]]

receipt, examination, quarantine, and release from quarantine of
components, packaging, labels, and product that are received for
packaging and labeling as dietary supplements must be conducted in a
consistent manner, regardless of who conducts the operation or when it
is conducted. Failure to carry out these operations in a consistent way
could lead to failure to ensure product quality if, for example, you
use a component that should not have been released for use in
manufacturing.
We include in final subpart G a requirement that you establish and
follow written procedures for fulfilling the requirements of subpart G
(final Sec. 111.153).
g. Written procedures for laboratory operations (final subpart J).
Testing and examination of components, packaging, labels, and product
that are received for packaging or labeling as a dietary supplement, or
packaged and labeled dietary supplements, must be conducted in a
consistent manner, regardless of who conducts the operation or when it
is conducted. The reason a firm conducts these tests and examinations
is to ensure that a dietary supplement meets established
specifications. Failure to conduct tests and examinations in a
consistent manner could lead to failure in ensuring the quality of the
dietary supplement. For example, a test designed to determine the
concentration of a product before it is diluted to the appropriate
concentration could provide different results if it is conducted in a
different manner by different individuals.
In addition, laboratory operations such as use of criteria for
establishing appropriate specifications and use of sampling plans for
obtaining representative samples must be conducted in a consistent
manner, regardless of who conducts the operation or when it is
conducted. For example, failure to consider that specifications are
needed to ensure that a dietary supplement derived from a botanical
source does not contain contaminants, such as an unlawful pesticide,
could result in a dietary supplement that contains unsafe levels of a
contaminant.
We include in final subpart J a requirement that you establish and
follow written procedures for laboratory operations, including written
procedures for the tests and examinations that you conduct to determine
whether specifications are met (final Sec. 111.303).
h. Written procedures for manufacturing operations (final subpart
K). We agree with the comments that written procedures for
manufacturing operations would be an effective way to train personnel,
provide a means to hold operators accountable to a quality standard,
and improve quality and consistency in a manufacturing operation. The
final provisions for manufacturing operations require you to design or
select manufacturing processes to ensure that dietary supplement
specifications are consistently achieved, conduct all manufacturing
operations in accordance with adequate sanitation principles, and take
all necessary precautions to prevent contamination of components and
dietary supplements. These manufacturing operations must be conducted
in a consistent manner, regardless of who conducts the operation or
when it is conducted. Failure to perform these operations in a
consistent way could lead to failure to ensure the quality of the
dietary supplement. For example, surfaces that come in contact with a
dietary supplement are potential sources of microbial contamination if
consistent procedures are not in place to ensure good sanitary
practices. We are including in final subpart K a requirement that you
establish and follow written procedures for manufacturing operations
(final Sec. 111.353).
i. Written procedures for packaging and labeling operations (final
subpart L). We agree with the comments that written procedures for
packaging and labeling operations are an effective means to hold
operators accountable to ensure the quality of the dietary supplement
and that the dietary supplement is packaged and labeled as specified in
the master manufacturing record. The final provisions for packaging and
labeling operations require that you fill, assemble, package, label,
and perform other related operations in a way that ensures the quality
of the finished product, including practices such as cleaning and
sanitizing all filling and packaging equipment, utensils, and
containers; protecting manufactured dietary supplements against
airborne contamination, using sanitary handling procedures; taking
actions to prevent mixups; and suitably disposing of obsolete packaging
and labels. These packaging and labeling operations must be conducted
in a consistent manner, regardless of who conducts the operation or
when it is conducted. Failure to perform these operations in a
consistent way could lead to a failure to ensure the quality of the
dietary supplement and that the dietary supplement is labeled and
packaged as specified in the master manufacturing record. For example,
if you do not have procedures for identifying filled, but unlabeled,
containers of dietary supplements, mixups could occur before the labels
are applied. The final product could contain ingredients other than
those identified on the label specified in the master manufacturing
record. Therefore, we include in final subpart L a requirement that you
establish and follow written procedures for packaging and labeling
operations (final Sec. 111.403).
j. Written procedures for holding and distributing operations
(final subpart M). We agree with the comments that written procedures
for holding and distributing operations are an effective means to hold
operators accountable to CGMP standards, and that mixups and other
problems that affect the final product will be more likely to occur if
there are no written procedures for operations such as control of
storage locations, manner of storage, and container and storage
location identification codes. The final provisions for holding and
distributing operations require, among other things, that you hold
components and dietary supplements under appropriate conditions of
temperature, humidity, and light so that the identity, purity,
strength, and composition of the components and dietary supplements are
not affected; that you hold components, dietary supplements, and in-
process materials under conditions that do not lead to the mixup,
contamination, or deterioration of components or dietary supplements;
and that you distribute dietary supplements under conditions that will
protect them against contamination and deterioration.
These holding and distributing operations must be conducted in a
consistent manner, regardless of who conducts the operation or when it
is conducted. Failure to follow these requirements for holding and
distributing in a consistent manner could lead to a failure to ensure
the quality of the dietary supplement product. For example, if
employees do not know how to store an in-process batch of a botanical
dietary supplement to control humidity, the growth of mold could be
promoted. Furthermore, if a distributor does not refrigerate a dietary
supplement that requires refrigeration to ensure its strength, the
dietary supplement may not meet its specification for strength.
Therefore, we include in final subpart M a requirement that you
establish and follow written procedures for holding

[[Page 34773]]

and distributing operations (final Sec. 111.453).
k. Written procedures for returned dietary supplements (final
subpart N). We agree with the comments that written procedures for
returned dietary supplements would help to ensure appropriate handling
of such supplements prior to a disposition decision. The final rule
requires you, among other things, to identify and quarantine returned
dietary supplements until quality control personnel conduct a material
review and make a disposition decision. You must destroy, or otherwise
suitably dispose of, any returned dietary supplement that quality
control personnel do not approve for salvage or reprocessing. These
operations for returned dietary supplements must be conducted in a
consistent manner, regardless of who conducts the operation or when it
is conducted. Failure to comply with these requirements for quarantine,
salvage, and disposition in a consistent way could lead to a failure to
ensure the quality of the dietary supplement. For example, if an
investigation leads to a conclusion that a dietary supplement requiring
refrigeration to ensure its strength was not refrigerated while held at
a customer's warehouse, and this dietary supplement was not quarantined
while quality control personnel conducted a material review, the
dietary supplement could be inadvertently co-mixed with other
containers of that same lot of product and then inadvertently
redistributed. Therefore, we are including in final subpart N a
requirement that you establish and follow written procedures to fulfill
the requirements of subpart N (final Sec. 111.503).
l. Written procedures for product complaints (final subpart O). We
agree with the comments that written procedures for handling consumer
complaints (now called product complaints) will encourage companies to
handle product complaints in a consistent manner and help ensure the
essential information is captured during investigation of a product
complaint. The final rule requires you, among other things, to review
all product complaints to determine whether the product complaint
involves a possible failure of a dietary supplement to meet any of its
specifications; investigate any product complaint that involves a
possible failure of a dietary supplement to meet any of its
specifications; and extend the review and investigation of the product
complaint to all relevant batches and records. These operations must be
conducted in a consistent manner, regardless of who conducts the
operation or when it is conducted. Failure to comply with these
requirements for review and investigation of a product complaint in a
consistent way could lead to a failure to ensure the quality of the
dietary supplement. For example, if you do not have a procedure in
place to determine whether the product complaint involves a possible
failure of a dietary supplement to meet any of its specifications, you
may not recognize that a particular product complaint is indicative
that a problem has occurred with one of your manufacturing processes.
That undiscovered problem may lead to continued distribution of product
that is contaminated or otherwise not consistent with your
specifications in the master manufacturing record. Therefore, we
include in final subpart O a requirement that you establish and follow
written procedures to fulfill the requirements of subpart O (final
Sec. 111.553).
3. Written Procedures That Are Not Required by This Final Rule
a. Written procedures for final subpart E (``Requirement to
Establish a Production and Process Control System''). In the CGMP
proposal, we did not specifically request comments on whether we should
require that you establish and follow written procedures to fulfill the
requirements of proposed Sec. 111.35 (``What Production and Process
Controls Must You Use?''), and we received no specific comments
regarding whether we should establish and follow such written
procedures. Given the strong support in the comments for the use of
written procedures in a production and process control system, we
nonetheless considered whether the requirements that we establish in
final subpart E, Requirement to Establish a Production and Process
Control System, would require written procedures.
Final subpart E requires that you implement a system of production
and process controls that covers all stages of manufacturing,
packaging, labeling, and holding of the dietary supplements and that
your system be designed to ensure the quality of the dietary supplement
and that the dietary supplement is packaged and labeled as specified in
your master manufacturing record (final Sec. Sec. 111.55 and 111.60);
implement quality control operations to ensure the quality of dietary
supplements and that the dietary supplement is packaged and labeled as
specified in your master manufacturing record (final Sec. 111.65);
establish specifications (final Sec. 111.70); determine whether
specifications are met (final Sec. Sec. 111.73 and 111.75); collect
representative samples (final Sec. 111.80); hold reserve samples of
packaged and labeled dietary supplements (final Sec. 111.83); have
quality control personnel conduct all required material reviews and
make all required disposition decisions (final Sec. 111.87); and
adhere to certain requirements for treatment, in-process adjustments,
and for reprocessing (final Sec. 111.90).
In considering whether we should require that you establish and
follow written procedures to fulfill the requirements of final subpart
E, we evaluated whether requirements in other subparts that address
specific operations for the production and process control system
substitute for the requirement of written procedures in final subpart
E.
Final subparts F through M establish specific requirements for
manufacturing, packaging, labeling, and holding dietary supplements,
including requirements for quality control operations (final subpart
F); components, packaging, labels, and product that is received for
packaging and labeling as a dietary supplement (final subpart G);
establishing a written master manufacturing record and batch record
(final subparts H and I); laboratory operations (final subpart J);
manufacturing operations (final subpart K); packaging and labeling
operations (final subpart L); and holding operations (final subpart M).
We require you to establish and follow written procedures to fulfill
the requirements of final subparts F, G, J, K, L, and M. Given these
requirements, we conclude it would be redundant to require you to
establish and follow written procedures to fulfill the requirements of
final Sec. Sec. 111.55, 111.60, and 111.65 in subpart E.
Final subpart J requires you to establish and follow laboratory
control processes that include the use of criteria for establishing
appropriate specifications (final Sec. 111.315(a)); use of sampling
plans for obtaining representative samples (final Sec. 111.315(b));
use of criteria for selecting appropriate examination and testing
methods (final Sec. 111.315(c)); use of criteria for selecting
standard reference materials used in performing tests and examinations
(final Sec. 111.315(d)); and use of test methods and examinations in
accordance with established criteria (final Sec. 111.315(e)). In
addition, under final Sec. 111.303 you must establish and follow
written procedures for laboratory operations. Given the requirements of
final subpart J, we conclude it would be redundant to require you to
establish and follow written procedures to fulfill

[[Page 34774]]

the requirements of final Sec. Sec. 111.70, 111.75, and 111.80 in
subpart E.
Final subpart M establishes requirements for holding reserve
samples. Under final Sec. 111.453, you must establish and follow
written procedures for holding operations. Given the requirements of
final subpart M, we conclude that it would be redundant to require you
to establish and follow written procedures to fulfill the requirements
of final Sec. 111.83 in subpart E for reserve samples.
Final subpart F establishes requirements for quality control
personnel to conduct a material review and make a disposition decision
(final Sec. 111.113); approve any reprocessing (final Sec.
111.123(a)(5)); and document any material review and disposition (final
Sec. 111.140(b)(3)). In addition, as discussed, under final Sec.
111.103 you must establish and follow written procedures for quality
control operations. Given the requirements of final subpart F, we
conclude that it would be redundant to require that you establish and
follow written procedures to fulfill the requirements of final
Sec. Sec. 111.87 and 111.90 in subpart E.
We conclude that it would be redundant to require you to establish
and follow written procedures for each of the requirements established
in final subpart E. We, therefore, do not require you to establish and
follow written procedures to fulfill the requirements established in
subpart E.
b. Written procedures for preparing the master manufacturing record
(final subpart H) and for preparing the batch record (final subpart I).
As discussed in the 2003 CGMP Proposal (68 FR 12157 at 12203), 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 quantity the recipe
calls for. 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 might not add all of the necessary components in the
appropriate strength or amount, and this could result in a final
product not consistent with the master manufacturing record. Thus, you
must follow a written master manufacturing record in a consistent
manner, regardless of who conducts the operation or when it is
conducted.
However, we agree with the comments that the specific requirements
for what must be in the master manufacturing record make it unnecessary
to require written procedures for preparing the master manufacturing
record. Under final subpart H, the master manufacturing record must
include written instructions, including specifications for each point,
step, or stage in the manufacturing process where control is necessary
to ensure the quality of the dietary supplement and that the dietary
supplement is packaged and labeled as specified in the master
manufacturing record; procedures for sampling, testing, and
examinations; specific actions necessary to perform and verify points,
steps, or stages in the manufacturing process where control is
necessary to ensure the quality of the dietary supplement and that the
dietary supplement is packaged and labeled as specified in the master
manufacturing record; special notations and precautions to be followed;
and corrective action plans for use when a specification is not met.
With all of this detail specified for the written instructions the
master manufacturing record must include, we believe a written
procedure for developing a master manufacturing record can be optional.
Therefore, we do not require you to establish and follow written
procedures for preparing the master manufacturing record.
A batch is prepared by following the written instructions provided
in the master manufacturing record. The master manufacturing record
functions as a written procedure for the production of the batch.
Therefore, we do not require you to establish and follow written
procedures for the batch production record because such practices would
be redundant to the requirements for the master manufacturing record in
final subpart H.
c. Written procedures for records and recordkeeping (final subpart
P). Final subpart P establishes general requirements for making and
keeping records required in other subparts. We did not request comments
on written procedures, nor did we receive any comments that supported
such a requirement. Because we believe that requiring written
procedures to fulfill subpart P requirements would be redundant or
unnecessary, we do not require such written procedures.
d. Written procedures for product recalls. We acknowledge that a
product recall by persons who manufacture, package, label, or hold
dietary supplements must be conducted in a consistent manner,
regardless of who conducts the operation or when it is conducted.
However, the final rule does not establish any requirements for product
recalls. Therefore, we do not require you to establish and follow
written procedures for product recalls. However, we encourage you to
refer to our ``Guidance for Industry: Product Recalls, Industry
Removals and Corrections'' (Ref. 12) (available at http://www.fda.gov/opacom/7alerts.html
).

D. Other Comments on Written Procedures

(Comment 9) One comment stresses the need for flexibility in
requiring written procedures, based on differences between individual
activities and companies. The comment suggests companies should be
required to review and determine the need for written procedures at
each critical step of their operations and be prepared to defend those
determinations as necessary.
(Response) To the extent the comment suggests we do not require any
written procedures specific to a particular function or requirement,
and allow firms to decide when and when not to include them, we
disagree. We believe that written procedures for the specific
operations we have identified should not be optional. We have no
objection if firms decide to establish and follow additional written
procedures, beyond those we require in this final rule. Although we
require written procedures for entire subparts, or specific
requirements within certain subparts, we provide flexibility for firms
to establish those written procedures that will ensure the requirements
are met.
(Comment 10) Some comments stress the importance of written
procedures in enabling FDA to ensure compliance with the dietary
supplement CGMP requirements.
(Response) We believe written procedures will help us to ensure
compliance with these CGMP requirements because they will clearly
communicate the steps the firm must take to satisfy the requirements.
During an inspection, we observe the practices that employees follow.
However, to ensure that a firm is consistently complying with CGMP
requirements, our investigators need access to records that both
describe a firm's processes and procedures and demonstrate whether the
firm has been following them. Under the final rule, we require you to
make and keep records of the written procedures in each applicable
subpart. Such records would be available to us under the requirements
of final subpart P, Records and Recordkeeping.
(Comment 11) Many comments object to FDA's stated reasons for not
requiring written procedures for most activities, including concerns
about cost control and burden reduction. The comments contend that
written procedures

[[Page 34775]]

actually save time and other resources because they greatly facilitate
employee training and ensure that activities are performed consistently
and correctly. Some comments assert most companies already have written
procedures in place, so start-up costs associated with such
requirements would be minimal. One comment notes written procedures
would be among the least costly of all the procedural requirements
proposed by FDA.
(Response) We agree that requiring that operations be conducted
using written procedures can save time and other resources by
facilitating employee training and ensuring operations are performed
consistently and correctly. Because following written procedures can
help ensure uniformity in the process and ensure the quality of the
dietary supplement at every step, periodic end product testing can be
sufficient to determine whether your manufacturing process is
controlled. CGMP is premised upon quality assurance at every step of
the process. It is less costly to establish and follow written
procedures than it would be to test each finished batch for conformance
with specifications. As suggested by these comments, our analysis
(section XXIV of this document) shows that the overall costs are
reduced, in part, because requiring that certain operations be
conducted using written procedures enables us to reduce requirements
for testing at the finished batch stage.
(Comment 12) One comment states training employees on the required
hygienic practices prior to their first day of handling product is
critical to ensuring product safety.
(Response) The requirement to establish and follow written
procedures to fulfill the requirements of subpart B does not establish
any fixed requirement for when an employee must receive such training
relative to when the employee handles product. However, final Sec.
111.12(c) requires that any person engaged in manufacturing, packaging,
labeling, or holding, or in performing any quality control operations,
must have the education, training, or experience to perform the
person's assigned functions. We therefore assume that employees will
have the necessary education, training, or experience for each
operation that they perform before they perform it.
(Comment 13) Some comments make recommendations for what written
procedures should contain, including general parameters that should be
included in all written procedures and specific parameters that should
be included in specific written procedures. The general parameters
include identification of the company; title that reflects the
activities to be performed; identification or control number with a
revision level code; effective date; the number of pages in the
procedure (e.g., by a procedure such as listing page numbers using a
convention such as ``page 1 of 4''); approval date and signature(s);
references to linked or related procedures or forms; definitions of
technical terms and acronyms; list of equipment, materials, and
supplies needed in performing the task; who has the responsibility for
performing each task; when and where a task is to be performed; concise
step-by-step instructions for performing the task; the expected results
from performing the task; what data to collect; and how to analyze,
file, or report the collected data. In the specific case of written
procedures for cleaning equipment and utensils, some comments suggest
the written procedures include descriptions of appropriate cleaning
agents, methods of cleaning, and the intervals and schedules for
cleaning equipment.
(Response) We agree the suggestions provided by these comments are
useful to include in any written procedures. However, to provide the
flexibility necessary to address diverse dietary supplement
manufacturing processes, we are leaving details such as these to the
judgment of the company rather than prescribing them within the final
rule.
(Comment 14) Some comments request the final rule include
requirements for managing changes to written procedures. One comment
states changes to written procedures should be reviewed, justified,
documented, approved, and implemented in a defined manner. The comments
explain that ``Change control procedures'' define what is and what is
not covered by the written procedure and how proposed changes will be
identified or recommended, processed, reviewed, and approved.
(Response) As discussed in final subpart F, the final rule requires
that quality control personnel approve all written procedures. ``All''
written procedures includes revisions to written procedures. As
discussed in this section, the final rule requires you to establish and
follow written procedures for quality control operations. We believe
that procedures for managing changes to written procedures can be
addressed within the written procedures for quality control operations.
(Comment 15) Some comments assert the final rule should not require
written procedures for key operations because the rule should stay
focused on end results and not process.
(Response) We disagree. The essence of good manufacturing practice
that is established by this final rule is a production and process
control system that is designed to ensure the quality of the dietary
supplement.

E. What Other General Comments Did We Receive?

(Comment 16) Some comments say any final rule should not require
written procedures, should not propose a definition of appropriate
tests, and generally should not include requirements for procedures
better left to ``normal business practices.'' The comments cited
Executive Order 12866 and the Small Business Regulatory Enforcement
Flexibility Act (SBREFA). The comment added that there is no such
requirement in the food CGMPs or in the 1997 ANPRM.
(Response) We disagree the final rule violates either Executive
Order 12866 or SBREFA and discuss this in section XXIV of this
document. We address SBREFA's regulatory flexibility issues by
staggering compliance dates so that certain businesses would have 24
and 36 months, respectively, to comply with the final rule. As for the
assertion that food CGMPs do not require written procedures, we discuss
the requirements of food CGMPS in relation to the requirements of these
dietary supplement CGMPs in section V of this document. The comment's
assertion that the 1997 ANPRM did not contain written procedures is
incorrect. The industry draft that we published in the 1997 ANPRM had
multiple written procedures, including written procedures for:
Cleaning and maintaining equipment and utensils used in
the manufacture of products;
The receipt, identification, examination, handling,
sampling, testing, and approval or rejection of raw materials;
Appropriate tests and/or examinations to be conducted to
assure the purity, composition, and quality of the finished product;
The method for reprocessing batches or operational start-
up materials that do not conform to finished goods standards or
specifications;
The control procedures employed for the receipt, storage,
handling, sampling, examination, and/or testing that may be necessary
to assure the identity of labeling and the appropriate identity,
cleanliness, and quality characteristics of packaging materials for
dietary products;

[[Page 34776]]

Ensuring correct labels, labeling, and packaging materials
are issued and used for dietary products; and
Describing the handling of all written and oral complaints
regarding a product.
(62 FR 5700 at 5704 through 5706).
(Comment 17) In the analysis of impacts in the 2003 CGMP Proposal
(68 FR 12157 at 12222), we stated that we had considered imposing fewer
CGMP requirements for the manufacture of vitamins and minerals.
Although this issue arose as a discussion of regulatory options that we
had considered and rejected, we received several comments on this
subject. Some comments state we should not create different CGMP
standards based upon the type of dietary ingredient. These comments
state that one set of appropriately flexible standards would be more
efficient and less confusing to industry than separate standards for
each portion of the industry. Some comments say that different
requirements for vitamins and minerals would cause problems because
most people who use these products take a multivitamin/mineral
preparation as their primary and sole dietary supplement, so the risk
of adverse events arising from adulteration, misidentification, or
misformulation of products would be much higher if vitamins and
minerals were subject to fewer requirements compared to other dietary
supplements. Other comments supported the concept of differing
standards. Some comments assert, in order for the CGMP regulations to
set minimum quality standards for all dietary supplements, we would
have to regulate each facet of the manufacture, packaging, and storage
of a dietary supplement independently of product type. These comments
state reducing the requirements for vitamin and mineral manufacturers
would not allow the development of minimum quality standards across the
entire dietary supplement industry.
(Response) The concept of fewer requirements for vitamins and
minerals was simply one regulatory option we considered as part of the
2003 CGMP Proposal's analysis of impacts (see 68 FR 12157 at 12220
through 12223). We rejected it (id.). We disagree with the comments
that there should be fewer CGMP requirements for vitamins and minerals.
Neither the 2003 CGMP Proposal, nor this final rule, imposes fewer
requirements on vitamin or mineral firms compared to firms that make
other types of dietary supplements.

V. What Legal Authority Comments Did We Receive?

Many comments were submitted from individuals, companies, and trade
groups concerning our legal authority for this rule. Most of the
comments question the scope of the rule based on the language in
section 402(g) of the act (21 U.S.C. 342(g)) stating that ``regulations
shall be modeled after current good manufacturing practice regulations
for food.'' Other comments question our authority for records access.
Some comments assert that certain provisions of the proposed rule are
unconstitutionally vague, and therefore violate the Fifth Amendment. A
few comments disagree with our rationale for why dietary supplements
are different than conventional food and need separate CGMP
requirements. We address these comments immediately below in this
section.

A. Modeled After CGMP for Food

(Comment 18) Some comments support our approach of proposing
requirements that are more comprehensive than the CGMP requirements for
food. One comment states that the current requirements for food CGMP
are less comprehensive than the CGMP requirements in current use by
both the food and dietary supplement industries and the current ``best
practices'' should be incorporated into the dietary supplement CGMP
rule. Several comments state that the requirements for dietary
supplement CGMP do not need to be identical to the requirements in
existing food CGMP regulations, that appropriate manufacturing controls
are needed for dietary ingredients contained in dietary supplements to
protect the public health, that some borrowing of drug CGMP concepts
may be necessary, and that we should balance effective control with
necessary flexibility in the dietary supplement CGMP rule. In addition,
one comment states that the USP manufacturing guidelines, which contain
wording from the drug CGMP requirements, are a model for dietary
supplement CGMP for many in industry.
Several comments express concern about not deviating too
drastically from the requirements in existing food CGMP regulations.
Although several comments recognize that additional CGMP provisions for
dietary supplements, such as those related to identity, purity,
strength, quality, and composition, are needed, the comments say that
we should not regulate dietary supplement manufacturing in the same
manner as drug manufacturing because it would entail overly burdensome
methods for production and process controls. Some comments contend that
some of the proposed rule requirements exceed the drug CGMP
requirements.
Most of the comments assert that the proposed dietary supplement
CGMP requirements are not modeled after the CGMP regulations for food.
The reasons for this assertion vary. Some assert that certain
provisions in the proposed rule were not found in, or differ from, the
provisions in part 110. Examples of proposed requirements that comments
indicate exceeded food CGMP included batch testing, packaging and
labeling, recordkeeping, consumer complaints, and the use of validated
methods. Other comments state that the proposed requirements exceeded
those for food because the proposed rule provided for finished testing
of certain substances when used as dietary supplements, such as garlic
and ginger, whereas no such testing is required under existing food
CGMP regulations when those same substances are used as conventional
food. One comment says the rule was modeled after juice hazard analysis
and critical control point (HACCP) and therefore goes beyond existing
food CGMP regulations.
Some comments assert that the proposed requirements exceed the
existing food CGMP regulations because certain proposed provisions
contained a level of detail that is not in the food or the drug CGMP
regulations, or because elements of a provision in the proposed rule
were similar to a provision in part 210 (21 CFR part 210) (drug CGMP
regulation). Other comments disagree with our rationale that the
proposed rule was designed on the same principles as the existing food
CGMP regulations to address the characteristics and hazards specific to
dietary supplements, or to prevent adulteration in preparing,
packaging, or holding dietary supplements. The comments also disagree
that we may include provisions in the dietary supplement CGMP final
rule that were not found in the food CGMP regulations at the time DSHEA
was enacted.
Several comments state that we exceed our legal authority for the
proposed rule because it used too broad a definition of ``modeled
after.'' Some comments offer their own definitions of ``model;'' others
object to the use of the noun form ``model'' and provide dictionary
definitions of the verb form ``modeled.'' A few comments assert that
the meaning of ``model'' is clear, despite different dictionary
meanings, and that the statute is not ambiguous under Chevron U.S.A.
Inc. v. Natural Resources Defense Council, 467 U.S.

[[Page 34777]]

837 (1984) (``Chevron''). One comment states that, even if the language
is ambiguous and our interpretation merits deference, our
interpretation is too expansive and not based on a permissible
construction of the statute. Another comment states that we did not
explain why our interpretation was consistent with our congressional
mandate.
(Response) We agree with the comments stating that the dietary
supplement CGMP requirements in this final rule need not be identical
to the existing food CGMP regulations and that a system of
manufacturing controls specific to dietary supplements is needed. We do
not agree that we exceeded the scope of our authority under section
402(g) of the act in issuing the proposed requirements for dietary
supplement CGMP or these final requirements. Our interpretation of the
language in section 402(g) of the act, including the ``modeled after''
language, as to what requirements of the act we have authority to
issue, is based on a permissible construction of the statute.
The comments present the following general questions: (1) Whether
the statute gives us authority to promulgate CGMP requirements for
dietary supplements that are not identical to the requirements in
existing CGMP regulations for food and (2) if so, whether the
requirements in this final rule that differ from those in existing CGMP
regulations for food are fairly encompassed within Congress' direction
that the dietary supplement regulations shall be ``modeled after'' food
regulations and, therefore, are based on a permissible construction of
the statute.
Under section 402(g)(1) of the act, a dietary supplement is deemed
to be adulterated if it has ``been prepared, packed, or held under
conditions that do not meet current good manufacturing practice
regulations, including regulations requiring, when necessary,
expiration date labeling, issued by the Secretary under subparagraph
(2).'' Section 402(g)(2) of the act authorizes the Secretary, by
regulation, to ``prescribe good manufacturing practices for dietary
supplements.'' Congress further provided that 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 construing the meaning of section 402(g) of the act, and, in
particular, the language in that section stating that such regulations
shall be ``modeled after current good manufacturing practice
regulations for food,'' we are confronted with two questions. First,
has Congress directly and unambiguously spoken to the precise question
at issue? (``Chevron step one'') (see Chevron, 467 U.S. at 842.) To
find no ambiguity, Congress must have clearly manifested its intention
with respect to the particular issue (see Young v. Community Nutrition
Institute, 476 U.S. 974, 980 (1986)). If Congress has spoken directly
and plainly, we must implement Congress's unambiguously expressed
intent (see Chevron, 467 U.S. at 842-843). Second, if the act is silent
or ambiguous with respect to a particular issue in section 402(g) of
the act, is our interpretation based on a permissible construction of
the statute (``Chevron step two'') (Chevron, 467 U.S. at 843; FDA v.
Brown & Williamson Tobacco Corp., 529 U.S. 120, 132 (2000))? When
Congress leaves a gap for the agency to fill by regulation, the
regulation will pass muster so long as it is not ``arbitrary,
capricious, or manifestly contrary to the statute'' (Chevron, 467 U.S.
at 843-844).
We believe that the language in section 402(g) of the act provides
an express delegation of authority to us to promulgate a regulation to
``prescribe good manufacturing practices for dietary supplements'' so
long as those regulations are ``modeled after the current good
manufacturing practice regulations for food.'' The express language in
section 402(g) of the act contemplates broad, but not unlimited, agency
discretion as to what to include in a dietary supplement CGMP
regulation.
Congress has also spoken to the precise question of whether the
dietary supplement CGMP requirements must be identical to the
requirements in existing food CGMP regulations. If Congress had wanted
dietary supplement CGMP to be identical to food CGMP, it easily could
have required that by statute. Indeed, if Congress had intended for
CGMPs for dietary supplements to be the same as food CGMPs, there would
have been no need for Congress to have addressed the issue at all; as a
type of food, dietary supplements would otherwise be governed by the
food CGMPs. See section (ff) of the act (21 U.S.C. 321(ff)). Instead,
the statute calls for us to issue regulations that are ``modeled
after'' CGMP regulations for food. The plain meaning of a ``model'' or
``modeled after,'' as discussed in the 2003 CGMP Proposal (68 FR 12157
at 12165) and in the comments, relates to a pattern, plan,
representation, or simulation. The use of the term ``modeled after''
makes it clear that the regulations need not be identical to the
original, but instead are contemplated to differ from the original.
Thus, the additional, independent authority to promulgate CGMP
regulations for dietary supplements that Congress provided in section
402(g) of the act, without delineating what requirements such a
regulation could or could not include, left us with considerable
authority to fill in the gaps in ways that recognize the differences
between dietary supplements and other foods that warrant different
manufacturing controls. A contrary interpretation, as some comments
suggested, that the ``modeled after'' language means the requirements
for dietary supplement CGMP must be precisely found in current part
110, or other food CGMP regulations, would so narrowly circumscribe our
discretion as to make it impossible to tailor the regulation to fit the
products it is designed to address. Such an interpretation would lead
to a rule that would ``frustrate the success of the regulation
undertaken by Congress'' because it would not take into consideration
the characteristics, hazards, and manufacturing practices specific to
dietary supplements (American Trucking Ass'ns v. U.S., 344 U.S. 298,
311 (1953)).\4\
---------------------------------------------------------------------------

\4\The Senate Report on DSHEA states that Congress inserted
section 402(g) because it recognized that ``dietary supplements may
require different manufacturing and quality controls'' when compared
to food CGMP (S. Rep. No. 140, 103rd Cong., 2d Sess., at 31 (1994)).
However, the report is not considered legislative history. Congress
issued a Statement of Agreement (140 Cong. Rec. S14801 (Oct. 7,
1994), reprinted in 1994 U.S.C.C.A.N. 3523) that stated ``it is the
intent of the chief sponsors of the bill * * * that no other reports
or statements be considered as legislative history for the bill'').
---------------------------------------------------------------------------

Congress has also spoken to the precise question of which
requirements CGMP ``regulations for food.'' The plain meaning of
``regulations'' is plural (more than one), and the plain meaning of
``food'' is as Congress defined in section 201(f) of the act, including
articles ``used for food or drink.'' At the time DSHEA was enacted,
there were five food CGMP regulations: Those for infant formula (part
106), thermally processed low-acid canned food (part 113), acidified
food (part 114), bottled water (part 129), and general food (part 110,
often referred to as the ``umbrella'' regulations). All of these
regulations appear in Subchapter B of Chapter 1 of Title 21 of the Code
of Federal Regulations, entitled ``Food for Human Consumption.''
Nothing in the language of section 402(g) or elsewhere suggests that
Congress meant to limit the term CGMP ``regulations for food'' to only
the regulation in part 110. Thus, it is

[[Page 34778]]

consistent with our statutory authority for us to look to all of our
food CGMP regulations--including infant formula, low-acid canned foods,
acidified foods, and bottled water, as well as our general food CGMP
regulations--after which to model our dietary supplement CGMP
regulations.
Congress has not spoken to the precise question of what specific
requirements for dietary supplements may be imposed under the ``shall
be modeled after'' language. Given this ambiguity, therefore, under
Chevron step two, we may determine what requirements to include in this
final rule for dietary supplement CGMP, provided that our
interpretation is not arbitrary, capricious, or manifestly contrary to
the statute (Chevron, 467 U.S. at 844).
Accordingly, we considered the types of requirements in the
existing food CGMP regulations and used those as models for the dietary
supplement CGMP requirements. We considered both the objectives and the
means of achieving the objectives in the existing food CGMP
regulations. These CGMP food regulations include those for infant
formula (part 106), general food (``umbrella'' regulations) (part 110),
thermally processed low-acid canned food (part 113), acidified food
(part 114), and bottled water (part 129). Each of these food CGMP
regulations provides objectives and means upon which we modeled the
dietary supplement CGMP regulations. Just as the precise requirements
of the other food CGMP regulations are tailored to the particular
characteristics and hazards of the foods and manufacturing processes
being addressed, the dietary supplement CGMP requirements are also so
tailored.
For example, the infant formula CGMP regulation is intended to
ensure that the ``safety and nutritional potency'' of a formula are
``built into the manufacturing process'' in order to establish a
quality control system to make sure that infant formula products are
properly manufactured (47 FR 17016 at 17017, April 20, 1982). The
specific criteria in the regulations apply in determining whether the
infant formula meets the safety, quality, and nutrient requirements of
the act (Sec. 106.1(a)). The means to achieving the objectives in the
infant formula regulations include, for example, requirements for
ingredient control (through a supplier's guarantee or certification or
through analysis of the ingredient) (Sec. 106.20); preparation of a
master manufacturing order and a system to assure and verify the
addition of each ingredient (Sec. 106.25); either in-process batch
testing (Sec. 106.25(b)) or sampling and testing of each batch to
ensure nutrient requirements are met (Sec. 106.30); and coding to
enable ready identification of lots during their sale and distribution
(Sec. 106.90).
The infant formula CGMP regulation also includes numerous
requirements that manufacturers maintain records, e.g., records on
certain food-packaging materials; records on nutrient premix testing;
certificate and guarantees from premix suppliers for required
nutrients; records of results of testing conducted by suppliers;
records of tests to establish the purity of each nutrient, the weight,
and amounts of nutrients; records to ensure proper nutrient quality
control; records to ensure required nutrient control at the final
product stage; distribution records; records on microbiological quality
and purity of raw materials; and records of audits (Sec. 106.100). The
infant formula CGMP regulation also requires manufacturers to maintain
procedures describing how complaints will be handled, to follow those
procedures, and to investigate when a complaint shows a possible health
hazard (Sec. 106.100(k)). Quality control records must contain enough
information to permit a public health evaluation of any batch of infant
formula (Sec. 106.100(o)). All required records must be available for
authorized inspection (Sec. 106.100(l)).
Many provisions of the dietary supplement CGMP final rule are
similar in objective and means and are ``modeled after'' the provisions
of the infant formula CGMP regulation. For example, like the infant
formula regulation, the dietary supplement CGMP regulation is designed
to establish a quality control system to make sure that dietary
supplements are properly manufactured. The dietary supplement
regulation uses similar means to ensure this goal, such as requirements
for ingredient control (through supplier's certificate of analysis or
testing or examination) (final Sec. 111.75(a)); preparation of a
master manufacturing record (final Sec. 111.205); in-process batch
monitoring (final Sec. 111.75(b)) or batch testing or examination
(final Sec. 111.75(c)); and coding to provide a batch, lot, or control
number (final Sec. 111.260(a)). Like the infant formula CGMP
regulations, the dietary supplement CGMP final rule contains
recordkeeping requirements related to packaging materials; certificates
of analysis from suppliers; results of tests that you conduct, for
example, on ingredients or the finished batch; and results of chemical,
microbiological, or other tests that you conduct as necessary to
prevent the use of contaminated components (final Sec. Sec. 111.95,
111.180(b)(2), 111.260(h), 111.325(b)(2), and 111.365(d)). Also similar
to the infant formula CGMP regulation, the dietary supplement CGMP
final rule requires manufacturers to maintain procedures for handling
complaints (final Sec. Sec. 111.553 and 111.570(b)(1)); to investigate
certain complaints (final Sec. 111.560(a)(2)); and to keep records of
complaints (final Sec. 111.570(b)(2)). Required dietary supplement
records must also, as with infant formula records, be available for
inspection by FDA (final Sec. 111.610(a)).
The ``umbrella'' food CGMP regulation in part 110 details practices
to ensure ``(1) that food is manufactured, processed, packed, and held
under conditions that are sanitary, and (2) that such food is safe,
clean, and wholesome'' (44 FR 33238 at 33239, June 8, 1979).
Promulgated primarily under the adulteration provisions of section
402(a)(3) and (a)(4) of the act, as well as section 361 of the Public
Health Service Act (the PHS Act) (42 U.S.C. 264), the umbrella CGMP
food regulation requires a quality control operation whose main purpose
is ``to provide a systematic procedure for taking all actions necessary
to prevent food from being adulterated within the meaning of the act''
(51 FR 22458 at 22461, June 19, 1986), as well as to prevent the spread
of food-borne communicable diseases (44 FR 33239, June 8, 1979) (see
Sec. 110.5(a)). Part 110 also ``specifies requirements that must be
met to produce safe and wholesome food'' (51 FR 22461). These umbrella
food CGMP requirements not only pertain to food safety, but also are
``concerned with contamination by filth or decomposition which may or
may not raise safety concerns'' (51 FR 22458 at 22462).
The detailed requirements of the umbrella food CGMP regulation
accomplish these objectives through a variety of means. For example,
there are specific personnel provisions requiring employees who may be
sources of microbial contamination to be excluded from certain
operations (Sec. 110.10(a)); persons working in contact with food,
food-contact surfaces, and food-packaging materials to follow hygienic
practices (Sec. 110.10(b)); and that certain personnel have sufficient
education or experience to produce clean and safe food (Sec.
110.10(c)). The umbrella food CGMP regulation also includes detailed
requirements concerning the grounds surrounding a food plant and the
design of buildings and structures to protect against contamination or
to maintain sanitary operations and produce safe food (Sec. 110.20).
Detailed provisions also require that physical facilities be

[[Page 34779]]

maintained in sanitary condition and in sufficient repair to prevent
food from being adulterated (Sec. 110.35). Any water that contacts
food or food-contact surfaces must be ``safe and of adequate sanitary
quality'' (Sec. 110.37(a)); plumbing, sewage, and other disposal, as
well as toilet facilities, must also protect against contamination
(Sec. 110.37(b), (c), and (d)). Similarly, equipment and utensils must
be designed and maintained to preclude adulteration and food contact
surfaces must be maintained to protect food from being contaminated by
any source, including unlawful indirect food additives (Sec.
110.40(a)). All operations for receiving, inspecting, transporting,
segregating, preparing, manufacturing, packaging, and storing food must
be conducted using adequate sanitation principles (Sec. 110.80).
Appropriate quality control operations must be used to ensure that food
is suitable for human consumption and that food-packaging materials are
safe and suitable (Sec. 110.80). Foods must be stored and transported
under conditions to protect against physical, chemical, and microbial
contamination, as well as against deterioration of the food and the
container (Sec. 110.93).
The provisions of the umbrella food CGMP regulation serve as the
model for many dietary supplement CGMP provisions. For example, the
dietary supplement CGMP requirements concerning personnel and microbial
contamination (final Sec. 111.10(a)); hygienic practices (final Sec.
111.10(b)); and education, training, or experience (final Sec. 111.12)
are very similar to provisions in part 110. In addition, the dietary
supplement CGMP requirements concerning the grounds, physical plant
facilities, cleaning materials, pest control, water supply, plumbing,
sewage disposal, bathrooms, and trash disposal (final Sec. Sec. 111.15
and 111.20) closely resemble the analogous part 110 requirements.
Because of the particular hazards associated with low-acid canned
foods and with acidified foods, the CGMP regulations for these foods
contain detailed provisions to ensure safe manufacturing. Specifically,
the CGMP regulations for these foods protect the public health against
microbial contamination from these foods. Part 113 sets out safe
manufacturing, processing, and packaging procedures for low-acid foods
in hermetically sealed containers. The CGMP criteria in this part apply
in determining whether the facilities, methods, practices, and controls
used by commercial processors of such foods are operated ``in a manner
adequate to protect the public health'' (Sec. 113.5). Processors of
low-acid canned foods must have a ``scheduled process'' that is
established by a qualified person and is ``adequate under the
conditions of manufacture for a given product to achieve commercial
sterility'' (Sec. Sec. 113.3 and 113.83). ``Commercial sterility'' of
thermally processed food means a condition achieved by applying heat to
render the food free of certain microorganisms (Sec. 113.3). Part 113
requires that supervisors satisfactorily complete training at a school
approved by FDA (Sec. 113.10).
Part 113 also contains extremely detailed requirements on equipment
and procedures. For example, each vessel used for pressure processing
in steam must be equipped with a mercury thermometer that is tested for
accuracy at least once a year, or more frequently if necessary, to
ensure its accuracy (Sec. 113.40(a)(1)). Critical factors (variation
of which may affect the attainment of commercial sterility) must be
specified in the scheduled process and must be measured and recorded on
processing records frequently enough to ensure that the factors are
within the specified limits (at least every 15 minutes) (Sec. Sec.
113.40(a)(13) and 113.83). Observations and measurements of certain
operating conditions must be made and recorded at intervals of
sufficient frequency to ensure that commercial sterility of the food
product is being achieved (at least every hour) (Sec.
113.40(g)(2)(ii)(c)). There must also be a system to stop packaging
operations (or to segregate products) when the packaging conditions
fall below scheduled processes (Sec. 113.40(g)(2)(ii)(b)). Regular
observations of container closures are required to be made and recorded
(Sec. 113.60). Each container must be coded ``to enable ready
identification of lots during their sale and distribution'' (Sec.
113.60(c)).
Before using raw materials and ingredients susceptible to
microbiological contamination, the low-acid food processor must ensure
that they are ``suitable for use in processing low-acid food'' (Sec.
113.81(a)). Complete records covering all aspects of the establishment
of the scheduled process and of certain confirmation tests must be
maintained permanently (Sec. 113.83). Scheduled processes must be
readily available to any duly authorized FDA employee (Sec.
113.87(a)). Whenever any process is less than the scheduled process or
when critical factors are not in control, the low-acid food must be
reprocessed or set aside for further evaluation as to public health
significance (Sec. 113.89). Unless the evaluation demonstrates that
the product is free of microorganisms of potential public health
significance, the product either must be reprocessed to render it
commercially sterile or destroyed (Sec. 113.89).
All process deviations involving a failure to satisfy the minimum
requirements of the scheduled process must be recorded and kept in a
separate file detailing the deviations and actions taken (Sec.
113.89). Detailed information on processing and production must be
entered on forms (Sec. 113.100(a)). Not later than 1 working day after
the actual process, and before the food is shipped or released for
distribution, a qualified representative of management must review all
processing and production records for completeness and to ensure that
the product was subjected to the scheduled process (Sec. 113.100(b)).
Records to identify the initial distribution of the finished product
must be kept to facilitate segregation of lots that may have become
contaminated or otherwise rendered unfit for their intended use (Sec.
113.100(d)). Records must be maintained at the processing plant for at
least 1 year after the date of manufacturing and at a reasonably
accessible location for another 2 years (Sec. 113.100(e)).
Similarly, the CGMP regulation for acidified food in part 114
requires supervision by personnel trained at an FDA-approved school
(Sec. 114.10); manufacturing in accordance with a scheduled process
established by a qualified person (Sec. Sec. 114.80 and 114.83);
processing sufficient to destroy the vegetative cells of certain
microorganisms (Sec. 114.80(a)(1)); sufficient control, including
frequent testing and recording of results, to ensure that the finished
hydrogen-ion concentration (pH) values are not higher than 4.6 (Sec.
114.80(a)(2)); testing and examinations of containers to ensure that
the food is suitably protected from leakage or contamination (Sec.
114.80(a)(4)); and coding to enable ready identification of lots during
their sale and distribution (Sec. 114.80(b)).
Whenever any acidified food process operation deviates from the
scheduled process or the pH of the finished product exceeds 4.6, the
processor must reprocess it, process it under part 113 requirements, or
set it aside for evaluation as to any potential public health
significance (Sec. 114.89). Unless the evaluation demonstrates that
the food has undergone a process that has rendered it safe, the food
must be fully reprocessed to render it safe or be destroyed (Sec.
114.89).
A record must be made of the procedures used in the public health

[[Page 34780]]

evaluation and the results of the evaluation (Sec. 114.89). Records
must be kept of examinations of raw materials, packaging materials, and
finished products, and of suppliers' guarantees or certifications that
verify compliance with our regulations (Sec. 114.100(a)). Processing
and production records showing adherence to scheduled processes must be
maintained and must have sufficient additional information such as
product code, date, container size, and product, to permit a public
health hazard evaluation of the processes applied to each lot, batch,
or other portion (Sec. 114.100(b)). Departures from scheduled
processes having a possible bearing on public health or the safety of
the food must be recorded and kept in a separate file or log, along
with the action taken to rectify the departure and the product
disposition (Sec. 114.100(c)). Records must be kept identifying
initial distribution of the finished product to facilitate segregation
of lots that may have become contaminated or otherwise unfit for their
intended use. Copies of certain required records must be kept at a
reasonably accessible location for 3 years from the date of manufacture
(Sec. 114.100). The criteria in the part 114 regulation, as well as
those in part 110, apply in determining whether an article of acidified
food is adulterated under section 402(a)(3) of the act in that it has
been manufactured under such conditions that it is unfit for food or
under section 402(a)(4) of the act in that 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 (Sec. 114.5).
Many provisions of parts 113 and 114 also serve as models for
provisions in the dietary supplement final rule. In many instances, the
analogous provision in the dietary supplement final rule allows more
flexibility in the means to achieve the goal. For example, under final
Sec. 111.13 qualified personnel must be assigned to supervise the
manufacturing, packaging, labeling, or holding of dietary supplements.
Although the supervisor must be qualified by education, training, or
experience to supervise, the more restrictive requirement of parts 113
and 114 to attend an FDA-approved school is not included. The
``scheduled process'' for low-acid and acidified food manufacturing,
processing, and packing is analogous to the required ``system of
production and process controls'' that dietary supplement manufacturers
must design and implement (final Sec. Sec. 111.55 and 111.60(a)).
Similarly, the ``critical factors'' required to be specified in the
scheduled process for low-acid and acidified foods are akin to the
``specifications'' that dietary supplement manufacturers must establish
for certain points in the manufacturing process (final Sec. 111.70).
Just as low-acid food processors must establish procedures to ensure
that ingredients are suitable for use, so too must dietary supplement
manufacturers establish component and finished product specifications
(final Sec. 111.70(b) and (e)). Just as containers for acidified food
must ensure suitable protection from contamination, packaging that
comes into contact with dietary supplements must be safe and suitable
for use (final Sec. 111.70(d)). Dietary supplement in-process points,
like the ``critical factors'' for low-acid and acidified food, must be
monitored to detect any deviation or unanticipated occurrence that may
result in adulteration (final Sec. 111.75(b)(2)).
Rejected dietary supplements must also be held under quarantine
(final Sec. Sec. 111.370 and 111.425); dietary supplements which have
been reprocessed, treated, or which have had in-process adjustments
must meet all established product specifications and be approved before
release (final Sec. 111.90(c)). Similar to coding low-acid or
acidified foods, dietary supplements must have assigned batch, lot, or
control numbers (final Sec. 111.415(f)). The design, calibrations, and
cleaning of equipment and utensils must also result in the equipment
and utensils being suitable for their intended uses and not result in
contamination of components or dietary supplements (final Sec.
111.27). Written procedures for the various controls are required (see,
e.g., final Sec. Sec. 111.8, 111.25, and 111.103), and required
written records (see, e.g., final Sec. Sec. 111.14, 111.23, 111.35,
and 111.95) must be kept for 1 year past the shelf life date, if shelf
life dating is used, or 2 years after the date of distribution of the
last associated batch of dietary supplement (final Sec. 111.605). All
required dietary supplement CGMP records must be readily available for
inspection and copying by FDA (final Sec. 111.610(a)).
Finally, the bottled water CGMP regulation was promulgated to
ensure the safety and sanitary quality of these products, which include
all water processed and bottled for human consumption (38 FR 32563,
November 26, 1973). The criteria in part 129, as well as in part 110,
apply in determining whether the facilities, methods, practices, and
controls used to process, bottle, hold, and ship bottled drinking water
conform with good manufacturing practice ``to assure that bottled
drinking water is safe and that it has been processed, bottled, held,
and transported under sanitary conditions'' (Sec. 129.1). Part 129
requires plant construction and design features, such as a separate
bottling room and an enclosed room for washing and sanitizing
containers, to protect against contamination (Sec. 129.20). All plant
equipment and utensils must be suitable for their intended use (Sec.
129.40(a)).
Both the product water supply and the operations water supply must
be of a ``safe, sanitary quality'' in conformance with ``the applicable
laws and regulations of the government agency or agencies having
jurisdiction'' (Sec. 129.35(a)). Samples of source water must be
analyzed at least once a year for chemical contaminants and once every
4 years for radiological contaminants (Sec. 129.35(a)(3)). Source
water from other than a public water system must be sampled and
analyzed for microbiological contaminants at least once a week (id.).
The product water-contact surfaces of all containers and equipment must
be clean and adequately sanitized and protected from contamination
(Sec. 129.37(a) and (b)). Filling, capping, closing, sealing, and
packaging of containers must be done so as to preclude contamination of
the water (Sec. 129.37(d)). All product water contact surfaces must be
nontoxic and in compliance with section 409 of the act (21 U.S.C. 348)
(concerning food additives) (Sec. 129.40(a)(2)).
Numerous production processes and controls for bottled water are
also required. For example, all treatment of product water must be
effective in accomplishing its intended purpose and in accordance with
section 409 of the act (Sec. 129.80(a)). The treatment processes must
be performed with equipment and substances that will not adulterate the
product (Sec. 129.80). Product water samples must be taken before
bottling and analyzed as often as necessary to assure uniformity and
effectiveness of the processes performed by the plant (Sec.
129.80(a)). Cleaning and sanitizing solutions must be sampled and
tested to assure adequate performance (Sec. 129.80(c)).
Each unit package from a batch or segment of continuous production
run must be identified by a production code (Sec. 129.80(e)). The
plant must maintain information on the kind of product, volume, date,
lot code, and distribution of finished product to wholesale and retail
outlets (id.). During the process of filling, capping, or sealing the
containers, performance must be monitored and the filled containers
inspected to assure that they are sound, properly capped or sealed, and
coded

[[Page 34781]]

and labeled (Sec. 129.80(f)). All containers and closures must be
sampled and inspected to ascertain that they are free from
contamination (id.).
To assure that the plant's production of bottled water complies
with applicable standards, laws, and regulations, the plant must
analyze product samples at specified intervals (Sec. 129.80(g)). The
methods used to analyze the samples must be approved by the government
agency with jurisdiction (Sec. 129.80(g)(3)). Records of the date of
sampling, type of product sampled, production code, and results of
analysis must be maintained (Sec. 129.80(g)(3)). All required records
must be maintained at the plant for at least 2 years (Sec. 129.80(h))
and be available for official review by FDA at reasonable times (id.).
Provisions of the bottled water CGMP regulation also serve as a
model for provisions of the dietary supplement CGMP regulation. For
example, water that is used in a manner such that the water may become
a component of a dietary supplement must at a minimum comply with
applicable Federal, State, and local requirements and not contaminate
the dietary supplements (final Sec. Sec. 111.15(e)(2) and 111.365(c)).
Precautions that must be taken to prevent contamination of components
or dietary supplements include performing chemical, microbiological, or
other testing (final Sec. 111.365(d)). Filling, assembling, packaging,
labeling, and related operations must be performed to protect the
dietary supplement against adulteration (final Sec. 111.415).
Equipment and utensils must be suitable for their intended use (final
Sec. 111.27(a)). Safe and adequate cleaning compounds and sanitizing
agents must be used (final Sec. 111.15(c)(1)). Representative samples
of each batch must be examined to ensure that the product meets
established specifications (final Sec. 111.415(g)). Each lot of
packaged and labeled dietary supplement must be assigned a batch, lot,
or control number (final Sec. 111.415(f)).
Moreover, our interpretation of permissible requirements for the
dietary supplement CGMP regulation is also consistent with the use of
the terms ``good manufacturing practice'' and ``current good
manufacturing practice'' in section 402(g) of the act. Although these
terms are not defined in the act, GMP is generally used to refer to
methods used in, and the facilities and controls used for, product
manufacturing and related activities.\5\ The umbrella food CGMP
regulation, for example, defines the ``plant'' covered by the
requirements of that regulation as the facility used for, or in
connection with, ``the manufacturing, packaging, labeling, or holding
of human food'' (Sec. 110.3(k)). As we have described in detail, the
objectives of the existing food CGMP regulations and the precise means
(or requirements) used to achieve the objectives vary depending on the
particular hazards and characteristics of the products and their
manufacturing. For example, the umbrella food CGMP regulation is
specifically designed to ensure that food is manufactured, processed,
packed, and held under sanitary conditions and that the food is safe,
clean, and wholesome. Low-acid and acidified food CGMP requirements
focus on facilities, methods, practices, and controls to protect the
public health against the particular risks of microbial contamination
from these foods. The infant formula CGMP regulation is aimed at
ensuring both the safety and nutritional potency of these special
foods. Infant formula is often the sole item in the diet. An infant
formula that does not meet the requirements for nutritional potency may
cause a hazard to the health of the infant (see 61 FR 36154, July 9,
1996). The bottled water CGMP regulation embodies requirements for
facilities, methods, practices, and controls used in processing,
bottling, holding, and shipping of bottled water to ensure its safety
and sanitary quality.
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\5\Although the act does not define ``current good manufacturing
practice,'' the term is used elsewhere in the statute (see, e.g.,
sections 501(a)(2)(B) (drug CGMP) and 520(f)(1)(A) of the act
(device CGMP) (21 U.S.C. 351(a)(2)(B) and 21 U.S.C. 360j(f)(1)(A),
respectively). Case law supports the agency's view that ``current''
does not mean ``actually prevailing manufacturing practice'' in an
industry and that such a practice need not be accepted by a majority
of manufacturers (National Ass'n of Pharmaceutical Mfr's v.
Department of Health and Human Services, 586 F. Supp. 740, 752
(S.D.N.Y. 1984)). Nevertheless, the requirements of this final rule
embody current practices of many food and dietary supplement
manufacturers, as reflected in the comments supporting the
provisions of the proposed rule.
---------------------------------------------------------------------------

Like the food CGMP regulations after which they are modeled, the
dietary supplement CGMP final rule contains criteria for facilities,
methods, practices, and controls used in manufacturing, packaging,
labeling, or holding dietary supplements to ensure the quality of the
dietary supplement. Quality includes consistently meeting the
established specifications for identity, purity, strength, and
composition of the dietary supplement and limits on contaminants, in
addition to manufacturing the dietary supplement under conditions to
prevent adulteration. As Congress recognized in DSHEA, identity,
purity, strength, and composition are essential characteristics for
dietary supplements (see, e.g., section 403(s)(2) of the act (a dietary
supplement is misbranded if its labeling fails to list the name and
quantity of each dietary ingredient and if it fails to have the
identity and strength or the quality, purity, or compositional
specifications it is represented to meet)). Yet without information
about the identity, purity, strength, or composition, the manufacturer
could not know the final contents of the dietary supplements it
manufactures or whether its processes are reliably and consistently
producing the correct combination and amounts of ingredients in a
dietary supplement. Accordingly, the final rule requires a manufacturer
to establish specifications for the identity, purity, strength, and
composition and for limits on contaminants of the dietary supplements
it manufactures and ensure that such specifications are consistently
met in the finished batch of dietary supplement (Sec. 111.75(e)).
Dietary supplements, like infant formula, are relied upon by consumers
not only to be safe, but also in many instances to provide specific and
important claimed health benefits (see, e.g., section 403(r) of the
act). In the preamble to the 2003 CGMP Proposal, we discussed a number
of examples illustrating adulteration and improper formulation of
dietary supplements caused by manufacturing, packaging, or holding
practices (68 FR 12157 at 12162 and 12163). These dietary supplement
CGMP requirements will help to protect consumers against similar types
of adulteration and against reliance on products that are not properly
formulated.
Generally recognized principles underlying CGMP also support our
interpretation of section 402(g) of the act. Our interpretation of
permissible CGMP regulations is reasonable based on recognized
principles for controlling the quality of manufactured products in
general (Ref. 9). As many comments asserted, if the dietary supplement
CGMP requirements are to be meaningful, they must ensure quality in the
finished product (see, for example, the discussion in section X of this
document of comments regarding the production and process control
system). Controls to ensure quality include planning processes to
determine desired product features or characteristics, a system of
controls to ensure that the desired product will be consistently
produced, and making necessary improvements to the process (section 2.6
of Ref. 9). Manufacturers must plan what they intend to produce,
institute adequate controls to achieve the desired outcome, and ensure
that the controls

[[Page 34782]]

work so that the desired outcome is consistently achieved. If the
outcome is not consistently achieved, corrective actions need to be
implemented in order to reach the desired outcome.
This final rule, like the other food CGMP regulations, embodies the
basic concepts of controlling quality, i.e., planning, control, and
improvement. As discussed earlier in the ``Overview of CGMP'' (section
III.A of this document), we have defined the term ``quality'' for this
dietary supplement CGMP regulation to mean ``that the dietary
supplement consistently meets the established specifications for
identity, purity, strength, and composition and has been manufactured,
packaged, labeled, and held under conditions to prevent adulteration
under section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the Federal
Food, Drug, and Cosmetic Act.'' Identifying the desired characteristics
of identity, purity, strength, and composition of a dietary supplement,
as required in this final rule, is an essential part of the planning
process to manufacture a dietary supplement. Without identifying
specifications for each of these characteristics of a dietary
supplement, it is not possible to control for, and repeatedly and
reliably produce, the desired end product. Similarly, requirements for
batch testing ensure that there is consistency from batch to batch.
Packaging and labeling requirements ensure that suitable packaging is
used and that the label identified in the master manufacturing record
for the product is placed on the finished product. In addition,
requirements related to consumer complaints help to ensure that
manufacturers are made aware of problems related to their manufacturing
processes, including those that may result in illness or injury, so
that they can take corrective actions to prevent any future problems
from occurring. The procedures for production and process control in
this final rule also include as key elements measures to prevent
contamination that could adulterate the product. Requirements to
protect against contamination during the manufacturing, packaging,
labeling, and holding operations help ensure that this aspect of
``quality'' is also achieved for dietary supplements. In sum, this
final rule embodies principles for controlling quality through
requirements designed to ensure both that the dietary supplement meets
its established specifications for identity, purity, strength, and
composition and that it is not adulterated.
The dietary supplement CGMP requirements are also reasonable
because they take into consideration the different product forms in
which these products will be manufactured. Unlike conventional foods,
such as fruit, vegetables, cereals, and dairy products, dietary
supplements will be sold in tablet, capsule, powder, or softgel form.
They may also be sold as a concentrate, metabolite, constituent, or
extract of a vitamin, mineral, herb, botanical, or dietary substance.
Because dietary supplements are often sold in different forms than
conventional foods, different processes and controls are needed to
manufacture dietary supplements than to manufacture conventional foods.
For example, equipment must be able to manufacture dietary supplements
in tablet or softgel form. Therefore, the final rule requires that
controls be established to ensure that the equipment functions in
accordance with its intended use (final Sec. 111.30(e)) and will
consistently manufacture a product in whatever form is desired.
Consistent with basic CGMP principles, ensuring the quality of the
dietary supplement product requires that the manufacturer establish
precisely what it will produce (specifications for its product), how it
will make the product (processes), and which process controls and tests
it will use to ensure reliable, reproducible results. These CGMP
requirements will help to achieve these results.
The dietary supplement CGMP requirements are also reasonable when
viewed in the context of the act as a whole. See Brown & Williamson,
529 U.S. at 133. Our mission is, in part, to protect the public health
by ensuring that foods are safe, wholesome, sanitary, and properly
labeled (section 903(b)(2)(A) of the act) (21 U.S.C. 393(b)(2)(A))).
Section 701(a) of the act (21 U.S.C 371(a)) gives us the authority to
promulgate regulations for the efficient enforcement of the act in
order to ``effectuate a congressional objective expressed elsewhere in
the Act'' (Association of American, Physicians and Surgeons, Inc. v.
FDA, 226 F. Supp. 2d 204 (D.D.C. 2002) (citing Pharm. Mfrs. Ass'n. v.
FDA, 484 F. Supp. 1179, 1183 (D. Del. 1980)). The final rule is
designed to help ensure that dietary supplements consistently are
manufactured to produce the product established by the manufacturer, to
bear the label identified in the master manufacturing record, and to
prevent adulteration. The requirements are written to facilitate
efficient and effective action to enforce their terms when necessary.
Some provisions of the dietary supplement CGMP final rule may be
similar to the existing drug CGMP regulations. However, we have not
modeled these regulations after the drug CGMP regulations. Controls
that relate to certain product forms (e.g., tablets, capsules, powder,
softgel) are required in this final rule based on the specific
characteristics of dietary supplements and the hazards associated with
these forms, not, as some comments imply, based on a desire to emulate
drug CGMP requirements. The act does not state that there may not be
similarities between the dietary supplement CGMP requirements and the
CGMP requirements for drugs or other non-food products. Inasmuch as
food CGMP regulations and other CGMP regulations are all based on CGMP
principles, it is neither surprising nor impermissible that there are
similarities between the dietary supplement CGMP requirements and drug
or device CGMP requirements. Although we do not agree that any of the
CGMP requirements exceed drug GCMP requirements, even if a particular
requirement did, it is not prohibited under the statute. As long as the
CGMP final rule is ``modeled after'' the food CGMP regulations, we have
satisfied the statutory requirements. As noted, our interpretation of
``modeled after'' means that the dietary supplement CGMP final rule
provisions share similar objectives and/or use similar means as the
existing food CGMP regulations. To the extent that there are
similarities to drug CGMP regulations, those similarities are
appropriate and not prohibited by section 402(g) of the act.
Consistent with our role ``to fill in, through interpretation,
matters of detail related to [the statute's] administration,'' Barnhart
v. Walton, 535 U.S. 212, 225 (2002), we applied our scientific
expertise, policy judgment, and experience to promulgate dietary
supplement CGMP requirements that will protect the public health and
effectively implement our statutory authority to prescribe dietary
supplement CGMP. See United States v. Mead, 533 U.S. 218, 227-228
(2001); Nationsbank of North Carolina v. Variable Annuity Life Ins.
Co., 513 U.S. 251, 256-58 (1995); Chevron, 467 U.S. at 844; Forester v.
Consumer Product Safety Com., 559 F.2d 774, 783 (D.C. Cir. 1977).

B. Records Authority

(Comment 19) Some comments state that requirements related to
record keeping and access to such records are necessary to allow our
inspectors to assess the adequacy of a dietary supplement
manufacturer's practices. Additional comments state that access to
records is necessary to ensure that CGMP requirements are followed and
to protect the public health. Several comments identify specific types
of

[[Page 34783]]

records we should require in a final rule, including written
procedures, batch and master manufacturing records, distribution
records, and lot numbers. Another comment states that training records
should be required because the qualifications and training of employees
affects product quality.
Other comments, however, state that the record retention and access
requirements seem to be modeled after drug CGMP and not food CGMP.
Other comments state that, even though records may be necessary to
ensure that CGMP requirements are followed, we do not have authority to
require access to and copying of such records. Some comments assert the
authority to establish regulations for dietary supplement CGMP does not
imply there is authority to inspect records. Several comments state we
cannot rely on section 701 of the act because there is not another
section of the act that authorizes us access to company records for
dietary supplement CGMP and section 701(a) of the act does not itself
give us the authority we need to require records inspection. Another
comment suggests that the absence of an express grant of records
inspection authority means that records inspection is not necessary for
the efficient enforcement of the act.
Some comments assert that we have no record inspection authority
under section 704(a) of the act (21 U.S.C 374(a)). A few comments
suggest that, because records inspection authority was not expressly
granted in DSHEA's statutory language, as it was for OTC drugs and
medical devices, Congress provided no authority for records inspection
for dietary supplement CGMP. The comments state that we have a
longstanding interpretation that section 704 of the act does not give
us access to a food manufacturer's records. Several comments state that
it was sufficient to have voluntary records access, stating that many
companies are willing to provide access to records.
Other comments say that our record inspection authority for dietary
supplement CGMP is limited to that under section 306(a) of the Public
Health Security and Bioterrorism Preparedness and Response Act of 2002
(Bioterrorism Act) (21 U.S.C. 350(c)), i.e., when we have a
``reasonable belief that an article of food is adulterated and presents
a threat of serious adverse health consequences * * *'' Another comment
suggests an alternative standard to that in section 306(a) of the
Bioterrorism Act of a ``reasonable belief that there is a public health
hazard'' for when we may access records.
One comment cites In the Matter of Establishment Inspection of
Medtronic, Inc., 500 F. Supp 536 (D. Minn. 1980), to support its
assertion that we exceeded our statutory inspection authority in the
dietary supplement CGMP record requirements. One comment states that a
warrantless inspection of dietary supplement CGMP records and criminal
consequences that may be imposed under the act for failure to comply
with the act provide a ``powerful argument against expanding the
Agency's inspection authority any further'' and raise ``serious
constitutional concerns.'' Several comments ask us to clarify our
jurisdiction for records inspection requirements or delete proposed
Sec. 111.125(c).
Still other comments seek confirmation that the confidential and
trade secret information obtained by us under the rule would be
protected from disclosure under applicable statutes. Among other
things, the comments cite the Trade Secrets Act, 18 U.S.C. 1905, and
the Freedom of Information Act (FOIA), 5 U.S.C. 552(b)(4). Some
comments express concern that records inspection would violate ``rights
to privacy of corporate manpower'' or would compromise trade secrets.
The comments request the rule specifically reconfirm our obligations
under these laws.
(Response) We disagree with the comments suggesting that we have no
authority to require dietary supplement manufacturers to maintain
records to comply with CGMP under section 402(g) of the act; that the
absence of an express grant of records authority means records are not
needed for the efficient enforcement of the act; and that Congress
meant, by its silence, that we have no authority to issue records
requirements. Clearly, just as Congress is not expected to express
``every single evil sought to be corrected'' in a grant of authority to
promulgate a rule, it can not be expected to articulate every
requirement that is within an agency's delegated authority (American
Trucking Assoc. v. United States, 344 U.S. 298, 309-10 (1953)).
Agencies are expected to bring their expertise to bear on what
requirements are necessary that will not ``directly frustrate the
success of the regulation undertaken by Congress'' (id. at 311). In
this instance, Congress has not expressed any specific intent regarding
recordkeeping for dietary supplements but has directed FDA to use other
food CGMP regulations, which require recordkeeping and FDA access to
records, as models for these regulations. Congress has delegated
substantial and sufficiently specific authority to us to promulgate
recordkeeping and access regulations (Cf. United States v. Storer
Broadcasting, 351 U.S. 192, 202-03 (1956) (upholding a rule that
established limitations on broadcast licensing that were ``not
specifically authorized by statute'')). As stated earlier in this
section, the ``modeled after'' language in section 402(g) of the act is
ambiguous with respect to what specific CGMP requirements we are to
include in this final rule. At the time Congress enacted section 402(g)
of the act there were several food regulations that contained
recordkeeping and record access requirements. We included records
requirements in the food CGMP regulations for infant formula (part
106), low acid food (part 113), acidified food (part 114), and bottled
water (part 129). Accordingly, the directive in section 402(g) of the
act is sufficient authority for our recordkeeping requirements in this
final rule. In addition, our authority to establish records
requirements has been upheld under other provisions of the act, which
lacked explicit recordkeeping authority for FDA, where we have found
records to be necessary (National Confectioners Assoc. v. Califano, 569
F.2d 690, 693-94 (D.C. Cir. 1978) (upholding requirements for source
coding and distribution records based on the statutory scheme as a
whole)).
Moreover, records are an indispensable component of CGMP. The
records required by this final rule provide the foundation for the
planning, control, and improvement processes that constitute a quality
control system. Implementation of these processes in a manufacturing
operation serves as the backbone to CGMP. The records will show what is
to be manufactured; what was, in fact, manufactured; and whether the
controls that the manufacturer put in place to control the identity,
purity, strength, and composition and limits on contaminants and to
prevent adulteration were effective. Further, records will show whether
and what deviations from control processes occurred, facilitate
evaluation and corrective action concerning these deviations
(including, where necessary, whether associated batches of product
should be recalled from the marketplace), and enable a manufacturer to
assure that the corrective action was effective. Written procedures
also will help ensure that personnel follow hygienic practices; permit
evaluation of whether equipment, including software that may run the
equipment, performs as it is intended; and help ensure that the

[[Page 34784]]

equipment is properly maintained and adequately cleaned.
The CGMP final rule establishes the parameters for the production
and process control system in which dietary supplements are to be
manufactured. The dietary supplement manufacturer establishes the
identity, strength, purity, and composition of the supplement it
manufactures (final Sec. 111.70); determines whether the established
specifications are met (final Sec. 111,73); uses the tests it needs to
ensure that those characteristics are consistently met (final
Sec. Sec. 111.75 and 111.315); and identifies the steps necessary to
ensure that any necessary tests or examinations are completed,
reviewed, and recorded in a timely fashion before the dietary
supplement is released for distribution to the public (final Sec. Sec.
111.110 and 111.325(b)(2)). The CGMP final rule also requires that the
manufacturer establish written procedures for its quality control
operations to ensure the personnel performing this function provide
proper review and oversight of the production and process control
system, have the knowledge and experience to identify and anticipate
possible problems in the manufacturing of the dietary supplement, and
ensure corrective measures are taken promptly when problems occur
(final Sec. Sec. 111.103 through 111.140). The final rule also
requires that the manufacturer establish the ``master recipe(s)'' for
the dietary supplement(s) it manufactures so that such recipe(s) can be
followed for each batch produced (final Sec. Sec. 111.205 through
111.210). In sum, manufacturers cannot operate without records because
critical elements in a manufacturing process are entirely dependent on
information written or captured in the form of a record.\6\ Such
records are also necessary to protect consumers by enabling
manufacturers to identify and recall problematic products as necessary
and make necessary corrections to deviations in their processes.
---------------------------------------------------------------------------

\6\It is also worth noting that standard references used in many
industries establish clear expectations for documentation and
recordkeeping practices for assuring quality control in
manufacturing operations (Refs. 9 and 13).
---------------------------------------------------------------------------

The authority granted us under sections 402(g) and 701(a) of the
act not only includes the authority to establish record requirements,
but also includes access to such records. Without such authority, the
dietary supplement CGMP requirements are, practically speaking, not
enforceable. Under section 402(g)(1) of the act, the failure to meet
any CGMP requirements, including the failure to have a record that is
required by this final rule, renders a dietary supplement so
manufactured to be adulterated as a matter of law. The introduction or
delivery for introduction into interstate commerce of an adulterated
dietary supplement is a prohibited act under section 301(a) of the act
(21 U.S.C. 331(a)), and acts done to an ingredient in a dietary
supplement, or to a dietary supplement, while held for sale after
shipment in interstate commerce that result in the ingredient or
dietary supplement being adulterated violates section 301(k) of the act
(21 U.S.C. 331(k)). Thus, in order for us to determine whether the
dietary supplement product is adulterated and whether a manufacturer
has committed a prohibited act, we must have access to the
manufacturer's records that we are requiring to be kept under section
402(g) of the act.
In light of the foregoing, without access to such records, we would
not know whether a manufacturer was complying with the procedures and
processes required in this final rule. For example, our investigator
must have access to the test results for the identity of a dietary
ingredient to determine whether such ingredient meets the
manufacturer's specification for identity. The investigator needs to
understand, by reviewing a record, what the software that runs a
production operation is set up to do and whether it performs those
functions to achieve the desired product characteristics. Observation
of these processes alone, by an investigator, would not allow that
investigator to evaluate compliance with this final rule. Moreover,
records often cannot be thoroughly evaluated by the investigator on
site. In such cases, records must be readily available to food experts
at the Center for Food Safety and Applied Nutrition (CFSAN) and agency
consultants. We must have accurate, reliable, and objective data about
the manufacturing specifications to be able to achieve an enforceable
rule.
We also disagree with comments stating our records inspection
authority is limited to that provided by section 306(a) of the
Bioterrorism Act. There is no basis to conclude that Congress intended
to limit our authority to inspect records, to enforce section 402(g) of
the act, to the records inspection authority under the Bioterrorism
Act. The Bioterrorism Act, enacted almost 8 years after section 402(g),
to address credible threats of serious adverse health consequences or
death to humans and animals, required recordkeeping to identify the
immediate previous sources and the immediate subsequent recipients of
food (21 U.S.C. 350c).
There is nothing in the Bioterrorism Act that reflects any
Congressional intent to modify section 402(g) of the act. In fact,
section 414(d)(1) of the act (21 U.S.C. 350c(d)(1)), added by section
306(a) of the Bioterrorism Act, shows a contrary intent. Section
414(d)(1) provides that ``This section shall not be construed--(1) to
limit the authority of the Secretary to inspect records or to require
establishment and maintenance of records under any other provision of
this Act.'' Moreover, Congress, in the legislative history to the
Bioterrorism Act, supported our general approach of requiring
recordkeeping pursuant to authority in section 701(a) of the act in
combination with other provisions.\7\ We are not relying on section 704
of the act for its underlying authority to require recordkeeping and
records access in this final rule. Those comments asserting that we do
not have such authority and the underlying references, for example, to
past hearings on records inspection authority under section 704 of the
act, are not controlling with regard to the action we are taking under
sections 402(g) and 701(a) of the act. When there are other bases for
jurisdiction and tools to protect the public interest, we may use what
``will be the most effective in advancing the Congressional objective''
(U.S. v. Midwest Video Corp., 406 U.S. 649, 656 (1972)).
---------------------------------------------------------------------------

\7\In discussing section 306 of the Bioterrorism Act
(Maintenance and Inspection of Records for Foods), Congress stated,
``The managers did not adopt a Senate proposal to authorize the
Secretary to require the maintenance and retention of other records
for inspection relating to food safety, because the Secretary has
authority under section 701(a) of the [act] to issue regulations for
the `efficient enforcement of this Act' and this authority, in
combination with other provisions (such as section 402 [of the
act]), gives the Secretary the authority to require appropriate
record keeping in food safety regulations.'' (H.R. Conf. Rep. No.
107-481, at 135 (2002), (Ref. 14)).
---------------------------------------------------------------------------

Some comments stated that our access to dietary supplement records
is not consistent with constitutional jurisprudence. We disagree. The
comment which expressed concern about ``constitutional issues'' in the
context of an FDA inspection of records during a warrantless FDA
inspection expressed concern about the criminal liability that could be
imposed on a manufacturer under the act (citing United States v.
Dotterweich, 320 U.S. 277 (1944) and United States v. Park, 421 U.S.
658 (1975)). To the extent that the comment asserts that the records
access established in this final rule constitutes an improper search
and seizure under the Fourth Amendment, we disagree.
The dietary supplement industry, as the food industry as a whole,
is a

[[Page 34785]]

pervasively regulated industry that is subject to warrantless
inspections (see, e.g., United States v. Biswell, 406 U.S. 311, 315
(1972) (``In the context of a regulatory inspection system of business
premises * * * the legality of the search depends not on consent but on
the authority of a valid statute.''); United States v. New England
Grocers Supply Co., 488 F. Supp. 230, 238 (D. Mass. 1980) (holding that
a warrantless inspection under 21 U.S.C. 374 is ``fully consistent with
the Fourth Amendment''); United States v. Acri Wholesale Grocery Co.,
409 F. Supp. 529, 533 (S.D. Iowa 1976) (holding that a warrantless
inspection, which includes photographic activities, conducted under 21
U.S.C. 374 does not violate the Fourth Amendment); United States v.
Business Builders, Inc., 354 F. Supp. 141, 143 (N.D. Okla. 1973) (``the
statute takes the place of a valid search warrant''); United States v.
Del Campo Baking Mfg. Co., 345 F. Supp. 1371 (D. Del 1972) (finding
warrantless inspection of food establishment lawful under 21 U.S.C.
374)).
As explained earlier in this section, we have ample authority,
under sections 402(g) and 701(a) of the act, to require that certain
records be kept and accessible to us upon inspection. Records access is
imperative to the efficient enforcement of the dietary supplement CGMP
final rule, and we are not prohibited from requiring access to these
records under sections 402(g) and 701(a) of the act (See Permian Basin
Area Rate Cases, 390 U.S. 747, 780 (1968) (``in the absence of
compelling evidence that such was Congress' intention * * * [the court
should not] prohibit administrative action imperative for the
achievement of an agency's ultimate purposes.'')).
We also disagree with the comment suggesting that voluntary records
access is sufficient. In our experience, many manufacturers are not
willing, as the comments suggest, to provide records voluntarily to us
(Ref. 15). Moreover, it is often the case that the most uncooperative
manufacturers are the very ones whose records and processes are
deficient. Without mandatory requirements for agency access to records
required by the final rule, we could not enforce and there would be
minimal incentives for manufacturers to comply with the rule, which
would frustrate Congressional intent in enacting section 402(g) of the
act.
We also disagree with the comment that cited In the Matter of
Establishment Inspection of Medtronic, Inc., 500 F. Supp. 536 (D. Minn.
1980), to suggest that our proposed recordkeeping requirements exceed
our statutory inspection authority. As already discussed, we are not
relying on section 704 of the act for our authority to require access
to dietary supplement CGMP records. Thus, to the extent the comment
cited to Medtronic as an example of the statutory authority for
inspection of device records under section 704 of the act, Medtronic is
not pertinent to our authority for records access in this final rule.
Finally, we disagree that the records access in this final rule
will violate any protection a manufacturer has with respect to
protection of confidential commercial or financial information or trade
secrets. Trade secrets and commercial or financial information that is
privileged or confidential are protected from disclosure under FOIA and
other laws (see, e.g., 21 U.S.C. 331(j), 18 U.S.C. 1905). Further, our
FOIA regulations set forth the specific procedures for assuring such
protection.
It was not clear from the comments what was meant by ``rights to
privacy of corporate manpower.'' We note that Sec. Sec. 20.63 and
20.64 contain provisions for the protection of personal privacy.

C. Public Health Service Act Authority

(Comment 20) One comment acknowledges that we have authority under
the PHS Act to regulate intrastate activities that may cause the spread
of communicable diseases. The comment states that, in any situation in
which we need to exercise our authority over any disease-causing
substance within the State where a component or dietary supplement is
manufactured, packed, or held, we can and should exercise our authority
under the PHS Act. However, the comment asserts that nothing in the
preamble clearly states whether we believe that the final rule will be,
in its entirety, binding on manufacturers, packers, and holders of
dietary supplements who are engaged solely in intrastate commerce, and
that we have not requested comment on this specific issue. The comment
requests that we clearly state that the final rule applies only to
interstate commerce, except for activities that may spread communicable
diseases.
(Response) We address each of these issues in turn.
1. The Communicable Disease Risk Posed by Dietary Supplements
There are communicable disease risks related to the manufacture of
dietary supplements that are appropriately addressed not only under the
act, but, as the comment acknowledges, also under the PHS Act.
Microorganisms, including Salmonella enterica (Salmonella),
Campylobacter jejuni, and enterohemorrhagic Escherichia coli 0157:H7
(EHEC), are well-known causes of communicable diseases, and may be
present in dietary supplements and their components. There are a number
of microorganisms that cause communicable diseases and that may be
found in components or dietary supplements. These microorganisms cause
serious effects and symptoms. For example, Salmonella causes
salmonellosis, which affects the gastrointestinal (GI) tract and is
characterized by diarrhea, fever, abdominal cramps, headache, nausea,
and vomiting (Ref. 16). In a small portion of healthy people (1 to 4
percent), infection spreads from the GI tract into the blood stream,
which can be life-threatening. Persons with immune compromising
conditions (such as cancer, Acquired Immunodeficiency Syndrome (AIDS),
autoimmune disorders) are at greater risk of blood stream infection
(Ref. 16).
Campylobacteriosis, often due to infection with Campylobacter
jejuni, is characterized by diarrhea, fever, and abdominal cramps,
which can be severe (Ref. 17). These symptoms frequently relapse, and
the disease may become chronic in immune compromised persons. People
with campylobacteriosis are also at increased risk of developing
certain post-infectious complications, which will prolong their
recovery.
EHEC may cause infections with a very low infectious dose (as low
as 2 to 45 organisms), and may result in non-bloody and bloody
diarrhea, hemolytic-uremic syndrome (a cause of red blood cell
destruction, damage of blood vessel walls, and, in severe cases, kidney
failure (especially in young children)), thrombotic thrombocytopenic
purpura (i.e., a blood disorder characterized by low platelets, low red
blood cell count, abnormalities in kidney function, and neurological
abnormalities (especially in adults)), and death (Ref. 18).
Animal tissues (e.g., organs from livestock), as well as
botanicals, used as components in dietary supplements may contain EHEC,
Salmonella, and Campylobacter jejuni. In addition, because the same
microorganisms are also present in the environment, they may
contaminate components during manufacturing activities. Moreover,
people who harbor those pathogens could transmit them to components and
dietary supplements during processing. Therefore, components and
dietary supplements, as potential sources of communicable diseases, may
be regulated under the PHS Act.
For these microorganisms (e.g., EHEC, Salmonella, and Campylobacter
jejuni)

[[Page 34786]]

humans carry and transmit infections through their feces or by direct
contact with other persons. For other microorganisms, domestic and wild
animals serve as the reservoir, and humans become infected when
contaminated tissues of infected animals are used in dietary
supplements. For both categories of microorganisms, dietary supplements
can also become contaminated indirectly by human and animal fecal
contamination of water or through the production or processing
environment.
Dietary supplements may contain a variety of components derived
from domestic and wild animals, such as powders prepared from whole or
partial gecko, deer antler velvet, and organs, such as cow liver and
brain, pork stomach, or sheep spleen from common domestic livestock.
Each of these tissues may be contaminated with microorganisms such as
Salmonella, Campylobacter jejuni, and EHEC. Even clinically normal
animals obtained from safe sources may harbor these communicable
pathogens and result in contaminated products (Ref. 19). (Information
on these animals and potential pathogens can be accessed at http://www.fsis.usda.gov/Science/Microbiology/index.asp
). Dietary supplements

also may contain crustacean or molluscan shellfish or components
prepared from them, such as glucosamine from shrimp exoskeletons and
oyster extract, that may be contaminated with Vibrio species, including
V. parahaemolyticus. Vibrio species are natural inhabitants of
shellfish harvest waters, and shellfish are commonly naturally
contaminated, especially during times of the year when harvest waters
are warm (Refs. 20 through 23). V. parahaemolyticus most often causes
gastroenteritis characterized by diarrhea, abdominal cramps, nausea,
vomiting, and fever (Ref. 24).
Dietary supplements may also contain botanicals (plants) that may
harbor microorganisms, including organisms from animal feces
(Salmonella and Shigella spp., Escherichia coli), and organisms arising
from handling (Staphylococcus aureus), harvesting, processing, and
transportation.
Components contaminated with microorganisms must be treated to
prevent the finished dietary supplements from being contaminated. The
processes used to manufacture dietary supplements do not, by
themselves, always eliminate the microorganisms. Studies show, for
example, that microorganisms, such as EHEC and Salmonella, can even
survive the tablet production process and thereby expose consumers
(Ref. 25).
The industry is aware of the dangers of using components
contaminated with Salmonella and other microorganisms. For example, in
2001, a component manufacturer recalled 2,400 pounds of pepsin
contaminated with Salmonella. As a result, a number of dietary
supplement manufacturers issued recalls for their dietary supplements
that contained the pepsin. In the press releases accompanying the
recalls, the dietary supplement manufacturers warned consumers of the
possible dangers of Salmonella contamination, and encouraged consumers
to either destroy or return the supplements (Ref. 26).
Therefore, because of the communicable disease concerns associated
with dietary supplements, we are asserting legal authority under the
PHS Act in support of the final rule. As discussed in the following
section of this document, our authority under the PHS Act is not
limited to interstate activities. It also covers intrastate activities.
2. Activities For Which We Are Asserting Legal Authority Under the PHS
Act
There are many opportunities for components and dietary supplements
to become contaminated with microorganisms that spread communicable
diseases. The final rule requires firms to take all the necessary
precautions during the manufacture of a dietary supplement to prevent
such contamination.
These precautions, for example, include: Performing manufacturing
operations under conditions and controls that protect against potential
microorganism growth; washing or cleaning components that contain soil
or other contaminants; performing microbiological testing, as
necessary, to prevent the use of contaminated components;
sterilization, pasteurization, freezing, refrigeration, and controlling
pH, humidity, and water activity (aw), or using other
effective means to remove, destroy, or prevent the growth of
microorganisms and decomposition; and holding components and dietary
supplements that can support the growth of infectious microorganisms of
public health significance in a manner that prevents them from becoming
adulterated.
Failure to properly clean components, or take any other appropriate
steps, such as those listed in the previous paragraph, could lead to
pathogen growth and the spread of communicable diseases. If, for
example, a dietary supplement manufacturer purchased an animal-derived
ingredient that harbored Salmonella enterica, but failed to take the
steps necessary to inactivate the pathogen, the consumption of the
dietary supplement could lead to the spread of salmonellosis.
The final rule also requires firms to take measures to exclude from
certain operations any sick persons who might contaminate material,
including components, dietary supplements, and contact surfaces used to
manufacture, package, label, or hold a dietary supplement.

D. The Interstate Commerce Nexus for the Final Rule

1. The PHS Act
(Comment 21) Several comments assert that, although the PHS Act may
extend to some intrastate activities, its reach is very limited. The
comments appear to conclude that the reach of the PHS Act and the act
extends only to situations in which the finished dietary supplement is
shipped in interstate commerce.
(Response) We do not agree that this view is correct. The PHS Act
extends to intrastate commerce. Under section 361 of the PHS Act (42
U.S.C. 264), we may ``make and enforce such regulations as in [our]
judgment are necessary to prevent the introduction, transmission, or
spread of communicable diseases from foreign countries into the States
or possessions, or from one State or possession into any other State or
possession.''
In Louisiana v. Mathews, 427 F. Supp. 174, 176 (E.D. La. 1977), the
court upheld FDA's regulation that banned the sale of small turtles to
prevent the spread of disease caused by turtles harboring Salmonella
and Arizona microorganisms. The ban covered both interstate and
intrastate sales. The court held that the intrastate ban is not only
authorized by the law, but, under modern conditions of transportation
and commerce ``is clearly reasonable to prevent the interstate spread
of disease'' (id.).
We are authorized under the PHS Act to regulate conduct that occurs
within a State to the extent necessary to prevent the interstate spread
of communicable diseases. Such is the present case with respect to the
provisions of the dietary supplement CGMP final rule for which section
361 of the PHS Act provides authority.
2. The Act
The act extends to the sale of a dietary supplement that was
manufactured and

[[Page 34787]]

distributed entirely in one State, if the supplement contains any
ingredient or uses any component that came from outside of that State.
Such a dietary supplement is subject to section 301(k) of the act,
which prohibits ``[t]he alteration, mutilation, destruction,
obliteration, or removal of the whole or any part of the labeling of,
or the doing of any other act with respect to, a food, drug, device, or
cosmetic, if such act is done while such article is held for sale
(whether or not the first sale) after shipment in interstate commerce
and results in such article being adulterated or misbranded.''
(emphasis added). See also 21 U.S.C. 321(b)(3) (defining food to
include articles used as components of food).
The interstate commerce prerequisite under section 301(k) or
section 304(a) (21 U.S.C. 334(a)) of the act is established when one or
more components used in the manufacture of the product have crossed
State lines. This principle is known as ``component jurisdiction''
(See, e.g., Baker v. United States, 932 F.2d 813, 814-15 (9th Cir.
1991); United States v. Article of Food * * * Coco Rico, Inc., 752 F.2d
11, 14 (1st Cir. 1985); United States v. Dianovin Pharmaceuticals,
Inc., 475 F.2d 100, 103 (1st Cir.), cert. denied, 414 U.S. 830 (1973)
(``appellants' use of components shipped in interstate commerce to make
vitamin K for injection brought their activities within Sec.
331(k)''); United States v. Cassaro, Inc., 443 F.2d 153, 155-56 (1st
Cir. 1971); United Statesv. Detroit Vital Foods, Inc., 330 F.2d 78, 81-
82 (6th Cir.), cert. denied, 379 U.S. 832 (1964); United States v.
Allbrook Freezing & Cold Storage, Inc., 194 F.2d 937, 939 (5th Cir.
1952); United States v. Varela-Cruz, 66 F.Supp.2d 274, 277-281 (D. P.R.
1999)).
Nor does it matter that the interstate product component comprises
only a minute part of the article, United States v. Miami Serpentarium
Laboratories, [1981--1982 Transfer Binder] Food Drug Cosm. L.Rep. (CCH)
paragraph 38,164 at 38,930 (S.D. Fla. 1982); United States v. 14 Cases
* * * Naremco, 374 F.Supp. 922, 925 (W.D. Mo. 1974), or if the
interstate ingredient combines with others to form a different product.
Detroit Vital Foods, 330 F.2d at 81; United States v. 40 Cases * * *
Pinocchio Brand * * * Oil, 289 F.2d 343, 346 (2d Cir.), cert. denied,
368 U.S. 831 (1961).
Finally, we note that section 709 of the act creates a presumption
of interstate commerce (see 21 U.S.C. 379a (``In any action to enforce
the requirements of this Act respecting a device, food, drug, or
cosmetic the connection with interstate commerce required for
jurisdiction in such action shall be presumed to exist.'')).
In conclusion, the final rule covers not only finished products
that have moved in interstate commerce but also products made from
ingredients or components that have moved in interstate commerce. This
is true regardless of the amount of the ingredient or component in the
product and regardless of whether the finished dietary supplement has
itself moved in interstate commerce. The final rule also covers
products, components, and ingredients that may contribute to the spread
of communicable disease, regardless of whether the component,
ingredient, or product has itself moved in interstate commerce.
3. Commerce Clause
(Comment 22) One comment states that we must be ``mindful of the
limits'' imposed on the regulation of intrastate commerce by the
Supreme Court in United States v. Lopez, 514 U.S. 549 (1995). The
comment asserts that we may only regulate intrastate activity that has
a ``substantial effect'' on interstate commerce and activity that
``exerts a substantial economic effect on interstate commerce.''
(Response) The final rule is consistent with the Lopez decision.
Among the cases cited by the Court in Lopez as support for its decision
is Wickard v. Filburn, 317 U.S. 111 (1942), which involved the
production and consumption of homegrown wheat. In that case, the Court
explained: ``although Filburn's own contribution to the demand for
wheat may have been trivial by itself, that was not enough to remove
him from the scope of federal regulation where, as here, his
contribution, taken together with that of many others similarly
situated, is far from trivial'' (Lopez, 514 U.S. at 556). The same is
true for dietary supplement manufacturers. Therefore, the requirements
of the final rule are consistent with the Commerce Clause of the
Constitution.

E. Fifth Amendment

(Comment 23) Several comments allege a number of the sections of
the proposed regulation are unconstitutionally vague and violate the
Administrative Procedure Act (APA) because the rule would be ``contrary
to constitutional right, power, privilege, or immunity.'' The comments
express concern that if such terms are not defined or deleted, there
would be no fair notice on what conduct is prohibited and would result
in ``unbridled discretion'' in how the rule will be enforced. The
comments focus on provisions containing words such as ``adequate,''
``qualified,'' ``readily accessible,'' ``convenient,'' ``suitable,''
``appropriate,'' and ``necessary.'' For example, one comment notes that
proposed Sec. 111.15(e) would require physical plant plumbing to be of
an adequate size and design and to be adequately installed and
maintained. The comment objects to the section on the ground that
``what constitutes `adequate' in those contexts is left undefined.''
(Response) We disagree these terms are vague or that the identified
terms should be deleted from the final rule. The qualifying terms
objected to in the comments have been in use since the umbrella food
CGMP rule (part 110) was first promulgated in 1969. For example, this
regulation included requirements that: ``[p]lant buildings and
structures shall be suitable in size;'' there must be ``sufficient
space'' for equipment and storage materials; there must be ``adequate
lighting;'' and protection against pests must be provided ``where
necessary'' (see 34 FR 6977 at 6978, April 26, 1969). The court in
National Association of Pharmaceutical Manufacturers. v. Department of
Health & Human Services, 586 F.Supp. 704 (S.D.N.Y 1986), addressed the
very question of whether terms such as ``adequate,'' ``appropriate,''
``proper,'' ``sufficient,'' and ``suitable,'' in the drug CGMP
regulation were vague. The court found that the drug CGMP regulation
containing such terms was ``sufficiently definite to give notice of the
required conduct to one who would avoid [their] penalties, and to guide
the judge in [their] application * * *'' (Id. at 753). The court so
held, in part, in light of the fact that the drug CGMP statute was
upheld against a constitutional vagueness attack in United States v.
Bel-Mar Laboratories, Inc., 284 F. Supp. 875, 883 (E.D.N.Y. 1968)
(``the phrase `current good manufacturing practice' is not strange to
those in the trade to whom the subject section is directed.'').
Furthermore, the use of such ``ordinary terms to express ideas which
find adequate interpretation in common usage and understanding'' are
not the types of terms that have been held to be unconstitutionally
vague (Boyce Motor Lines v. United States, 342 U.S. 337, 342 (1952)).
Some of these very terms have been in use for over 30 years in food
CGMP regulations.
No comments were submitted objecting to the use of such terms, when
the umbrella food CGMP rule was revised in 1986 (see 51 FR 22458, June
19, 1986). Also, when we began work on the dietary supplement CGMP
rule, we

[[Page 34788]]

received and published for comment an industry draft of a CGMP
regulation for dietary supplements. The industry draft used many of the
same terms. For example, it provides in part: ``Plumbing shall be of
adequate size and design and adequately installed and maintained'' (62
FR 5700 at 5703, February 6, 1997). Thus, there has been sufficient
common usage of these terms in the food industry and, in particular,
the dietary supplement industry to enable manufacturers, and those who
enforce the requirements, to comprehend and apply such terms ``with a
reasonable degree of certainty'' to their particular operations (Boyce
Motor Lines v. United States, 342 U.S. at 340 (``[F]ew words possess
the precision of mathematical symbols, most statutes must deal with
untold and unforeseen variations in factual situations, and the
practical necessities of discharging the business of government
inevitably limit the specificity with which legislators can spell out
prohibitions [and therefore] no more than a reasonable degree of
certainty can be demanded.'')). The same reasoning applies here. It
addresses ``untold and unforeseen variations in factual situations''
and, as such, ``no more than a reasonable degree of certainty can be
demanded.''
Agencies are permitted to, and indeed must, use such qualifying
terms to address the variety of conditions that exist at different
companies. We do not need to, nor could we, predict with mathematical
precision how many inches or feet, for example, would be ``adequate
space'' to allow for cleaning a particular piece of equipment that
could be applied to every size of facility and every operation (id.).
Moreover, defining such terms too precisely would unduly restrict the
application of the regulation to a very narrow, limited set of
circumstances and not provide industry with the needed flexibility to
address the number and variety of types of manufacturing operations
that Congress intended for this rule to cover (see Freeman United Coal
Mining Company v. Federal Mine Safety and Health Review Commission, 108
F.3d 358, 363 (D.C. Cir. 1997) (citations omitted) (upholding a
regulation that required equipment to be ``maintained in good repair,''
the court rejected the vagueness challenge: ``specific regulations
cannot begin to cover all of the infinite variety of [conditions at
firms and that] * * * [b]y requiring regulations to be too specific
[courts] would be opening up large loopholes allowing conduct which
should be regulated to escape regulation.''); United States v. Bel-Mar
Laboratories, Inc., 284 F. Supp. at 883 (rejecting a vagueness
challenge to the CGMP requirements for drugs, noting that ``[a]s a
matter of fact, there are responsible segments of opinion within the
industry itself which oppose a greater degree of specificity in this
area.'').
Finally, it is important to understand that rules are not
unconstitutionally vague simply because they require interpretation by
regulated persons. For example, courts have held that the term
``insanitary conditions'' in the act is not unconstitutionally vague
(See Golden Grain Macaroni Co. v. United States, 209 F.2d 166, 168 (9th
Cir. 1953) (citing Boyce Motor Lines, supra); Berger v. United States,
200 F.2d 818 (8th Cir. 1952)). In Berger, the court rejected the claim
that the term ``insanitary condition'' is unconstitutionally vague on
the ground that it does not specify the ``degree of insanitation''
required for a violation (id. at 822). A law may require a person to
make ``estimates of the degree of dirtiness and lack of sanitation''
which may result in a violation (id., see alsoBoyce Motor Lines v.
United States, 342 U.S. at 340 (It is not ``unfair to require that one
who deliberately goes close to an area of proscribed conduct shall take
the risk that he may cross the line'')). There are sufficient
protections under the act to overcome any concerns related to how it
will be criminally enforced. We disagree that such terms will lead to
``unbridled discretion'' on how the rule is enforced.
In short, we find that the rule is not unconstitutionally vague,
and does not violate section 706(2)(B) of the APA (5 U.S.C. 706(2)(B)).

F. Miscellaneous

(Comment 24) One comment states that the proposed rule violates
section 402(f)(1)(A)(i) and (f)(1)(A)(ii) of the act (21 U.S.C. 342
(f)(1)(A)(i) and (f)(1)(A)(ii)), which deems a dietary supplement
adulterated if it contains a dietary ingredient that presents an
unreasonable risk of illness or injury under conditions of use in
labeling or ordinary conditions of use, if none are suggested or
recommended in labeling. Under section 402(f) of the act, the
Government bears the burden of proof to show that a dietary supplement
is adulterated. The comment states that the proposed rule reversed the
presumption under section 402(f) of the act, and would revise the rule
to require us to first show a violation under section 402(f) of the act
before we could take any enforcement action under section 402(g).
Another comment states that, because the rule was intended to enable
manufacturers to be able to detect and avoid adulteration through CGMP,
the proposed rule created a presumption that dietary supplements are
adulterated until proven otherwise.
(Response) The final rule does not violate section 402(f) of the
act. Section 402(f) and (g) of the act provide two independent bases
under which we may take enforcement action against dietary supplements.
A dietary supplement may be adulterated either because a manufacturer
has failed to follow a CGMP requirement, or because a dietary
supplement presents an unreasonable risk of illness or injury, or both.
There would be no reason to assert a second basis for adulteration
under section 402(g) of the act if one always had to demonstrate
adulteration under section 402(f) of the act as a prerequisite.
We also disagree with the comment that the proposed rule creates a
presumption that the dietary supplement is adulterated simply because
the proposed requirements would enable a manufacturer to detect and
avoid adulteration. The requirements for CGMP are prophylactic and are
designed in part to ensure that all aspects of manufacturing, from
receipt through distribution, provide the necessary controls and
monitoring to ensure the quality of the dietary supplement, including
that it is manufactured, packaged, labeled, and held in a manner to
prevent adulteration.
(Comment 25) One comment states that, if there is reduced
competition through the enforcement of the rule, there will be a
secondary effect of elimination of speech on dietary supplement
innovative uses.
(Response) The comment seems to conclude that, if a dietary
supplement manufacturer is not able to stay in business due to adverse
enforcement actions against it by us, or elects to not go into business
based on the possibility of enforcement action by us, there will be
reduced competition due to fewer products, less labeling, and
``elimination of speech on innovative uses.'' To the extent that the
comment is suggesting that the dietary supplement CGMP requirements are
unconstitutionally overbroad, this argument is wholly without merit
(Cf. Wisconsin v. Mitchell, 508 U.S. 476, 488-89 (1993) (finding no
merit to an overbreadth argument that the possibility of enhanced
sentences based on prior racially motivated speech or associations
constitutes an impermissible chill on free speech)). Manufacturing a
dietary supplement in a manner that violates the CGMP requirements
causes the product to be adulterated, and therefore, unlawful.

[[Page 34789]]

The fact that a manufacturer may not stay in business, or elects not
to enter business, due to: (1) Our implementation of CGMP requirements
or (2) our enforcement against a product that violates CGMP
requirements, does not mean that we are somehow prohibiting speech. In
any event, there is no First Amendment protection for speech that
concerns unlawful activity under the first prong of the test set out in
Central Hudson Gas & Electric Corp. v. Public Service Commission, 447
U.S. 557 (1980). Therefore, the comment's suggestion that there is
elimination of speech based on the rulemaking is not supportable. The
requirements in the final rule do not infringe on a manufacturer's
right to lawfully label and market a dietary supplement.

VI. What Comments Did We Receive on the General Provisions? (Subpart A)

A. Organization of Final Subpart A

Proposed subpart A contained five provisions regarding the scope of
the proposed rule, definitions, and exclusions. Table 2 of this
document lists the sections in final subpart A and identifies the
proposed sections that form the basis of the final rule.

Table 2.--Derivation of Sections in Final Subpart A
------------------------------------------------------------------------
Final Rule 2003 CGMP Proposal
------------------------------------------------------------------------
Sec. 111.1 Who is subject to this part? Sec. 111.1
------------------------------------------------------------------------
Sec. 111.3 what definitions apply to this Sec. 111.3
part?
------------------------------------------------------------------------
Sec. 111.5 Do other statutory provisions Sec. 111.5
and regulations apply?
------------------------------------------------------------------------

B. Who Is Subject to This Part? (Final Sec. 111.1)

Section 111.1 explains who is subject to the dietary supplement
CGMP requirements. In brief, final Sec. 111.1(a) states that you are
subject to the dietary supplement CGMP requirements if you manufacture,
package, label, or hold a dietary supplement. This requirement includes
a dietary supplement you manufacture but that is packaged or labeled by
another person, and a dietary supplement that is imported, offered for
import in any State or Territory of the United States, the District of
Columbia, or the Commonwealth of Puerto Rico. Final Sec. 111.1(b),
however, excludes certain persons from the rule. Specifically, Sec.
111.1(b) states that the requirements pertaining to holding dietary
supplements do not apply to you if you are holding those dietary
supplements at a retail establishment for the sole purpose of direct
retail sale to individual consumers. This section also states that a
retail establishment does not include a warehouse or other storage
facility for a retailer or a warehouse or other storage facility that
sells directly to individual consumers.
This exclusion represents specific changes sought by the comments.
We provide detail on the comments and our reasons for revising final
Sec. 111.1 in the following paragraphs.
(Comment 26) Some comments interpret the proposal as not applying
to persons who perform labeling operations. For example, one comment
claims that proposed Sec. 111.35(e), which would require
manufacturers, packagers, and persons who hold dietary supplements to
establish specifications, did not apply to ``labelers'' because the
proposed definition of ``you'' did not expressly mention persons who
label dietary supplements.
(Response) We disagree with the comments. Various provisions in the
proposal expressly mentioned or pertained to labels and labeling
operations (see, e.g., proposed Sec. Sec. 111.20(c)(6) (which would
require your physical plant to have separate or defined areas for
packaging and label operations), 111.30(a) (which would impose certain
requirements on automatic, mechanical, or electronic equipment used to
``manufacture, package, label, and hold'' a dietary supplement),
111.35(a) (which would require you to implement a system of production
and process controls that cover, among other things, all stages of
labeling dietary supplements), 111.37(a) (which would require you to
use a quality control unit to ensure, among other things, your label
operations are performed in a manner that prevents adulteration and
misbranding), 111.40(b) and (c) (which would impose certain
requirements on packaging and labels you receive and on persons who
perform label requirements), and 111.70 (which would impose various
requirements on packaging and label operations)). Although the proposed
definition of ``you'' and proposed Sec. 111.1 did not include the word
``label'' or ``labeling,'' we considered label operations to be part of
a broader manufacturing process, and it would be illogical to interpret
the proposal's specific references to label operations as somehow being
inapplicable to labelers simply because a proposed definition of
``you'' or a general ``scope'' provision did not mention labels or
otherwise distinguish label operations from the broader context of
manufacturing.
In any case, to correct such misinterpretation, we have revised
Sec. 111.1 to include the word ``label.'' Thus, under final Sec.
111.1(a), you are subject to the dietary supplement CGMP requirements
if you ``manufacture, package, label, or hold a dietary supplement.''
We also have made corresponding changes to other sections in this final
rule; for example, we have revised the definition of ``you'' in final
Sec. 111.3 to state that ``you'' means ``a person who manufactures,
packages, labels, or holds'' a dietary supplement, and we also have
inserted the word ``labeling'' in the title to this final rule. We have
not explained this change in the preamble each time it is made in the
codified provision.
In addition, we refer to ``label'' and ``labeling'' in the context
of CGMP requirements related to operations for ensuring the correct
label is on the product. To help clarify that we are referring to
labeling requirements in this final rule for labeling operations and
not, for example, to the labeling requirements in part 101, we inserted
the word ``operations'' in the title of part 111 to read ``Current Good
Manufacturing Practice in Manufacturing, Packaging, Labeling, or
Holding Operations for Dietary Supplements.''
(Comment 27) Several comments ask for clarification about the
rule's applicability to different types of businesses and practices.
Some comments ask for a clear listing of who is subject to the rule,
stating that it is difficult to apply the rule's specific provisions.
According to these comments, the rule's level of detail and
inflexibility does not account for variations in manufacturing needs
within the entire industry.
Several comments on various proposed sections ask who would be
responsible for complying with CGMP requirements if more than one party
was involved in the manufacturing, packaging, labeling, or holding of
the dietary supplement. For example, some comments ask whether
consultants are subject to a specific proposed section; others ask who
would be responsible if a firm employed another firm to handle
packaging or labeling operations.
Other comments request clarification regarding the rule's
applicability to distributors. Some comments claim that a person who
holds and sells packaged products should not be subject to dietary
supplement CGMP requirements. Other comments state that dietary
supplement CGMPs should apply to distributors as well as

[[Page 34790]]

manufacturers. These comments assert many supplement distributors are
merely marketers who employ contract manufacturers. The comments said
that, because marketers are the parties providing supplements to
consumers, we should hold marketers responsible for their products and
require marketers to ensure that their contract manufacturers adhere to
CGMP requirements. These comments argue we should not permit marketers
to transfer their responsibilities in delivering safe supplements.
Other comments assert questions about the rule's applicability are
underscored by typical dietary supplement labeling practices where the
contact information listed on the product label pertains to the
distributor/marketer instead of the actual manufacturer.
Collectively, these comments raise a basic question as to which
party or parties are responsible for complying with the dietary
supplement CGMP requirements where more than one party is involved in
the manufacture, packaging, labeling, or holding of that dietary
supplement.
(Response) In the 2003 CGMP Proposal, we stated that it would apply
to a wide variety of activities associated with the manufacture,
packaging, and holding of a dietary supplement, including labeling,
testing, quality control, holding, and distribution (68 FR 12157 at
12175). We stated under proposed part 111 you would need to comply with
those regulations directly applicable to the operations that you
perform and provided examples (id.). All activities may not be
performed by the same person. For example, a manufacturer may contract
with another firm to package and label the dietary supplement in the
containers used for distribution to consumers. Alternatively, a
distributor may contract with one firm to manufacture a dietary
supplement, and another firm to package and label the dietary
supplement that the distributor ultimately distributes under its own
name.
Under this final rule, you must comply with the CGMP requirements
that apply to your operations related to the manufacture, packaging,
labeling, and holding of dietary supplements. It is not practical to
list all possible contractual relationships that persons may enter into
in the manufacture of a dietary supplement, or to list all businesses
or practices that may be subject to the requirements of this final rule
in order for persons to know whether they are subject to requirements
of this final rule. To provide additional clarity about how this rule
may apply to various persons, we provide some examples in the following
paragraphs.
A manufacturer that manufactures a dietary supplement, and then
packages and labels and distributes the dietary supplement, is subject
to all the requirements in this final rule. If that manufacturer
contracts with another person to package and label the dietary
supplement, then the packager/labeler is responsible for complying with
the requirements for packaging and labeling operations, in addition to
other relevant requirements. The packager/labeler, in this example,
would need to comply, not only with the specific requirements related
to packaging and labeling operations in subpart L, but also with the
general requirements related to personnel, physical plant, quality
control, and other requirements that apply to that firm's operations.
However the packager/labeler would not need to comply with requirements
that do not apply to it; for example, the packager/relabeler would not
have to conduct testing on the finished batch of dietary supplement
since it does not manufacture the finished batch of dietary supplement.
A manufacturer who contracts with a person to do packaging and
labeling, but who later distributes the packaged and labeled product,
is ultimately responsible for the dietary supplement it releases for
distribution. The manufacturer would be responsible for the CGMP
requirements for the operations that it performs, including those
related to the release of the product for distribution. For example,
the manufacturer must determine whether the packaged and labeled
dietary supplement it receives from the packager/labeler conforms to
applicable specifications (final Sec. 111.127(d)), and must approve
the release of the packaged and labeled dietary supplement for
distribution (final Sec. 111.127(h)). Although the manufacturer is not
performing the specific activities related to the packaging and
labeling operations done by another person, the manufacturer has an
obligation to know what and how such activities are performed so that
it can make decisions related to whether the packaged and labeled
product conforms to applicable specifications and whether to approve
and release the product for distribution.
Some manufacturers may sell their finished batch of dietary
supplement to a packager/labeler that the packager/labeler may package,
label, and then hold and distribute. The manufacturer and packager/
labeler would each be responsible for complying with the applicable
CGMP requirements related to the operations that they perform. The
manufacturer would not be responsible for the oversight of the
packager/labeler, since the packager/labeler is not under the control
of the manufacturer and has control over the release of the packaged
and labeled dietary supplement.
A manufacturer may decide to hire a contractor or a consultant for
specific operations within the scope of the manufacturer's
responsibilities under the final rule. For example, a manufacturer may
hire a person to calibrate its equipment. The manufacturer is
responsible for complying with the requirements related to its
responsibilities, e.g., calibration requirements in this example, even
though the manufacturer has hired another person to perform that job
task.
In another example, a distributor who purchases a packaged and
labeled dietary supplement and who then holds the product in a
warehouse for distribution to another physical location is subject to
the requirements related to its operations. The codified uses the word
``hold'' since it is a broad term which encompasses the activities of a
distributor. Thus, the distributor would be responsible for complying
with requirements in subpart M, Holding and Distributing, in addition
to other requirements related to its operations (e.g., Personnel,
Physical Plant and Grounds).
In cases where a distributor contracts with a manufacturer to
manufacture a dietary supplement that the distributor then distributes
under its own label, the distributor has an obligation to know what and
how manufacturing activities are performed so that the distributor can
make decisions related to whether the packaged and labeled product
conforms to its established specifications and whether to approve and
release the product for distribution.
(Comment 28) Some comments state that the proposed rule
requirements would require the manufacturer to report adverse events to
us, but would not require those who distribute the product and whose
name is likely to be on the product label, to report adverse events to
us. The comments state that reports of adverse events submitted by
consumers to those who distribute, but do not make, dietary supplements
could be hidden from the public if such persons are not required to
submit those reports to us.
(Response) The comments may have misinterpreted the proposed rule.
The requirement to review and investigate a product complaint is
distinct from any report about the product complaint to

[[Page 34791]]

us. Reporting a complaint to us is not covered by these CGMP
requirements and would be voluntary, unless the complaint is subject to
the statutorily mandated reporting requirements for ``significant
adverse events'' pursuant to the ``Dietary Supplement and Non-
Prescription Drug Consumer Protection Act'' (Public Law 109-462),
signed into law on December 22, 2006 (see discussion in section XX of
this document).
Under the procedures that are set forth in subpart O, Product
Complaints (see section XX of this document), a distributor and a
manufacturer are both subject to the requirements related to the review
and investigation of a product complaint that they receive.
(Comment 29) Some comments argue against including minimum CGMPs
necessary for activities related to manufacturing, packaging, labeling,
or holding dietary ingredients in the final rule. Several comments
argue the proposed rule is overly broad and inconsistent with
congressional intent. These comments question whether Congress intended
that CGMP apply to persons involved in the manufacture, packaging,
labeling, and holding of dietary ingredients. The comments also argue
that, if the rule applies to dietary ingredient manufacturers, we would
be establishing precedent and that we lack legal authority to regulate
ingredients rather than the finished products themselves. The comments
state that neither food CGMP nor drug CGMP offers precedent or guidance
on regulating ingredients. The comments argue those who provide dietary
ingredients should be subject to the existing general food CGMP
requirements in part 110 rather than to the dietary supplement CGMP
requirements.
Several comments argue that many dietary ingredients are used in
regular foods and in drugs as well as in dietary supplements. The
comments argue, for some dietary ingredients, their use in dietary
supplements represents a very small percentage of the dietary
ingredient's worldwide usage. The comments say we should allow those
who deal only with dietary ingredients to operate under one set of
regulations, such as the general food CGMP requirements in part 110.
According to these comments, we have not demonstrated either a failure
of the current system or a compelling need to create different
regulations for raw materials common to both the food and dietary
supplement industries. The comments would revise the title of part 111
and proposed Sec. 111.1 and make conforming revisions throughout the
proposed rule to limit the rule's applicability to dietary supplements.
In contrast, other comments say the rule should apply to dietary
ingredient manufacturers as well as to dietary supplement
manufacturers. The comments state that excluding those who provide or
supply dietary ingredients would mean those who have the greatest
expertise in these goods would not be subject to dietary supplement
CGMP requirements and thus fail to cover a crucial step in preventing
the adulteration or contamination of dietary supplements. The comments
argue that, for some dietary ingredients (especially raw botanical and
agricultural goods), the most critical point in ensuring an
ingredient's quality and purity is at time of harvest or creation, and
that this is particularly true with new or original ingredients.
The comments state problems with dietary supplements often arise
from substandard ingredients, and the difficulty in testing the
properties of some botanical and other dietary ingredients at the in-
process or finished product stage makes it necessary to include dietary
ingredient manufacturers in the final rule. Furthermore, these comments
assert a flexible testing scheme that they recommend (which emphasizes
establishing specifications for components, relying on certificates of
analysis from qualified suppliers, qualifying component suppliers, and
establishing written procedures, with testing of finished batches
serving as a check on the overall manufacturing process) makes it
important to regulate dietary ingredient manufacturers.
Other comments suggest we issue a separate or modified set of CGMP
requirements that would apply to persons who manufacture, package,
label, or hold dietary ingredients. These comments say the proposed
rule does not work for all dietary ingredients, especially those
converted from non-food grade to food grade during the manufacturing
process. These comments said the rule should be modified for dietary
ingredients.
(Response) Two issues seem to be raised by these comments: (1)
Whether dietary ingredients are within the scope of this final rule and
(2) whether dietary ingredient manufacturers are subject to this final
rule. Dietary ingredients are included within the scope of this final
rule but dietary ingredient manufacturers are not necessarily subject
to this rule. The definition of ``component'' in this final rule
includes ``any substance intended for use in the manufacture of a
dietary supplement including those that may not appear in the finished
batch of the dietary supplement. Component includes dietary ingredients
(as described in section 201(ff) of the act) and other ingredients''
(final Sec. 111.3). The proposed rule, Sec. 111.3, recognized that
``dietary ingredients'' are ``components'' (68 FR 12157 at 12176)
(describing how dietary ingredients would fall within the proposed
definition of ``component'').
There are specific requirements in this final rule that relate to
components, and thus dietary ingredients, that are used in the
manufacture of a dietary supplement. For example, final Sec. 111.70(b)
requires you to establish certain component specifications. Such
requirements would include specifications for dietary ingredients as
``components.'' It is important to control the components used in the
manufacture of dietary supplements to ensure consistency and to ensure
the quality of the dietary supplement. Since dietary ingredients are
considered components, the various requirements apply to dietary
ingredients as part of the production and process control. Therefore,
we disagree to the extent comments were suggesting that there should be
no CGMP requirements related to the dietary ingredients used by a
manufacturer in the manufacture of dietary supplements.
Dietary ingredients are included within the meaning of
``component.'' In those requirements in the proposed rule where
``component'' encompasses ``dietary ingredient'' we are, in the final
rule, removing ``dietary ingredient'' in those requirements and only
refer to ``component.'' Given the scope of the final rule, it is
redundant to refer to both ``component'' and ``dietary ingredient''
where the latter is subsumed in the former.
In response to comments that questioned the need to include
manufacturers of dietary ingredients within the scope of part 111, we
have made changes to the scope of the rule, as applied to dietary
ingredient manufacturers. As we explain more fully in our discussion of
final Sec. Sec. 111.70, 111.73, 111.75, and 111.77 (see section X of
this document), after considering comments about the overall production
and process control system, we revised the final rule's approach to
ensuring product quality. This approach emphasizes that it is important
to ensure the quality of the dietary supplement throughout the
production and process control system. This approach emphasizes
establishing specifications for components and ensuring those
specifications are met.

[[Page 34792]]

You may rely on a certificate of analysis for specifications (except
for the identity of the dietary ingredient) only if you satisfy certain
criteria, which include qualifying the supplier of the components. With
this approach, the goal of ensuring the quality of dietary supplements
can be achieved without applying the rule specifically to persons who
manufacture, package, label, or hold dietary ingredients that will be
further processed as a dietary supplement by other persons.
Consequently, we revised Sec. 111.1 by deleting ``dietary
ingredient.'' Therefore, those who manufacture, package, label, or hold
dietary ingredients are not subject to the final rule. To illustrate,
assume you manufacture a dietary ingredient and sell that bulk dietary
ingredient to Company X. Company X then utilizes the bulk dietary
ingredient in a dietary supplement. Under final Sec. 111.1(a), you
would not be subject to these dietary supplement CGMP requirements
because you are not manufacturing a dietary supplement, rather you are
manufacturing a dietary ingredient for further incorporation into a
dietary supplement by Company X. If, however, you sell herbs in bulk to
Company X, and Company X simply packages the herbs into smaller units
for sale as a dietary supplement, you would be subject to the dietary
supplement CGMP requirements because you are manufacturing a dietary
supplement that Company X is simply packaging and labeling, and not
further processing into a dietary supplement. In other words, in the
latter example, you would have acted as a manufacturer whose finished
product is simply repackaged or relabeled.
Under final Sec. 111.1(a) persons engaged solely in activities
relating to the harvesting, storage, or distribution of raw
agricultural commodities that will be incorporated into a dietary
supplement by others are not included within the scope of the rule as a
dietary supplement manufacturer. This is because those persons simply
``supply'' a component (i.e., the raw agricultural commodity) that
another person will process into a dietary supplement; thus you do not
manufacture, package, label, or hold a dietary supplement.
Note, too, that if you manufacture and supply a component directly
to consumers as a dietary supplement, you would be considered a dietary
supplement manufacturer within the scope of final Sec. 111.1(a).
Likewise, if you manufacture a component and sell part of the batch to
another person who, in turn, will further process the component as a
dietary supplement and sell the remainder of the batch to consumers as
a dietary supplement, you would be subject to the dietary supplement
CGMP requirements, as a manufacturer, for the product sold to consumers
and not subject to an exclusion under final Sec. 111.1(b), discussed
in this section. In other words, final Sec. 111.1(a) refers to the
nature of your activity, and simply engaging in some activities that do
not bring you within the scope of the final rule does not necessarily
mean that all your activities are outside the scope of the final rule.
We do not agree, as some comments suggested, that we need to issue
a separate or modified set of CGMP requirements for dietary
ingredients. That is because there are adequate controls established in
this final rule for the use of dietary ingredients used by the
manufacturer of a dietary supplement. However, if you manufacture,
package, label, or hold dietary ingredients that will be further
processed as a dietary supplement by another person, you must comply
with food CGMP requirements in part 110. A dietary ingredient is a food
under section 201(f) of the act, as a food, or as a component of food.
Because the final rule gives manufacturers an incentive to qualify
suppliers of dietary ingredients, persons who manufacture, package,
label, or hold dietary ingredients may wish to familiarize themselves
with these dietary supplement CGMP requirements and use them in
manufacturing, packing, labeling, or holding operations for dietary
ingredients.
(Comment 30) Some comments argue if the final rule ultimately
covers dietary ingredient suppliers then we should clarify what
constitutes a ``consumer.'' According to these comments, dietary
ingredient suppliers do not typically supply their products directly to
those individuals who will ultimately consume or ingest them. Thus,
``consumers'' of dietary ingredients are other companies, not
individuals. The comments express concern about the possible
application of proposed Sec. 111.95 which would require procedures for
handling complaints.
(Response) The final rule applies only to persons who manufacture,
package, label, or hold dietary supplements and are not subject to an
exclusion in final Sec. 111.1. However, as explained in the previous
response to comment 29, if a dietary ingredient manufacturer also
supplies or sells a dietary ingredient as a dietary supplement, such a
manufacturer would be subject to final Sec. 111.1(a) and subject to
all relevant dietary supplement CGMP requirements.
Some comments expressed concern about dietary ingredient
manufacturers having to comply with proposed Sec. 111.95 on product
complaints. If a dietary ingredient manufacturer receives a product
complaint, we encourage the manufacturer to evaluate the complaint to
determine if it may involve a problem with the manufacture of the
dietary ingredient. In addition, we encourage the dietary ingredient
manufacturer to notify the dietary supplement manufacturer so that it
can review the complaint and investigate, as needed.
(Comment 31) Several comments question the proposal's applicability
to persons who sell packaged products or seek clarification as to
whether the rule applies to dietary supplement manufacturers that
operate from homes and those that distribute product to other
distributors.
(Response) To the extent that the comments question whether
retailers or individuals who sell dietary supplements directly to
individual consumers are subject to the dietary supplement CGMP
requirements, we have revised the final rule by creating a new Sec.
111.1(b) which states that: ``The requirements pertaining to holding
dietary supplements do not apply to you if you are holding those
dietary supplements at a retail establishment for the sole purpose of
direct retail sale to individual consumers. A retail establishment does
not include a warehouse or other storage facility for a retailer or a
warehouse or other storage facility that sells directly to individual
consumers. '' This means, for example, if you operate a storefront
retail establishment where you stock dietary supplements on your
shelves for purchase by individual consumers, we do not consider you to
be ``holding'' those dietary supplements in a manner that would require
you to comply with the holding provisions in this final rule. Sale to
individual consumers, where you are not storing bulk dietary
supplements as one would in a warehouse or storage facility, does not
fall within the manufacturing, packaging, labeling, or holding
activities that would subject you to dietary supplement CGMP
requirements.
However, if you operate storefront retail establishments, and those
retail establishments obtain their stocks from your warehouse, we would
consider your warehouse operations to be ``holding'' dietary
supplements and expect your warehouse operations to comply with the
rule's holding requirements. Such distribution is no different than
other warehouse operations that are normally subject to CGMP
requirements. Consequently, to

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distinguish between ``holding'' dietary supplements for retail sale to
consumers and ``holding'' dietary supplements in a warehouse for
further distribution, final Sec. 111.1(b) limits the exclusion to
persons holding dietary supplements ``at a retail establishment for the
sole purpose of direct retail sale to individual consumers.'' Final
Sec. 111.1(b) also makes it clear that a retail establishment does not
include a warehouse or other storage facility that a retailer uses to
hold the dietary supplements or an operation that sells directly to
consumers, but that itself distributes the product to the consumer from
a warehouse or storage facility and not from a storefront retail
establishment.
(Comment 32) Many comments question the rule's applicability to
various practitioners such as herbalists, acupuncturists, naturopaths,
and other health care providers who prepare individualized herbal
formulas for specific individuals on a case-by-case basis. Most
comments say such practitioners should not be covered by the rule.
These comments give various reasons to justify their position,
including:
These practitioners do not broadly sell products;
These practitioners make very small quantities of
individualized formulas, and can therefore be very selective as to the
quality of ingredients used;
The testing and storage requirements of each finished
batch cannot apply to a small dispensary where several different
modified herbal formulas are prepared each day;
Based on the projected costs to implement CGMPs, it would
be virtually impossible for an individual practitioner or university
clinic to develop the necessary quality control unit, maintain reserve
samples, maintain the required paperwork, or retrofit clinics to comply
with the rule;
Many States regulate or license these practitioners, so
further Federal regulation is unnecessary;
Some practitioners do not consider themselves to be
manufacturers;
In an analogous situation, compounding pharmacists are not
required to comply with drug CGMPs; and
Despite the growing number of such practitioners, there is
no proof that greater harm has occurred to the general public from the
herbs these practitioners sell.
(Response) We stated in the 2003 CGMP Proposal (68 FR 12157 at
12175) that we declined to exempt herbalist practitioners from the
proposed rule. We continue to believe that the risks of adulteration
are not eliminated just because the practitioner is an herbalist, and
therefore, such an exemption should not be included in this final rule.
However, after further consideration, we have determined that it would
be appropriate for us to consider the exercise of our enforcement
discretion in deciding whether to apply the requirements of this final
rule to certain health care practitioners, such as herbalists,
acupuncturists, naturopaths, and other related health care providers.
We find it noteworthy that the comments identified two potential
safeguards that could support the exercise of our enforcement
discretion on whether to apply the requirements of the final rule to
certain practitioners: (1) Adequate training in the professional
practice and (2) an individual client and practitioner relationship.
For example, comments claimed that the practitioners receive adequate
training to formulate dietary supplements and that they provide the
dietary supplements to individuals in the course of a one-on-one
consultation on the premises of the practitioner. One comment from a
practitioner states that she received her training from an accredited
4-year university and it included didactic and clinical training in
acupuncture and Chinese herbs. Another comment from an organization
provides detailed training guidelines for practitioners, including
1,600 hours of training, 400 hours of which should include clinical
work. Moreover, many comments also assert that the practitioners are
different from dietary supplement manufacturers because they formulate
the dietary supplements in the course of a one-on-one consultation at
their premises. That enables them to ensure the formulations are made
to meet the specific needs of the individuals.
We believe that a one-on-one consultation by a practitioner who is
adequately trained in their profession may not necessitate the same
types of controls as we are establishing in this final rule for
manufacturing activities that are on a larger scale. Such a
practitioner may make some formulations in advance of the consultation
and still make the formulations in very limited quantities for the
individual client. We believe that it would be appropriate to consider
the exercise of our enforcement discretion, on a case-by-case basis, to
determine whether to apply the requirements of this final rule to such
persons.
We do not expect the number of those subject to the consideration
of our enforcement discretion to be very large. Many products that are
manufactured by practitioners would not necessarily be considered to be
dietary supplements (e.g., certain products used by traditional Asian
medicine practitioners). Further, we are not considering exercising our
enforcement discretion with respect to practitioners who prepare
batches of herbs and sell them to individual consumers without
determining whether the dietary supplement is appropriate for each
consumer's needs in a one-on-one personal consultation, or those that
prepare batches of a dietary supplement for which there is a known or
suspected safety concern.
(Comment 33) Several comments asked us to exempt academic
institutions that provide training for therapeutic disciplines that
use, for example, herbal formulas in their practice regardless of
whether the dietary supplements they produce enter into interstate
commerce. Specifically, these comments would revise the final rule to
state that it does not apply ``to academic institutions that provide
training in dispensing of nutritional or herbal products and formulas
related to courses in therapeutic disciplines that provide such
products and formulas as a part of their therapy, for example,
naturopathy, herbalism, traditional Chinese medicine, and
acupuncture.''
(Response) Similar to what we stated in response to comment 32, we
believe that it may be appropriate to consider the exercise of our
enforcement discretion in circumstances where an academic institution's
actions are similar to those of a practitioner who is adequately
trained in their profession and who provides dietary supplements within
the context of an individual client and practitioner relationship. In
general, it is not our policy to inspect an academic institution that
provides training for therapeutic disciplines that use, for example,
dietary supplements in their practice. We intend to consider the
exercise of our enforcement discretion in those situations where there
is a one-on-one consultation that includes a practitioner with adequate
training. We intend to issue guidance to further clarify how the agency
intends to exercise its enforcement discretion on the application of
this final rule to certain academic institutions.
(Comment 34) Several comments discuss the position taken by certain
nations, notably Australia and Canada, that have developed CGMP
requirements and related guidance for botanicals. According to these
comments, these nations recognize that there are various types of
practitioners who sell herbs and herbal preparations in a clinical
setting, and do not consider such persons to be manufacturers. The

[[Page 34794]]

comments ask us to follow the example of these nations.
(Response) We intend to consider the positions taken by other
nations to inform us in our decisionmaking in any future guidance on
how we intend to exercise our enforcement discretion on the application
of this final rule to certain practitioners.
(Comment 35) Many comments say we should define when a dietary
supplement will be said to have entered interstate commerce. The
comments state herbal practitioners (and academic institutions) often
purchase source herbs from outside their State, even if they prepare
these herbs for their specific customers within the State. These
comments request we clarify that the rule does not apply to herbs
purchased out of State if prepared for local use. Other comments
request clarification regarding clients who have moved across State
lines, yet maintain a relationship with an herbalist practitioner.
(Response) In section V of this document we explain the interstate
and intrastate issue related to the final rule.
(Comment 36) A few comments assert individual practitioners and
practitioner organizations often are unaware of the opportunity to
comment on CGMP or regulatory issues. Therefore, the comments say these
practitioners and organizations often fail to provide comment or
otherwise participate in rulemaking and say we should give these
practitioners and practitioner organizations a chance to comment.
(Response) We provided many opportunities for comment and,
therefore, we decline to adopt the comments' suggestion. As we discuss
in section I of this document, we published an ANPRM concerning dietary
supplement CGMPs on February 6, 1997 (62 FR 5700); the 1997 ANPRM
provided an opportunity for public comment. On March 7, 2003, we issued
a Talk Paper, along with other background documents, announcing the
issuance of a proposed dietary supplement CGMP rule. We made the
proposed rule available when it went on display (before it published)
in the Federal Register on March 13, 2003 (68 FR 12157), and, again,
provided an opportunity for public comment. We also held public
meetings on April 29, 2003, in College Park, MD and on May 6, 2003, in
Oakland, CA. We also held a public meeting (via satellite downlink) on
May 9, 2003, with viewing sites at our district and regional offices
throughout the country. Thus, we provided numerous opportunities for
interested persons to learn about the rule and to submit comments or
otherwise participate in the rulemaking process. Consequently, we
decline to provide yet another opportunity for comment.
(Comment 37) The preamble to the 2003 CGMP Proposal noted that
comments submitted in response to our 1997 ANPRM state we should not
distinguish between dietary supplements made in the United States and
those made in a foreign country (68 FR 12157 at 12174). Although we
agreed with the comments and made no distinction between foreign and
domestic firms in the proposed rule, we invited comment on how we might
ensure dietary ingredients and dietary supplements exported to the
United States have been manufactured, packaged, labeled, and held
consistent with part 111 (68 FR 12157 at 12175).
Several comments argue the rule should apply to foreign firms as
well as domestic manufacturers to ensure a ``level playing field'' and
to protect American consumers. Some comments say we should work with
foreign countries to harmonize our requirements and thus avoid
potential trade disputes under international trade agreements such as
the General Agreement on Tariffs and Trade. Other comments suggest
compliance by foreign firms could be achieved through the use of third
party certification programs, such as the dietary supplement
verification program administered by USP, or the adoption of importer
verification provisions similar to those used in our HACCP requirements
for seafood (see Sec. 123.12).
In contrast, another comment says we should inspect foreign firms
to ensure compliance, whereas other comments claim we lack jurisdiction
over foreign firms.
(Response) We are amending proposed Sec. 111.1 to clarify the
regulation's applicability to foreign firms. We explain in this section
how we may enforce the rule against foreign firms. We, however, are not
making any changes in response to the comments calling for the
harmonization of the rule with foreign rules because this request is
beyond the scope of the final rule.
In response to comments, and for clarification, we have revised
final Sec. 111.1(a) to clarify that the regulation applies to the
extent that you manufacture, package, label, or hold a dietary
supplement, including a dietary supplement imported or offered for
import in any State or Territory of the United States, the District of
Columbia, or the Commonwealth of Puerto Rico.
With respect to the comments requesting that we make clear our
position for enforcing the rule against foreign firms, we explain our
position as follows. Section 801(a) of the act (21 U.S.C. 381a)
authorizes us to refuse admission of an imported food if it appears
from the examination of such samples or otherwise that such article is,
among other things, adulterated. A foreign firm's refusal to allow us
to obtain records via an inspection for CGMP purposes, as required by
final Sec. 111.610 (for the dietary supplements the foreign firm
offers for import into the United States), would create the appearance
that such imported dietary supplements are adulterated under section
402(g) of the act, and thus, could lead to a refusal of admission under
section 801(a) of the act.
Foreign firms who ship to the United States must operate under
conditions that satisfy our regulations, including the requirement that
records be made available during the course of an FDA inspection. We
note that except in circumstances where there is a public health
emergency or we receive information that would indicate the appearance
of adulteration of products shipped to the United States, foreign
inspections are generally scheduled well, e.g., weeks, in advance.
Thus, we believe that taking action under section 801 of the act is
appropriate if companies do not accommodate our inspectional request.

C. What Definitions Apply to This Part? (Final Sec. 111.3)

Section 111.3 defines various terms that we use in the final rule
and notes that definitions or interpretations of terms in section 201
of the act also apply. In general, we adopted the definitions that we
proposed, although, in some cases, we deleted words or concepts as a
result of other changes we made to the final rule. We have added a
definition of ``quality'' for purposes only of this final rule.
A recurring change we made is the deletion of the words ``dietary
ingredient'' in several definitions. In some cases, the use of the
words ``dietary ingredient'' was redundant to the use of ``component''
and thus not necessary in the final rule. Because a ``dietary
ingredient'' is subsumed within the definition of ``component,'' as
explained in our response to comment 29, we deleted ``dietary
ingredient'' in those definitions where ``component'' was used to avoid
redundancy.
In other provisions, we deleted ``dietary ingredient'' from the
definition because the use of those words was no longer necessary given
the narrowing of the scope of the rule as it applies to dietary
ingredient manufacturers (explained in the response to comments

[[Page 34795]]

29 and 30). For example, we deleted ``dietary ingredient'' from the
proposed definition of ``ingredient'' that referred to the
``manufacture of a dietary ingredient or dietary supplement'' and the
``finished batch of the dietary ingredient or dietary supplement.'' We
did not need to state ``manufacture of the dietary ingredient'' or
refer to ``finished batch of dietary ingredient'' because dietary
ingredient manufacturers that only supply such ingredients to other
persons for processing into a dietary supplement are not subject to the
final rule.
We discuss changes to the definitions, other than the changes we
have made globally such as the deletion of ``dietary ingredients,'' the
change from ``include, but not limited to'' to ``includes'' or
``include,'' the addition of labels and labeling, and the deletion of
the word ``quality'' from the phrase ``identity, purity, quality,
strength, and composition,'' as well as comments asking us to define
more terms or to delete certain definitions, in more detail in the
following paragraphs.
1. Actual Yield
The final rule defines ``actual yield'' as ``the quantity that is
actually produced at any appropriate step of manufacture or packaging
of a particular dietary supplement.''
We received no substantive comments to the proposed definition.
2. Batch
The final rule defines ``batch'' as ``a specific quantity of a
dietary supplement that is uniform, that is intended to meet
specifications for identity, purity, strength, and composition, and
that is produced during a specified time period according to a single
manufacturing record during the same cycle of manufacture.''
This definition differs from the proposed definition of ``batch''
by stating that a batch is a specific quantity of a dietary supplement
that is ``uniform.''
We inserted the word ``uniform'' in response to comments asking
that we define ``lot'' to be consistent with ``batch.'' We explain our
reasons for harmonizing the definitions and for inserting ``uniform''
into the definition of ``batch'' in the response to comment 42 of this
document.
We discuss the comments on our proposed definition of ``batch'' and
our changes to the definition in our responses to the following
comments.
(Comment 38) Several comments ask us to clarify what the ``same
cycle of manufacture'' is in the definition of ``batch.'' One comment
asks if it meant the same product made with the same lot(s) of raw
materials regardless of how many days it took to produce the batch, or
if it meant a quantity produced in 1 day. The comment also asks whether
batches produced on consecutive days, using the same formula, can be
considered to be the same batch with respect to the proposed testing
requirements if the quality control unit determined that different lots
of raw materials are equivalent (e.g., by meeting all specifications).
(Response) The ``same cycle of manufacture'' refers to a process
during which equipment remains dedicated to the manufacture of the
batch. The terms do not limit you to any particular time period or
require you to operate equipment continuously until you have completed
the ``same cycle of manufacture.'' The ``same cycle of manufacture''
also does not limit the number of lots of components you use.
You may consider, as one batch, a product produced using different
lots of raw materials where the production of the batch is a continuous
process on a dedicated line. However, for each component that you use
in the manufacture of the batch of dietary supplement, you would need
to establish specifications under final Sec. 111.70, determine whether
these specifications are met under final Sec. 111.73, and ensure that
these component specifications are met using the criteria under final
Sec. 111.75. Further, you may not consider different batches of
product produced on consecutive days using the same formula to be the
same batch for purposes of testing requirements. The term ``different
batches'' suggests that the production is not a continuous process on a
dedicated line.
3. Batch Number, Lot Number, or Control Number
The final rule defines these terms as ``any distinctive group of
letters, numbers, or symbols, or any combination of them, from which
the complete history of the manufacturing, packaging, labeling, and/or
holding of a batch or lot of dietary supplements can be determined.''
We received no substantive comments on the definition. We added the
word ``and'' before ``or'' to emphasize that the history of each
activity must be able to be determined.
4. Component
The final rule defines ``component'' as ``any substance intended
for use in the manufacture of a dietary supplement, including those
that may not appear in the finished batch of the dietary supplement.
Component includes dietary ingredients (as defined in section 201(ff)
of the act) and other ingredients.''
The definition of component now refers only to the manufacture of a
dietary supplement (whereas the proposal also referred to the
manufacture of dietary ingredients). We also made a nonsubstantive,
editorial revision in the last sentence to put parentheses around the
reference to section 201(ff) of the act and to change the word order so
that ``component'' includes ``dietary ingredients * * * and other
ingredients.'' (The proposed definition had ``components'' including
``ingredients and dietary ingredients.'')
(Comment 39) Some comments would distinguish among ``raw
material,'' ``components,'' and ``starting material'' because the
comments said that defining ``component'' to include all these
materials is confusing. One comment adds that many starting materials
are not food grade or approved food ingredients until they have been
processed. One comment states the term ``raw material'' is typically
used to describe the materials (such as dietary ingredients, fillers,
and processing aids) that will be used to make the final product. The
comment further states ``component'' is typically used to describe the
specific items used to assemble the finished product for the end user.
The components would include packaging components such as bottles,
caps, and labels, as well as the bulk dietary supplement. This comment
also suggests that we use the term ``starting material'' to distinguish
substances used in the manufacture of dietary ingredients from
substances used in the manufacture of dietary supplements.
(Response) We decline to revise the rule as suggested by the
comments. There may be differences in how components are referred to by
certain manufacturers and how we refer to it in this final rule.
However, for purposes of this final rule we refer to all substances
used in the manufacture of dietary supplements as ``components,''
whether or not those substances appear in the finished product.
Please note that, although ingredients are ``components'' under our
definition, not all components are ingredients. For example, a solvent
used to make an herbal extract is not an ingredient when it is removed
from the extract by a process such as drying, because the solvent was
not intended to be present in the finished dietary supplement. However,
the solvent would be a ``component'' because it was used in the
manufacture of the dietary supplement.

[[Page 34796]]

As for materials that might not be food grade or approved food
ingredients until processing, see the discussion in response to comment
240 in section XII of this document.
(Comment 40) Several comments express concern that ``component''
could be interpreted to mean any constituent present in a botanical
extract or other natural product. The comments say a single botanical
can contain tens of thousands of constituents or metabolites and that
chemists have not identified all constituents of a single botanical.
According to the comments, the cost of testing for all constituents
would exceed a product's total annual revenues.
(Response) In general, we would consider the botanical extract or
the other natural product to be the ``component'' as defined in this
final rule rather than consider that all the various chemical
substances contained in the botanical extract or other natural product
are components. Thus, if you are manufacturing a dietary supplement
that is intended to provide a certain substance (e.g., vitamin C ) and
you add a natural product which is intended to supply the vitamin C
(e.g., vitamin C in the form of rosehips), we would consider the
natural product (e.g. rosehips that contain a certain amount of vitamin
C) to be a component which must be listed in the master manufacturing
record. The component specifications for the rosehips must include a
specification for the strength of the substance (e.g., vitamin C) in
whatever amount you determine is necessary to meet the specification
for the strength of the vitamin C in the finished batch of dietary
supplement. Under final Sec. 111.70, we expect you to establish
specifications for the natural product and ensure that the
specifications are met. As an example relevant to an extract, if you
are manufacturing a dietary supplement that is intended to provide a
certain amount of vitamin C that derives from the natural product
rosehips, and the substance that you purchase from a supplier to add as
a component is a purified extract of rosehips (rather than rosehips
themselves), we would consider the purified extract to be a component
(as an ingredient). The component specifications for the purified
extract must include a specification for the strength of the substance
(i.e., vitamin C) in whatever amount you determine is necessary to meet
the specification for the strength of the vitamin C in the finished
batch of dietary supplement. However, in this example ``rosehips''
would not be considered a component, because ``rosehips'' is not what
you added.
5. Contact Surface
The final rule defines ``contact surface'' as ``any surface that
contacts a component or dietary supplement, and those surfaces from
which drainage onto the component or dietary supplement, or onto
surfaces that contact the component or dietary supplement, occurs
during the normal course of operations.'' The final rule lists
containers, utensils, tables, contact surfaces of equipment, and
packaging as examples of ``contact surfaces.''
We did not receive any substantive comments on the proposed
definition. We deleted ``ordinarily'' from ``ordinarily occurs during
the normal course of operations'' because ``ordinarily'' is redundant
to ``normal.''
6. Ingredient
The final rule defines ``ingredient'' as ``any substance that is
used in the manufacture of a dietary supplement and that is intended to
be present in the finished batch of the dietary supplement. An
ingredient includes, but is not necessarily limited to, a dietary
ingredient as defined in section 201(ff) of the act.'' We did not
receive any substantive comments on this definition. We made a
nonsubstantive, editorial change to replace ``finished dietary
supplement'' with ``finished batch of the dietary supplement.''
(Comment 41) One comment says we should define ``ingredient''
better to ensure consistent interpretation of CGMP at all levels
throughout the dietary supplement industry.
(Response) We disagree with the comment. We believe the definition
is adequate, including as it does both dietary ingredients as described
in section 201(ff) of the act and other ingredients that do not fit
that description, such as an emulsifier used to establish a uniform
dispersion in a liquid dietary supplement or a color additive used to
color a capsule. Moreover, the comment did not explain or specify which
aspects of the proposed definition should be revised or explain why the
proposed definition would lead to inconsistent interpretations of CGMP.
7. In-Process Material
The final rule 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 supplement.''
We did not receive any substantive comments on the proposed
definition.
8. Lot
The final rule defines ``lot'' as ``a batch, or a specific
identified portion of a batch, that is uniform and that is intended to
meet specifications for identity, purity, strength, and composition;
or, in the case of a dietary supplement produced by continuous process,
a specific identified amount produced in a specified unit of time or
quantity in a manner that is uniform and that is intended to meet
specifications for identity, purity, strength, and composition.''
The final rule differs from the proposed definition in that the
proposed definition of ``lot'' would have the batch or specific
identified portion of a batch be intended to have ``uniform identity,
purity, quality, strength, and composition.''
(Comment 42) One comment agrees with the proposed definition for
``lot,'' but several other comments would revise the definition to be
more consistent with the proposed definition of ``batch.''
Specifically, the comments note the proposed definition of ``batch''
would refer to a quantity of dietary supplement that is ``intended to
meet specifications for identity, purity, quality, strength and
composition,'' whereas the proposed definition of ``lot'' would refer
to a batch or specific identified portion of a batch that is ``intended
to have uniform identity, purity, quality, strength, and composition.''
The comments would revise the definition of ``lot'' by deleting the
phrase ``intended to have uniform'' and inserting the phrase ``intended
to meet specifications for'' in order to make the definitions of
``batch'' and ``lot'' consistent.
(Response) We agree that the definitions for ``batch'' and ``lot''
should be consistent, but we disagree with the comments' suggestion to
delete the term ``uniform'' from the definition of ``lot.'' The
attributes of a lot or batch should be uniform throughout the lot or
batch and meet established specifications for those attributes. If
samples from a lot or batch were tested for appropriate specifications
of identity, purity, strength, and composition, the attributes should
be consistent throughout the sample and be uniform from sample to
sample regardless of whether the test samples are taken from the
beginning, middle, or end of the lot or batch. Consequently, we revised
the definition of ``lot'' to state, in relevant part, that a ``lot'' is
a batch or specific identified portion of a batch that ``is uniform and
that is intended to meet specifications

[[Page 34797]]

for identity, purity, strength, and composition'' or, for dietary
supplements produced by a continuous process, a specific identified
amount produced in a specified unit of time or quantity in a manner
that is uniform and that is intended to meet specifications for
identity, purity, strength, and composition.''
Similarly, we revised the definition of ``batch'' so that it
states, in relevant part, that a ``batch'' is a specific quantity of a
dietary supplement ``that is intended to meet specifications for
identity, purity, strength, and composition.''
These revisions make the definitions of ``batch'' and ``lot''
consistent.
9. Microorganisms
The final rule defines ``microorganisms'' as ``yeasts, molds,
bacteria, viruses, and other similar microscopic organisms having
public health or sanitary concern.'' It adds that the definition
includes species that: (1) May have public health significance; (2) may
cause a component or dietary supplement to decompose; (3) indicate that
the component or dietary supplement is contaminated with filth; or (4)
otherwise may cause the component or dietary supplement to be
adulterated.
(Comment 43) One comment would revise the definition to identify
specific microorganisms that have public health or sanitary concern
(i.e., Salmonella species, Escherichia coli, Pseudomonas aeruginosa,
and Staphylococcus aureus). The comment says this would be consistent
with USP requirements.
(Response) We disagree with the comment. A list of specific
microorganisms could easily become outdated as new pathogens emerge,
and constantly issuing new rules to revise the list would be both
inefficient and impractical.
(Comment 44) One comment expresses concern that the proposed
definition for microorganisms would include microorganisms that are a
natural part of the ecology of all natural products. The comment says
certain levels of microorganisms are expected on botanical raw
materials (i.e., those naturally occurring or introduced through
organic cultivation techniques) and that many do not present a public
health risk. The comment expresses concern that nonpathogenic
microorganisms that are not a public health risk would be a
``sanitary'' concern that would render a product adulterated. The
comment argues there should be little concern about the presence of
microorganisms that present no public health consequence, and so we
should revise the definition accordingly. The comment further discusses
the difficulties in ``sterilizing'' botanicals to render them free of
microorganisms associated with insanitary conditions. The comment notes
that some international organizations have established ``upper limits''
for these organisms for botanical supplements, which, in the comment's
opinion, represent more realistic standards than trying to attain a
``sterile'' botanical supplement.
(Response) We disagree with the comment. We do not interpret the
definition of ``microorganism'' as making the presence of nonpathogenic
microorganisms that are not a public health risk a ``sanitary concern''
that would render a product adulterated. Instead, we interpret the
definition as saying that microorganisms of public health significance
and microorganisms presenting sanitary concerns are ``microorganisms''
under this rule. These are the types of microorganisms that may cause a
component or dietary supplement to become adulterated.
As for upper limits on microbial contamination, the comment offered
no suggested limits, and we decline to establish such limits in this
rule. The final rule requires manufacturers to establish limits for
those types of contamination that may adulterate or lead to
adulteration of components or dietary supplements. Thus, for example, a
manufacturer of a botanical dietary supplement would have to determine
what, if any, microorganisms are likely or certain to be present and
establish limits, as appropriate to prevent adulteration of the
finished batch of the dietary supplement.
We have modified the word ``have'' with the word ``may'' to
indicate that the determination or evaluation of whether there is a
``public health significance'' is not made after the fact. There does
not have to be a factually established determination of public health
significance for you to conclude that the microorganisms ``may
adulterate'' the dietary supplement. The change from ``could cause'' to
``may cause'' is to be consistent with the previous change to ``may
have.''
10. Must
The final rule explains that the word ``must'' is ``used to state a
requirement.''
(Comment 45) One comment would revise the definition to say that
the term ``must'' be used to state mandatory requirements ``unless
shown to be inapplicable or replaced by an alternative demonstrated to
provide at least an equivalent level of quality assurance.''
(Response) We decline to revise the rule as suggested by the
comment. The comment's revision would undermine the reasons for issuing
a rule. Rules create enforceable requirements. It is not clear, nor did
the comment discuss, how we could enforce the requirements in this
final rule if firms were able to avoid a particular requirement by
declaring them to be ``inapplicable'' or substituting alternatives
which they felt they had demonstrated were ``at least an equivalent
level of quality assurance.'' There would be inconsistency in the
general CGMP practices used within the dietary supplement industry and
uncertainty as to whether the process and production controls ensure
the quality of the dietary supplement. Consequently, we decline to
revise the rule as suggested by the comment.
We have, however, made a nonsubstantive, editorial change to the
definition so that ``must'' is used to state ``a requirement.'' The
proposed definition had referred to ``mandatory requirements.'' Since a
requirement by its nature is mandatory, the word ``mandatory'' is
unnecessary.
11. Pest
The final rule defines ``pest'' as ``any objectionable insect or
other animal, including birds, rodents, flies, mites, and larvae.''
We did not receive any substantive comments on this definition.
However, on our own initiative, we made nonsubstantive, editorial
changes to delete the words, ``but not limited to'' after ``including''
and to place the word ``animals'' in the singular.
12. Physical Plant
The final rule defines ``physical plant'' as ``all or any part of a
building or facility used for or in connection with manufacturing,
packaging, labeling, or holding a dietary supplement.''
We received no substantive comments on this definition. The final
rule is substantially similar to the proposed rule's definition of
``physical plant.'' We added ``any'' and placed ``part'' in the
singular to clarify that individual parts of a building or facility are
subject to the CGMP requirements.
13. Product Complaint
The final rule defines ``product complaint'' as ``any communication
that contains any allegation, written, electronic, or oral, expressing
concern, for any reason, with the quality of a dietary supplement, that
could be related to current good manufacturing practice. Examples of
product complaints are: Foul odor, off taste, illness or injury,
disintegration time,

[[Page 34798]]

color variation, tablet size or size variation, under-filled container,
foreign material in a dietary supplement container, improper packaging,
mislabeling, or dietary supplements that are superpotent, subpotent, or
contain the wrong ingredient, or contain a drug or other contaminant
(e.g., bacteria, pesticide, mycotoxin, glass, lead).''
This definition modifies the proposed rule's definition of
``consumer complaint,'' which would define such a complaint as any
``communication that contains any allegation, written or oral,
expressing dissatisfaction with the quality of 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. 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.''
We explain the reasons for revising the proposed definition in our
response to the following comments.
(Comment 46) Some comments would broaden the definition of consumer
complaint to include complaints from dietary ingredient suppliers. One
comment would change ``consumer complaint'' to ``customer complaint.''
(Response) As discussed in section VI of this document, the final
rule does not apply to those who only manufacture dietary ingredients.
However, we encourage such firms that receive complaints about a
dietary supplement to share those complaints with those in the
manufacturing chain associated with that dietary supplement's
manufacture so others may take corrective action as needed. Those who
engage in the manufacture of a dietary supplement, including
manufacturing, packaging, labeling, and holding operations, are
responsible for complying with this final rule's product complaint
requirements.
Furthermore, we encourage packagers, labelers, and distributors who
receive a product complaint to notify those in a dietary supplement's
manufacturing chain about product complaints they receive or they,
themselves, generate that may relate to operations outside the
packagers', labelers', or distributors' control. For example, a
distributor who purchases a dietary supplement in bulk for packaging
and labeling may complain about product quality to the dietary
supplement manufacturer. The manufacturer who receives the complaint
must then take appropriate action to determine whether the complaint
involves a possible failure of a dietary supplement to meet any CGMP
requirements. Thus, the final rule revises the term ``consumer
complaint'' to ``product complaint'' to emphasize that the complaint is
about the product regardless of the complaint's source.
(Comment 47) One comment disagrees that ``disintegration time'' and
``tablet size'' are appropriate examples of complaints about product
quality specifications.
(Response) We disagree with this comment. Complaints about
disintegration time or tablet size could indicate a problem with the
production and process control system that may affect the quality of
the dietary supplement.
(Comment 48) Some comments disagree with the proposed definition of
``consumer complaint'' because it excluded an adverse event, illness,
or injury related to the safety of a particular dietary ingredient. The
comments say there should be a consistent approach for handling all
complaints, including adverse events. One comment states consumers will
not be able to determine whether a product quality issue related to
CGMP caused an adverse event. This comment expresses concern that not
classifying adverse events as consumer complaints could lead
manufacturers to avoid investigating certain adverse events and,
therefore, prevent them from determining the appropriate cause and
implementing the associated corrective action. The comments stress we
should not treat complaints related to CGMP issues differently from
other complaints and urged us to classify all adverse events as
consumer complaints, whether or not they might have been caused by a
particular dietary ingredient.
A few comments state the proposal, which did not specifically
address adverse event reporting, but did address the broader category
of consumer complaints and would require companies to investigate
``adverse event reports,'' may simply create more confusion and may
contradict the overall objective of a comprehensive adverse event
reporting system. The comments also state neither the food CGMP
regulations nor the 1997 ANPRM defined ``consumer complaints.'' The
comments say we should delete this definition and deal with consumer
complaints separately as part of the new CFSAN Adverse Event Reporting
System (CAERS).
One comment states we should define the term ``serious adverse
dietary supplement experience.'' The comment would define a ``serious
adverse dietary supplement experience'' as ``any adverse dietary
supplement experience occurring at any dose that results in any of the
following outcomes: death, a life-threatening adverse dietary
supplement experience, inpatient hospitalization or prolongation of
existing hospitalization, a persistent or significant disability/
incapacity, or a congenital anomaly/birth defect. Important medical
events that may not result in death, be life-threatening, or require
hospitalization may be considered a serious adverse dietary supplement
experience and, based upon appropriate medical judgment, they may
jeopardize the patient or subject and may require medical or surgical
intervention to prevent one of the outcomes listed in this
definition.''
(Response) We decline to include in the definition of ``product
complaint'' an adverse event related to the safety of a particular
dietary ingredient. The final rule establishes CGMP requirements for
dietary supplements and does not focus on whether dietary ingredients
that manufacturers may use in their dietary supplements are inherently
safe. Nevertheless, we encourage firms to investigate all complaints,
regardless of whether the complaints relate to CGMP. Furthermore,
mandatory reporting to FDA of serious adverse events is now required as
a result of the enactment of the ``Dietary Supplement and Non-
Prescription Drug Consumer Protection Act'' (Public Law 109-462),
signed into law on December 22, 2006. In any event, consistent with
these CGMP requirements, manufacturers must establish limits on
contamination, as needed, for all ingredients or any component they use
in manufacturing a dietary supplement.
We agree it may be unclear whether a particular product complaint
is related to CGMP. Final Sec. 111.560, relating to product
complaints, applies in situations where the product complaint involves
a ``possible failure of a dietary supplement to meet any of its
specifications or any other requirements of this part.'' Thus, if a
firm is unclear whether a particular complaint it receives relates to a
CGMP issue, we would consider that complaint to be related to a
``possible failure'' to meet CGMP. Consequently, the firm must

[[Page 34799]]

comply with the requirements in subpart O, unless the firm
affirmatively determines that the complaint is not related to a
``possible failure'' to meet CGMP, and therefore, is not a ``product
complaint.'' To make this clear, we revised the definition so that it
applies to any ``communication * * * that could be related to good
manufacturing practice'' rather than to be any ``communication * * *
that is related to good manufacturing practice.''
We disagree with comments that suggested that the requirements for
product complaints would somehow contradict the overall objective of
the CAERS. This final rule has no effect on the mandatory or voluntary
reporting of adverse events. We agree some adverse events may be
related to a failure to ensure the quality of the dietary supplement as
required by the final rule. To the extent that an adverse event is
associated with CGMP, it would be considered a ``product complaint''
under the final rule. The fact that it is considered a product
complaint does not mean that such complaint could not be voluntarily
reported as an adverse event through CAERS. Such a complaint may be
required to be reported under the mandatory reporting requirements of
the ``Dietary Supplement and Non-Prescription Drug Consumer Protection
Act'' (Public Law 109-462), signed into law on December 22, 2006. We
have added ``illness or injury'' to the final rule's definition of
``product complaint'' as an example of a product problem relating to
CGMP to help clarify that there may be some overlap in the type of
complaints related to product quality that may also be considered an
adverse event.
As for defining ``serious adverse dietary supplement experience,''
we decline to add such a definition to the final rule. We define
certain terms in a rule to give those terms a clear and consistent
meaning. None of the provisions in this rule addresses or even mentions
``serious adverse dietary supplement experiences,'' so there would be
no advantage in codifying a definition for the term in this final rule.
If, however, the comment meant to narrow the definition of ``consumer
complaint'' to ``serious'' illness, or injury, we decline to do so. If
a consumer reports an illness or injury, which he or she attributes to
consuming a dietary supplement, the report may indicate a problem with
the production and process control system for that dietary supplement,
even if the injury or illness is not ``serious'' or severe.
We have, however, decided to delete the last two sentences in the
proposed definition of ``consumer complaint'' (now ``product
complaint'' in the final rule). These sentences explained, in part,
that 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 CGMP. We deleted
those sentences because they are unnecessary to include in the
definition and can be included as further explanation of what the
definition of ``product complaint'' means in the preamble discussion.
The proposed definition of ``consumer complaint'' used the phrase
``expressing dissatisfaction with the quality of a dietary * * *
supplement;'' the final rule uses the phrase ``expressing concern, for
any reason, with the quality of a dietary supplement.'' This change is
to ensure that even if the consumer is not actually dissatisfied with
the product, but has a concern with the product, this is still handled
as a product complaint.
We made several editorial or grammatical changes to the definition
of product complaint in this final rule for simplicity and revised the
order of the listed examples of product complaints. For example, the
proposed definition of ``consumer complaint'' states the term ``means
communication that contains any allegation * * *.'' The final rule
defines ``product complaint'' as meaning ``any communication that
contains any allegation * * *.'' Another nonsubstantive change was to
insert the words ``dietary supplements that are'' before ``superpotent,
subpotent'' to give the reader a clear understanding as to the article
that is superpotent or subpotent.
Finally, we added ``electronic'' as an example of how a product
complaint could be communicated to ensure that all forms of
communication are included and added ``current'' to modify ``good
manufacturing practice'' for consistency.
We discuss in section V of this document, our general response to
the comment that stated that neither the food CGMP regulations nor the
1997 ANPRM contains a definition of ``consumer complaint,'' is in our
discussion of whether this final rule exceeds our authority or it has
to be identical to the food CGMP regulations. More specifically, we
acknowledge that the industry draft that we published in the 1997 ANPRM
did not define ``consumer complaint.'' The industry draft did contain
provisions that would be directed to ``complaint files.'' The
provisions for complaint files would require the use of written
procedures to handle complaints, retention of records of complaints for
a certain time period, and the inclusion of specific information in the
record of a complaint.
14. Quality
For purposes solely of this final rule we have decided to define
``quality.'' Quality means that the dietary supplement consistently
meets the established specifications for identity, purity, strength,
and composition and limits on contaminants and has been manufactured,
packaged, labeled, and held under conditions to prevent adulteration
under section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act.
(Comment 49) Some comments asked that we define ``quality.'' Some
comments claimed the proposal described ``quality'' in terms of
``identity,'' ``purity,'' and ``composition.'' One comment would define
``quality'' as ``the total characteristics of a product that bear on
its ability to satisfy stated (i.e., labeled) or implied needs of
identity, purity, strength and composition.'' Another comment would
define ``quality'' as ``having the appropriate identity, purity, and
strength for the intended purpose.'' Another comment would define
quality using all the other attributes of identity, purity, strength
and composition.
(Response) For purposes only of this final rule, we have added a
definition of quality. This definition is not intended to apply to CGMP
requirements other than those that apply to dietary supplements. In
section III of this document, in the overview discussion, we discuss
the concept of ``quality'' as it applies to these dietary supplement
CGMP requirements and the distinction between the use of the term in
the final rule and in the proposed rule.
Because we have defined ``quality'' as encompassing identity,
purity, strength, and composition, we have revised each section with
requirements for the ``identity, purity, quality, strength, and
composition'' to remove the word ``quality.'' The affected sections in
this final rule are: Sec. 111.3 (definition of batch); Sec. 111.3
(definition of lot); Sec. 111.65 (``What are the requirements for
quality control operations?''); Sec. 111.70 (``What specifications
must you establish?''); Sec. 111.75 (``What must you do to determine
whether specifications are met?''); Sec. 111.80 (``What representative
samples must you collect?''); Sec. 111.95 (``Under this subpart E,
what records must you make and keep?''); Sec. 111.105 (``What must
quality control personnel do?''); Sec. 111.455 (``What requirements
apply to holding components, dietary supplements, packaging, and
labels?''); and Sec. 111.515

[[Page 34800]]

(``When must a returned dietary supplement be bestroyed, or otherwise
suitably disposed of?'').
15. Quality Control
The final rule defines ``quality control'' as ``a planned and
systematic operation or procedure for ensuring the quality of a dietary
supplement.'' The proposed rule defined ``quality control'' as ``a
planned or systematic operation for preventing a dietary ingredient or
dietary supplement from being adulterated.''
(Comment 50) One comment suggests revising the definition to use
more positive language. Specifically, the comment would define
``quality control'' as ``a planned and systematic operation or
procedure for ensuring the quality of dietary supplement products.''
(Response) We agree that the comment's suggested language conveys a
positive concept about quality control's role and value and adopt the
language in part. The final rule's quality control requirements will
help ensure compliance with other CGMP requirements and, therefore,
will help ensure the quality of the dietary supplement and that the
dietary supplement is packaged and labeled as specified in the master
manufacturing record. We have defined the term ``quality'' in this
final rule as including preventing a dietary supplement from being
adulterated. Consequently, we revised the definition of ``quality
control'' to state that ``quality control'' means a planned and
systematic operation or procedure ``for ensuring the quality of a
dietary supplement.'' We deleted ``for preventing a dietary ingredient
or dietary supplement from being adulterated'' in the proposed
definition since the concept of quality includes preventing
adulteration.
16. Quality Control Personnel
The final rule defines ``quality control personnel'' as ``any
person, persons, or group, within or outside your organization, who you
designate to be responsible for your quality control operations.''
(Comment 51) Some comments seem to suggest that the reference in
the 2003 CGMP Proposal to a ``quality control unit'' mandates a
separate unit or department with responsibility for all quality control
operations. One comment explains many companies do not have one quality
control unit with oversight of all operations within the facility. This
comment states companies commonly have each separate section of an
operation perform both its function and its own quality control. A few
comments would clarify the definition by indicating that a distinct or
separate unit need not perform the quality control function. These
comments say the quality control function is best performed by a person
or persons qualified by training, education, or experience in the
different processing areas.
Many comments say we should consider any individual carrying out a
quality control function to be part of the quality control unit for
purposes of this rule.
(Response) We agree that the quality control function is best
performed by a person or persons qualified by training, education, or
experience in relevant areas. To the extent that the comments
interpreted the proposed definition as requiring firms to have a
separate person or group whose sole function in the company is to
perform quality control operations or that the quality control
functions are limited to those who are employed within the firm, we
disagree. As discussed in the preamble to the proposal, the quality
control unit should consist of as many people as necessary to perform
the quality control operations (68 FR 12157 at 12252). We have
reconsidered the use of the term ``unit.'' In order to clarify that we
do not intend to require a separate division or office be created, we
instead use the term ``personnel.'' Although we have eliminated
references to ``unit,'' we still agree that personnel can be a person,
persons, or a group, and as many persons as necessary, who perform the
quality control operations. The manufacturer must identify the
appropriate person or persons to be responsible for the quality control
operations associated with a particular manufacturing operation. For
example, the manufacturer may designate one individual as a packaging
expert who is responsible for the quality control operations related to
packaging, designate a second individual as an expert in deciding
whether to accept or reject incoming components, and designate a third
individual as an expert in deciding whether in-process specifications
are met at certain control points. The definition does not limit the
other activities that these designated individuals may perform within
the manufacturing operations; thus, for example, the packaging expert
who performs the quality control function for packaged dietary
supplements could also have responsibilities in the actual packaging
operation. Quality control responsibilities and specific activities are
distinct and separate from any other responsibilities and specific
activities that an employee might perform for any other operation. In
addition, the quality control operations may be performed by someone
outside the organization (such as a contractor).
To clarify these points and to prevent potential misinterpretation
of quality control operations, we revised the definition of ``quality
control unit.'' Instead of a unit, quality control personnel who
perform quality control operations may be a person, persons, or group
and may be ``within or outside of your organization.'' We also added a
new Sec. 111.12(b) to require you to identify who is responsible for
your quality control operations. Under final Sec. 111.12(b) each
person who is identified to perform quality control operations must be
qualified to do so and have distinct and separate responsibilities
related to performing such operations from those responsibilities that
the person otherwise has when not performing such operations.
Throughout the codified, we use the term ``quality control personnel''
when referring to the performance of specific quality control
operations. The term ``quality control personnel'' refers to the person
or persons designated to perform the particular quality control
operation.
17. Representative Sample
The final rule defines ``representative sample'' as ``a sample that
consists of an adequate number of units that are drawn based on
rational criteria, such as random sampling, and that are intended to
ensure that the sample accurately portrays the material being
sampled.'' This definition is similar to the proposed definition of
``representative sample.'' We have added ``an adequate'' before
``number'' to emphasize that the sample must be sufficient for its
purpose. We also made nonsubstantive grammatical changes to insert
``that are'' between ``and'' and ``intended.''
(Comment 52) Some comments note the proposed rule would use the
terms ``representative sample,'' ``reserve sample,'' and
``representative reserve sample'' but would only define
``representative sample.'' The comments ask us to clarify the
distinction, if any, between these terms.
(Response) A ``reserve sample'' is a sample that is to be held or
kept for a designated time. It differs from a ``representative sample''
in the sense that a representative sample is not always kept; for
example, one might take a representative sample to test product
quality, but one would not necessarily keep every tested sample.
To clarify this distinction, the final rule now defines a ``reserve
sample'' as ``a representative sample of product that

[[Continued on page 34801]]

From the Federal Register Online via GPO Access [wais.access.gpo.gov]
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[[pp. 34801-34850]] Current Good Manufacturing Practice in Manufacturing, Packaging,
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[[Page 34801]]

is held for a designated period of time.'' We also revised the rule to
refer solely to a ``reserve sample'' rather than use both ``reserve
sample'' and ``representative reserve sample.''
18. Reprocessing
The final rule defines ``reprocessing'' as ``using, in the
manufacture of a dietary supplement, clean, uncontaminated components
or dietary supplements that have been previously removed from
manufacturing and that have been made suitable for use in the
manufacture of a dietary supplement.'' We modified the definition that,
in part, read ``* * * dietary supplements that have been previously
removed from manufacturing for reasons other than insanitary
conditions'' by removing ``for reasons other than insanitary
conditions'' to expand the scope of what may be reprocessed. We explain
the reason for the latter change in our response to the following
comments. We also changed ``unadulterated'' to ``uncontaminated'' to be
consistent with the revisions we have made in other sections, including
the definition of quality.
(Comment 53) Some comments ask us to clarify whether components or
dietary supplements that have been successfully treated to reduce
microbial levels to acceptable levels can be reprocessed. Some comments
object to the proposed definition of ``reprocessing'' because it did
not include components or dietary supplements removed for insanitary
conditions, and several comments object to the restrictions to
reprocessing described in proposed Sec. Sec. 111.35(i)(4)(iii) and
111.50(f), because, they argue, the definition and sections associated
with reprocessing would not permit the reprocessing of previously
insanitary ingredients even if there are processes available that are
safe and effective in removing foreign matter, microorganisms, or
chemicals that may have rendered the ingredient ``insanitary.'' One
comment would revise the definition as follows: ``Reprocessing means
using, in the manufacture of a dietary supplement, clean, unadulterated
components * * * or dietary supplements that have been previously
removed from manufacturing for reasons other than insanitary conditions
or that have been successfully reconditioned so that they are suitable
for use.''
(Response) We agree that materials can be treated, subjected to in-
process adjustments, or reprocessed when there are suitable processes
available, and we revised the definition of ``reprocessing'' to reflect
this. However, there must be appropriate oversight of the treatment,
in-process adjustments, and reprocessing so the dietary supplement will
still meet required specifications. Therefore, we added a conforming
requirement to final Sec. Sec. 111.90(b) and 111.140(b)(3)(vi) to
require oversight by quality control personnel for any reprocessing,
treatment, or in-process adjustment of a dietary supplement that have
been previously removed from manufacturing and that have been made
suitable for use in the manufacture of a dietary supplement (see
sections X and XI of this document).
19. Reserve Sample
The final rule contains a new definition of ``reserve sample.''
``Reserve sample'' is defined as ``a representative sample of product
that is held for a designated period of time.'' We explain our reasons
for creating this definition in this section under the definition of
``representative sample.''
20. Sanitize
The final rule defines ``sanitize'' as ``to adequately treat
cleaned equipment, containers, utensils, or any other cleaned contact
surface by a process that is effective in destroying vegetative cells
of microorganisms of public health significance, and in substantially
reducing numbers of other microorganisms, but without adversely
affecting the product or its safety for the consumer.''
The final rule's definition of ``sanitize'' differs from the
proposal in that the proposed definition would have specified a
reduction of 5 logs or 99.999 percent reduction of ``representative
disease microorganisms of public health significance'' and ``other
undesirable microorganisms'' and would have specified the use of heat
or chemicals. The preamble to the 2003 CGMP Proposal explained that we
based the proposed definition of ``sanitize'' on the definition of
``sanitization'' in the ``Food Code'' (which is a model that gives food
control authorities a scientifically sound technical and legal basis
for regulating the retail and food service segment of the industry)
because dietary supplements are often consumed without further
processing, similar to foods consumed in retail outlets (68 FR 12157 at
12179). The preamble to the 2003 CGMP Proposal also explained that, to
achieve the reduction levels in the proposed definition, one would need
to validate control measures to ensure they are both appropriate to
their operation and scientifically sound. The preamble explained that
in many cases, manufacturers 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 99.999 percent reduction in the
target pathogen, to ensure the process is adequate to destroy
microorganisms of public health significance or to prevent their
growth.
(Comment 54) Many comments object to the proposed text concerning
the application of heat or chemicals to a food contact surface to yield
a reduction of 5 logs or 99.999 percent of representative disease
organisms of public health significance. The comments state the aspect
of the proposed definition is overly prescriptive, beyond our legal
authority, and would not provide additional public health benefits.
Many comments say it is inappropriate to use the definition of
sanitization from our Food Code because retail and manufacturing
operations are distinct. A few comments assert the process of
manufacturing dietary supplements shares more in common with food or
drug manufacturing than with retail operations. Most comments recommend
that we define ``sanitize'' in the manner that was presented in the
1997 ANPRM and consistent with the current food CGMP definition at
Sec. 110.3 so that ``sanitize'' means ``to adequately treat dietary
product contact surfaces by a process that is effective in destroying
vegetative cells of microorganisms of public health significance, and
in substantially reducing numbers of other undesirable microorganisms,
but without adversely affecting the product or its safety for the
consumer.''
One comment states that consistently validating the effectiveness
of the sanitizing procedure is impractical and recommended we state
instead that equipment, utensils, etc., should be cleaned and sanitized
in a manner that keeps undesirable microorganisms and other adulterants
from contaminating all components, ingredients, in-process materials,
and finished product. The comment claims that, by this approach, the
microbial and analytical test results of product produced on a
facility's equipment, coupled with random testing of final rinse water
after cleaning and sanitizing equipment and utensils, would provide
sufficient and continuous evidence of a proper and effective cleaning
and sanitizing plan.
Two comments claim that the proposed definition for sanitize
denotes ``validation methodology'' found in drug CGMP, and that we must
base dietary supplement CGMP on food rather than on drug standards.

[[Page 34802]]

Other comments express concern about validating control measures to
ensure that they are scientifically sound and appropriate to operations
and the economic burden to do the testing. A few comments state it
would be difficult to show a 100,000-fold reduction on an already
cleaned surface, particularly if the pre-sanitization level is at or
near the lower limit of the test method employed.
One comment states the definition required the manufacturer to
demonstrate a 100,000-fold reduction in microbial count every time a
food contact surface is sanitized. A few comments express concern that
processing lines would have to be closed down each time they are
sanitized in order to test them, creating a financial hardship
especially on smaller operations. Other comments ask us to give
companies the flexibility necessary to monitor sanitation needs based
on individual products and manufacturing operations to be consistent
with existing industry practices and food and drug CGMPs.
One comment requests we clarify that a sanitizing agent for use on
food processing equipment must be approved in accordance with part 178,
Indirect Food Additives: Adjuvants, Production Aids, and Sanitizers (21
CFR part 178) and our expectations with respect to what documentation
would be necessary to prove the effectiveness of the sanitizer used.
Two comments say the proposed definition of sanitize means that
manufacturers must perform validation studies to demonstrate that the
sanitizers they are using reduce the microbial load on equipment by
100,000-fold, a requirement for a ``sanitizer'' under regulations
issued by the Environmental Protection Agency. The comments say a
sanitizer should not be held to this standard for the purpose of
reducing microbial loads on food product contact surfaces, and that
manufacturers of a solid dosage form may not need to ``sanitize'' their
equipment because the processing environment is not suitable for
microbial growth due to the low water activity. One comment recommended
using the approach in the Food Code, which specifies conditions under
which chemical sanitizers listed in Sec. 178.1010 may be used,
including the requirement that they be used in accordance with the
Environmental Protection Agency-approved manufacturer's label use
instructions, and be used for dietary supplements rather than imposing
a validation requirement on manufacturers.
Some comments would divide the definition of ``sanitize'' by
creating separate definitions for ``sanitize'' and ``sanitizing
agent.'' The comments would define ``sanitize'' as meaning ``to
adequately treat equipment, containers, utensils, or any other dietary
product contact surface by applying a sanitizing agent on cleaned food
contact surfaces.'' One comment would define ``sanitizing agent'' as
``cumulative heat or chemicals 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.'' Another comment would define ``sanitizing agent'' in a
similar manner, except it would omit references to a 5-log reduction.
(Response) The proposed definition of ``sanitize'' was intended to
give firms the flexibility to monitor sanitation needs based on their
products and operations. We did not intend to suggest that
manufacturers had to demonstrate a 100,000-fold reduction in microbial
count every time they sanitized a contact surface, nor did we intend,
as some comments claimed, to have firms close down processing lines
every time they were sanitized to test them for microbial reduction.
Rather, the language of the proposed rule was intended to make it clear
that processes used to sanitize contact surfaces should be effective.
However, we recognize that the proposed definition caused confusion as
to our intent. The proposed definition may have been interpreted as
proposing validation to ensure an area was sanitized; however our
intent was simply to require that effective sanitizers and sanitizing
processes be used, just as in food establishments. Therefore, in order
to clarify the provision, we have revised the definition of
``sanitize'' to be consistent with Sec. 110.3(o). The final rule
defines ``sanitize'' as adequately treating ``cleaned equipment,
containers, utensils, or any other cleaned contact surface by a process
that is effective in destroying vegetative cells of microorganisms of
public health significance, and in substantially reducing numbers of
other microorganisms, but without adversely affecting the product or
its safety for the consumer.'' The final definition of sanitize does
not include any statements about mechanisms that you may use to achieve
compliance because including such nonbinding information is
inconsistent with our current practices for establishing regulations.
We note that the Environmental Protection Agency has regulatory
authority over certain uses of sanitizers as pesticide chemicals and we
have regulatory authority over certain uses of sanitizers as food
additives. Under section 201(q)(1)(B) of the act, as amended by the
Food Quality Protection Act (FQPA) (Public Law 104-170) and the
Antimicrobial Regulation Technical Corrections Act (ARTCA) (Public Law
105-324), certain substances used as food contact surface sanitizing
solutions are subject to the Environmental Protection Agency's
regulatory authority as pesticide chemicals. The Environmental
Protection Agency recently codified tolerance exemptions under section
408 of the act (21 U.S.C. 346a) for those food contact surface
sanitizing solutions that were previously subject to our authority at
Sec. 178.1010 and transferred to the Environmental Protection Agency's
authority under FQPA and ARTCA (see 40 CFR 180.940 (69 FR 23113, April
28, 2004). Such pesticide chemicals must comply with the Pesticide
Tolerance regulations in 40 CFR 180.940. Sanitizers used on food
packaging must comply with our regulations at Sec. 178.1010. For an in
depth discussion of appropriate sanitizers for food contact surface
use, see the Environmental Protection Agency's Pesticides; Tolerance
Exemptions for Active and Inert Ingredients for Use in Antimicrobial
Formulations (Food Contact Surface Sanitizing Solutions) (69 FR 23113,
April 28, 2004) and DIS/TSS-4 Efficacy Data Requirements Sanitizing
Rinses (for previously cleaned food-contact surfaces) (January 30,
1979) (Ref. 27) (available on the Internet at http://www.epa.gov/oppad001/dis_tss_docs/dis-04.htm
).

21. Theoretical Yield
The final rule defines ``theoretical yield'' as ``the quantity that
would be produced at any appropriate step of manufacture or packaging
of a particular 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 received no substantive comments on the proposed definition.
22. Water Activity
The final rule defines ``water activity'' as ``a measure of the
free moisture in a component 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 received no substantive comments on the proposed definition.

[[Page 34803]]

23. We
The final rule explains that ``we'' means the United States Food
and Drug Administration.
The final rule's definition is identical to the proposed
definition. We received no substantive comments on the proposed
definition.
24. You
The final rule defines ``you'' as a ``person who manufactures,
packages, labels, or holds dietary supplements.''
25. What Other Terms Did the Comments Want Defined?
(Comment 55) Some comments ask us to define ``adulteration'' (based
on the provisions of section 402 of the act), ``dietary ingredient,''
and ``dietary supplement'' (based on the definition in section 201(ff)
of the act).
(Response) We decline to revise the rule as suggested by the
comments. The terms have meaning within the context of the act and case
law. Further, under final Sec. 111.3 the act's definitions and
interpretations ``apply to such terms when used in this part.'' Thus,
there is no need for us to define the terms as requested by the
comments.
(Comment 56) Proposed Sec. 111.35(e)(2) would require a person to
establish a specification for any point, step, or stage in the
manufacturing process where control is necessary to prevent
adulteration, and proposed Sec. 111.35(f) would require monitoring of
the in-process control points, steps, or stages to ensure these
established specifications are met and to detect any unanticipated
occurrence that may result in adulteration. Some comments ask us to
define the term ``control point'' as ``any point, step or stage in the
manufacturing process where control is necessary to prevent
adulteration.''
(Response) We decline to add a definition of ``control point'' as
requested by the comments. Instead, we revised final Sec. 111.75(b)
(formerly proposed Sec. 111.35(f)) to state that you must monitor the
in-process points, steps, or stages where control is necessary to
ensure the quality of the finished batch of dietary supplement; this
revision eliminates the need to define ``control point.''
(Comment 57) Several comments would have us define one or more of
the following terms: Identity, purity, strength, and composition. Some
comments suggest specific text for the definitions.
Similarly, some comments suggest codifying the preamble description
that we used for these terms, i.e., 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) (68 FR 12157 at 12176). One comment says ``identity''
should mean ``a substance or product is what it is represented on the
label to be.''
One comment says that it does not seem appropriate to define the
term ``purity'' to mean ``without impurities.'' The comment states it
would be difficult to consider an herbal extract as being ``pure''
because it is a mixture of naturally occurring compounds in a solvent.
Another comment suggests the term ``purity'' be defined to mean ``free
from objectionable and/or deleterious levels of impurities including,
but not limited to, heavy metals, pesticides, mycotoxins,
radioactivity, filth, extraneous material, molds, yeasts and
bacteria.'' Another comment suggests defining the term ``purity'' as
``having the intended identity and composition and being without
significant impurities.'' However, the comment does not explain what is
meant by ``without significant impurities.''
One comment suggests defining the term ``strength'' as ``having the
intended concentration, that is, the amount of the dietary ingredient
per unit of use (tablet, capsule, soft gel, teaspoon, or other unit).''
Another comment expresses concern about the use of the term
``strength'' in relationship to nonstandardized herbals because there
are no current industry standards for these products. This comment
suggests we clarify the term ``strength'' so it refers to having the
correct amount of a stated ingredient. One comment notes St. Johns wort
has a composition of approximately 40 different constituents in
addition to the essential oil that contains numerous constituents. The
comment asks which constituent it should use to determine ``strength.''
Another comment would use the term ``quantity'' instead of
``strength.''
One comment would define ``composition'' as ``having the intended
mix of components or ingredients, including dietary ingredients.''
Another comment would delete ``composition'' from the rule because, the
comment claimed, an FDA investigator might conclude that
``composition'' refers to every constituent of every botanical.
According to this comment, there are many tests that could be used to
identify the botanical constituents, but that it would be economically
exhausting considering the number of botanical constituents, and it
would not contribute to quality or safety.
(Response) We decline to revise the rule to define identity,
purity, strength, or composition. The exact way in which the dietary
supplement industry uses these terms may vary, and defining these terms
could limit the flexibility that is needed to accommodate such
variations.
Nevertheless, to elaborate on our interpretation of identity,
purity, strength, and composition, and to respond to the particular
concerns raised by some comments, we provide the following information.
a. Identity. The ``identity'' of a dietary supplement refers to the
dietary supplement's consistency with the master manufacturing record
and/or that it is the same as described in the master manufacturing
record.
b. Purity. The ``purity'' of a dietary supplement refers to that
portion or percentage of a dietary supplement that represents the
intended product. For example, amino acids generally can exist in two
forms (i.e., dextro (D-, or right) and levo (L-, or left) forms) called
enantiomers. Enantiomers have the same chemical formula and the same
chemical structure, but differ in their three-dimensional orientation.
If you manufacture a dietary supplement to provide the amino acid L-
arginine, and you determine that 90 percent of the manufactured product
is L-arginine and 10 percent of the manufactured product is D-arginine,
you could describe your L-arginine product as ``90 percent pure.'' As
another example, if you manufacture a mixture of triglycerides that
provides polyunsaturated fatty acids in the diet, the manufactured
triglycerides may contain small amounts of free fatty acids and
sterols. The free fatty acids and sterols could derive, for example,
from the source of the triglycerides or could be byproducts of the
manufacturing process. If you determine that 95 percent of the
manufactured product is the mixture of the triglycerides that provides
the polyunsaturated fatty acids, and 5 percent of the product is free
fatty acids and sterols, you could describe the purity of your product
as ``95 percent pure.''
Just as we use the term ``purity'' to refer to the identity and
amount of a dietary supplement that is the desired product, we use
``impurity'' to refer to the identity and amount of a dietary
supplement that is not the desired product. In the previous examples,
we

[[Page 34804]]

view the D-arginine that is present in the product that is intended to
be L-arginine as an ``impurity,'' and we view the free fatty acids and
sterols that are present in the product that is intended to be a
mixture of triglycerides that provide polyunsaturated fatty acids in
the diet as ``impurities.'' For the purposes of these examples, we do
not view these ``impurities'' as ``contaminants.''
If the comments were concerned that the dietary supplement CGMP
requirements regarding a dietary supplement's ``purity'' mean that we
expect you to characterize each constituent of a natural product to
determine whether each constituent is present in a certain pre-
established quantity (i.e., purity specification) to determine whether
it contributes to the ``purity'' of the dietary supplement or would be
considered as an ``impurity,'' we do not consider such constituents to
be ``components'' of a dietary supplement (see discussion of the
definition of component in this section). For example, if you
manufacture a dietary supplement containing fish oil, we would not
consider the triglycerides, which are constituents of the fish oil, to
be components. Likewise, we would not consider particular fatty acids
(such as the polyunsaturated fatty acids docosahexaenoic acid (DHA) and
eicosapentaenoic acid (EPA)), which are constituents of the
triglycerides, to be components of the dietary supplement. In this
example, you would be required to establish a purity specification for
the amount of triglycerides in the fish oil. (Note that if you are
manufacturing fish oil to provide the fatty acids DHA and EPA in the
dietary supplement, the component specifications for the fish oil must
include a strength specification for DHA and EPA in whatever amount you
determine is necessary to meet the specification for strength of DHA
and EPA in the dietary supplement.) We do, however, expect you to set
appropriate limits on contaminants (e.g., toxic substances) that are
known to be constituents of botanical extracts or other natural
products that are likely or certain to contain constituents that are
harmful.
c. Strength. The strength of a dietary supplement relates to its
concentration. By concentration, we mean the quantitative amount per
serving (for example, weight/weight, weight/volume, or volume/volume).
Therefore, for purposes of this final rule, strength does not refer
simply to the quantity of an ingredient, rather it refers to the amount
of a stated ingredient per a specified unit of measure.
If the comments were concerned that the ``strength'' of a dietary
supplement meant that you need to establish the quantitative amount per
unit of measure of each constituent in a dietary ingredient, such as a
botanical extract or natural product, we do not consider such
constituents to be ``components'' of a dietary supplement, unless you
add such constituents as components (as in an extract) (see discussion
of the definition of component in this section).
We do not consider the rule's requirements on dietary supplement
strength as necessarily relating to the individual constituents of such
products. Whether the requirements regarding dietary supplement
strength apply to one or more constituents of dietary ingredients in a
dietary supplement depends on what you are manufacturing. For example,
if you are manufacturing vitamin C, and your source of vitamin C is
rosehips, you would establish a strength specification for vitamin C in
the finished batch of the dietary supplement (e.g., ``x milligrams (mg)
of vitamin C per tablet''). You are required to ensure that the dietary
supplement does in fact contain ``x mg of vitamin C per tablet.''
Alternatively, if you are manufacturing rosehips and not vitamin C from
rosehips, the strength specification that you establish for the
finished batch of the dietary supplement is the strength of the
rosehips themselves (i.e., the concentration of rosehips in the final
product, such as ``x mg of rosehips per tablet''). You are required to
ensure that the product does in fact contain ``x mg of rosehips per
tablet.''
We discuss the requirements to establish and meet specifications in
our discussion of subpart E (see section X of this document).
d. Composition. A dietary supplement's ``composition'' refers to
the specified mix of product and product-related substances in a
dietary supplement. For example, a dietary supplement manufactured to
provide vitamin C may contain, in addition to vitamin C, a tablet
coating agent and substances used as binders. The composition could be
described as the percent of the dietary supplement that is vitamin C,
the tablet-coating agent, and each binder.
e. Other terms.
(Comment 58) Several comments would revise the rule to define
``manufacturer.'' Many comments ask whether the rule applies to certain
types of companies or professionals and said a definition of
``manufacturer'' would clarify the rule's applicability.
Some comments suggest specific text for a definition. For example,
one comment would define ``manufacturer'' as ``a person who formulates
or changes the composition or physical characteristics of a dietary
supplement or who packages or labels the product in a container for
distribution'' to clarify that a company that does not manufacture a
specific dietary supplement, but purchases a dietary supplement in bulk
and then packages or labels the bulk dietary supplement for sale to
consumers, is still subject to dietary supplement CGMP requirements.
The comment cites our proposed definition of ``manufacturer'' in our
infant formula CGMP proposal (see 61 FR 36154 at 36209, July 9, 1996
(proposing to define a ``manufacturer'' as ``a person who prepares, re-
constitutes or otherwise changes the physical or chemical
characteristics of an infant formula or packages or labels the product
in a container for distribution'')).
Other comments would define ``manufacturer'' to exclude a health
care practitioner or herbalist and noted the Canadian Natural Health
Product regulations do not apply to health care practitioners.
(Response) We decline to define ``manufacturer'' in the final rule.
In section III, footnote 1 of this document, we explain that
``manufacture'' is a broad term and is not limited to production,
packaging, or labeling activities. Consequently, we prefer to explain
our interpretation of the final rule in this preamble and to have the
codified provisions state general principles rather than attempt to
capture subtleties in a definition of ``manufacturer.''
(Comment 59) Proposed Sec. 111.35(e)(1) through (e)(3) would
require you to establish specifications for identity, purity, quality,
strength, and composition at receipt, in-process, and finished batch
stages, while proposed Sec. 111.35(g)(1) would require you to test
each dietary supplement at the finished batch stage before release for
distribution to confirm that specifications are met, provided that
there are scientifically valid analytical methods available to perform
such testing. If your quality control unit determined that finished
batch testing could not be completed for any specification because a
scientifically valid analytical method was not available, proposed
Sec. 111.35(g)(2) and (g)(3) would require you to perform testing on
components and at the in-process stage to determine whether that
specification is met. The preamble to the 2003 CGMP Proposal explained
that a scientifically valid analytical method is one that is based on
scientific data or

[[Page 34805]]

results published in, for example, scientific journals, references,
text books, or proprietary research (68 FR 12157 at 12198).
Several comments agree that scientifically valid analytical methods
are those that are based on scientific data or results published in
scientific journals, references, textbooks, or proprietary research.
However, several comments ask us to define or better explain the terms
``test'' or ``scientifically valid analytical method'' as used in the
dietary supplement CGMP final rule. One comment argues that, because of
the evolving nature of methodology for ingredients used in dietary
supplements, we should give the industry more guidance as to what can
be considered authoritative for the purpose of compliance with CGMP.
Some comments state we should acknowledge methods from the Institute
for Nutraceutical Advancement (INA), American Herbal Pharmacopoeia
(AHP), European Pharmacopoeia, and the World Health Organization (WHO)
as scientifically valid analytical methods. One comment notes the USP
establishes scientifically valid procedures in its compendia and
encouraged us to designate compendial procedures as ``scientifically
valid'' by defining ``scientifically valid'' to include compendial
procedures. The comment further argues that failure to acknowledge
compendial procedures as scientifically valid would be inconsistent
with section 403(s)(2)(D) of the act, which acknowledges the role of
compendia, by considering a dietary supplement misbranded if the
supplement is covered by the specifications of an official compendium,
is represented as conforming to the specifications of an official
compendium, and fails to so conform.
Other comments would define ``validation'' and ``verification'' and
directed us to ``ANSI Standard A8402-1994'' (a description of
validation and verification standards).
(Response) We decline to define ``test,'' ``scientifically valid
analytical method,'' or ``scientifically valid method'' in this final
rule. As the comments recognized, the analytical methods for components
are evolving. A regulatory definition for ``test,'' ``scientifically
valid analytical method,'' or ``scientifically valid method'' could
become obsolete if we based it on specific sources such as INA, AHP, or
USP that may or may not themselves stay current or that may be modified
in a manner that did not enjoy widespread support.
The preamble to the 2003 CGMP Proposal acknowledged that compendia
can have a role in establishing tests used to determine whether
specifications are met. For example, we noted that compendial standards
may be appropriate reference materials for use in conducting tests or
examinations (68 FR 12157 at 12208). However, we did not list specific
compendia that would be suitable sources or scientifically valid
analytical tests, and are not listing such compendia in this final
rule. The compendia identified in the comments, i.e., INA, ANSI, AHP,
and USP, may include some methods that are based on scientific data or
results published in scientific journals, references, textbooks, or
proprietary research, but also contain some methods that are not based
on such data or results. Thus, whether or not a method is
scientifically valid is not determined solely by its inclusion in a
compendium. Rather, it is the responsibility of quality control
personnel to approve the use of those scientifically valid tests that
will ensure a product's identity, purity, strength, and composition
whether or not such tests are contained in a particular compendium.
We also decline to define ``validation'' and ``verification''
because the final rule does not establish any requirements that use
these terms.
(Comment 60) One comment asks us to define the terms ``adequate,''
``sufficient,'' and ``qualified'' and argues that, without these
definitions, an FDA investigator may assert that something or someone
is not adequate, sufficient, or qualified.
(Response) We decline to define ``adequate,'' ``sufficient,'' or
``qualified'' in this final rule. Deciding what is ``adequate'' or
``sufficient,'' or who is ``qualified'' must be done on a case-by-case
basis, depending on the operations and the particular facts. As
explained in section V of this document, we do not need to, nor could
we, predict with mathematical precision how many inches or feet, for
example, would be ``adequate space'' to allow for cleaning a particular
piece of equipment that could be applied to every size of facility and
every operation. Furthermore, defining ``adequate,'' as defined in part
110, as ``that which is needed to accomplish the intended purpose in
keeping with good public health practice'' would still require context
to determine whether, in a particular operation and based on a
particular set of facts the particular practice was ``adequate.''
Moreover, for terms such as ``adequate,'' ``sufficient,'' and
``qualified,'' where there has been common usage in the food industry
to enable manufacturers and FDA investigators to comprehend and apply
such terms to a particular operation, we do not believe a definition
for these terms is necessary.
(Comment 61) Several comments would define the terms ``certificate
of analysis,'' ``certificate of compliance/conformance,'' and
``continuing product guarantee.'' Most comments include these terms in
a list of terms that they want us to define to ensure consistent
interpretation of the rule throughout the industry. One comment says a
standard for documentation, such as a certificate of analysis, would
put greater emphasis on the firm's responsibility to comply with CGMP.
(Response) We decline to define these terms as suggested by the
comments. We have included, in the codified, the use of a certificate
of analysis as an option to determine whether certain specifications
have been met. The final Sec. 111.75(a)(2)(ii)(B) requires that
certain information be provided in a ``certificate of analysis.'' This
provision states that the certificate of analysis must include a
description of the test or examination method(s) used, limits of the
test or examinations, and actual results of the tests or examinations,
provided you satisfy certain other criteria.
As for the claim that a standard for documentation, such as a
certificate of analysis, would emphasize a firm's responsibility to
comply with CGMP, we encourage firms who are excepted from the scope of
the rule in final Sec. 111.1 and who supply dietary ingredients and
other components to follow dietary supplement CGMP requirements.
We decline to define ``certificate of compliance/conformance'' or
``continuing product guarantee'' because the final rule does not
establish any requirements that use these terms.
26. What Definitions Did the Comments Want Us to Delete?
(Comment 62) Some comments would delete certain definitions (e.g.,
``component'' and ``ingredient'') because these terms do not appear in
the food CGMP, the 1997 ANPRM, or both.
(Response) We decline to delete any definition for the reasons
stated by the comments. As discussed in section V of this document,
Congress did not require dietary supplement CGMP requirements to be
identical to the food CGMP requirements, so the mere fact that a
definition may not appear in a food CGMP regulation does not mean we
must delete that definition from this final rule, especially when the
comments offered no other justification for deleting the definition.
Definitions

[[Page 34806]]

provide clarity and consistency in interpreting various terms in a
rule.

D. Do Other Statutory Provisions and Regulations Apply? (Final Sec.
111.5)

Final Sec. 111.5 states: ``In addition to this part, you must
comply with other applicable statutory provisions and regulations under
the act related to dietary supplements.'' Proposed Sec. 111.5 stated
that, in addition to the dietary supplement CGMP requirements, ``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.''
Section 111.5 reminds you that other statutory or regulatory
requirements, not included in the dietary supplement CGMP requirements,
may apply to your particular products, operations, or activities. In
our further review of this provision, we determined that we do not need
to elaborate on the individual operations and have shortened the
provision to eliminate the references to particular operations. You are
required to comply with other applicable statutory and regulatory
requirements, and we have retained this provision to ensure you
understand that this final rule does not relieve you of your
responsibilities to comply with other applicable statutory and
regulatory requirements related to dietary supplements.

E. What Sections Did We Remove From the Rule, and Why?

The final rule omits sections that were in the proposed rule.
Proposed Sec. 111.2, ``What Are These Regulations Intended to
Accomplish,'' would have described the rule's purpose as establishing
the minimum CGMP you must use to the extent that you manufacture,
package, or hold a dietary supplement. Proposed Sec. 111.6,
``Exclusions,'' would have excluded ``persons engaged solely in
activities related to the harvesting, storage, or distribution of raw
agricultural commodities that will be incorporated into a dietary
supplement by other persons'' from the dietary supplement CGMP
requirements.
1. ``What Are These Regulations Intended to Accomplish?'' (Proposed
Sec. 111.2)
We elected to remove proposed Sec. 111.2 from the final rule
because we realized that it created no enforceable obligations and
provided little, if any, helpful information. The few comments that
address proposed Sec. 111.2 either disagreed with its general
statement or sought to weaken the provision; the comments' arguments
prompted us to reconsider whether proposed Sec. 111.2 was necessary at
all, and, in the end, we decided to delete the proposed section. We
describe the comments on proposed Sec. 111.2 in the following
paragraphs.
(Comment 63) Several comments argue the proposed rule went beyond
the ``minimum standards'' mentioned in proposed Sec. 111.2. These
comments also assert the proposed rule lacked flexibility.
(Response) We disagree with the comments. In several instances, the
proposed requirement is practically identical to requirements in the
umbrella food CGMP regulations. For example, most of the proposed
requirements for personnel, physical plants, and equipment and utensils
correspond to long-established, similar requirements in the umbrella
food CGMP regulations in part 110. In other instances, the proposed
rule would require a particular action or result (such as establishing
specifications for components, in-process controls, manufactured
dietary supplements, and packaged and labeled dietary supplements under
proposed Sec. 111.35(e)), but gave firms the flexibility and the
responsibility to decide what those specifications will be. We have
included flexibility where it is appropriate to do so, and, after we
revised parts of the rule in response to the comments, the final rule
provides more flexibility than the proposal. For example, final Sec.
111.75 sets forth criteria for relying on a certificate of analysis to
ensure that certain specifications for components are met and for when
you can test a subset of finished batches for a select number of
specifications; this differs considerably from the proposal which would
have required testing all batches for all specifications.
(Comment 64) One comment would revise proposed Sec. 111.2 to read
as follows: ``These regulations recommend general minimum current good
manufacturing practices that, when modified by manufacturer product
specifications, will extend to the manufacture, package, or holding of
dietary ingredients or dietary supplements for that manufacturer.''
(Response) We decline to revise the rule as suggested by the
comment. Section 402(g) of the act states that ``The Secretary may by
regulation prescribe good manufacturing practices for dietary
supplements.'' If a dietary supplement has been prepared, packaged,
labeled, or held under conditions that do not meet the final rule's
requirements, the dietary supplement is deemed to be adulterated under
section 402(g)(1) of the act. Here, the comment's suggestion that
dietary supplement CGMP requirements could be ``modified by
manufacturer product specifications'' would create uncertainty over
whether manufacturers could unilaterally ``modify'' their product
specifications to fit a batch that failed to meet specifications or
claim that a violation was ``cured'' by a manufacturer's new product
specification. In any event, given that we decided to omit proposed
Sec. 111.2 altogether, the change sought by the comment is moot.
2. ``Exclusions'' (Proposed Sec. 111.6)
As we stated earlier in this section, proposed Sec. 111.6 would
exclude from the dietary supplement CGMP requirements persons who
engage solely in activities related to the harvesting, storage, or
distribution of raw agricultural commodities that would be incorporated
into a dietary supplement by other persons. However, as we explained in
our response to comment 27 of this document, we decided that the
exclusion was not necessary, given the changes that we made to final
Sec. 111.1(a).
Nevertheless, we received several comments on proposed Sec. 111.6,
and we address those comments here.
(Comment 65) One comment would revise the rule to exclude or use
different requirements for small businesses. The comment suggested we
categorize small businesses by employment levels or dollar sales and
adopt a tiered enforcement strategy similar that used in other
government programs, such as those under the Occupational Safety and
Health Act, the Americans with Disabilities Act, and the Family Leave
Act. Another comment would exempt small businesses from the specific
requirements for testing if those businesses produce annual batch runs
of 25,000 capsules and tablets.
(Response) We decline to exclude small businesses from the final
rule or to have different criteria for such businesses. As we stated in
our response to comments 1, 3, and 16, there is no reason to assume
that Congress meant to apply different or lesser CGMP requirements, or
no CGMP requirements at all, to dietary supplements made by small
businesses. Dietary supplement CGMP requirements help to ensure the
quality of the dietary supplement and, among other things, that a
dietary supplement meets its specifications, that it contains the
ingredients specified in its master manufacturing record, and that it
is not contaminated. Consumers should be able to expect that the
dietary supplements they purchase meet CGMP requirements regardless of
the manufacturer's size. However, to help

[[Page 34807]]

businesses comply with dietary supplement CGMPs, we are giving
businesses with fewer than 500 employees but 20 or more employees a
compliance date of 24 months after the date of publication of this
final rule, and we are giving businesses with fewer than 20 employees a
compliance date of 36 months after the date of publication of this
final rule.
We carefully considered the size of a business when developing
these regulations. The most common Small Business Association size
standard applicable to manufacturers covered by this final rule is 500
employees. Based on comments and our knowledge of the dietary
supplement industry, we know that there are a number of dietary
supplement manufacturers who fall significantly below the standard of
500 employees. To accommodate these manufacturers, we have established
different compliance dates as noted.
(Comment 66) One comment would exempt ``consolidators'' (whom it
described as individuals who purchase raw agricultural commodities for
sale to raw ingredient manufacturers) from the rule. Some comments
suggest expanding the exclusion pertaining to harvesting, storage, and
distribution of raw agricultural commodities to include other common
and basic raw botanical processing activities, such as drying,
chopping, cutting, size reduction, sifting, grinding, and storage. One
comment would delete the word ``solely'' to make the rule more flexible
and make it possible to exclude producers, who do not manufacture a
distinct product, from the CGMP rule. Another comment expresses concern
about potential safety issues that can arise from the early stages of
manufacturing, such as the use of improper handling of agricultural
commodities and the risk of adulteration; the comment says businesses
involved in producing or distributing raw agricultural commodities
should be subject to some requirements under the rule. A few comments
ask us to draft guidance documents to address activities such as
wildcrafting, plant identification, good agricultural practices, and
good hygienic practices for wildcrafters (persons who harvest plants
grown in the wild), and growers and brokers and specific service
providers (millers, extractors). Some comments would exempt individual
wildcrafters because wildcrafters deal in relatively small amounts of
material at a time and sell their material to larger brokers who
combine materials from different pickers together.
(Response) As explained in our responses to comments 29 and 30,
persons who only manufacture or supply a component that will be further
processed as a dietary supplement by another person are not within the
scope of this final rule. Thus, a ``consolidator'' who simply buys raw
agricultural commodities and then sells them to dietary ingredient
manufacturers would not be subject to this final rule. Similarly,
persons engaged in drying, chopping, cutting, size reduction, sifting,
and grinding of raw agricultural commodities which they then sell to
others for processing into a dietary supplement would not be subject to
this final rule. We note, however, that such persons are not exempt
from other regulatory requirements. We remind readers that a dietary
ingredient is a food under section 201(f)(3) of the act. Consequently,
a raw agricultural commodity that is a dietary ingredient is still
subject to the umbrella food CGMP requirements in part 110, and
activities such as drying, chopping, and cutting are what we have long
considered to be types of food processing.
As for ``wildcrafters,'' if they package and label raw agricultural
commodities as dietary supplements or sell them to consumers for use as
a dietary supplement, we would consider them to be manufacturers of a
dietary supplement and subject to the rule. If, however, the
wildcrafter simply sells the raw agricultural commodity to another for
incorporation into a dietary supplement, it would not be subject to
this final rule, but might be subject to the CGMP requirements in part
110. Persons engaged in the harvesting, storage, or distribution of raw
agricultural commodities, whether for distribution as a dietary
supplement or for distribution as a dietary ingredient to a dietary
supplement manufacturer, may want to read our guidance entitled ``Guide
to Minimize Microbial Food Safety Hazards for Fresh Fruits and
Vegetables'' available at http://www.cfsan.fda.gov/~dms/prodguid.html

(Ref. 28). This guidance addresses common areas of food safety concern
in the growing, harvesting, sorting, packing, and distribution of fresh
produce, and contains principles that would apply to raw agricultural
commodities, such as herbs and botanicals.
As for the comment that would delete the word ``solely'' from
proposed Sec. 111.6, we note that such a change is no longer necessary
since we are deleting Sec. 111.6. However, we caution that only those
persons or entities that manufacture or supply components that will be
further processed as a dietary supplement by others are not subject to
the final rule. If you manufacture and sell dietary supplements, in
addition to supplying components to others, you would be subject to
this final rule under Sec. 111.1(a).
As for potential safety issues arising from the early stages of
manufacturing, such as the use of improper handling of agricultural
commodities and the risk of adulteration, the final rule, at Sec.
111.75, describes criteria that enable a manufacturer of a dietary
supplement to rely on a certificate of analysis. One criterion is that
the manufacturer must first qualify the firm providing the component by
establishing the reliability of the firm's certificate of analysis
through confirmation of the results of the firm's tests or
examinations. Firms that improperly handle raw agricultural
commodities, such that the commodities that they provide are
adulterated, are not likely to be qualified as suppliers of those
commodities.
In the future, we will consider the requests to develop guidance
for subsets of agricultural and post-harvest activities (such as for
hygienic practice for wildcrafters, identifying botanicals) associated
with dietary supplement manufacturing, along with other guidance we may
find useful as they relate to certain CGMP requirements for dietary
supplements.

VII. Comments on Personnel (Final Subpart B)

A. Organization of Final Subpart B

Proposed subpart B contained three provisions regarding personnel.
Table 3 of this document lists the sections in final subpart B and
identifies the proposed sections that form the basis of the final rule.

Table 3.--Derivation of Sections in Final Subpart B
------------------------------------------------------------------------
Final Rule 2003 CGMP Proposal
------------------------------------------------------------------------
Sec. 111.8 What are the requirements under N/A
this subpart B for written procedures?
------------------------------------------------------------------------
Sec. 111.10 What requirements apply for Sec. 111.10
preventing microbial contamination from sick
or infected personnel and for hygienic
practices?
------------------------------------------------------------------------

[[Page 34808]]

Sec. 111.12 What personnel qualification Sec. 111.12
requirements apply?
------------------------------------------------------------------------
Sec. 111.13 What supervisor requirements Sec. 111.13
apply?
------------------------------------------------------------------------
Sec. 111.14 Under this subpart B, what N/A
records must you make and keep?
------------------------------------------------------------------------

B. Highlights of Changes to the Proposed Requirements for Personnel

1. Revisions
The final provisions in subpart B include revisions that clarify
that the final rule applies only to persons who manufacture, package,
label, or hold dietary supplements unless subject to an exclusion in
Sec. 111.1.
The final provisions also include revisions that clarify the
applicability of the rule to persons who perform labeling operations
for dietary supplements.
2. Changes After Considering Comments
The final rule:
Requires you to establish and follow written procedures to
fulfill the requirements of subpart B;
Provides flexibility regarding the requirement to exclude
personnel who might be a source of microbial contamination (e.g., due
to illness or open lesions) so that such personnel must be excluded
only from operations where such contamination may occur;
Clarifies that the qualification of personnel and
supervisors may be done through education, training, or experience;
Sets forth a new requirement that you identify qualified
personnel to perform quality control operations and requires that such
personnel have distinct and separate responsibilities related to
performing quality control operations from those responsibilities that
the person otherwise has when not performing quality control
operations; and
Sets forth a new requirement to make and keep records that
document training of personnel.

C. General Comments on Proposed Subpart B

(Comment 67) Some comments assert one or more proposed requirements
are unconstitutionally vague under the Fifth Amendment and arbitrary
and capricious under section 706(2)(B) of the Administrative Procedure
Act (APA) and therefore should be deleted. The comments focus on:
Proposed Sec. 111.12(a) which would require ``qualified
employees'' and
Proposed Sec. 111.13(a) which would require ``qualified
personnel to supervise.''
In general, these comments say the proposal's failure to define the
term ``qualified'' means that persons who are subject to the rule could
not discern the meaning of the term. These comments also say the
proposal imposes no limits on enforcement officers as to what would
satisfy the requirements and, thus would represent an exercise of
unbridled discretion and disparate decisionmaking. These comments argue
proposed Sec. 111.12(b), which would require employees to have ``the
training and experience to perform the person's duties,'' and proposed
Sec. 111.13(b), which would require supervisors to be ``qualified by
training and experience to supervise,'' would suffice.
(Response) We are not deleting Sec. Sec. 111.12(a) and 111.13(a)
as requested by these comments. As discussed in section V of this
document, we disagree that the terms in question are unconstitutionally
vague, need to be defined, or may result in discriminatory enforcement.
There has been sufficient common usage of these terms in the food
industry to enable manufacturers, and those who enforce the
requirements, to comprehend and apply such terms ``with a reasonable
degree of certainty'' to their particular operations (see Boyce Motor
Lines v. United States 342 U.S. at 340). Further, agencies are
permitted to use qualifying terms to enable them to address a wide
variety of conditions at companies. For these reasons, we have retained
the use of the terms in the final rule. The provisions at issue also
give firms the flexibility to determine how to comply with the
regulations. We also explain in section V of this document that the
final rule does not violate the APA.

D. What Are the Requirements Under This Subpart for Written Procedures?
(Final Sec. 111.8)

We received many comments that recommended written procedures for
various provisions. We address the need for written procedures
generally in section IV. We also respond to individual comments on
specific provisions in the same section. Final Sec. 111.8 requires you
to establish and follow written procedures to fulfill the requirements
of subpart B. Additionally, to ensure that we can evaluate firms'
compliance with their written procedures, final Sec. 111.14 requires
that a person who manufactures, packages, labels, or holds dietary
supplements make and keep records of such procedures. Such records
would be available to us under subpart P.

E. What Requirements Apply for Preventing Microbial Contamination From
Sick or Infected Personnel and for Hygienic Practices? (Final Sec.
111.10)

The title of this provision has been changed from proposed Sec.
111.10 to clarify that the requirements are related to the prevention
of microbial contamination due to the health condition of personnel and
not other sources.
1. Final Sec. 111.10(a)
Final Sec. 111.10(a) requires you to take measures to exclude from
any operations any person who might be a source of microbial
contamination, due to a health condition, where such contamination may
occur, of any material including components, dietary supplements, and
contact surfaces used in the manufacture, packaging, labeling, or
holding of a dietary supplement. This provision is similar to proposed
Sec. 111.10. We added ``due to a health condition'' for clarity.
(Comment 68) Several comments suggest that employees who are sick
should be allowed to work in areas where they will not come into
contact with components, dietary supplements, or contact surfaces, and
that the requirements of proposed Sec. 111.10 are too strict. These
comments say proposed Sec. 111.10(a) is too broad in stating that such
persons be excluded ``from working in any operation.'' These comments
explain that such persons may be suitable for performing other tasks,
such as warehouse functions or administrative work. These comments
would revise proposed Sec. 111.10(a) so that it is acceptable for such
persons to work so long as they will not be a vessel for microbial
contamination.
Other comments agree with proposed Sec. 111.10(a), and state that
employees who are sick should be excluded from the plant, even from
areas where products are not processed. These comments state excluding
such personnel should be mandatory as the microbes from an open sore,
wound, or other source of contamination could contaminate the
surrounding air, personnel, etc. For example, if the production area is
a closed loop air handling system, then contamination could spread to
the other areas through the common air handling units/ducts.

[[Page 34809]]

(Response) We agree that some tasks may be suitable for a person
who might be a source of microbial contamination. Certain warehouse
functions or administrative tasks may be appropriate for such a person
to do, provided that these functions or tasks do not expose components,
dietary supplements, or contact surfaces to microbial contamination
from the person, and provided that the person would not infect others
who would then expose components, dietary supplements, or contact
surfaces to microbial contamination.
A requirement to exclude employees from being present at work would
limit potential microbial contamination, which is the basis of the
point made by some comments that employees who are sick should be
excluded from the plant. However, the comments do not persuade us to
deny firms the flexibility to determine whether it would be appropriate
for an employee who may be a source of microbial contamination to work
in some areas of the physical plant that are sufficiently separated
from areas where product contamination could occur. When considering
whether an employee may be permitted to work and whether he/she
represents a potential source of microbial contamination, one should
look beyond the obvious potential sources of contamination, and
consider possibilities such as the forms of indirect contamination
discussed by the comments. Therefore, we are revising proposed Sec.
111.10(a) to require you to take measures to exclude ``from any
operations any person who might be a source of microbial contamination,
due to a health condition, where such contamination may occur, of any
material including components, dietary supplements, and contact
surfaces used in the manufacture, packaging, labeling, or holding of a
dietary supplement.''
As one measure to reduce potential microbial contamination, final
Sec. 111.10(a)(1) requires you to exclude, from working in any
operations that may result in contamination, any person who, by medical
examination, the person's acknowledgement, or supervisory observation,
is shown to have, or appears to have an illness, infection, open
lesion, or any other abnormal source of microbial contamination, that
may result in microbial contamination of components, dietary
supplements, or contact surfaces, until the health condition no longer
exists. Final Sec. 111.10(a)(1) is similar to proposed Sec.
111.10(a)(1). We have added that the person can acknowledge that he or
she may be a source of microbial contamination. We are moving and
modifying the prepositional phrase concerning ``working in any
operation.'' We also have added the word ``infection'' to clarify the
sources of potential abnormal contamination.
(Comment 69) Several comments suggest employees who may be the
source of microbial contamination should be permitted to work in areas
of the plant where they pose no risk of contamination, and therefore
should not be excluded unless they pose such a risk.
(Response) We agree with the comments and are revising proposed
Sec. 111.10(a)(1) accordingly. Therefore, you may allow persons with
certain health conditions to work in areas of a plant where they pose
no risk of contamination even though they must be excluded from other
areas where they would pose such a risk.
Final Sec. 111.10(a)(2) requires you to instruct your employees to
notify their supervisor(s) if they have, or if there is a reasonable
possibility that they have, a health condition stated in Sec.
111.10(a)(1) that could contaminate any components, dietary
supplements, or any contact surface.
We did not receive comments specific to proposed Sec.
111.10(a)(2).
2. Final Sec. 111.10(b)
Final Sec. 111.10(b) requires, if you work in an operation during
which adulteration of the component, dietary supplement, or contact
surface may occur, you to use hygienic practices to the extent
necessary to protect against contamination of components, dietary
supplements, or contact surfaces. Final Sec. 111.10(b) lists nine
hygienic practices, such as wearing outer garments in a manner that
protects against contamination, washing hands thoroughly, and wearing,
where appropriate, hair nets, caps, beard covers, or other effective
hair restraints.
We did not receive any comments concerning proposed Sec.
111.10(b)(1) (wearing outer garments in a manner that protects against
contamination), Sec. 111.10(b)(2) (maintaining adequate personal
cleanliness), Sec. 111.10(b)(3) (washing hands thoroughly), Sec.
111.10(b)(4) (removing all unsecured jewelry and other objects that
might fall into components, dietary supplements, equipment, or
packaging and removing hand jewelry that cannot be adequately
sanitized), Sec. 111.10(b)(6) (wearing, where appropriate, hair nets,
caps, beard covers, and other effective hair restraints), Sec.
111.10(b)(7) (not storing clothing or other personal belongings where
components, dietary supplements, or contact surfaces are exposed or
where contact surfaces are washed), and Sec. 111.10(b)(9) (taking any
other precautions necessary to protect against contamination).
Proposed Sec. 111.10(b)(5) would require the hygienic practices
that you use to include maintaining gloves used in handling components,
dietary ingredients, or dietary supplements in an intact, clean, and
sanitary condition and ensuring that gloves be of an impermeable
material.
(Comment 70) One comment asks us to clarify the requirements for
the use of gloves in proposed Sec. 111.10(b)(5). The comment says
there are situations in which gloves are ineffective or cumbersome. The
comment provides as an example, if a person is packaging a bulk
material in fiber packs with metal ring lids, bulky gloves can
interfere with the finer work such as attaching security tabs, and
thin, flexible gloves can be easily damaged by the sharp edges of the
metal rings on the lid.
(Response) Final Sec. 111.10(b)(5) requires you to maintain gloves
in an intact, clean, and sanitary condition; it does not require you to
use gloves in any specific situation. Although there is no requirement
for wearing gloves while performing specific operations, you must wear
gloves when they are necessary to protect against contamination of any
components, dietary supplements, or contact surfaces.
(Comment 71) Proposed Sec. 111.10(b)(8) would require that the
hygienic practices that you use, to the extent necessary to protect
against contamination, include not eating food, chewing gum, drinking
beverages, or using tobacco products in areas where components, dietary
ingredients, dietary supplements, or any contact surfaces are exposed,
or where contact surfaces are washed.
One comment would substitute the word ``processed'' for the word
``exposed'' in proposed Sec. 111.10(b)(8). The comment says, although
areas where components, dietary supplements, and contact surfaces are
exposed pose the greatest risk, adulteration is also possible where
these items are held (i.e., stored in containers and, thus, not
exposed). Furthermore, the comment explains the use of the word
``processed,'' rather than ``exposed,'' would cover all areas intended
to be covered by CGMPs and would alleviate the need to specify that the
requirement applies to areas where contact surfaces are washed.
(Response) We decline to revise the rule as suggested by the
comment. We believe the word ``exposed'' covers all areas intended to
be covered by the

[[Page 34810]]

requirement, including areas where contact surfaces are washed. We
consider an area where contact surfaces are washed to ``expose'' the
contact surface. To avoid any confusion, we are modifying Sec.
111.10(b)(8) to say ``* * * any contact surfaces are exposed, or where
contact surfaces are washed.'' As written, the requirement to not eat,
chew gum, drink, or use tobacco products in areas where components,
dietary supplements, and contact surfaces are exposed gives firms
appropriate flexibility to determine areas where employees may or may
not eat, chew gum, drink, or use tobacco products.

F. What Personnel Qualification Requirements Apply? (Final Sec.
111.12)

Final Sec. 111.12(a) requires you to have qualified employees who
manufacture, package, label, or hold dietary supplements. Final Sec.
111.12(a) is similar to proposed Sec. 111.12(a), except that the final
rule includes an editorial change to clarify that the requirement is to
have the qualified employees do the work rather than merely to have
qualified employees.
(Comment 72) The 2003 CGMP Proposal invited comment on whether
there is a minimum number of employees needed to manufacture dietary
supplements (68 FR 12157 at 12183). Several comments state the final
rule should not include such a minimum number because firms should be
able to decide for themselves how many qualified personnel they need.
(Response) The final rule does not stipulate a minimum number of
employees. However, there should be enough employees to manufacture,
package, label, and hold dietary supplements to ensure compliance with
the final rule. In general, CGMP suggests the need for a minimum of two
persons: One to perform the work, and a second to check the work
performed to ensure that a manufacturing deviation or an unanticipated
occurrence is not overlooked.
(Comment 73) Some comments about the proposed definition of
``quality control unit'' say the quality control function need not be
performed by a distinct or separate unit. These comments say the
quality control function is best performed by a person or persons
qualified by training, education, or experience in the different
processing areas.
(Response) As discussed, we have revised the proposed definition
and substituted the term ``personnel'' for ``unit.'' (For the
definition of quality control personnel, see section VI of this
document.) We agree the quality control functions do not need to be
performed by a distinct or separate unit or person and that a person
who is qualified by training, education, or experience can serve a
quality control function. Therefore, we are adding a new Sec.
111.12(b) to clarify that you must identify who is responsible for
quality control operations. Under final Sec. 111.12(b) each person
identified must be qualified to perform such operations, and must have
distinct and separate responsibilities related to performing such
operations from those responsibilities that the person otherwise has
when not performing such operations. The quality control personnel can
have dual functions within the facility but should separately perform
the different responsibilities.
Final Sec. 111.12(c) requires that each person engaged in
manufacturing, packaging, labeling, or holding, or in performing any
quality control operations, have the education, training, or experience
to perform the person's assigned functions. Final Sec. 111.12(c)
includes a revision associated with final Sec. 111.12(b) by including
persons who perform quality control operations as persons who also need
to have the education, training, or experience for the assigned
functions.
(Comment 74) Several comments state we should revise the rule to
allow for any combination of ``training or experience.'' These comments
explain it is not always possible for an employee to have both
``training and experience.'' These comments would revise proposed Sec.
111.12(b) to read, ``each person engaged in the manufacture of a
dietary product should have the proper education, training, and
experience (or any combination thereof) needed to perform the assigned
functions. Training should be in the particular operations(s) that the
employee performs as they relate to the employee's functions.'' Another
comment asks for guidance as to what type of education, training, or
experience is required for an employee to be considered qualified.
(Response) We agree with the point made by the comments. We
acknowledge that some positions will require an appropriate educational
background in addition to any on-the-job training. In the preamble to
the 2003 CGMP Proposal (68 FR 12157 at 12183) we noted ``training'' may
be considered a form of ``education'' and elected to require that
employees be qualified by ``training and experience'' rather than
``education, training, and experience.'' The 2003 CGMP Proposal used
the conjunction ``and'' because we considered ``experience'' to be
different from training, in that ``experience'' is knowledge that a
person gains over time, e.g., as he or she becomes increasingly
familiar with a particular action or piece of equipment.
These comments persuade us that the rule would be clearer if we
added ``education'' to the list of attributes that are used to qualify
an employee. We also agree there are some employees who could be
qualified based solely on their education or experience and other
employees who would become qualified through, for example, on-the-job
training before they are left on their own to perform their assigned
duties. Rather than revise the rule to list all three attributes and
then explain that an employee can be qualified by any combination of
the attributes, we have changed the conjunction from ``and'' to ``or.''
Additionally, on our own initiative, we have replaced ``person's
duties'' with ``person's assigned functions.'' This change reinforces
the principle that the employee's training relates to the functions
that he or she is assigned to perform.
We will consider whether it would be useful to provide guidance on
what type of education, training, or experience would be sufficient for
an employee to be properly qualified. We believe that such education,
training, or experience may vary by job function and that it would be
difficult to provide generic guidance that would be sufficient for all
specific job tasks. We decline to suggest that training should be
limited, as the comments suggest, to the particular operation(s) that
the employee performs as they relate to the person's functions. These
CGMP requirements apply to many types of manufacturing operations of
various size and complexity, so the training may vary depending on the
circumstances and may include more than the employee's assigned
functions.
(Comment 75) One comment states we should provide training
materials such as texts, videos, Internet training, or seminars, to
help companies properly train their employees.
(Response) We have no plans at this time to provide companies with
training materials for their employees. We expect that most companies
already have trained or will train their employees and that where
additional training is needed to comply with these regulations,
companies will develop the training materials that are appropriate for
the functions their employees perform. We may consider providing
guidance in the future if circumstances warrant such guidance.

[[Page 34811]]

G. What Supervisor Requirements Apply? (Final Sec. 111.13)

Final Sec. 111.13(a) requires you to assign qualified personnel to
supervise the manufacturing, packaging, labeling, or holding of dietary
supplements. Final Sec. 111.13(a) derives from proposed Sec.
111.13(a).
We did not receive comments specific to proposed Sec. 111.13(a).
Final Sec. 111.13(b) requires each supervisor you use to be
qualified by education, training, or experience to supervise. Final
111.13(b) derives from proposed Sec. 111.13(b) which would require you
and your supervisors to be qualified by training and experience to
supervise.
(Comment 76) Several comments ask us to revise the rule so that
supervisors may be qualified by any combination of training or
experience. These comments would revise proposed Sec. 111.13(b) to
read, ``supervisors must be qualified by education, training, and
experience (or any combination thereof) to supervise the manufacturing,
packaging, or holding of dietary ingredients and dietary supplements in
compliance with this rule.'' One comment, however, would make an
exception for quality control and sanitation supervisors, stating we
should require these supervisors to have both training and experience.
(Response) Consistent with the change we made to proposed Sec.
111.12(c), we are revising proposed Sec. 111.13(b) to require the
supervisors you use to be qualified by ``education, training, or
experience.'' We acknowledge that some supervisory personnel may need a
different range of education, training, or experience than others, and
expect firms to determine the appropriate balance of education,
training, and experience.
(Comment 77) Several comments say our use of the phrase ``you and
the supervisors you use'' in proposed Sec. 111.13(b) was unclear.
According to these comments, the term ``you'' as defined in the
proposal, is quite expansive and could be read so broadly as to require
the Chief Executive Officer (CEO) of a company be ``qualified'' to
supervise.
(Response) We agree that the phrase ``you and the supervisors you
use'' could be clearer. Therefore, we are revising proposed Sec.
111.13(b) to say that ``each supervisor whom you use'' must be
qualified to supervise. Section 111.13(b) applies to any person who
supervises the manufacturing, packaging, labeling, or holding of
dietary supplements, even if that person also is an executive such as
the CEO. Thus, final Sec. 111.13(b) states, ``Each supervisor whom you
use must be qualified by education, training, or experience to
supervise.''
(Comment 78) Several comments say the term ``to supervise'' is
ambiguous and would revise the rule to clarify what a supervisor must
be qualified to supervise: The manufacture, packaging, or holding of
dietary ingredients and dietary supplements. Another comment would
revise proposed Sec. 111.13(b) to clarify what type of training and
experience are required so that firms would have more guidance as to
what is expected to confirm that personnel are qualified.
(Response) We decline to revise the rule as suggested by the
comments. We disagree that the term ``to supervise,'' which is commonly
used in the industry, is ambiguous. These CGMP requirements apply to
many types of manufacturing operations of various size and complexity,
and the training must be suited to the circumstances.

H. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.14)

As discussed in this section, the final rule contains a new Sec.
111.8 requiring you to establish and follow written procedures to
fulfill the requirements of subpart B. Those written procedures are
records. Therefore, we are adding a new Sec. 111.14(a) requiring you
to make and keep records in accordance with subpart P. Final Sec.
111.14(b)(1) requires you to make and keep a record of the written
procedures for fulfilling the requirements of subpart B.
The preamble to the 2003 CGMP Proposal invited comment on whether
we should require documentation and records regarding each employee's
training (68 FR 12157 at 12183). After considering comments and for the
reasons discussed in the following paragraphs, Sec. 111.14(b)(2)
requires you to make and keep documentation of training, including the
date of training, the type of training, and the person(s) trained.
We also invited comment on whether the final rule should contain
requirements for documentation about consultants that you use (68 FR
12157 at 12183). We specifically suggested any such requirement include
the consultant's name, address, qualifications, and a description of
services provided. After considering the comments and for the reasons
discussed in the following paragraphs, the final rule does not include
any requirements to make and keep records regarding consultants.
(Comment 79) Several comments state employee training records are
critical and should be required under the final rule. The comments
explain that these records should show the content of the training, the
date of the training, and the signature of the employee trained. These
comments assert that a formal (written) GMP training program is
necessary to track which employees have been trained in the CGMP
requirements. These comments add, without a written and documented
training program, it is likely that some employees may not receive
sufficient training, or in some cases, any CGMP training at all. These
comments say successful quality control programs are inextricably
connected to appropriate training programs, and written documentation
of employee training is an important safeguard to ensuring safe and
accurately labeled dietary supplements. These comments also state it is
already an industry standard to document training.
Other comments question our ability to evaluate whether a firm's
employees have been adequately trained without written documentation of
the training.
(Response) As discussed more fully in the discussion of subpart E
in section X of this document, the final rule focuses on ensuring the
quality of the dietary supplement at every stage of the production and
process control system. Such a system begins with the proper training.
We agree that documentation of employee training is necessary to track
which employees have been trained in which operations. Therefore, final
Sec. 111.14(b)(2) requires you to keep documentation of training,
including the date of the training, the type of training, and the
person(s) trained.
(Comment 80) One comment says we should not require manufacturers
to document and keep records regarding each employee's training. The
comment says the rule should focus on end results and not on process.
(Response) We disagree with the comment. As we have explained in
this section, each person engaged in an activity covered by these CGMP
regulations must have the education, training, or experience to perform
the person's assigned functions. Some employees will be considered
qualified based in part on training taken as company employees. To show
that such training is appropriate to the employee's functions and has
in fact occurred, the training must be properly documented. This
documentation is an important aspect of ensuring adequate training and,
therefore, helping to ensure the result of having qualified employees
who perform their functions properly.

[[Page 34812]]

(Comment 81) Several comments state the documentation of the
training program should include the title of the person doing the
training, an evaluation of the employee's understanding of the
training, and recommendations for the frequency of refresher training.
One comment describes a specific method for training and for tracking
training. The comments state an evaluation of the employee's
understanding of the training would ensure that employees who receive
training understand what they have been taught.
(Response) We decline to require specific additional documentation
of employee training. We believe a firm should have some flexibility in
how it wants to document training.
(Comment 82) Several comments respond to our question as to whether
the final rule should require documentation about consultants,
including each consultant's name, address, qualifications, and a
description of services provided. Several comments say that documenting
this information is useful and could be done on a voluntary basis, but
that such information is not necessary to ensure safe and accurately
labeled supplements and, thus, should not be required. One comment
notes that recommendations from consultants may or may not be used, and
that a company should not have to explain at a later date why such
decisions were made. Another comment asserts that we and the company
may have different opinions on whether a consultant is qualified and
that the consultant's qualification is not our concern if a product is
not adulterated. One comment says documenting the name and services of
the GMP consultants should be required to facilitate contact in case of
need.
(Response) The proposal noted documentation of the name, address,
qualifications, and services rendered for each consultant may help you
know whom to contact and if questions arise concerning the advice that
the consultant has given. Thus, our intent in suggesting such
documentation was to help you rather than to make the information
available for us to determine whether we agreed with you that a
particular individual was qualified to be a consultant. However, the
comments persuade us that such information is not necessary to help
ensure dietary supplement quality. Therefore, the final rule does not
require documentation regarding consultants.

VIII. Comments on Physical Plant and Grounds (Final Subpart C)

A. Organization of Final Subpart C

Proposed subpart C contained two provisions regarding physical
plants. Table 4 of this document lists the sections in final subpart C
and identifies the corresponding proposed sections that form the basis
of the final rule.

Table 4.--Derivation of Sections in Final Subpart C
------------------------------------------------------------------------
Final Rule 2003 CGMP Proposal
------------------------------------------------------------------------
Sec. 111.15 What sanitation requirements Sec. 111.15
apply to your physical plant and grounds?
------------------------------------------------------------------------
Sec. 111.16 What are the requirements N/A
under this subpart C for written
procedures?
------------------------------------------------------------------------
Sec. 111.20 What design and construction Sec. 111.20
requirements apply to your physical
plant?
------------------------------------------------------------------------
Sec. 111.23 Under this subpart C, what Sec. 111.15(d)(3) and
records must you make and keep? (e)(2)
------------------------------------------------------------------------

B. Highlights of Changes to the Proposed Requirements for Physical
Plant and Grounds

1. Revisions
The final rule:
Reflects that the rule applies to persons who manufacture,
package, label, or hold dietary supplements unless subject to an
exclusion in Sec. 111.1.
Requires you to have documentation or otherwise be able to
show that water that is used in a manner such that the water may become
a component of the dietary supplement, e.g., when such water contacts
components, dietary supplements, or any contact surface, meets
applicable Federal, State, and local requirements and does not
contaminate the dietary supplement.
2. Changes After Considering Comments
The final rule:
Includes requirements similar to the food CGMP
requirements in Sec. 110.20(a) for keeping the grounds bordering your
physical plant in a condition that protects against contamination.
Clarifies that sanitation supervisors can be qualified by
education, training, or experience.
Modifies the minimum requirements for water that is used
in a manner such that the water may become a component of the dietary
supplement, e.g., when such water contacts components, dietary
supplements, or any contact surface. Such water must, at a minimum,
comply with applicable Federal, State, and local requirements and not
contaminate the dietary supplement.
Simplifies the sanitation requirements for toxic
materials, bathroom facilities, and hand-washing facilities.
Simplifies and clarifies the design requirements for
floors, walls, and ceilings; fans and other air-blowing equipment;
equipment that controls temperature and humidity; and the use of
safety-type glass or glass-like materials.
Requires written procedures for cleaning the physical
plant and for pest control.
Requires that you make and keep records of the written
procedures.

C. General Comments on Proposed Subpart C

(Comment 83) Several comments say we should have different
sanitation requirements for dietary ingredient manufacturers than for
dietary supplement manufacturers. These comments state that the
manufacture of synthetic or highly processed dietary ingredients
includes extensive purification steps, especially toward the end of the
manufacturing process, and that these steps remove contaminants that
may have been introduced at earlier stages in the manufacturing
process. These comments consider some stages of the dietary ingredient
manufacturing process to not be subject to the same strict controls as
those used for manufacturing finished dietary supplements.
(Response) As discussed in section VI of this document (subpart A),
the final rule applies to persons who manufacture, package, label, or
hold dietary supplements and who are not subject to an exclusion in
Sec. 111.1, and does not apply to establishments that only manufacture
dietary ingredients. We addressed this comment in the response to
comment 29.
(Comment 84) Some comments assert that one or more proposed
requirements are unconstitutionally vague under the Fifth Amendment and
are arbitrary and capricious under section 706(2)(B) of the APA. The
comments would delete the following proposed requirements:
Sec. 111.15(e), which would require plumbing to be ``of
an adequate size and

[[Page 34813]]

design and be adequately installed and maintained;''
Sec. 111.15(g), which would require bathrooms to be
``adequate'' and ``readily accessible; ''
Sec. 111.15(h), which would require hand-washing
facilities ``to be adequate, convenient, and furnish running water at a
suitable temperature;''
Sec. 111.15(h)(i), which would require 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;
Sec. 111.20(a), which would require your physical plant
to ``be suitable in size, construction, and design to facilitate
maintenance, cleaning, and sanitizing operations;'' and
Sec. 111.20(d)(6), which would require aisles or working
spaces between equipment and walls to be adequately unobstructed and of
adequate width.
In general, these comments assert the 2003 CGMP Proposal did not
define terms or phrases (such as ``adequately'' or ``at each
location'') in a way that persons who are subject to the rule can
discern the meaning of the term or phrase. These comments argue that
the proposed rule imposes no limitations on enforcement officers on the
exercise of their discretion and, thus, invites exercise of unbridled
discretion and disparate decisionmaking.
(Response) As discussed in section V of this document, we disagree
that the terms that the comments objected to in the 2003 CGMP Proposal
are unconstitutionally vague, need to be defined, or may result in
discriminatory enforcement. We are retaining the terms in the final
rule.

D. What Sanitation Requirements Apply to Your Physical Plant and
Grounds? (Final Sec. 111.15)

1. Final Sec. 111.15(a)
The preamble to the 2003 CGMP Proposal (68 FR 12157 at 12184)
stated that we were not proposing 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 or dietary supplements in order to limit the burden to
manufacturers. However, we invited comment on whether we should include
such requirements in a final rule. After considering the comments, we
have drafted final Sec. 111.15(a) to require you to keep the grounds
of your physical plant in a condition that protects against the
contamination of components, dietary supplements, or contact surfaces.
The methods for adequate ground maintenance include:
Properly storing equipment, removing litter and waste, and
cutting weeds or grass within the immediate vicinity of the physical
plant so that it does not attract pests, harbor pests, or provide pests
a place for breeding;
Maintaining roads, yards, and parking lots so that they do
not constitute a source of contamination in areas where components,
dietary supplements, or contact surfaces are exposed;
Adequately draining areas that may contribute to the
contamination of components, dietary supplements, or contact surfaces
by seepage, filth or any other extraneous materials, or by providing a
breeding place for pests;
Adequately operating systems for waste treatment and
disposal so that they do not constitute a source of contamination in
areas where components, dietary supplements, or contact surfaces are
exposed; and
If your plant grounds are bordered by grounds not under
your control, and if those other grounds are not maintained in the
manner described in this section, you must exercise care in the plant
by inspection, extermination, or other means to exclude pests, dirt,
and filth or any other extraneous material that may be a source of
contamination.
(Comment 85) Several comments say the final rule should require the
maintenance of external areas similar to the food CGMP requirement at
Sec. 110.20(a) for keeping the grounds outside the facility adequately
maintained. These comments state that such a requirement is basic, is
equally important to facilities that manufacture conventional foods and
to facilities that manufacture dietary supplements, and that there is
no reason why this requirement should differ from food CGMPs. One
comment asserts such a requirement is basic to the industry and it
should not be dismissed as a burden to the industry. Some comments also
assert that a provision similar to Sec. 110.20(a) would help train
staff and would explain to plant maintenance personnel what is required
and why.
One comment says there should be some minimum requirement for
sanitation and cleanliness in the area surrounding the plant and that
requirements for drainage and trash removal should be adequate.
(Response) We agree that a requirement to maintain grounds is
equally important for facilities that manufacture conventional foods
and for facilities that manufacture dietary supplements. Although some
requirements in Sec. 110.20(a) are not strictly limited to drainage
and trash disposal, the comment suggesting the requirements to maintain
grounds be limited to drainage and trash disposal did not explain why,
for example, it would not be as important for a facility that
manufactures dietary supplements to maintain roads, yards, and parking
lots so that they do not become a source of contamination as it already
is for facilities that manufacture conventional foods. Therefore, the
final rule is adding Sec. 111.15(a), which is similar to Sec.
110.20(a) with editorial revisions consistent with the rest of this
final rule.
2. Final Sec. 111.15(b)(1)
Final Sec. 111.15(b)(1) (proposed Sec. 111.15(a)) requires you to
maintain your physical plant in a clean and sanitary condition. Final
Sec. 111.15(b)(2) requires you to maintain your physical plant in
repair sufficient to prevent components, dietary supplements, or
contact surfaces from becoming contaminated.
We did not receive comments specific to proposed Sec. 111.15(a).
3. Final Sec. 111.15(c)
Final Sec. 111.15(c) (proposed Sec. 111.15(b)) sets forth
requirements for cleaning compounds, sanitizing agents, pesticides, and
other toxic materials.
Final Sec. 111.15(c) includes changes that we are making for
clarity and consistency. We added other ``toxic'' materials because
some paragraphs within final Sec. 111.15(c) simply refer to the
cleaning compounds, sanitizing agents, and pesticides as ``toxic
materials,'' and because proposed Sec. 111.15(b)(2) addressed the use
and storage of toxic materials that are not within the general category
of cleaning compounds, sanitizing agents, or pesticides.
Final Sec. 111.15(c)(1) requires you to use cleaning compounds and
sanitizing agents that are free from microorganisms of public health
significance and that are safe and adequate under the conditions of
use. Final Sec. 111.15(c)(1) is similar to proposed Sec.
111.15(b)(1), except that we inserted ``that are'' before ``safe and
adequate.'' We consider this to be a nonsubstantive, editorial change.
Proposed Sec. 111.15(b)(1) was, itself, patterned after Sec.
110.35(b)(1), which: (1) Requires cleaning compounds and sanitizing
agents used in cleaning and sanitizing procedures to be free from
undesirable microorganisms and safe and adequate under the conditions
of use and (2) provides that compliance may be verified by any
effective means including purchase of these substances

[[Page 34814]]

under a supplier's guarantee or certification or examination of these
substances for contamination.
(Comment 86) Several comments ask us to clarify our expectations
with respect to substantiating that a cleaning compound or sanitizing
agent is free from microorganisms of public health significance and is
safe and adequate under conditions of use. Some comments suggest
proposed Sec. 111.15(b)(1) provide for the use of certifications or
guarantees from a supplier because our investigators otherwise may not
recognize such documents as evidence of compliance. Several comments
say it is not necessary for a manufacturer to test these types of
products, and that a continuing product guarantee, combined with a
statement of intended use from the manufacturer of the cleaning
compound or sanitizing agent, should satisfy the requirements.
(Response) When assessing compliance with final Sec. 111.15(c)(1),
we would not treat a firm that manufactures, packages, labels, or holds
a dietary supplement differently than we would treat a facility that
manufactures, packages, labels, or holds conventional foods. Therefore,
we intend to accept, as the comments request, a supplier's guarantee or
certification that a cleaning compound or sanitizing agent is free from
microorganisms of public health significance and is safe and adequate
under the conditions of use for the purpose of determining compliance
with final Sec. 111.15(c)(1).
Final Sec. 111.15(c)(2) requires you to not use or hold toxic
materials in a physical plant in which components, dietary supplements,
or contact surfaces are manufactured or exposed, unless those materials
are necessary: (1) To maintain clean and sanitary conditions, (2) for
use in laboratory testing procedures, (3) for maintaining or operating
the physical plant or equipment, or (4) for use in the plant's
operations.
We did not receive comments specific to proposed Sec.
111.15(b)(2). We have made a nonsubstantive edit to Sec. 111.15(c)(2)
by moving ``contact surfaces'' to be the last item on the list.
Final Sec. 111.15(c)(3) requires you to identify and hold cleaning
compounds, sanitizing agents, pesticides, pesticide chemicals, and
other toxic materials in a manner that protects against contamination
of components, dietary supplements, or contact surfaces. Final Sec.
111.15(c)(3) is similar to proposed Sec. 111.15(b)(3).
We did not receive comments specific to proposed Sec.
111.15(b)(3), but replaced ``toxic cleaning compounds'' with ``cleaning
compounds,'' and added ``other toxic materials.''
4. Final Sec. 111.15(d)
Final Sec. 111.15(d) (proposed Sec. 111.15(c)) sets forth
requirements for pest control. Section Sec. 111.15(d) is almost
identical to proposed Sec. 111.15(c).
Final Sec. 111.15(d)(1) requires you to not allow animals or pests
in any area of your physical plant. Final Sec. 111.15(d)(1) allows
guard or guide dogs in some areas of your physical plant if the
presence of the dogs will not result in contamination of components,
dietary supplements, or contact surfaces. Final Sec. 111.15(d)(2)
requires that you take effective measures to exclude pests from your
physical plant and to protect against the contamination of components,
dietary supplements, and contact surfaces on the premises by pests.
Final Sec. 111.15(d)(3) requires that you not use insecticides,
fumigants, fungicides, or rodenticides unless you take precautions to
protect against the contamination of your components, dietary
supplements, or contact surfaces.
(Comment 87) Several comments claim proposed Sec. 111.15(c) would
require that sealed equipment outside of the plant (e.g. storage tanks,
vessels, piping) be enclosed to prevent pests from roaming around these
areas. The comments say there is no need to shelter outdoor equipment
if it is properly sealed. These comments state that dietary supplements
are sometimes manufactured in extensive, highly automated facilities in
which large tanks and vessels are interconnected via piping, and that
in these cases ``the physical plant'' and ``the equipment in the
plant'' converge so that some or much of the equipment is effectively
located outdoors. Thus, the comments ask us to revise proposed Sec.
111.15(c) to clarify that it applies only to interior areas of the
physical plant.
(Response) Equipment such as that described by the comments, if
properly sealed, should protect components, dietary supplements, and
contact surfaces from contamination with pests. Final Sec. 111.15(d)
does not require that sealed equipment outside of the plant, such as
storage tanks, vessels, or piping, be enclosed, e.g., inside a
building. Final Sec. 111.15(d)(2) requires that you take effective
measures to exclude pests from your physical plant and to protect
against the contamination of components, dietary supplements, or
contact surfaces on the premises by pests. Moreover, final Sec.
111.15(a) includes several requirements designed to limit or exclude
pests around all parts of the exterior of your physical plant.
Therefore, although you do not have to enclose your outside equipment,
you must take measures to exclude pests from areas outside of the
plant.
5. Final Sec. 111.15(e)
Final Sec. 111.15(e) (proposed Sec. 111.15(d)) sets forth
requirements for the water supply of your physical plant.
Final Sec. 111.15(e)(1) requires that you must provide water that
is safe and sanitary at suitable temperatures and under pressure as
needed for all uses where water does not become a component of the
dietary supplement.
We did not receive comments specific to proposed Sec.
111.15(d)(1). We have modified the phrase ``safe and of adequate
sanitary quality'' to read ``safe and sanitary.'' To avoid confusion
with the definition of ``quality'' we have adopted solely for purposes
of this final rule, we deleted the references to ``quality'' as it
applies to water standards. We consider this change to be
nonsubstantive and still require water that is not a component of a
dietary supplement to meet a safe and sanitary standard.
Final Sec. 111.15(e)(2) requires that water used in a manner such
that the water may become a component of the dietary supplement, e.g.,
when such water contacts components, dietary supplements, or any
contact surface, must, at a minimum, comply with applicable Federal,
State, and local requirements and not contaminate the dietary
supplement. Final Sec. 111.15(e)(2) derives from proposed Sec.
111.15(d)(2) which would require that water that contacts components,
dietary supplements, or any contact surfaces must, at a minimum, comply
with the applicable National Primary Drinking Water (NPDW) regulations
and any State and local government requirements. Final Sec.
111.15(e)(2) includes changes we are making after considering comments
discussed in the following paragraphs.
(Comment 88) Several comments state the water quality that is
required for conventional foods is sufficient for dietary supplements.
The comments argue that no additional water standards are listed in the
CGMPs for low-acid canned foods in part 113 or in the CGMPs for
acidified foods in part 114. These comments argue that, if ``safe and
of adequate sanitary quality'' is sufficient to ensure the quality of
the water used in most food products, then it is also adequate to
ensure the quality of the water used in dietary supplements.
Other comments would revise the final rule to allow different
standards and requirements for water that contacts or is used in
dietary supplements

[[Page 34815]]

compared to water that contacts components, including dietary
ingredients. These comments state current food CGMP regulations require
only that water supplies that contact food (defined to include
ingredients and raw materials) be ``safe and of adequate sanitary
quality.'' These comments say that this would be consistent with the
act's basis for CGMP requirements for foods, i.e., that food is not
prepared ``under unsanitary conditions whereby it may have become
contaminated with filth, or whereby it may have been rendered injurious
to health'' (section 402(a)(4) of the act). Several comments state the
final rule should adopt a similar rationale for components, including
dietary ingredients. These comments explain that components, including
dietary ingredients, are not in a form in which they will be consumed
and are subject to further processing prior to consumption.
Several comments say that requiring water used for cleaning contact
surfaces to meet Environmental Protection Agency regulations is an
unnecessary burden for companies that do not have access to municipal
water. According to these comments, potable water should be sufficient.
(Response) In the preamble to the 2003 CGMP Proposal (68 FR 12157
at 12185), we stated that water should, at a minimum, be potable and
that water that is ``safe and of adequate sanitary quality'' should be
potable. We also said water that contacts components, dietary
supplements, or contact surfaces should, at a minimum, meet the
Environmental Protection Agency's NPDW regulations and State, and local
requirements. We proposed to require that water used in operations
where water contacts components, dietary supplements, or any contact
surfaces meet the NPDW regulations because of the potential for
contamination if water were used that did not adhere to the microbial
standards, for example, in the NPDW regulations. Finally, we stated
these requirements were minimum requirements and that water that is
more pure than that required under the NPDW regulations may be desired.
The comments stated some manufacturers may not have access to
municipal water, and therefore, that meeting the NPDW regulations for
cleaning contact surfaces would be too burdensome. These comments
asserted that potable water would be sufficient. The comments do not
provide a definition of ``potable water.'' We have defined ``potable
water,'' in the regulations on interstate conveyance sanitation in 21
CFR part 1250 to be, in part, water that meets the standards prescribed
in the Environmental Protection Agency's NPDW regulations in 40 CFR
part 141.
We would consider it to be a rare situation where a dietary
supplement manufacturer uses well water and has no access to municipal
water. Nonetheless, to the extent that a manufacturer uses water that
is not subject to Federal oversight, the manufacturer would have to
comply with any State or local regulations that apply to food
manufacturing facilities using such water in food processing.
Manufacturers that use water from a municipal source, which is
subject to the Environmental Protection Agency NPDW regulations, should
not be subject to a lesser standard in this final rule than what is
already required of them by the Environmental Protection Agency. Thus,
to accommodate manufacturers subject to the Environmental Protection
Agency's NPDW regulations for the water that they use in the
manufacture of dietary supplements, as well as those dietary supplement
manufacturers who are not subject to the Environmental Protection
Agency's NPDW regulations, we are modifying the rule to state water
that is used in a manner such that the water may become a component of
the dietary supplement, e.g., when such water contacts components,
dietary supplements, or any contact surface, must, at a minimum, comply
with applicable Federal, State, and local requirements and not
contaminate the dietary supplement. We decline to use ``safe and of
adequate safety'' that some comments state is sufficient because it is
for conventional foods. We believe that requiring that water comply
with Federal, State and local requirements and not contaminate dietary
supplements provides a clear standard as to what is required.
(Comment 89) Some comments assert that water that is used to
manufacture components or dietary ingredients where such components or
dietary ingredients are subject to further processing prior to
consumption, should be subject to the ``safe and of adequate sanitary
quality'' standard in Sec. 110.37.
(Response) We acknowledge that such components and dietary
ingredients are subject to the requirement in Sec. 110.37. If the
manufacturers do not fall within the scope of final Sec. 111.1, such
manufacturers would be subject to the CGMP requirements in part 110.
To the extent that such comments request the ``safe and of adequate
sanitary quality'' language apply to water used in the manufacture of a
dietary supplement, we decline to make that change. Water that is safe
and sanitary would not necessarily comply with, for example, the NPDW
regulations. A requirement stating ``safe and of adequate sanitary
quality'' or, as stated in the final rule, the requirement of ``safe
and sanitary'' could be seen as a lesser standard than water that
complies with ``applicable Federal, State, and local requirements.'' We
want to make clear that you must comply with applicable Federal, State,
and local requirements related to the water that you use for food
processing that would otherwise be required of you, and not to some
lesser standard that you may consider is ``safe and sanitary'' when
water is used in a manner such that the water may become a component of
the dietary supplement, e.g., when such water contacts a component,
dietary supplement, or any contact surface. Foreign manufacturers would
need to comply with the water standard required in this final rule and
achieve the same level of performance as is required of domestic
manufacturers. The water used in domestic or foreign manufacturing must
not contaminate the dietary supplement. To clarify that the water used,
whether by a domestic or foreign manufacturer, must not be a source of
contamination, we are adding the words ``and not contaminate the
dietary supplement'' in final Sec. 111.15(e)(2). We also want to make
it clear that water includes what is in the water, e.g., any of its
contaminants in addition to H2O. For example, when we speak
of drinking water, we do not just mean the H2O, we mean the
iron, lead, sulfur, and any other contaminants contained in the water.
(Comment 90) Several comments suggest water should meet some or all
standards of the USP monograph for sterile, purified water and say that
the standard in the USP monograph is a higher, and presumably safer,
standard than the NPDW standard. The comments state the USP's water
deionization and purification systems requirements are already common
in the industry.
(Response) We do not discourage firms from using water in dietary
supplement manufacturing that meets USP standards, including deionized
or purified water, but we do not require, as a CGMP, the use of USP
standards. This final rule sets forth minimum requirements for persons
who manufacture, package, label, or hold a dietary supplement. Thus,
firms may use water that exceeds our minimum requirements.
(Comment 91) The preamble to the 2003 CGMP Proposal recognized that
foreign firms might not be subject to Environmental Protection Agency
water

[[Page 34816]]

requirements or adhere to such requirements, but also stated that water
quality is an important part of CGMP (68 FR 12157 at 12185). Thus, in
the preamble to the 2003 CGMP Proposal, we invited comment on how we
might ensure that foreign firms meet the same water quality
requirements as domestic firms. Several comments respond to our request
for comments specific to the applicability of the water standards to
foreign firms. Several comments recommend we not distinguish between
domestic and foreign firms with regard to water quality. The comments
claim all firms must compete on a ``level playing field.'' These
comments state water quality standards vary from country to country,
and many countries do not have requirements that are comparable to
those in the United States. The comments say foreign manufacturers
should not be permitted to import products into the United States that
do not meet the same safety standards as domestic goods.
Other comments ask us to consider the water quality requirement to
be met if the water complies with the NPDW standard or any equivalent
water quality standard that is ensured by a foreign public agency.
(Response) We agree that foreign firms should be required to meet
the water safety and sanitary requirements required of domestic firms
and achieve the same level of performance of domestic firms. As
discussed in this section, foreign firms are required to meet all
requirements and would need to comply with their own national or local
water safety requirements and not contaminate the dietary supplement.
(Comment 92) One comment would combine proposed Sec. 111.15(d)(1)
and (d)(2) into a single paragraph. The comment says the two proposed
paragraphs are redundant. 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: (1) Manufacturing dietary ingredients or
dietary supplements; (2) making ice that comes in contact with
components, dietary ingredients, dietary supplements, or contact
surfaces; (3) cleaning any surface; and (4) 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 surface must at a minimum comply with the
NPDW regulations prescribed by the Environmental Protection Agency
under 40 CFR part 141 and any State and local government requirements.
(Response) We disagree that proposed Sec. 111.15(d)(1) and (d)(2)
were redundant. For example, as described in the proposed sections,
nonpotable water that would have been ``safe and of adequate sanitary
quality'' for use in flushing toilets may not have been ``safe and of
adequate sanitary quality'' for use in the manufacture of a liquid
dietary supplement.
Final Sec. 111.15(e)(1) requires that you provide water that is
safe and sanitary, at suitable temperatures, and under pressure as
needed, for all uses where water does not become a component of the
dietary supplement. Final Sec. 111.15(e)(2) requires that water that
is used in a manner such that the water may become a component of the
dietary supplement, e.g., when such water contacts components, dietary
supplements, or any contact surface, must, at a minimum, comply with
applicable Federal, State, and local requirements and not contaminate
the dietary supplement. As an example of how the requirements would
apply, water that contains lead at a level that is 20 times higher than
the maximum accepted level in the Environmental Protection Agency's
NPDW standards for lead may not be safe for use in the manufacture of
dietary supplement that is consumed in four 2-ounce portions per day,
but may be safe for use in cleaning the floors of the physical plant.
Therefore, to emphasize that water that is ``safe and sanitary'' may be
different depending on its use, the final rule continues to separate
Sec. 111.15(e)(1) and (e)(2) (formerly proposed Sec. 111.15(d)(1) and
(d)(2)).
Additionally, to emphasize the importance of the water that is used
in the manufacture of a dietary supplement, where the water is used in
a manner such that the water may become a component of the dietary
supplement, final Sec. 111.23(c) (proposed Sec. 111.15(d)(3))
requires you to have documentation and keep records that such water
meets the requirements of final Sec. 111.15(e)(2). In contrast, there
is no corresponding requirement for documentation in final Sec. 111.23
that other water, such as water that is used to clean floors or used in
employee bathrooms, meets requirements of final Sec. 111.15(e)(1).
(Comment 93) Several comments state, if we retain a water standard
requirement based on the Environmental Protection Agency NPDW standard,
then it is important to include provisions recognizing the
acceptability of municipal water sources and the frequency of testing
required for other water sources. Some comments recommend water should
meet the USP standard for purified water and point out that the USP
standard provides an assurance of the water's consistency and provides
a system that can be monitored.
Several comments suggest we include timetables for water testing or
describe water testing frequency requirements. These comments state we
should apply something analogous to the proposed requirements for
infant formula which would require manufacturers to conduct the tests
with sufficient frequency to ensure that the water meets the
Environmental Protection Agency's NPDW standard, but not less
frequently than annually for chemical contaminants, every 4 years for
radiological contaminants, and weekly for bacteriological contaminants.
Other comments refer to the amendments to the bottled water regulations
at Sec. 165.110 which require a minimum yearly monitoring of source
water and finished bottled water products for chemical contaminants for
which allowable levels have been established in the bottled water
quality standard.
(Response) Final Sec. 111.23(c) requires you to have documentation
that water, when used in a manner such that the water may become a
component of the dietary supplement, e.g., when such water contacts a
component, dietary supplement, or contact surface, meets the
requirements of final Sec. 111.15(e)(2). You must meet the requirement
for final Sec. 111.15(e)(2) at the point of use, rather than at the
point of delivery, i.e., at the point the water may become a component
of the dietary supplement, such as when the water contacts components,
dietary supplements, or any contact surface (such as when the water
comes out of the faucet or comes out of a spigot from a holding tank
where you store water). Thus, you must ensure that the water used in a
manner such that the water may become a component of the dietary
supplement, not the water source before it enters your facility, meets
the NPDW regulations, or if not subject to the NPDW regulations, that
it meets any other applicable Federal, State, and local requirements
and does not contaminate the dietary supplement.
For example, if the water that enters your facility is subject to
the Environmental Protection Agency NPDW regulations, then the water
must comply with such requirements at the point of use, i.e., when it
contacts the components, dietary supplement, or any contact surface
(such as when the water comes out of the faucet or out of a spigot from
a holding tank where you store water). You could rely on a certificate
of analysis under final Sec. 111.75(a)(2)(ii)

[[Page 34817]]

from the supplier of the water (e.g., the municipality) to ensure that
the water entering your facility complies the applicable Federal,
State, and local requirements. However, you must ensure that nothing
happens to the water that may contaminate the water once it enters your
facility and before the water may become a component of the dietary
supplement at the point of use. Certain contaminants or microorganisms
may be introduced into the water from the facility. Thus, you may need
to establish specifications and procedures to prevent contamination
from pipes through which the water travels in the facility or from
vessels in which the water is held in the facility prior to use. You
may need to test for certain contaminants, e.g., lead or
microorganisms, at point of use to ensure there is no contamination of
the water within your facility. Such tests may not need to include all
of the chemical, microbiological, or contaminant testing already
certified by the supplier to determine whether the water entering your
facility complies with Federal, State and local requirements. Rather,
you would need to evaluate what, if any, introductions of contaminants
are likely to occur within your facility and determine whether
additional tests are needed to verify that the water, at point of use,
will comply with Federal, State, and local requirements and not
contaminate the dietary supplement. Alternatively, you may decide not
to rely on a certificate of analysis and instead conduct your own
testing at point of use to determine if the water complies with
applicable Federal, State, and local requirements. We decline to set
out testing requirements or frequency of testing in this final rule in
lieu of giving manufacturers the flexibility to decide on the
appropriate testing and frequency of such testing to ensure that the
water meets the requirements in final Sec. 111.15(e)(2). We may
consider issuing guidance, as needed, on our recommendation for testing
based on water sources and the purposes for which the water is used. If
you rely on a certificate of analysis from the supplier of the water,
we recommend that you qualify your facility by conducting appropriate
tests at the point of use to verify that no other tests are necessary
or that any additional tests you have chosen are sufficient to
establish that the water that is used in a manner such that the water
may become a component of the dietary supplement, e.g., when such water
contacts components, dietary supplements or any contact surface, meets
the requirements of final Sec. 111.15(e)(2). We also recommend that
you requalify your facility at the point of use at appropriate
intervals.
If you use water from a private source, you must use water that
complies with any State and local requirement and does not contaminate
the dietary supplement. You may need to perform appropriate water
treatment procedures, including filtration, sedimentation, and
chlorination to satisfy final Sec. 111.15(e)(2).
(Comment 94) Several comments would delete proposed Sec.
111.15(d)(2), arguing that it is unnecessary to state a requirement
that water meet the Environmental Protection Agency's NPDW standards.
These comments state that if water is used in processing or at critical
points in the cleaning process, then a manufacturer will already have
established specifications for its appropriate use.
(Response) We agree that a manufacturer will need to establish
specifications, under final Sec. 111.70(a), for any point, step, or
stage in the manufacturing process where control is necessary to ensure
the quality of the dietary supplement, and for water that is used in a
manner such that the water may become a component of the dietary
supplement. For reasons set forth in response to comment 88, final
Sec. 111.15(e)(2) establishes the minimum standards for water that
will be used in a manner such that the water may become a component the
dietary supplement, e.g., when such water contacts components, dietary
supplements, or any contact surface. Thus, we disagree that proposed
Sec. 111.15(e)(2) be eliminated.
6. Final Sec. 111.15(f)
Final Sec. 111.15(f) (proposed Sec. 111.15(e)) sets forth
requirements for the plumbing of your physical plant.
Final Sec. 111.15(f) requires your plumbing to 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 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
supplements, for cleaning contact surfaces, or for use in bathrooms and
hand-washing facilities.
We did not receive comments specific to proposed Sec. 111.15(e),
other than comments arguing that certain text was unconstitutionally
vague and arbitrary and capricious. We address those comments in
section V of this document.
7. Final Sec. 111.15(g)
Final Sec. 111.15(g) (proposed Sec. 111.15(f)) sets forth
requirements for sewage disposal and requires you to dispose of sewage
into an adequate sewage system or through other adequate means.
We did not receive comments specific to proposed Sec. 111.15(f).
8. Final Sec. 111.15(h)
Final Sec. 111.15(h) (proposed Sec. 111.15(g)(1)) sets forth
requirements for the bathrooms of your physical plant. Final Sec.
111.15(h) requires you to provide your employees with adequate, readily
accessible bathrooms, and that the bathrooms be kept clean and not be a
potential source of contamination to your components, dietary
supplements, or contact surfaces.
(Comment 95) Several comments state companies should be given
flexibility in designing their bathrooms. These comments assert the
food CGMP requirements allow flexibility in bathroom design, so the
dietary supplement CGMP rule should do the same. The comments would
delete proposed Sec. 111.15(g)(1) through (g)(3), which pertained to:
(1) Keeping the bathrooms in good repair at all times; (2) providing
self-closing doors; and (3) providing 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.
(Response) We agree that it is unnecessary to require specific
bathroom features such as those in proposed Sec. 111.15(g)(1) through
(g)(3) because you may be able to achieve compliance through other
means better suited to your operations. Accordingly, we are revising
the rule by deleting proposed Sec. 111.15(g)(1) through (g)(3) as
requested by the comments. However, we continue to believe that
mechanisms such as self-closing doors and doors that do not open onto
areas where components, dietary supplements, or contact surfaces are
exposed to

[[Page 34818]]

contamination will help protect against contamination.
9. Final Sec. 111.15(i)
Final Sec. 111.15(i) (proposed Sec. 111.5(h)) sets forth
requirements for the hand-washing facilities of your physical plant.
Final Sec. 111.15(i) requires you to provide hand-washing facilities
that are designed to ensure that an employee's hands are not a source
of contamination of components, dietary supplements, or any contact
surface, by providing facilities that are adequate, convenient, and
furnish running water at a suitable temperature.
Final Sec. 111.15(i) differs from the proposal in that the
proposal would list six specific features of a hand-washing facility,
such as effective hand-cleaning and sanitizing preparations (proposed
Sec. 111.15(h)(2)), air driers, sanitary towel service, or other
suitable drying devices (proposed Sec. 111.15(h)(3)), and trash bins
that are constructed to protect against recontamination (proposed Sec.
111.15(h)(4)).
(Comment 96) Several comments state we should give firms the
flexibility to design their hand-washing facilities. According to these
comments, substituting the word ``may'' for the word ``must'' would
accomplish this. The comments argue that, as with bathrooms, an overall
sanitation requirement should be sufficient, and that, as long as there
is a strong and enforceable standard, firms should have the flexibility
to adopt only those measures that are needed to meet the underlying
requirement.
(Response) We agree that it is unnecessary to require specific
hand-washing mechanisms because you may be able to achieve compliance
through other means better suited to your operations. However, we
disagree that an overall sanitation requirement would be sufficient,
because such a requirement would not clearly state the purpose of the
requirement, which is to ensure that an employee's hands are not a
source of contamination of components, dietary supplements, or any
contact surface.
We are revising proposed Sec. 111.15(h) (final Sec. 111.15(i)) in
the final rule in two respects. First, the final rule states that the
hand-washing facilities are to be designed to ensure that an employee's
hands are not a source of contamination. Second, final Sec. 111.15(i)
states that the hand-washing facilities are to be adequate, convenient,
and furnish running water at suitable temperatures but does not provide
the specific hand-washing mechanisms detailed in the 2003 CGMP
Proposal.
10. Final Sec. 111.15(j)
Final Sec. 111.15(j) (proposed Sec. 111.15(i)) sets forth
requirements for trash disposal at your physical plant. Final Sec.
111.15(j) requires that you convey, store, and dispose of trash to: (1)
Minimize the development of odors; (2) minimize the potential for trash
to attract, harbor, or become a breeding place for pests; (3) protect
against contamination of components, dietary supplements, any contact
surface, water supplies, and grounds surrounding your physical plant;
and (4) control hazardous waste to prevent contamination of components,
dietary supplements, and contact surfaces.
(Comment 97) One comment suggests deleting proposed Sec.
111.15(i)(1) concerning minimizing the development of odors, because,
the comment claimed, minimizing odors is not a ``true'' CGMP
requirement.
(Response) We disagree that minimizing the development of odors is
not part of CGMP. Odor from trash is often an indication of problems
with microbial contamination, such as decomposition, decay, and the
growth of harmful bacteria. In addition, odor from trash can attract
pests. By conveying, storing, and disposing of trash to minimize the
development of odors, you will help reduce the potential for problems
with microbial contamination and pests.
11. Final Sec. 111.15(k)
Final Sec. 111.15(k) (proposed Sec. 111.15(j)) sets forth
requirements for sanitation supervisors at your physical plant. Final
Sec. 111.15(k) requires that you assign one or more employees to
supervise overall sanitation. Each supervisor must be qualified by
education, training, or experience to develop and supervise sanitation
procedures. Final Sec. 111.15(k) differs from proposed Sec. 111.15(j)
in that the proposal would require that each supervisor be qualified by
training and experience.
(Comment 98) Several comments suggest revising proposed Sec.
111.15(j) to state that sanitation supervisors may be qualified by
education, training, or experience (or any combination thereof) to
develop and supervise sanitation procedures. In contrast, several
comments say that sanitation supervisors should be qualified by both
training and experience.
(Response) Consistent with our response to comment 76 in section
VII of this document, final Sec. 111.15(k) provides that sanitation
supervisors, like other supervisors, must be qualified by education,
training, or experience to develop and supervise sanitation procedures.
As we also stated in response to comment 76, we acknowledge that some
supervisory personnel may need a different range of education,
training, or experience than others. However, we have decided to give
firms the flexibility to decide the appropriate amount of education,
training, or experience for a given job function. If that includes a
combination of attributes, the firm should select and train employees
accordingly.

E. What Are the Requirements Under This Subpart for Written Procedures?
(Final Sec. 111.16)

We received many comments that recommend written procedures for
various provisions. We address the need for written procedures
generally in section IV of this document. We also respond to comments
on specific provisions in the same section.
We are adding a new final Sec. 111.16 entitled ``What Are the
Requirements Under This Subpart for Written Procedures?,'' to require
you to establish and follow written procedures for fulfilling certain
requirements of subpart C. You must establish and follow written
procedures for cleaning the physical plant and for pest control.

F. What Design and Construction Requirements Apply to Your Physical
Plant? (Final Sec. 111.20)

Final Sec. 111.20 addresses physical plant design and construction
requirements.
1. Final Sec. 111.20(a) and (b)
Final Sec. 111.20(a) and (b) require that any physical plant that
you use in the manufacturing, packaging, labeling, or holding of
dietary supplements: (1) Be suitable in size, construction, and design
to facilitate maintenance, cleaning, and sanitizing operations and (2)
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 and
dietary supplements during manufacturing, packaging, labeling, or
holding.
We did not receive comments specific to proposed Sec. 111.20(a) or
(b), other than comments arguing that certain text in proposed Sec.
111.20(b) was unconstitutionally vague and arbitrary and capricious. We
address those comments in this section and section V of this document.

[[Page 34819]]

2. Final Sec. 111.20(c)
Final Sec. 111.20(c) requires that any physical plant you use in
the manufacturing, packaging, labeling, or holding of dietary
supplements provide for the use of proper precautions to reduce the
potential for mixups or contamination of components, dietary
supplements, or contact surfaces, with microorganisms, chemicals,
filth, or other extraneous material.
Under final Sec. 111.20(c) 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 and
dietary supplements during the following operations: (1) Receiving,
identifying, holding, and withholding from use, components, dietary
supplements, packaging, and labels that will be used in or during the
manufacturing, packaging, labeling, or holding of dietary supplements;
(2) separating, as necessary, components, dietary supplements,
packaging, and labels that are to be used in manufacturing from
components, 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,
labeling, and holding of different product types including different
types of 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
components or dietary supplements.
(Comment 99) Several comments would change ``computerized inventory
controls'' to ``adequate inventory controls'' in proposed Sec.
111.20(c). The comments say that a requirement to use a computerized
system is too prescriptive and that inventory controls that are not
computerized may be equally effective in achieving compliance with
proposed Sec. 111.20(c).
(Response) These comments may have misinterpreted proposed Sec.
111.20(c). Computerized inventory controls are an example of the type
of system that may be appropriate; Sec. 111.20(c) does not require you
to have a computerized system in the first instance. Thus, final Sec.
111.20(c) continues to use computerized inventory controls as an
example of a central system.
(Comment 100) Several comments ask us to clarify the degree of
separation that is intended under proposed Sec. 111.20(c) when it
referred to ``separate or defined areas'' of a physical plant. These
comments state that it is unclear if we expect a firm not to
manufacture multiple products in a single room or area. The comments
state that, if this is the case, this would be equivalent to the drug
CGMP requirements and would be excessive. The comments argue that, if
the proper controls are in place, manufacturing and packaging of
multiple products is possible in a single room or area without
compromising product identity, quality, strength, purity, and
composition.
(Response) Final Sec. 111.20(c) states that you must have and use
separate or defined areas of adequate size or other control systems,
such as computerized inventory controls or automated systems of
separation. The preamble of the 2003 CGMP Proposal explained that if
your physical plant does not allow for physically separate areas, you
could develop an alternative approach for segregating components and
dietary supplements at points when they are received, stored, and
rejected (68 FR 12157 at 12188). We interpret the comments as asking
whether alternative approaches for segregating products could be used,
even if physically separate areas were available in a facility, so that
different materials could be processed in the same area. Final Sec.
111.20(c) allows you to use ``separate or defined areas of adequate
size or other control systems;'' thus, you can comply with this
requirement by manufacturing multiple products in the same room or area
instead of using a physically separate location, as long as you have
systems in place to prevent contamination and mixups of components and
dietary supplements.
3. Final Sec. 111.20(d)
Final Sec. 111.20(d) requires that any physical plant you use in
the manufacturing, packaging, labeling, or holding of dietary
supplements be designed and constructed in a manner that prevents
contamination of components, dietary supplements, or contact surfaces.
Final Sec. 111.20(d)(1) requires the design and construction to
include: (1) Floors, walls, and ceilings that can be adequately cleaned
and kept clean and in good repair; (2) fixtures, ducts, and pipes that
do not contaminate components, dietary supplements, or contact surfaces
by dripping or other leakage 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 supplements, or contact surfaces; (4)
equipment that controls temperature and humidity, when such equipment
is necessary to ensure the quality of the dietary supplement; and (5)
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 supplements, or contact surfaces with clothing or
personal contact.
Final Sec. 111.20(d)(1)(i) through (d)(1)(v) is similar to
proposed Sec. 111.20(d)(1), (d)(2), (d)(3), (d)(5), and (d)(6),
respectively. Additionally, as explained in the following paragraphs,
we have made other changes to proposed Sec. 111.20(d)(1) (final Sec.
111.20(d)(1)(i)) and proposed Sec. 111.20(d)(5) (final Sec.
111.20(d)(1)(iv)).
(Comment 101) Several comments argue that the requirement of
proposed Sec. 111.20(d)(1) that floors, walls, and ceilings be made of
``smooth and hard surfaces,'' if read literally, could be interpreted
to prohibit the use of ceilings with drop-in tiles. These comments
assert that, while there may be areas in a manufacturing plant where
drop-in ceilings are inappropriate given the height of the ceiling, the
nature of the product, or the type of operation conducted in that area,
such ceilings are adequate in many areas of a manufacturing facility,
and certainly are appropriate in places where product is labeled or
stored. The comments argue that replacing such ceilings with surfaces
that are ``smooth and hard'' is unnecessary. Several other comments
argue that they could find no precedent in any food CGMP regulations
for a provision specifying ``smooth and hard surfaces'' for ceilings,
but did identify a precedent in the section of drug CGMP requirements
relating to ``aseptic processing.'' The comments state that adopting
such a drug CGMP requirement is inappropriate for dietary supplements.
The comments say the overall purpose of proposed Sec. 111.20(d)(1)
should be to ensure that facilities can be kept in a clean and sanitary
condition. The comments would revise proposed Sec. 111.20(d)(1) to
require physical plants to have surfaces that can be adequately
cleaned, but would give manufacturers the flexibility to use
appropriate surfaces in different parts of a plant.
The comments also argue that the rule's specificity establishes a
conundrum for certain manufacturers to conform to other Federal
regulations,

[[Page 34820]]

e.g., Occupational Safety and Health Administration (OSHA) noise
levels. The comments argue that firms should be allowed to
simultaneously conform to both OSHA and FDA requirements.
(Response) We agree that a smooth and hard surface may not be
necessary in every case to prevent contamination of the dietary
supplement. However, you may need floors, walls, and ceilings that are
constructed of smooth and hard surfaces to prevent contamination of the
dietary supplement when, for example, physical attributes of components
(e.g., particle size or electrostatic charge) would make it difficult
to keep floors, walls, and ceilings clean. Consequen