[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.
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\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.
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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\
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\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).
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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
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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