[Federal Register: March 13, 2003 (Volume 68, Number 49)]
[Proposed Rules]
[Page 12157-12263]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr13mr03-31]
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Part II
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Parts 111 and 112
Current Good Manufacturing Practice in Manufacturing, Packing, or
Holding Dietary Ingredients and Dietary Supplements; Proposed Rule
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 111 and 112
[Docket No. 96N-0417]
RIN 0910-AB88
Current Good Manufacturing Practice in Manufacturing, Packing, or
Holding Dietary Ingredients and Dietary Supplements
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing current
good manufacturing practice (CGMP) regulations for dietary ingredients
and dietary supplements. The proposed rule would establish the minimum
CGMPs necessary to ensure that, if you engage in activities related to
manufacturing, packaging, or holding dietary ingredients or dietary
supplements, you do so in a manner that will not adulterate and
misbrand such dietary ingredients or dietary supplements. The
provisions would require manufacturers to evaluate the identity,
purity, quality, strength, and composition of their dietary ingredients
and dietary supplements. The proposed rule is one of many actions
related to dietary supplements that we (FDA) are taking to promote and
protect the public health.
DATES: Submit written or electronic comments by June 11, 2003. Submit
written or electronic comments on the collection of information by
April 14, 2003.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/
dockets/ecomments.
Fax written comments on the information collection to the Office of
Information and Regulatory Affairs, Office of Management and Budget
(OMB), Attn: Stuart Shapiro, Desk Officer for FDA, Fax (202) 395-6974,
or electronically mail comments to sshapiro@omb.eop.gov.
FOR FURTHER INFORMATION CONTACT: Karen Strauss, Center for Food Safety
and Applied Nutrition (HFS-821), Food and Drug Administration, 5100
Paint Branch Pkwy., College Park, MD 20740, 301-436-2375.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Background
A. Dietary Supplement Health and Education Act (DSHEA)
B. The Advance Notice of Proposed Rulemaking
C. Industry and Consumer Outreach
1. Dietary Supplement Strategic Plan Meetings
2. Small Business Outreach Meetings
3. Site Visits to Dietary Supplement Manufacturing Firms
D. Food Advisory Committee Report
E. FDA's Decision To Propose a Rule
1. Why Are CGMPs Needed?
a. CGMPs help protect the public health
b. CGMPs benefit consumers
2. How Will CGMP Regulations Take Into Account Technical
Feasibility?
3. How Can FDA Help Industry Achieve Compliance With CGMPs?
F. Proposal Highlights and Requests for Comments
II. General Issues
A. Legal Authority
B. Issues From the ANPRM
III. Description of the Proposed Rule
A. General Provisions (Proposed Subpart A)
1. Who Is Subject to These Part III Regulations? (Proposed Sec.
111.1)
2. What Are These Regulations Intended to Accomplish? (Proposed
Sec. 111.2)
3. What Definitions Apply to this Part? (Proposed Sec. 111.3)
4. Do Other Statutory Provisions and Regulations Apply?
(Proposed Sec. 111.5)
5. Exclusions (Proposed Sec. 111.6)
B. Personnel (Proposed Subpart B)
1. What Microbial Contamination and Hygiene Requirements Apply?
(Proposed Sec. 111.10)
2. What Personnel Qualification Requirements Apply? (Proposed
Sec. 111.12)
3. What Supervisor Requirements Apply? (Proposed Sec. 111.13)
C. Physical Plant (Proposed Subpart C)
1. What Sanitation Requirements Apply to Your Physical Plant?
(Proposed Sec. 111.15)
2. What Design and Construction Requirements Apply to Your
Physical Plant? (Proposed Sec. 111.20)
D. Equipment and Utensils (Proposed Subpart D)
1. What Requirements Apply to the Equipment and Utensils You
Use? (Proposed Sec. 111.25)
2. What Requirements Apply to Automatic, Mechanical, or
Electronic Equipment? (Proposed Sec. 111.30)
E. Production and Process Controls (Proposed Subpart E)
1. What Production and Process Controls Must You Use? (Proposed
Sec. 111.35)
2. What Requirements Apply to Quality Control? (Proposed Sec.
111.37)
3. What Requirements Apply to Components, Dietary Ingredients,
Dietary Supplements, Packaging, and Labels You Receive? (Proposed
Sec. 111.40)
4. What Requirements Apply to Establishing a Master
Manufacturing Record? (Proposed Sec. 111.45)
5. What Requirements Apply to Establishing a Batch Production
Record? (Proposed Sec. 111.50)
6. What Requirements Apply to Laboratory Operations? (Proposed
Sec. 111.60)
7. What Requirements Apply to Manufacturing Operations?
(Proposed Sec. 111.65)
8. What Requirements Apply to Packaging and Label Operations?
(Proposed Sec. 111.70)
9. What Requirements Apply to Rejected Components, Dietary
Ingredients, Dietary Supplements, Packaging, and Labels? (Proposed
Sec. 111.74)
F. Holding and Distributing (Proposed Subpart F)
1. What Requirements Apply to Holding Components, Dietary
Ingredients, Dietary Supplements, Packaging, and Labels? (Proposed
Sec. 111.80).
2. What Requirements Apply to Holding In-Process Material?
(Proposed Sec. 111.82)
3. What Requirements Apply to Holding Reserve Samples of
Components, Dietary Ingredients, and Dietary Supplements? (Proposed
Sec. 111.83)
4. What Requirements Apply to Returned Dietary Ingredients or
Dietary Supplements? (Proposed Sec. 111.85)
5. What Requirements Apply to Distributing Dietary Ingredients
or Dietary Supplements? (Proposed Sec. 111.90)
G. Consumer Complaints--What Requirements Apply to Consumer
Complaints? (Proposed Subpart G, Sec. 111.95)
H. Records and Recordkeeping--What Requirements Apply to
Recordkeeping? (Proposed Subpart H, Sec. 111.125)
IV. Statement Concerning the Use of Plain Language
V. Paperwork Reduction Act of 1995
VI. Environmental Impact Considerations
VII. Analysis of Impacts
A. Introduction
B. Preliminary Regulatory Impact Analysis
1. The Need for the Proposed CGMP Regulations
2. Regulatory Options
a. No new regulatory action
b. Fewer requirements for vitamins and minerals
c. More restrictive CGMP regulations than the proposed
regulations
d. HACCP without the other elements of CGMP regulations
e. Require final product testing only
f. Regulate only high-risk products
3. Coverage of the Proposed Rule
4. Baseline Practices
5. Baseline Risk
6. Benefits and Costs
a. Reduced illnesses
b. Fewer products recalled
c. Reduced hypothetical search costs as a measure of the benefit
from increased assurance of quality
d. Other benefits
e. Total measured benefits
7. Costs
a. Description of the costs
b. Costs of general activity
c. Major costs by type of activities
d. Estimating costs
8. Summary of Benefits and Costs
C. Initial Regulatory Flexibility Analysis
1. Introduction
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2. Economic Effects on Small Entities
a. Number of small entities affected
b. Costs to small entities
3. Regulatory Options
a. Exemptions for small entities
b. Longer compliance periods
4. Description of Recordkeeping and Reporting
5. Summary
VIII. Federalism
IX. Request for Comments
X. References
I. Background
A. Dietary Supplement Health and Education Act (DSHEA)
DSHEA (Pub. L. 103-417) was signed into law on October 25, 1994.
DSHEA, among other things, amended the Federal Food, Drug, and Cosmetic
Act (the act) by adding section 402(g) (21 U.S.C. 342(g)). Section
402(g)(2) of the act provides, in part, that the Secretary of Health
and Human Services (the Secretary) may by regulation prescribe good
manufacturing practices for dietary supplements. Such regulations shall
be modeled after CGMP regulations for food and may not impose standards
for which there is no current and generally available analytical
methodology. No standard of CGMP may be imposed unless such standard is
included in a regulation issued after notice and opportunity for
comment in accordance with 5 CFR chapter V.
Congress enacted DSHEA to ensure consumers' access to safe dietary
supplements. In the findings accompanying DSHEA, Congress stated that
improving the health status of U.S. citizens is a national priority and
that the use of dietary supplements may help prevent chronic diseases
and maintain good health (Ref. 1). If dietary supplements are
adulterated because they contain contaminants (such as filth), because
they do not contain the dietary ingredient they are represented to
contain (for example, a product labeled as vitamin C that actually
contains niacin), or because the amount of the dietary ingredient
thought to provide a health benefit (for example, folic acid to reduce
the risk of neural tube defects or calcium in an amount to reduce the
risk of osteoporosis) is not actually present in the supplement, then
the consumer may suffer harm or may not obtain the purported health
benefit from their consumption. CGMP regulations for dietary
ingredients and dietary supplements will help to ensure that the
potential health benefits that Congress identified as the basis for
DSHEA are obtained and that consumers receive the dietary ingredients
that are stated on the product label.
DSHEA directed the President to appoint a Commission on Dietary
Supplement Labels (the Commission) to consider several issues under
DSHEA needing clarification. The Commission was to conduct a study on,
and provide recommendations for, the regulation of label claims and
statements for dietary supplements, including the use of literature in
connection with the sale of dietary supplements and procedures for the
evaluation of such claims. In making its recommendations, the
Commission was to evaluate how best to provide truthful, scientifically
valid, and nonmisleading information to consumers so that such
consumers could make informed and appropriate health care choices for
themselves and their families. The Commission's report (Ref. 80) states
that the Commission supports the efforts of industry and FDA to develop
appropriate CGMPs for dietary supplements. Guidance on the type of
information that a responsible manufacturer should have to substantiate
statements of nutritional support and safety is also included in the
Commission's report. The Commission's report states that the
substantiation files should include assurance that CGMPs were followed
in the manufacture of the product.
B. The Advance Notice of Proposed Rulemaking
On November 20, 1995, representatives of the dietary supplement
industry submitted to FDA an outline for CGMP regulations for dietary
supplements and dietary supplement ingredients. We evaluated the
outline and determined that it provided a useful starting point for
developing CGMP regulations. Nonetheless, we believed that the industry
outline did not address certain issues that should be considered when
developing a proposed rule on CGMPs for dietary ingredients and dietary
supplements. For example, the industry outline did not address the need
for specific controls for automatic, computer-controlled or assisted
systems.
In addition to identifying a number of issues that were not
included in the industry outline but on which we wanted public comment,
we also recognized that other interested parties, such as consumers,
other industry segments who had not participated in developing the
outline, and the health care community should have an opportunity to
provide comments on CGMPs for dietary supplements before we developed a
proposal. Therefore, in the Federal Register of February 6, 1997 (62 FR
5700), we issued an advance notice of proposed rulemaking (ANPRM)
asking for comments on whether to institute rulemaking to develop CGMP
regulations for dietary ingredients and dietary supplements and what
would constitute CGMP regulations for these products.
The ANPRM contained the entire text of the industry outline. We
also asked nine questions (which we discuss later in section II.B of
this document) in the ANPRM. The questions focused on issues that the
industry outline did not address such as those issues noted above. We
received approximately 100 letters in response to the ANPRM. Each of
those letters contained one or more comments. The comments came from
consumers, consumer advocacy groups, health care professionals, health
care professional organizations, industry, and industry trade
associations. The majority of comments responded both to the nine
questions we asked in the ANPRM and on certain provisions in the
industry outline. We also address the comments on the nine questions in
section II.B of this document. We discuss significant comments about
certain provisions in the industry outline in our discussion of related
proposed requirements.
Included with its comments to the ANPRM, the United States
Pharmacopeia (USP) submitted a copy of its general chapter,
``Manufacturing Practices for Nutritional Supplements,'' (Ref. 2) and
in March/April 2002, USP proposed revisions to this general chapter to
introduce provisions pertaining to botanical preparations (Ref. 82). In
February 2000, we received a copy of the National Nutritional Foods
Association's (NNFA) ``NNFA Good Manufacturing Practice in
Manufacturing, Packing, or Holding Dietary Supplements'' (Ref. 3). We
found that the industry outlines published in the ANPRM, the USP
manufacturing practices, and the NNFA standards were useful in
developing this proposed rule. We included certain provisions found in
these outlines in this CGMP proposed rule. These three outlines
indicate that dietary ingredient and dietary supplement manufacturers
already recognize that there are basic, common steps needed to
manufacture a dietary ingredient or dietary supplement that is not
adulterated although, as established in the regulatory impact analysis,
a large percentage of manufacturers do not follow a good manufacturing
model. For example, these practices include requirements for:
[sbull] Designing and constructing physical plants that facilitate
maintenance, cleaning, and proper
[[Page 12160]]
manufacturing operations or to prevent mixup between different raw
materials and products;
[sbull] Establishing a quality control unit;
[sbull] Establishing and following written procedures for:
1. Maintaining and cleaning equipment and utensils;
2. Receiving, testing, or examining materials received and testing
of finished product;
3. Using master and batch control records;
4. Handling consumer complaints; and
5. Maintaining records for laboratory tests, production control,
distribution, and consumer complaints.
Based on the ANPRM, the comments that we received in response to
the ANPRM, our outreach activities (which we discuss below), and our
own knowledge and expertise about CGMPs for foods, drugs, cosmetics,
devices, and biologics, we are proposing to establish these CGMP
regulations for dietary ingredients and dietary supplements. The
proposed regulations would impose requirements for: (1) Personnel, (2)
physical plants, (3) equipment and utensils, (4) production and process
controls, (5) holding and distributing, (6) consumer complaints related
to good manufacturing practices, and (7) records and recordkeeping.
C. Industry and Consumer Outreach
During 1999, we conducted a number of outreach activities related
to dietary supplements. We held several public meetings to obtain input
from the public on developing our overall strategy for achieving
effective regulation of dietary supplements, which could include
establishing CGMP regulations. We also held public meetings focused
specifically on CGMPs and the economic impact that any CGMP rule for
dietary ingredients and dietary supplements may have on small
businesses. Additionally, FDA staff toured several dietary supplement
manufacturing firms to better understand the manufacturing processes
and practices that potentially would be subject to a CGMP regulation
for dietary ingredients and dietary supplements. Each of these
activities contributed to our knowledge about the industry.
1. Dietary Supplement Strategic Plan Meetings
We held public meetings on June 8 and July 20, 1999, to collect
stakeholder comments on the development of our overall strategy for
achieving effective regulation of dietary supplements. We designed the
meetings to provide an opportunity for public comment on both the
activities we should undertake as part of an overall strategy and the
prioritization of those activities. In the notices for these meetings,
we identified the development of CGMPs for dietary supplements as one
activity that should be considered in an overall strategy.
During and after the strategic meetings, we received comments from
consumers, consumer advocacy groups, health care professionals, health
care professional organizations, industry, and industry trade
associations. The comments addressed a wide range of activities related
to regulating dietary supplements. (These comments can be seen at our
Dockets Management Branch (see ADDRESSES) in docket number 99N-1174.)
The comments generally identified the development of CGMP regulations
as a high priority activity that should be included in any FDA
strategic plan for regulating dietary supplements. Some comments that
addressed the development of CGMPs are summarized as follows:
[sbull] It would be useful to industry to have FDA establish CGMPs
especially for small and intermediate-size firms that are not clear on
what they should be doing;
[sbull] CGMPs would establish a level playing field for industry,
which would help prevent irresponsible firms from making and selling
adulterated products;
[sbull] CGMPs should be able to accommodate a wide variety of
firms, that is, small and large firms that manufacture a wide array of
different types of products and ingredients;
[sbull] CGMPs should ensure that consumers get dietary supplements
with the strength and the purity that consumers expect;
[sbull] CGMPs should ensure that every dietary supplement on the
market has the safety, identity, purity, quality, and strength it
purports in the label to possess;
[sbull] CGMPs should include ingredient identity testing and other
testing;
[sbull] CGMPs should ensure that dietary supplements are produced
using a master formula procedure and produced in a sanitary facility;
[sbull] CGMPs should require that manufacturers have documented
evidence that their manufacturing process is under control on a
consistent basis;
[sbull] CGMPs should require manufacturers to test dietary
ingredients, particularly imported botanicals, for heavy metals,
pesticides, and industrial contaminants;
[sbull] CGMPs should require expiration dating and testing for
dissolution and bioequivalence;
[sbull] CGMPs should require that companies report adverse
reactions; and
[sbull] CGMPs should include guidance on testing for ingredient
identity and adulteration with toxic substances.
2. Small Business Outreach Meetings
We held public meetings on July 12, September 28, and October 21,
1999, to collect information from industry and others that would help
us to understand the economic impact on small businesses of CGMP
regulations for dietary supplements. Transcripts of these public
meetings (docket number 96N-0417, ``Development of Strategy for Dietary
Supplements'') are available at our Dockets Management Branch or
electronically at http://www.fda.gov/ohrms/dockets/dockets/96n0417/
tr00001.pdf.
Public comments from small businesses included both
support of and concern for CGMP regulations. Small businesses expressed
concerns about the cost and the time involved in complying with any
rule that contains the following requirements:
[sbull] Conducting tests to determine identity, purity, quality,
strength, and composition of dietary ingredients and dietary
supplements;
[sbull] Maintaining written procedures and records documenting that
procedures are followed; and
[sbull] Providing data that support expiration dating.
Public comments from small business expressed support for dietary
supplement CGMP regulation. Some small businesses (1 with 15 employees)
commented that they have CGMPs in place with written procedures
tailored to the size of their operations. One small business with sales
under $1 million commented that their plant materials received in fresh
form are identified onsite by a botanist, and when the onsite botanist
is not able to confirm identity, the plant material is sent to an
outside laboratory that conducts chemical analysis to confirm identity.
3. Site Visits to Dietary Supplement Manufacturing Firms
During the summer and fall of 1999, we visited eight dietary
supplement manufacturing firms. These visits included firms that: (1)
Manufacture a vitamin using a fermentation process; (2) grind, sift,
blend, and otherwise treat raw agricultural commodities (e.g.,
botanicals); (3) manufacture dietary ingredients for use in
manufacturing dietary supplement tablets, capsules, softgels, and
powders; (4) manufacture dietary supplements for packaging and labeling
by others; and (5) manufacture, package, and label dietary supplements
under their own and others' labels. The
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firms varied in size and were located in several parts of the country.
We found an array of manufacturing, packaging, and holding
practices in the firms. The practices included the following:
[sbull] Using CGMPs similar to those included in the ANPRM;
[sbull] Using automatic systems to quarantine, segregate, approve,
and release inventory;
[sbull] Following written procedures;
[sbull] Having quality control units with the responsibility and
authority outlined in the ANPRM;
[sbull] Performing one or more tests on dietary ingredients and
dietary supplements to determine the identity, purity, quality,
strength, and composition;
[sbull] Verifying the reliability of suppliers' certifications; and
[sbull] Documenting and maintaining records for certain procedures,
such as master and batch production, quality control and laboratory
operations, distribution, and processing consumer complaints.
D. Food Advisory Committee Report
In February 1998, the Food Advisory Committee (FAC) established a
Dietary Supplement Working Group to consider what constitutes adequate
testing for identity of different dietary ingredients and what records
are necessary to demonstrate that CGMPs are maintained throughout the
manufacturing and distribution process. The working group issued a
report that discussed the selection of the most appropriate and
reliable identity test and the general principles for consideration in
setting performance standards for such tests (Ref. 4). The report also
identified the types of records that would be necessary to demonstrate
that CGMPs are maintained throughout the manufacturing and distribution
process. On June 25, 1999, the working group presented its report, in
draft form, during an FAC public meeting. We received public comments
during and after the June 25, 1999, public meeting.
Although this proposal does not address dietary ingredient identity
testing in the same detail as the working group's report, we considered
the report in developing requirements for identity testing and CGMP
records requirements in this proposal. The working group's report may
be useful in developing industry guidance to supplement a CGMP
regulation for dietary ingredients and dietary supplements. We discuss
dietary ingredient and dietary supplement identity testing and
recordkeeping for CGMP proposed requirements in more detail later in
this document.
E. FDA's Decision To Propose a Rule
This proposed regulation, which sets forth proposed CGMPs for
dietary ingredients and dietary supplements, is part of our overall
strategy for regulating dietary supplements in a manner that promotes
and protects the public health. Before drafting the proposal, FDA
considered public comment in response to the ANPRM and to public
meetings, observations at site visits to dietary supplement
manufacturers, and advisory group reports. In drafting this proposal,
FDA used, in part, the industry coalition outline that was published as
an ANPRM (62 FR 5700) in which the industry adopted broad provisions
beyond those found in part 110 (21 CFR part 110). FDA's purpose at this
proposed rule stage is to present a broad enough scope so that it may
receive comment on the depth and breadth of what should be considered
by the agency in developing a final rule. Our intent is to provide the
proper balance of regulation so that dietary ingredients and dietary
supplements are manufactured in a manner to prevent adulteration using
recognized scientific principles and both industry and consumer
expectations that are reasonable and appropriate. Therefore, FDA seeks
comment on whether each of the proposed provisions are necessary to
ensure the safety and quality of dietary ingredients and dietary
supplements and whether they are adequate to protect the public health.
In addition, we seek comment on whether there are certain provisions
that are not proposed but that may be necessary. Comments should
include justification for why provisions may or may not be necessary,
including supporting data where appropriate. If comments assert that
certain provisions are not necessary, comments should include an
explanation on how, in the absence of the requirement, one can ensure
that there would be adequate protection of the public health when there
is risk of adulteration. Comments also should address whether the gains
to consumers in product safety and quality are warranted. Moreover,
assuming that this proposal does advance the public health, comments
should address whether there is any reason to apply different
requirements, including greater or lesser requirements on small firms
as compared to larger firms and the rationale for doing so. Finally,
comments should address the agency's legal authority to issue these
regulations.
In deciding whether to propose CGMP regulations for dietary
supplements, we asked ourselves:
[sbull] Why Are CGMP regulations needed?
[sbull] How will CGMP regulations take into account technical
feasibility? and
[sbull] How can FDA help industry achieve compliance with CGMPs?
1. Why Are CGMPs Needed?
CGMP regulations for dietary ingredients and dietary supplements
are necessary to promote and protect the public health. In addition,
CGMP regulations would benefit consumers economically and would benefit
industry.
a. CGMPs help protect the public health. The dietary supplement
industry is one of the fastest growing product areas that FDA
regulates. In 1999, Prevention magazine conducted a survey entitled
``Consumer Use of Dietary Supplements'' (Ref. 5). The survey used data
from telephone interviews with a nationally-representative sample of
2,000 adults living in households with telephones in the continental
United States. The telephone interviews were done in April and May,
1999. Using population estimates based on the Census Bureau's March
1998 Current Population Survey Estimates, the survey stated that
approximately 186,014,712 adults live in the households with telephones
in the United States and that an estimated 158.1 million of these
Americans in households with telephones use dietary supplement
products. These consumers spend approximately $8.5 billion a year on
dietary supplements. The survey also found that:
[sbull] Only 41 percent of the surveyed consumers who use vitamins
and minerals think they are very safe and only 50 percent think they
are somewhat safe;
[sbull] Only 24 percent of the surveyed consumers who use herbal
products think they are very safe; and only 53 percent think they are
somewhat safe; and
[sbull] Twelve percent of the surveyed consumers who have used
dietary supplements say they have experienced side effects or adverse
reactions from their use of dietary supplements.
The survey also found strong public support for increased
Government regulation of dietary supplements; 74 percent of the
surveyed consumers reported that they think that the Government should
be more involved in ensuring that these products are safe and do what
they claim to do.
However, unlike other major product areas, there are no FDA
regulations that
[[Page 12162]]
are specific to dietary ingredients and dietary supplements that
establish a minimum standard of practice for manufacturing, packaging,
or holding. The absence of minimum standards has contributed to the
adulteration and misbranding of dietary ingredients and dietary
supplements by contaminants or because manufacturers do not set and
meet specifications for their products, including specifications for
identity, purity, quality, strength, and composition. Thus, CGMP
regulations are necessary to protect the public health because a CGMP
rule would establish a minimum standard of practice for manufacturing,
packaging, and holding dietary ingredients and dietary supplements.
The following examples illustrate the wide range of dietary
ingredient and dietary supplement adulteration caused by manufacturing,
packaging, or holding practices. The examples, although not exhaustive,
demonstrate why CGMPs are necessary to protect public health:
[sbull] In 1997, we received an adverse event report (AER)
regarding a young woman who had taken a dietary supplement and
experienced a life-threatening abnormal heart function (Ref. 6). We
investigated the AER and determined that the dietary supplement the
woman consumed contained Digitalis lanata, a plant that can cause life-
threatening heart reactions (Refs. 6 through 10). We found D. lanata in
samples of raw material labeled ``plantain'' that was a dietary
ingredient in one of the dietary supplement products used by this woman
(Ref. 6). A nationwide listing of manufacturers indicated that 183
firms may have used the contaminated dietary ingredient in dietary
supplements. The proposed CGMP regulations, had they been in effect,
would have required identity and purity tests of dietary ingredients
and dietary supplements and would likely have prevented the use of the
D. lanata in these dietary supplements.
[sbull] In 1998, the American Herbal Products Association (AHPA)
surveyed its members about commonly adulterated botanicals and methods
useful in detecting adulteration in botanicals (Ref. 11). AHPA members
identified 43 botanicals, including D. lanata contaminated plantain,
that are commonly adulterated with contaminants, the common adulterant
for each botanical, and a method for identifying the adulterant. For
example, aflatoxin and mycotoxin (toxic compounds produced by certain
molds) are known to contaminate certain herbal and botanical dietary
supplements (Refs. 11 through 14). Under this proposed rule, a
manufacturer would have to establish specifications for botanicals that
may contain toxic compounds and conduct testing to ensure that there
are not toxic compounds present that may adulterate the dietary
ingredient or dietary supplement.
[sbull] We have found manufacturers using nonfood-grade chemicals
to manufacture dietary supplements (Ref. 15). The proposed rule would
require that manufacturers establish specifications for components used
in manufacturing and also would require manufacturers to establish and
follow laboratory control procedures that include criteria for
establishing appropriate specifications. The proposal would further
require manufacturers to conduct testing to confirm that their
specifications are met. These requirements, if finalized, would ensure
that manufacturers establish and use appropriate criteria, such as
using food-grade rather than industrial-grade chemicals, and would
ensure that manufacturers conduct testing to confirm that food-grade
chemicals were received from the supplier.
[sbull] Also during inspections, we have found insanitary
conditions in physical plants where dietary ingredients or dietary
supplements were manufactured, packaged, or held (Ref. 16). Pest
infestation, building and equipment defects, and leaking pipes that
drip onto dietary supplements are examples of insanitary conditions
that we have found that may lead to product adulteration and could
cause consumer illnesses and injuries. The proposed rule would require
a manufacturer, packager, or holder to maintain its physical plant used
for these activities in a sanitary condition.
[sbull] In the past, we have been involved in the recall of dietary
supplements contaminated with lead (Ref. 17), salmonella (Ref. 18),
Klebsiella pneumonia (Ref. 19), botulism (Ref. 20), and glass (Ref.
21). These contaminants can cause serious illness or injury and, in the
case of lead, may result in chronic irreversible cognitive defects in
children and progressive renal failure in adults. The proposed rule
would require dietary ingredients and dietary supplements to be
manufactured, packaged, and held in a manner that prevents
adulteration, including adulteration by the contaminants such as those
described.
[sbull] We also have been involved in recalls for super- and
subpotent dietary supplements. Recalls of superpotent dietary
supplements have included the following dietary ingredients: Vitamin A
(Ref. 22), vitamin D (Ref. 23), vitamin B6 (Ref. 24), and selenium
(Ref. 25). Each of these dietary supplements contained dietary
ingredient levels that could have caused serious illness or injury.
Illnesses or injuries such as nausea, vomiting, liver damage, and heart
attack were reported from superpotent niacin at an average level of 452
milligrams (mg) niacin, well above the upper limit for adults of 45 mg
daily (Ref. 26). Recalls for subpotent dietary supplements have
included a recall of folic acid because the dietary supplement
contained 34 percent of the declared level (Ref. 27). Such a product
would be misbranded under section 403 of the act (21 U.S.C. 343).
Folate plays a well-documented and important role in reducing the risk
of neural tube defects. Neural tube birth defects, primarily spina
bifida and anencephaly, cause serious lifetime debilitating injuries
and disabilities, and even death. Thus, use of subpotent folic acid by
women who are or may become pregnant may result in increased risk of
having a child with a neural tube defect. The proposed rule would
require manufacturers to establish specifications for the dietary
supplement the manufacturer makes and then meet those specifications.
Therefore, if the proposed rule is finalized, if the label for a folic
acid supplement declares that the dietary supplement contains a certain
level of folic acid, the folic acid supplement must actually contain
that level, or we would consider the folic acid supplement to be
adulterated under section 402(g) of the act.
[sbull] Other recalls have been necessary because of undeclared
ingredients, including color additives (Refs. 28 and 29), lactose (Ref.
30), and sulfites (Ref. 31). Undeclared ingredients, such as color
additives, lactose, and sulfites, may cause potentially dangerous
reactions in susceptible persons (Ref. 32). The proposed rule would
require manufacturers to verify that the correct labels have been
applied to dietary ingredients and dietary supplements produced. The
master manufacturing record would have to identify each ingredient
required to be declared on the ingredient list under section 403 of the
act.
[sbull] A study found that dietary ingredient content varied
considerably from the declared content (Ref. 33). The study examined
ephedra alkaloids in 20 herbal dietary supplements containing ephedra
(Ma Huang) to determine their ephedra alkaloid content. This study
found that norpseudoephedrine was often present in the ephedra dietary
supplements. The study also observed significant lot-to-lot variations
in alkaloid content for four products,
[[Page 12163]]
including one product that had lot-to-lot variations of ephedrine,
pseudoephedrine, and methylephedride that exceeded 180 percent, 250
percent, and 1,000 percent, respectively. Half of the products tested
differed in their label claims for ephedra alkaloid content and their
actual alkaloid content. In some cases, the discrepancy exceeded 20
percent. One product did not have any ephedra alkaloids. Lot-to-lot
variation in dietary ingredients is a public health problem
particularly because conditions of use recommended or suggested in the
labeling of dietary supplements are presumably based on the dietary
supplement containing a certain amount of the dietary ingredient. If
the dietary supplement contains more or less than the amount that the
manufacturer represents, then the consumer does not receive the
potential health benefit from the dietary supplement or is exposed to
an amount that could present risk of injury or illness. The proposed
rule would require manufacturers to establish controls, including
master manufacturing and batch production records to ensure that they
use the correct amount of the dietary ingredient to produce the dietary
supplement, and that they apply the correct label to the dietary
supplement.
[sbull] A private company analyzed a sample of dietary supplements
and found that some dietary supplements did not contain the dietary
ingredients claimed on the label (Ref. 34). The study found that 25
percent of gingko biloba products, 20 percent of saw palmetto, 33
percent of glucosamine, chrondroitin and combined glucosamine/
chondroitin, and 50 percent of SAMe did not contain the dietary
ingredients claimed in their product labels. The proposed rule would
require manufacturers to establish and meet specifications for the
identity, purity, quality, strength, and composition of dietary
supplements.
Given the wide range of public health concerns presented by the
manufacturing, packaging, and holding practices for dietary ingredients
and dietary supplements, a comprehensive system of controls is
necessary to prevent adulteration and misbranding. CGMPs are intended
to establish such a comprehensive system. Manufacturers who operate in
accordance with CGMPs would be less likely to distribute adulterated
and misbranded dietary ingredients or dietary supplements than those
who do not meet the requirements. Quality assurance will maximize the
probability that unadulterated dietary supplements will reach the
marketplace.
Establishing CGMP regulations for dietary supplements is only part
of our broad science-based regulatory program for dietary supplements
that is necessary to give consumers a high degree of confidence in the
safety, composition, and labeling of dietary supplements. Aside from
our CGMP efforts, we have taken other steps to protect the public
health, such as:
[sbull] Reviewing claim notifications under section 403(r)(6) of
the act to identify unlawful claims;
[sbull] Reviewing new dietary ingredient notifications to ensure
that new dietary ingredients are reasonably expected to be safe under
section 413 of the act (21 U.S.C. 350b);
[sbull] Evaluating the nutrition labeling of dietary supplements;
[sbull] Monitoring, through AERs voluntarily submitted to FDA, the
occurrence of adverse events to identify potentially unsafe products;
and
[sbull] Taking compliance actions against products that are
adulterated or misbranded.
The CGMP regulation, if finalized, would, along with our other
dietary ingredient and dietary supplement initiatives, contribute
further to the protection of public health.
b. CGMPs benefit consumers. In addition to the public health
benefits for consumers, CGMP regulations for dietary ingredients and
dietary supplements will benefit consumers in other ways. Consumers
should not have to wonder whether the dietary supplements they buy are
adulterated or whether they contain the correct dietary ingredients or
contain the dietary ingredients in the amount stated on the product's
label. Consumers who purchase a product that does not contain the
amount or strength listed on the label experience an economic loss
because they are paying for something that they did not receive. CGMPs
would require manufacturers to establish and meet specifications for
identity, purity, quality, strength and composition of dietary
supplements to help ensure that consumers buy dietary supplements that
are not adulterated, contain the dietary ingredients declared on the
product's label, and contain the amount or strength listed on the
label. Therefore, CGMPs would benefit consumers.
2. How Will CGMP Regulations Take Into Account Technical Feasibility?
In developing this proposed rule, we were careful not to propose
requirements that are not technically feasible to meet. In some areas
where there has been scientific study but where the science is still
evolving, the proposal recognizes the evolving state of the science,
but would give you maximum flexibility in meeting the requirement. For
example, there are tests available for identity, purity, quality,
strength, and composition of certain dietary ingredients or dietary
supplements. Because many tests for identity, purity, quality,
strength, and composition of dietary ingredient or dietary supplements
have not been officially validated, the proposal would permit tests
using methods other than those that are officially validated. By using
the term ``officially validated,'' we mean that the method is validated
using an interlaboratory collaborative study by which a proposed method
is validated by independent testing in separate laboratories under
identical conditions (Ref. 35). An AOAC International (formerly the
Association of Official Analytical Chemists) Official Method is an
example of an officially validated method. We discuss test methods
validation in more detail later in this document.
In areas where scientific study is still evolving, we did not
propose specific requirements. For example, we did not propose
requirements for dissolution, disintegration, bioavailability, or
expiration dating. In those areas, it may be premature to propose a
requirement at this time. In the preamble to this rule, we identify
those areas where additional scientific study is necessary before we
can propose a dietary supplement CGMP requirement. For example, we did
not identify defect action levels (DALs) for dietary ingredients
because there are not enough data available to identify an appropriate
DAL for most dietary ingredients. Likewise, further study is needed for
some dietary ingredients before dissolution, disintegration,
bioavailability, expiration dating, or other quality standard
requirements can be proposed.
3. How Can FDA Help Industry Achieve Compliance With CGMPs?
During small business outreach public meetings and in comments to
the ANPRM, members of the dietary supplement industry told us that they
would like our help in determining how to implement CGMP regulations
for dietary ingredients and supplements. We have heard that issuing
guidance documents and education and training would be helpful. We
invite comment on the use of guidance documents, education, training,
or other approaches and potential sources of education and training
that you believe would assist industry efforts to implement the
proposed CGMP regulations, if finalized as proposed.
[[Page 12164]]
F. Proposal Highlights and Requests for Comments
This proposed rule is intended to ensure that manufacturing
practices will not result in an adulterated dietary supplement and that
supplements are properly labeled. This proposed rule, if finalized as
proposed, will give consumers greater confidence that the dietary
supplements they choose to use will have the identity, strength,
purity, quality, or composition claimed on the label. A manufacturer of
a dietary ingredient or a dietary supplement cannot make claims that
state or imply that the dietary ingredient or dietary supplement is
safe and/or effective simply because it has been manufactured in
compliance with current good manufacturing practice (CGMP)
requirements. However, we believe that a voluntary labeling statement
about the fact that a dietary ingredient or dietary supplement has been
made in compliance with CGMP requirements might be made lawfully under
the act, provided that such a statement is made in an appropriate
context and with adequate disclaimers so that consumers fully
understand it and are not misled by it. The proposed rule governing
CGMP requirements for dietary supplements address manufacturing
controls to ensure that dietary ingredients and dietary supplements are
produced in a manner that will not adulterate or misbrand such
products. Compliance with any final rule, based on the proposal, will
not ensure that the dietary ingredient or dietary supplement itself is
safe or effective. Thus, the agency believes that an unqualified
statement saying simply ``produced in compliance with dietary
supplement current good manufacturing practice requirements,'' without
more, could well suggest that a product may be safe and effective or
somehow superior to other dietary ingredient and dietary supplement
products that are subject to the same CGMP requirements. Such a
statement would likely be considered misleading by FDA under sections
403(a)(1) and 201(n) of the act. We believe however, that it might be
possible to cure an unqualified statement by including language
clarifying to consumers that all dietary ingredients and dietary
supplements must be manufactured in compliance with CGMP requirements
and that such compliance does not mean that the dietary ingredient or
dietary supplement is safe or effective. As usual, the manufacturer
would be responsible for ensuring that any such voluntary labeling
statements on its dietary ingredient and dietary supplement products
are truthful and not misleading. The agency would review the lawfulness
of such statements under sections 403(a)(1) and 201(n) of the act.
We propose requirements for: (1) Personnel, (2) the physical plant
environment, (3) equipment and utensils, (4) production and process
controls, (5) holding and distributing, (6) consumer complaints related
to CGMPs, and (7) records and recordkeeping. Key provisions of the
proposed rule are highlighted below. We also seek comment on whether
certain additional provisions should be included as requirements in a
final rule.
Proposed ``personnel'' requirements would require that you have
qualified employees and supervisors, to take measures to exclude any
person from your operations who might be a source of microbial
contamination, and to use hygienic practices to the extent necessary to
protect against contamination.
Proposed ``physical plant'' requirements are intended to help
prevent contamination from your physical plant environment. You would
be required to design and construct your physical plant in a manner to
protect dietary ingredients and dietary supplements from becoming
adulterated during manufacturing, packaging, and holding. You would be
required to keep your physical plant in a clean and sanitary condition
and in sufficient repair to prevent contamination of components,
dietary ingredients, dietary supplements, or contact surfaces.
Proposed ``equipment and utensils'' provisions would require that
you use equipment and utensils that are of appropriate design,
construction, and workmanship for their intended use and that you
provide for adequate cleaning and maintenance. You would be required to
maintain and calibrate your instruments and controls for accuracy and
precision and to ensure that automatic, mechanical, and electronic
equipment works as intended. You would also be required to maintain,
clean, and sanitize, as necessary, all equipment utensils and contact
surfaces that are used to manufacture, package, or hold dietary
ingredients or dietary supplements.
Under the proposed ``production and process controls''
requirements, you would be required to establish and use a quality
control unit in your manufacturing, packaging, and label operations. We
propose requirements for establishing and using master manufacturing
records and batch control records to ensure batch-to-batch consistency.
Specifications would be required for any point, step, or stage in the
manufacturing process where control is necessary to ensure that the
dietary supplement contains the identity, purity, quality, strength,
and composition claimed on the label. We propose flexible testing
requirements: You would be required to test final products for
adherence to specifications, unless a scientifically valid analytical
method does not exist; in the latter case, you would be required to
test incoming shipment lots of components, dietary ingredients, or
dietary supplements for any such specification, and to test in-process
for any such specification in accordance with the master manufacturing
record where you determine control is necessary to ensure the identity,
purity, quality, strength, and composition of the product.
Proposed ``holding and distributing'' requirements would protect
components, dietary ingredients, dietary supplements, packaging, and
labels against contamination and deterioration. You would be required
to hold components, dietary ingredients, dietary supplements,
packaging, and labels under appropriate conditions of temperature,
humidity, and light so that their quality is not affected; and under
conditions that do not lead to the mixup, contamination, or
deterioration.
Proposed ``consumer complaints'' requirements would require that
you keep a written record of each consumer complaint related to good
manufacturing practices; review such complaints to determine whether
the consumer complaint involves a possible failure of a dietary
ingredient or dietary supplement to meet any of its specifications, or
any other requirements of this part, including those that may result in
a possible risk of illness or injury (i.e., an adverse event); and
investigate a consumer complaint when there is a reasonable possibility
of a relationship between the consumption of a dietary supplement and
an adverse event. For the purposes of this regulation, a consumer
complaint about product quality may or may not include concerns about a
possible hazard to health. However, a consumer complaint does not
include an adverse event, illness, or injury related to the safety of a
particular dietary ingredient independent of whether the product is
produced under good manufacturing practices.
Proposed ``records and recordkeeping'' requirements would tell you
how long you must keep certain records to show how you complied with
the CGMP requirements. We would require that you keep written records
for 3 years beyond the date of manufacture of the last batch of dietary
ingredients
[[Page 12165]]
or dietary supplements associated with those records and have all
required records, or copies of such records, readily available during
the retention period for authorized inspection and copying by FDA when
requested.
CGMP records document the manufacturer's operation throughout time
and are essential to an enforceable regulation. Because FDA does not
observe the manufacturer's operation fulltime, records can ensure that
the FDA has the information needed to identify noncompliance and to
bring a non-compliant manufacturer into compliance. Records can show
that appropriate monitoring is performed, pinpoint with confidence when
a deviation began and ended, and prove that required quality control
measures and practices were performed as often as necessary to ensure
control. Review of manufacturing records with sufficient frequency can
ensure that any problems are uncovered promptly and can facilitate
prompt modification, have an impact on the production of subsequent
batches of the product, and prevent introduction of potentially
hazardous dietary supplements into the market place. Review of consumer
complaint records can facilitate the identification of trends in
reports of illness or injury, identify related batch records to
identify previously undetected manufacturing deviation, and have an
impact on the prompt recall of any potentially hazardous dietary
supplement.
We seek comment on whether the proposed recordkeeping requirements
are not necessary to prevent adulteration; to ensure the identity,
purity, quality, strength, and composition of the dietary ingredient or
dietary supplement; to an enforceable regulation; and for the other
reasons cited. If comments assert that recordkeeping provisions are not
necessary, comments should include an explanation of why recordkeeping
requirements are not necessary including how, in the absence of the
requirements, one can prevent adulteration, ensure the identity,
purity, quality, strength, and composition of the dietary ingredient or
dietary supplement, ensure an enforceable regulation, and the other
reasons cited. If comments agree that the recordkeeping requirements
are necessary for reasons other than those we have provided, the
comments should so state and provide an explanation.
Although records are not required in 21 CFR Part 110, CGMPs in
manufacturing, packing, or holding human food, records are required in
the other commodity-driven food CGMPs (i.e., 21 CFR Part 129,
Processing and bottling of bottled drinking water; 21 Part CFR 120,
Hazard Analysis and Critical Control Point (HAACP) Procedures for the
Safe and Sanitary Processing and Importing of Juice; 21 CFR Part 123,
Fish and fishery products; 21 CFR Part 106 Infant formula quality
control procedures; and 21 CFR Part 113, Thermally processed low-acid
foods packaged in hermetically sealed containers). Further, records are
included in the CGMPs submitted to FDA by industry, the National
Nutritional Foods Association Standards, the NSF International draft
standards (Ref. 83), and the USP draft Manufacturing Practices for
Dietary Supplements.
We seek comment on whether certain additional provisions should be
included as requirements in a final rule. For example, we invite
comment on whether a final rule should include a requirement for
certain personnel records; for written procedures in a number of areas;
for equipment verification; and for expiration dating and related
testing. Written procedures are included in the dietary supplement CGMP
outline submitted to FDA by industry, National Nutritional Foods
Association standards, the NSF International draft standards, and the
USP draft Manufacturing Practices. In order to limit the burden to
manufacturers, FDA is not proposing to require written procedures.
However, FDA is proposing that manufacturers maintain appropriate
records to ensure the identity, purity, quality, strength, and
composition of a given product and records that are necessary for
efficient enforcement and to permit trace back. Although we have not
proposed requirements for written procedures as did these other groups,
we seek comment on whether such practices should be included in a final
rule. Later in this document, we request comments on specific written
procedures and describe FDA's current thinking concerning what could be
included in such a written procedure.
We also seek comment on whether this rule should include specific
requirements for the use of animal-derived dietary ingredients, and
requirements for persons who handle raw agricultural commodities.
Specific requests for comment of this type are contained below in
relevant sections of this preamble.
II. General Issues
A. Legal Authority
We are proposing these regulations under sections 201, 393, 409,
701(a), 704, and 801 of the act (21 U.S.C. 321, 903, 348, 371(a), 374,
and 381) and sections 402 and 403 of the act and section 361 of the
Public Health Service Act (the PHS Act) (42 U.S.C. 264).
Section 402(g) of the act gives us explicit authority to issue a
rule regulating conditions for manufacturing, packaging, and holding
dietary supplements. Section 402(g)(1) of the act states that a dietary
supplement is adulterated if ``it has been prepared, packed, or held
under conditions that do not meet current good manufacturing practice
regulations.'' Section 402(g)(2) of the act authorizes us to, by
regulation, ``prescribe good manufacturing practices for dietary
supplements.'' In addition, section 402(g)(2) of the act states that
any such regulations ``shall be modeled after current good
manufacturing practice regulations for food and may not impose
standards for which there is no current and generally available
analytical methodology.''
In section 402(g)(2) of the act, which describes the general
parameters of CGMPs for dietary supplements, Congress stated that the
regulations were to be ``modeled after current good manufacturing
practice regulations for food.'' To determine what Congress meant, we
look to the plain meaning of the phrase. Webster's II New Riverside
University Dictionary defines ``model'' as ``[a] preliminary pattern
serving as the plan from which an item not yet constructed will be
produced'' (Ref. 81). Thus, when Congress used the term ``modeled
after'' Congress intended that we use the food CGMPs as a ``preliminary
pattern'' for the dietary supplement CGMPs. If Congress had intended
for the agency to adopt food CGMPs as the CGMPs for dietary
supplements, Congress could have explicitly stated that dietary
supplements were subject to food CGMPs.
The provisions in the dietary supplement CGMP proposal are modeled
after food CGMPs. The general CGMP provisions for food in part 110
relate not only to insanitary production practices, but other
practices, such as having appropriate quality control operations, to
ensure that a food is manufactured in a manner that will not adulterate
the food. Further, the CGMPs in part 110 describe the minimally
acceptable practices for all food handling operations. They are not
intended to cover specific issues that may relate to a particular
product type, rather, are general provisions concerned with practices
relating to the receiving, inspecting, quality control operations,
packaging, segregating, processing, storing, and transporting of food.
The specific provisions of the food CGMPs
[[Page 12166]]
are linked to hazards that are inherent to foods (e.g., microbial
contamination and contamination with macroscopic filth).
The proposed dietary supplement CGMPs are modeled after the food
CGMPs in part 110 in that they cover the scope of practices related to
the receiving, inspecting, quality control operations, packaging,
segregating, processing, storing, and distribution of dietary
ingredients and dietary supplements. Dietary supplements require many
of the same types of sanitary practices and other practices as
conventional food production in order to produce a product that is not
adulterated; dietary supplements are subject to many of the same
hazards as are conventional foods. However, dietary supplements have
their own set of unique requirements as a result of the characteristics
and hazards due to their ``hybrid'' nature, e.g., dietary supplements
can be considered as falling somewhere along the continuum between
conventional foods on the one hand and drugs on the other. Thus, the
CGMPs for dietary supplements need to address the characteristics and
hazards of dietary supplements, the operations and processes used to
manufacture dietary supplements, particularly those necessary to ensure
the identity, purity, quality, strength, and composition claimed on the
label.
Dietary supplements, unlike conventional foods, contain ingredients
that are consumed in very small quantities, for example, in a tablet or
capsule. Such ingredients may be intended to have an anticipated,
specific physiological response. Such ingredients are more ``drug-
like'' than ``food-like,'' in part, because very small changes in the
strength, purity, or quality of the ingredient can have significant,
and possibly adverse, health consequences to those who ingest it. Thus,
the dietary supplement CGMPs, by necessity, need to include provisions
related to identity, purity, strength, quality, and composition of the
product so that the dietary supplement ``food'' product will be
manufactured in a manner that will not result in adulteration.
Further, plant products that are used to produce dietary
supplements may be ground or in a powder and not easily recognized
compared to conventional food that is readily identifiable (e.g., one
can readily distinguish between white flour and white sugar, but not
between ground plaintain and ground D. lanata). Thus, for the
manufacturer to be sure that the dietary supplement contains the
correct ingredient and the amount of the ingredient that is intended,
the manufacturer must test or examine the ingredient using appropriate
methods. The ``modeled after'' language in section 402(g) of the act
provides the agency with the flexibility to devise CGMPs that make
sense for dietary supplements, and that are based on the same
principles as food CGMPs in part 110, i.e., to prevent adulteration
related to insanitary conditions or other conditions that may be
necessary to prevent adulteration, given the nature of the specific
food product and the characteristics of, and hazards inherent in, that
food.
The scope of the legal authority for the proposed dietary
supplement CGMPs includes the legal authorities upon which the food
CGMPs are based. For example, section 402(a)(3) of the act states that
a food is deemed adulterated if ``it consists in whole or in part of
any filthy, putrid, or decomposed substance, or if it is otherwise
unfit for food.'' Section 402(a)(4) of the act states that a food is
deemed adulterated if ``it has been prepared, packed, or held under
insanitary conditions whereby it may have become contaminated with
filth, or whereby it may have been rendered injurious to health.''
While section 402(a)(3) of the act focuses on the food itself, section
402(a)(4) of the act focuses on the conditions under which the food is
prepared, packed, or held. Courts have adopted a broad reading of
section 402(a)(4) of the act when we have taken actions to advance the
public health (see U.S. v. Nova Scotia Food Products Corp., 568 F. 2d
240, 248 (2d Cir. 1977)). The agency tentatively concludes that the
authorities that it relied on for its umbrella CGMPs in part 110 for
food are relevant to the authorities that it needs for this proposed
rule for dietary supplement CGMPs. In addition, section 409 of the act
is another provision that is relevant to dietary supplement CGMPs.
Section 409 of the act addresses circumstances under which a food may
be deemed adulterated based on the use of a food additive. Section 409
of the act is relevant to good manufacturing practices for foods,
including dietary supplements, because a food would be deemed
adulterated if it contained a food additive that was not used in a
manner consistent with the statutory and regulatory requirements under
section 409 of the act (see sections 402(a)(2)(C) and 409 of the act).
Although Congress explicitly excluded ``dietary ingredients,'' as
defined in section 201(ff) of the act, from the definition of food
additive, (see section 201(s)(6) of the act), ingredients other than
dietary ingredients in a dietary supplement are subject to regulation
as a food additive under section 409 of the act, unless they are
subject to an exception to the definition of ``food additive'' under
section 201(s) of the act.
Moreover, dietary ingredients and dietary supplements may contain
pathogenic bacteria or viruses that pose serious public health and
safety concerns (Ref. 36). Botanical dietary ingredients are living
plants that may contain different microorganisms. These include
Lactobacillus, Leuconostoc, Pseudomonas, and Xanthomonas species and
molds. Potential pathogens such as Listeria monocytogens, Pseudomonas
aeruginosa and Enterobacteriacae may also be present. Secondary
microbial contamination from soil (Bacillus cereus, Clostridium
perfringens and mycotoxin-producing molds, etc.), animal feces
(Salmonella and Shigella spp., Escherichia coli) and handling
(Staphylococcus aureus) can also occur during harvesting, processing,
and transportation (Ref. 36). Animal-derived dietary ingredients or
dietary supplements may also pose a risk. For example, bovine
colostrum, the lacteal secretion which precedes milk after a cow gives
birth, is a substance that is used in dietary supplements and likely
presents the same potential health risks as does milk. Bovine milk may
contain pathogenic organisms capable of causing diseases in man such as
tuberculosis or undulant fever. Glands and other animal tissues may
contain the infective agent that causes transmissible spongiform
encephalopathy (TSE) if they originate from an animal infected with the
disease (Ref. 37).
We have authority to issue regulations under section 361 of the PHS
Act. The Secretary delegated authority to the Commissioner of FDA (the
Commissioner) to exercise the functions vested in the Secretary under
section 361 of the PHS Act (see 21 CFR 5.10(a)(3)). This authority
authorizes the Commissioner to issue and enforce regulations that, in
the Commissioner's judgment, are necessary to prevent the introduction,
transmission, or spread of communicable diseases from one State to
another. Because this authority is designed to eliminate the
introduction of diseases from one State to another, the Commissioner
may exercise the authority over the disease-causing substance within
the State where the food is manufactured, packaged, or held. The
Commissioner, therefore, assumes the authority to issue regulations
under the PHS Act to assure that foods are manufactured, packaged, and
held under conditions that will prevent the introduction, transmission,
[[Page 12167]]
or spread of communicable diseases between States. Thus, the agency is
invoking its authority under the PHS Act in this proposed rule to
prevent the spread of communicable disease from dietary ingredients or
dietary supplements in intrastate and interstate commerce.
In developing proposed CGMPs for dietary supplements, we relied on
the basic concept underlying the food CGMPs and upheld by the courts.
As a result, the basic concept for the food CGMPs and the proposed
dietary supplement CGMPs is the same: To establish regulations that
will help ensure that your practices for preparing, packaging, and
holding dietary ingredients and dietary supplements do not result in an
adulterated food entering interstate commerce.
In addition to relying on the broad authority in relevant sections
of the act that we used to issue the food CGMP regulations, we look to
the other relevant statutory language in section 402(g) of the act and
the act as a whole in deciding the basis for our legal authority in
proposing regulations related to the manufacture, packaging, and
holding of dietary ingredients and dietary supplements. We note that
certain terms Congress used in section 402(g)(2) of the act, i.e.,
``standards'' and ``current and generally available analytical
methodology,'' show that Congress intended to give us the authority to
establish regulations in this rule that do not have parallel provisions
in other food CGMPs. Specifically, the second phrase of the second
sentence in section 402(g)(2) of the act states that we ``may not
impose standards for which there is no current and generally available
analytical methodology.'' ``Standards'' and ``current and generally
available analytical methodology'' are terms of art in the scientific
field, and we are relying on the meaning of these terms in the field of
science in these proposed CGMPs regulations, which implement that
provision. This statutory language does not limit CGMPs for dietary
supplements solely to the food CGMP regulations at the time DSHEA was
enacted. If Congress had intended for the CGMPs for dietary supplements
to be identical to the CGMPs for food, the language in section
402(g)(2) of the act relating to ``standards'' and ``current and
generally available analytical methodolog[ies]'' would be meaningless.
Thus, CGMP regulations for dietary ingredients and dietary supplements
may include provisions relevant to dietary ingredients and dietary
supplements that were not in current food regulations at the time DSHEA
was enacted.
In addition to the broad authority in section 402(g) of the act, we
look to the statutory scheme of DSHEA as a whole in proposing
regulations related to the manufacture, packaging and holding of
dietary ingredients and dietary supplements. Section 403(q)(5)(F) of
the act (section 7(b) of DSHEA) requires that a dietary supplement
product provide nutrition information. To comply with section
403(q)(5)(F) of the act, you must be able to identify the dietary
ingredient or ingredients in a dietary supplement and the quantity of
each. Moreover, the provisions in section 403(s) of the act relate to
identity, purity, quality, strength, and compositional specifications
of a dietary supplement. Thus, Congress sought to ensure in DSHEA that
dietary supplements would provide accurate information to the consumer
on the identity of the dietary ingredient and, if an herb or botanical,
the source from which it is derived. Moreover, Congress sought to
ensure that the dietary supplement would have the strength or meet the
quality, purity, and compositional specifications that the dietary
supplement is represented to meet. Because Congress established section
403(s) of the act--a provision that requires that a dietary supplement
that bears representations about identity, purity, quality, strength,
and compositional specifications meet those representations--it is
reasonable for us to establish regulations for manufacturing,
packaging, and holding addressing those same features. These
representations relate to characteristics and hazards to which dietary
supplements are subject. Further, in section 402(f) of the act,
Congress identified circumstances under which a dietary supplement or a
dietary ingredient would be deemed adulterated because it may present a
significant or unreasonable risk of illness or injury. Congress
expected that a dietary supplement would be manufactured in a way that
ensures that the dietary supplement contains dietary ingredients that
do not present an unreasonable risk of illness or injury and for which
the conditions of use are based. Because one must be able to measure or
analyze a dietary ingredient in order to determine whether a supplement
in fact contains that dietary ingredient, it is reasonable for a
proposed rule on CGMPs to include provisions related to identity,
purity, quality, strength, and composition of a dietary ingredient or a
dietary supplement. Moreover, it is reasonable to propose a requirement
that records of complaints be kept and investigations be done, as
necessary, so that the manufacturer and FDA can be aware of any
potential problems relating to a particular dietary ingredient and
these CGMPs, and so that a manufacturer can take appropriate action
when necessary. The proposed CGMPs would reflect the act's regulatory
scheme generally and, more specifically, DSHEA's provisions that
contemplate consistent, controlled manufacture of dietary supplements
(see sections 402(f) and 403(q)(5)(F) and (s) of the act). We
tentatively conclude that, therefore, section 402(g)(2) of the act
gives us the authority to develop dietary supplement CGMPs that are not
identical to our food CGMPs and that are appropriately tailored to the
manufacturing, packaging, and holding of dietary ingredients and
dietary supplements.
Sections 701(a) and 704 of the act also give us authority to
establish regulations related to CGMPs for dietary ingredients and
dietary supplements. Under section 701(a) of the act, we have the
authority to issue regulations for the efficient enforcement of the
act, and such regulations have been held to have the force and effect
of law (see National Nutritional Foods Ass'n v. Weinberger, 512 F.2d
688, 697-98 (2d Cir. 1975)). Section 704 of the act gives us the
authority to inspect factories, warehouses, and other establishments in
which foods, including dietary ingredients and dietary supplements, are
manufactured, processed, packed, or held and to inspect their
facilities, equipment, finished and unfinished materials, containers,
and labeling.
In addition to having the authority to establish broad regulations
for manufacturing, packaging, and holding dietary ingredients and
dietary supplements, we also have the authority to require
recordkeeping as part of these regulations. Two questions that we
considered in deciding whether to propose requirements for
recordkeeping included whether the statutory scheme as a whole
justified the proposed regulation and whether the proposed
recordkeeping requirements would be limited, would clearly assist in
the efficient enforcement of the act, and would not create an
unreasonable recordkeeping burden. In the other relevant sections of
this document, we explain in more detail the recordkeeping provisions
that we believe are limited to what are necessary for the efficient
enforcement of the act, and because the requests are limited, would
therefore not create an unreasonable recordkeeping burden.
For this proposed CGMP rule for dietary ingredients and dietary
supplements, recordkeeping is necessary to provide the type of
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documentation that would demonstrate that dietary ingredients and
dietary supplements are manufactured, packaged, and held under the
conditions that would be required under the proposed CGMP regulations.
Further, FDA is using its authority under sections 801 and 701(a) of
the act in proposing recordkeeping requirements for dietary ingredients
and dietary supplements that may not be marketed or sold in the United
States and that are exported under section 801(e) of the act.
In addition to having the authority under the act to require
recordkeeping, we also have authority to require access to the records.
Because the practices set forth in the proposed CGMP rule are necessary
to providing consumers with dietary supplements that are not
adulterated, access to records that demonstrate that firms follow CGMPs
is essential to confirming systematic compliance with CGMPs. We also
have the authority to copy the records when necessary. We may consider
it necessary to copy records when, for example, our investigator may
need assistance in reviewing a certain record from relevant experts in
headquarters. If we were unable to copy the records, we would have to
rely solely on our inspector's notes and reports when drawing
conclusions. A failure to have a required record would mean that a food
is adulterated under section 402(g) of the act.
Recordkeeping will not only help the agency to determine whether
dietary ingredients or dietary supplements were manufactured, packaged,
and held consistent with CGMP regulations, but also will provide a
public health benefit to consumers. When manufacturers keep records,
for example, of lot or batch numbers, the records facilitate a
manufacturer's recall of suspect products in case a recall becomes
necessary. This benefits consumers because the manufacturer can recall
its products that may be adulterated or misbranded more quickly.
B. Issues From the ANPRM
As stated previously, in addition to inviting comment on the
industry-drafted CGMP outline, we asked nine questions in the ANPRM on
CGMP issues for dietary supplements that the industry outline did not
address. In this section, we summarize each question and the principal
comments we received, and we respond to the comments. We address other
significant comments about the ANPRM, other than the nine questions we
asked, elsewhere in this document.
The nine questions in the ANPRM, comments, and our responses are as
follows:
Question 1. Is there a need to develop specific defect action
levels (DALs) for dietary ingredients?
The ANPRM stated that the use of a botanical in a dietary
supplement may result in a much greater exposure to the botanical
ingredient for consumers because the dietary supplement will be
consumed in greater amounts than if the ingredient was in a food as a
spice or flavoring agent.
Several comments stated that establishing DALs for dietary
ingredients that are different than DALs for food is not necessary. The
comments disagreed with our statement that dietary ingredients in
dietary supplements and conventional foods are consumed in different
quantities. For example, the comments stated that generally botanical
ingredients are present in dietary supplements in approximately the
same amounts normally consumed in conventional foods.
Other comments generally opposed applying the current DALs for
foods to dietary ingredients and instead supported the development of
DALs for dietary ingredients, especially for botanicals and herbals.
Many comments recommended that we cooperate with industry, outside the
rulemaking process, to develop DALs for dietary ingredients.
We disagree with the comments that state that establishing DALs for
dietary ingredients that are different than DALs for food is not
necessary because an ingredient in food and in a dietary supplement
would be consumed in the same amounts. The comment did not provide
evidence or examples to support the comment. Some food ingredients for
which DALs have been established also are dietary ingredients used in
dietary supplements. For example, a DAL has been established for whole
ginger used in a conventional food. Ginger is also a dietary ingredient
used in dietary supplements. We have found dietary supplements that
recommend a daily intake of ginger of 4,815 mg, 1,260 mg, and 2,200 mg
(Ref. 38). One teaspoon of raw ginger root is equal to 2,000 mg (2
grams (g)) and one teaspoon of ground ginger is equal to 1,800 mg of
ginger (1.8 g) (Ref. 39). A recipe for gingersnaps yielding 18 cookies
specifies 1 teaspoon ginger (Ref. 40). Thus, ginger would be consumed
in greater amounts as a dietary supplement than as an ingredient in a
conventional food. However, we have tentatively concluded that we do
not have sufficient information to determine whether a DAL for a
dietary ingredient should be established at a different level than what
has been established for the same ingredient used in conventional food.
DALs are established for a food ingredient on a per weight basis.
The DALs for whole ginger for ``insect filth and/or mold'' is an
``average of 3 percent or more pieces by weight are insect-infected
and/or moldy'' and for ``mammalian excreta'' is an ``average of 3 mg or
more of mammalian excreta per pound'' (Ref. 41). Because the DAL is
established by weight of the whole ginger, the DAL for ginger would
apply whether it is used as an ingredient in a conventional food or a
dietary ingredient in a dietary supplement. Therefore, if we have
established a DAL in the industry compliance document for a
conventional food ingredient, that DAL also would apply to that
ingredient when used as a dietary ingredient in a dietary supplement
until such time that we would establish a different DAL for its use as
a dietary ingredient (Ref. 41). However, we do not have many dietary
ingredients that are included in the DAL compliance guide. We agree
that DALs may be needed for some dietary ingredients, especially
ingredients like botanicals that are subject to the same type of
defects (such as mold and insect parts) as other food for which DALs
have been established. We base DALs on scientific information such as
literature surveys, scientific market surveys, and laboratory analyses
and also on information gained through physical plant inspections. If
and when we determine that we have sufficient information to develop
DALs for dietary ingredients, we will consider whether to do so.
Question 2. We requested comments on appropriate testing
requirements to provide positive identification of dietary ingredients,
particularly plant materials, used in dietary supplements.
The ANPRM explained that the misidentification of dietary
ingredients, particularly plant materials, used in dietary supplements
may present a significant public health and economic concern. The ANPRM
also noted that the analytical methodology available for identifying
many dietary ingredients is limited. We invited comments on the
technical and scientific feasibility of identifying different types of
dietary ingredients. We also solicited information on what constitutes
``adequate testing'' for identity of different types of dietary
ingredients, and, in the absence of testing, what types of practices
would be effective alternatives to testing to ensure the
[[Page 12169]]
identity of different types of dietary ingredients.
Comments generally supported requiring tests of some kind to
positively identify dietary ingredients and to verify dietary
ingredient identity. The comments put forth different reasons, which
ranged from ensuring public safety to preventing economic adulteration.
Some comments suggested that suppliers should be responsible for
identifying the dietary ingredients they supply to manufacturers and
that manufacturers should be responsible for only verifying the
identity of the finished product. Other comments stated that the
manufacturer should be responsible for identification and should not
rely on a supplier's certification.
Some comments raised issues relating to the actual identity tests
that should be recommended or required and discussed analytical method
selection and method options, use of and availability of official
validated analytical methods, and certification of testing facilities
that conduct identity tests on natural products. Some comments
suggested that identity test method options should include organoleptic
and microscopic methods and chemical analytical methods. The comments
noted that selecting the appropriate method is dependent on the type
and form of the ingredient. Other comments said that manufacturers
should be responsible for selecting the appropriate method to confirm
ingredient identity. Most comments recommended that we provide guidance
to industry in defining what comprises adequate testing for different
types of ingredients, but did not support regulations prescribing the
test method or methods for specific ingredients.
Comments generally supported the use of a standard compendial
method, such as those published by the USP or AOAC International. Where
no published method exists, the comments suggested that manufacturers
should be responsible for developing adequate and effective
identification testing procedures, requirements, or practices to ensure
the identity of the dietary ingredients they use. One comment from a
vitamin manufacturer noted that most of its products have recognized
and established identity tests as part of their compendial status.
Other comments from botanical dietary supplement manufacturers noted
that their current methods for identifying plant material are adequate,
but that they will, over time, be enhanced by the availability of more
widely recognized methods and techniques as a result of current work in
this field. The comments noted that test methods that are presently
available and used for identifying botanicals are not officially
validated. If an officially validated method is not available for a
dietary ingredient, several comments suggested working towards AOAC
International validation and, in the interim, instituting peer review
of less formal test methods. Other comments noted that the dietary
supplement industry has begun an effort to develop validated test
methods for several botanical ingredients. One comment suggested that
it is important to develop methods that are subject to peer review and
to institute a certification program for testing facilities because the
analysis of natural products requires specialized training in natural
product chemistry. The comment did not indicate who (e.g., FDA or
another organization) should develop a certification program.
Some comments only addressed identity testing of unprocessed
botanicals. These comments said that for unprocessed botanicals in
whole or in part (e.g., flowers, roots, leaves, etc.), organoleptic
techniques are sufficient provided that accurate records are maintained
and that the manufacturing process provides a paper trail of positive
identification. One comment suggested that a ``voucher specimen'' (a
sample of the plant material) from the supplier along with a
certificate of botanical identity would be an adequate record. The
certificate of botanical identity would follow the material through the
manufacturing process, thus creating a paper trail. The voucher
specimen would be held for a specific period of time or, if necessary,
serve as a permanent record.
Dietary ingredient identification is an important part of CGMPs. We
agree with the comments that identity testing requirements are needed
but that no single approach or test method may be appropriate for every
dietary ingredient. For example, microscopic or organoleptic tests
might be appropriate for herbs or plant parts (because you can see,
taste, or smell them), but not appropriate for amino acids (which
cannot be identified by the naked eye or identified by using your
senses). A microscopic test might be appropriate for herbs that still
have their leaves or other distinguishing marks or characteristics, but
not for ground-up herbs. Thus, we agree with the comments stating that
the key principle in dietary ingredient identification testing is to
establish an appropriate procedure that will identify, with certainty,
the dietary ingredients used in making a dietary supplement. We agree
that a guidance document on ingredient identity testing may be useful,
and we will consider future development of ingredient identity testing
guidance documents.
Manufacturers should be responsible for identifying the ingredients
that they use in their products and, in addition, for verifying that
the dietary ingredients or dietary supplements they make contain the
identity, purity, quality, strength, and composition that the
manufacturer intends the product to have. As discussed previously in
this document, we have found serious adverse events to be related to
dietary ingredient misidentification. The manufacturer must conduct
identity tests to ensure that they used the correct ingredient to
prevent potential serious adverse events. We discuss identity testing
for dietary ingredients and dietary supplements later in this document.
We agree with the comments that certification of testing facilities
could be an important step in ensuring analytical quality. However,
certification of testing facilities is outside the scope of this rule.
Question 3. FDA requested comments on standards that should be met
in certifying that a dietary ingredient or dietary supplement is not
contaminated with filth; that it is free of harmful contaminants,
pesticide residues, or other impurities; that it is microbiologically
safe; and that it meets specified quality and identity standards.
The ANPRM noted that, under Sec. 110.80, a food manufacturer may
accept a supplier's certification that its products do not contain
microorganisms, filth, or other foreign material that would adulterate
the product instead of testing or evaluating the supplier's products
itself. As a result, we asked for comments on whether a certification
will provide assurance that dietary ingredients are not contaminated or
whether specific testing requirements are necessary.
Comments generally supported relying on a supplier's certification
that a dietary ingredient is what it purports to be and is not
contaminated. The comments stated that reliance on the supplier's
certification should be an alternative to testing raw materials to
detect microorganisms, filth, or foreign material so long as the
reliability of the supplier's certification is confirmed. Most comments
stated that manufacturers are responsible for determining, on a case-
by-case basis, whether a supplier's certification provides adequate
assurance that a dietary ingredient is what it purports to be and is
not adulterated. Some comments based their support for
[[Page 12170]]
relying on a supplier's certification on Sec. 110.80(a)(2) through
(a)(4); these provisions allow food manufacturers to rely on a
supplier's guarantee or certification that raw materials or other
ingredients do not contain levels of microorganisms or toxins that may
produce illness or are otherwise contaminated. The comments suggested
various means for determining the reliability of a supplier's
certification, including independent analysis, in-house testing, and
review of protocols.
Other comments stated that, because the CGMP regulations in part
110 permit reliance on a supplier's certification and because section
402(g)(2) of the act specifies that the CGMP regulations for dietary
supplements should be modeled after the CGMP regulations for food, a
supplier's certification for dietary supplements must be acceptable.
We have considered the comments on whether a supplier's
certification could provide adequate assurance that a dietary
ingredient is what it purports to be and is not adulterated. We
disagree that manufacturers may rely on such certifications to
determine that an ingredient is not contaminated, for example, with
filth or microorganisms. Using a supplier certification, guarantee, or
certification in lieu of performing testing on each shipment lot of
components, dietary ingredients, or dietary supplements is not
appropriate because a supplier's certification or guarantee would not
necessarily ensure that the identity, purity, quality, strength, or
composition of a component, dietary ingredient or dietary supplement is
met. We discuss testing requirements and why we believe that the use of
supplier's guarantee or certification is not sufficient in lieu of a
manufacturer's own testing in more detail later in this document.
Question 4. We asked for comments on whether a CGMP rule should
require manufacturers to establish procedures to document, on a
continuing or daily basis, that they followed preestablished procedures
for making dietary supplements.
The ANPRM noted that the food CGMP regulations under part 110 do
not require manufacturers to document that they are following
established procedures prescribed for manufacturing a food. However,
the ANPRM also noted that section 402(g) of the act does not preclude
us from adopting CGMP requirements for dietary ingredients and dietary
supplements that have no counterpart in part 110 if we have an
appropriate basis for doing so.
Most comments generally supported requiring manufacturers to
develop and follow written procedures and noted that the industry
outline in the ANPRM would require written procedures for many
processes and functions. Some comments noted that written procedures
and day-to-day records documenting that the procedures were followed
will ensure that products are safely and properly manufactured on a
day-to-day basis and that this can be confirmed by periodic independent
internal audits. One comment stated that the manufacturer should be
responsible for ensuring, through employee training, self-audit
programs, and batch records, that quality control and other procedures
prescribed for the manufacture of a dietary supplement are properly and
diligently executed. Other comments stated that it is good business
practice to ensure product quality through periodic review of records
and quality control audits and that failure to establish procedures
will result in product recalls, potential injury, and litigation for
damages for defective goods.
Some comments objected to any requirement for written procedures or
documentation that the procedures were followed. The comments stated
that section 402(g)(2) of the act states that dietary supplement CGMPs
must be modeled after the food CGMP regulations and the food CGMP
regulations do not require written procedures or documentation that
procedures were followed.
We agree with those comments that support the development and use
of written procedures by manufacturers and are considering whether we
should require written procedures in a final rule. We are proposing
requirements for documenting certain operations and processes while not
requiring written procedures to remove underlying costs for
establishing and updating such written procedures while preserving the
records necessary to permit trace back. When manufacturers develop and
follow written procedures such procedures help to ensure that
manufacturers produce a consistent dietary ingredient or dietary
supplement that is of a predictable quality and that is not
adulterated. Following written procedures and documenting compliance
with those procedures will ensure regular performance of a firm's
established programs and procedures and will provide additional
assurance of effective communication of appropriate information from
the firm management to the line personnel. We invite comment on whether
written procedures should be required in a final rule, and whether
there are other procedures, that we should include in a final rule. We
discuss written procedures for various stages of manufacturing,
packaging, labeling, holding, and for handling consumer complaints
later in this document.
We disagree, however, that records are not necessary to show that
certain operations and processes are being performed. Records document
that quality control operations and processes such as calibrating
instruments and controls; manufacturing a dietary ingredient or dietary
supplement batch; and handling consumer complaints were performed. We
further discuss the basis for the proposed recordkeeping requirement
for certain operations and processes later in this document. We believe
that section 402(g) of the act allows us to require written procedures
and documentation that the procedures were followed. As explained
previously, such records may be necessary for ensuring that dietary
ingredients and dietary supplements are manufactured, packaged, and
held consistent with these regulations. Moreover, we believe that the
fact that the food CGMPs in part 110 do not have recordkeeping
requirements does not preclude us from proposing recordkeeping
requirements in this proposed rule, although we seek further comment on
the issue.
Question 5. We invited comment on whether dietary supplement CGMP
regulations should require that firms have competent medical
authorities evaluate reports of injuries or illnesses and to determine
if followup action is necessary to protect the public health.
The ANPRM explained that many dietary supplements contain
pharmacologically active substances, which distinguish dietary
supplements from many foods, and some dietary supplements may contain
potential allergens. Because the characteristics may result in adverse
events in certain consumers, we asked whether we should consider
requiring firms to take certain actions with respect to reviewing AERs.
We also sought comments on whether a CGMP rule should require firms to
establish procedures for determining whether a reported injury
constitutes a serious problem, and what actions are to be taken when
serious problems are identified.
Comments generally opposed requiring manufacturers to establish a
procedure for evaluation and followup of reports of illness and
injuries. Comments also opposed requiring that a competent medical
authority evaluate all reports of illness or injuries to determine if
followup action is necessary to protect the public health. Some
comments, opposing requiring written procedures and evaluation,
[[Page 12171]]
suggested alternatives to requirements, such as using the Centers for
Disease Control and Prevention, poison control centers, FDA's MedWatch
program, and consumer complaint files to monitor and record injuries
and illnesses attributed to marketed products.
In contrast, several comments supported a requirement for written
procedures or medical evaluation of serious adverse events. Some
comments stated that an evaluation procedure is necessary and that
manufacturers are and should be responsible for establishing procedures
to respond appropriately to reports of serious illness and injury that
may have resulted from using a dietary supplement. Other comments
stated that medical evaluations are not necessary because manufacturers
should be using appropriate internal quality control procedures within
their quality control units or elsewhere to identify the cause of
adverse events and respond appropriately.
We agree with those comments stating that manufacturers are and
should be responsible for evaluating consumer complaints. Manufacturers
have an obligation to ensure that the dietary supplements that they put
on the market are not adulterated or misbranded. Consumer complaints
about a dietary supplement might indicate a CGMP-related problem
associated with a dietary supplement. For example, a consumer complaint
might identify a previously unknown manufacturing deviation that caused
a batch of dietary supplements to be adulterated. Thus, a procedure for
reviewing and investigating consumer complaints is recommended. Records
of consumer complaints related to CGMPs, and the review and
investigation of such records, are necessary and we discuss such a
record requirement later in this document. In that discussion, we
address what we mean by a consumer complaint and we address the
comments on the type of evaluation that would be necessary for consumer
complaints and whether the comments' suggested alternatives to written
procedures and medical evaluations are sufficient to identify potential
concerns.
Some comments objected to written procedures and medical evaluation
arguing that such requirements go beyond the CGMP regulations for food
and, therefore, would be contrary to section 402(g)(2) of the act.
Other comments claimed that written procedures would present
unwarranted potential criminal liability, that there are many
unsubstantiated injuries and illness inherent in the food industry, and
that dietary supplement safety problems are rare. These comments also
stated that a costly and burdensome safety surveillance system is not
warranted for these products, that the term ``serious adverse event''
is ambiguous, and that most manufacturers lack trained medical
personnel to serve this function.
Because we have found dietary supplement problems that could have
been prevented by CGMPs and that resulted in product recalls, we find
that manufacturers must be able to identify these types of problems
with their products. It is a manufacturer's responsibility to do so. We
disagree with those comments stating that we do not have legal
authority to require a manufacturer to evaluate consumer complaints as
we propose to define that term in this proposed rule.
We also disagree that written procedures would present unwarranted
potential criminal liability. Persons subject to regulation under the
act and its implementing regulations may face civil or criminal action
if they fail to comply with the act or our regulations (see, e.g.,
sections 301, 302, and 303 (21 U.S.C. 331, 332, and 333) of the act).
The fact that such an outcome is possible under the statutory scheme
does not mean that a provision that would require written procedures
and evaluation of consumer complaints is ``unwarranted.'' If we were to
accept such a claim, then we would find it difficult to issue any
regulation to implement the act, and that result would conflict with
our obligation to protect the public health. Therefore, we reject the
comments' argument regarding potential criminal liability and its
effect on rulemaking.
We also disagree with the claim that there is no basis for
requiring an evaluation of adverse events because there are many
unsubstantiated reports of injuries or illness and because dietary
supplement safety problems are rare. In the past, voluntary reports of
injury or illness have identified adulterated dietary supplements.
Consumer complaint reports associated with the use of marketed dietary
supplements, such as D. lanata contaminated plantain, identified the
need for further investigation and led to recalls or warnings to
protect the public health (Ref. 6). Evaluation of consumer complaint
reports can reveal patterns of adverse events that assist us and
manufacturers in identifying the need for further investigation to
determine what public health actions are needed.
For example, assume that, after you investigate an AER, you find
that the product contained an ingredient that should not have been used
and that the ingredient caused the adverse event. The fact that the
wrong ingredient appeared in your product would indicate that some type
of problem occurred in your manufacturing process of that product. Once
you identify the ingredient as the cause of the problem, you would be
able to take steps to remove any such product from the market and
prevent the problem from recurring, helping to ensure product quality
and purity, and restore consumer confidence that your products contain
the correct ingredients. In short, investigations of consumer
complaints benefit both manufacturers and consumers and these benefits
will exist regardless of whether there are many or few injuries or
illnesses believed to be associated with your product.
Question 6. We invited comment on whether a CGMP regulation for
dietary supplements should require manufacturers to establish
procedures to identify, evaluate, and respond to potential safety
concerns with dietary ingredients. We asked whether such an evaluation
is necessary, and, if so, what elements need to be included in such an
evaluation and their relative importance (e.g., the presence and
potency of pharmacologically active substances, the presence of
different microorganisms, the presence of different contaminants and
impurities). We also asked whether we should require that these
evaluations be documented in a firm's records, and, if so, what type of
records would be adequate to document that such an evaluation had
occurred.
In general, the comments opposed requiring manufacturers to
establish procedures to identify, evaluate, and respond to potential
safety concerns with dietary ingredients. Most comments claimed that
such procedures are unnecessary because dietary ingredients have a
history of safe use in food and that DSHEA is based on this history of
prior use in food. Other comments argued that, because DSHEA is based
on a history of prior use of existing dietary supplements and
established a notification procedure for new dietary ingredients, a
requirement concerning potential safety concerns for dietary
ingredients would be beyond the scope of this rulemaking.
Several comments noted that for those dietary ingredients that do
not have a history of safe use in food and are considered ``new dietary
ingredients,'' as defined in section 413(c) of the act, DSHEA
established procedures for evaluating safety concerns. Section
413(a)(2) of the act requires a manufacturer to submit a ``new dietary
ingredient'' notification to FDA 75 days
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before introducing or delivering a dietary supplement containing a new
dietary ingredient into interstate commerce. The notification must
provide the basis upon which the petitioner has concluded that the
dietary supplement containing the new dietary ingredient is reasonably
expected to be safe. Therefore, the comments argued that procedures to
identify, evaluate, and respond to potential safety concerns are not
necessary in a CGMP rule.
Other comments stated that FDA should not require procedures to
identify, evaluate, and consider potential safety concerns with dietary
ingredients because manufacturers already have an essential and
critical responsibility to substantiate the safety of the dietary
ingredients they use in manufacturing a product. The comments suggested
that FDA does not need to require written procedures because
manufacturers must consult the generally known and generally available
scientific literature to determine that a dietary ingredient is safe.
Some comments suggested that, instead of FDA requiring safety
evaluations, a third-party could evaluate safety concerns. Several
comments suggested that manufacturers who use dietary ingredients that
have little history of use in food in the United States should retain
documentation concerning the dietary ingredient's safety. One comment
suggested that we issue a guidance document to identify the types of
acceptable ``history of use'' standards for dietary ingredients having
little history of use in food in the United States and to describe the
documentation that would be needed regarding a dietary ingredient's
safety.
Although the comments focused on the safety of using particular
dietary ingredients, the safety concerns described in question 6
actually consist of two concepts: (1) Is the product formulated using
safe dietary ingredients; and (2) is the product manufactured,
packaged, and held in a manner that would not adulterate or misbrand
the product? The proposed rule focuses on safety concerns related to
the latter concept. Specifically, the proposed rule focuses on the
steps and processes used in the manufacturing, packaging, and holding
of the product to ensure, for example, that the product has the
identity, purity, quality, strength, and composition claimed and does
not become adulterated or misbranded. The agency notes that no comments
appeared to argue that safety issues relating to potential
contamination or adulteration related to manufacturing processes are
outside CGMPs. As the comments recognize, manufacturers have an
essential and critical responsibility to substantiate the safety of the
dietary ingredients they use in manufacturing a product.
Section 402(g) of the act is not the only provision relevant to
whether a dietary ingredient or dietary supplement may be deemed to be
adulterated. Section 402(f)(1) of the act, in part, declares a dietary
supplement to be adulterated if it:
[sbull] Presents a significant or unreasonable risk of illness or
injury under conditions of use described in the labeling or, if no
conditions of use are suggested or recommended in the labeling, under
ordinary conditions of use;
[sbull] Is a new dietary ingredient for which there is inadequate
information to provide reasonable assurance that the dietary ingredient
does not present a significant or unreasonable risk of illness or
injury; or
[sbull] Is or contains a dietary ingredient that renders it
adulterated under section 402(a)(1) of the act under the conditions of
use recommended or suggested in the labeling. (Section 402(a)(1) of the
act declares a food to be adulterated if it contains substances that
are poisonous or deleterious substance that may render it injurious to
health.)
Additionally, section 301(a) of the act prohibits the introduction
of adulterated food into interstate commerce.
So, for a dietary ingredient or dietary supplement manufacturer to
comply with sections 301(a) and 402(f)(1) of the act, it must take
steps regarding potential safety concerns before it markets the
product. Otherwise, if the manufacturer had no obligation to evaluate
possible safety concerns before marketing a product, sections 301(a)
and 402(f)(1) of the act would not make sense and the manufacturer
would be acting contrary to the basic congressional intent behind
DSHEA, which was to ensure that safe dietary supplements are available
to consumers. For example, assume that a manufacturer wanted to market
a new dietary ingredient but lacked evidence to show that it is safe.
Under section 402(f)(1)(B) of the act, the manufacturer must have
adequate information to provide reasonable assurance of the dietary
ingredient's safety before it markets the dietary ingredient;
otherwise, the dietary ingredient is adulterated under section
402(f)(1)(B) of the act, and section 301(a) of the act would prohibit
its sale in interstate commerce. Thus, the manufacturer has a statutory
obligation to examine safety concerns relating to the dietary
ingredients it uses before it markets the product.
The proposed CGMP rule focuses on ensuring that the manufacturer
knows what it is putting in its product and is manufacturing,
packaging, and holding the product in a manner that will not adulterate
or misbrand the product. For example, assume that you use a particular
herb as your dietary ingredient. However, there are different species
of that herb. Some species are poisonous; others are not. Additionally,
there are variations within the same species of herb depending on where
the herbs were grown. Some variants may contain higher levels of a
particular dietary ingredient or marker compound than other variants.
So, how do you know whether you have the right herb (nonpoisonous
species of herb intended for use) and whether it meets your
specifications? CGMPs would require that you check the identity of the
herbs you receive; by doing so, you would be able to tell whether you
have the correct herbs, whether your herbs are poisonous, or whether
they meet your specifications. In this example, the potential safety
concerns involve the dietary ingredient itself rather than any issue
concerning contamination which would adulterate or may lead to
adulteration of the dietary ingredient, and thus, the dietary
supplement which contains the dietary ingredient.
As for the comments' arguments concerning a dietary ingredient's
history of use, we do not need to address history of use as part of
this CGMP proposal. CGMPs focus on how a product is made under current
manufacturing processes. A dietary ingredient's history of use does not
provide any assurance that a particular product has the identity,
purity, quality, strength, and composition that it purports to have.
Further, history of use does not necessarily provide any assurance that
a particular product would not pose a significant or unreasonable risk
of illness or injury under conditions of use recommended or suggested
in the labeling or under ordinary conditions of use.
As for those comments discussing whether manufacturers or other
parties should evaluate potential safety concerns, the proposed rule
would require a manufacturer to evaluate a consumer complaint to
determine whether the complaint relates to good manufacturing
practices. Such an evaluation would include possible hazards to health
resulting from the manufacturing, packaging, or holding of a product.
Nevertheless, you should note that, insofar as compliance with the act
and any CGMP regulations are
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concerned, persons who market dietary ingredients and dietary
supplements always remain responsible for their products. If the
manufacturer markets the product, it would have to meet all proposed
CGMP requirements, if the agency finalizes the rule as proposed. If
another person buys a product (such as bulk dietary ingredients) from a
manufacturer and distributes the product under its own name, that
person must meet all applicable CGMP requirements.
Question 7. We invited comment on whether specific controls are
necessary for computer-controlled or assisted operations and how best
to ensure that the software programs and equipment used to direct and
monitor the manufacturing process are properly designed, tested,
validated, and monitored.
Comments generally supported specific controls for computer-
controlled or computer-assisted operations. One comment suggested
requiring manufacturers to confirm, by adequate and documented testing,
that their computer software programs perform their intended functions
when computers are used as part of an automated production system
having a significant and direct impact on product safety. Another
comment suggested requiring that software programs and equipment used
to direct and monitor manufacturing processes are properly designed,
tested, evaluated, and monitored. The comment added that, if we
consider imposing specific requirements on how firms document the
adequacy of their computer-controlled or assisted operations, we should
address those recommendations through a guidance document instead of
issuing regulations.
We agree that computer-controlled or computer-assisted operations
need to be properly designed, tested, evaluated, and monitored to
ensure that the computers do what they are supposed to do.
Manufacturers should confirm, by adequate and documented testing, that
their computer software programs perform their intended functions
because computer use as part of an automated production system has a
significant and direct impact on product safety. Computers are an
important controlling piece of equipment in the manufacture of dietary
supplements because they often direct and control key steps or
processes in the manufacture of dietary supplements. If computers do
not operate correctly, the dietary supplements manufactured using those
computers may be adulterated.
Several comments supported requirements for specific controls, but
opposed using validation-of-operation mandates like those in the CGMP
regulations for drugs. One comment suggested that we regulate computer-
controlled and computer-assisted operations for dietary supplements in
the same way that we regulate such operations in the pharmaceutical
industry, but only where an operation is directly related to the
product's concentration or purity. One comment suggested that we
consider adopting the computer-controlled and computer-assisted
procedures specified in the proposed infant formula CGMP.
We propose general requirements to ensure that equipment is
suitable for its intended use. However, we seek comment, in the
proposed rule, about whether we should include requirements, written
procedures, and records for equipment verification and re-verification.
We request comment on what verification manufacturers should be using
in their computer-controlled or computer-assisted operations to ensure
that a dietary ingredient or a dietary supplement that is produced is
not adulterated during manufacturing. In addition, we request comment
on whether we should issue guidance documents on verification
procedures for use with computer-controlled or computer-assisted
operations. Guidance documents generally represent FDA's advice or
current thinking on a particular matter and are not binding on any
person. In contrast, regulations create enforceable requirements that
apply to all persons engaged in the same action or who make the same
product.
As discussed in greater detail later in this document, certain
processes are necessary to ensure that computer-controlled or computer-
assisted equipment functions properly. This is because of the important
role of such equipment in manufacturing. For example, if computer-
controlled or computer-assisted equipment is used to control
components, inprocess materials, and rejected materials unsuitable for
use, the operation must function as expected to ensure that components
suitable for use in manufacturing dietary ingredients and dietary
supplements are not mixed up with components held under quarantine such
as those components that have been rejected as unsuitable for use. If
computer-controlled or computer-assisted operations are used for the
addition and mixing of components, they must function properly to
ensure that the correct components are added and appropriately mixed to
avoid producing a dietary ingredient or dietary supplement that is
adulterated. Computer-controlled or computer-assisted operations are
not perfect; computers are subject to malfunctions and ``bugs''
(errors) in the software they use. Problems with data entered into the
computer may produce unreliable results. For these reasons, specific
controls for computer-controlled or computer-assisted operations are
necessary to prevent the manufacture of an adulterated dietary
ingredient or dietary supplement.
A few comments stated that no specific requirements for computer-
controlled or computer-assisted operations are needed because computer
hardware and software are simply specialized plant equipment so that no
special regulations are needed.
We agree that computers are specialized pieces of plant equipment
and, therefore, should be subject to additional requirements beyond
those which would apply to plant equipment. Computers are specialized
pieces of equipment because they are subject to malfunctions and
``bugs'' (errors) in the software, they are reliant upon data entered
into a computer, and they may be used to perform important roles such
as component or dietary ingredient identification, measuring components
and dietary ingredients, and quarantining materials. Consequently,
proposed Sec. 111.30 would establish requirements for automatic,
mechanical, or electronic equipment. The proposed requirements would
cover, among other things, automatic equipment design, and routine
calibration, inspection, and checks to ensure proper performance. As
stated previously, we are seeking comment on whether we should include
requirements for verification and re-verification of automatic,
mechanical, or electronic equipment and processes and whether we should
include requirements for computerized systems that are separate from
requirements for other mechanical or automatic equipment. We discuss
proposed Sec. 111.30 in greater detail later in this document.
Question 8. We asked for comments on whether certain, or all, of
the requirements for manufacturing and handling dietary ingredients and
dietary supplements may be more effectively addressed by a regulation
based on the principles of Hazard Analysis and Critical Control Point
(HACCP), rather than the system outlined in the industry submission.
In the ANPRM, we noted that, because of the wide variety of dietary
ingredients and dietary supplements and because of the heterogenous
composition of the dietary supplement
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industry, CGMPs based on HACCP principles may provide a more flexible
and less burdensome regulatory framework for manufacturers and
distributors than the approach set out in the industry submission.
Most comments opposed basing a CGMP regulation for dietary
ingredients and dietary supplements on HACCP principles. Most comments
supported applying traditional CGMP requirements on manufacturing,
packaging, and holding to dietary ingredients and dietary supplements.
In general, the comments that opposed requiring HACCP for dietary
ingredients and dietary supplements asserted that: (1) A HACCP program
would not be appropriate because HACCP focuses on microbial
contamination of products that provide a favorable environment for
growth of microbes that may be present, and these hazards are not a
major concern for dietary supplements; (2) CGMPs are the best means of
assuring the safety, quality, and composition of dietary ingredients
and dietary supplements; (3) HACCP is not required for the food
industry as a whole; and (4) HACCP would provide minimal incremental
value at significant additional costs.
Other comments opposed mandatory HACCP regulations for dietary
ingredients and dietary supplements, but said manufacturers could
implement voluntarily HACCP instead. One comment, which supported
voluntary implementation of HACCP, wanted manufacturers to be exempt
from having to disclose HACCP records to any Federal agency.
HACCP principles can be applied to a broad range of manufacturing
practices and HACCP principles are not solely focused on microbial
contamination, but instead, are intended to identify and appropriately
control steps in manufacturing where any type of adulteration can
occur. Nevertheless, after considering the comments, we have decided to
propose a CGMP approach for dietary ingredients and dietary
supplements. We believe that CGMPs would establish a system of controls
that, given the variations in size, technological sophistication, and
regulatory experience among dietary ingredient and dietary supplement
firms, would create a strong regulatory foundation throughout the
industry.
You may voluntarily choose to implement a HACCP plan that meets the
requirements of the National Advisory Committee on Microbiological
Criteria for Foods, however, proposed part 111 would still apply to you
(Ref. 42). Any HACCP plans that also are intended to meet the records
requirements under proposed part 111 would be treated as records under
this proposal.
Question 9. We invited comment on whether broad CGMP regulations
will be adequate, or whether it will be necessary to address the
operations of particular segments of the dietary supplement industry.
Most comments supported broad CGMP regulations covering all
segments of the dietary supplement industry instead of specific
regulations tailored to distinct segments of the industry. One comment
stated that the differences between distinct segments of the dietary
supplement industry, such as manufacturers of raw materials or
distributors of finished products, are no more pronounced than similar
segments in the food industry. Another comment stated that having
numerous CGMPs could subject raw materials and dietary ingredients to
multiple CGMPs, thus making manufacturing operations more complex. This
comment also questioned whether issuing multiple regulations is
necessary or economically justified in an era of limited corporate and
government regulatory resources. Other comments emphasized the
importance of ensuring that all dietary supplement manufacturers (i.e.,
both small and large manufacturers, and foreign manufacturers planning
to import dietary supplements into the United States) follow the same
CGMP requirements.
In contrast, some comments supported drafting regulations for
particular segments of the dietary supplement industry. One comment
stated that certain stages of the manufacturing process, such as the
distribution of raw dietary ingredients, should be more strictly and
comprehensively regulated than other stages because potential hazards
are more prevalent during these manufacturing stages. The comment
stated that conversely, the holding, distribution, and sale of a
finished dietary supplement may require less comprehensive regulations
because they are subject to fewer potential hazards. Other comments
supported different levels of safety testing for different types of
dietary supplement products. For example, some comments said that
products such as melatonin and dehydroepiandrosterone resemble drugs,
so we should require safety testing in animals and humans and impose
druglike CGMP requirements for manufacturing. Another comment stated
that less stringent CGMPs would be appropriate for herbal dietary
supplements because they have long histories of food use and safety.
We agree that some manufacturing operations are subject to greater
hazards than others, and have drafted the proposed rule accordingly.
For example, there are microbial hazards associated with raw
botanicals. To address these hazards, the proposal would require that
you perform tests on the botanicals. On the other hand, there are fewer
hazards associated with holding and distributing finished dietary
supplements, so the proposal would impose less comprehensive
requirements for holding and distributing operations.
We are persuaded by the comments that support a broad CGMP
regulation as preferable to multiple regulations focused on particular
segments of the industry. We agree with the comments that multiple
regulations might be confusing and burdensome, especially to firms that
manufacture products that fall into multiple categories. For instance,
it would be easier for regulated firms and for us if firms were
required to adhere to one set of CGMP requirements rather than follow,
for example, one set of CGMP requirements for vitamins and a different
set of CGMP requirements for minerals.
We also recognize, though, that there may be some reasons to treat
different types of dietary ingredients or dietary supplements
differently in specific instances. For example, it may be appropriate
to require one type of test for confirming the identity of amino acids
and another type of test for confirming the identity of herbals.
However, for the reasons discussed previously, we are proposing to
establish one set of broad CGMP regulations for all types of products.
Because we recognize that one set of specific requirements may not be
appropriate for all types of dietary ingredients and dietary
supplements, we have proposed regulations that allow manufacturers to
develop practices to meet CGMP requirements. Depending on our
experience with this proposed rule, we will consider whether we need to
reevaluate our decision to establish one set of requirements for all
dietary ingredients and dietary supplements.
We agree with the comments that the proposed rule should not make
any distinction between dietary ingredients or dietary supplements made
in the United States and those made in a foreign country. The proposed
rule would require that foreign firms that want to export dietary
ingredients and dietary supplements to the United States manufacture,
package, and hold dietary ingredients and dietary supplements
consistent with proposed part 111. Moreover, under this proposed rule,
if a U.S. firm contracts with a
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foreign firm to