![](media/image1.png){width="4.883333333333334in"
height="0.8819444444444444in"}

August 11, 2003

Dockets Management Branch (HFA 305)

Food and Drug Administration

5630 Fishers Lane, Room 1061

Rockville, MD 20852

**RE: DOCKET NO. 96N-0417, GOOD MANUFACTURING PRACTICES**

**FOR DIETARY SUPPLEMENTS**

**TOPIC: PROCESS CONTROL**

This is the [third]{.underline} in a series of comments submitted by the
Council for Responsible Nutrition regarding the above-mentioned proposed
rule.

**This comment will address what we believe to be the critical core
issue in considering the framework of Good Manufacturing Practices** \--
the essentiality of establishing a quality assurance system of process
controls that serve the purpose of preventing errors throughout the
processing system, from the selection of ingredient suppliers and the
receipt of bulk materials through the entire processing operation. It is
axiomatic in the quality assurance literature that quality cannot be
"tested into" a product but must be "built into" the product from
beginning to end. We believe the proposed rule is overly focused on
end-product testing and fails to fully incorporate the elements of a
well-controlled system. Such a system, once established, is a more
reliable guarantee of quality than exhaustive finished-product testing.

This comment also includes a statement of concerns about the proposed
rule from Carl Reynolds, a GMP expert with 36 years of experience at
FDA. He is now a Senior Consultant to AAC Consulting Group, where he
conducts GMP training seminars, advises companies on GMP issues, and
performs audits of GMP procedures. CRN retained Mr. Reynolds to assist
our members in analyzing the proposed rule and to provide guidance to us
in preparing our response. We refer to his statement in the course of
this comment and include its full text in Attachment C.

This comment covers the following specific topics:

[Page Topic]{.underline}

2 Process control systems critical to quality assurance

5 Essentiality of written procedures

6 Elements of appropriate written procedures (SOPs)

8 Rigorous process control is effective in ensuring quality

and can justify a reduced testing burden

10 Need to define criteria for acceptability of vendor certificates

of analysis for ingredients

11 Applicability of the rule to foreign firms

12 Cost of FDA's proposed testing requirements

13 Test methods and the cost of method development

14 Expiration dating

16 Employee qualifications, education and/or training

16 Water quality

17 Physical plant

17 Animal-derived ingredients

18 Ingredients other than "dietary ingredients"

19 Compliance period

19 Conclusion and recommendations

**Attachment A**: List of CRN members and their products

**Attachment B**: Qualifying the production process control system

**Attachment C**: Statement of GMP expert Carl Reynolds, Senior
Consultant,

AAC Consulting Group

On this same date, CRN is submitting separate comments on the purpose
and scope of the rule and on legal aspects of the proposal. In addition,
we will submit a separate comment summarizing our section-by-section
recommendations. At a later date, but before September 9, we will submit
comments on the economic impact of the proposed rule. CRN has requested
and been granted this additional time for submission of economic data
based on new information we have just obtained pursuant to a FOIA
request for underlying data not previously included in the
administrative record, relating to FDA's assumptions and calculations on
the estimated economic impact of the rule. The first comment in this
series (July 8, 2003) provided a four-way comparison of the proposed GMP
with current food GMPs, the industry draft published as the ANPR in
1997, and current drug GMPs.

**PROCESS CONTROL SYSTEMS CRITICAL TO QUALITY ASSURANCE**

CRN member companies currently include 35 manufacturers of finished
dietary supplement products and 31 manufacturers and suppliers of bulk
dietary ingredients or other components of dietary supplements, as well
as a number of associate members that provide services to the industry.
**Attachment A is a list of our manufacturer and supplier members,
together with examples of the types and brands of products they
market.** The list is designed in such a way that readers of the
electronic version can click on a company name and access its website.
CRN's membership includes some very large companies that manufacture the
leading U.S. brands of dietary supplement products, that manufacture the
store brands marketed by large food and drug chains, and that
manufacture and supply key ingredients used both in conventional foods
and in dietary supplements. Our membership also includes a number of
companies that are "small businesses" as defined by the Small Business
Administration but that also have reputations as leading quality
manufacturers of numerous products or ingredients.

CRN member companies account for a substantial fraction of the dietary
supplement market in the U.S. in terms of sales volume. Using sales data
from *Nutrition Business Journal*, we calculate that nine of the top
fifteen manufacturers and marketers of dietary supplements in the U.S.
are CRN members. These companies, plus a number of smaller CRN member
manufacturers, account for about 40% of the wholesale sales volume of
dietary supplements marketed through supermarkets, natural food stores,
drug stores, and discount department stores. Six of the top twenty
companies in direct sales (called multilevel marketing by *NBJ*) are CRN
member companies, accounting for 26% of the sales volume marketed
through that channel. Eight of the top ten vitamin ingredient suppliers
are CRN member companies, providing 71% of the sales volume for
commercial vitamins used in dietary supplements annually. Another 23
supplier members of CRN provide the industry with other key dietary
ingredients including calcium and other minerals, lutein and other
carotenoids, botanicals, omega-3 fatty acids, and specialty ingredients
such as glucosamine and chondroitin sulfate.

The draft GMPs submitted to FDA by CRN and other associations in 1995
and published in the ANPR in 1997 were modeled after food GMPs and
current "best practices" observed by leading large and small companies
in the industry. Some of these "best practices" incorporated some
elements of current drug GMP regulations. The industry draft GMPs were
based on modern concepts of quality assurance and were heavily
process-oriented, requiring extensive written procedures for key
processing operations in order to ensure uniform practices and to
provide a strong basis for employee training and supervision. CRN and
its members are fully supportive of the need for the application of an
appropriate process control system for the manufacturing of dietary
supplements.

The Dietary Supplement Health and Education Act (DSHEA) authorized FDA
to establish dietary supplement GMPs "modeled after food GMP
regulations." **CRN and its members do not believe the current proposal
is sufficiently modeled after food GMPs, and in addition we are
concerned that it is not sufficiently based on sound quality assurance
theory and practice.**

CRN believes that FDA's proposed exhaustive finished-product testing
provisions are not appropriate, are duplicative and unnecessary in the
context of a rigorous process control system, and would be excessively
costly to manufacturers. This is the single greatest point of
discrepancy between the industry draft GMPs and the agency's proposed
GMPs. The industry draft is heavily focused on defining and regulating
the whole production process, while the agency's proposal covers some
aspects of the process but is more heavily focused on finished-product
testing. One CRN member representative who is a recognized expert in
dietary supplement manufacturing and quality assurance commented that
FDA's proposal would "set us back 20 years" by requiring resources to be
diverted to excessive testing at the endstage of production rather than
being appropriately utilized to enhance overall process control based on
modern approaches to quality assurance.

An appropriate and rigorous process control system would provide the
following benefits:

1.  Assure the identity, purity, quality, strength and composition of
    the dietary supplement.

2.  Provide consistency in training, education and supervision of
    employees.

3.  Provide consistency from batch to batch.

4.  Define control points requiring monitoring.

5.  Incorporate written standards and specifications for all parts of
    the process.

6.  Allow tracing of deviations and facilitate corrective actions.

7.  Permit verification of reliability of processes and systems.

8.  Justify reliance on sampling and testing of indicator nutrients to
    verify output.

FDA recognizes the importance of process control, but does not make
process control the focus of the proposed rule. At 68 FR 12194-5, the
agency states that "using a production and inprocess control system
covering all aspects of processing is necessary to insure that the
dietary ingredient or dietary supplement is manufactured in an manner
that will prevent adulteration." Also, FDA recognizes that "a production
and inprocess control system is necessary to provide consistency in
producing different batches of dietary ingredients and dietary
supplements and to facilitate preparing each batch." However, FDA does
not recognize that the existence of an appropriate process control
system justifies reliance on sampling the finished product as a test of
the system, but rather proposes also to require exhaustive finished
product testing.

CRN urges FDA to recognize that a rigorous system of process controls
can and should reduce the need for exhaustive testing of the finished
product. The elements of a rigorous process control system are outlined
in **Attachment B**. Such a system would include a strong supplier
qualification program, including verification of the supplier's
reliability and test results, supported by **identity testing of every
incoming ingredient** by the finished product manufacturer. In addition,
the system would require extensive in-process controls including master
and batch records, written specifications, verification of ingredient
additions, calculated yield, and data demonstrating that the process
consistently delivers expected results. Criteria relevant to the
finished product would include written specifications and representative
testing of chemical, physical, and microbiological parameters.

CRN urges that the proposed rule be modified to recognize that an
effective system of process controls (as exemplified by the outline in
**Attachment B**) is required and that such a systematic approach to
process control justifies a parametric approach to finished-product
testing, in place of the exhaustive testing scheme proposed by the
agency.

**ESSENTIALITY OF WRITTEN PROCEDURES**

FDA's proposal does not include any requirements for written procedures
for key elements of the processing system, except in the sole area of
calibration. The stated reason for the agency's failure to require
written procedures in the proposed rule is to contain costs. However,
CRN and its member companies do not believe written procedures can be
viewed merely as a cost and a recordkeeping burden. Rather, written
procedures are essential to the development and maintenance of a
well-controlled production process. Written procedures are necessary for
the definition, operation and documentation of a process control system,
without which uniformity of operations cannot be assured and adequate
training and supervision cannot be undertaken. GMP expert Carl Reynolds,
whose separate statement is included with these comments in **Attachment
C**, shares this view and refers to written procedures or SOPs as "one
of the hallmarks or cornerstones of good manufacturing practices."

In the preamble to the proposed rule at 68 FR 12170, FDA says: "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
program and procedures and will provide additional assurance of
effective communication from the firm's management to the line
personnel."

A requirement for written procedures was a key element of the industry
draft published in the ANPR, and is also prominent in drug GMPs and in
the proposed infant formula GMPs. Written procedures are important in
the control of dietary supplement production processes for the same
reasons they are critical to the control of procedures used in
manufacturing formulated nutritional products such as infant formula.
CRN members have identified the following areas as ones in which written
procedures should be required:

-   Cleaning and maintaining equipment and utensils used in the
    manufacture of dietary products.

-   The receipt, identification, examination, handling, sampling,
    testing and approval or rejection of raw materials.

-   Appropriate tests and/or examinations to be conducted that may be
    necessary to assure the purity, composition and quality of the
    finished product, and to establish release specifications.

-   The method for reprocessing batches or operational start-up
    materials that do not conform to finished goods standards or
    specifications.

-   Control procedures employed for the receipt, storage, handling,
    sampling, examination, and/or testing that may be necessary to
    assure the identity of labeling and the appropriate identity,
    cleanliness and quality characteristics of packaging materials for
    dietary products.

-   Procedures to assure that correct labels, labeling, and packaging
    materials are issued and used.

-   Handling of all written and oral complaints.

As to the issue of the costs involved in preparing and following written
procedures, CRN and its member companies believe that requiring written
procedures would be more effective and less costly for achieving the
goals of the regulation than the exhaustive testing program proposed by
FDA. Also, FDA's Survey of Manufacturing Practices in the Dietary
Supplement Industry indicates that a very high proportion of
manufacturers are already utilizing Standard Operating Procedures
(written procedures). Overall, 65% of all respondents indicated they
were currently following a published GMP model, but 80% reported that
they were using Standard Operating Procedures for key procedures. Some
specific responses by size of company are shown in **Table A**, below:

**Table A: Percent of Companies that Use Written Procedures (SOPs),**

**As Reported in FDA's Survey of Manufacturing Practices**

+-----------------------------------+----------+----------+----------+
|                                   | **Very   | *        | *        |
|                                   | Small**  | *Small** | *Large** |
+-----------------------------------+----------+----------+----------+
| Have written personnel procedures | 54-70%   | 71-84%   | 93-100%  |
|                                   |          |          |          |
| (4 procedures surveyed)           |          |          |          |
+-----------------------------------+----------+----------+----------+
| Have written equipment procedures | 61%      | 81%      | 100%     |
+-----------------------------------+----------+----------+----------+
| Have written QC/lab procedures    | 64-75%   | 81-86%   | 94-100%  |
|                                   |          |          |          |
| (2 procedures surveyed)           |          |          |          |
+-----------------------------------+----------+----------+----------+
| Have written production/process   | 71-88%   | 91-93%   | 94-95%   |
| control                           |          |          |          |
|                                   |          |          |          |
| (2 procedures surveyed)           |          |          |          |
+-----------------------------------+----------+----------+----------+
| Have written consumer complaint   | 55%      | 78%      | 95%      |
| procedure                         |          |          |          |
+-----------------------------------+----------+----------+----------+

Due to the relatively high current usage of written procedures, CRN does
not believe a requirement for written procedures would be a large
additional burden, even for small and very small manufacturers. As
written procedures tend to be fixed and less expensive to maintain than
to develop, they ultimately would be less of a burden than the proposed
exhaustive testing program, which is a continuing cost that does not
decline \-- but rather increases \-- with time and with volume of
production.

**ELEMENTS OF APPROPRIATE WRITTEN PROCEDURES (SOPs)**

Written procedures are also commonly referred to as Standard Operating
Procedures (SOPs). Written procedures or SOPs should be clear and
concise and define policies, procedures or instructions for operating
processes, practices and equipment.

SOPs should be written appropriately for the target audience and should
generally follow a standardized format. General information should
include:

-   Company identification

-   Title that reflects the activities to be performed

-   Identification or control number with a revision level code

-   Effective date

-   The number of pages in the procedure (e.g., 1 of 4, 2 of 4, etc.)

-   Approval date and signature(s)

Typically there is a final approval date and an effective date. The
effective date may be later in order to allow for training employees on
the new or revised procedures.

The ultimate goals of an SOP are to consistently achieve the desired
quality output and to reduce or eliminate variation in day to day
operations. To achieve this, SOPs should contain enough detail to allow
different personnel on different days to perform the necessary
operations consistently. The task description for each procedure should
cover appropriate details, unless these are covered in other referenced
documents such as master batch records, for example. The SOP should
cover the following topics, as appropriate:

-   Purpose and scope

-   References to linked or related procedures or forms

-   Definitions of technical terms and acronyms

-   List of equipment, materials, and supplies needed in performing the
    task

-   Who has the responsibility for performing each task

-   What activity or task is to be performed

-   When and where the task is to be performed

-   Concise step by step instructions for performing the task

-   The expected results from performing the task

-   What data to collect and how to analyze, file, and/or report the
    information

Background information will often help employees better understand their
assignment and remember how to perform it. It is especially important
for newer employees to understand the reason for the procedure and why
it must be performed in a certain, prescribed manner.

When a manufacturer makes permanent changes or modifications to
specifications, procedures or documentation, the changes should be
reviewed, justified, documented, approved and implemented in a defined
manner. Change control procedures define what is and what isn't covered
by the procedure and how proposed changes will be identified or
recommended, processed, reviewed and approved.

While the proposed rule assigns final approval responsibility to the
quality control unit, other specialty groups may also be assigned or
required to review and approve proposed changes or procedures. These may
include personnel with special expertise including engineers,
scientists, or computer experts, for example.

The quality control unit or function is also responsible for maintaining
the master copies of all current and approved SOPs, for distributing
copies of approved written procedures to relevant personnel, and for
collecting and destroying outdated SOPs (except designated historical
SOP files).

**RIGOROUS PROCESS CONTROL IS EFFECTIVE IN ENSURING QUALITY AND CAN
JUSTIFY A REDUCED TESTING BURDEN**

CRN fully agrees with FDA's assertion at 68 FR 12176 that the end result
of improved GMPs throughout the industry will be to "provide consumers
with greater confidence that dietary supplements contain the dietary
ingredients that they are supposed to contain and that these dietary
ingredients were evaluated for their identity, purity, quality,
strength, or composition."

However, CRN believes the agency's proposal for an extensive and
exhaustive level of testing of finished products would be much more
costly in terms of time and resources but would be less effective than
rigorous process control in fulfilling the goal of good manufacturing
practices. The maxim of quality assurance theory and practice is that
**"you can't test in quality."** Rather, quality must be built into the
product through a rigorous process control system. In an appropriate
process control system, testing is a means to monitor the functioning of
the control system, relying on process monitoring and parametric testing
as indicators of the adequacy of the system. Reliance on end-product
testing alone can identify failures of the product or the system, but
does not facilitate tracing the cause of the failure in order to
promptly correct any problem that may exist.

Comments prepared by GMP expert Carl Reynolds (**Attachment C**)
emphasize this same concern. He says, "One familiar with the concepts of
GMPs recognizes that end process controls are not adequate because they
cannot build quality into a product."

Of course, any rigorous process control system will include appropriate
testing of incoming materials for identity, control by monitoring or
testing of in-process materials and processes, and sampling of the final
product. Complete testing of every ingredient in every batch is not
necessary to maintain sufficient control over the process to accomplish
the goals of the program. The agency itself has stated at 68 FR 12172
that the focus of the rule is on "ensuring that the manufacturer knows
what it is putting in its products and is manufacturing, packaging and
holding the product in a manner that will not adulterate or misbrand the
product." This can be accomplished through careful attention to the
quality of bulk ingredients and thorough control over the process,
without testing every ingredient in every batch of finished product.

The proposed rule requires testing of all dietary ingredients and
relevant specifications in each batch of the finished product. The
testing must cover the "identity, purity, quality, strength and
composition" of the product. Other specifications are to be established
by the manufacturer, based on knowledge of the ingredient or product and
its potential contaminants. If testing of the finished product is not
possible because of methodology issues, then testing is required of the
bulk ingredients [and]{.underline} of in-process materials. The cost
estimates for the rule assume that only one or the other of these tests
are required \-- that is, testing at the end [or]{.underline} testing at
the beginning and the middle.

Some of FDA's assumptions in suggesting these alternative testing
schemes are faulty. For example, if a product cannot be tested at the
final product stage for technical reasons or due to "complex finished
product matrices that would make such testing impracticable," then it
also cannot be tested at the final blending stage in the process. The
composition and nature of the product at the final blending stage is
virtually the same as the nature of the product when it is finished,
except for compression into a tablet or encapsulation in a softgel or
hard capsule, and the methodological issues are the same at both points.

Testing at the end point or finished product stage is extremely costly
and wasteful if materials are out of specification, because the full
costs of materials, labor and overhead have already been applied to the
product at that stage. FDA recognizes this fact at 68 FR 12198: "If you
are able to perform testing on each finished batch of dietary
ingredients or dietary supplements to confirm that specifications are
met for the identity, purity, quality, strength and composition
intended, then we would recommend, but would not require, that you also
test materials received for these same specifications to ensure that
they are the right ingredients and so that you do not end up having to
destroy an entire batch of finished product after using an erroneous
ingredient that could have otherwise been identified earlier before
being added to a batch." CRN's members believe relying on finished
product testing as a key component of quality assurance is not
representative of good manufacturing practices.

The proposed rule indicates that testing is also required at key control
points in the process. At a minimum these control points must include
the receipt of bulk materials and a check on in-process quality. As FDA
states at 68 FR 12197, "Proposed 111.35(e) would require that you
establish a specification for any point, step, or stage in the
manufacturing process where control is necessary to prevent
adulteration...These specifications are regulatory specifications and
you would be required to perform testing or examination to confirm such
regulatory specifications are met.... In addition, proposed 111.35(e)
identifies certain points, steps, or stages where a regulatory
specification is required. Regulatory specifications are required for
materials that you receive, at the inprocess stage, and that you
manufacture, e.g. at the finished product stage. Specifically, we are
proposing to require that you establish specifications at these control
points for the identity, purity, quality, strength and composition of
the components (upon receipt only) and for dietary ingredients or
dietary supplements (at all of these control points)."

Given that an appropriate process control system will test all incoming
ingredients for identity; that economic necessity requires that testing
be in place to identify deviations as early in the process as possible;
and that the proposed regulations require testing (or other monitoring
if it can show the identity, purity, quality, strength and composition
of the material) at multiple specified points; then the proposed rule
*de facto* requires testing at all stages -- incoming, inprocess and
finished -- unless technically not feasible at the end stage. This level
of testing is unnecessary, duplicative, and prohibitively expensive.

**NEED TO DEFINE CRITERIA FOR ACCEPTABILITY OF VENDOR CERTIFICATES OF
ANALYSIS FOR INGREDIENTS**

In the preamble to the proposed GMPs for dietary supplements, FDA
indicates that manufacturers would not be allowed to accept an
ingredient or component supplier's Certificate of Analysis (C of A) as
evidence that the content of a shipment is in compliance with the
specifications and labeling of the material. **CRN and its members take
strong exception to this position, which is contrary to existing
provisions in specific food GMPs and even in drug GMP regulations.**

The general food GMPs in 21 CFR 110 specifically allow the use of
Certificates of Analysis to verify that ingredients meet requirements
for safety, for allowable microorganism content, and for
non-contamination with toxins, pests and extraneous materials. Part
110.35 specifies that the safety and adequacy of cleaning compounds "may
be verified by any effective means including purchase of these
substances under a supplier's guarantee or certification." Part 110.80
indicates that the microbiological quality of raw materials or
ingredients, as well as their compliance with tolerances for natural
toxins, extraneous material, or other contaminants, may be "verified by
any effective means including purchase of these substances under a
supplier's guarantee or certification."

GMPs for low-acid canned foods in 21 CFR 113.81 specifically allow the
use of Certificates of Analysis to certify that ingredients meet
requirements for allowable microorganism content.

Even the proposed Infant Formula GMPs, which apply to nutrient-critical
products for a vulnerable population, allow the use of supplier
Certificates of Analysis under appropriate conditions. 21 CFR 106.20
provides that, in general, "no analysis before use in manufacturing is
needed for ingredients that are generally stable in shipping and
storage, and that either are received under a supplier's guarantee or
certification that the mixture has been analyzed as to nutrient
composition or are labeled as having nutrient compositions complying
with specifications in the U.S. Pharmacopoeia, the National Formulary,
the Food Chemicals Codex, or other similar recognized standards."

Drug GMP regulations also permit reliance on certificates of analysis.
21 CFR Part 211.84 requires that each component of a drug product be
tested for conformity with specifications for purity, strength, and
quality, but provides that in lieu of testing by the manufacturer of the
finished product, "a report of analysis may be accepted from the
supplier of a component, provided that at least one specific identity
test is conducted on such component by the manufacturer and provided
that the manufacturer establishes the reliability of the supplier's
analyses through appropriate validation of the supplier's test results
at appropriate intervals."

As CRN has discussed above in other sections of these comments,
manufacturers of dietary supplements should have strict process control
systems in place, including rigorous provisions relating to the receipt
of all ingredients and components. Manufacturers should conduct an
identity test (using a scientifically valid method) on incoming
materials to verify that the material is correctly labeled. Information
regarding other specifications could reasonably be based on a
Certificate of Analysis from a qualified vendor, provided the
certificate is based on actual scientifically valid testing by the
vendor of the particular lot or batch of material in the shipment, which
should be identified with a lot or batch tracking number. An appropriate
test-based Certificate of Analysis needs to be distinguished from a more
general Certificate of Compliance or a Continuing Guarantee. These two
latter documents may not be based on actual testing of a specific
shipment of materials.

Responsible manufacturers of dietary supplements will rely on a
relatively extensive "vendor qualification program" for key material
vendors. Such programs are essential to permit the manufacturer to
assess the reliability of the vendor and accordingly determine the
amount of incoming material testing that may be required to provide the
necessary level of confidence that the material will meet
specifications.

Vendor qualification programs may include plant visits and inspections,
GMP audits or process reviews, verification of laboratory test results
against certificates of analysis, and 100% inspection and testing of
incoming materials for a specified period of time while reliability is
being assessed. By extending process control mechanisms back into the
supplier environment, the manufacturer can make appropriate use of the
expertise of the vendor and eliminate the need for extensive and
duplicative testing of received materials. In a properly defined
supplier/manufacturer relationship, the supplier's testing should be
considered to be as reliable as testing performed by any other qualified
laboratory.

Manufacturers who have process control systems and written
specifications and procedures in place will be able to identify the
conditions under which certificates of analysis can be considered
reliable, and the final rule should recognize the appropriateness of
such reliance.

**APPLICABILITY OF THE RULE TO FOREIGN FIRMS**

FDA indicates in the preamble to the proposed rule that its provisions
are applicable to foreign as well as domestic manufacturers. CRN's
member companies are concerned that there be teeth in this requirement,
to ensure a level playing field for U.S. firms and foreign competitors.
It would not be appropriate for foreign firms to be permitted a "free
ride" while U.S. firms are incurring the additional costs of compliance
with any final GMP rule. Failure to require compliance by foreign firms
would also expose U.S. consumers to risk, since the GMPs are intended to
prevent the manufacture or distribution of adulterated products.

Third-party certification programs have been initiated by the U.S.
Pharmaceopeia and by NSF International, based on the auditing of GMP
practices and the testing of specific products. These programs may have
applicability as a means of certifying compliance of foreign firms with
required GMPs, just as they currently certify GMP compliance of U.S.
firms that choose to participate in their respective programs.

Even if dietary ingredient manufacturers are not ultimately covered by
the GMP rule, as CRN is proposing, responsible finished product
manufacturers will seek to procure materials from ingredient suppliers
that are in compliance with sound GMPs. Large firms may verify the
reliability of their suppliers by conducting their own audits of the
ingredient manufacturers, foreign as well as domestic. Third-party
certification would provide another option for identifying reliable
ingredient manufacturers.

GMP expert Carl Reynolds also emphasizes the importance of securing
compliance by foreign firms (see separate statement in **Attachment
C**). He calls attention to the difficulties of ensuring compliance of
foreign firms and makes note of special requirements for imports set
forth in the seafood HACCP rule (21 CFR part 123) in this regard. These
include provisions encouraging audits or third party certifications as
tools for evaluating whether foreign firms are in compliance.

**COST OF FDA'S PROPOSED TESTING REQUIREMENTS**

FDA estimates that the total increased cost of the proposed GMP
requirements for large manufacturers would be \$83,000 in the first year
and \$47,000 in subsequent years, and this includes the additional costs
related to exhaustive testing of finished products. For small companies,
FDA estimates an incremental cost of \$99,000 in the first year and
\$61,000 in subsequent years. CRN's member companies include a number of
large firms as well as many companies that qualify as "small businesses"
under the criteria established by the Small Business Administration.

**CRN believes the agency's cost estimates are massively understated.**
To take testing costs as a single example, FDA estimates that for large
companies there will be an average of 309 batches per year to be tested.
CRN's large members are reporting that they produce 2000 to 6000 batches
of finished products per year \-- or about an order of magnitude more
than FDA's estimate. Since FDA's cost estimates are based on the amount
of testing required per batch, the low estimate for the number of
batches produced per year by large companies would lead to a drastically
low estimate of testing costs. Similar issues exist with regard to the
production volume of smaller companies.

FDA's basic economic analysis assumes that only finished product testing
will be required. However, the language of the rule in 111.35(e) appears
to require additional testing at critical control points where a
specification is necessary to prevent adulteration. The preamble at 68
FR 12196-7 indicates that, at a minimum, control points should include
the receiving of materials and at least one in-process step, in addition
to final product testing. Thus, the actual requirements of the rule as
written appear to be more in line with the "more restrictive"
alternative considered in FDA's economic analysis.

CRN will be submitting separate comments on the estimated costs of the
proposed rule. We have recently received some additional information
from FDA regarding the agency's underlying assumptions and calculations
of economic impact, and we have requested additional time to analyze
these materials and utilize them in the preparation of our comments on
the costs and benefits of the proposal. We have received assurance from
FDA that our comments will be considered, provided they are submitted
within 29 days after the official close of the comment period on August
11.

**TEST METHODS AND THE COST OF METHOD DEVELOPMENT**

The proposed rule requires in 111.35(h) that a "scientifically valid
analytical method" be utilized in determining whether specifications are
met. In the preamble, FDA cites AOAC and USP methods as examples of
scientifically valid methods, but recognizes that other published
methods as well as internally developed methods supported by scientific
research may also be scientifically valid. CRN recommends that the term
"scientifically valid" be defined in the rule and that recognition be
given to methods developed by the American Herbal Pharmacopeia (AHP) in
that context.

In the preamble, the agency says it is "not aware of a situation where
an appropriate scientifically valid analytical method is not available,"
and FDA's economic analysis does not address costs of method
development. However, industry members have been deeply involved in
numerous efforts to develop valid methods for many ingredients,
including the longstanding efforts of USP and the INA/MVP testing
initiative. The NIH Office of Dietary Supplements (ODS) recently
received special funding by Congress for the development of analytical
methods, and AOAC is working with ODS on this project. These ongoing
activities in our view are testimony to the fact that there will be an
extensive need for method development into the future, and that its cost
will continue to be substantial. We will providing more information on
these efforts and their associated cost in our analysis of economic
impacts, which we have received FDA permission to submit within 29 days
following the close of this comment period.

In our separate comments on legal issues raised by the FDA proposal, CRN
notes that the language of DSHEA specifies that any GMP regulations
prescribed by the agency "may not impose standards for which there is no
current and generally available analytical methodology." The proposed
rule requires that "scientifically valid" tests be used in testing for
specifications, and section 111.60 requires that these tests must be not
only scientifically valid but must be "validated." Given the substantial
ongoing efforts directed toward method development, we believe the
agency's expectations as described in the preamble would in fact for
many ingredients and products impose standards which cannot be met
through current and generally available analytical methodology. In
addition, CRN believes the agency goes beyond food models for GMPs in
suggesting that analytical methodologies must be "validated."

The comments included from GMP expert Carl Reynolds in **Attachment C**
also express these concerns, saying FDA's proposal "assumes
scientifically valid analytical methodology exists when such may not be
the case."

**EXPIRATION DATING**

The current proposed GMP regulations for dietary supplements do not
require shelf life or expiration dating for dietary supplements. The
proposal also does not address what type of evidence may be needed to
support expiration dating voluntarily provided by the manufacturer,
although FDA offers some suggestions in preamble language.

FDA has not proposed shelf life or expiration dating requirements
because, the agency says, not all dietary supplement materials have a
commonly accepted "active" or "marker" component. FDA believes this is
particularly the case for many botanical components.

FDA also comments on the presumed difficulty of documenting the basis
for an expiration date for dietary supplement products, at 68 FR
12203-12204: "The agency considered whether to propose requirements in
this proposed rule for expiration dating, shelf-life dating, or best if
used by dating (hereinafter referred to as expiration dating). Although
we recognize that there are current and generally available methods to
determine the expiration date of some dietary ingredients, for example
vitamin C, we are uncertain whether there are current and generally
available methods to determine the expiration dating of other dietary
ingredients, especially botanical dietary ingredients. We are not
proposing expiration dating at this time because we have insufficient
scientific information to determine the biological activity of certain
dietary ingredients used in dietary supplements, and such information
would be necessary to determine an expiration

date. Further, because official validated testing methods (i.e., AOAC or
FDA) for dietary supplements are evolving, especially for botanical
dietary ingredients, few official methods are available to assess the
strength of a dietary ingredient in a dietary supplement. Nevertheless,
if you use an expiration date on a product, you should have data to
support that date. You should have a written testing program designed to
assess the stability characteristics of the dietary supplement, and you
should use the results of the stability testing to determine appropriate
storage conditions and expiration dates."

As a practical matter, CRN members believe expiration dating or shelf
life dating is essential to the ability to market most dietary
supplements in today's business environment. Consumers expect and demand
expiration dating, major retail chains will not accept dietary
supplements without expiration dating, and virtually all responsible
manufacturers already utilize expiration dating and have stability
programs in place to support the establishment of shelf life or
expiration dating.

Nutrition labeling regulations for dietary supplements in 21 CFR 101.36
require that products provide at least 100% of the level of added
substances quantified in the Nutrition Facts box, throughout the shelf
life of the product. In addition, the language of DSHEA declares a
dietary supplement to be misbranded under Section 403 of the FD&C Act if
it "fails to have the identity and strength that the supplement is
represented to have..." Thus, both FDA regulations and the law itself
require that dietary supplements provide 100% of label claim. In order
to define the period of time during which 100% of the label claim can be
assured, it is essential for products to bear shelf life or expiration
dating. Without such labeling, the manufacturer would theoretically be
responsible for assuring 100% of label claim in perpetuity \-- and this
is not a feasible requirement.

Labeled potency may not be the only factor to be considered in
establishing shelf life or expiration dating. The language of DSHEA also
declares a dietary supplement to be misbranded under Section 403 of the
FD&C Act if it "fails to meet the quality (including tablet or capsule
disintegration), purity, or compositional specifications, based on
validated assay or other appropriate methods, that the supplement is
represented to meet."

All or most dietary supplements contain some quantification of dietary
ingredients in the Supplement Facts box. These quantitative declarations
would provide the primary basis for expiration dating. If substances are
being quantified in labeling, then by definition there are tests being
utilized for determining the quantities stated. Those same tests can be
utilized in evaluating stability. Other product attributes relevant to
shelf life dating may include disintegration performance, appearance,
color, odor, taste, texture, and integrity of the dosage form (tablet,
capsule, or softgel, for example).

CRN urges FDA to require shelf life or expiration dating for dietary
supplements when needed to support quantitative claims made in labeling
and to specify that such dating should be based on appropriate
substantiation. Appropriate substantiation might include accelerated
stability testing or might be based initially on the known stability
profile of similar types of products manufactured by the company. Real
time testing should also be undertaken to confirm the selected shelf
life or expiration dating for the product.

If the product is stable under normal ambient conditions, then no
special instructions are needed in labeling to support the shelf life or
expiration dating. Only if special storage conditions are required would
any specific label instructions be needed (e.g., "keep refrigerated").

The language of the Dietary Supplement Health and Education Act (DSHEA)
suggests that expiration dating was envisioned as a feature of current
industry practice and potentially as a feature of current GMP
regulations. DSHEA added a new subsection 402 (g) to the FD&C Act,
providing that a dietary supplement is adulterated "if it is a dietary
supplement and it has been prepared, packed or held under conditions
that do not meet current good manufacturing practice regulations,
**including regulations requiring, when necessary, expiration date
labeling...**" (emphasis added)

**EMPLOYEE QUALIFICATIONS, EDUCATION AND/OR TRAINING**

## The general food GMPs in 21 CFR part 110 require that employees have "a background of education [or]{.underline} experience, or a combination thereof, to provide a level of competency necessary for production of clean and safe food." (emphasis added)

The requirement in part 111.12 of the proposed dietary supplement GMPs
is that employees "must have the training [and]{.underline} experience
to perform the person's duties." (emphasis added)

In the preamble to the proposed dietary supplement GMP rule, FDA
disagreed with comments on the ANPR that suggested use of the word "or"
in this section, saying that "the proposed rule uses the conjunction
'and' because, while some might consider experience to be a form of
training, most consider experience to be knowledge that a person gains
over time as he or she becomes increasingly familiar with a particular
action or piece of equipment." FDA added that training is not meant to
include just on-the-job training, but could also include formal
instruction. FDA pointed out at 68 FR 12183: "The word 'and' includes
situations where on-the-job training may be adequate and also situations
where educational training may be required."

Earlier in the preamble, FDA also states at 68 FR 12183: "The extent and
frequency of the training is left to the manufacturer's discretion."

CRN does not object to the use of the term "and" in the phrase "training
and experience" in the proposed regulation, as long as the
manufacturer's discretion in defining the required training is
recognized. This is particularly important in light of the diversity of
the industry, where the size of the company, the procedures utilized,
the types of equipment employed, and the nature of the ingredients
handled may vary widely from one firm to another, with each firm having
unique requirements.

**WATER QUALITY**

Under the general food GMP regulations in 21 CFR part 110, the water to
be used as a component of food products, for washing of foods, in
processing operations and on food contact surfaces "shall be of safe and
of adequate sanitary quality." No higher requirement is set forth for
food products. No water standards are listed in the GMPs for low-acid
canned foods in part 113 or in the GMPs for acidified foods in part 114.
If this requirement is adequate to ensure the quality of the water used
in most food products, then CRN believes it is also adequate to ensure
the quality of the water used in dietary supplements.

Under the amended standards for bottled water (63 FR 25764-69), the
proposed GMPs for infant formula (61 FR 36153-36219) and the currently
proposed dietary supplement GMPs, the agency uses a new and higher
standard for water based on the EPA Primary Drinking Water Regulations
in 40 CFR part 141. If the agency retains the requirement based on the
EPA standard, then it is important to include provisions recognizing the
acceptability of municipal sources of water and the frequency of testing
required for other sources of water.

In the infant formula proposed GMPs, FDA describes an acceptable
frequency for testing of water sources as follows: "Manufacturers shall
conduct the tests....with sufficient frequency to ensure that the water
meets the EPA's Primary Drinking Water Regulations but shall not conduct
these tests less frequently than annually for chemical contaminants,
every 4 years for radiological contaminants, and weekly for
bacteriological contaminants."

The amendments to the bottled water regulations also specify an
acceptable testing frequency as follows: "The bottled water CGMP
regulations require a minimum yearly monitoring of source water and
finished bottled water products for chemical contaminants for which
allowable levels have been established in the bottled water quality
standard."

**PHYSICAL PLANT**

FDA's proposed rule on GMPs would require in 111.20 that the physical
plant have "floors, walls, and ceilings that are of smooth and hard
surfaces that can be adequately cleaned and kept clean and in good
repair." We can find no precedent in any food GMP for a provision
specifying "smooth and hard surfaces" for ceilings, and indeed the only
precedent we can identify is in the section of the drug GMPs relating to
"aseptic processing." Regulations applicable to the aseptic processing
of drugs are not an appropriate model for these dietary supplement GMPs.
There are many portions of the plant in which smooth and hard ceilings
are not necessary and where dropped ceilings, for example, are both
suitable and commonly utilized. The cost of converting all ceilings in
all parts of the plant to "smooth and hard surfaces" would be immense
and unjustified. The language of the general food GMP specifies that the
construction of floors, walls and ceilings must be such as to permit
them to "be adequately cleaned and kept clean and kept in good repair."
In CRN's view, such a provision would be the appropriate food model for
the dietary supplement GMPs.

**ANIMAL-DERIVED INGREDIENTS**

FDA inquires whether the GMP rule should include additional provisions
regarding the handling of imported animal-derived ingredients. The
preamble indicates that FDA is "not aware of dietary supplement
manufacturers' current procurement and handling practices" relating to
animal-derived ingredients. This is a surprising assertion, since CRN
and others have made significant efforts to inform FDA officials of the
industry's practices in this regard. CRN and the other industry trade
associations have been working actively with their member companies to
ensure adherence to the requirements set forth in FDA's various letters
regarding the need to develop plans "that ensure, with a high degree of
certainty" that animal-derived ingredients are used only in accordance
with FDA and USDA policies designed to protect against BSE. CRN convened
an industry working group on this topic in February 2001, in which FDA
and USDA officials participated. The various industry trade associations
jointly surveyed the industry regarding procurement and handling
practices and submitted to FDA five large volumes containing lists of
animal-derived ingredients used by various companies, along with
examples of the certificates of origin and other documentation required
for import of any animal-derived materials.

FDA has convened a TSE advisory committee within the Center for
Biologics, and the deliberations of the advisory committee have been
followed closely by all FDA-regulated industries, including the dietary
supplement industry. Although FDA's efforts to protect against BSE
(recently broadened to TSE) started with concerns relating to the safety
of blood products regulated by the Center for Biologics, appropriate
procedures and policies have since been enunciated for pharmaceuticals
and for food products, including dietary supplements. Thus, there is no
need at this point for FDA to continue to refer back to biologics as the
model for provisions applicable to other product categories.

CRN believes the general reference that already appears in the GMP rule,
emphasizing the obligation to comply with other applicable laws and
regulations, is sufficient to cover the BSE issue. The dietary
supplement industry is fully cognizant of both FDA's policies and
guidance and the regulatory activities of USDA relating to the risk of
BSE, and companies are making every effort to ensure compliance.

**INGREDIENTS OTHER THAN "DIETARY INGREDIENTS"**

Section 111.35(d) of the proposed rule contains specifications relative
to the use in dietary supplements of ingredients other than "dietary
ingredients." To the extent that this section is merely a restatement of
existing FDA policy and regulations, it is unnecessary. Section 111.5
already requires observance of "other statutory provisions and
regulations."

To the extent that section 111.35(d) is meant to break new ground, it is
inappropriate in the context of a GMP rulemaking. For example,
subparagraph (3) would require that color additives used in dietary
supplements must specifically be listed for such use. Various color
additives are currently approved generally for "food" use, but none are
approved specifically for dietary supplements within the food category.
If FDA intended by this provision to assert an additional requirement
for dietary supplements, that would be beyond the scope of a GMP
rulemaking.

Section 111.35(d)(4) contains requirements pertaining to substances that
FDA has determined to be GRAS (Generally Recognized as Safe) or that
have been have been determined by their manufacturers or marketers to be
GRAS. The rule requires that companies be prepared to support the GRAS
status of the ingredient by a citation to FDA regulations or "by an
explanation for why there is general recognition of safety of the use of
the substance in a dietary ingredient or dietary supplement." In the
preamble to the proposed rule, FDA asserts that an FDA response letter
cannot be relied upon to support the safety of an ingredient, when a
manufacturer or one of its suppliers has determined the ingredient to be
GRAS and has so notified FDA. This provision would undermine the GRAS
self-determination process, including especially the entire rationale
for notifying FDA of the determination. If FDA in this section means to
alter its position with regard to self-determination of GRAS status,
that would appear to go beyond the scope of a GMP rulemaking.

CRN urges FDA to delete section 111.35(d) and rely on section 111.5 and
existing policy and regulations with regard to the status of dietary
supplement ingredients other than "dietary ingredients."

**COMPLIANCE PERIOD**

FDA proposes to provide for a one-year compliance period for large
manufacturers, once a GMP rule is finalized, with a three-year
compliance period for small firms. This would be reasonable for large
firms only if the final rule is modified to better reflect existing GMPs
among responsible companies whose practices should ideally provide the
model for the rule. If the final rule, like the proposal, represents a
great departure from current "best practices" and from sound GMP theory,
then a one-year compliance period will not be realistic.

A three-year compliance period for small firms may be reasonable, with
respect to any new GMP rule, but it should be recognized that even
during that period \-- and today and every day for the past several
decades \-- those firms will be and have been subject to general food
GMP regulations and should be in compliance with them. Accordingly, FDA
should be inspecting those firms to ensure such compliance. The agency's
survey of manufacturing practices indicated that small and (especially)
very small firms were less likely to be observing any formal GMP rule.
FDA and the states should not wait until finalization of new dietary
supplement GMPs to enforce compliance with basic food GMP requirements.

**CONCLUSION AND RECOMMENDATIONS**

CRN and its members have played a key role in bringing the topic of GMPs
for dietary supplements to the table and in pursuing it to this point.
We are committed to remaining engaged and to supporting the need for
enhanced GMPs, but we do not believe the FDA proposal hits the right
balance between sufficient control and essential flexibility. CRN urges
FDA, as it crafts a final rule on GMPs for dietary supplements, to
adjust the emphasis of the rule toward a focus on process controls
rather than reliance on exhaustive finished-product testing. These
process controls should include written specifications for key
operations, in order to ensure uniformity of practice and to provide a
sound basis for employee training and supervision. A key aspect of
process control involves rigorous oversight over incoming ingredients,
which is best accomplished through a vendor qualification program that
will identify reliable suppliers and permit acceptance of
analytically-based certificates of analysis documenting that bulk
ingredients meet appropriate specifications.

We do not believe the prescriptive finished-product-based approach
adopted by the agency is consistent with good quality assurance practice
or theory, and we do not believe the proposal is sufficiently modeled
after food GMP regulations, as required by DSHEA.

**CRN urges the agency to carefully consider all the comments it
receives on this proposal and then to schedule a public meeting or
perhaps a series of public workshops to evaluate the numerous important
issues involved and to develop a more workable solution.**

Sincerely,

![](media/image2.png){width="2.2569444444444446in" height="0.6in"}

Annette Dickinson, Ph.D.

President

  ----------------------------------------------------------------------------------------- ------------------------------------
  **Manufacturers of Finished Products**                                                    

  **Member Company**                                                                        **Products**

  [Access Business                                                                          Nutrilite®, Trim Advantage®
  Group/Nutrilite](http://www.alticor.com/products/nutritional_supplements.html)            

  [Accucaps Industries Limited](http://www.accucaps.com/defaultframe.htm)                   Private Label Manufacturer of
                                                                                            Vitamins and Minerals, Oils,
                                                                                            Specialty Supplements, and Herbals

  [Arkopharma, LLC](http://www.arkopharma.com/english/index.html)                           Sokoja®, Azinc®, Potensium®,
                                                                                            Arkocaps®, Memoboost®, Turbodiet®

  [B&C Nutritional Products, Inc.](http://www.bcnutritional.com/product_offerings.htm)      Private Label Manufacturer of
                                                                                            Vitamins and Minerals, Specialty
                                                                                            Supplements, and Herbals

  [Bayer HealthCare LLC](http://www.bayer.com/en/index.php)                                 One-A-Day®, Flintstones®

  [Bio San Laboratories Inc.](http://www.biosan.net/)                                       Private Label Manufacturer of
                                                                                            Vitamins and Minerals, MegaFood®,
                                                                                            DailyFoods®, Essentials®

  [Enzo Nutraceuticals](http://www.enzo.co.nz/)                                             Enzogenol®

  [Experimental and Applied Sciences, Inc. (EAS)](http://www.eas.com/)                      AdvantEdge®, BetaGen®, CytoVol®,
                                                                                            EcdyMax®, Lean DynamX®, Mass
                                                                                            Factor®, Muscle Drive®, Myoplex®,
                                                                                            Precision Protein®, Simply
                                                                                            Creatine®, SimplyProtein®, Synthe
                                                                                            Vol®, Thermo DynamX®, ZMA®

  [GNC Incorporated](http://www.gnc.com/)                                                   GNC ProPerformance®, Preventive
                                                                                            Nutrition®, Herb Plus®, GNC Natural
                                                                                            Brand®, Total Lean®, Mega Men®,
                                                                                            Womens Ultra Mega®, Herbal Plus®

  [GNLD International](http://www.gnld.com/)                                                Carotenoid Complex®, GR^2^ Control®

  [Herbalife International](http://www.herbalife.com/uk/)                                   Herbalife, Thermo Complete®,
                                                                                            Thermojetics®,

  [Jamieson Laboratories Ltd.](http://www.jamiesonvitamins.com/)                            Mega Cal®, Vita Vim®

  [Kemin Consumer Care, L.L.C.](http://www.kemin.com/)                                      Satise®

  [Mannatech, Inc.](http://www.mannatech.com/default.asp)                                   Glycentials®, Ambrotose®,
                                                                                            Phyt•Aloe®, CardioBALANCE®,
                                                                                            ImmunoStart®, Glyco•Bears®,
                                                                                            Phyto•Bears®, EM•Pact®, GlycoLEAN®,
                                                                                            Plus®, Ambrostart®, Sport®,
                                                                                            Emprizone®

  [Mary Kay, Inc.](http://www.marykay.com/)                                                 Daily Benefits for Women®, Daily
                                                                                            Benefits for Men®

  [Natural Alternatives International Inc.](http://www.nai-online.com/)                     Pathway to Healing®, Jennifer
                                                                                            O'Neill Essentials®, Private Label
                                                                                            Manufacturer

  [NBTY,                                                                                    Nature\'s Bounty®, Vitamin World®,
  Inc.](http://www.corporate-ir.net/ireye/ir_site.zhtml?ticker=NBTY&script=2100&layout=8)   Puritan\'s Pride®, Holland &
                                                                                            Barrett®, Nutrition Headquarters®,
                                                                                            American Health® and Nutrition
                                                                                            Warehouse®, Private Label
                                                                                            Manufacturer

  [Nu Skin International                                                                    LifePAK®, Phamanex Solutions®,
  Inc.](http://www.nuskinenterprises.com/corp/index.shtml)/[Pharmanex                       Pharmanex Bodydesign®
  LLC](http://www.pharmanex.com/)                                                           
  ----------------------------------------------------------------------------------------- ------------------------------------

+----------------------------------+-----------------------------------+
| ######## Ma                      |                                   |
| nufacturers of Finished Products |                                   |
+----------------------------------+-----------------------------------+
| **Member Company**               | **Products**                      |
+----------------------------------+-----------------------------------+
| [Nutraceutical                   | Solaray®, KAL®, NaturalMax®,      |
| Corporation                      | VegLife®, Premier One®, Sunny     |
| ](http://www.nutraceutical.com/) | Green®, Natural Sport®, ActiPet®, |
|                                  | Action Labs®, Miztique®, Ultimate |
|                                  | Nutrition® and Thompson®, Private |
|                                  | Label Manufacturer                |
+----------------------------------+-----------------------------------+
| [Nutramax Laboratories,          | Senior Moment®, Cosamin® DS       |
| Inc                              |                                   |
| .](http://www.nutramaxlabs.com/) |                                   |
+----------------------------------+-----------------------------------+
| [Perrigo                         | Private Label Manufacturer and    |
| Company](http://                 | Branded Contract Manufacturer     |
| www.perrigo.com/index_flash.htm) |                                   |
+----------------------------------+-----------------------------------+
| [Pharmaton Natural Health        | Ginsana®, Ginkoba®, Flexium®,     |
| Products](http://ww              | Kyolic®, Venastat®, Supplifem®,   |
| w.pharmaton.com/us/homepage.jsp) | Prostatonin®                      |
+----------------------------------+-----------------------------------+
| [Pharmavite                      | Nature Made®, Nature's Resource®, |
| LLC](http://www.pharmavite.com/) | Private Label Manufacturer, Olay™ |
|                                  | Vitamins                          |
+----------------------------------+-----------------------------------+
| [Proper Nutrition,               | SeaCure®, SeaVive®                |
| Inc.](                           |                                   |
| http://www.propernutrition.com/) |                                   |
+----------------------------------+-----------------------------------+
| [Pulse                           | Pulse® Water + Nutrients          |
| Nutrition](http://www.pul        | (Vitamins and Minerals)           |
| senutrition.com/html/index.html) |                                   |
+----------------------------------+-----------------------------------+
| [Rainbow Light Nutritional       | Active Health®, Complete          |
| System                           | Nutritional System®, Complete     |
| s](http://www.rainbowlight.com/) | Prenatal System®, Nutristars®,    |
|                                  | Performance Energy®, Women's      |
|                                  | Answer® and other Single          |
|                                  | Nutrient, Herbal, and Specialty   |
|                                  | Supplements                       |
+----------------------------------+-----------------------------------+
| [Rexall Sundown,                 | Sundown®, Osteo Bi-Flex®,         |
| Inc.                             | Pokemon®, Private Label           |
| ](http://www.rexallsundown.com/) | Manufacturer                      |
|                                  |                                   |
| (now part of NBTY, Inc.)         |                                   |
+----------------------------------+-----------------------------------+
| [Ross                            | Glucerna®, Ensure®, Infant        |
| Products](http://www.ross.com/)  | Formula                           |
+----------------------------------+-----------------------------------+
| [Shaklee                         | CorEnergy®, Mood-Lift®,           |
| Corpo                            | Vita-Lea®, CoQHeart®, Immunity    |
| ration](http://www.shaklee.com/) | Formula I®, Herb-Lax®,            |
|                                  | Optiflora®, EZ-Gest®, Shaklee     |
|                                  | Fitness®, Performance®,           |
|                                  | Physique®, Liver DTX®, Fiber      |
|                                  | Plan®                             |
+----------------------------------+-----------------------------------+
| [Sigma Tau Health                | ProXeed®, Megasol®, Megasol Q10®, |
| Sciences](http:/                 | Phototrop®, Avant®, Biorecord     |
| /www.sigmatau-hs.it/default.htm) | Plus®                             |
+----------------------------------+-----------------------------------+
| [Tom's of                        | Botanicals                        |
| Mai                              |                                   |
| ne](http://www.tomsofmaine.com/) |                                   |
+----------------------------------+-----------------------------------+
| [Vitamin Shoppe Industries,      | Vitamins and Minerals, Specialty  |
| Inc.                             | Supplements, and Botanicals       |
| ](http://www.vitaminshoppe.com/) | distributed under the Vitamin     |
|                                  | Shoppe® name                      |
+----------------------------------+-----------------------------------+
| [VitaTech International,         | Private Label Manufacturer        |
| Inc.](http://www.vitatech.com/)  |                                   |
+----------------------------------+-----------------------------------+
| [Warner Lambert Consumer Group   | Finished Product Manufacturer     |
| of                               |                                   |
| Pfizer](                         |                                   |
| http://www.pfizer.com/main.html) |                                   |
+----------------------------------+-----------------------------------+
| [Weider Nutrition International, | Schiff®, Schiff® Move Free®,      |
| Inc.](http                       | Tiger's Milk®, Weider®, Fi Bar®   |
| ://www.weidernutrition.biz/weide |                                   |
| r_interior.asp?strLink=investor) |                                   |
+----------------------------------+-----------------------------------+
| [Wyeth](http://www.wyeth.com/)   | Centrum®, Centrum Silver®,        |
|                                  | Centrum Performance®, Centrum     |
|                                  | Kids®, Caltrate®                  |
+----------------------------------+-----------------------------------+

+----------------------------------+-----------------------------------+
| **Suppliers**                    |                                   |
+----------------------------------+-----------------------------------+
| **Member Company**               | **Products/Ingredients/Services** |
+----------------------------------+-----------------------------------+
| [Access Business Group - Trout   | Grower and Processor of Botanical |
| Lake                             | Ingredients, Ocean Essentials®    |
| Farms](http://www.acce           |                                   |
| ssbusinessgroup.com/default.asp) |                                   |
+----------------------------------+-----------------------------------+
| [Albion Laboratories,            | Bulk Minerals                     |
| Inc.](http://www.albion-an.com/) |                                   |
+----------------------------------+-----------------------------------+
| [American Laboratories,          | Processor and Supplier of         |
| Inc.](http:                      | Enzymes, Peptones, Liver Products |
| //www.americanlaboratories.com/) | and Glandulars                    |
+----------------------------------+-----------------------------------+
| [Archer Daniels Midland          | Vitamin E, Soy Isoflavones,       |
| Co                               | Lecithin                          |
| mpany](http://www.admworld.com/) |                                   |
+----------------------------------+-----------------------------------+
| [B&D Nutritional Ingredients,    | Supplier of Vitamin E, Lecithin,  |
| Inc.](http://www.bndni.com/)     | Lutein, Phytosterols, Grape Seed  |
+----------------------------------+-----------------------------------+
| [BASF                            | Vitamins A, C, D & E, B Vitamins, |
| Co                               | Carotenoids, Excipients,          |
| rporation](http://www.basf.com/) | Clarifying Agents, Aroma          |
|                                  | Chemicals                         |
+----------------------------------+-----------------------------------+
| [Biotron Laboratories,           | Supplier of Various Mineral Amino |
| In                               | Acid Chelates                     |
| c.](http://www.biotronlabs.com/) |                                   |
+----------------------------------+-----------------------------------+
| [Cap                             | Encapsulated Products and         |
| sugel](http://www.capsugel.com/) | Capsules                          |
+----------------------------------+-----------------------------------+
| [Cargill Health & Food           | Soy Isoflavones, Chondroitin,     |
| Techno                           | Vitamin E                         |
| logies](http://www.cargill.com/) |                                   |
+----------------------------------+-----------------------------------+
| [Cognis Nutrition &              | Natural Vitamin E, Tonalin® CLA,  |
| Health](ht                       | Vegapure®, Sterols/Sterol Esters, |
| tp://www.cognis.com/cognis.html) | Lutein Esters, Natural Mixed      |
|                                  | Carotenoids, ALA, Botanicals,     |
|                                  | Emulsifiers, Food Technology      |
|                                  | Ingredients                       |
+----------------------------------+-----------------------------------+
| [Col                             | Excipients, Colors, Coating       |
| orcon](http://www.colorcon.com/) | Systems, Printing Inks            |
+----------------------------------+-----------------------------------+
| [Daiichi Fine Chemicals,         | B Vitamins, Vitamin D,            |
| Inc.](http://www                 | Carotenoids                       |
| .daiichi-fcj.co.jp/en/home.html) |                                   |
+----------------------------------+-----------------------------------+
| [E.T. Horn                       | Bulk Ingredients Including:       |
| Company](http://www.ethorn.com/) | Calcium Carbonate, Glucosamine,   |
|                                  | Cellulose                         |
+----------------------------------+-----------------------------------+
| [Generichem                      | Bulk Supplier of Minerals         |
| Corporat                         |                                   |
| ion](http://www.generichem.com/) |                                   |
+----------------------------------+-----------------------------------+
| [Indena USA,                     | Botanicals Supplier               |
| Inc.](http://www.indena.com/)    |                                   |
+----------------------------------+-----------------------------------+
| [Kaneka America                  | Supplier of Co-Enzyme Q10         |
| Corporation](ht                  |                                   |
| tp://www.kaneka.com/kacfine.htm) |                                   |
+----------------------------------+-----------------------------------+
| [Kemin Foods,                    | Lutein - FloraGLO®, Antioxidants  |
| L.C.](http://www.kemin.com/)     |                                   |
+----------------------------------+-----------------------------------+
| [Linnea,                         | Botanicals Supplier               |
| Inc.](http://www                 |                                   |
| .linnea-worldwide.com/home1.asp) |                                   |
+----------------------------------+-----------------------------------+
| [Loders-Cro                      | Supplier of Oils Including:       |
| klaan](http://www.croklaan.com/) | Clarinol®, Marinol®, Membranol®,  |
|                                  | Safflorin®                        |
+----------------------------------+-----------------------------------+
| [Lonza,                          | Supplier of L-Carnitine and B     |
| Inc.](http://w                   | Vitamins                          |
| ww.lonzagroup.com/group/en.html) |                                   |
+----------------------------------+-----------------------------------+
| Mingtai Chemical, LLC            | Microcrystalline Cellulose,       |
|                                  | Comprecal®                        |
+----------------------------------+-----------------------------------+
| [Nashai Biotech                  | Supplier of Ingredients Including |
| LLC](http://www.nashai.com/)     | TeaFlavin®                        |
+----------------------------------+-----------------------------------+
| [Nutrinova](http://www.nu        | DHActive®, Fiber - Caromax®,      |
| trinova.com/easy2web/internet.ns | Nutrinova® Sorbates               |
| f/directframe/home?OpenDocument) |                                   |
+----------------------------------+-----------------------------------+
| [Nutrition 21,                   | Chromax® Chromium Picolinate,     |
| In                               | Zinmax® Zinc Picolinate,          |
| c.](http://www.nutrition21.com/) | Selenomax® High Selenium Yeast,   |
|                                  | Selenopure® l-selenomethionine,   |
|                                  |                                   |
|                                  | Zenergen™ Chromium Picolinate     |
|                                  | plus CLA                          |
+----------------------------------+-----------------------------------+
| [Ocean Nutrition Canada          | Omega-3 Fatty Acids               |
| Ltd.](                           |                                   |
| http://www.ocean-nutrition.com/) |                                   |
+----------------------------------+-----------------------------------+
| ######## Suppliers               |                                   |
+----------------------------------+-----------------------------------+
| **Member Company**               | **Products/Ingredients/Services** |
+----------------------------------+-----------------------------------+
| [Omya,                           | Supplier of Calcium Carbonate     |
| Inc.](http://www.omya-na.com/)   |                                   |
+----------------------------------+-----------------------------------+
| [Polyphenolics                   | MegaNatural® Gold Grape Seed      |
| ](http://www.polyphenolics.com/) | Extract, MegaNatural® Grape Skin  |
|                                  | Extracts, MegaNatural® Rubired    |
|                                  | Grape Juice Extract, MegaNatural® |
|                                  | Red Wine Extract                  |
+----------------------------------+-----------------------------------+
| [Pronova Biocare,                | Omega-3 Fatty Acids - EPAX®,      |
| a.s.](http://w                   | Triomega®, Pikasol®, Omacor®      |
| ww.pronovabiocare.com/index.php) |                                   |
+----------------------------------+-----------------------------------+
| [Rhodia,                         | Antioxidants - Embanox®, Calcium  |
| Inc.](http://www.us.rhodia.com/) | Phosphate, Probiotics             |
+----------------------------------+-----------------------------------+
| [Roche Vitamins,                 | Vitamins A, C, D, & E, B          |
| Inc.]                            | Vitamins, Carotenoids, Omega-3    |
| (http://www.roche.com/home.html) | Fatty Acids                       |
+----------------------------------+-----------------------------------+
| [Seven Seas                      | Fish Oils, Multivitamins, Evening |
| Limited                          | Primrose Oil, Herbals,            |
| ](http://www.seven-seas.ltd.uk/) | ActionPlan50+®                    |
+----------------------------------+-----------------------------------+

> **Attachment B to CRN Comments:**
>
> **Qualifying the Production Process Control System**

**There should be a written plan for qualifying the production process
if process control is to be sufficiently rigorous as to justify
parametric testing of finished products. There should also be written
procedures for each stage of the process.**

### Raw Material and Primary Packaging

-   Supplier qualification program based on manufacturer's evaluation of
    the supplier's process and testing procedures

-   Appropriate written specifications for raw materials and packaging

-   **Identity testing of every ingredient received**

-   Specification testing of ingredients based on Vendor qualification
    data

-   Review of Certificate of Analysis or Report of Analysis and other
    data as appropriate -- must be actual testing and specific to
    batch/lot received

-   Verification of supplier's test results at appropriate intervals

# **In - Process Controls**

-   Master and batch records for every product

-   Appropriate written specifications for in-process materials

-   Dual signature verification of identity and weight of ingredients
    added

-   Calculation of yields -- plan vs. actual

-   Data demonstrating that equipment is suitable and that the process
    consistently delivers expected results over time

-   Specific in-process tests appropriate to specifications for unit
    operations

# **Finished Product Approvals**

-   Appropriate written specifications for finished product

-   Representative testing of chemical, physical and microbiological
    parameters based on an appropriate parametric sampling plan and data
    from raw material data and in-process testing and procedures

**A qualified process including the above features will assure that the
product meets regulatory requirements more effectively than testing
every ingredient in every batch.**

**ATTACHMENT C TO CRN COMMENTS**

**STATEMENT OF GMP EXPERT CARL REYNOLDS,**

**SENIOR CONSULTANT, AAC CONSULTING GROUP**

**CONCERNS RELATING TO THE FDA PROPOSED RULE**

**ON GOOD MANUFACTURING PRACTICES**

**FOR DIETARY SUPPLEMENTS**

**August 11, 2003**

The Dietary Supplement Health and Education Act of 1994 (DSHEA)
authorizes FDA to prescribe good manufacturing practices (GMP) for
dietary supplements, but what are GMPs? In the more than 60 years that
FDA has used good manufacturing practices as a quality and regulatory
standard, they have yet to define the term(s). DSHEA does not nor did
the comprehensive Drug Amendments of 1962. Absent a definition of this
important concept, the regulated industries have been forced to develop
one of their own. I crafted the following definition for use during
training programs:

> Good Manufacturing Practices: A system of procedures and
> documentation, written or analytical, to ensure that the product
> produced has the identity, strength, quality, composition and purity
> which it purports or is represented to possess.

While DSHEA authorizes FDA to prescribe cGMPs for dietary supplements,
the Act prohibits FDA from imposing standards for which there are no
current and generally available analytical methodology.

This proposed rule, as drafted, seems to ignore that restriction as well
as some of the basic premises of GMPs especially as they relate to in
process and finished product testing and documented policies and
procedures. The proposed rule at § 111.35(g)(1) requires comprehensive
testing of each finished batch of dietary supplements for *all*
(emphasis added) components (every ingredient) to ensure the batch meets
specifications for identity, purity, quality, strength, and composition
provided scientifically valid analytical methodology exists. The
proposed rule mentions "flexibility" but at § 111.35(g)(2)(i) and
(g)(2)(ii) it requires testing of incoming components, dietary
ingredients or dietary supplements to determine if specifications are
met *and* requires in-process testing where control is necessary to
ensure the identity, purity, quality, strength, and composition of
dietary supplements.

This concept is flawed because it assumes scientifically valid
analytical methodology exists when such may not be the case. One could
read this and argue that FDA would expect the firm to validate any
methods used in this regard. If this assumption is correct, it would
appear to deviate from the provision of § 402(g)(1) of the Food, Drug,
and Cosmetic Act as amended by DSHEA.

The heavy reliance on comprehensive end product testing allows one to
argue against the need for good manufacturing practices at all. Why not
just rely on comprehensive end product testing? The economic analysis
discusses this approach before rejection based on 4 issues: (1) Finished
product testing cannot build quality into a product; (2) Lack of
comprehensive analytical methodology; (3) Possibility of false
negatives, and

\(4\) Reduce the ability to perform trace back investigation in the
event defective products are discovered in the marketplace.

One familiar with the concepts of GMPs recognizes that end process
controls are not adequate because they cannot build quality into a
product. In testing protocols, all units or doses of a particular batch
are not tested. Rather it is necessary to rely on inferences and
assumptions. There is always the possibility of false analytical results
but that's why you have defined sampling protocols and formal,
documented procedures for addressing and investigating Out of
Specification results. It's critical to understand that samples only
produce meaningful information if the process is controlled.

The Agency has taken an interesting approach to one of the hallmarks or
cornerstones of good manufacturing practices. They propose requiring
documented procedures for some operations (calibration) but not in
others (customer complaints). They do not define a written procedure nor
is there differentiation between standard operating procedures (SOPs)
and procedures required in the master manufacturing record to ensure
that each batch of dietary supplement or dietary ingredient meets
specifications. It would be preferable for FDA to clearly require
written procedures for key operations identified in the proposed rule.

A general rule of thumb for the drug industry is that an SOP should be
in place for operating or controlling each piece of equipment, system or
process that must be cleaned, maintained, calibrated or otherwise
affects the quality, composition or purity of the finished product. For
dietary supplements, written policies and procedures should be required
at least for those areas mentioned in the ANPR. SOP documents must be
clear and concise and define policies, procedures or instructions for
operating processes, practices and equipment. This same approach should
also be considered for the dietary supplement industry.

When a manufacturer makes permanent changes or modifications to
specifications, procedures or documentation to address regulatory
changes or improvements or modifications in or with their procedures or
facilities, the changes should be reviewed, justified, documented,
approved and implemented in a defined SOP driven procedure know as
change control. Temporary changes could be addressed in a formal SOP
driven procedure for deviations.

The proposed rule discusses the application of HACCP in manufacturing
dietary supplements and dietary ingredients and makes the following
comment: ""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." This comment mistakenly describes HACCP. The
HACCP approach addresses safety, not adulteration, and utilizes a
preventive approach that addresses biological, chemical and physicals
hazards through anticipation and prevention, rather than through
end-product inspection and testing. The principles in and of themselves
do not address sanitation or similar aspects of adulteration. I consider
HACCP to be a companion program that becomes effective after
implementation and enforcement of sanitation standard operating
procedures (SSOPs.)

The rule at § 111.35(e) speaks of specifications being required for any
point, step, or stage in the manufacturing process where control is
necessary to prevent adulteration. It goes on to define such
specifications as regulatory specifications that would require testing
or examination to confirm they were met. A deviation from such
specification would require investigation and a disposition decision
approved by the quality control unit. The term specification(s) is not
defined and some might consider specification to be synonymous with a
numerical value. It would be helpful if specification were defined. In
training sessions, I have defined specifications as being a defined
parameter established for a specific characteristic that is ensured
through visual, chemical, microbiological or physical testing.

The provisions of § 111.35(e) could be called the HACCP component of the
rule. It requires compliance with five of the 7 principles of HACCP,
including conducting a hazard analysis, determine the critical control
points (CCP), establish critical limits, monitor the CCP, and establish
corrective actions.

The proposed rule would not allow use of Certificate of Analysis (COA)
as a basis for accepting ingredients or components. This is a
significant issue that requires serious consideration. The drug GMPs at
§ 211.184 allows accepting a COA from a supplier "provided that at least
one specific identity test is conducted on such component by the
manufacturer and provided that the manufacturer establishes the
reliability of the supplier's analysis through appropriate validation of
the supplier's test results at appropriate intervals." Many
manufacturers of dietary supplements have vendor certification programs
that may include visits to plants, inspections, verification of
laboratory procedures and data and comprehensive testing to confirm
specifications. Only after satisfactory compliance with established
specifications, will the manufacture consider accepting COAs in lieu of
comprehensive testing. Even after acceptance, there are periodic SOP
driven schedules to confirm continued conformance to specifications. For
example, a firm may completely test the first 10 shipments of a raw
material or component before they consider reducing the level of
analysis. After acceptance, the firm will still test every 3^rd^ or
5^th^ shipment for conformance to specifications. Usually a vendor
certification program is reevaluated annually. Identity testing is
performed on every incoming shipment.

The proposed rule at § 111.1 identifies who would be subject to these
regulations and the preamble states that foreign firms that manufacture,
package, or hold dietary supplements that are imported or offered for
import into the U.S. would be subject to these regulations. This is
certainly important, but there are no provisions for effective
enforcement. One could say that a foreign firm is subject to FDA
inspection(s) but the likelihood of FDA inspecting foreign dietary
supplement or dietary ingredients firms is small unless there is a
health issue that can be tied to the firm or material. Even then, FDA
would not have foreign jurisdiction and any inspection or investigation
would require advance notification and scheduling as well as consent of
the firm and foreign government.

I contrast this approach with the requirements of Seafood HACCP (21 CFR
123) that outlines special requirements for imports and places certain
requirements on the importer implementing affirmative steps to ensure
that HACCP is practiced. Some aspects of this program could be used for
dietary supplements including:

1.  Obtaining products from a country that has a cGMP focused regulatory
    program for dietary supplements or dietary ingredients that is at
    least equivalent to that of the U.S.

2.  Take affirmative steps to ensure that cGMPs are in place and
    enforced including obtaining a copy of the firm's SOP procedures and
    a written guarantee that they are being followed.

3.  Obtaining third party certification that products are processed
    according to requirements.

4.  Conduct your own inspection the ensure cGMPs are in place and being
    followed.

The benefits and cost analysis by FDA boldly declares "introducing cGMPs
will reduce the probability of a recall to zero." They further state
that cGMPs, if strictly used, "cause the discovery of all adulteration."
This is certainly a hopeful goal but one that will probably not be
achieved. Even with the long-term use of GMPs and enormous devotion of
resources by the industry and FDA, recalls have not been reduced to zero
in the drug and medical device industries. In fact, there have been more
than 250 recalls of drug products this fiscal year.

\# \# \# \# \# \# \#

Carl Reynolds is a Senior Consultant at AAC Consulting Group, Inc. where
he assists clients in regulatory compliance and conducts audits of FDA
regulated firms including dietary supplementary manufacturers and their
suppliers. Prior to joining the firm, Mr. Reynolds had a 36-year career
at the FDA, most recently as Director, Office of Field Programs in
CFSAN. In that position, he served as the chief compliance official for
foods and cosmetics and managed and directed all CFSAN programs
affecting FDA's field organizations. Mr. Reynolds supervised all
domestic and import regulatory activities, Federal/State cooperative
programs, and inspection programs, including those designed to implement
HACCP. He is an approved auditor for the NNFA GMP Certification Program
and the USP Dietary Supplement Quality Demonstration Program.