X.   Comments on Requirement to Establish a Production

and Process Control System

(Final Subpart E)

A.  Reorganization of Proposed § 111.35

Into Final Subpart E

     In the 2003 CGMP Proposal, the requirements for a production and
process control system were set forth in § 111.35.  As shown in table
6, we are reorganizing proposed § 111.35 into subpart E. Table 6 lists
the sections in final subpart E and identifies the sections in the 2003
CGMP Proposal that form the basis of the final rule.

	Table 6. - Derivation of Sections in Final Subpart E

Final Rule

2003 CGMP Proposal

§ 111.55 What Are the Requirements to Implement a Production and
Process Control System?

§ 111.35(a)

§ 111.60 What Are the Design Requirements for the Production and
Process Control System?

§ 111.35(b)

§ 111.65 What Are the Requirements to use for  a Quality Control
OperationsUnit?

§ 111.35(c)

§  111.70 What Specifications Must You Establish?

§ 111.35(e),

(f), (g), and (k)

§ 111.73 What is Your Responsibility for Determining Whether
Established Specifications are Met?	§ 111.35 (f), (g), and (h)

§ 111.75 What Must You do to Determine Whether Specifications are Met?

§ 111.35(e),

(f), (g), (h),

(i), (k), and (l)

§ 111.37 (b)(11(iv)

§ 111.40(a)(2)

§ 111.77 What Must You do if Established Specifications Are not Met?

	§ 111.50(d)(2)

§ 111.50(f)

§ 111.50(g)

§ 111.35(i) (4)(i)

§ 111.35(i) (4)(ii)

§111.80  What Representative Samples Must You Collect?
§ 111.37(b)(11)

§ 111.83 What are the Requirements for Reserve Samples?
§ 111.37(b)(12)

§ 111.50(h)

§ 111.83(b)(2)

§ 111.87 Who Conducts a Material Review and Makes a Disposition
Decision?	§ 111.35(i) and

 (n)

§ 111.37(b)(5) and (b)(14)

§ 111.40(a)(3)

§ 111.50(d)(1)

§ 111.85(a) and

(c)

§ 111.90 What Requirements Apply to treatment, In-process Adjustments,
and Reprocessing When There is a Deviation or Unanticipated Occurrence
or When a Specification Established in Accordance with § 111.70 is not
Met?

§ 111.35(i)(4)

§ 111.50(d)(1), (f), and (g)

§ 111.65(d)

§ 111.95 Under this Subpart, What Records Must You Make and Keep?

§ 111.35(m) and(o)

B.  General Comments on Proposed § 111.35

	(Comment 145) Several comments emphasize the first step in ensuring
safe, high quality products is to use high quality components that meet
well-defined specifications.  Some of these comments assert the 2003
CGMP Proposal does not encourage development of such specifications.

	Several comments assert that a more appropriate balance is needed
between an effective process control system and a reasonable testing
scheme that is calculated to confirm the quality of dietary supplements,
and that it is important to provide companies with more flexibility in
developing a specific CGMP program that satisfies the requirements.  The
comments stress it is important to build quality into a product
throughout the entire production process by relying on strong process
controls rather than by testing at the finished batch stage.  One
comment asserts that, in an appropriate process control system, testing
is a means to monitor and ensure that the control system is functioning
as intended.  Many comments recommend the final rule include rigorous in
process controls plus a requirement for one identity test of incoming
components to ensure quality and safety.

     Many comments assert a certificate of analysis can be a key element
of the manufacturing process provided that a manufacturer certifies that
a vendor consistently supplies suitable product through a combination of
vendor audits and product testing.  (A certificate of analysis is a
document, provided by the supplier of a component prior to or upon
receipt of the component, that documents certain characteristics and
attributes of the component.)  Comments also assert that, with use of a
certificate of analysis from a properly qualified supplier, the amount
of required testing could be reduced.  One comment notes that, although
a certificate of analysis may not be relied upon completely to forgo
testing of a received ingredient, the extent of testing could be reduced
to take into account the history of the supplier in providing quality
ingredients.  This and other comments recommend the dietary supplement
manufacturer conduct identity tests to ensure that the correct component
has been received.  A few comments note that the drug CGMP regulations
permit the use of a supplier’s certificate of analysis based upon
certification of the supplier by a program of complete testing for
conformance with the certificate of analysis.

     Several comments support the use of a qualified supplier’s
certificate of analysis in lieu of testing at the finished batch stage.
One comment recommends testing be strategically employed to verify that
other control procedures have accomplished their intended result; if
other controls are adequate, a statistically-based testing program
should be permitted for finished batches rather than the proposed
requirement for testing every batch for every specification.

     Many comments note that section 402(g)(2) of the act directs us to
develop dietary supplement CGMP requirements that are modeled after the
CGMP regulations for food.  These comments point out that, because the
food CGMPs allow the use of a verified certificate of analysis, it is
unfair and illogical to disallow a certificate of analysis in the
dietary supplement CGMP final rule.  One comment states the proposed
requirements for production and process controls are more stringent than
the requirements for drug products.

	Several comments stress that the most critical aspect of a successful
CGMP system is effective process control, which includes a requirement
for written procedures and documentation for all key processing
operations.  Many comments argue that effective process control,
including extensive written procedures, should allow for a decreased
testing burden with respect to the finished product.  One comment
suggests we exempt manufacturers from the requirement to test each batch
of finished product if they have a qualified manufacturing process that
meets certain basic criteria, including a requirement for written
procedures for each stage of the process and a written plan for
qualifying this process.

	Several comments urge us to build more flexibility into the testing
requirements, in both the type and number of tests required and the
point(s) in the supply chain at which they would be required.  Some
comments recommend that the frequency of testing be established under a
statistically valid method to ensure that in-process controls are
adequate to guarantee production of a safe and effective dietary
supplement or ingredient.  Several comments recommend we require
manufacturers to test incoming ingredients and raw materials, in lieu of
testing each finished batch of product.  These comments state it is more
prudent to test to ensure that the materials used in formulating a
product are appropriate and safe than to risk making an adulterated
product and, in so doing, contaminate manufacturing equipment.

     Several comments recommend we allow manufacturers to employ
skip-lot testing as an alternative to testing each finished batch of
product.  One comment states that, with adequate process controls in
place, periodic or skip-lot testing is sufficient, and notes that
skip-lot testing is acceptable under the regulatory frameworks for
herbal products in other countries, including Canada and countries in
the European Union.

     In summary, the comments suggest an approach that stresses the
importance of establishing specifications for components, relying on a
certificate of analysis from a qualified supplier for certain
specifications with qualification of the suppliers, qualifying suppliers
for components, and establishing and following written procedures.  This
overall approach would focus on building quality into a dietary
supplement throughout the production and process control system.  The
role of testing at the finished batch stage would become a check on
whether the overall manufacturing process is, in fact, under control.

	(Response)  Based upon a review of the comments, we have reconsidered
the approach taken in the 2003 CGMP Proposal.  The 2003 CGMP Proposal
would require that all finished batches of dietary supplements be tested
at the finished batch stage to ensure that the products met
specifications for identity, purity, strength and composition.  The 2003
CGMP proposal recommended, but would not require, testing of incoming
components to ensure that component specifications, including identity,
were met.  However, if a specification (such as identity) could not be
tested at the finished batch stage, the proposed rule would require a
firm to test incoming components for that specification and to test for
that specification at the in-process stage as necessary to ensure that
products met specifications.  We are persuaded that, as an alternative
to testing each finished batch of product, we can allow for the use of a
statistically sound sampling and testing program for finished batches of
dietary supplements unless a manufacturer chooses to test every batch.
Such a sampling and testing program is feasible when controls are
implemented earlier than the final product stage in the manufacturing
process.  Controls include the use of a certificate of analysis from a
qualified supplier for specifications other than the identity of a
dietary ingredient, and the establishment and monitoring of in-process
manufacturing controls.  We agree with the comments that if we reduce
the requirements for testing at the finished batch stage, then First, as
we discussed in the preamble to the 2003 CGMP Proposal (68 FR 12157 at
12198), it is critical that you determine whether components meet
specifications.  We address this issue in the following two ways: (1)
Each manufacturer must confirm the identity of each component prior to
use (you must test or examine dietary ingredients to verify the
identity, but may rely on a certificate of analysis to confirm the
identify of components other than dietary ingredients); and (2) each
company must confirm other required specifications for components prior
to use, either by relying upon a certificate of analysis or by testing
or examining the component.

As the comments have suggested, specifications for the “identity” of
components of dietary supplements are critically important.  These
comments included references to industry proposals that supported
identity testing.  The 1997 ANPRM (62 FR 5700) included an industry
proposed outline of CGMP provisions which contained a provision that
required identity testing as follows:

(iv) Each lot of raw material shall undergo at least one test by the
manufacturer to verify its identity. Such tests may include any
appropriate test with sufficient specificity to determine identity,
including chemical and laboratory tests, gross organoleptic analysis,
microscopic identification, or analysis of constituent markers.

60 FR 5700 at 5705.

	In January 2004, a group of trade associations representing dietary
supplement manufacturers and others submitted text of proposed CGMP
requirements to the docket as an alternative to the 2003 CGMP Proposal.
This submission also included a provision which required identity
testing as follows:

(1) For components, dietary ingredients, or dietary supplements that you
receive, you must:

(i) conduct at least one test or examination to verify that the
specifications for identity are met;. . .

96N-0417-EMC000261-02 at 20.

	Both the 1997 ANPRM industry outline and the January 2004 industry
docket submission included provisions that allowed certificates of
analysis to establish specifications other than for identity for
ingredients and components.

In the preamble to the 2003 CGMP Proposal (68 FR 12157 at 12162), for
example, we discussed a case in which Digitalis lanata was labeled as
plantain and, as a result, a young woman experienced a life-threatening
abnormal heart function after consuming a dietary supplement containing
Digitalis lanata in lieu of plantain.  The problem occurred
notwithstanding the fact that certificates of analysis furnished by the
supplier provided assurances that the component was indeed plantain.

Because of the critical importance of ensuring the proper identity of
dietary ingredients -- they are the central defining ingredients of a
dietary supplement -- we are requiring each firm that uses a dietary
ingredient to perform its own testing or examination for identity of
each dietary ingredient prior to use. This requirement is similar to the
proposed requirement set forth by industry in both the 1997 ANPRM and in
the January 2004 industry comment to the proposed rule.  Firms may not
rely upon a certificate of analysis provided by suppliers to determine
the identity of a dietary ingredient before use.  We recognize, however,
that it may be possible for a manufacturer to demonstrate, through
various methods and processes in use over time for its particular
operation, that a system of less than 100 percent identity testing would
provide no material diminution of assurance of the identity of the
dietary ingredient as compared to the assurance provided by 100 percent
identity testing.  To provide an opportunity for a manufacturer to make
such a showing and reduce the frequency of identity testing of
components that are dietary ingredients from 100 percent to some lower
frequency, we decided to provide, in an Interim Final Rule published
elsewhere in this FEDERAL REGISTER, a procedure that allows for
submission to, and review by, FDA of an alternative to the required 100
percent identity testing of components that are dietary ingredients,
provided certain conditions are met.

	In the preamble to the 2003 CGMP Proposal (68 FR 12157 at 12198), we
explained that we would not permit firms to rely upon supplier
certifications.  The decision was based, in large part, on problems that
have occurred with faulty certificates in the past.  We have, however,
reconsidered our position on certificates for specifications, other than
for the identity of the dietary ingredients, based on comments
discussing how firms have taken steps to ensure that their certificates
are reliable. We believe that the minimum criteria that we are
establishing for a certificate of analysis, together with the
requirement that a firm relying on a certificate of analysis must
qualify a supplier and periodically repeat that qualification process,
can prevent the problems that have occurred with faulty certificates in
the past.  Therefore, for component specifications, other than the
identity of a dietary ingredient, including confirming the identity of
components that are not dietary ingredients, we are permitting firms to
rely upon certificates of analysis provided by suppliers, if the
certificates meet the requirements of the final rule.  Under final §
111.75(a), a firm may rely upon a certificate of analysis from its
supplier of a component, provided that certain criteria are met which
include the following: (1) The firm first qualifies the supplier by
establishing the reliability of the supplier’s certificate of analysis
through confirmation of the results of the supplier’s tests or
examinations; (2) the certificate of analysis includes a description of
the test or examination method(s) used, limits of the test or
examinations, and actual results of the tests or examinations; (3) the
firm maintains documentation of how it qualified the supplier; (4) the
firm periodically reconfirms the supplier’s certificate of analysis;
and (5) the firm’s quality control personnelunit reviews and approves
the documentation setting forth the basis for qualification (and
requalification) of any supplier.

	As we discussed in the preamble to the 2003 CGMP Proposal, in-process
controls are necessary to ensure that dietary supplements are
manufactured in accordance with their specifications (68 FR 12157 at
12197).  Under final § 111.75(b), firms must monitor the in-process
points, steps, or stages where control is necessary to ensure the
quality of the finished batch of the dietary supplement to: (1)
Determine whether the in-process specifications are met; and (2) detect
any deviation or unanticipated occurrence that may result in a failure
to meet specifications.  In addition, we have strengthened the
requirements for in-process controls by requiring that the quality
control personnelunit conduct all required material reviews and make all
required disposition decisions using written procedures to ensure that
deviations or unanticipated occurrences that occur are consistently
handled.

	Because of the strengthened requirements regarding component and
in-process specifications, the final rule permits testing of a subset of
finished batches rather than requiring testing of each finished batch.
Consistent with several suggestions in the comments, we built more
flexibility into the testing requirements so that a firm may test a
subset of finished dietary supplement batches that the firm identifies
through a sound statistical sampling plan for selected specifications
rather than test every batch of the finished dietary supplement for
every specification. Finally, the quality control personnel unit must
review and approve any exceptions from testing requirements that are
allowed under the rule and the basis for such exceptions.  This approach
is consistent with the comments that we received and will achieve a high
degree of integrity in the manufacturing process, while at the same time
provide flexibility to the industry.

	Additional discussion on the requirements for identity testing of
dietary ingredients and the appropriate reliance on a certificate of
analysis for components other than dietary ingredients is found in this
section in response to comment 174.

C.  Final Subpart E and Highlights of

Changes to the Proposed Regulations

1.  Revisions

	The provisions in final subpart E reflect that the final rule applies
only to persons who manufacture, package, label, or hold a dietary
supplement unless subject to an exclusion in final § 111.1.  The
approach that we are incorporating into the final rule requires changes
in most of the individual paragraphs of proposed § 111.35.

D.  What Are The Requirements to Implement

 a Production and Process Control System?

(Final § 111.55)

     Final § 111.55 requires you to implement a system of production
and process controls that covers all stages of manufacturing, packaging,
labeling, and holding of the dietary supplement to ensure the quality of
the dietary supplement and that the dietary supplement is packaged and
labeled as specified in the master manufacturing record.  Final
§ 111.55 derives from proposed § 111.35(a).

     (Comment 146) A few comments say the production and process
controls outlined in proposed § 111.35 are critical in ensuring that
dietary supplements meet specifications for identity, purity, quality,
strength and composition.  One comment recommends proposed § 111.35(a)
be revised to state “* * * that covers all stages of manufacturing,
packaging, labeling, and holding of * * * dietary supplements that occur
in your facility or for which you otherwise have responsibility.”
This comment explains that the production of dietary supplements is
often broken up into several stages which are under the control of
different entities.  The comment gives the following examples: a
marketing company may manufacture and package a product itself; or it
may contract with one company to manufacture and package the product; or
it may contract with one company to manufacture the product and another
company to package the product; and contract manufacturers and packagers
may subcontract portions of the manufacturing or packaging.

     (Response)  We decline to revise the rule as suggested by the
comments.  As we discussed in response to comment 37 in section VI, you
must comply with the CGMP requirements that apply to your operations
related to the manufacturing, packaging, labeling, and holding of
dietary supplements.  We decline to include codified language that may
not capture all of the possible relationships that exist in a given
operation.

E.  What Are the Design Requirements for The

Production and Process Control System?

(Final § 111.60)

     Final § 111.60(a) requires that your production and in-process
control system be designed to ensure that the dietary supplement is
manufactured, packaged, labeled, and held in a manner that will ensure
the quality of the dietary supplement and that the dietary supplement is
packaged and labeled as specified in the master manufacturing record.
Final § 111.60(b) requires that the production and in-process control
system include all requirements of subparts E through L of part 111 and
be reviewed and approved by the quality control personnel unit.  Final
§ 111.60(a) and (b) derive from proposed § 111.35(b).

     As discussed in section III, we are clarifying a number of
provisions that did not explicitly identify labeling as an operation
that is covered by the rule.  Final § 111.60 is one such provision.
Under proposed § 111.35(a) we would require that you implement a
system of production and process controls that covers all stages of
manufacturing, packaging, labeling, and holding of the dietary
supplements.  In an oversight, proposed § 111.35(b) would require your
production and in-process control system to be designed to ensure that
the dietary supplement is manufactured, packaged, and held -- but not
labeled -- in a manner that would prevent adulteration of the dietary
supplement. To correct this oversight, final § 111.60 explicitly
identifies labeling as an operation that the design of your production
and process control system must address.

	(Comment 147)  A few comments recommend that the phrase “designed to
ensure” in proposed § 111.35(b) be deleted because it requires that
formal, prospective studies (similar to a process validation) must be
performed and such a requirement would be unduly burdensome.

     (Response)  We disagree with the comments’ interpretation of the
proposed regulation and decline the request.  Final § 111.60(a) relates
to the overall design of your production and process control system.  It
does not require validation based on scientific studies, but rather that
your process contain all the controls necessary to ensure the quality of
your dietary supplements and that the dietary supplement is packaged and
labeled as specified in the master manufacturing record.  The process,
for example, must ensure that the dietary supplement meets all
specifications established under § 111.70(e).

F.  What Are the Requirements forto Use a

 Quality Control Operations Unit?

(Final § 111.65)

     Final § 111.65 requires that you implement use a quality control
operations unit in your manufacturing, packaging, labeling, and holding
operations for producing the dietary supplement to ensure that these
operations are performed in a manner that ensures the quality of the
dietary supplement and that the dietary supplement is packaged and
labeled as specified in the master manufacturing record.  Final
§ 111.65 derives from proposed § 111.35(c).

Proposed § 111.35(c) referred to the role of the quality control unit
in manufacturing, packaging, and label operations - but not in holding
operations.  This was an oversight.  We, therefore, revised proposed §
111.35(c) to include “holding” as an operation that is subject to
the oversight of the quality control personnel unit for consistency with
final § 111.105 (proposed § 111.37(a)), which provides for the
performance of quality control operations unit to “ensure that your
manufacturing, packaging, label, and holding operations ensure the
quality of the dietary supplement and that the dietary supplement is
packaged and labeled as specified in the master manufacturing record.”

     (Comment 148)  One comment recommends proposed § 111.35(c) be
revised to state “ensures that the *** dietary supplement meets
manufacturing specifications for identity, purity, quality, strength,
and composition.”

     (Response)  We are not making this change because it is unnecessary
in the context of the provisions of final § 111.65.

     (Comment 149)  One comment argues that proposed § 111.35(c) is
too wordy and needs clarification.  The comment recommends it be revised
to state “You must use a quality control unit to ensure that the
dietary supplement meets specifications for identity, purity, quality,
strength, and composition.”

     (Response)  We disagree with this comment.  The change requested by
the comment would emphasize a single responsibility of the quality
control personnel unit (i.e., releasing final product) and would obscure
the fact the that quality control personnel unit haves a role in the
design and conduct of most of your operations.

     (Comment 150)  One comment recommends proposed § 111.35(c) be
revised to state “ensures that the * * * dietary supplement meets
specifications for identity, purity, quality, strength, and composition
as appropriate to protect the public health; and quality, strength, and
composition as appropriate for the * * * product.”  This comment
states it is confusing and unnecessary to require that all five of these
attributes be addressed for all dietary supplements.  The comment also
states the term “purity” requires explanation because not all
ingredients or supplements are subject to the same types of
contamination.

     (Response)  We are not making any changes in the provision as
suggested by this comment.  The comment provides no basis for the
assertion that the proposed requirement to use a quality control unit to
ensure that a dietary supplement meets specifications for identity,
purity, strength, and composition is confusing and unnecessary.  In
section VI, we explain that purity means that portion or percentage of a
dietary supplement that represents the intended product.

	G.  What Specifications Must You Establish?

	(Final § 111.70)

	Final § 111.70 derives from proposed §§ 111.35(e), (f), (g) and
(k), 111.37(b)(11)(iv), and 111.70(c).

	(Comment 151)  Some comments state proposed § 111.35(k), which would
require that you test or examine components and dietary supplements for
those types of contamination that may adulterate or lead to
adulteration, is more appropriate for, and should be incorporated into,
proposed § 111.35(e) which would require, in part, that you establish
specifications for the identity, purity, quality, strength, and
composition of components that you receive and of dietary supplements
that you manufacture.  The comments note this suggestion would help
simplify and eliminate some redundancy in proposed § 111.35.  One
comment would revise proposed § 111.35(k) to state “Purity
specifications for purchased or manufactured components and dietary
supplements must be established for those types of contamination which
can reasonably be expected to affect the component, ingredient, or
supplement in question***.”  According to the comment not all
ingredients or supplements are subject to the same types of
contamination, and it would be unduly burdensome to require that all
ingredients and supplements be tested for all possible contaminants (as
opposed to all likely contaminants).

     (Response)  We agree that not all ingredients or dietary
supplements are subject to the same types of contamination.  It would
not be practicable or necessary to require testing for all possible
contaminants for every dietary supplement, or for every component used
to manufacture a dietary supplement.  As we explained in the 2003 CGMP
Proposal (68 FR 12157 at 12199-200), the manufacturer has the
responsibility to determine what types of contamination are likely or
certain to contaminate a given product and to determine what types of
tests to conduct and when to test for such contamination.  We explained
that botanicals are likely or certain to contain filth and
microorganisms of public health significance based on the areas in which
they are harvested (id.)  As another example, fungal growth on a
botanical component can provide the environment for mycotoxin
production, especially aflatoxin (id).  If fungal growth is present, the
manufacturer would need to perform an appropriate test that can detect
the toxic substance.  We stated that the manufacturer must be aware of
potential contamination, regardless of whether due to filth, insects,
microorganisms, or toxins and to test or examine, as appropriate, the
components and dietary supplements for those types of contamination that
may adulterate or that may lead to adulteration (id.)  Thus, the types
of contamination that we were referring to in proposed § 111.35(k) are
those that are likely or certain to be present in or on components
received, based on the nature of the product, its source, handling prior
to receipt by the facility, or other reason, and not due to poor
manufacturing practices that resulted in their presence in the first
instance.

	It is the responsibility of the manufacturer to identify those
contaminants and to establish limits to prevent adulteration under
sections 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act.  For
example, if you manufacture a polysaccharide that derives from seaweed,
it is likely that you would include a limit on cadmium, because cadmium
is a common contaminant that can be present in marine-derived
ingredients.  If you manufacture a polysaccharide that has a composition
similar to seaweed-derived polysaccharide, but derives from a land-based
plant, it is not likely that you would include a limit on cadmium,
because cadmium is not a common contaminant of land-based plants.
Likewise, if you manufacture a mineral that contains phosphates, it is
likely that you would include a limit on arsenic, because phosphates are
generally mined and arsenic is a common contaminant that can be present
in ingredients that are mined.  If you manufacture a mineral that does
not include ingredients that are mined, it is not likely that you would
include a limit on arsenic.

	We agree that controlling contamination is critical to the quality of
the dietary supplement.  However, we do not agree that the types of
contamination addressed by proposed § 111.35(k) should be considered
as a purity specification.  We have described purity in this final rule
to mean something that you intend to be present in the final product.
As explained in section VI, purity means that portion or percentage of a
dietary supplement that represents the intended product.  For example,
you may manufacture a dietary supplement that uses a natural  product
such as fish oil to provide triglycerides that are a source of the
polyunsaturated fatty acids DHA and EPA.  The purity refers to the
percent of the fish oil that is triglycerides.  (Note that if you are
manufacturing fish oil to provide the fatty acids DHA and EPA in the
dietary supplement, the component specifications for the fish oil must
include a strength specification for DHA and EPA in whatever amount you
determine is necessary to meet the specification for strength of DHA and
EPA in the dietary supplement.)  If the natural product also contains
lead, or other unwanted ingredients that may adulterate or may lead to
adulteration, you would have to establish limits for such contaminants.
Thus, to distinguish the proposed requirement in § 111.35(k), which
relates to contaminants that may be present on or in the components that
you receive, from the requirements related to specifications for desired
characteristics of identity, purity, strength, and composition, we are
including a separate requirement on establishing limits on such
contaminants for components that you receive (final § 111.70(b)).  We
also include a requirement for establishing an in-process specification
for any point, step, or stage in the master manufacturing record where
control is necessary to help ensure that specifications are met, as
necessary, for limits on contamination.  In addition, we are including a
requirement for such limits on contaminants in the finished batch of
dietary supplement (or subset of finished batches) (final § 111.70(e))
to ensure that the manufacturing process has not adversely affected such
levels, e.g., has not contributed an additional source of such
contaminant or failed to remove the contaminant, when necessary.  Such
limits would need to ensure the quality of the dietary supplement; i.e.,
to ensure that the dietary supplement has been manufactured, packaged,
labeled, and held under conditions to prevent adulteration under
sections 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act.

	Thus, in addition to the presence of contaminants that may be in or on
components that you receive, there may be sources of contamination that
you need to control for in your facility.  As discussed in this section,
you must establish specifications under final § 111.70(a) and (c) to
prevent adulteration from such sources.  The specifications established
under final § 111.70(a) and (c) may or may not include limits on such
contaminants.  By “limits on those types of contamination” in final
§ 111.70, we do not mean contamination from, for example, the presence
of rodent pellets or other filth that would constitute an insanitary
condition under sections 402(a)(3) or (a)(4) of the act, if such filth
was present in your facility.  You are not allowed to establish
specifications for limits on contaminants that would otherwise
adulterate your product under the act if such contaminants were present.

	Further, in proposed § 111.35(k), we included a listing of the types
of contamination we considered to be applicable to dietary supplements
(68 12157 FR at 12258).  We stated that the types of contamination
include; (1) filth, insects, or other extraneous material; (2)
microorganisms; and (3) toxic substances.  We have deleted the listing
of the types of contamination in the final rule because the listing is
simply informative and establishes no independent requirement.  We
received several comments, discussed below, on the types of
contamination that may be present, some which were solicited by us in
the 2003 CGMP Proposal (68 FR 12157 at 12179-81).

	In the 2003 CGMP Proposal, we solicited comment on whether we should
include in the final rule specific requirements for manufacturing,
packaging, or holding animal-derived dietary ingredients, because
animal-derived dietary ingredients present important public health and
safety issues.

     In the 2003 CGMP Proposal, the example we used was an
animal-derived dietary ingredient potentially contaminated with the
agent that causes bovine spongiform encephalopathy (BSE), which is a
type of transmissible spongiform encephalopathy (TSE). TSEs are fatal,
neurodegenerative disorders, which have been identified in humans and a
number of animal species (e.g., cattle, sheep, goats, elk, deer, cats,
and mink), but primarily in ruminants (cattle, sheep, elk, deer) (69 FR
42255 at 42256 (July 14, 2004)).  Most scientists believe that variant
Creutzfeldt-Jakob Disease (vCJD), a progressive neurological disease in
humans, is caused by consumption of cattle products contaminated with
the agent that causes BSE (69 FR 42255 at 42257).

	In the 2003 CGMP Proposal (62 FR 12157 at 12180), we stated that we had
communicated with the public and manufacturers of FDA-regulated products
about appropriate steps to increase product safety and minimize the risk
of products contaminated with the BSE agent.  We referenced a notice in
the FEDERAL REGISTER of August 29, 1994 (59 FR 44591), entitled
“Bovine-Derived Materials; Agency Letters to Manufacturers of
FDA-Regulated Products.”  We sent letters to dietary supplements
manufacturers to alert them to the developing concern about TSEs in
animals and Creutzfeldt-Jakob Disease in humans.  We recommended they
investigate the source of any bovine and ovine material used in their
products.  We suggested that manufacturers develop plans to ensure, with
a high degree of certainty, that bovine and ovine materials used in
their products were not from BSE countries or from sheep flocks (foreign
or domestic) infected with scrapie.  We stated that our Center for
Biologics Evaluation and Research (CBER) had developed guidances for
industry that describe steps manufacturers should take to ensure the
safety and suitability for human use of animal-derived biologics.  We
also stated that we were considering whether the procedures that CBER
recommends for a product with animal-derived materials, substances, or
tissues would be appropriate for dietary ingredients and dietary
supplements that contain animal-derived materials, substances, or
tissues.  We believed that the use of an animal-derived material,
substance, or tissue in a dietary supplement may raise many of the same
serious public health and safety issues as animal-derived materials,
substances, or tissues, in a biologic.  We invited comment on whether
there is a scientific basis for us to treat animal-derived dietary
ingredients in a manner different from, or that would offer less
protection than, what is recommended for animal-derived biologics when
the same public health and safety risks may be present.

     (Comment 152)  Several comments state there should not be specific
requirements for manufacturing, packaging, or holding animal-derived
dietary ingredients because BSE issues are not specific to dietary
supplements, and because other guidance and regulations, issued by FDA
and by the U.S. Department of Agriculture (USDA), already address BSE
and public health.  Other comments state it would be appropriate to
include specific CGMP requirements for BSE as long as the requirements
reflect the thinking in currently existing regulations and guidance.

     Several comments do not support the need for additional provisions
regarding the handling of imported animal-derived ingredients because
the industry has already taken steps to comply with the requirements or
recommendations issued by either USDA or FDA.  The comments state that
the regulations issued by USDA for meat related products in the food
industry provide adequate control over the use of animal tissues that
might contain microorganisms, specifically viruses, of public health
concern.

     One comment argues that if purchases of domestic raw tissues have
been inspected by USDA, it is unfair to impose additional regulations
simply because these tissues are included in dietary supplements.  This
comment asserts it would be unfair to require testing of animal-derived
products given the fact that there are no tests for BSE available; and
that reliance on USDA and FDA is the best way to stop the spread of BSE.

     Another comment states that industry trade associations have been
working actively with their member companies to ensure adherence to the
requirements set forth in our 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.  The comment states that a
summary of industry procurement and handling practices regarding
animal-derived ingredients (submitted to us) contains lists of
animal-derived ingredients used by various companies, with examples of
the certificates of origin and other documentation required for import
of any animal-derived materials.  One comment states that industry
members who handle animal-derived ingredients already have implemented
many of the controls that originated either from USDA or the dietary
ingredient suppliers in response to demands by various governments or
consumers, and that such matters should remain with USDA to avoid
duplication of effort.

	Some comments oppose any recommendation that guidance issued by CBER
for ensuring the safety and suitability for human use of animal-derived
biologics apply to dietary supplement products.  One comment includes a
review of literature on BSE and claims the review justifies not applying
the CBER guidances on BSE to dietary supplement products under part 111.

     (Response)  For cattle derived materials, you must comply with the
requirements of the interim final rule on Bovine Spongiform
Encephalopathy (BSE) set forth in § 189.5 (See 70 FR 53063 (September
7, 2005)) and any subsequent modifications.  Under the interim final
rule, no human food, including dietary supplements, shall be
manufactured from, processed with, or otherwise contain, prohibited
cattle materials as defined in the rule.  In addition, manufacturers and
processors of such food that is manufactured from, processed with, or
otherwise contains, cattle material must make existing records relevant
to compliance available to us for inspection and copying.  For both
cattle-derived and other animal-derived materials, you must comply with
all applicable provisions of this final rule.  For example, under final
§ 111.70, you must establish specifications for any point, step, or
stage in the manufacturing process where control is necessary to ensure
the quality of the dietary supplement.  Thus, you must establish
specifications for your animal-derived materials that are necessary to
ensure the quality of the dietary supplement.  Ensuring quality includes
preventing contamination that may adulterate the product under
402(a)(1), (a)(2), (a)(3), or (a)(4) of the act.  In addition, you must
take actions to determine whether the specifications are met (final §
111.73).   Therefore, if you used animal-derived materials other than
prohibited cattle materials subject to the BSE interim final rule, you
would need to establish specifications necessary to ensure the quality
of the dietary supplement.

	The guidances issued by CBER are still in effect for animal-derived
biologics, and we continue to recommend that you use them as appropriate
for your products that contain animal-derived ingredients.

     (Comment 153)  One comment agrees with the provisions of proposed
§ 111.35(k) but requests that we provide guidance to the industry on
allowable limits for the types of contamination listed.  Another comment
asks us to develop specific DALs for dietary supplements as more
information becomes available, rather than rely on existing DALs from
the food industry.

     (Response)  In the 2003 CGMP Proposal (68 FR 12157 FR at 12163), we
stated that we were not identifying DALs for the types of contaminants
for dietary ingredients because there are not enough data available to
identify an appropriate DAL for most dietary ingredients.  These
comments do not provide data, or evidence that data are available, to
enable us to issue guidance for DALs for specific contamination.
Therefore, we are not taking the action requested by these comments.  We
discuss DALs in this section in response to comment 1574.

     (Comment 154)  Some comments suggest the provisions in proposed §
111.35(k), testing for contamination that could adulterate a product,
would be more appropriate to include in proposed § 111.35(e), which
concerns the establishment of specifications.

     (Response)  We agree with these comments and are including
requirements to include limits on contamination in final § 111.70.  The
requirements set forth in final §§ 111.70 and 111.75 are consistent
with this comment.  Under final § 111.70(b) you must establish limits
on those types of contamination that may adulterate or may lead to
adulteration of the finished batch of the dietary supplement to ensure
the quality of the dietary supplement.  Under final § 111.70(c) you
must establish in-process specifications for any point, step, or stage
in the master manufacturing record where control is necessary to help
ensure that specifications are met for the identity, purity, strength,
and composition of the dietary supplements, and as necessary, limits on
contamination for those types of contamination that may adulterate or
may lead to adulteration of the finished batch of the dietary
supplement.  Under final § 111.70(e), you must establish product
specifications for the identity, purity, strength and composition of the
finished batch of the dietary supplement, and for limits on those types
of contamination that may adulterate, or that may lead to adulteration
of, the finished batch of the dietary supplement to ensure the quality
of the dietary supplement.  As we explained in the response to comment
151, by “limits on those types of contamination” in final § 111.70,
we do not mean contamination from, for example, the presence of rodent
pellets or other filth that would constitute an insanitary condition
under sections 402(a)(3) or (a)(4) of the act, if such filth was present
in your facility.  You are not allowed to establish specifications for
limits on contaminants that would otherwise adulterate your product
under the act if such contaminants were present.

     (Comment 155)  Several comments object to proposed § 111.35(k)
because the provision would be more stringent than the food or drug CGMP
requirements.  Some point out that the consumption levels for food are
higher than for dietary supplements.  A few comments argue that proposed
§ 111.35(k) is too broad as it requires testing or examination for
those contaminants that “may” adulterate or “may lead to”
adulteration, which could be interpreted to mean testing for unknown
contaminants of every description.  The comments suggest that this
provision be revised to require testing or examination for those types
of contamination that “may be present in an amount or at a level”
that may adulterate or lead to adulteration or that “may reasonably be
expected” to adulterate or lead to adulteration.  Other comments agree
that to test for all possible contaminants would be burdensome.

     Several comments state that manufacturers should be allowed to rely
on a supplier’s certificate of analysis and that testing should not be
required for every potential contaminant.  One comment recommends that
CGMPs should be specific to the source and that testing should depend on
the nature of the material.

     Some comments note that for botanicals it is sometimes nearly
impossible to identify and analyze all naturally occurring substances.

     (Response)  The final rule does not include any specific
requirements to test or examine components or dietary supplements for
contamination.  Rather, under final § 111.70(b) (c), and (e), you are
required to establish specifications for limits on those types of
contamination that may adulterate or may lead to adulteration of the
finished batch of the dietary supplement.  Under final § 111.73, you
must determine whether the specifications established under § 111.70
are met.  Final § 111.75(a) through (d) sets forth the criteria you
must use to determine whether the specifications that you establish
under final § 111.70(b), (c), and (e) are met.  Consistent with these
comments, under final § 111.75(a) you may rely on a certificate of
analysis (other than for the identity of a dietary ingredient) from a
qualified supplier of components to ensure that specifications that
include limits on contamination are met, provided you satisfy the
criteria set forth in final § 111.75(a). This would include, for
example, relying on a certificate of analysis to ensure that the level
of lead in each of your components would not adulterate the dietary
supplement.

	In determining compliance with the requirements to set limits for those
types of contamination that may adulterate the dietary supplement or
lead to adulteration for received components, we would not expect you to
set limits for every potential contaminant or for every naturally
occurring constituent of a botanical.  Rather, we agree with the
comments that the substances you would consider when determining whether
to set limits for particular types of contamination would vary depending
on the source of a component, such as a plant source, an animal source,
a microbial source, or a marine source.

(Comment 156)  Some comments point out that some compounds, such as
mycotoxins, that are toxic at higher levels are detectable in nearly all
plant ingredients and are found in the food supply.  A few comments
assert that dietary ingredients should not contain levels of certain
toxic compounds that are higher than reasonable or higher than
recognized maximum allowable limits as opposed to the zero tolerance for
toxic compounds contained in the 2003 CGMP Proposal.

One comment requests clarification of the term “toxic substances.”
One comment points out that information for identifying potential
adulterants is provided in monographs.  Another comment requests
clarification on whether dietary supplement manufacturers will be
required to test for toxins while food manufacturers, who may use some
of the same ingredients, will not.

(Response)  As the comments point out, the food supply does contain some
degree of contaminants such as mycotoxins that can be found, for
example, in certain grain.  We do not have a “zero tolerance” policy
for such unavoidable contaminants but we have issued some regulations
and guidance to address certain common contaminants.  We also have
issued a booklet entitled “Action Levels For Poisonous Or Deleterious
Substances In Human Food And Animal Feed” (Ref. 3027; available at
http://www.cfsan.fda.gov). The booklet is a useful resources for
manufacturers who seek information about common contaminants that may
adulterate a dietary supplement product or lead to adulteration. Another
resource is the Foods Chemical Codex, which includes monographs on many
substances, such as salts that are used as sources of minerals used in
both dietary supplements and conventional food. These monographs include
limits on common contaminants, such as lead or other heavy metals.  In
addition, the regulations in part 109 provide information about certain
contaminants.

     (Comment 157)  One comment recommends that all finished products be
tested for microorganisms.  Another comment contends the manufacturer
should be allowed to restrict testing to the raw material if the
facility and equipment are monitored for contamination.  Some comments
point out that contaminants may be detectable in raw materials but not
in the finished product.

     (Response)  We disagree that all finished products must, as a
matter of course, be tested for contamination with microorganisms.
Whether it is necessary to test the finished product for microorganisms
would depend, for example, on the characteristics of your product, the
nature and source of your components, the specifications you establish
for microbial contaminants in your components and whether these
specifications are addressed in a certificate of analysis, the
in-process specifications you establish, and the nature of your
manufacturing process.  However, these comments raise an important point
-- i.e., that microbial contamination could occur at your facility even
if an incoming component is free of microorganisms.  Final subpart K,
section XVI,  sets forth requirements for your manufacturing operations.
 Many of these requirements are designed to limit the potential for
contamination with microorganisms.

     (Comment 158)  Some comments would revise the requirements for
establishment of specifications for in-process controls (proposed §
111.35(e)(2)) and the finished batch of dietary supplements (proposed
§ 111.35(e)(3), so that specifications for attributes of quality,
strength, and composition are not required for a product that does not
purport to possess such attributes.

     (Response)  We decline to reword the provision as requested by
these comments.  The requirement to establish specifications for
strength and composition relate to the manufacturers’ responsibility
to know what their finished dietary supplement is composed of so that
their products are consistently manufactured. Establishing
specifications and following these CGMP requirements will help ensure
the quality of the dietary supplement.  The requirement to establish
specifications is not limited to when a manufacturer purports that its
product possesses attributes of strength and composition on the label.
As discussed in the 2003 CGMP Proposal (68 FR 12157 at 12162), the
absence of minimum standards has contributed to the adulteration and
misbranding of dietary supplements because of contaminants or because
manufacturers do not set and meet specifications for their products,
including specifications for identity, purity, strength, and composition
and do not set and meet limits on contaminants, when necessary.  The
comment does not persuade us otherwise.  We note, however, that the
final rule’s requirements to establish specifications for components
do, in fact, provide flexibility so that you are not required to
establish a component specification for certain attributes, such as the
strength of a tablet coating agent (see the discussion of final §
111.70(b) in this section).

(Comment 159)  One comment asks for guidance as to what constitutes an
official or scientifically valid standard for specifications.

(Response)  We are not aware of any officially recognized standard for
specifications.  Specifications are critical standards that are proposed
and justified by the manufacturer for each product that the manufacturer
produces.  The manufacturer establishes the set of criteria to which a
product should conform to be considered acceptable for its intended use.
 In general, a specification may include a list of tests, references to
analytical procedures, and appropriate acceptance criteria that are
numerical limits, ranges, or other criteria for the tests described.

(Comment 160)  One comment asks that we clarify whether every
specification sheet must include separate, specific qualitative or
quantitative standards, and tests to be established for each attribute,
or whether a specification sheet can be modeled after a compendial
monograph.  Some comments state that product specification sheets should
be modeled after pharmacopoeia monographs other than those listed in the
preamble to the 2003 CGMP Proposal.

(Response)  These CGMP requirements do not establish any requirements to
have a “specification sheet.”  Rather, the final rule (final
§ 111.70(a)) requires you to establish a specification for any point,
step, or stage in the manufacturing process where control is necessary
to ensure the quality of the dietary supplement and that the dietary
supplement is packaged and labeled as specified in the master
manufacturing record.  We require that you establish specifications for
components (final § 111.70(b)), in-process production (final
§ 111.70(c)), labels and packaging (final § 111.70(d)), the finished
batch of dietary supplement (final § 111.70(e)), product that you
receive from a supplier for packaging and labeling (final
§ 111.70(f)), and the packaging and labeling for the finished packaged
and labeled dietary supplement (final § 111.70(g)).  The general
requirement for establishing specifications in final § 111.70(a)
includes specifications, not otherwise required in final § 111.70(b)
through (g), that the manufacturer determines are necessary to achieve
quality, i.e., that are necessary to meet the identity, purity,
strength, or composition of the dietary supplement or that are necessary
to prevent adulteration under section 402(a)(1), (a)(2), (a)(3), and
(a)(4) of the act.

Requirements to establish specifications to control for contamination
are included in final § 111.70(a), (b), (c) and (e).  As discussed
earlier, the specifications for contaminants in final § 111.70(b)
refer to those types of contamination of a component or dietary
supplement that may adulterate or that may lead to adulteration that are
due to contaminants that may be present in or on the components that you
receive, based on the nature of the product, its source, its handling
prior to receipt, or other reason.  Limits are established by the
manufacturer for such contaminants at receipt.

The requirement to establish specifications to control for contamination
under final § 111.70(a) and (c) include specifications necessary to
prevent adulteration under 402 (a)(1), (a)(2), (a)(3), and (a)(4) of the
act as a result of what the manufacturer may do or fail to do in its
manufacturing operation, and not as a result of contaminants that are in
or on the components received.  For example, it may be critical that a
certain piece of equipment be cleaned and/or sanitized after handling
certain raw materials to ensure that there is no microbial contamination
from microorganisms of public health significance to components
processed on the equipment.  If the manufacturer failed to establish a
specification for cleaning and/or sanitizing after handling those raw
materials before processing components, the manufacturer would have
failed to establish a specification required by final § 111.70(a) or
(c) necessary to prevent a type of contamination that may lead to
adulteration under § 402(a)(4) of the act.  We would consider it a
failure to follow CGMP requirements if a manufacturer allowed conditions
in the manufacture of a dietary supplement that would not ensure the
quality of the dietary supplement.

We have specified in final § 111.70(b) that you must establish certain
types of specifications that are critical to ensuring that you know what
the components are that you use in manufacturing a dietary supplement
and that are necessary to ensure that the dietary supplements you
manufacture meet their specifications for identity, purity, strength,
composition, and do not exceed their limits for contaminants.  The
identity, purity, strength, and composition, and the limits that you
establish for contaminants, for a finished batch of dietary supplement
are what we call “product specifications” in final § 111.70(e).
These product specifications must be met in order for you to ensure the
quality of your finished batch of dietary supplement.  A specification
may include a list of tests, references to analytical procedures, and
appropriate acceptance criteria that are numerical limits, ranges, or
other criteria for the tests described.  For example, a specification
for a component may include information about the test used to verify
the identity of the component and the range of test results that are
acceptable.  Under final § 111.70(c) a specification for an in-process
control may include information about the viscosity that must be
achieved during a batch production of a liquid product and information
about the test or equipment used to measure the viscosity.  Under final
§ 111.70(d) a specification for packaging may include the specific
type or grade of plastic. Under final § 111.70(e) a specification for
the finished batch may include the quantitative amount of a dietary
ingredient, such as vitamin C.

Under this final rule, the manufacturer has the flexibility -- and the
responsibility -- to develop specifications that are appropriate to the
circumstances, including whether information in any particular monograph
is an appropriate model for a given dietary supplement.

1.  Final § 111.70(a)

     Final § 111.70(a) requires you to establish a specification for
any point, step, or stage in the manufacturing process where control is
necessary to ensure the quality of the dietary supplement and that the
dietary supplement is packaged and labeled as specified in the master
manufacturing record.  Final § 111.70(a) derives from the opening
statement in proposed § 111.35(e).

     As we discussed in the preamble to the 2003 CGMP Proposal(68 FR
12157 at 12196), the points, steps, or stages where specifications must
be established may include heating steps, cooling steps, points where
specific sanitation procedures are needed, product formulation control
steps, points where cross contamination may occur, and steps where
employee and environmental hygiene are necessary to ensure the quality
of the dietary supplement.  These specifications are regulatory
specifications addressed by these CGMP regulations.  The final rule does
not prevent you from establishing additional, nonregulatory
specifications that are not at points, steps, or stages where control is
necessary to ensure the quality of the dietary supplement.  For example,
you could establish specifications that largely address the appearance
of the dietary supplement in an aesthetic sense.  Such nonregulatory
specifications are not addressed by the final rule.

     (Comment 161)  One comment notes that labelers would not be subject
to proposed § 111.35(e).

     (Response)  Consistent with final § 111.1, persons who perform
labeling operations are, in fact, subject to the final rule, including
the requirements to establish specifications.  As discussed in this
section, the final rule includes an explicit requirement that, if you
receive a product from a supplier for packaging or labeling as a dietary
supplement (and for distribution rather than for return to the
supplier), you must establish specifications to ensure that the product
that you receive is adequately identified and is consistent with your
purchase order (final § 111.70(f)).

     (Comment 162)  One comment asks whether the manufacturer determines
where control is “necessary” to prevent adulteration.

     (Response)  In accordance with the changes made to the section, the
manufacturer does determine where control is necessary to ensure the
quality of the dietary supplement.

     (Comment 163)  Some comments express concern that manufacturers who
must confirm the validity of subjective criteria established as
specifications may set the specifications as low as possible or set
meaningless specifications.

     (Response)  The specifications you must establish under this final
rule are designed to ensure the quality of the dietary supplement that
you manufacture.  It is not meaningless to establish requirements that
will ensure, for example, the product meets the established
specifications for identity, purity, strength, and composition, and is
within specified limits on contaminants to prevent adulteration.

     (Comment 164)  Some comments express concern that the language of
proposed § 111.35(e) may require specifications beyond those already
required in the master manufacturing record, as stated in proposed
§ 111.45(a)(1), to identify specifications for the points, steps, or
stages, in the manufacturing process where control is necessary to
prevent adulteration, or may require specifications for attributes that
are not present at all stages.  These comments urge us to be flexible
during inspections as to what specifications are appropriate.

     (Response)  Final § 111.70(a) provides the manufacturer with
flexibility in determining what specifications may be necessary for its
operation.  Moreover, final § 111.70(a) through (g) provide the
manufacturer with flexibility to determine what the specifications
require in order to ensure the quality of the dietary supplement.

2.  Final § 111.70(b)

     Final § 111.70(b) requires you to establish component
specifications for each component you use in the manufacture of a
dietary supplement. Under final § 111.70(b)(1), you must establish an
identity specification for each component that you use in the
manufacture of a dietary supplement.   A specification for identity may
include more than one attribute.  For example, a specification for the
identity of a salt used in the manufacture of a vitamin and mineral
supplement may include the physical characteristics of the solid (e.g.,
as a crystal or as a powder), the color, and the state of hydration
(e.g., with two or three molecules of water).  A specification for the
identity of a botanical may include the part of the plant (e.g., roots
or leaves), the color, and whether the part of the plant is in a native
state or has been ground.  Under final § 111.70(b)(2), you must
establish component specifications that are necessary to ensure that
specifications for the purity, strength, and composition of dietary
supplements manufactured using the components are met.  Under final §
111.70(b)(3) you must establish limits on those types of contamination
that may adulterate or may lead to adulteration of the finished batch of
the dietary supplement to ensure the quality of the dietary supplement.
Final § 111.70(b) derives from proposed §§ 111.35(e)(1) and (k).
Final § 111.70(b) is consistent with comments, already discussed, that
recommended the provisions of proposed § 111.35(k) regarding
contaminants that could adulterate a product be incorporated into
proposed § 111.35(e).  In addition, as discussed above with respect to
final § 111.55, final § 111.70(b) provides that the required component
specifications you must establish for a dietary supplement include
identity, purity, strength, and composition.

     (Comment 165)  A few comments state it is appropriate and
acceptable to establish a requirement for a specification for the
identity and purity of components, insofar as such specifications are
necessary to ensure that components are not contaminated with substances
having public health significance.  However, these comments argue that
specifications for quality, strength, and composition of components
should only be required for the quality, strength, and composition that
a component is purported to possess.  One comment notes this would
provide the same requirement that is currently established for drug
products and processing.  Some comments recommend that specifications
should be established “as appropriate” or “where control is
necessary to assure production of a quality product.”

	(Response)  After considering the comments that questioned the need to
establish specifications for the identity, purity, quality, strength,
and composition of components, as well as the general comments that led
to the overall approach that focuses on building quality into a dietary
supplement at every stage of the production and process control system
(see discussion in section IV), we are requiring in final §
111.70(b)(1) that you establish an identity specification for components
that you use.  This identity specification is necessary to ensure that
the finished dietary supplement meets its specification for identity,
because you could not know what your final product contains if you do
not know what you put into it.  In addition, final § 111.70(b)(2)
requires you to establish those component specifications for purity,
strength, and composition that are necessary to ensure that
specifications for the purity, strength, and composition of dietary
supplements manufactured using the components are met.

	Final § 111.70(b)(2) provides flexibility for you to determine which
component specifications other than identity are, or are not, necessary
to ensure that the final dietary supplement meets its specifications.
For example, it is likely that you will need to establish a
specification for the strength of vitamin C added as a component, that
you use to make a multivitamin supplement, so that you will know how
much vitamin C to add to satisfy the specification for the strength of
the vitamin C in the final product.  Thus, if you are manufacturing a
vitamin C tablet with a strength of 50 milligrams (mg) per tablet, you
must determine how much vitamin C, of a given strength, you must add in
order to produce tablets that will contain 50 mg, after accounting for
the theoretical yield at each step in the manufacturing process.
However, you may not need to establish a specification for the strength
of the tablet coating agent for that multivitamin supplement, if your
final specifications include the amount of the tablet coating agent as
part of the specifications for the composition, but not the strength of
the multivitamin supplement.  In most cases, a specification for the
composition of the dietary supplement would be sufficient to ensure that
the tablet coating agent is used within the established level.

     (Comment 166)  A few comments express concern about how to
determine certain specifications for botanicals, such as the strength of
peppermint leaf.  The comments explain that a specification for strength
of peppermint leaf could be based on a number of different attributes.
One comment argues that establishing specifications for all dietary
ingredients may not contribute to any assurance of product quality and
will not protect public health.  Some comments assert that “quality,
strength, and composition” are subjective with respect to botanical
ingredients for which no potency claim is made, and, thus, these
attributes should not be included in the rule.  Another comment asserts
proposed § 111.35(e)(1) goes beyond either food or drug CGMPs and that
the composition of approximately 1,200 botanicals used in the industry
will be impossible to determine in an economically feasible manner.

     (Response)  To the extent that these comments assert that this
final rule should not require you to establish specifications for the
strength and composition of botanical ingredients, we disagree.  As
explained in response to comment 145, it is fundamental to CGMPs that
you know what components are used to manufacture your dietary supplement
and to ensure that the finished batch of dietary supplement contains the
established identity, purity, strength, and composition.  As explained
in response to comment 40, this final rule does not require that you
establish specifications for the identity, purity, strength, or
composition of the various constituents that are inherently present in a
natural product such as a botanical.  However, as previously discussed
in section VI, depending on what you are manufacturing, the product
specifications for the finished batch of a dietary supplement may
include a specification, for example, of the strength of a substance
that is present in the dietary supplement because it is a constituent of
a natural product that you add as a component.  For example, you may
establish a specification for the amount of vitamin C in a dietary
supplement that you manufacture by adding the component rose hips.  If
this is the case, then the component specifications for the natural
product must include a specification for the strength of the constituent
(e.g., vitamin C) in whatever amount you determine is necessary to meet
the specification for the constituent (vitamin C) in the finished batch
of dietary supplement.

	(Comment 167)  One comment asserts it would be more appropriate for
proposed § 111.35(e)(1) to address components “that you purchase”
than to address components “that you receive,” because customers
sometimes provide the ingredient or product to be processed and the
customer, rather than the manufacturer, establishes the specifications.

	(Response)  Final § 111.70(b) (derived from proposed § 111.35(e)(2))
requires that component specifications be established for each component
that you use in the manufacture of a dietary supplement.  Thus, the firm
must establish specifications for the components it uses to manufacture
a dietary supplement, regardless of whether it manufactures the
components itself or contracts with another firm to manufacture the
components.  The firm that conducts the manufacturing operations, as
explained in section VI, would be responsible for complying with all
relevant CGMP requirements in this final rule related to its operations.

     (Comment 168)  One comment asserts that proposed § 111.35(e)(1) is
unnecessary because the requirements for testing to meet the
manufacturer’s specifications are described elsewhere.

     (Response)  We disagree.  The requirements to establish
specifications are distinct from what you must do to determine whether
specifications are met.  Under the final rule (§ 111,73), you have a
responsibility to determine whether the established specifications are
met.  What criteria you must use in order to determine whether
specifications are met are set forth in final § 111.75.

3.  Final § 111.70(c)

     Final § 111.70(c)(1) requires you, for in-process production, to
establish in-process specifications for any point, step, or stage in the
master manufacturing record where control is necessary to help ensure
that specifications are met for the identity, purity, strength, and
composition of the dietary supplements and, as necessary, for limits on
those types of contamination that may adulterate or may lead to
adulteration of the finished batch of the dietary supplement.  Final
§ 111.70(c)(1) derives from proposed § 111.35(e)(2). Final
§ 111.70(c)(1) includes a nonsubstantive, editorial change that we are
making for consistency with other regulations in Part 111. This change
is to refer to “in-process specifications for any point, step, or
stage in the master manufacturing record where control is necessary”
rather than “in-process controls in the master manufacturing record
where control is necessary.”

	We also have added that you must establish in-process specifications,
as necessary, for limits on those types of contamination that may
adulterate or may lead to adulteration of the finished batch of the
dietary supplement.  This clarifies that if it is necessary to establish
limits on contaminants in-process, due to contamination that may occur
in the facility you do so under final § 111.70(c)(1).  With a
requirement to set, as necessary, limits on contamination in-process,
aspects of the production and process system from receipt to finished
product are covered with respect to contamination.  For example, under
final § 111.70(e) you may determine that you need to establish a
microbiological specification that the aerobic plate count of your
finished batch of the dietary supplement will not exceed a certain
number of colony forming units per gram of product. Under the written
instructions in your master manufacturing record (final § 111.210(h))
and your written procedures for manufacturing operations (final §
111.353), you would establish controls to prevent microbial
contamination at each point, step or stage in the manufacturing process
where control is necessary to prevent microbial contamination.  To
ensure that you will meet the microbiological specification that you set
for the finished batch of the dietary supplement, you may determine that
it is necessary to establish a specification for the aerobic plate count
at an intermediate stage of the in-process production.

     Final § 111.70(c)(2) requires you, for in-process production, to
provide adequate documentation of your basis for why meeting the
in-process specifications, in combination with meeting component
specifications, will help ensure that the specifications are met for
identity, purity, strength, and composition of the dietary supplements
and for limits on those types of contamination that may adulterate or
may lead to adulteration of the finished batch of the dietary
supplement.  Final § 111.70(c)(3) requires that the quality control
personnel unit review and approve the documentation you provide under
final § 111.70(c)(2).  Final § 111.70(c)(3) also derives in part from
proposed § 111.37(b)(1) which would require the quality control unit to
approve or reject all processes that may affect the identity, purity,
strength, or composition of a dietary supplement.

	In final § 111.70(c)(2), we are requiring documentation that includes
the basis for why meeting the in-process specifications, in combination
with meeting the component specifications will help ensure the
specifications for the identity, purity, strength, and composition of
the dietary supplement and limits on contamination are met.  Meeting
in-process specifications alone may not ensure the identity, purity,
strength or composition of the dietary supplement, but information about
the component specification may be needed in order to put the results
from the in-process specification in perspective.  For example, if the
manufacturer establishes a component specification for lead that it not
be greater than “x” mg and establishes a specification that all
piping that comes into contact with the component be lead free in the
facility, and there are no other components or equipment that would be a
source of lead, then there should be no added lead from processing,
provided that the material only came in contact with the lead-free pipes
and only the other lead-free components and equipment are used.  Thus,
we would not know by looking solely at the in-process specification
whether the lead in the final product is not greater than “x” mg. We
would need to evaluate the component specification, in addition to the
in-process specification, to ensure that the final product contains no
greater than "x" mg lead.  To emphasize the interplay of the
specifications and component specifications in ensuring the
specifications are met for the identity, purity, strength, and
composition of dietary supplements, and, as necessary, for limits on
contamination, final § 111.70(c)(1) and(c)(2) state “help ensure”
rather then “ensure” the identity, purity, strength, and composition
of dietary supplements and for limits on contamination.

	(Comment 169) One comment asserts monitoring and process controls are
more practical and effective than the proposed requirements for
in-process testing, which the comment asserts are overly broad and could
impose an undue burden on small businesses.

     (Response)  The comment’s objection is unclear.  The final rule
requires that you establish in-process specifications for any point,
step, or stage in the master manufacturing record where control is
necessary in the manufacturing process to help ensure that
specifications are met for the identity, purity, strength, and
composition of the dietary supplement and, as necessary, for limits on
contamination.  You must monitor the in-process points, steps, or
stages, where control is necessary to ensure the quality of the finished
batch of dietary supplement, to determine whether the in-process
specifications are met and to detect any deviation or unanticipated
occurrence that may result in a failure to meet specifications (see
final § 111.75(b)).  The final rule does not establish specific
requirements for in-process monitoring.  The manufacturer must determine
any in-process monitoring that is necessary to ensure that the
specifications are met for the finished batch.  Examples of such
monitoring include measuring pH or viscosity.

4.  Final § 111.70(d)

	Final § 111.70(d) requires you to establish specifications for
dietary supplement labels (label specifications) and for packaging that
may come in contact with dietary supplements (packaging specifications).
 Final § 111.70(d) derives from proposed § 111.35(e)(4).  Further,
§ 111.70(d) requires that packaging that may come into contact with
dietary supplements must be safe and suitable for its intended use and
must not be reactive or absorptive or otherwise affect the safety or
quality of the dietary supplements, consistent with proposed
§ 111.35(e)(4).  We deleted the phrase “comply with other statutory
and regulatory provisions” from proposed § 111.35(e)(4) because the
requirement was redundant with final § 111.5.

5.  Final § 111.70(e)

     Final § 111.70(e) requires you, for each dietary supplement that
you manufacture, to establish product specifications for the identity,
purity, strength, and composition of the finished batch of the dietary
supplement, and for limits on those types of contamination that may
adulterate or may lead to adulteration of the finished batch of the
dietary supplement, all to ensure the quality of the dietary supplement.
 Final § 111.70(e) derives from proposed § 111.35(e)(3) and (k).
Final § 111.70(e) is consistent with comments, already discussed,
recommending that the provisions of proposed § 111.35(k) regarding
contaminants that could adulterate a product be incorporated into
proposed § 111.35(e).

6.  Final § 111.70(f)

     Final § 111.70(f) requires you, if you receive a product from a
supplier for packaging or labeling as a dietary supplement (and for
distribution rather than for return to the supplier), to establish
specifications to provide sufficient assurance that the product you
receive is adequately identified and is consistent with your purchase
order.  Final § 111.70(f) derives from proposed § 111.35(e)(1) which
would require, in part, you to establish specifications for dietary
supplements that you receive.  Final § 111.70(f) includes changes we
are making after considering comments.

     (Comment 170)  One comment notes that labelers would not be subject
to proposed § 111.35(e).  Other comments request we clarify the roles
of the various parties in the “pre-consumer supply chain” for
dietary supplements.  One comment suggests that manufacturers and
packagers be responsible for establishing specifications only for the
operations occurring in their own facility or for which they are
otherwise responsible (e.g. subcontracted operations), not for upstream
or downstream operations over which they may not have any control.  This
comment states that we intended to relieve packagers from establishing
specifications for the dietary supplements that they package, and also
states that such requirements should not be in the CGMP regulations.

     (Response)  We have discussed, in section VI, who is subject to the
final rule under § 111.1 in what the comment describes as the
“pre-consumer supply chain” and do not repeat that discussion.  We
agree that packagers and labelers must establish specifications for the
dietary supplements that they package and did not intend to relieve them
of complying with relevant CGMP requirements.  We recognize that a firm
that only packages and labels a product may rely on information about
the content of the product that it receives from the manufacturer.  The
information may consist of an invoice, certificate, guarantee, or other
form of verification as to what the product consists of so that the
packager or labeler has adequate information about the dietary
supplement it receives to label the product and to ensure that the
product is consistent with its purchase order.  Therefore, we are
setting forth certain requirements that distinguish a product you
receive for packaging or labeling as a dietary supplement (and for
distribution rather than for return to the supplier) from a product you
manufacture.  One such requirement is final § 111.70(f) which requires
you to establish specifications for a product you receive for packaging
or labeling as a dietary supplement (and for distribution rather than
for return to the supplier).

	The inclusion of final § 111.70(f), or any other provision that
relates explicitly to a product you receive for packaging or labeling as
a dietary supplement, does not alter the fact that such a product is no
different from any other dietary supplement as far as the applicability
of these CGMP requirements.

     Under final § 111.70(f), the specifications you establish for a
product you receive for packaging or labeling as a dietary supplement
must provide sufficient assurance that the received product is
adequately identified and is consistent with your purchase order.  For
example, you may be purchasing tablets that provide 500 mg (strength)
(quantitative amount per serving) of vitamin C (identity).  Therefore,
your purchase order would need to include the identity and amount of
vitamin C per tablet to distinguish it from other tablets of vitamin C
that may contain only 60 mg, or from other vitamin tablets of 500 mg
that you may also purchase.

     Final § 111.70(f) sets forth a requirement for a product you
receive for packaging or labeling as a dietary supplement that will be
distributed by you, rather than returned to the firm from which you
receive the product.  Thus, § 111.70(f) applies to product that has
left the control of the person who manufactured the batch.

	If you are a packager or labeler who packages and labels for the
manufacturer and you will return the packaged and labeled dietary
supplement to the manufacturer, we would not consider that you are
“receiving” product within the meaning of final § 111.70(f).
Thus, you would not be subject to final § 111.70(f).

     (Comment 171)  Some comments assert that “packaging” should be
included with “manufacturing process,” but that a firm involved only
in “holding” a product should not have to set specifications.

     (Response)  Under final § 111.70(a), a person who holds packaged
and labeled dietary supplements for distribution and who does no
manufacturing, packaging, or labeling, would be required to establish a
specification for any point, step, or stage in the manufacturing process
where control is necessary to ensure the quality of the dietary
supplement.  For example, a person may need to establish a specification
for the temperature at which the product will be held.  However, a
person who only holds packaged and labeled dietary supplements for
distribution is not required to establish component specifications
(final § 111.70(b)), in-process specifications (final § 111.70(c)),
specifications for labels and for packaging (final § 111.70(d)),
product specifications (final § 111.70(e)), specifications for product
received from a supplier for packaging as a dietary supplement (and for
distribution rather than for return to the supplier) (final
§ 111.70(f)), or specifications for the packaging and labeling of the
finished packaged and labeled dietary supplements (final § 111.70(g))
because the person does not engage in any of those activities.  This is
consistent with the views expressed by the comments regarding the
applicability of proposed § 111.35(e) to persons who only hold
packaged and labeled dietary supplements for distribution.

7.  Final § 111.70(g)

	Final § 111.70(g) requires you to establish specifications for the
packaging and labeling of the finished packaged and labeled dietary
supplements, including specifications that ensure you used the specified
packaging and you applied the specified label.

     Final § 111.70(g) is a new provision we are adding for clarity
and consistency.  We had proposed to require that you conduct a material
review and make a disposition decision of any packaged and labeled
dietary supplements that do not meet specifications (proposed
§ 111.70(c)).  We proposed minimum standards for packaged and labeled
dietary supplements -- i.e., we would require that the quality control
unit collect representative samples of each batch of packaged and
labeled dietary supplements to determine whether you used the packaging
specified in the master manufacturing record and applied the label
specified in the master manufacturing record (proposed
§ 111.37(b)(11)(iv)).  Final § 111.70(g) includes the minimum
standards that we proposed to establish for packaged and labeled dietary
supplements in proposed § 111.37(b)(11)(iv).

	To make clear that the use of packaging and labels for a final packaged
and labeled product must be that which is specified in the master
manufacturing record, we have created a separate provision (under final
§ 111.70(g)) requiring you to create the relevant specifications to be
met.

     Final § 111.70(g) requires you to establish specifications that
ensure you use the “specified packaging” and to apply the
“specified label” as we proposed under proposed
§ 111.37(b)(11)(iv).  We removed the words “specified in the master
manufacturing record” as an editorial change that we are making to
simplify the language of the requirement.

	As already explained (see discussion of final § 111.70(a)), the
specifications you establish under final § 111.70 are regulatory
specifications required by these final CGMP requirements.  The final
rule would not prevent you from establishing additional, nonregulatory
specifications, such as specifications that largely address the
appearance of the dietary supplement in an aesthetic sense.

H. What is Your Responsibility for Determining Whether

 Established Specifications are Met?

(Final § 111.73)

  Final § 111.73

     Final § 111.73 requires you to determine whether all
specifications you establish under final § 111.70 are met.  The
criteria for determining whether the specifications that you establish
under final § 111.70 are met are set forth in final § 111.75.  The
oversight by the quality control personnel unit for determining whether
specifications established under final § 111.70 are met in accordance
with the criteria established under final § 111.75 and under what
conditions the quality control personnel unit can approve deviations
from specifications are set forth in final § 111.77 and final subpart
F.  Although final § 111.73 requires you to determine whether
specifications are met, it is the responsibility of the quality control
personnel unit to conduct a material review and make a disposition
decision if a specification established in accordance with final
§ 111.70 is not met.

	Final § 111.73 derives, in part, from proposed §§ 111.35(f), (g),
and (h).  Final § 111.73 includes changes associated with
reorganization, and other revisions associated with final § 111.70.
Final § 111.73 neither includes any finished batch testing
requirements that derive from proposed § 111.35(g)(3) nor specifies
what you must do to determine whether all specifications are met because
the requirements for what means and methods you must use to determine
whether specifications are met, including certain requirements for
testing, are set forth in final § 111.75.

     The comments relevant to final § 111.73 are the general comments
that recommend an overall approach that focuses on building quality into
a dietary supplement throughout the production and process control
system.  Because the primary focus of the relevant comments is on the
proposed requirements for testing, we discuss those comments when we
describe the derivation of the testing requirements in final § 111.75.

I.  What Must You Do to Determine Whether Specifications Are Met?

(Final § 111.75)

     Final § 111.75 derives from proposed §§ 111.35(f),(g),(h), (k),
and (l), 111.37(b)(11), and 111.40(a) and (b).  Final § 111.75
describes the steps you must take to determine whether specifications
are met.

     (Comment 172)  Many comments assert that the CGMPs for dietary
supplements should place greater emphasis on in-process  controls and
HACCP principles.  The comments state FDA’s narrow focus on finished
product testing is not in line with the philosophy of HACCP, in which
manufacturing steps are controlled and verified so as to result in end
products that are safe, with minimal finished product testing.  One
comment cites a 1997 document entitled “Hazard Analysis and Critical
Control Point Principles and Application Guidelines” in which we state
that “[A]n effective HACCP system requires little end-product testing,
since sufficient validated safeguards are built-in early in the
process.” (Ref. 3128).

     (Response)  In the 1997 ANPRM, we asked for comments on whether
certain, or all, of the requirements for manufacturing and handling
dietary ingredients and dietary supplements may be more effectively
addressed by a regulation based on the principles of HACCP, rather than
the system outlined in the industry submission (62 FR 5708).  HACCP is a
science-based, systematic approach to preventing food safety problems by
anticipating how such problems are most likely to occur and by
installing effective measures to prevent them from occurring.  The HACCP
concept is a systematic approach to the identification and the
assessment of risk (likelihood of occurrence and severity), and control
of the biological, chemical, and physical hazards associated with a
particular food production process or practice.  HACCP is a preventive
strategy.  It is based on development by the food producer of a plan
that anticipates food safety hazards and identifies the points in the
production process where a failure would likely result in a hazard being
created or allowed to persist; these points are referred to as critical
control points (CCPs).

	Under HACCP, identified CCPs are systematically monitored, and records
kept of that monitoring.  Corrective actions are taken when control of a
CCP is lost, including proper disposition of the food produced during
that period, and these actions are documented.  Thus, the focus of a
HACCP-based approach is to anticipate food safety hazards, take actions
to prevent them, and keep records of both the actions taken to prevent
problems and the actions taken if a problem nonetheless occurs.

	As discussed in the preamble to the 2003 CGMP Proposal (68 FR 12157 at
12174), most of the comments that we received to the ANPRM opposed
basing a CGMP regulation for dietary supplements on HACCP principles.
Consistent with those comments, we proposed certain requirements that,
although consistent with a HACCP-based approach, did not require a
HACCP-based approach.  For example, proposed § 111.65 would establish
requirements for manufacturing operations, including several proposed
requirements to prevent contamination of components or dietary
supplements, but would not require that you develop a specific plan for
the precautions that you would take, or that you keep records of any
monitoring that was directed solely at preventing specific types of
contamination.

     In contrast to the specific focus of HACCP to anticipate food
safety hazards, take actions to prevent them, and keep records of both
the actions taken to prevent problems and the actions taken if a problem
nonetheless occurs, CGMP requires that you take all necessary steps to
both prevent hazards and ensure that the product that you manufacture is
what you established in your specifications.  The proposed testing
requirements were directed at ensuring that a dietary supplement meets
all of its established specifications, including specifications for the
identity, purity, strength, and composition, rather than on ensuring
only that specific food safety hazards that you take steps to prevent
are not, in fact, present in the dietary supplement.  The comments that
assert that the CGMP requirements should place greater emphasis on HACCP
principles and, in so doing, reduce the requirements to test product at
the finished batch stage, did not explain how the preventive measures
that are associated with a HACCP plan would be effective at ensuring
that a dietary supplement is what you established it to be in your
specifications.  Therefore, we are not, as the comments request,
including additional HACCP requirements as part of the overall approach
set forth in this final rule.

     In the 2003 CGMP Proposal, we noted that you may voluntarily choose
to implement a HACCP plan that meets the requirements of the National
Advisory Committee on Microbiological Criteria for Foods, but that
proposed part 111 would still apply to you. (68 FR 12157 at 12174)  We
also noted that any HACCP plans that are intended to meet the records
requirements under proposed part 111 would be treated as records under
the CGMP regulations.

	(Comment 173)  One comment states that it supports a requirement that a
firm ensure that specifications have been met and asserts that the 2003
CGMP Proposal failed to do so.  This comment asserts the specific
testing requirements in proposed § 111.35(g)(l) and (2) must be
significantly modified and suggests that a more effective approach would
be to establish separate requirements for ensuring that specifications
are met in each of the four categories addressed by proposed §
111.35(e): goods received (§ 111.35(e)(1)); in-process controls
(§ 111.35(e)(2)); manufactured goods (§ 111.35(e)(3)); and labels
and packaging (§ 111.35(e)(4)).

     (Response)  The final rule is consistent with this comment. Final
§ 111.70 requires you to establish certain specifications (including
specifications for components, in-process controls, the finished batch
and packaging and labels), and final § 111.75 sets forth the
requirements for what you must do to determine whether those
specifications are met.

1.  Final § 111.75(a)

     Final § 111.75(a)(1) requires you, before you use a component
that is a dietary ingredient, to conduct at least one appropriate test
or examination to verify the identity of the dietary ingredient.  We
recognize, however, that it may be possible for a manufacturer to
demonstrate, through various methods and processes in use over time for
its particular operation, that a system of less than 100 percent
identity testing would provide no material diminution of assurance of
the identity of the dietary ingredient as compared to the assurance
provided by 100 percent identity testing.  To provide an opportunity for
a manufacturer to make such a showing and reduce the frequency of
identity testing of components that are dietary ingredients from 100
percent to some lower frequency, we decided to provide, in an Interim
Final Rule published elsewhere in this FEDERAL REGISTER, a procedure
that allows for submission to, and review by, FDA of an alternative to
the required 100 percent identity testing of components that are dietary
ingredients, provided certain conditions are met.

	Final § 111.75(a)(2) requires you, before you use a component, to
confirm the identity of other components and determine whether other
applicable component specifications established in accordance with §
111.70(b) are met.  To do so, final § 111.75(a)(2) requires you to
either conduct appropriate tests or examinations (final
§ 111.75(a)(2)(i)); or rely on a certificate of analysis from the
suppler of the component that you receive (final § 111.75(a)(2)(ii)).
Final § 111.75(a)(2)(ii) sets forth the criteria that you must satisfy
in order to rely on a certificate of analysis from a supplier:

(1) You must first qualify the supplier by establishing the reliability
of the supplier’s certificate of analysis through confirmation of the
results of the supplier’s tests or examinations;

(2) The certificate of analysis must include a description of the test
or examination method(s) used, limits of the test or examinations, and
actual results of the tests or examinations;

(3) You must maintain documentation of how you qualified the supplier;

(4) You must periodically reconfirm the supplier’s certificate of
analysis; and

(5)  Your qQuality control personnel unit must review and approve the
documentation setting forth the basis for qualification (and
requalification) of any supplier.

     Final § 111.75(a)(1) and (a)(2) derive, in part, from proposed
§ 111.35(g) and (h) and proposed § 111.40(a)(2) and (a)(3).  Final
§ 111.75(a)(1) and (2) include changes that we are making after
considering comments to proposed § 111.35 and proposed § 111.40(a).

     (Comment 174) Many comments assert that a certificate of analysis
from a properly certified supplier can be a key element of the
manufacturing process, and reduce the need for testing at the finished
batch stage.  Some comments specifically recommend the dietary
supplement manufacturer conduct identity tests to ensure that the
correct component has been received.  (Also, see Comment 145.)

     Some comments recommend an appropriate vendor qualification
program, including a combination of vendor audits and product testing,
to alleviate the need for complete testing of every lot of incoming
components.

     Several comments stress that a meaningful certificate of analysis
must be based on the results of actual analytical testing.  One comment
adds that reliance on a supplier’s certificate of analysis should be
conditioned on a qualification program whereby the recipient
independently verifies the supplier’s ability to conduct tests and
verifies test results through confirmatory testing.

     Many comments provide suggestions for ways in which manufacturers
could demonstrate the reliability of a certificate of analysis, which
include the following:  (1) identity testing of ingredients and
components; (2) maintenance of documentation of appropriate test
results; (3) appropriate verification of the information provided
initially and at appropriate intervals; and (4) documentation that any
suppliers have adequate CGMP programs in place.

     Some comments recommend that vendor certification programs include
plant visits and inspections, while other comments do not believe
manufacturers should be required to conduct plant inspections.  Other
comments recommend that vendor certification programs include CGMP
audits or process reviews at supplier facilities; verification of
laboratory test results against a certificate of analysis; and 100
percent inspection and testing of incoming materials for a specified
period of time while reliability is being assessed.

     Some comments provide suggestions for the types of information that
should be included on an acceptable certificate of analysis, such as
moisture, sieve analysis, identity, and results of tests against
established raw material specifications and specifications of any
compendia referenced on the label.   One comment suggests that a
certificate of analysis could be converted into sworn affidavits to
guarantee their reliability.  Some comments suggest that a system of
testing one batch for agreement with the certificate of analysis, and
then relying on this information for future purchases, would work well
if the suppliers are required to provide reliable and valid certificate
of analysis documents.  One comment suggests we issue guidelines as to
what should be included in a properly verified certificate of analysis.

     Some comments address the requirement in proposed § 111.40(a)(2)
to “Visually examine the suppliers invoice, guarantee, or
certification * * * and perform testing, as needed, to determine whether
specifications are met.”  One comment agrees with this proposed
requirement and asserts that the supplier’s certification is not
sufficient to ensure that appropriate standards are met.  Other
comments, however, disagree with this aspect of the proposed requirement
or ask for further clarification.  A few comments assert that
manufacturers should not have to retest material already tested by a
supplier.  Some comments note that a certificate of analysis can be used
for ensuring received materials are consistent with the purchase order,
and assert the certificate of analysis can be an appropriate way to
ensure specifications are met without requiring testing.  One comment
suggests the phrase “perform testing, as needed” be replaced with
“perform testing, if necessary” and that the CGMP regulations allow
for the use of a certificate of analysis that has been verified through
a vendor certification process.  Another comment states that the
provisions requiring testing in proposed § 111.40(a)(2) are more
burdensome than those required of food and pharmaceutical products and
cites the drug CGMP provision that permits the use of certificates of
analysis in lieu of testing for conformity with written specifications.
One comment supports the idea of testing upon receipt in the specific
circumstance when testing cannot be performed on the finished product.

     Several comments contend that there is a conflict between the 2003
CGMP Proposal and our position during our stakeholder meetings.  The
comments assert that, at the meetings, FDA representatives recognized
that a verified certificate of analysis is acceptable, provided it is
based on appropriate testing from suppliers who are audited by their
customers as to their testing and manufacturing practices.

     A few comments say the 2003 CGMP Proposal should allow more
reliance on strict chain of custody and documentation requirements.
Other comments recommend that manufacturers not be required to retest
previously tested incoming ingredients if they arrive with the
vendor’s seal intact.  Rather, the purchaser should be able to rely on
the vendor’s test results, as presented in a verified certificate of
analysis, unless there has been a breach in quality control during
distribution and subsequent manufacture.  One comment notes the Canadian
regulations for Natural Health Products allow periodic testing of
ingredients if a manufacturer has satisfactory evidence that the raw
materials sold to him/her are consistently manufactured in compliance
with established specifications.

     (Response)  We agree that CGMP requires that a person who
manufactures a dietary supplement conduct at least one appropriate test
or examination to verify the identity of each dietary ingredient that
will be used in the manufacture of the dietary supplement.  For example,
because some botanicals require microscopic examination and comparison
to a reference to be distinguished, and because suppliers of such
botanicals may manufacture several of these botanicals, it is important
to verify that a botanical that you receive from a supplier is the
correct botanical.    In some cases, a single test or examination may be
all that is needed to verify the identity of a dietary ingredient; in
other cases, it may be necessary to conduct more than one test or
examination.  It is the responsibility of the manufacturer to determine
the appropriate test(s) or examination(s) necessary to verify the
identity of a dietary ingredient.

     The comments discussed the importance of testing all components for
identity and did not appear to limit their recommendation for conducting
identity tests to those components that are dietary ingredients.  Based
on the comments, we conclude that many firms would conduct an identity
test for most ingredients and other components rather than limit
identity testing to dietary ingredients.  However, because dietary
ingredients are the central defining ingredient of a dietary supplement,
final § 111.75(a) only requires you to conduct tests or examinations to
verify the identity of any component that is a dietary ingredient.  As
discussed previously in this section, we recognize, however, that it may
be possible for a manufacturer to demonstrate, through various methods
and processes in use over time for its particular operation, that a
system of less than 100 percent identity testing would provide no
material diminution of assurance of the identity of the dietary
ingredient as compared to the assurance provided by 100 percent identity
testing.  To provide an opportunity for a manufacturer to make such a
showing and reduce the frequency of identity testing of components that
are dietary ingredients from 100 percent to some lower frequency, we
decided to provide, in an Interim Final Rule published elsewhere in this
FEDERAL REGISTER, a procedure that allows for submission to, and review
by, FDA of an alternative to the required 100 percent identity testing
of components that are dietary ingredients, provided certain conditions
are met.  For components other than dietary ingredients you must confirm
the identity of the component and you have the flexibility of relying on
a certificate of analysis, in lieu of conducting a test or examination,
to confirm identity. The preamble to the 2003 CGMP Proposal discussed
why we were not proposing that you could rely on a certificate of
analysis, but did not express a view as to whether the establishment of
minimum criteria for how you would qualify the supplier, and for what
must be included on the certificate of analysis, could alleviate our
concerns about whether the certificate of analysis could ensure certain
attributes of dietary supplements.

	After considering the comments, we also are persuaded that it is
possible to rely on a certificate of analysis from the supplier, for
attributes other than identity of the dietary ingredient, provided you
satisfy certain minimum criteria set forth in final § 111.75(a)(2)(ii).
 These criteria include qualifying the supplier, maintaining
documentation of how you qualified the supplier, periodically
reconfirming the supplier’s certificate of analysis, and having your
quality control personnel unit review and approve the documentation
setting forth the basis for qualifying the supplier.  These criteria
also require that the certificate of analysis, at a minimum, includes a
description of the test or examination method(s) used, limits of the
tests or examinations, and the actual results of the tests or
examinations.  Under final § 111.75(a)(2)(ii)(A), to qualify the
supplier you must establish the reliability of the supplier’s
certificate of analysis through confirmation of the supplier’s tests
or examinations.

	Certain comments request that we provide guidance on what should be
included in a certificate of analysis.  As stated earlier in this
section, a certificate of analysis is a document, provided by the
supplier of a component prior to or upon receipt of the component, that
documents certain characteristics and attributes of the component.
Instead of guidance, we are establishing, in final §
111.75(a)(2)(ii)(B), minimum criteria that a certificate of analysis
must meet to satisfy these CGMP requirements.  As we gain experience in
applying the CGMP regulations, we will consider whether it is
appropriate to provide guidance on certificates of analysis.

    (Comment 175)  One comment asks if a raw material contains an
unknown amount of excipients, is it necessary to quantify the excipients
or can a company simply assess the active material and rely on a
vendor’s specification for the excipient content?

     (Response)  To the extent that this comment is asking whether it is
necessary to set a component specification for the strength of
excipients that are present in a dietary supplement, the final rule does
not require you to do so provided that such a component specification is
not necessary to ensure that the specifications for the purity,
strength, composition, or contamination limit for the dietary supplement
manufactured using the excipients are met (final § 111.70(b)(2)).  If
such a strength specification for an excipient is necessary to ensure
that the purity, strength, or composition specifications are met, or
that a contamination limit is met for the dietary supplement, you could,
as the comment suggested, rely on a certificate of analysis for that
quantitative information  provided that you satisfy the criteria set
forth in final § 111.75(a).

2.  Final § 111.75(b)

     Final § 111.75(b) requires that you monitor the in-process
points, steps, or stages where control is necessary to ensure the
quality of the finished batch of dietary supplement, to determine
whether the in-process specifications are met, and to detect any
deviation or unanticipated occurrence that may result in a failure to
meet specifications.  Final § 111.75(b) derives from proposed
§ 111.35(f) with revisions associated with final § 111.70(c)(1).

      (Comment 176)  A few comments argue that it is not possible to
monitor in-process for those specifications required under proposed §
111.35(e).  One comment states that a specification such as identity is
no longer identifiable at an in-process stage.  This comment also notes
any such requirement in proposed § 111.35(e) would be redundant,
because proposed § 111.35(h) requires a firm to ensure, through testing
or examination, that all established specifications are met.  Another
comment contends that some specifications are not met until processing
is complete, such as with liquid extracts.  A few comments recommend
that the requirement for monitoring be limited to ensuring that
specifications established for in-process controls under proposed §
111.35(e)(2) and finished product under proposed § 111.35(e)(3) are
met.

     One comment states it is not always possible for a manufacturer to
monitor for strength and purity of raw materials during in-process
steps.  The comment suggests this proposed requirement be removed or
revised.

	(Response) The comments may have misunderstood what we refer to as
“in-process” specifications.  Under final § 111.75(b), you must
monitor the in-process points, steps or stages where control is
necessary to ensure the quality of the finished batch of dietary
supplement, to determine whether the in-process specifications are met,
and to detect any deviation or occurrence that may result in a failure
to meet specifications.  The in-process specifications that you
establish ensure that, for example, the specification for strength is
achieved.  If you must deliver a certain amount of powdered Vitamin C to
a mixture at a certain point in the process in order to achieve a final
product that contains 60 mg of Vitamin C, a critical point in the
process is where “x” mg of Vitamin C is added to ensure that the
final product contains 60 mg of Vitamin C.  You would monitor the
operation to ensure that “x” mg of Vitamin C is added.  Your
strength specification may be tested at the end of the process as a
product specification, but your in-process specification to ensure the
addition of “x” mg of Vitamin C is a specification that is separate
and distinct from the specification that you establish for strength,
i.e., 60 mg Vitamin C.  You may determine that in-process specifications
are met through a test or examination.  You could monitor for the
vitamin C product by checking the equipment you use to mix the vitamin
C-containing product to ensure that the mixing process was carried out
during the time period specified in the master manufacturing record to
ensure uniformity in the finished batch.  Other examples could include a
measurement, such as checking pH during the course of a process, or
removing samples during the course of a process to conduct a test for
viscosity.  There may be no need for certain in-process specifications
to ensure that specifications for identity, purity, strength, and
composition of the finished batch of dietary supplement are met.  If
there are no in-process points, steps, or stages at which any test or
examination is needed to ensure that the identity specification for the
finished batch of dietary supplement is met, then you would not need to
establish an in-process specification to ensure identity in the finished
batch, and, therefore, would not need to conduct in-process monitoring
for identity.

	(Comment 177)  One comment requests clarification on what would be
considered “in-process” for materials that are simply blended
together to form a final product.  The comment asks how a firm would
test the samples if a final material cannot be tested due to
interferences or lack of an available method.

	(Response)  Examples of in-process specifications when materials are
simply blended together are the mixing time and speed.

  	(Comment 178)  One comment points out that in-process testing for
“unanticipated occurrences” required under proposed § 111.35(f)
would be difficult, because the manufacturer would not know what to test
for.

	(Response)  This comment may have misunderstood the provision, which
did not propose to require that you test for an unanticipated
occurrence.  Rather, proposed § 111.35(i)(2) would require you to
review the results of any monitoring, and conduct a material review and
make a disposition decision, if there is any unanticipated occurrence
that adulterates or could result in adulteration of a component or
dietary supplement.  An example of such an occurrence is leakage of
extraneous material from a pipe onto a component.  The qQuality control
personnel unit, under final § 111.113(a)(3), must conduct a material
review and make a disposition decision if there is such an unanticipated
occurrence during the manufacturing operations.

     (Comment 179)  One comment suggests that the provision is a HACCP
requirement and is unnecessary for dietary supplements whose production
generally does not involve bacterial contamination.

     (Response)  We disagree.  It is not a HACCP requirement because the
provisions deal with unanticipated occurrences.  Dietary supplement
production can involve bacterial contamination as discussed in section
V.  The purpose of final § 111.75(b) is to ensure that the product
meets all specifications, which include specifications associated with
contamination, and, therefore, is a necessary provision.

3.  Final § 111.75(c) and (d)

     Final § 111.75(c) requires you, for a subset of finished dietary
supplement batches, which you identify through a sound statistical
sampling plan (or for every finished batch), to verify that your
finished batch of the dietary supplement meets product specifications
for identity, purity, strength, composition, and limits on those types
of contamination that may adulterate or that may lead to adulteration of
the finished batch of the dietary supplement.  Final § 111.75(c) also
sets forth the following verification requirements:

     (1) You must select one or more established specifications for
identity, purity, strength, composition, and limits on those types of
contamination that may adulterate or that may lead to adulteration of
the dietary supplement that, if tested or examined on the finished batch
of the dietary supplement, would verify that the production and process
control system is producing a dietary supplement that meets all product
specifications (or only those product specifications not otherwise
exempted from this provision by the quality control personnelunit under
final § 111.75(d));

     (2) You must conduct appropriate tests or examinations on the
specifications selected in final § 111.75(c)(1);

     (3) You must provide adequate documentation of your basis for why
meeting the specification(s) selected under final § 111.75(c)(1),
through the use of appropriate tests or examinations conducted under
final § 111.75(c)(2), will ensure that your finished batch of the
dietary supplement meets all product specifications for identity,
purity, strength, composition, and the limits on those types of
contamination that may adulterate, or that may lead to the adulteration
of, the dietary supplement; and

     (4) Your qQuality control personnel unit must review and approve
the documentation that you provide under final § 111.75(c)(3).

     Final § 111.75(c) requires you to verify that your finished batch
of dietary supplement meets specifications for identity, purity,
strength, composition, and limits that you established for those types
of contamination that may adulterate or that may lead to adulteration of
the finished batch.  You may verify this by either testing or examining
(1) every finished batch for each of these specifications, or (2) a
subset of finished batches for the dietary supplement.  The subset of
batches tested must be identified using a sound statistical sampling
plan.

	If you choose to test or examine a subset of finished batches of
dietary supplement, you may test or examine each subset of batches for
identity, purity, strength, composition and limits on contamination that
you established.  Alternatively, you may determine that you can select
one, two, or three, or other number of these specifications that, if
determined to be in compliance with specifications, would be able to
verify that the other untested specifications are met.  For example, you
may be able to substantiate that, if you determine compliance with the
specification for the identity and composition of a product for which no
contamination limits are needed, the system is adequately controlling
for the purity and strength of the product, without the need to test for
compliance with the specifications for purity and strength.  If so, you
must document, under final § 111.75(c)(3) your basis for why this is
so.  Your qQuality control personnel unit must review and approve such
documentation under final § 111.75(c)(4).

	Under final § 111.75(d), you may determine, in the above example,
that you could not verify, by testing for compliance with the
specifications for identity and composition, that the purity
specification is met, and there may be no scientifically valid method
for testing or examining the finished batch to evaluate the purity in
the finished batch of dietary supplement. In that case, you could exempt
the specification for purity from the requirement in final
§ 111.75(c)(1) if you can document why the purity specification is met
without such testing or examination.  You could do so through, for
example, documentation that meeting component and specifications for
strength is sufficient, or through documentation that in-process
monitoring is sufficient.  Your qQuality control personnel unit must
review and approve such documentation (final § 111.75(d)).

     Final § 111.75(c) and (d) derive from proposed § 111.35(g) and
(h) and include changes that we are making after considering comments.

     (Comment 180)  Several comments assert that a more appropriate
balance is needed between an effective process control system and a
reasonable testing scheme calculated to confirm the quality of dietary
supplements.  The comments stress it is important to build quality into
a product throughout the entire production process by relying on strong
process controls rather than by testing at the finished batch stage.
One comment asserts that in an appropriate process control system,
testing is a means to monitor and ensure that the control system is
functioning as intended.  Several comments make a specific
recommendation that the final rule include rigorous controls.

	Some comments support the requirement under proposed § 111.35(g) to
test each batch of finished product when possible, and to perform
testing of components and in-process when testing the finished product
is not possible.  Other comments object to the proposed requirements for
finished product testing on the grounds that they are overly burdensome,
duplicative, and unnecessary.

     Some comments suggest that a more practical approach to finished
product testing would be to conduct identity testing of each component,
combined with certification of the vendor by a program of complete
testing for conformance with a certificate of analysis, as is allowed
under the drug CGMP regulations.  Some comments suggest manufacturers
that have written procedures for each stage of their process, including
raw material certification, production, and finished product analysis,
and a written plan for qualifying the process, should be exempt from the
proposed requirements to test each finished batch.  Some comments urge
us to give companies the flexibility to devise testing procedures.

     (Response)  The approach in final § 111.75(c) and (d) is
consistent with these comments and is part of the overall approach of
this final rule, which focuses on ensuring the quality of the dietary
supplement throughout the production and process control system.

     The concept behind final § 111.75(c) and (d) is analogous to the
overall concept of proposed § 111.35(g).  Under proposed § 111.35(g)
you could rely on a combination of meeting component specifications and
in-process specifications when you are unable to test for a
specification, provided you satisfied certain criteria.  Under the final
rule, you may rely on a combination of meeting component specifications
and in-process specifications to verify that your product meets
specifications, rather than test every batch to determine whether
specifications are met, regardless of whether a test is available,
provided you satisfy certain criteria.  Thus, the final rule provides
flexibility that is needed to build adequate controls early in the
process to reduce the need for end product testing on every batch of
finished dietary supplement.

	(Comment 181)  One comment expresses concern that the requirement to
use appropriate tests to determine compliance with specifications could
be interpreted as requiring companies to test dietary supplements not
only for compliance with company specifications, but also for compliance
with any labeled specifications of the ingredient suppliers, such as for
contaminants.  The comment believes this would be redundant and overly
burdensome.

     (Response)  As explained in section XXIV, we have made changes to
reduce the testing burden on companies while still requiring steps
necessary to ensure the quality of dietary supplements.  For example,
under final § 111.75(a), instead of testing (other than for identity
of the dietary ingredients), firms may rely upon supplier certificates
of analysis in certain circumstances.  Also, we recognize, however, that
it may be possible for a manufacturer to demonstrate, through various
methods and processes in use over time for its particular operation,
that a system of less than 100 percent identity testing would provide no
material diminution of assurance of the identity of the dietary
ingredient as compared to the assurance provided by 100 percent identity
testing.  To provide an opportunity for a manufacturer to make such a
showing and reduce the frequency of identity testing of components that
are dietary ingredients from 100 percent to some lower frequency, we
decided to provide, in an Interim Final Rule published elsewhere in this
FEDERAL REGISTER, a procedure that allows for submission to, and review
by, FDA of an alternative to the required 100 percent identity testing
of components that are dietary ingredients, provided certain conditions
are met.  In addition, under final § 111.75(c), testing or examination
for a portion of the finished batches is an option, and exemptions are
provided for in final § 111.75(d).

	(Comment 182)  One comment points out that, if a product cannot be
tested for technical reasons at the final product stage, then it also
cannot be tested at the final blending stage in the process, because the
nature and composition of the product at both stages are virtually the
same.  Another comment asks whether a verification of content in the
final product will suffice if there is no valid testing procedure.

     (Response) Under final § 111.75(c), you have flexibility to select
one or more established specifications for identity, purity, strength,
composition, and limits on those types of contamination that may
adulterate or that may lead to adulteration of the dietary supplement
that, if tested or examined on the finished batch of the dietary
supplement, would verify that the production and process control system
is producing a dietary supplement that meets all product specifications.
 Under final § 111.75(d), you have flexibility to exempt one or more
product specifications from verification requirements, provided that you
satisfy the criteria established under final § 111.75(d).

     (Comment 183)  Some comments request that the rule include
requirements for dissolution, disintegration, and bioavailability
testing for dietary supplements.  These comments note that, although a
product may contain the labeled amount, it may not dissolve readily in
the body or be available for absorption.

     (Response)  We decline to revise the rule as suggested by the
comments.  As discussed in the preamble to the 2003 CGMP Proposal (68 FR
12157 at 12163), tests for dissolution, disintegration, and
bioavailability of dietary supplements are examples of areas where
scientific study is still evolving; thus it is premature to impose
requirements for such tests.  The comments provide no specific