Document ID: FDA-1996-N-0028-0064
Agency: fda
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-08-01T04:00Z

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 have limited the
requirement for identity testing or examination by the manufacturer, to
dietary ingredients. However, to determine the identity of other
ingredients or components that are not dietary ingredients, we will
permit the manufacturer to rely on a certificate of analysis, provided
that certain criteria 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)).  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 154. 

     (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.

	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.  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.  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
information that would alter this view or support the technical
feasibility of conducting such tests for all types of dietary supplement
products.  However, nothing in this final rule would preclude a
manufacturer from establishing such requirements.  A manufacturer should
have data to support any specifications it establishes for parameters
such as dissolution, disintegration, and bioavailability.

     (Comment 184)  One comment questions the requirements in the 2003
CGMP Proposal that all manufacturers quantify certain marker compounds
in their products.  The comment offers two reasons why such testing
should not be required for botanical products: their food-like
composition and legal status; and the assertion that scientifically
valid analytical methods may prove to be irrelevant or even hinder the
development of superior products.

     (Response)  The final rule does not require any specific testing
requirements, such as testing for marker compounds.  You would determine
the specific testing requirements, and whether to use a marker compound
in those tests, depending on your product and process. In the 2003 CGMP
Proposal (68 FR 12157 at 12172), we merely discussed how a marker
compound could help you identify whether you have a particular species
of an herb to differentiate, for example, between a poisonous and
nonpoisonous species.  

4.  Final § 111.75(e)

     Final § 111.75(e) requires you, before you package or label a
product you receive for packaging or labeling as a dietary supplement
(and for distribution rather than for return to the supplier), to
visually examine the product and have documentation to determine whether
the specifications that you established under final § 111.70 (f) are
met.  Final § 111.75(e) derives from proposed § 111.35(e)(1) and (g)
and from proposed § 111.40(a)(2).

     (Comment 185)  Some comments request we clarify the roles and
testing obligations of the various parties in the “pre-consumer supply
chain” for dietary supplements.  Some comments argue that redundant
tests should not be required at every transaction point in the
pre-consumer supply chain.  The comments contend that any testing
already performed by a supplier, manufacturer, or packager should
suffice, so long as other CGMP certification, and chain of custody
standards, are met.  Other comments urge us to give companies the
flexibility to devise testing procedures and point out that different
testing is needed for different roles in the supply chain. 

     One comment requests clarification of the testing requirements
applicable to packagers/labelers.  The comment states it is unclear how
a packager or labeler/distributor could conduct testing of component
ingredients if all the firm receives is a finished product for which
there is no scientifically valid testing method. 

     (Response)  As discussed in section VI, you are responsible for the
CGMP requirements that are applicable to your operations. We agree that
redundant tests should not be required.  Further, we agree that it is
the responsibility of the manufacturer to do component testing.  The
packager or labeler does not need to do any required component testing
because the packager or labeler does not receive components, rather it
receives a finished dietary supplement.  Under final § 111.70(f) 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 provide sufficient
assurance that the product you receive is adequately identified and is
consistent with your purchase order. 

	Under final § 111.75(e), before you package or label such a product,
you must visually examine the product and have documentation to
determine whether the specifications that you established under final
§ 111.70(f) are met.  Your documentation may consist of an invoice,
certificate, guarantee, or other documentation from the supplier to
ensure that the product is adequately identified and is the product that
you ordered.  Final § 111.75(e) does not require that the
documentation consist of the result of testing or examination by the
packager or labeler of such a product.

     As with final § 111.70(f), final § 111.75(e) applies to
“product that you receive for *** for distribution rather than for
return to the supplier” and, thus, 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 a dietary supplement 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 § 111.75(e). 
Thus, you would not be subject to final § 111.70(f).  

5. Final § 111.75(f)

	Before you use packaging, final § 111.75(f)(1) requires you, at a
minimum, to conduct a visual identification of the containers and
closures and review the supplier’s invoice, guarantee, or
certification to determine whether packaging specifications are met. 
Before you use labels, final § 111.75(f)(2) requires you, at a minimum,
to conduct a visual examination of the label and review the supplier’s
invoice, guarantee, or certification to determine whether labeling
specifications are met.  Final § 111.75(f)(1) and (2) derive from
proposed § 111.40(b)(2) which, in part, would require you, for
packaging and labels you receive, to conduct at least a visual
identification on the containers and closures.  Proposed § 111.40(b)(2)
also would require you, in part, for packaging and labels you receive,
to quarantine the packaging and labels until your quality control unit
tests or examines a representative sample to determine whether
specifications are met.  Consistent with changes that we are making to
the requirements for packaging and labels that you receive (see
discussion of final § 111.160 in section XII), final § 111.75(f)(1)
and (f)(2) include a requirement analogous to proposed § 111.40(a)(2)
which would require you to visually examine the supplier’s invoice,
guarantee, or certification to determine whether the components, dietary
ingredients, or dietary supplements you receive are consistent with your
purchase order and to perform testing, as needed, to determine whether
specifications are met.

6. Final § 111.75(g)

	Final § 111.75(g) requires you, at a minimum, to conduct a visual
examination of the packaging and labeling of the finished packaged and
labeled dietary supplements to determine whether you used the specified
packaging and applied the specified label.  Final § 111.75(g) derives
from proposed § 111.37(b)(11)(iv) which would require the quality
control unit to collect representative samples of each batch of packaged
and labeled dietary ingredients or 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.  Final § 111.75(g) is associated with final § 111.70(g) which
requires you to establish specifications for the packaging and labeling
for the finished packaged and labeled dietary supplements, including
specifications that ensure you used the specified packaging and applied
the specified label.

7.  Final § 111.75(h)

     Final § 111.75(h)(1) requires you to ensure that the tests and
examinations you use to determine whether the specifications are met are
appropriate and scientifically valid methods.  Final § 111.75(h)(1)
derives from proposed § 111.35(h).  Final § 111.75(h)(1) includes
editorial changes associated with the reorganization and changes that we
are making after considering comments.

     Final § 111.75(h)(2) requires that the tests and examinations you
use include at least one of the following: (i) gross organoleptic
analysis; (ii) macroscopic analysis; (iii) microscopic analysis; (iv)
chemical analysis; or (v) other scientifically valid methods.  Final
§ 111.75(h)(2) derives from proposed § 111.35(l).  

     (Comment 186)  Some comments suggest that the tests listed in
proposed § 111.35(l) be incorporated into proposed § 111.35 (h),
relating to appropriate test methods.

     (Response)  We agree with the comment, and final § 111.75(h)(2)
combines these requirements as requested.

     (Comment 187)  One comment states that the list of tests should be
deleted because it is not sufficient to cover the types of testing that
will be required for compliance with proposed § 111.35(g).             

	(Response)  The comment does not identify the types of tests that would
not be covered.  We believe that final § 111.75(h)(2)(v)’s
“catch-all” provision, which requires that one of the tests that you
use be an “other scientifically valid method” is sufficient to cover
all other types of testing required under this final rule. 

     (Comment 188)  One comment states that the final rule should make
clear that organolepsis is an acceptable method for identity testing. 
The comment contends it is imperative for the survival of small
businesses that organolepsis be allowed, coupled as necessary with
macroscopic and morphological examination and comparison with voucher
specimens or photographs. Another comment requests clarification of
whether gross organoleptic analysis alone can be a test for releasing
finished products.  Some comments assert that several organizations have
published relevant methods that include macroscopic methods that can be
used in identifying herbal ingredients.

     (Response)  Organolpetic analysis would be an acceptable method
under the 2003 CGMP Proposal and remains an acceptable method under the
final rule, which clarifies that the method you use, including
organoleptic analysis, must be appropriate.  Organoleptic analysis may
not be an appropriate method of testing for certain substances.  This is
particularly true when the nature of the substance decreases the
reliability of organoleptic analysis.  For example, while organoleptic
analysis may be an appropriate identity test for whole or coarsely-cut
botanical parts, it may not be an appropriate identity test for powdered
or extracted botanicals because of decreased reliability, or in those
instances where misidentification of botanicals is known to occur. 
Additionally, we recognize “macroscopic analysis” is one of the
tests or examinations you may select to determine whether specifications
are met.

     (Comment 189)  One comment remarks that the appropriateness of the
test depends on the material being tested, and the method selected by
the manufacturer may be inappropriate.  One comment believes the methods
stated in proposed § 111.35(l) (organoleptic, microscopy, chemical)
for establishment of identity and purity would not be applicable to
animal products.  This comment suggests that a separate list of test
methods should be identified for those materials.

(Response)  We agree that the appropriateness of the test depends on the
material being tested.  However, we are not revising the rule to
identify methods that are, or are not, appropriate for specific
circumstances (such as the case of animal-derived ingredients).  There
are so many distinct circumstances that such a list would be neither
practical nor useful.  Beyond that, the manufacturer is responsible for
choosing the appropriate test.     

(Comment 190)  One comment asks us to clarify in the final rule the
requirement that methods be scientifically valid applies only to
quantitative methods.

(Response)  In proposed § 111.35(h), we did not intend that the
proposed requirement that you use scientifically valid methods apply
only to quantitative methods, because we also proposed that tests in
accordance with proposed § 111.35 must include at least one of the
following: (1) Gross organoleptic analysis; (2) microscopic analysis;
(3) chemical analysis; or (4) other appropriate test.  To clarify that
the requirement that methods be scientifically valid applies to all the
tests and examinations you use, rather than to quantitative tests alone,
final § 111.75(h)(1) does not use the term “analytical.”

(Comment 191)  One comment states that the proposed definition of
“appropriate test” (i.e., “a scientifically valid analytical
method”) is extremely onerous and violates Congressional intent. The
comment believes that mandating specific methods is inappropriate, and
dietary supplement CGMPs should comply with E.O. 12866 and not impose
additional requirements on small businesses that are better left to
normal business practices. 

	Several comments take issue with our statement that we were not aware
of a situation where an appropriate scientifically valid method is not
available when, in fact, valid test methods are not always available for
testing dietary ingredients or dietary supplements.  One comment
contends the 2003 CGMP Proposal contains conflicting information about
available test methods.  For example, the preamble to the 2003 CGMP
Proposal states that we are “not aware of a situation where an
appropriate scientifically valid analytical method is not available,”
and our cost analysis does not address costs of method development.  At
the same time, however, we set out alternatives to finished product
testing in cases where adequate methods are unavailable, and we decline
to require expiration dating because there may not be adequate methods
available for assessing the strength of a dietary ingredient.  The
comment cites numerous ongoing efforts in methods development by both
industry and government that illustrate the lack of existing methods
necessary to confirm compliance with all quality specifications. 

(Response)  These comments appear to take our statements out of context.
 In the 2003 CGMP Proposal, we stated: “If an AOAC or FDA method is
not available, a scientifically valid analytical method is one that is
based on scientific data or results published in, for example,
scientific journals, references, text books, or proprietary research. 
Although there may not be an Association of Official Analytical Chemist
(AOAC) or FDA method available, we are not aware of a situation where an
appropriate scientifically valid analytical method is not available”
(68 FR 12157 at 12198). We also stated: “We recognize that certain
tests for identity, purity, quality, strength, or composition for
certain finished product may not be available due to complex finished
matrices that would make such testing impracticable” (68 FR 12157 at
12197).  We disagree that our statement acknowledging that the available
tests may not be practicable in certain matrices is inherently
inconsistent with our statement that we are not aware of a situation
where an appropriate scientifically valid analytical method is not
available.  One statement relates to the availability of methods, the
other relates to the practicality of using an available method in
particular circumstances.

In any case, under final § 111.75(d)(1) you may exempt a product
specification from the verification requirements of final §
111.75(c)(1) if you show that: (1) the specifications selected to verify
that the product meets all product specifications are not able to verify
that the control system is producing a dietary supplement that meets the
exempted product specification and (2) there is no scientifically valid
method for testing or examining the exempted product specification at
the finished batch stage.  Section 111.75(c)(1) also requires you to
document why other information, such as component and in-process
testing, will determine whether the exempted product specification is
met without finished batch testing.  Although we agree that there may be
some circumstances where there is not a scientifically valid method
available for finished product testing, we believe that there would be
some scientifically valid method available for component or in-process
testing.

(Comment 192) One comment encourages flexibility toward the development
of a quality system that is based on a balance of prevention, appraisal,
and process verification activities.  Another comment asks whether the
industry should use industry standards and tests now used. 

A few comments request that we clarify proposed § 111.35(h) to make it
clear whether the section recommends or requires the use of available
USP, AOAC or FDA methods.  One comment recommends that the final rule
give companies flexibility to use the method(s) most suitable to the
ingredient they are testing and the specification they have set.  The
comment adds that companies should then be required to ensure, through
appropriate rationale and data, that the method is indeed suitable and
produces accurate and reproducible results. 

(Response)  We agree that companies should have the flexibility to adopt
the method most suitable to the ingredient they are testing.  As
discussed in the preamble to the proposal (68 FR 12157 at 12163, 12208),
official methods, such as AOAC International methods, are validated in
collaborative studies using several laboratories under identical
conditions and the AOAC International methods are often cited as
“official validated methods.”  Other method validations are
conducted in a single laboratory by repeating the same test multiple
times.  In the case of methods used to support specific regulatory
applications to FDA, data and information about methods that are
developed and conducted in a single laboratory by repeating the test
multiple times are sent to us, together with appropriate samples and
reference materials so the test can be repeated in an agency laboratory.
 Typical validation characteristics include accuracy, precision,
specificity, detection limit, quantitation limit, linearity, range, and
robustness. 

The process of method validation discussed above is a formal process for
demonstrating that procedures are suitable for their intended use. 
Although many methods that are scientifically valid have been formally
validated, other methods may not have been subject to the formal
validation process, (e.g., by collaborative studies using multiple
laboratories) but nonetheless remain scientifically valid because they
are, in fact, suitable for their intended use.  For this reason, we
stated that the 2003 CGMP Proposal would permit tests using methods
other than those that are officially validated (68 FR 12157 at 12163). 
Consistent with the view that we expressed in the 2003 CGMP Proposal, we
believe a scientifically valid method is one that is accurate, precise,
and specific for its intended purpose.  In other words, a scientifically
valid test is one that consistently does what it is intended to do.

Under final § 111.75(h)(1), you must ensure the tests and examinations
you use to determine whether the specifications are met are appropriate,
scientifically valid methods.  Under final § 111.75(h)(2) the tests and
examinations you use must include at least one of the following: (1)
Gross organoleptic analysis, (2) Macroscopic analysis, (3) Microscopic
analysis, (4) Chemical analysis, or (5) Other scientifically valid
methods.

(Comment 193)  One comment questions how a company would know of all the
available scientifically valid methods when it deals with hundreds of
items.  The comment states it cannot be expected to have expertise in
the assay methodology for so many different ingredients.  

Several comments suggest we make fuller use of available monographs and
other resources on test methods and method development.  These sources
include USP and American Herbal Pharmacopoeia monographs, AOAC
International, the European Pharmacopoeia, and the WHO.  The comments
urge us to disseminate information on these additional resources. 

Many comments assert that several organizations have published relevant
analytical methods, such as macroscopic, microscopic, and chemical
methods, that can be used in identifying herbal ingredients.  These
comments suggest that we should acknowledge those methods and
organizations as authoritative sources of quality standards.

(Response) In the preamble to the 2003 CGMP Proposal (68 FR 12157 at
12209), we acknowledged that validated methods exist in official
compendia for vitamins, minerals, and several botanicals, and we
recommended you use validated methods whenever such methods are
available.  We explicitly stated that you may use validated methods that
can be found in official references, such as AOAC International, USP,
and others.  

As discussed in this section (see response to comment 196), we believe
that it is sufficient to provide in this preamble general guidance on
what we consider to be scientifically valid tests, such as those based
on scientific data or results published in, for example, scientific
journals, references, text books, or proprietary research, and leave it
to the manufacturer to decide what scientifically valid tests or
examinations to use in a given operation.  In the future, we may
consider issuing guidance as to sources of appropriate tests or
examinations, along with other guidances that we may find useful that
relate to certain dietary supplement CGMP.

     (Comment 194)  One comment states the act prohibits us from
imposing testing requirements for which scientifically valid methods are
not generally available, and other comments believe that not all
components have scientifically valid identification tests.  Given the
substantial ongoing efforts towards method development, the comments
believe that the proposed requirements for testing would impose
standards on many products and ingredients that cannot be met through
current and generally available methods.   

     (Response) We disagree that the statute prohibits us from imposing
testing requirements.  Section 402(g)(2) of the act states that dietary
supplement CGMP regulations “may not impose standards for which there
is no current and generally available analytical methodology.”  We are
not imposing such standards.  The manufacturer must establish
specifications for its product and components, and we have provided
flexibility  for how the manufacturer can determine whether those
specifications are met. The manufacturer can  test, examine, rely on a
certificate of analysis (other than to verify the identity of dietary
ingredients), or, in the case of a specification that is exempted from
periodic testing of a finished batch, rely on other information that
ensures that such an exempted product  specification is met.

	(Comment 195)  One comment requests clarification on the definition of
“examination” and asks whether it includes monitoring of process
parameters as established in the master manufacturing record.  If so,
the comment questions whether this practice would satisfy the
requirement now in final § 111.75(h)(1).

     (Response)  Under final § 111.75(h) scientifically valid tests and
examinations include techniques such as gross organoleptic analysis,
macroscopic analysis, chemical analysis, and other scientifically valid
methods.  As discussed in the response to comment 169, monitoring
in-process parameters could encompass tests such as measuring pH or
viscosity.  Such tests would fall under “other scientifically valid
methods.”  

    (Comment 196)  One comment contends that botanical identification is
largely ignored in the 2003 CGMP Proposal.  The comment states that
botanical identification forms the basic foundation for botanical
authenticity and that manufacturers have a legal responsibility to
ensure the authenticity of claimed ingredients.  The comment recommends
that specific requirements for authentication of botanical ingredients
be included in the final rule.

      One comment points out the difficulty in identifying and analyzing
all naturally occurring ingredients in herbs and plants and suggests
several alternatives to testing for all such ingredients.  Another
comment requests that an herbal product containing 20 percent or more
ethanol have relaxed testing requirements due to the bacteriostata
properties of ethanol.  One comment lists some alternatives for testing
naturally occurring ingredients. 

     One comment requests clarification on the testing requirements for
bovine cartilage products.  The comment states there is no published
method for extracting chondroitin sulfate from bovine cartilage.  As a
result, the comment assumes that testing for chondroitin sulfate would
not be required for these products.  

	(Response)  We believe that it is sufficient to provide in this
preamble general guidance about testing, such as our discussion that
scientifically valid tests include official, validated methods as well
as tests based on scientific data or results published in, for example,
scientific journals, references, text books, or proprietary research. 
It is the manufacturer’s responsibility to choose which scientifically
valid tests or examinations to use in a given operation.  Therefore, the
final rule does not address the specific testing circumstances described
in these comments, such as testing requirements for an herbal product
that contains 20 percent or more ethanol, or for bovine cartilage
products.  The manufacturer is responsible for establishing
specifications and meeting such specifications, consistent with the
requirements in this final rule.  In the future, we may consider issuing
detailed guidance as to specific tests or examinations, along with other
guidances that may be useful that relate to certain dietary supplement
CGMP.

	With respect to the comments that discuss botanical identification, we
note that the 2003 CGMP Proposal referred to the draft report of the
Dietary Supplement Working Group of FDA’s Food Advisory Committee
(FAC)(68 FR 12157 at 12161) (Ref. 329).  The draft report discusses the
selection of the most appropriate and reliable identity test and the
general principles for consideration in setting performance standards
for such tests (Ref. 329).  This report may provide useful guidance.

8.  Final § 111.75(i)

     Final § 111.75(i) requires you to establish corrective action
plans for use when an established specification is not met.  Final
§ 111.75(i) derives from proposed § 111.35(i)(1).

	(Comment 197) One comment asks whether the proposed requirement to
establish corrective action plans for use when an established
specification is not met (proposed § 111.35(i)(1)) would apply to
specifications for raw materials and finished goods as well as to
in-process specifications.  

     (Response) The requirement to establish corrective action plans
(final § 111.75(i)) applies to components, in-process specifications,
and to the finished batch.  

	(Comment 198) One comment states that corrective action plans would be
difficult to prepare for a variety of situations, such as for complex
multivitamin and mineral formulas.  One comment recommends this
requirement be deleted.  Another comment asserts that establishment of
corrective action plans should be at the manufacturer’s discretion.

     (Response)  We disagree that the final rule should not require you
to establish corrective plans or that having such plans should be at the
manufacturer’s discretion.  The purpose of having corrective action
plans in place before a problem occurs is to help you to deal quickly
and efficiently with problems as they arise.  

	You may have a corrective action plan to determine the steps to take if
something goes wrong such as not meeting a specification. Moreover, a
corrective action plan may include steps not only for dealing with an
acute problem, but also for dealing with steps you would take to
followup after the acute problem is resolved.  For example, after you
resolve an acute problem, such as a failure to meet an in-process
specification, your corrective action plan may include testing of every
finished batch, rather than a subset of finished batches, for some
period of time to verify that the problem is resolved.  

     We acknowledge that it may not be practical to establish a
corrective action plan for all circumstances, because not all
circumstances are foreseeable.  However, the comment asserting that it
would be difficult to establish corrective action plans for the variety
of situations that could come up for complex multivitamin and mineral
formulas provided no basis for why manufacturers of such formulas could
not anticipate specific situations that present potential problems. 

     (Comment 199)  Some comments recommend that proposed §
111.35(i)(1) state “Establish procedures,” rather than “Establish
corrective action plans.”

     (Response)  The comments did not explain what, if any, practical
difference would exist between “procedures” and “corrective action
plans.”  A corrective action plan is a procedure for which you must
have a record in the master manufacturing record (final §
111.210(h)(5)).  Because “corrective action plans” is a term that is
commonly used in the industry, we have retained it in the final rule.

J. What Must You do if Established 

Specifications are Not Met?

(Final § 111.77)

	1. Final § 111.77

	As we explain in section II, we reorganized the final rule to make it
more “user-friendly” and to clarify the rule’s applicability to
certain persons, items, or activities.  Final § 111.77 is a new
provision that clarifies your responsibilities and identifies those
responsibilities in a more “user-friendly” fashion.  We have
identified in one final § 111.77 the consequences of not meeting the
specifications you establish under this subpart and when you can
consider a treatment, in-process adjustment, or reprocessing to correct
a failure to meet and established specification for a component, dietary
supplement, packaging, or label.  Subpart F does identify these
consequences in several provisions which deal with the responsibility of
the quality control personnel unit to review and approve or reject
components, dietary supplements, packaging, and labels.  We determined
it would add clarity to state the consequences for not meeting a
specification in the same subpart in which the requirements to establish
specifications are located. 

	2. Final § 111.77(a)

	Final § 111.77(a) requires that for specifications established under
§ 111.70(a), (b)(2), (b)(3), (c), (d), (e), and (g) that you do not
meet, the quality control personnel unit, in accordance with the
requirements in subpart F of this part, must reject the component,
dietary supplement, package or label unless it approves a treatment, an
in-process adjustment, or reprocessing that will ensure the quality of
the finished dietary supplement and that the dietary supplement is
packaged and labeled as specified in the master manufacturing record. 
No finished batch of dietary supplements may be released for
distribution unless it complies with final § 111.123(bB).

	This provision identifies those specifications, if not fully met, that
may be able to be corrected by treatment, in-process adjustment, or
reprocessing and approved by the quality control personnelunit.  We
emphasize, however, that even if, for example, corrections are approved,
the finished batch of dietary supplement can not be released for
distribution unless it is compliance with the requirements of final §
111.123(b) (discussed in section XI).

	Final § 111.77(a) derives from the following proposed provisions:

•   § 111.50(d)(2) which would require the quality control unit not
to approve and release for distribution any batch of dietary supplement
that does not meet all specifications; 

•   § 111.50(f) which would require you to not reprocess a batch that
deviates from the master manufacturing record unless approved by the
quality control unit.

•    § 111.50(g) which would require that a reprocessed batch of
dietary supplement meet all specifications and that the quality control
unit approve its release for distribution.  

•    § 111.35(i)(4)(i) which would require, for any deviation or
unanticipated occurrence which resulted in or could lead to adulteration
of the component, dietary supplement, packaging, or label, you to reject
the component, dietary supplement, packaging, or label, unless the
quality control unit determines that in-process adjustments are possible
to correct the deviation or occurrence. 

•    § 111.35(i)(4)(ii) which would require, for any deviation or
unanticipated occurrence which resulted in or could lead to adulteration
of the component, dietary supplement, packaging, or label, you to not
reprocess a rejected component or dietary supplement unless approved by
the quality control unit.

	3. Final § 111.77(b)

	Final § 111.77(b) requires that for specifications established under
final § 111.70(b)(1) that you do not meet, the quality control
personnel unit must reject the component and the component must not be
used in manufacturing the dietary supplement.  Final § 111.77(b)
complements final § 111.70(b)(1) which requires you to establish an
identity specification for components; final § 111.75(a)(1) which
requires you to conduct at least one appropriate test or examination to
verify the identity of any component that is a dietary ingredient; and
final § 111.75(a)(2) which requires you to confirm the identity of all
other components.  As discussed earlier in this section, many comments
recommended the final rule include a requirement for an identity test of
incoming components to ensure quality and safety.  We agree with these
comments and earlier comments that point out it may not be possible to
confirm the identity of some components after they have been processed
into the finished batch of the dietary supplement.  For these reasons,
we have concluded that, if the component specification for identity is
not met, you may not use the component in the manufacture of the dietary
supplement.  This component specification must be met and the quality
control personnel unit is are restricted in what action it must be taken
if this specification is not met. 

	4. Final § 111.77(c)

	Final § 111.77(c) requires that if you do not meet the specifications
established under § 111.70(f), the quality control personnelunit must
reject the product and the product must not be packaged or labeled for
distribution as a dietary supplement.  As with final § 111.77(b), final
§ 111.77(c) limits the actions you can take to package and label
product you receive for packaging and labeling from a supplier for
packaging or labeling as a dietary supplement (and for distribution
rather than for return to the supplier).  Final § 111.77(c) complements
final § 111.70(f), which requires you to establish a specification for
such received product and final § 111.75(e), which requires you to
visually examine the product, before you package or label it, and have
documentation to determine whether the specifications that you
established under § 111.70(f) are met.  If you do not meet the
specifications under final § 111.70(f), you must reject the product
and not package or label the product for distribution as a dietary
supplement.  

	K.  Comments on Shelf-Life

	In the preamble to the 2003 CGMP Proposal (68 FR 12157 at 12203), we
stated that we had considered whether to propose requirements for
expiration dating, shelf-life dating, or “best if used by” dating
(referred to in this preamble as shelf-life or expiration dating).  We
recognized that there are current and generally available methods to
determine the expiration date of some dietary ingredients, such as
vitamin C.  However, we were uncertain whether there are current and
generally available methods to determine the expiration dating of other
dietary ingredients, especially botanical dietary ingredients.  We did
not propose to require expiration dating because we had insufficient
scientific information to determine the biological activity of certain
dietary ingredients used in dietary supplements, and such information
would be necessary to determine an expiration date.  Further, because
official validated testing methods (i.e., AOAC or FDA) for dietary
supplements are evolving, especially for botanical dietary ingredients,
such methods are not always available to assess the strength of a
dietary ingredient in a dietary supplement. 

     The preamble to the 2003 CGMP Proposal emphasized that, if you use
an expiration date on a product, you should have data to support that
date (68 FR 12157 at 12204).  We recommended that you have a written
testing program designed to assess the stability characteristics of the
dietary supplement, and that you use the results of the stability
testing to determine appropriate storage conditions and expiration
dates.

    In the 2003 CGMP Proposal (68 FR 12157 at 12204), we invited comment
on whether any final rule should contain provisions regarding expiration
dating and the feasibility of conducting tests needed to support such
dates.  We also invited comment on whether to require expiration dating
on certain dietary ingredients and not others, for example, require
expiration dating of vitamin, mineral, and amino acid, but not of
botanical dietary ingredients.

     (Comment 200)  Several comments agree with our decision not to
require expiration dating on labels for dietary supplements at this
time, because of the wide range of products and the need for additional
data.  Most of these comments state, however, that manufacturers should
be allowed to include a “best if used by” date.  One comment
suggests addressing the issue in a separate rulemaking.  Other comments
support an expiration date because consumers and retailers expect one,
and some markets require one. Some comments state that the expiration
date or statement of product shelf life will help ensure that the
product meets its label claims and potency.

     Many comments state an expiration date on a label must be supported
by a rationale or data on stability testing.  Some of those comments
suggest that manufacturers should have flexibility in the type of
supporting data used.  Although label claims should be confirmed by
shelf-life testing when analytical methods exist, data could come from a
manufacturer’s experience with the product or accelerated stability
testing on similar products with the same storage container.  One
comment points out that some manufacturers already use stability
testing.  Another comment recommends that we provide a guidance document
on supporting data. 

     One comment suggests stringent supporting data are not needed for a
“best if used by” date, because that date provides a recommended
time frame to ensure the best quality.  Another comment asserts that the
discussion about expiration dates in the 2003 CGMP Proposal gives the
impression that the required level of supporting data is similar to the
requirements for drug labeling, rather than the requirements for food
shelf life labeling.  Another comment recommends that a general maximum
shelf life of four or five years should be included in the rule, with
shortened or lengthened shelf lives for individual products as data
become available.

     (Response)  These comments do not provide data or information that
would reduce the uncertainty about the feasibility of conducting tests
to support an expiration date and, thus, do not persuade us to alter our
position not to require that you establish an expiration date for your
product.  Indeed, the comments generally concur with that position. 
Because the final rule does not require that you establish an expiration
date, we decline to offer guidance on the type of data that are
acceptable to support an expiration date, other than to repeat that any
expiration date that you place on a product label (including a “best
if used by” date) should be supported by data. 

	L.  What Representative Samples Must You Collect?

	(Final § 111.80)

	Final § 111.80 sets forth requirements to collect representative
samples of components, packaging, and labels (final § 111.80(a));
in-process materials (final § 111.80(b)); the finished batch of
dietary supplement (final § 111.80(c)); product you receive for
packaging or labeling as a dietary supplement (and for distribution
rather than for return to the supplier) (final § 111.80(d)); and
packaged and labeled dietary supplements (final § 111.80(e)).  Final
§ 111.80(a) through (e) derive from proposed § 111.37(b)(11)(i)
through (b)(ll)(iv).

1.  Final § 111.80(a)

     Final § 111.80(a) requires you to collect representative samples
of each unique lot of components, packaging, and labels that you use to
determine whether the components, packaging, and labels meet
specifications established in accordance with § 111.70(b) and (d), and
as applicable, final § 111.70(a) (and, when you receive components,
packaging, or labels from a supplier, representative samples of each
unique shipment, and of each unique lot within each unique shipment). 
Final § 111.80(a) derives from proposed § 111.37(b)(11)(i).  Final
§ 111.80(a) includes changes related to our review of the proposed
requirements for clarity.  We had used the term “shipment lot” in
several proposed requirements, including § 111.35(g)(1)(i) (requirement
to test components that you receive), § 111.37(b)(11)(i) (requirement
to collect representative samples of components that you receive), §
111.40(a)(4) (requirements for components that you receive), §
111.40(b)(5) (requirements for packaging and labels that you receive)
and § 111.50(c)(5) (requirement to identify materials that you use in
the batch production record).  Some of these proposed requirements
(e.g., those in §§ 111.40(a)(4), 111.40(b)(3), and 111.50(b)(5)) make
clear that you must be able to trace each lot of materials you receive
to each separate shipment that contains that lot.  To clarify and
emphasize this meaning of shipment lot, we are revising proposed §
111.37(b)(11)(i) so that the representative samples you collect must
come from “each unique shipment, and of each unique lot within each
unique shipment.”  We make analogous revisions throughout the final
rule as necessary.

	As discussed in this section, final § 111.70(b) sets forth the
requirements to establish specifications for components, final § 111.73
requires you to determine if the specifications established are met, and
final § 111.75(a) sets forth the criteria you use to determine whether
these specifications are met.  Likewise, final § 111.70(f) sets forth
the requirements to establish specifications for product that you
receive from a supplier for packaging or labeling as a dietary
supplement (and for distribution rather than for return to the
supplier), final § 111.73 requires you to determine if specifications
established are met, and final § 111.75(e) sets forth the criteria to
use to determine whether these specifications are met.

	 For consistency with the regulations in final §§ 111.70 and 111.75,
we are separating the requirement to collect representative samples of
components (final § 111.80(a)) from the requirement to collect
representative samples of product that you receive from a supplier for
packaging or labeling as a dietary supplement (and for distribution
rather than for return to the supplier)(final § 111.(80)(d)).

	We did not receive comments specific to proposed § 111.37(b).

2.  Final 111.80(b)

     Final § 111.80(b) requires you to collect representative samples
of in-process materials for each manufactured batch at points, steps, or
stages, in the manufacturing process as specified in the master
manufacturing record, where control is necessary to ensure the identity,
purity, strength, and composition of dietary supplements, to determine
whether the  materials meet specifications established under final
§ 111.70(c), and as applicable, final § 111.70(a).  Final §
111.80(b) derives from proposed § 111.37(b)(11)(ii).

     We did not receive comments specific to proposed §
111.37(b)(11)(ii).

3.  Final 111.80(c)

     Final § 111.80(c) requires you to collect representative samples
of a subset of finished batches of each dietary supplement you
manufacture, which you identify through a sound statistical sampling
plan (or otherwise every finished batch), before releasing for
distribution, to verify that the finished batch of dietary supplement
meets product specifications established in accordance with final §
111.70(e), and as applicable, final § 111.70(a).  Final § 111.80(c)
derives from proposed § 111.37(b)(11)(iii).  Final § 111.80(c)
includes changes associated with final § 111.75(c) which provides
flexibility for you to test or examine a subset of finished batches you
select through a sound statistical sampling plan rather than to test or
examine all finished batches.  Under final § 111.75(c) the tests or
examinations you conduct at the finished batch stage verify that your
process is in control.

     We did not receive comments specific to proposed §
111.37(b)(11)(iii). 

4.  Final § 111.80(d)

	Final § 111.80(d) requires you to collect representative samples of
each unique shipment, and of each unique lot within each unique
shipment, of product you receive for packaging or labeling as a dietary
supplement (and for distribution rather than for return to the supplier)
to determine whether the received product meets the specifications
established under final § 111.70(f), and as applicable, final
§ 111.70(a).  Final § 111.80(d) derives from proposed
§ 111.37(b)(11)(i).  We did not receive comments specific to this
proposed requirement.  However, we are making changes to final
§ 111.80(d) consistent with those described for final § 111.80(a). 

5.  Final § 111.80(e)

     Final § 111.80(e) requires you to collect representative samples
of each lot of packaged and labeled dietary supplements to determine
whether the packaging and labeling of the packaged and labeled dietary
supplements meet specifications established in accordance with final
§111.70 (g), and as applicable, final § 111.70(a).  Final
§ 111.80(e) derives from proposed § 111.37(b)(11)(iv).  Final §
111.80(e) includes revisions associated with final § 111.70(g), which
requires you to establish specifications for the packaging and labeling
of the finished packaged and labeled dietary supplements.  Final
§ 111.70(g) includes specifications that determine whether you used
the packaging specified in the master manufacturing record and you
applied the label specified in the master manufacturing record.  Under
final § 111.70(a) and (g) the parameters that we proposed to specify
under proposed § 111.37(b)(11)(iv) are the required specifications for
packaged and labeled dietary supplements.

	Final § 111.80(e) includes a change to clarify the exact 
specifications by citing the relevant sections.  Final § 111.80(e)
also includes an editorial change in that you are required to
“determine whether” specifications are met rather than to
“determine that” specifications are met.  We are making this change
because “determine that specifications are met” may be interpreted
as a predetermined outcome -- i.e., that specifications will, in fact,
be met.  

     We did not receive comments specific to proposed §
111.37(b)(11)(iv).

	M.  What Are the Requirements for Reserve Samples?

	(Final § 111.83)

     Final § 111.83 sets forth requirements to collect and hold
reserve samples of dietary supplements.  Final § 111.83 derives from
proposed §§ 111.37(b)(12), 111.50 and 111.83(b)(2).

     Under proposed § 111.37(b)(12) we would require holding reserve
samples as an operation performed by the quality control unit.  Under
proposed § 111.50(h) we proposed that you collect representative
reserve samples of each batch of dietary supplement.  Consistent with
the changes that we are making to final § 111.80, final § 111.83
does not specify who must collect and hold the required reserve samples.
 However, under final § 111.105(g) the quality control personnelunit
retains oversight of the collection and holding of the required reserve
samples.  Because the requirement to collect and hold reserve samples is
not an operation that must be performed by the quality control
personnelunit, we are including the requirement to collect reserve
samples in subpart E as part of the elements of a production and process
control system rather than in subpart F as part of the requirements for
the quality control personnelunit. 

     For consistency with terms used elsewhere in the final rule, final
§ 111.83 requires that you “hold” reserve samples rather than
“keep” them.

1.  Final § 111.83(a)

     Final § 111.83(a) requires you to collect and hold reserve
samples of each lot of packaged and labeled dietary supplements that you
distribute.  Final § 111.83(a) derives, in part, from proposed §
111.37(b)(12) which would require the quality control unit to keep the
reserve samples and, in part, from § 111.50(h), which would require you
to collect representative reserve samples from each batch of dietary
supplement. 

     (Comment 201)  Several comments ask for clarification of the
requirements for representative and reserve samples as proposed in §
111.37(b)(11) and (12).  One comment notes that proposed
§ 111.37(b)(11) does not indicate whether representative samples are
also collected to serve as the reserve samples described in proposed §
111.37(b)(12) and asks whether the items in proposed
§ 111.37(b)(11)(i) through (b)(11)(iv) are to be kept as reserve
samples. 

     (Response)  As discussed in section VI, we are adding a definition
of “reserve sample” to reduce the potential for confusion between
requirements for reserve samples and requirements for representative
samples.  A reserve sample is a representative sample that is held for a
designated period of time.  

2.  Final § 111.83(b)(1)

     Final § 111.83(b)(1) requires the reserve samples to be held
using the same container-closure system in which the packaged and
labeled dietary supplement is distributed, or if distributing dietary
supplements to be packaged and labeled, using a container-closure system
that provides essentially the same characteristics to protect against
contamination or deterioration as the one in which it is distributed for
packaging and labeling elsewhere.  Final § 111.83(b)(1) derives from
proposed § 111.83(b)(2) which we proposed to include with the
requirements for holding and distributing.  The final sections that
derive from proposed § 111.83(b)(2) are in subpart M (final
§ 111.465). However, we are duplicating these requirements in final
§ 111.83(b)(1) for clarity and ease of use, so that you have
information about the requirements for the container-closure system for
holding reserve samples of packaged and labeled dietary supplements in
the same section as the requirements to collect the samples.  

3.  Final § 111.83(b)(2)

     Final § 111.83(b)(2) requires that reserve samples be identified
with the batch, lot, or control number.  Final § 111.83(b)(2) derives
from proposed § 111.37(b)(12)(i) with editorial changes associated with
the reorganization.  We have added “control” number to the provision
for consistency with other provisions of the final rule which refer to a
“control number” in addition to a “batch or lot number.”

     We did not receive comments specific to proposed
§ 111.37(b)(12)(i).

4.  Final § 111.83(b)(3)

	Final § 111.83(b)(3) requires that reserve samples be retained for
one year past the shelf life date (if shelf life dating is used), or for
23 years from the date of distribution of the last batch of dietary
supplements associated with those reserve samples, for use in
appropriate investigations.  Final § 111.83(b)(3) derives from
proposed § 111.37(b)(12) which would require the quality control unit
to keep the reserve samples for 3 years from the date of manufacture for
use in appropriate investigations including, but not limited to,
consumer complaint investigations to determine, for example, whether the
dietary supplement associated with a consumer complaint failed to meet
any of its specifications for identity, purity, quality, strength, and
composition, as well as from proposed § 111.50(h) which would require
reserve samples to be kept for 3 years from the date of manufacture.  We
discuss the change from 3 years to 2 years and the change from “date
of manufacture” to “the date of distribution” in connection with
the recordkeeping requirements in subpart P, section XXI.

    Final § 111.83(b)(3) thus provides flexibility in determining how
long you must hold reserve samples of packaged and labeled dietary
supplements. 

    Final § 111.83(b)(3) does not include the proposed examples of
investigations that may require the use of reserve samples because these
examples are not requirements.

     (Comment 202) Many comments address the requirement to keep the
reserve samples after manufacture and recommend that expiration dates be
a factor when determining the amount of time reserve samples should be
kept and maintained.  Most of the comments recommend holding reserve
samples of packaged and labeled dietary supplements for three years from
the date of manufacture or, when an expiration date has been established
by the manufacturer, for 1 year after the expiration date.  Other
comments recommend holding reserve samples for time periods ranging from
6 months to 2 years after the expiration date.

     (Response)  The final rule contains requirements similar to the
suggestions made by the comments.  The final rule provides flexibility
to hold reserve samples for one year past the shelf life date, when such
dating is used.  Any shelf life date that you include on the label of
the product should be supported by scientific data.

 5.  Final § 111.83(b)(4)

     Final § 111.83(b)(4) requires that reserve samples consist of at
least twice the quantity necessary for all tests or examinations to
determine whether or not the dietary supplement meets product
specifications.  Final § 111.83(b)(4) derives from proposed
§ 111.37(b)(12)(ii) which would require that the reserve samples
consist of at least twice the quantity necessary for tests.

     Final § 111.83(b)(4) provides that the reserve samples may be
used for examinations or tests and to determine whether or not the
dietary supplement meets product specifications, as a revision
associated with final § 111.75.

     (Comment 203)  One comment agrees that twice the quantity necessary
for testing should be collected and held.

     (Response) The final rule is consistent with this comment.

N. Who Conducts a Material Review and

 Makes a Disposition Decision?

(Final § 111.87)

     Final § 111.87 requires the quality control personnel unit to
conduct all required material reviews and make all required disposition
decisions.  Final § 111.87 derives from a number of proposed
requirements for conducting a material review and making a disposition
(§§ 111.35(i), 111.35(n), 111.37(b)(5), 111.37(b)(14), 111.40(a)(3),
111.50(d)(1), 111.85(a), and 111.85(c)).  Under each of these
provisions, the quality control unit would have an oversight role and
would review and approve all material reviews and all disposition
decisions.  Under some of these provisions (i.e., §§ 111.50(d)(1),
111.85(a), and 111.85(c)) the quality control unit would conduct the
material review itself and make the disposition decision.

     (Comment 204)  One comment disagrees that the quality control unit
must conduct the material review and make the disposition decision.  The
comment argues that manufacturing personnel are better qualified to
conduct the review and make disposition decisions because they are often
engineers and have the relevant expertise regarding the use of machinery
and people to produce a product.  In contrast, the comment asserts that
quality control unit personnel generally are chemists with expertise
only in testing and little expertise in manufacturing.  The comment
asserts that the quality control unit should not be expected to make
decisions concerning manufacturing operations; however, it should be
informed of changes so it can evaluate the results of reprocessing on
the finished product. 

     (Response)  We agree, in part, with the comments and the final rule
simplifies the provisions regarding a material review and disposition
decision.  The qQuality control personnel unit can conduct the material
review and disposition decision by reviewing the underlying information
gathered or obtained by other qualified personnel and then making the
final decision.     	Under the final rule, we retain the principle that
qualified individuals other than those in the quality control personnel
unit can contribute to the quality control personnelunit’s material
review and disposition
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●    Under final § 111.87 the quality control personnel unit must
conduct all required material reviews and make all required disposition
decisions;

●    Under final § 111.103 you must establish and follow written
procedures for conducting a material review and making a disposition
decision; and

●    Under final § 111.140(b)(3)(vii) documentation of a material
review and disposition decision and followup must include the signature
of the individual(s) designated to perform the  from the quality control
operations, unit who conducted the material review and made the
disposition decision, and of any qualified individual who provided
information relevant to that material review and disposition decision.

     Taken in total, the final rule establishes a system in which you
have flexibility to develop procedures that suit your organization,
including having qualified individuals, other than outside of the
designated quality control personnel, unit provide information relevant
to the material review and disposition decision.  For example, under
final § 111.140(b)(3), you could have a qualified individual in the
production department prepare a report that includes all the required
documentation and information and provide a signed copy of that report
to designated the quality control personnel unit.  An individual from
the designated to perform quality control operations unit would then
read that report, add to it if necessary, conduct any additional
investigations if necessary, and if he or she agrees with the report,
co-sign the report or an amended report that includes additional
documentation or information, thus completing a material review and
disposition decision.

	The final rule provides for the participation of qualified individuals,
other than those designated to perform in the quality control operations
unit, in conducting the material review.  In addition, as already
discussed, under final § 111.12(b) you may assign a qualified
individual who has responsibilities for operations other than quality
control to perform quality control operations, provided that the
individual has distinct and separate responsibilities related to
performing quality control operations.

O.  What Requirements Apply to Treatments, In-process Adjustments, and
Reprocessing When There 

is a Deviation or Unanticipated Occurrence or When a Specification
Established in Accordance with § 111.70 is not Met?

	(Final § 111.90)

1.  Final § 111.90

    Final § 111.90 is a unified provision that clarifies your
responsibilities regarding treatment or in-process adjustments to a
component, and in-process adjustments or reprocessing of a dietary
supplement, in a more “user-friendly” fashion.  We have identified
in one provision the restrictions that apply to these operations.  Final
§ 111.90 derives from proposed §§ 111.35(i)(4)(i), (ii) and (iii),
111.50(d)(1), (f), and (g), and 111.65(d). 

       Final § 111.90 includes the following changes we are making to
the proposed provisions for consistency and clarity. 

•	We are making revisions to make the section consistent with the
definition of “reprocessing” in final § 111.3, which refers only to
“components or dietary supplements that have been previously removed
from manufacturing.”  

•	We are adding “treatments” as a step that the quality control
personnel unit could approve, because that term better describes actions
that could be taken to correct a deviation or unanticipated occurrence
with a component, packaging or label.

•	We are clarifying that it is the quality control personnel unit that
who rejects components, packaging, or labels. 

•	We are clarifying that the quality control personnel unit approves
the treatment, in-process adjustment, or reprocessing rather than
determines whether the treatment, in-process adjustment, or reprocessing
is possible.

•	We are clarifying that, with respect to labels, the provision
applies to the potential that a label not specified in the master
manufacturing record could be used. 

• 	We are making changes to be consistent with the new provision,
final § 111.77.

     (Comment 205) One comment recommends deletion of proposed §
111.35(i)(4) and (i)(4)(i), arguing that the principles of those
sections are covered under proposed § 111.35(i)(2) and (i)(3).

     (Response) We disagree with the comment’s assertion.  The
requirements of proposed § 111.35(i)(4) and (i)(4)(i) are not covered
by proposed § 111.35(i)(2) and (i)(3).  All the sections are related,
but deal with different aspects of corrective action.  Proposed
§ 111.35(i)(2) and (i)(3) would require the firm to conduct a material
review and make a disposition decision, while proposed § 111.35(i)(4)
would prohibit the use of rejected ingredients unless the quality
control unit determines that in-process adjustments are possible to
correct the deviations or occurrence.  We are making no changes as
suggested by this comment and the primary elements of proposed §
111.35(i)(4) are retained in final § 111.90.  

    (Comment 206)  A few comments state their support for the
requirement that the quality control unit have the authority to
determine whether adjustments are possible to correct a deviation.

     (Response)  We are retaining the proposed requirement for quality
control personnel in  final § 111.90.

2.  Final § 111.90(a)

     Final § 111.90(a) requires that you must not reprocess a rejected
dietary supplement, treat or provide an in-process adjustment to a
component, packaging, or label  to make it suitable for use in the
manufacture of a dietary supplement, unless: (1) the quality control
personnel unit conducts a material review and makes a disposition
decision to approve the reprocessing, treatment, or in-process
adjustment; and (2) the reprocessing, treatment, or in-process
adjustment is permitted by § 111.77.

	Final § 111.90(a) derives from proposed §§ 111.35(i)(4)(ii) and
111.50(d)(1).  We revised this provision to be consistent with the
changes in final § 111.77.

     (Comment 207) Several comments state their support for proposed
§ 111.35(i)(4)(ii) which would require the quality control unit to
approve the reprocessing of any rejected component, dietary ingredient,
or dietary supplement.  However, not all comments agree that the quality
control should have to conduct (under proposed § 111.50(d)(1)), rather
than review and approve, a material review and disposition decision. 

(Response) As discussed in this section, by “conduct a material review
and make a disposition decision,” we do not intend to limit those who
may participate in a material review and disposition decision to only
those persons acting in their capacity as the designated quality control
personnelunit.  Others may assist the quality control personnel unit in
gathering and considering information relevant to the review and
decision, however the quality control personnelunit havehas the
responsibility to conduct a material review and make disposition
decisions.  Thus, we are retaining the requirements in proposed
§§ 111.25(i)(4)(ii) and 111.50(d)(1) in final § 111.90(a).  

3.  Final § 111.90(b)

     Final § 111.90(b) requires that you must not reprocess anyor
dietary supplement, treat or provide and in-process adjustment to a
component to make it suitable for use in the manufacture of a dietary
supplement, unless: (1) your quality control personnelunit conducts a
material review and makes a disposition decision based on a
scientifically valid reason and approves the reprocessing, treatment, or
in-process adjustment; and (2) the reprocessing, treatment or in-process
adjustment is permitted by § 111.77.  Final § 111.90(b) derives from
proposed §§ 111.35(i)(4)(iii), 111.50(f), and 111.65(d).  We revised
this provision to be consistent with the changes in final § 111.77.

     (Comment 208) As discussed in section VI (discussion of the
definition of “reprocessing”), some comments object to the
restrictions in the definition of reprocessing in proposed § 111.3,
because the definition would not permit the reprocessing of ingredients
that may have been removed because of insanitary conditions even if
there are processes available that are safe and effective in removing
foreign matter, microorganisms, or chemicals that may have rendered the
ingredient “insanitary.”  These comments also object to proposed §
111.35(i)(4)(iii) for the same reasons.  A few comments argue that a
manufacturer should be able to reprocess a component or dietary
supplement if it has been rejected because of contamination with
microorganisms or types of contamination, such as heavy metals, if the
quality control unit approves the reprocessing.  These comments indicate
this is the industry practice, one based on a scientific rationale for
doing the reprocessing and that ensures other quality attributes of the
product are not affected.  

     Some comments state that the requirement is more strict than the
food or drug CGMP requirements, noting that reprocessing is widely
accepted and allowed in the food CGMPs.  Other comments believe that the
prohibition in proposed § 111.35(i)(4)(iii) against reprocessing
materials contaminated with microorganisms should be limited to
materials contaminated with health-hazardous microorganisms.

     (Response) As we discussed in the response to comment 53 for the
definition of “reprocessing”, we agree with the comments that state
that in-process materials can be reprocessed when there are suitable
processes available.  However, as noted by the comments, it is critical
that there be appropriate oversight of the reprocessing so the quality
of the dietary supplement is not compromised.  Final § 111.90(b)
provides for the flexibility requested by the comments, provided that
there is oversight by the quality control personnelunit.

     (Comment 209) Proposed § 111.35(i)(4)(iii) mentions
“microorganism or other contaminants, such as heavy metals.”  One
comment proposes that other contaminants, such as pesticides and
aflatoxin, should be mentioned.  Another comment suggests that the final
rule should specify limits for heavy metals in dietary supplements.

     (Response)  We decline to revise the final rule as suggested by the
comments.  It is impractical to provide an exhaustive list of relevant
types of contamination, and a list that is longer, but not exhaustive,
is more likely to be misunderstood as suggesting that the only types of
contamination that are significant are the types of contamination in the
list.  For that reason, we have eliminated the reference to
contamination to clarify that in any instance where it is appropriate
the quality control unit personnel must ensure that the disposition
decision is based on a scientifically valid reason and it also approves
the reprocessing.

     (Comment  210)  One comment notes that in the May 9, 2003,
satellite broadcast concerning the 2003 CGMP Proposal, we indicated that
treating a component or dietary supplement with irradiation as a means
to reduce or eliminate the microbial load was acceptable as long as the
treatment was part of the process for producing that material.  The
comment asks for confirmation that irradiation of components or dietary
supplements is allowed under part 179, even though such treatments are
not listed in the table provided in § 179.26 (b). 

    (Response)  We are unable to provide the requested confirmation. 
Under section 201(s) of the act, irradiation intended for use in
producing, manufacturing, packing, processing, preparing, treating,
packaging, transporting, or holding food is a food additive that
requires premarket review and approval before it can be used in food. 
Our Office of Food Additive Safety is currently reviewing a food
additive petition for the use of irradiation on dietary ingredients and
dietary supplements.  Until that review process is completed and we have
authorized this use of irradiation through a final rule codified in part
179, irradiation of dietary ingredients and dietary supplements as a
means to reduce or eliminate microbial loads is not permitted.  However,
you may use an irradiated component (such as a spice that is used to
flavor a dietary supplement) when the irradiation of that component is
allowed under § 179.26.

4.  Final § 111.90(c)

     Final § 111.90(c) requires that any batch of dietary supplement
that is reprocessed, that contains components that you have treated, or
to which you have made in-process adjustments to make them suitable for
use in the manufacture of the dietary supplement must be approved by the
quality control personnel unit and comply with final § 111.23(b) before
releasing for distribution. Final § 111.90(c) derives from proposed
§ 111.50(g).

     Final § 111.90(c) also includes conforming revisions to clarify
that a dietary supplement that contains a component treated before use
or adjusted in-process, or that has had in-process adjustments to make
it suitable for use in the manufacture of a dietary supplement, must be
approved by the quality control personnelunit and comply with final §
111.23(b) before releasing for distribution.  We revised this provision
to be consistent with the changes in final § 111.77 and final §
111.23(b). 

     Final § 111.90(c) also includes revisions to reflect the final
provisions that relate to reprocessing and in-process adjustments (see
final §§ 111.113, 111.120, and 111.155).

     (Comment 211)  One comment asserts that a reprocessed product
should be retested to confirm that it meets product specifications.

     (Response) Under final § 111.75(c) and (d) the quality control
personnel unit haves flexibility to determine whether tests or
examinations are necessary to ensure that a reprocessed product meets
product specifications.

	P.  Under this Subpart, What Records Must You Make and Keep? 

	(Final § 111.95)

1.  § 111.95(a)

     Final § 111.95(a) requires you to make and keep records required
under this subpart in accordance with subpart P.  Final § 111.95(a)
derives from proposed § 111.35(o).  Some of the records required under
subpart E are set forth as recordkeeping requirements in other subparts
of this final rule, such as those related to receiving records for
components, packaging, and labels in subpart G, and the results of
testing or examination in subpart J.  The record requirements not
specifically required in other related subparts are listed in subpart E.
 

     (Comment 212)  One comment supports the recordkeeping requirements,
states that the records provide a valuable paper trail that will allow
manufacturers to identify and fix problems in the process, and suggests
the requirements protect consumers from adulterated and misbranded
products.

     (Response)  We agree.  Under final § 111.95(a) firm must make and
keep records required by subpart E in accordance with subpart P.  As
discussed in this section, firms are required to keep the records
necessary for determining whether their products are made in accordance
with specifications.  This will help them identify and correct any
problems.  In addition, under subpart P, the records must be kept for 1
year past the shelf life date (if shelf life dating is used) or twothree
years beyond the date of distribution of the last batch of dietary
supplements associated with those records.  Moreover, firms must make
their records available to us for inspection and copying, which will
permit us to determine whether firms are manufacturing, packaging,
labeling, and holding dietary supplements in accordance with the
requirements of this rule. 

2.  § 111.95(b)

     Final § 111.95(b) specifies the records you must make and keep
under subpart E.  Under the reorganization several recordkeeping
requirements of proposed § 111.35 are set forth in other subparts. 

     Final § 111.95(b)(1) requires you to make and keep records of the
specifications established.  Final § 111.95(b)(1) derives from proposed
§ 111.35(o)(1).	

     Final § 111.95(b)(2) requires you to make and keep records of
your qualification of a supplier for the purpose of relying on the
supplier’s certificate of analysis.  Final § 111.95(b)(2) is a
record that is required under final § 111.75(a)(2)(B).

     Final § 111.95(b)(3) requires you to make and keep documentation
for why meeting in-process specifications, in combination with meeting
component specifications, helps ensure that the dietary supplement meets
the specifications for identity, purity, strength, and composition 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 § 111.95(b)(3) refers to records required under final
§ 111.70(c)(2). 

     Final § 111.95(b)(4) requires you to make and keep documentation
for why the results of appropriate tests or examinations for the product
specifications selected under final § 111.75(c)(1) ensures that the
dietary supplement meets all product specifications.  Final
§ 111.95(b)(4) is a record that is required under final
§ 111.75(c)(3). 

	Final § 111.95(b)(5) requires you to make and keep documentation for
why any component and in-process testing, examination, or monitoring,
and any other information, will ensure that a product specification that
is exempted under final § 111.75(d) is met without verification through
periodic testing of the finished batch, including documentation that the
selected specifications tested or examined under final § 111.75(c)(1)
are not able to verify that the production and process control system is
producing a dietary supplement that meets the exempted product
specification and there is no scientifically valid method for testing or
examining such exempted product specification at the finished batch
stage.  Final § 111.95(b)(5) refers to a record  required under final
§ 111.75(d)(1).

	(Comment 213)  One comment recommends the recordkeeping requirements of
proposed § 111.35(m) be moved to follow the requirements for
appropriate test methods, because these requirements are related and
probably best understood without intervening information. 

     (Response)  Consistent with this comment, the recordkeeping
requirements of proposed § 111.35(m) are set forth in final subpart J
instead of this subpart.

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hemicals and thus promote uniform quality and ensure safety in the use
of such chemicals. The First Edition of the resulting FCC, published in
1966, was limited to chemicals added directly to foods to achieve a
desired technological function. Succeeding editions upgraded the
specifications for these substances and added specifications for
substances that come into contact with foods and some that are regarded
as foods, rather than as additives. The FCC is available for purchase at
1-800-624-6242 or at www.nap.edu.

FDA-Internal-Deliberative-Confidential

Final Subpart E 9-28-05, 6-26-06

Page   PAGE  473