XV.  Comments on Production and Process Control System: Requirements for
Laboratory Operations

(Final Subpart J)

A.  Organization of Final Subpart J

     In the 2003 CGMP Proposal, the proposed requirements for production
and process controls for laboratory operations were set forth in
proposed § 111.60(a) through (d).  As shown in table 11, we are
reorganizing the requirements for laboratory operations into a distinct
subpart (final subpart J – Production and Process Control System:
Requirements for Laboratory Operations).  Table 11 lists the sections in
final subpart J and identifies the proposed sections that form the basis
of the final rule. 

Table 11. - Derivation of Sections in Final Subpart J

Final Rule 	2003 CGMP Proposal

§ 111.303 What Are the Requirements Under this Subpart for Written
Procedures?	N/A

§ 111.310 What Are the Requirements for the Laboratory Facilities?	§
111.60(a)

§ 111.315 What Are the Requirements for Laboratory Control Processes?
§ 111.60(b)(1)

§ 111.320 What Requirements Apply to Laboratory Methods for Testing and
Examination?	§ 111.60(c) and § 111.60(d)

§ 111.325 Under This Subpart, What Records Must You Make and Keep?	§
111.60(b)(2) and § 111.60(b)(3)



B.  Highlights of the Changes to the 

Proposed Requirements for Laboratory Operations

1.  Revisions

     The final rule applies to persons who manufacture, package, label,
or hold dietary supplements unless subject to an exclusion in § 111.1. 


2.  Changes Associated With the Reorganization

     This subpart contains fewer details, compared to the 2003 CGMP
Proposal, regarding the requirements for collecting representative
samples and for testing, because these details are set forth elsewhere
in this final rule (i.e., in final §§ 111.75 and 111.80) and would be
redundant in final subpart J.  

3.  Changes After Considering Comments

     The final rule: 

•	Includes a new requirement to establish and follow written
procedures for laboratory operations, including written procedures for
the tests and examinations you conduct to determine whether or not
specifications are met.

•	Requires you to identify and use the appropriate “scientifically
valid method,” rather than an appropriate “validated testing
method,” for each established specification for which testing or
examination is required to determine whether the specification is met.  


C.  What Are the Requirements Under This Subpart 

for Written Procedures? 

(Final § 111.303)

	We received many comments that recommended written procedures for
various provisions. We address the need for written procedures generally
in section IV.  We also respond to individual comments on specific
provisions in the same section.

	Final § 111.303 requires you to establish and follow written
procedures for laboratory operations, including written procedures for
the tests and examinations you conduct to determine whether
specifications are met. 

D. What are the Requirements for the 

Laboratory Facilities That You Use? (Final § 111.310)

     Final § 111.310 requires you to use adequate laboratory facilities
to perform whatever testing and examinations are necessary to determine
whether: (a) Components that you use meet specifications; (b) in-process
specifications are met as specified in the master manufacturing record;
and (c) dietary supplements that you manufacture meet specifications.
Final § 111.310(a) is substantially similar to proposed § 111.60(a). 
The requirement for “adequate laboratory facilities” is to ensure
that the facilities used are designed and suitable for carrying out the
necessary tests and examinations. Other CGMP requirements of this final
rule would apply to the manufacturer’s laboratory facilities, such as
subpart C, Physical Plant and Grounds, and subpart D, Equipment and
Utensils and should be considered in assessing the adequacy of the
laboratory facilities.  If the tests and examinations are carried out by
an outside laboratory, you will be responsible for ensuring that the
test and examinations are adequately performed.   

     (Comment 272) One comment states that proposed § 111.60(a) would
be highly disruptive to the dietary supplement industry and would impose
a great burden on companies that traditionally rely on certification of
ingredient suppliers.  Some comments assert it would be redundant to
require testing by companies who are suppliers of dietary ingredients,
as well as by companies who receive the dietary supplements, to
determine whether the dietary ingredients meet specifications.

     (Response) The final rule already includes changes that address the
concerns raised by these comments.  As discussed in final § 111.75(a),
section X, the final rule permits the use of certificates of analysis
for specifications other than the identity of a dietary ingredient.

E. What Are the Requirements for Laboratory Control Processes? (Final §
111.315)

     Final § 111.315 sets forth the minimum laboratory control
processes that you must establish and follow.  These laboratory control
processes must be reviewed and approved by the quality control unit.    

1.  Final § 111.315(a)

     Final § 111.315(a) requires the laboratory control processes you
establish and follow to include the use of criteria for establishing
appropriate specifications.  Final § 111.315(a) is identical to
proposed § 111.60(b)(1)(ii).

     We did not receive comments specific to proposed §
111.60(b)(1)(ii).

2.  Final § 111.315(b)

     Final § 111.315(b) requires you to establish and follow laboratory
control processes that are reviewed and approved by the quality control
unit, including the use of sampling plans for obtaining representative
samples, in accordance with subpart E, of: (1) Components, packaging,
and labels; (2) in-process materials; (3) finished batches of dietary
supplements; (4) product you receive for packaging or labeling as a
dietary supplement (and for distribution rather than for return to the
supplier); and (5) packaged and labeled dietary supplements.  Final §
111.315(b) derives from proposed § 111.60(b)(1)(iii)(A) through
(b)(1)(iii)(E).

     Final § 111.315(b) combines the proposed requirements of §
111.60(b)(1)(iii)(A) and (b)(1)(iii)(D) for consistency with final §
111.80(a) which combines the requirements to collect representative
samples of components, packaging, and labels.  However, for consistency
with other requirements established by this final rule, we are
separating the requirements to collect representative samples of
“dietary supplements received” (which the final rule refers to as
“product that you receive for packaging or labeling as a dietary
supplement (and for distribution rather than for return to the
supplier,” or “received product) from the requirements to collect
representative samples of components.       

(Comment 273) Some comments note that proposed § 111.60(b)(1)(iii)
restates the requirements, already contained in proposed §
111.37(b)(11)(i) through (b)(11)(iv), that the quality control unit
collect representative samples.  These comments request proposed §
111.60(b)(1)(iii) be deleted, because it is more appropriately described
as a quality control function rather than as a laboratory function.

      (Response) We disagree that the proposed requirement to use a
sampling plan is more appropriately described as a quality control
function than as a laboratory function.  Under both the proposed and the
final rule, the sampling plans that are part of the laboratory control
operations are subject to approval by the quality control unit but are
not developed by the quality control unit.  We are making no changes
based on this comment.

      (Comment 274) One comment asserts sampling can be better
accomplished at the point of packaging rather than at a laboratory
remote from the packaging operation. 

      (Response) This comment misinterprets proposed §
111.60(b)(1)(iii) which proposed to establish a process (i.e., the use
of a sampling plan) rather than to direct that a particular operating
unit (such as a laboratory) collect samples.  We are making no changes
based on this comment.

3.  Final § 111.315(c)

     Final § 111.315(c) requires the laboratory control processes you
establish and follow include use of criteria for selecting appropriate
examination and testing methods.  Final § 111.315(c) is identical to
proposed § 111.60(b)(1)(i).

     (Comment 275) One comment recommends that a contract laboratory
hired by a person who is subject to the final rule be able to determine
the specific type of test that is most appropriate.

     (Response) Nothing in the final rule would preclude you from
relying on the recommendation of the contract laboratory in selecting an
appropriate test or examination.  However, the manufacturer of the
dietary supplement has the responsibility to comply with these CGMP
requirements, including the requirement to select appropriate tests,
regardless of who conducts the tests.  

4.  Final § 111.315(d)

     Final § 111.315(d) requires the laboratory control processes you
establish and follow to include use of criteria for selecting standard
reference materials used in performing tests and examinations.  Final §
111.315(d) derives from proposed § 111.60(b)(1)(iv).

     (Comment 276) Several comments support the use of standard
reference materials.  Some comments distinguish between a reference
standard (which they describe as a highly purified compound that is well
characterized and is used in quantitative assays for single chemical
entities) and a reference material (which they describe as similar to a
reference standard but with less specificity).  These comments urge us
to recognize the difference between reference standards and reference
materials and to require the use of both in the final rule.

     (Response) The comments that request we recognize a difference
between certain types of reference materials are consistent with
proposed § 111.60(b)(1)(iv) and with statements that we made in the
preamble to the 2003 CGMP Proposal.  We distinguished two general types
of reference materials: (1) Compendia reference standards that do not
require characterization; and (2) noncompendia standards that should be
of the highest purity that can be obtained by reasonable effort and that
should be thoroughly characterized to ensure their identity, purity,
quality, and strength.  We recommended you use compendia reference
standards whenever possible, and that you establish appropriately
characterized in-house materials prepared from representative lots if no
compendia reference standard exists.

    We also discussed reference materials from the perspective of the
type of test or examination.  For organoleptic examinations, we
described an authenticated plant reference material as material that has
been authenticated as the correct plant species and correct plant
part(s) by a qualified plant taxonomist.  For microscopic and chemical
tests (including calibration tests), we described a reference material
as a highly purified compound that is well characterized. 

    To the extent that the comments are recommending that both compendia
reference standards and noncompendia reference standards comply with any
final rule, this final rule would allow for the use of both compendia
reference standards and noncompendia reference standards.  However, to
the extent that the comments are requesting this final rule require that
both types of reference materials be used, we disagree.  We see no
reason to require, for example, that a firm with access to compendia
standards be required to develop noncompendia standards.  Likewise,
given that we have acknowledged that noncompendia standards may be used,
we see no reason to require the use of compendia standards in all
circumstances. 

     (Comment 277) One comment expresses confusion about the preamble
discussion of proposed § 111.60(b)(1)(iv) and suggests the preamble
specify that reference standards be established appropriate to the assay
procedure for which they are used.

     (Response) Reference materials should be appropriate to the assay
procedure for which they are used.

     (Comment 278) Several comments recommend we acknowledge certain
reference materials as authoritative sources for botanical ingredients,
such as American Herbal Pharmacopoeia, European Pharmacopoeia, and the
World Health Organization, in part because other sources include only a
limited number of botanicals as supplements.  In the comments’ view,
explicit acknowledgment by FDA would encourage manufacturers to use
independent standards, increase CGMP compliance, and show that
validation is not limited to quantitative chemical methods.

     (Response) We decline to acknowledge certain reference materials as
authoritative sources for botanical ingredients.  Such a request is
outside the scope of this final rule.  

     (Comment 279) One comment believes we should designate USP to
develop appropriate standards.

     (Response) This comment is outside the scope of this final rule. 

5.  Final § 111.315(e)

     Final § 111.315(e) requires that the laboratory control processes
you must establish and follow include use of test methods and
examinations in accordance with established criteria.  Final §
111.315(e) derives from proposed § 111.60(b)(1)(vi).  

     We did not receive comments specific to proposed §
111.60(b)(1)(vi).            

F. What Requirements Apply to 

Laboratory Methods for Testing and Examination? 

(Final § 111.320)

1. Final § 111.320(a)

     Final § 111.320(a) requires you to verify that laboratory
examination and testing methodologies are appropriate for their intended
use.  Final § 111.320(a) is identical to proposed § 111.60(c).

     (Comment 280) One comment states that this decision should be made
by a qualified person, whether in-house or at a contract laboratory.

     (Response) We agree.  Nothing in the final rule would preclude you
from relying on the judgment of a qualified person at a contract
laboratory to satisfy the requirements of final § 111.320(a).  We would
not consider that a recommendation from a contract laboratory is any
different from a recommendation from an operating unit of the
manufacturer.  However, the manufacturer of the dietary supplement has
the responsibility to comply with these CGMP requirements, including the
requirement to select appropriate tests, regardless of who conducts the
tests.      

     (Comment 281) One comment suggests modifying proposed § 111.60(c)
to add “reference materials and/or reference standards” to the list
of elements that must be verified to be appropriate for their intended
use.

     (Response) If reference materials and reference standards are used
as part of the test or examination method, then such materials and
standards are already required to be verified under the language in
proposed § 111.60(c).  Thus, there is no need for the modification and
we decline to modify the language of final § 111.320(a).

2. Final § 111.320(b)

     Final § 111.320(b) requires you to identify and use the
appropriate scientifically valid method for each established
specification for which testing or examination is required to determine
whether the specification is met.  Final § 111.320(b) derives from
proposed § 111.60(d) which would require you to identify and use an
appropriate validated testing method for each established specification
for which testing is required to determine whether the specification is
met.  Final § 111.320(b) includes a provision associated with final §
111.75(h) which provides flexibility to use examinations as well as
tests to determine whether specifications are met.    

(Comment 282) Many comments express concern about the amount of testing
required for the validation of the appropriate test method.  Several
comments object to the use of the terms “validations” and
“validated” which they assert have a specific meaning in a
pharmaceutical context and would be overly burdensome in this rule. 
Other comments assert that methods already recognized as official
standards do not need to be “validated,” but simply “verified”
as to suitability.  Some comments suggest substituting “scientifically
valid testing method” for “appropriate validated testing method.” 
One comment suggests “qualifications” replace “validations.” 
Another comment suggests test methods need not be validated if they are
“proven to be suitable under actual conditions of use.”  Another
comment suggests adding “established by the manufacturer” after
“appropriate validated test method.” 

     One comment recommends the final rule give companies the
flexibility to adopt the method most suitable to the ingredient they are
testing, regardless of whether the method is, or is not, an “official
method” such as those established by AOAC International or FDA.

      (Response) In the preamble to the 2003 CGMP Proposal (68 FR 12157
at 12208), we stated that test method validation determines whether a
newly-developed or existing test method is accurate, precise, and
specific for its intended purpose and involves evaluating the test
method on multiple occasions or in multiple test facilities.  We
explained that official methods, such as AOAC International methods, are
validated in collaborative studies using several laboratories under
identical conditions and that the AOAC International methods are often
cited as “official validated methods.”  We also explained that other
method validations are conducted in a single laboratory by repeating the
same test multiple times.  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 all methods that are formally validated are
considered “scientifically valid,” other methods that are based on
scientific data or results published in, for example, scientific
journals, references, text books, or proprietary research can be
scientifically valid even if they are not formally “validated” in
collaborative studies

(68 FR 12157 at 12198).  

     We agree that companies should have flexibility to adopt the method
most suitable to the ingredient they are testing.  Consistent with the
view that we expressed in the preamble to 2003 CGMP Proposal (68 FR
12157 at 12198), we believe that a scientifically valid method is one
that is accurate, precise, and specific for its intended purpose.  In
other words, a scientifically valid method is one that consistently does
what it is intended to do.  

     Because we acknowledge that methods that are based on scientific
data or results published in, for example, scientific journals,
references, text books, or proprietary research can be scientifically
valid even if they are not formally “validated,” we are revising
proposed § 111.60(d).  Under final § 111.320(b) you must identify and
use an appropriate “scientifically valid method” (rather than a
“validated method”) for each established specification for which
testing or examination is required to determine whether the
specification is met.  However, we continue to recommend that you use
tests and examinations that already have been validated when such tests
are available.

      (Comment 283) One comment specifically asks how much modification
of a validated method is allowed before the method must be re-validated
by the laboratory.  The comment cites an example of moisture testing in
which the testing method needs to be modified to provide a more valid
moisture reading.

      (Response) In the preamble to the 2003 CGMP proposal (68 FR 12157
at 12209), we recommended that, if you modify an officially validated
method, you document the reason for the modification and have data to
show that the modified method produces results that are at least as
accurate and reliable as the established method for the material being
tested.  We also recommended that you have complete records of any
testing and standardization of laboratory reference standards, reagents,
and standard solutions that you use in your laboratory operations.  We
are making no changes to these recommendations in this final rule.

     (Comment 284) Several comments request the final rule incorporate
by reference authoritative sources of compendial methods.

     (Response) We decline this request for the reasons discussed in
response to comments 193 and 196.

 

G. Appropriate Test Method Validation

(Proposed § 111.60(b)(1)(v))

     Proposed § 111.60(b)(1)(v) would require the laboratory control
processes you establish and follow to include the use of appropriate
test method validations.  Because the final rule does not require that
you use a validated method for any tests or examinations that you
conduct, we are removing proposed § 111.60(b)(1)(v).

H. Under This Subpart, What Records must You 

Make and Keep? (Final § 111.325)

     Final § 111.325 sets forth the requirements for records that the
quality control unit must make and keep.  

1. Final § 111.325(a)

     Final § 111.325(a) requires you to make and keep records required
under subpart J in accordance with subpart P.  Final § 111.325(a)
derives from proposed § 111.60(b)(3), which would require you to keep
laboratory examination and testing records in accordance with proposed
§ 111.125.  Because final § 111.303 requires you to establish and
follow written procedures for laboratory operations, the records you
must make and keep under final § 111.325 are not limited to laboratory
examination and testing records, but also include the written
procedures.  Final § 111.325(a) also includes editorial revisions
associated with the reorganization and editorial revisions for
consistency with the recordkeeping requirements in subparts P. 

     We did not receive comments specific to proposed § 111.60(b)(3).

2. Final § 111.325(b)(1)

     The final rule includes a new requirement (final § 111.303) that
you establish and follow written procedures for laboratory operations,
including written procedures for the tests and examinations you conduct
to determine whether specifications are met.  Those written procedures
are records.  Therefore, final § 111.325(b)(1) requires you to make and
keep a record of the written procedures for laboratory operations,
including written procedures for the tests and examinations that you
conduct to determine whether specifications are met.

3. Final § 111.325(b)(2)

     Final § 111.325(b)(2) sets forth requirements for documenting that
you followed the laboratory methodology established in accordance with
this subpart.  Final § 111.325(b)(2)(i) requires that the person who
conducts the testing and examination document, at the time of
performance, that laboratory methodology established in accordance with
this subpart is followed.  Final § 111.325(b)(2)(ii) requires that the
documentation include the results of the testing and examination.  Final
§ 111.325(b)(2) derives from proposed § 111.60(b)(2) with revisions
associated with the reorganization.

     (Comment 285) One comment states that, without appropriate
documentation, there would be no assurance that the appropriate testing
was indeed performed and that the product’s identity, purity, quality,
strength, and composition are what they are represented to be.

     (Response)  We agree and have retained the requirement in this
final provision.  

HHS/FDA-Internal-Confidential-Deliberative

Final Subpart J 9-28-05

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