Document ID: FDA-1996-N-0028-0059
Agency: fda
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-08-01T04:00Z

XI.  Comments on Requirements for Quality Control

(Final Subpart F)

	A.  Organization of Final Subpart F

     Proposed § 111.37 set forth requirements for quality control
operations.  Other proposed requirements related to quality control
operations were set forth in other sections.  For example, proposed §
111.40(a) would require the quality control unit to perform operations
associated with components that you use in the manufacturing process. 
Proposed § 111.45 would establish requirements for the master
manufacturing record and would have the quality control unit review and
approve each master manufacturing record.  Proposed § 111.50 would have
the quality control unit review batch production records.       

	As shown in table 7, the final rule reorganizes the requirements
related to quality control operations into a distinct subpart (Final
subpart F - “Production and Process Control System – Requirements
for Quality Control Operations”).  Table 7 lists the sections in final
subpart F and identifies the proposed sections that form the basis for
the sections in the final rule. 

Table 7.- Derivation of Sections in Final Subpart F

Final Rule 	2003 CGMP Proposal

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

§ 111.105 What must the quality control personnelunit do?	§ 111.37(a),
(b)(1),

(b)(11) and (b)(12)

§ 111.110 What Quality Control Operations are Required for Laboratory
Operations Associated with the Production and Process Control system?	§
111.37(b)(9) and 

(b)(13)

§ 111.113 What Quality Control Operations are Required for a Material
Review and Disposition Decision?	§ 111.35(i)(2), (i)(3), (i)(4)(i),
(i)(4)(ii), (j), and (n)

§ 111.37(b)(3) 

§ 111.37(c)

§ 111.40(a)(3) and

(b)(2)

§ 111.50(d)(1)

§ 111.65(d)

§ 111.70(c)

§ 111.117 What Quality Control Operations are Required for Equipment,
Instruments, and Controls?	§ 111.30(b)(4), (b)(6), (b)(7), and 

(b)(8)

§ 111.120 What Quality Control Operations are Required for Components,
Packaging, and Labels Before Use in the Manufacture of a Dietary
Supplement?	§ 111.35(i)(4)(i) and (i)(4)(ii)

§ 111.37(b)(2) and 

(b)(10)

§ 111.40(a)(3) and

(b)(2)

§ 111.50(e)(1)

§ 111.123 What Quality Control Operations are Required for the Master
Manufacturing Record, the Batch Production Record, and Manufacturing
Operations?	§ 111.35(e)(2), 

(f), (i)(2), and 

(o)(2),

§ 111.37(b)(2), 

 (b)(4), 

 (b)(5), and (b)(11) (iii)

§ 111.45(c)

§ 111.50(d)(1) and

 (d)(2)

§ 111.50(g)

§ 111.127 What Quality Control Operations are Required for Packaging
and Labeling Operations?	§ 111.37(b)(2) and

(b)(10) 

§ 111.40(a)(2) and 

 (a)(3)

§ 111.70(c), (d), and (e)

§ 111.130 What Quality Control Operations are Required for Returned
Dietary Supplements?	§ 111.37(b)(2) and (b)(15)

§ 111.85(a)

§ 111.135 What Quality Control Operations are Required for Product
Complaints?	§ 111.95

§ 111.140 Under this Subpart, What Records Must the Quality Control
Unit Personnel Make and Keep?	§ 111.35(j)

§ 111.37(c) 

§ 111.37(d)

B.  Highlights of Changes to the Proposed Requirements 

for Quality Control Operations

1.  Revisions

     The final rule:

•    Reflects that the rule applies to persons who manufacture,
package, label, or hold dietary supplements unless subject to an
exclusion under § 111.1. 

▪	Changes the requirement for a quality control unit to a requirement
for quality control operations performed by quality control personnel.

•     Requires the quality control personnelunit to review and approve
documentation for why meeting in-process specifications will ensure the
specifications for identity, purity, strength, and composition of a
dietary supplement are met; 

•     Requires the quality control personnelunit to review and approve
documentation setting forth the basis for qualifying a supplier of a
component; 

•     Requires the quality control personnelunit to review and approve
documentation of your basis for why meeting certain selected
specifications in a subset of finished batches will ensure your finished
batch of the dietary supplement meets all product specifications for
identity, purity, strength, and composition and limits on those types of
contamination that may adulterate, or that may lead to the adulteration
of, the dietary supplement; and

•     Requires the quality control personnelunit to review and approve
documentation for why a product specification exempted from the
verification requirements in final subpart E is met without verification
through periodic testing of the finished batch.

2.  Changes Associated With the Reorganization

	The final rule:

•     Reduces redundant provisions.  

•     Combines parts of various proposed requirements that were
scattered throughout the 2003 CGMP Proposal. 

3.  Changes After Considering Comments

	The final rule:

•	Incorporates a new requirement to establish, and keep as a record,
written procedures for quality control operations; 

•	Simplifies the requirements associated with conducting a material
review and making a disposition decision;

•	Requires the quality control personnelunit to ensure that
representative samples are collected rather than collect these samples
itself themselves;

•	Requires the quality control personnelunit to ensure that reserve
samples are held rather than hold these samples itself;

•	Requires the quality control personnelunit to ensure tests or
examinations are appropriate rather than conduct these tests or
examinations itself; and

•	Requires review by the quality control personnelunit of all records
for calibration of instruments, and for calibrations, inspections and
checks of automatic, mechanical, or electronic equipment to be performed
on a periodic basis rather than at the time the record is made.

C.  General Comments on Proposed § 111.37 

(Final Subpart F)

     (Comment 214)  Some comments support the use of a quality control
unit and recognize it as an important need in manufacturing operations. 
Some comments assert the quality control unit may not have all the
responsibilities listed in proposed § 111.37 because there may be some
duties contracted out to someone else, such as testing that could be
sent to a contract laboratory, or some duties that may be better suited
for employees in other organizational units.  As an example, a few
comments note that the instrument and equipment calibration functions in
proposed § 111.37 may be better performed by individuals responsible
for the equipment in their particular operational area, by those in a
unit dedicated to equipment maintenance and calibration, or possibly by
a third party, who is qualified by training and/or experience, to do
these functions.  Similarly, other comments note that other groups with
the appropriate expertise may be assigned or required to review and
approve proposed changes or procedures in manufacturing operations or to
conduct material reviews and make disposition decisions.  These comments
assert the quality control unit should have overall responsibility and
oversight for quality control functions but also should be able to rely
on the expertise of other persons in the organization to accomplish the
tasks. 

     (Response) As already discussed with respect to the definition of
the quality control personnelunit in section VI, these comments may have
misunderstood the role of the quality control unit’s role under the
proposed rule.  Consequently, we have added final § 111.12(b) in
subpart B, discussed in section VII, to state you must identify who is
responsible for your quality control operations.  Each person who is
designated to perform quality control operations must be qualified to do
so and have distinct and separate responsibilities related to performing
such operations from those responsibilities that the person otherwise
has when not performing such operations.

	The final rule requires the quality control personnelunit to ensure all
appropriate tests and examinations are conducted, and review and approve
the results of all tests and examinations, but does not require that the
quality control personnelunit conduct the tests or examinations.  Thus,
you would not need to consider that an individual who conducts tests or
examinations at a laboratory under contract to your organization is
performing a quality control operation that must be performed by quality
control personnel. member of your quality control unit unless However,
you may choose to designate that individual as part of your quality
control personnel and require that the tests or examinations conducted
by that individual be quality control operations conducted by the
quality control unit.  

     Importantly, however, for the purposes of this final rule, we
consider that a quality control operation performed by an individual
under contract to you or by another third party is no different than a
quality control operation performed by your employees who are designated
to perform such operation.  If, during the course of an inspection, we
find the requirements of this final rule were not followed, we will hold
you, rather than the contractor or other third party, responsible.  The
applicability of this final rule to contractors is discussed in detail
in section VI.

     (Comment 215) Several comments request that the quality control
unit focus on reviewing tasks performed by others rather than on
performing the tasks itself.

     (Response) We agree with these comments and have revised several
provisions accordingly.  For example, in the 2003 CGMP Proposal we would
require the quality control unit to perform appropriate tests and
examinations of incoming materials, in-process materials, each finished
batch of dietary supplements, and each batch of packaged and labeled
dietary supplements (proposed § 111.37(b)(13)).  Under the final rule,
quality control operations include ensuring appropriate tests and
examinations are conducted (final § 111.110(b)), but do not include
conducting these tests and examinations. 

     (Comment 216) One comment asks whether we expect the quality
control unit to approve operational activities as soon as they occur or
collectively at the end of the process.  This and other comments argue
the quality control function is usually accomplished by a team of
qualified persons with the quality control unit having the overall
responsibility and authority to perform a collective, post processing,
final approval.

     (Response)  The time at which the quality control personnelunit
conducts its assigned duties will vary by the specific operation, the
size and complexity of the operation, and how quality control functions
are assigned to qualified persons.  For example, the final rule requires
the quality control personnel unit to determine whether components
conform to specifications, and release components from quarantine before
you use them in the manufacture of a dietary supplement (final §
111.120).  However, this final rule does not require, for example, that
the quality control personnelunit determine whether components conform
to specifications as soon as you receive them, although it may be common
business practice to do so.

     Regardless of when the quality control personnelunit performs
theirits operations, the quality control personnelunit havehas the
ultimate responsibility for ensuring manufacturing, packaging, labeling,
and holding operations are performed 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. 

D.  What Are the Requirements Under This Subpart 

for Written Procedures? 

(Final  § 111.103) 

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

	Final § 111.103 requires that you establish and follow written
procedures for the responsibilities of the quality control operations. 
Final § 111.103 specifically identifies two of the written procedures
you must establish and follow - i.e., written procedures for conducting
a material review and making a disposition decision and for approving or
rejecting any reprocessing.  

E.  What Must the Quality Control PersonnelUnit Do? 

(Final § 111.105)

     Final § 111.105 broadly captures the responsibility of the quality
control personnelunit to provide oversight for manufacturing, packaging,
labeling, and holding operations.  It requires the quality control
personnelunit to ensure that your manufacturing, packaging, labeling,
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.  Final § 111.105 derives from proposed §
111.37(a) which would require you to use a quality control unit to
ensure your manufacturing, packaging, labeling, and holding operations
in the production of dietary supplements are performed in a manner that
prevents adulteration and misbranding, including ensuring dietary
supplements meet specifications for identity, purity, quality, strength,
and composition. 

     This final rule focuses on ensuring that the manufacturer
establishes specifications for its dietary supplements, includes those
specifications in the master manufacturing record, meets those
specifications and manufactures, packages, labels, and holds the product
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.  Because of that focus, the labeling
requirements of the final rule address the operation of putting the
label that is specified in the master manufacturing record on the
product rather than the content of a product label that meets all of the
labeling requirements of the act and our implementing regulations.  The
failure to put the label identified in the master manufacturing record
on the finished product would be a violation of this final rule.  In
addition, if the label on the product does not correctly reflect the
ingredients, the label would misbrand the product under section 403 of
the act.  For purposes of this final rule, the labeling operations, are
CGMP requirements and relate to the label identified in the master
manufacturing record.  Therefore, we are deleting “misbranding” from
proposed § 111.37(a)(final § 111.105) since the act of misbranding
other than applying a label different from the one identified in the
master manufacturing record is not considered a CGMP violation in the
context of this final rule.  Any misbranding is still a violation of the
act, however, and manufacturers must comply with all applicable
statutory and regulatory requirements in addition to the requirements of
this final rule.   

This series of changes emphasizes the need to ensure the quality of a
dietary supplement and that the dietary supplement is packaged and
labeled as specified in the master manufacturing record.  As discussed
in detail in the rest of this section, final § 111.105 also requires
that the quality control personnelunit perform certain operations and
groups of operations. 

1.  Final § 111.105(a) 

	Final § 111.105(a) requires that the quality control personnelunit
approve or reject all processes, specifications, written procedures,
controls, tests, and examinations, and deviations from or modifications
to them, that may affect the identity, purity, strength, or composition
of a dietary supplement.   Final § 111.105(a) derives from proposed §
111.37(b)(1).  

     (Comment 217)  One comment recommends revising proposed §
111.37(b)(1) by replacing “... identity, purity, quality, strength,
and composition” with “... identity, purity, quality, strength, or
composition.”  The comment asserts the quality control unit must be
responsible for approving or rejecting anything that may affect one of
these attributes. 

     (Response)  We agree with this comment.  Under proposed §
111.37(b)(1) we had intended that the quality control unit be
responsible, for example, for approving a test that would establish the
identity of a component even if that test did not also establish the
strength of that component.  Final § 111.105(a) changes “and” to
“or” as requested by this comment.

     (Comment 218)  One comment recommends the quality control unit be
responsible for maintaining the master copies of all current and
approved written procedures, for distributing copies of approved written
procedures to relevant personnel, and for collecting and destroying
outdated Standing Operating Procedures (SOP) (except designated
historical SOP files).

     (Response)  This comment is consistent with the underlying
principle that the quality control personnelunit oversee the design and
conduct of the operations associated with the production of a dietary
supplement.  After considering these comments, final § 111.105(a)
requires the quality control personnelunit to approve all written
procedures that may affect the identity, purity, strength, or
composition of a dietary supplement.  With respect to the other
suggested duties of the quality control personnelunit, we are leaving
the decision as to who performs them, up to the individual firm to best
suit its overall operations. 

2.  Final § 111.105(b), (c), d), and (e) 

    Final § 111.105(b) requires the quality control personnelunit to
review and approve the documentation setting forth the basis for
qualification of any supplier.  Final § 111.105(c) requires the quality
control personnelunit to review and approve the documentation setting
forth the basis for why meeting in-process specifications, in
combination with meeting component specifications, will help ensure that
specifications for the identity, purity, strength, and composition of
the dietary supplement are met.  Final § 111.105(d) requires the
quality control personnelunit to review and approve the documentation
setting forth the basis for why the results of appropriate tests or
examinations for each product specification selected under final §
111.75(c)(1) will ensure that the finished batch of the dietary
supplement meets product specifications.  Final § 111.105(e) requires
the quality control personnelunit to review and approve the basis and
documentation for why any product specification is exempted from the
verification requirements in final § 111.75(c)(1), and for why any
component and in-process testing, examination, or monitoring, or other
methods will ensure that such exempted product specification is met
without verification through periodic testing of the finished batch. 

     Final § 111.105(b), (c), (d), and (e) are requirements associated
with the requirements established in final §§ 111.70(c)(3),
111.75(a)(ii)(2)(E), 111.75(c)(4), and 111.75(d)(1) and (2).

3.  Final § 111.105(f)

	Final § 111.105(f) requires the quality control personnelunit to
ensure that required representative samples are collected.  Final §
111.105(f) differs slightly from proposed § 111.37(b)(11)(i) through
(iv) which would require the quality control unit to collect
representative samples of incoming materials, in-process materials, each
finished batch of dietary supplements, and each batch of packaged and
labeled dietary supplements.  

     After considering comments requesting the quality control unit
focus on reviewing tasks performed by others rather than on performing
the tasks themselves, the final rule does not specify that the quality
control personnelunit itself must collect representative samples.  Under
final § 111.105(f), however, the quality control personnelunit retains
oversight of sample collection. 

4.  Final § 111.105(g) 

	Final § 111.105(g) requires the quality control personnelunit to
ensure that required reserve samples are collected and held.  Final §
111.105(g) derives from proposed § 111.37(b)(12) which would require
the quality control unit to keep reserve samples.  

     After considering comments requesting the quality control unit
focus on reviewing tasks performed by others rather than on performing
the tasks themselves, the final rule does not specify that the quality
control personnelunit itself must keep reserve samples.  Under final §
111.105(g), however, the quality control personnelunit retains oversight
of sample collection and holding. 

5. 	Final § 111.105(h)

	Final § 111.105(h) requires that quality control operations for the
master manufacturing record, the batch production record, and
manufacturing operations include determining whether all specifications
established in accordance with final § 111.70(a) are met.  Final §
111.105(h) derives from proposed § 111.37(b)(2) which would require
that the quality control unit determine whether all components, dietary
supplements, packaging, and labels conform to specifications.  Under the
final rule, we are identifying each of the specifications subject to
review by the quality control personnelunit under final § 111.77.  The
requirement for the quality control personnelunit to determine whether
specifications established under final § 111.70(a) are met is included
for consistency.  This requirement is also consistent with final §
111.73 which requires that the production and process control system
must include a determination of whether all of the established
specifications under final § 111.70(a) are met. 

6.  Final § 111.105(i)

     Final § 111.105(i) requires the quality control personnelunit to
perform other operations required under subpart F.  Final § 111.105(i)
is associated with the reorganization.  Under the 2003 CGMP Proposal,
proposed § 111.37(a) broadly captured the responsibility of the quality
control unit to provide oversight for your manufacturing, packaging,
labeling, and holding operations.  Proposed § 111.37(b) listed specific
operations that we would require the quality control unit to perform. 
Final § 111.105 now captures the responsibility of quality control
personnel unit’s responsibility to provide oversight for your
manufacturing, packaging, labeling, and holding operations.  The
specific operations that the quality control personnelunit must perform
to provide that oversight are set forth in final § 111.105(a) through
(h) and in final §§ 111.110, 111.113, 111.117, 111.120, 111.123,
111.127, 111.130, 111.135, and 111.140.

F.  What Quality Control Operations Are Required for 

Laboratory Operations Associated With the 

Production and Process Control System?

(Final § 111.110)

     Final § 111.110 sets forth the minimum required operations that
the quality control personnelunit must perform with respect to
laboratory operations associated with the production and process control
system.  

1.  Final § 111.110(a) 

     Final § 111.110(a) requires that quality control operations for
laboratory operations include reviewing and approving all laboratory
control processes associated with the production and process control
system.  Final § 111.110(a) derives, in part, from proposed §
111.37(b)(9) which would require that the quality control unit review
and approve all laboratory control processes.  For clarity, we are
adding that the laboratory operations covered by final § 111.110 are
those associated with the production and process control system.  We
want to make clear that laboratory operations such as those in your
research and development department are not subject to final § 111.110.

     We did not receive comments specific to quality control operations
under proposed § 111.37(b)(9).

2.  Final § 111.110(b) 

     Final § 111.110(b) requires that quality control operations for
laboratory operations associated with the production and process control
system include ensuring all tests and examinations required under final
§ 111.75 are conducted.  Final § 111.110(b) derives, in part, from
proposed § 111.37(b)(13) which would require the quality control unit
to perform appropriate tests and examinations of incoming materials,
in-process materials, each finished batch of dietary supplements, and
each batch of packaged and labeled dietary supplements.

     Proposed § 111.37(b)(13) would list the types of materials that
must be tested, including components, packaging, labels, dietary
ingredients, and dietary supplements that you receive; the batch
production at the in-process and finished batch stages; and packaged and
labeled dietary supplements.  This list would include materials that, at
a minimum, would be tested under the 2003 CGMP Proposal.  Under the
final rule, the minimum requirements for testing or examination of the
materials listed in proposed § 111.37(b)(13) are set forth in final §
111.75.  To simplify and clarify proposed § 111.37(b)(13), final §
111.110(b) replaces this list with “all tests and examinations
required under § 111.75.”

3.  Final § 111.110(c) 

     Final § 111.110(c) requires that quality control operations for
laboratory operations associated with the production and process control
system include reviewing and approving the results of all tests and
examinations required under final § 111.75.  Final § 111.110(c)
derives from proposed § 111.37(b)(9), which would require, in part,
that the quality control unit review and approve all testing results. 
Final § 111.110(c) requires that the quality control personnelunit
review and approve the results of examinations as well as tests.  This
revision reflects the flexibility provided in the final rule to use
either tests or examinations to determine whether specifications are
met, provided that the test or examination is an appropriate,
scientifically valid method.

     As with final § 111.110(b), we provide in final § 111.110(c) that
the tests and examinations are those required under final § 111.75.  

	We did not receive comments specific to quality control operations
under proposed § 111.37(b)(9).   

G.  What Quality Control Operations Are Required for 

a Material Review and Disposition Decision?

(Final § 111.113)

     Final § 111.113 derives from several proposed provisions,
including §§ 111.35(i), (j) and (n); 111.37(b)(3); 111.40(a)(3) and
(b)(2); 111.50(d(1); 111.65(d); and 111.70(c).  All these proposed
requirements related to one or more aspects associated with a material
review and disposition, including the circumstances that require a
material review and disposition decision, the documentation that must be
included in a material review and disposition decision, any restrictions
on who must conduct the material review and make the disposition
decision, and the need for oversight by the quality control unit.  As
discussed in section X, we simplified the provisions regarding a
material review and disposition decision (final § 111.87), emphasizing
the importance of oversight by the quality control personnelunit and
retaining the principle that qualified individuals other than those who
are designated those in the quality control personnelunit can contribute
to the material review and disposition decision. The final rule sets
forth the following requirements for the quality control personnelunit
that relate to final § 111.113:

•    Under final § 111.87 the quality control personnelunit 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 follow-up must include the signature
of the individual, designated to perform from the quality control
operation, 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.

     The final rule establishes a system in which you have the
flexibility to develop procedures that suit your organization, including
having qualified individuals, who are not designated to perform  outside
the  the quality control operation,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 assist the quality control personnelunit in
conducting a material review by preparing a report that includes all the
required documentation and information and providing a signed copy of
that report to the quality control personnelunit.  An individual who is
designated to performfrom  the quality control operation unit could then
use that report as part of theits material review, conduct any further
investigations, as necessary, and decide to accept, amend, or reject the
report.  

1.  Final § 111.113(a)

     Under final § 111.113(a), the quality control personnelunit must
conduct a material review and make a disposition decision if: 

(1) A specification established in accordance with § 111.70 is not met;

(2) A batch deviates from the master manufacturing record, including
when any step established in the master manufacturing record is not
completed and including any deviation from specifications; 

(3) There is any unanticipated occurrence during the manufacturing
operations that adulterates or may lead to adulteration of the
component, dietary supplement, or packaging, or could lead to the use of
a label not specified in the master manufacturing record; 

(4) Calibration of an instrument or control suggests a problem that may
have resulted in a failure to ensure the quality of a batch or batches
of a dietary supplement; or 

(5) A dietary supplement is returned.

     Final § 111.113(a) is substantially similar to proposed §
111.35(i)(3), which would require, in part, that you make a material
disposition decision for any component, dietary supplement, packaging,
or label: 

	(i) If a component, dietary supplement, packaging, or label fails to
meet established specifications; 

	(ii) If any step established in the master manufacturing record is not
completed; 

	(iii) If there is any unanticipated occurrence during the manufacturing
operations that adulterates or may lead to adulteration of the
component, dietary supplement, packaging, or label; 

	(iv) If calibration of an instrument or control suggests a problem that
may have caused batches of a dietary supplement to become adulterated;
or 

	(v) If a dietary supplement is returned.

     Final § 111.113(a) also incorporates elements from other proposed
sections regarding the circumstances that require a material review and
disposition decision as follows:

•    § 111.35(n) which would require you, for any specification that
is not met, to conduct a material review and disposition decision under
proposed § 111.35(i);

•    § 111.40(a)(3) which would require you, for components, dietary
ingredients, or dietary supplements you receive, to conduct a material
review and make a disposition decision if specifications are not met;

•    § 111.40(b)(2) which would require that for packaging and labels
you receive, you must conduct a material review and make a disposition
decision if specifications are not met;

•    § 111.50(d)(1) which would require that if a batch deviates from
the master manufacturing record, including any deviation from
specifications, the quality control unit must conduct a material review
and make a disposition decision and record any decision in the batch
production record;

•    § 111.65(d) which would require you to conduct a material review
and make a disposition decision in accordance with proposed § 111.35(i)
for any component, dietary ingredient, or dietary supplement that fails
to meet specifications or that is or may be adulterated; and 

•    § 111.70(c) which would require you to conduct a material review
and make a disposition decision of any packaged and labeled dietary
supplements that do not meet specifications.

      In final § 111.113(a) we are incorporating, into a single unified
provision, the various proposed circumstances that would require a
material review and disposition decision under the 2003 CGMP Proposal. 
We included revisions associated with final § 111.87 which requires the
quality control personnelunit to conduct any required material review
and make any required disposition decision.  We also included revisions
associated with final § 111.90 that relate to the impact on labeling
operations due to deviations and unanticipated occurrences.  

	In establishing final § 111.113(a)(1) we are deleting the specific
reference to the articles (components, dietary supplements, packaging,
and labels) required to undergo a material review.  We are deleting
these references, in part, to simplify the provision.  Under final §
111.113(a) the quality control personnelunit must conduct a material
review and make a disposition decision if any specification established
in accordance with final § 111.70 is not met.  It is not necessary to
repeat, in final § 111.113, the list of specifications that is clearly
set forth in final § 111.70. 

     We did not receive comments specific to quality control operations
under proposed §§ 111.35(i)(3) and (n), 111.40(a)(3) and (b)(2),
111.50(d)(1), 111.65(d), or 111.70(c). 

2.  Final § 111.113(b)

     Final § 111.113(b)(1) requires that, when there is a deviation or
unanticipated occurrence during the production and in-process control
system that results in, or could lead to, adulteration of a component,
dietary supplement, or packaging, or could lead to the use of a label
not specified in the master manufacturing record, the quality control
personnelunit must reject the component, dietary supplement, or
packaging, or label unless it approves a treatment, an in-process
adjustment, or reprocessing to correct the applicable deviation or
occurrence.   

	Final § 111.113(b)(1) derives from the following proposed provisions:

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

•    § 111.37(b)(3) which, in part, would require the quality control
unit to approve or reject all dietary ingredients, dietary supplements,
components, packaging, and labels.

	For consistency with other provisions in final subpart F, final §
111.113(b)(1) requires that the quality control personnelunit be the
entity that “rejects” a component, dietary supplement, packaging, or
label.  We also included revisions that are associated with final §
111.90.

	Final § 111.113(b)(2) requires that, when a specification established
in accordance with § 111.70 is not met, the quality control
personnelunit must reject the component, dietary supplement, package or
label, unless quality control personnel it approves a treatment, an
in-process adjustment, or reprocessing, as permitted in final § 111.77.
 This provision has been added as a result of the new provision, final
§ 111.77 which provides for what happens when certain specifications
are not met ,and the responsibilities of the quality control
personnelunit, and the changes made to final § 111.90. 

     (Comment 219)  Several comments request that the quality control
unit focus on reviewing tasks performed by others rather than on
performing the tasks itself.

     (Response)  We agree, and final § 111.113(b) provides that the
quality control personnelunit “approves” an in-process adjustment
rather than “determine whether” the in-process adjustment is
possible.

3.  Final § 111.113(c)

     Final § 111.113(c) requires the person who conducts a material
review and makes the disposition decision, at the time of performance,
to document that material review and disposition decision.  Final §
111.113(c) derives from proposed § 111.35(j) which, in part, would
require that the person who conducts the material review and makes the
disposition decision must, at the time of performance, document every
material review and disposition decision in proposed § 111.35(i). 

     As an editorial revision, final § 111.113(c) requires
documentation of “that” decision rather than “every” decision. 
As a practical matter, under final § 111.113(c) every material review
and disposition decision is documented.

     We did not receive comments specific to quality control operations
under proposed § 111.35(j).

H.  What Quality Control Operations Are Required for 

Equipment, Instruments, and Controls? 

(Final § 111.117)

     Final § 111.117 (proposed § 111.37(b)(6) through (b)(8)) sets
forth the minimum required operations that the quality control
personnelunit must perform with respect to equipment, instruments, and
controls. 

1.  Final § 111.117(a) through (c)

     Final § 111.117(a) through (c) requires the quality control
operations for equipment, instruments, and controls to include: 

(a) Reviewing and approving all processes for calibrating instruments or
controls;

(b) Periodically reviewing all records for calibration of instruments or
controls; and 

(c) Periodically reviewing all records for calibrations, inspections,
and checks of automated, mechanical, or electronic equipment.  

     Final § 111.117(a), (b), and (c) derive from proposed §
111.37(b)(6), (7), and (8) which would require the quality control unit
to:

•     Review and approve all processes for calibrating instruments or
controls; 

•     Review all records for calibration of instruments, apparatus,
gauges, and recording devices; and 

•     Review all records for equipment calibrations, inspections, and
checks.

     Final § 111.117 includes the following changes we are making for
consistency with the requirements, set forth in subpart D, for equipment
and utensils: 

•      We have deleted the terms “apparatus,” “gauges” and
“recording devices” from proposed § 111.37(b)(7) as they would fall
under the terms “instruments and controls” in final § 111.117, and
because subpart D does not use the terms “apparatus,” “gauges”
or “recording devices.”

•     We are characterizing the records for equipment calibrations,
inspections, and checks as records for calibrations, inspections, and
checks of “automated, mechanical, or electronic equipment,” because
final § 111.30(c) requires you to calibrate, inspect, or check
“automated, mechanical, or electronic equipment.”

     (Comment 220)  One comment argues the requirements for oversight by
the quality control unit in proposed § 111.37(b)(7) and (b)(8) are
excessive and go beyond requirements for both the drug CGMPs and food
CGMPs.  The comment recommends revising proposed subparagraphs §
111.37(b)(7) and (b)(8) to require a review of all records when there is
a negative impact on the product due to a calibration failure. 

     Other comments refer to the related requirements in proposed §
111.30(b)(1) that the quality control unit approve calibrations,
inspections, or checks of automatic, mechanical or electronic equipment.
 These comments assert the requirement for the quality control unit to
approve such calibrations, inspections, and checks of equipment is too
prescriptive and that qualified persons outside of the quality control
unit should be able to approve these calibrations, inspections, or
checks.  These comments also assert the quality control unit should
perform audits of the records generated to ensure the appropriate
calibrations, inspections, and checks are being adequately performed at
the required intervals.

     (Response)  As already discussed with respect to proposed §
111.30(b)((1) (final § 111.30(c)), we disagree that the review by the
quality control personnelunit should be limited to circumstances when
there has been a calibration failure.  One of the oversight functions of
the quality control personnelunit is to prevent problems with the
product you distribute by finding any problems with the equipment you
use to produce the product rather than to investigate the cause of a
problem with a product that you already distributed.  However, we agree
it is sufficient to review the records of calibrations, inspections, and
checks of automated, mechanical, or electronic equipment periodically,
for example, on an annual basis, rather than to approve each record when
it is made.  A periodic review can uncover trends in the performance of
the equipment that have the potential to adversely affect the quality of
the dietary supplement and that may not be obvious by merely approving
each record when it is made.  Seeing such trends would enable the
quality control personnelunit to recommend actions to correct the trend.
 Therefore, we have revised the proposed requirement so that under final
§ 111.117(c) the quality control personnelunit must review all records
of calibrations, inspections, and checks of automatic, mechanical, or
electronic equipment on a periodic basis.  Likewise, we have revised the
rule so that the quality control personnel’sunit’s review of all
records of equipment calibrations also is on a periodic basis.

      (Comment 221)  A few comments argue the review of calibration
records may be conducted by a qualified person other than the quality
control unit, such as by a supervisor or by a separate department
dedicated to equipment maintenance and calibration.  These comments
assert the quality control unit should approve calibration processes,
but review of completed calibration records by the dedicated department
is sufficient to assure compliance with the approved process.  

     (Response)  As already discussed, many comments about the quality
control unit may have misunderstood the proposed definition of
“quality control unit” (now replaced by “quality control
personnel”).  Under final § 111.12(b), you must identify who is
responsible for your quality control operations.  Each person who is
identified to perform quality control operations must be qualified to do
so and have distinct and separate responsibilities related to performing
such operations from those responsibilities that the person otherwise
has when not performing such operations.  Thus, in the situation
described by these comments, you could identify a qualified person in a
department dedicated to equipment maintenance and calibration to perform
quality control operations for equipment calibration.  Neither the
definition of the “quality control personnel”unit, nor the
requirements of final § 111.12(b), would preclude a person who performs
“Operation X” from being identified as the person who performs
quality control operations for “Operation X.”  However, we strongly
recommend that the person you identify to perform a given quality
control operation be a different person than the person who performed
the operation that is subject to quality control oversight.  

2.  Final § 111.117(d) 

     Final § 111.117(d) requires that quality control operations for
equipment, instruments, and controls include reviewing and approving
controls to ensure automated, mechanical, or electronic equipment
functions in accordance with its intended use.  Final § 111.117(d)
derives, in part, from proposed § 111.30(b)(4) (final § 111.30(e))
which would require that, for any automated, mechanical, or electronic
equipment you use, you must establish and use appropriate controls and
the controls are approved by your quality control unit to ensure that
the equipment functions in accordance with its intended use.  We are
clarifying the proposed requirement related to the quality control
personnelunit in final § 111.117(d). 

     We did not receive comments specific to this responsibility of the
quality control unit in proposed § 111.30(b)(4). 

I.  What Quality Control Operations Are Required for 

Components, Packaging, and Labels Before Use 

in the Manufacture of a Dietary Supplement?

(Final § 111.120)

     Final § 111.120 sets forth the minimum required operations that
the quality control personnelunit must perform with respect to
components, packaging, and labels before use in the manufacture of a
dietary supplement.  Some of the proposed provisions that form the basis
for final § 111.120 included requirements for “dietary supplements
that you receive.”  For example, proposed § 111.40(a) would require
you, for components or dietary supplements you receive, to visually
examine containers and documentation provided by the supplier,
quarantine the materials until they are released by the quality control
unit, and identify the materials in a manner that allows you to trace
the shipment you receive to the product that you manufacture and
distribute.  The final rule separates these and other requirements for
quality control operations for “product that you receive from a
supplier” for packaging or labeling as a dietary supplement from the
analogous requirements for components.  Thus, the requirements for
quality control operations for product you receive for packaging and
labeling as a dietary supplement (and for distribution rather than for
return to the supplier) are found in final § 111.127 rather than final
§ 111.120. 

1.  Final § 111.120(a) 

     Final § 111.120(a) requires that quality control operations for
components, packaging, and labels include reviewing all receiving
records for components, packaging, and labels before use.  Final §
111.120(a) derives from the following proposed provisions: 

•    § 111.37(b)(10) which, in part, would require the quality
control unit to review and approve all packaging and label records which
include, but are not limited to, cross-referencing receiving and batch
production records;  

•    § 111.40(a)(3) which, in part, would require that you quarantine
dietary supplements until your quality control unit reviews the
supplier’s invoice, guarantee, or certification; and

•    § 111.50(e)(1) which, in part, would require the quality control
unit to document its review of component receiving records.

     (Comment 222)  One comment asserts that the proposed requirement
that the review of the batch record by the quality control unit include
cross-referencing of receiving records with the batch production record
is redundant and should be mandatory only in cases where a specification
has not been met.  This comment asserts the quality control unit has
already reviewed and approved components, packaging, and labels prior to
their release and has used unique identifiers for these raw materials as
they are recorded on related documentation and records, which allow
traceability back to this documentation for review when necessary.  This
comment also asserts all material review and disposition decisions must
be documented and these will include the unique identifiers that tie
them to particular raw or in process materials.

     Another comment asserts that the quality control unit should only
need to repeat a review of the receiving records as a result of
conducting an investigation or a material review, as is required for
drugs, and to require otherwise would be redundant.  This comment also
states requiring the quality control unit to repeat its review of the
receiving records places a fairly large burden on the quality control
unit because this re-review must be performed for each and every batch
production record.  The comments assert the requirement should be
completed properly and only once.

     (Response)  In the preamble to the 2003 CGMP Proposal (68 FR 12157
at 12200), we stated that cross-referencing receiving and batch
production records means the quality control unit must verify that the
batch record includes certain documentation of the receiving records for
the components such as the unique identifier assigned to the shipment
lot of components, testing results, a material review and disposition
decision, if conducted, and approval for use by the quality control
unit.  We agree with the comments that the review of records such as
receiving records (including proper documentation of a unique identifier
for components, packaging and labels), if done properly the first time
it is performed, need not be repeated.  Therefore, the final rule does
not include any requirement for cross-referencing receiving records with
the batch production record as we would require under proposed §
111.37(b)(10).  As noted, we have changed “quality control unit” to
“quality control personnel”.

     We agree that cross-referencing receiving and batch production
records is an appropriate step to take when conducting a material review
and making a disposition when, for example, a specification is not met. 
We encourage firms to include this activity in the written procedures
for conducting a material review and making a disposition decision.

2.  Final § 111.120(b)

     Final § 111.120(b) requires that quality control operations for
components, packaging, and labels include determining whether all
components, packaging, and labels conform to specifications established
under § 111.70(b) and (d) before use.  Final § 111.120(b) derives from
proposed § 111.37(b)(2).

    We did not receive comments specific to quality control operations
under proposed § 111.37(b)(2).  For clarity, we have identified the
specifications as those required under final § 111.70(b) and (d).  

3.  Final § 111.120(c) 

     Final § 111.120(c) requires that quality control operations for
components, packaging, and labels include conducting any required
material review and making any required disposition decision before use.
 Final § 111.120(c) derives from the following proposed provisions:

•    § 111.40(a)(3) which, in part, would require you to conduct a
material review and make a disposition decision if specifications are
not met for components; and

•    § 111.40(b)(2) which, in part, would require you to conduct a
material review and make a disposition decision if specifications are
not met for packaging and labels.  

     Final § 111.120(c) includes revisions associated with final §
111.87 which requires the quality control personnelunit to conduct any
required material review and make any required disposition decision.

    (Comment 223)  One comment recommends the quality control unit have
authority to allow usage of material that has failed to meet
specifications if the defect will not significantly affect the overall
quality of the finished product even if reprocessing is not an option. 
The comment gives an example of a material that fails to meet particle
size specifications designed to maximize the efficiency of processing of
the material, but ultimately does not impair strength, and asserts the
quality unit should have the authority to release the material for use.

     (Response)  The final rule provides for a process in which the
quality control personnelunit determines whether a component meets
specifications and conducts a material review and makes a disposition
decision if a component does not meet one or more specifications.  The
final rule does not prohibit the use of a component that does not meet
all component specifications other than the identity specification.  For
example, under final § 111.120(d) the quality control personnelunit may
approve an in-process adjustment of a component to make it suitable for
use in the manufacture of a dietary supplement (see discussion of final
§ 111.120(d) immediately below).  Under final § 111.123(b) the quality
control personnelunit must not approve and release for distribution any
batch of dietary supplement, including any reprocessed batch, that does
not meet all product specifications or is not a quality product.  Thus,
although a disposition decision could be made under final § 111.120(c)
to use a component even if it does not meet certain specifications, that
decision should take into account whether the failure for the component
to meet specifications will ultimately cause the dietary supplement to
fail to meet product specifications. 

4.  Final § 111.120(d)

     Final § 111.120(d) requires that quality control operations for
components, packaging, and labels include approving, or rejecting, any
treatment and in-process adjustments of components, packaging, or labels
to make them suitable for use in the manufacture of a dietary
supplement.  Final § 111.120(d) derives from the following proposed
provisions:

•    § 111.35(i)(4)(i) which, in part, would require that you reject
the component, packaging, or label, unless the quality control unit
determines that in-process adjustments are possible to correct the
deviation or occurrence; and

•    § 111.35(i)(4)(ii) which would have prohibited you from
reprocessing a rejected component unless approved by the quality control
unit.   

    Final § 111.120(d) includes a revision associated with final §
111.90(c), and refers to “treatment and in-process adjustments to make
them suitable for use in the manufacture of a dietary supplement” (see
discussion of final § 111.90(c) in section X). 

     (Comment 224) Several comments request the quality control unit
focus on reviewing tasks performed by others rather than on performing
the tasks itself.

     (Response)  Final § 111.120(d) includes a revision that the
quality control personnelunit “approve” a treatment rather than
“determine that” the treatment is possible.

     (Comment 225)  A few comments support the proposed requirement that
the quality control unit have the authority to approve reprocessing
measures.

     (Response)  These comments are consistent with proposed
§ 111.35(i) and (i)(4)(ii) and final § 111.120(d), as applicable to
quality control personnel.

     (Comment 226)  One comment states that the decision to reprocess a
material belongs within the particular operational unit, and that the
role of the quality control unit should be to approve the results of the
reprocessing.

     (Response) We disagree that the role of the quality control
personnelunit  should be limited to approving the results of
reprocessing or, in this case, of the treatment or in-process
adjustments of components, packaging, or labels.  An underlying
principle of these CGMP requirements is that the quality control
personnelunit oversees the design and conduct of manufacturing,
packaging, labeling, and holding operations.  A decision about when
reprocessing is, or is not, appropriate requires oversight.  

     As already discussed, under final § 111.12(b) you must identify
who is responsible for your quality control operations.  Each person who
is identified to perform quality control operations must be qualified to
do so and have distinct and separate responsibilities related to
performing such operations from those responsibilities that the person
otherwise has when not performing such operations.

5.  Final § 111.120(e) 

     Final § 111.120(e) requires that quality control operations for
components, packaging, and labels include approving and releasing from
quarantine all components, packaging, and labels before they are used. 
Final § 111.120(e) derives from the following proposed provisions: 

•     § 111.40(a)(3) which, in part, would require that you
quarantine components until your quality control unit approves the
components and releases them from quarantine; and 

•    § 111.40(b)(2) which, in part, would require that you quarantine
packaging and labels until your quality control unit approves the
packaging and labels and releases them from quarantine.

     We did not receive comments specific to quality control operations
under proposed § 111.40(a)(3) or (b)(2).  

J.  What Quality Control Operations Are Required for the 

Master Manufacturing Record, the Batch Production 

Record, and Manufacturing Operations?

					(Final § 111.123)		

     Final § 111.123 sets forth the minimum required operations that
the quality control personnelunit must perform with respect to the
master manufacturing record, the batch production record, and
manufacturing operations.  

1.  Final § 111.123(a)(1) 

     Final § 111.123(a)(1) requires that quality control operations for
the master manufacturing record, the batch production record, and
manufacturing operations include reviewing and approving all master
manufacturing records and all modifications to the master manufacturing
records.  Final § 111.123(a)(1) derives from duplicate proposed
requirements, in proposed §§ 111.37(b)(4) and 111.45(c), with no
changes other than the editorial changes associated with the
reorganization.  

     We did not receive comments specific to quality control operations
under proposed §§ 111.37(b)(4) or 111.45(c), but have combined them as
§ final 111.123(a)(1).

2.  Final § 111.123(a)(2) 

     Final § 111.123(a)(2) requires that quality control operations for
the master manufacturing record, the batch production record, and
manufacturing operations include reviewing and approving all batch
production-related records.  Final § 111.123(a)(2) derives from
proposed § 111.37(b)(5), which would require, in part, the quality
control unit to review and approve all batch production-related records.
 Proposed § 111.37(b)(5) explicitly stated, in part, that the batch
record would include, but not be limited to, cross-referencing receiving
and batch production records.  

     (Comment 227)  One comment expresses concern that proposed §
111.37(b) does not state specifically that the complete batch history,
including batch record, analytical records, quality control records,
yields, and packaging records should be reviewed and approved by the
quality control unit before the batch is shipped.  The comment believes
these are important requirements that should be clearly stated.

     (Response)  Proposed § 111.37(b)(5) would require that the
quality control unit “review and approve all batch production-related
records, including but not limited to . . ..”  We disagree with the
comment that this proposed provision would not include what the comment
describes.  To the extent that the comments interpreted the list of
records to mean that only the partial listing of records was required,
we have modified final § 111.123(a)(2) to require the quality control
personnelunit to review all batch production-related records.  We do not
emphasize any particular aspect of the batch production record.  This
reduces the potential to misinterpret the requirement as being limited
to the specific items cited.

     (Comment 228)  As already discussed in detail with respect to final
§ 111.120(a) in this section, some comments assert the proposed
requirement that the review of the batch record by the quality control
unit include cross-referencing of receiving records with the batch
production record is redundant with other requirements that the quality
control unit review receiving records for components, packaging, and
labels.  In general, these comments assert the requirement should be
completed properly and only once.

     (Response)  We agree with the comments that the review of records,
such as receiving records, if done properly the first time that it is
performed, need not be repeated.  Therefore, the final rule does not
include any requirements for cross-referencing receiving records with
the batch production record as we would require under proposed §
111.37(b)(5). 

3.  Final § 111.123(a)(3) 

     Final § 111.123(a)(3) requires that quality control operations for
the master manufacturing record, the batch production record, and
manufacturing operations include reviewing all monitoring required under
subpart E.  Final § 111.123(a)(3) derives from the following proposed
provisions:

•    § 111.35(f) which would require you to monitor the in-process
control points, steps, or stages to ensure that specifications
established under proposed § 111.35(e) are met and to detect any
unanticipated occurrence that may result in adulteration; 

•    § 111.35(e)(2) which would require you to establish a
specification for any point, step, or stage in the manufacturing process
where control is necessary to prevent adulteration, including the
in-process controls in the master manufacturing record where control is
necessary to ensure the identity, purity, quality, strength, and
composition of dietary supplements;

•    § 111.35(i)(2) which would require you to review the results of
the monitoring required under proposed § 111.35(f) and conduct a
material review if an established specification is not met or if there
is any unanticipated occurrence that adulterates or could result in
adulteration;

•    § 111.35(o)(2) which would require you to make and retain
records to ensure you follow the requirements of proposed § 111.35,
including the actual results obtained during the monitoring operation;
and 

•    § 111.37(b)(5) which would require the quality control unit to
review and approve all batch production-related records.

     Under the final rule, the results of the monitoring required under
proposed § 111.35(f) must be kept in the batch record (see the
discussion of the batch record in section XIV).  The Qquality control
personnelunit must review the results of the required monitoring.

	(Comment 229)  One comment suggests the phrase “review the results of
the monitoring required by this section” be deleted from proposed §
111.35(i)(2) because it is unnecessary and can be read as narrowing any
final rule.  This comments points out the only required monitoring in
the proposal appears in § 111.35(f) related to monitoring of in-process
control points, steps, or stages, and that such monitoring would not
necessarily find all failures in specifications, for example,
specifications related to raw materials or labels.

     (Response)  We disagree with the comment that the quoted language
narrows the final rule.  Monitoring that relates to in-process control
points, steps, or stages would be required under proposed § 111.35(f)
and is now required in final § 111.123(a)(3).  However, in practice, a
manufacturer must monitor its entire operation to ensure that the
requirements of the final rule are met.  For example, under final
§ 111.73, a manufacturer must determine whether specifications
established under final § 111.70 are met and under final § 111.75(a)
and (f) a manufacturer must use certain criteria to determine whether
specifications for components and labels, respectively, are met.  Thus,
there are sufficient controls in other requirements to ensure the entire
production and process controls are functioning as intended.   

4.  Final § 111.123(a)(4) 

     Final § 111.123(a)(4) requires that quality control operations for
the master manufacturing record, the batch production record, and
manufacturing operations include conducting any required material review
and making any required disposition decision.  Final § 111.123(a)(4)
derives from the following proposed provisions:

•    § 111.37(b)(5) which, in part, would require the quality control
unit to approve a material review and disposition decision related to
batch production records; and  

•    § 111.50(d)(1) which, in part, would require, if a batch
deviates from the master manufacturing record, including any deviation
from specifications, the quality control unit to conduct a material
review and make a disposition decision. 

     We did not receive comments specific to quality control operations
under proposed §§ 111.37(b)(5) or 111.50(d)(1).

5.  Final § 111.123(a)(5) 

     Final § 111.123(a)(5) requires that quality control operations for
the master manufacturing record, the batch production record, and
manufacturing operations include approving or rejecting any
reprocessing.  Final § 111.123(a)(5) derives from proposed §
111.37(b)(5) which would require the quality control unit to approve any
reprocessing.  For consistency with other provisions in this final rule
(such as final § 111.90), final § 111.123(a)(5) includes a revision
that the quality control personnelunit must approve - or reject - any
reprocessing.

     We did not receive comments specific to quality control operations
under proposed § 111.37(b)(5).

6.  Final § 111.123(a)(6) 

     Final § 111.123(a)(6) requires that quality control operations for
the master manufacturing record, the batch production record, and
manufacturing operations include determining whether all in-process
specifications established in accordance with § 111.70(c) are met. 
Final § 111.123(a)(6) derives from the following proposed provisions:

•    § 111.35(f) which would require you to monitor the in-process
control points, steps, or stages to ensure specifications are met
(including the in-process specifications required under proposed §
111.35(e)(2)); and

•    § 111.37(a) which, in part, would require the quality control
unit to ensure your manufacturing, packaging, labeling, and holding
operations are performed in a manner that prevents adulteration,
including that such operations ensure the dietary supplement meets its
specifications for identity, purity, quality, strength, and composition.
 

     Final § 111.123(a)(6) is consistent with the overall approach, set
forth in final §§ 111.70, 111.73, and 111.75, that focuses on ensuring
the quality of the dietary supplement throughout the production and
process control system.

     We did not receive comments specific to quality control operations
under proposed § § 111.35(f), 111.35(e)(2), or 111.37(a). 

7.  Final § 111.123(a)(7) 

     Final § 111.123(a)(7) requires that quality control operations for
the master manufacturing record, the batch production record, and
manufacturing operations include determining whether each finished batch
conforms to product specifications established in accordance with final
§ 111.70(e).  Final § 111.123(a)(7) derives from proposed §
111.37(b)(2) which, in part, would require the quality control unit to
determine whether all dietary supplements conform to specifications.

     We did not receive comments specific to quality control operations
under proposed § 111.37(b)(2).

8.  Final § 111.123(a)(8) 

     Final § 111.123(a)(8) requires that quality control operations for
the master manufacturing record, the batch production record, and
manufacturing operations include approving and releasing, or rejecting,
each finished batch for distribution, including any reprocessed finished
batch.  Final § 111.123(a)(8) derives from the following proposed
provisions: 

•    § 111.37(b)(5) which, in part, would require the quality control
unit to approve batch production records for releasing finished batches
for distribution; 

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

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

     We did not receive comments specific to the proposed provisions
cited above.  

9.  Final § 111.123(b) 

     Final § 111.123(b) requires that the quality control personnelunit
must not approve and release for distribution:

	(1) any batch of dietary supplement for which any component in the
batch does not meet its identity specification;

	(2) any batch of dietary supplement, including any reprocessed batch,
that does not meet all product specifications established in accordance
with § 111.70(e);

	(3) any batch of dietary supplement, including any reprocessed batch,
or that has not 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;: and is not a quality product.

	(4) any product received from a supplier for packaging or labeling as a
dietary supplement (and for distribution rather than for return to the
supplier) for which sufficient assurance is not provided to adequately
identify the product and to determine that the product is consistent
with your purchase order.

	Final § 111.123(b) derives from the following proposed provisions:

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

•    § 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.  

•    § 111.37(b)(11)(iii) which would require the quality control
unit to collect representative samples of each batch of dietary
supplement manufactured to determine, before releasing for distribution,
whether the dietary supplement meets its specifications for identity,
purity, quality, strength, and composition. 

	The final provision clarifies all of the responsibilities of the
quality control personnelunit and includes provisions consistent with
changes made to final §§ 111.73, 111.77, and 111.90.

	We did not receive comments specific to those aspects of proposed §§
111.50(g) and 111.37(b)(11)(iii) that are relevant to final §
111.123(b).  We discuss below comments we received to proposed §
111.50(d)(2).

     (Comment 230)  Several comments object to proposed § 111.50(d)(2)
because it would prohibit the release of any batch that does not meet
all specifications.  Other comments suggest the prohibition should apply
to meeting “release specifications” or “essential manufacturer
specifications” rather than “all specifications” because
in-process deviations and minor deviations may not affect product
quality. 

     (Response)  A finished dietary supplement that is ready for release
for distribution must meet component specifications for identity
established under final § 111.70(b) and all product specifications
established for the batch under final § 111.70(e) and must be
manufactured in a manner to prevent adulteration under 402(a)(1),
(a)(2), (a)(3), and (a)(4).  The final rule does not prevent you from
establishing additional specifications that do not affect the identity,
purity, strength, composition, or contaminant levels of your finished
dietary supplement.  Such a specification is not a component
specification for identity or a product specification that is required
under the final rule.  Final § 111.123(b) would not preclude you from
releasing a product that fails to meet a specification that is not a
component specification for identity or a product specification
established under final § 111.70 provided your quality control
personnelunit approves such release.  Final § 111.123(b) would not
preclude you from releasing a product that you are permitted to release
under final § 111.77. 

	(Comment 231)  Some comments note that proposed § 111.50(d)(2) would
not allow the quality control unit to conduct an investigation, and make
a disposition decision, of the failure of a batch to meet
specifications.  These comments assert proposed § 111.50(d)(2)
therefore restricts the provision in proposed § 111.50(d)(1) which
would require that, if a batch deviates from the master manufacturing
record, including any deviation from specifications, the quality control
unit must conduct a material review and make a disposition decision. 
The comments argue the quality control unit should have the authority to
release products with minor deviations.

     (Response)  As discussed above (see discussion of final § 111.90
in subpart E in section X), we acknowledge that some specifications,
such as component, other than for identity, and in-process
specifications, that are not met may be able to be corrected by a
treatment or an in-process adjustment.  The Qquality control
personnelunit would need to conduct a material review and disposition
decision for any such specification not met.  If there are
specifications 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)), you
must determine whether these specifications are met (final § 111.73). 
	Final § 111.123(b) does not preclude you, for example, from releasing
a product that was the subject of a material review because sampling
procedures had not been followed if, as a corrective action, the
appropriate samples were collected and subjected to appropriate tests
and examinations.  

K.  What Quality Control Operations Are Required for 

Packaging and Labeling Operations?

(Final § 111.127)

     Final § 111.127 sets forth the required operations that the
quality control personnelunit must perform with respect to packaging and
labeling operations.  

1.  Final § 111.127(a) and (b)

     Final § 111.127(a) and (b) set forth requirements for product you
receive for packaging or labeling as a dietary supplement (and for
distribution rather than for return to the supplier).

	Final § 111.127(a) and (b) apply to product that has left the control
of the person who manufactured the batch; for example, the purchase of
dietary supplements in bulk for packaging or labeling by a person who
will distribute the packaged and labeled dietary supplements under a
private label.  If you are a packager or labeler who operates under
contract to the manufacturer, and you will return the dietary supplement
to the manufacturer, we would not consider that you are “receiving”
product within the meaning of final § 111.127(a) and (b).  We would
consider you to be no different than an operating unit of the
manufacturer.  In section VI, subpart A, we discuss in detail the scope
of this final rule and its applicability to contractors.

     a.  Final § 111.127(a) 

     Final § 111.127(a) requires that quality control operations for
packaging and labeling operations include reviewing the results of any
visual examination and documentation to ensure that specifications
established under final § 111.70(f) are met for product you receive for
packaging or labeling as a dietary supplement (and for distribution
rather than for return to the supplier).  Final § 111.127(a) derives
from the following proposed provisions: 

•    § 111.40(a)(2) which would require you to visually examine the
supplier’s invoice, guarantee, or certification to ensure that dietary
supplements you receive are consistent with your purchase order and
perform testing, as needed, to determine whether specifications are met;
and

•    § 111.40(a)(3) which would, in part, require you to quarantine
dietary supplements you receive until your quality control unit reviews
the supplier’s invoice, guarantee, or certification and performs
testing, as needed, of a representative sample to determine that
specifications are met. 

     Final § 111.127(a) includes revisions associated with final §§
111.70(f) and 111.75(e) which set forth requirements for all products
you receive from a supplier for packaging or labeling as dietary
supplements (and for distribution rather than for return to the
supplier).  As discussed in section X, under final § 111.70(f) if you
receive such product, you must establish specifications to provide
sufficient assurance that the product you receive is adequately
identified and is consistent with your purchase order.  In addition,
under final § 111.75(e) before you package or label such products, you
must visually examine the products and have documentation to determine
whether the specifications that you established under final § 111.70(f)
are met.  The documentation you have to satisfy the requirements of
final § 111.75(e) is not limited to a supplier’s invoice, guarantee,
or certification and, thus, final § 111.127(a) incorporates the
standard set by final § 111.75(e) (i.e., documentation) rather than the
proposed standard of the supplier’s invoice, guarantee, or
certification.  In addition, consistent with final § 111.75(e), final
§ 111.127(a) requires the quality control personnelunit to review the
results of the visual examination but not otherwise review the results
of tests or examinations.

     We did not receive comments specific to quality control operations
under proposed § 111.40(a)(2) or (3).

     b.  Final § 111.127(b) 

     Final § 111.127(b) requires that quality control operations for
packaging and labeling operations include approving, and releasing from
quarantine, all products you receive for packaging and labeling as a
dietary supplement (and for distribution rather than for return to the
supplier) before the products are used for packaging and labeling. 
Final § 111.127(b) derives from proposed § 111.40(a)(3) which, in
part, would require you to quarantine dietary supplements that you
receive until your quality control unit reviews the supplier’s
invoice, guarantee, or certification and performs testing, as needed, of
a representative sample to determine that specifications are met, and
approves and releases the dietary supplements from quarantine before you
use them.

     As with final § 111.127(a), final § 111.127(b) includes revisions
associated with changes made in final §§ 111.70(f) and 111.75(e).

     We did not receive comments specific to quality control operations
under proposed § 111.40(a)(3).

2.  Final § 111.127(c) 

     Final § 111.127(c) requires that quality control operations for
packaging and labeling operations include reviewing and approving all
records for packaging and label operations.  Final § 111.127(c) derives
from proposed § 111.37(b)(10) which, in part, would require the quality
control unit to review and approve all packaging and label records.

     We did not receive comments specific to quality control operations
under proposed § 111.37(b)(10). 

3.  Final § 111.127(d)

     Final § 111.127(d) requires that quality control operations for
packaging and labeling operations include determining whether the
packaging and labeling for the finished packaged and labeled dietary
supplement conforms to specifications established in accordance with
final § 111.70(g).  Final § 111.127(d) derives from the following
proposed provisions: 

•    § 111.37(b)(2) which, in part, would require the quality control
unit to determine whether all dietary supplements conform to
specifications; and 

•    § 111.37(b)(11)(iv) which, in part, would require the quality
control unit to collect representative samples of each batch of packaged
and labeled dietary supplements to determine that you used the packaging
specified in the master manufacturing record and applied the label
specified in the master manufacturing record.  

	For clarity, final § 111.127(d) identifies the specifications as those
established in final § 111.70(g). 

     We did not receive comments specific to quality control operations
under proposed § 111.37(b)(2) or (b)(11)(iv). 

4.  Final § 111.127(e) 

     Final § 111.127(e) requires that quality control operations for
packaging and labeling operations include conducting any required
material review and making any required disposition decision.  Final §
111.127(e) derives from the following proposed provisions:

•     § 111.70(c) which would require you to conduct a material
review and make a disposition decision of any packaged and labeled
dietary supplement that does not meet specifications; and

•     § 111.40(a)(3) which, in part, would require, if specifications
are not met for a received dietary supplement, you to conduct a material
review and make a disposition decision.  

     Final § 111.127(e) includes revisions associated with final §
111.87 which requires the quality control personnelunit to conduct any
required material review and makes any required disposition decision. 

     We did not receive comments specific to quality control operations
under proposed §§ 111.70(c) or 111.40(a)(3).  

5.  Final § 111.127(f) and (g)

     Final § 111.127(f) requires that quality control operations for
packaging and labeling operations include approving or rejecting any
repackaging of a packaged dietary supplement. Final § 111.127(g)
requires that quality control operations for returned dietary
supplements include approving or rejecting any relabeling of a packaged
and labeled dietary supplement.  Final § 111.127(f) and (g) derive from
the following proposed provisions: 

•    § 111.37(b)(10) which, in part, would require the quality
control unit to approve any repackaging and relabeling; and 

•    § 111.70(d) which would require the quality control unit to
approve and document any repackaging or relabeling of a dietary
supplement.  

	For consistency with other provisions in this final rule (such as final
§ 111.90), final § 111.127(f) and (g) provide that the quality control
personnelunit must clearly choose between approving - or rejecting - any
repackaged or relabeled dietary supplements.

     We did not receive comments specific to quality control operations
under proposed §§ 111.37(b)(10) or 111.70(d).

6.  Final § 111.127(h) 

     Final § 111.127(h) requires that quality control operations for
packaging and labeling operations include approving for release, or
rejecting, any packaged and labeled dietary supplement (including a
repackaged or relabeled dietary supplement) for distribution.  Final §
111.127(h) derives from the following proposed provisions:

•    § 111.37(b)(10) which, in part, would require the quality
control unit to approve the release of packaged and labeled dietary
supplements for distribution; and

•    § 111.70(e) which, in part, would require the quality control
unit to approve or reject the release of any repackaged or relabeled
dietary supplement. 

     We did not receive comments specific to quality control operations
under proposed §§ 111.37(b)(10) or 111.70(e). 

L.  What Quality Control Operations Are Required for 

Returned Dietary Supplements?

(Final § 111.130)

     Final § 111.130 sets forth the minimum required operations the
quality control personnelunit must perform with respect to returned
dietary supplements.  

    Final § 111.130 modifies proposed § 111.85 which set forth
requirements for returned dietary ingredients and dietary supplements,
including requirements for quality control operations for returned
dietary supplements.  We did not explicitly include quality control
operations with respect to returned dietary supplements under proposed
§ 111.37 but did include quality control operations in proposed §
111.85 for returned dietary supplements.  The provisions of the final
rule that pertain to returned dietary supplements are set forth in final
subpart N.  However, we are duplicating these requirements in subpart F
to make clear that, once returned products are back within your control,
the quality control personnelunit must perform appropriate operations
before the products are redistributed, if they are approved for
redistribution.  Any returned dietary supplements that are reprocessed
must be returned to your production and process control system, and,
therefore, must be properly reviewed by the quality control
personnelunit.

1.  Final § 111.130(a) 

     Final § 111.130(a) requires that quality control operations for
returned dietary supplements include conducting any required material
review and making any required disposition decision.  Final §
111.130(a) differs slightly from proposed § 111.85(a) which, in part,
would require the quality control unit to conduct a material review and
make a disposition decision for any returned dietary supplement. 

     (Comment 232)  Some comments support the proposed requirement to
specify that it is the quality control unit that conducts the material
review and makes the disposition decision regarding returned dietary
supplement products. 

     (Response)  These comments are consistent with proposed
§ 111.85(a) which is being incorporated into final § 111.130(a).

2.  Final § 111.130(a)(1) and (2)

     Final § 111.130(a)(1) requires that quality control operations for
returned dietary supplements include determining whether tests or
examination are necessary to determine compliance with product
specifications established in accordance with final § 111.70(e).  

Final § 111.130(a)(2) requires that the review and disposition decision
for returned dietary supplements include review of the results of any
tests or examinations that are conducted to determine compliance with
product specifications established in accordance with final §
111.70(e).  

3.  Final § 111.130(b)

     Final § 111.130(b) requires that quality control operations for
returned dietary supplements include approving or rejecting any salvage
and redistribution of any returned dietary supplement.  Final §
111.130(b) derives from proposed § 111.37(b)(15) which, in part, would
require the quality control unit to approve the distribution of returned
dietary supplements.  As discussed in the preamble to the 2003 CGMP
Proposal, “salvage” means to return to distribution without
reprocessing (68 FR 12157 at 12215).  

     For consistency with other regulations in this final rule (such as
final § 111.90), final § 111.130(e) provides that the quality control
personnelunit must clearly choose between approving - or rejecting - any
salvage and redistribution.

     (Comment 234)  Some comments support the proposed requirement to
specify that it is the quality control unit who approves, or rejects, a
returned dietary supplement for redistribution.  

     (Response)  These comments are consistent with proposed §
111.37(b)(15) which is being incorporated into final § 111.130(b).

4.  Final § 111.130(c)

     Final § 111.130(c) requires that quality control operations for
returned dietary supplements include approving or rejecting any
reprocessing of any returned dietary supplement.  Final § 111.130(c)
derives from proposed § 111.37(b)(15) which, in part, would require the
quality control unit to approve the reprocessing of returned dietary
supplements.  For consistency with other regulations in this final rule
(such as final § 111.90), final § 111.130(c) provides that the quality
control personnelunit must clearly choose between approving - or
rejecting - any reprocessing.

     (Comment 235)  One comment argues that the responsibility to decide
whether a returned dietary supplement is reprocessed belongs with
qualified persons in manufacturing operations, and the only
responsibility of the quality control unit is to approve the reprocessed
product for distribution.

     (Response)  We disagree with the comment.  An underlying principle
of these CGMP requirements is that the quality control personnelunit
oversees the design and conduct of manufacturing, packaging, labeling,
and holding operations.  A decision about when reprocessing is, or is
not, appropriate requires oversight.  

5.  Final § 111.130(d)

     Final § 111.130(d) requires that quality control operations for
returned dietary supplements include determining whether the reprocessed
dietary supplement meets product specifications and either approving for
release, or rejecting, any returned dietary supplement that is
reprocessed.  Final § 111.130(d) derives from the following proposed
provisions: 

•    § 111.37(b)(2) which, in part, would require the quality control
unit to determine whether all dietary supplements conform to
specifications; and

•    § 111.65(d) which, in part, would require you, if a material
review and disposition decision allows you to reprocess a dietary
supplement, to ensure it meets specifications and is approved by the
quality control unit.  

     For consistency with other regulations in this final rule (such as
final § 111.90), final § 111.130(d) provides that the quality control
personnelunit must clearly choose between approving - or rejecting - a
reprocessed dietary supplement. 

     We did not receive comments specific to quality control operations
under proposed §§ 111.37(b)(2) or 111.65(d).  

M.  What Quality Control Operations Are Required for 

Product Complaints?

(Final § 111.135)

     Final § 111.135 requires that quality control operations for
product complaints include reviewing and approving decisions about
whether to investigate a product complaint and reviewing and approving
the findings and follow-up action of any investigation performed.  

    Final § 111.135 derives from proposed § 111.95 which would set
forth requirements for consumer complaints (now “product
complaints”), including requirements for quality control operations
for consumer complaints.  We did not explicitly include quality control
operations with respect to consumer complaints under proposed § 111.37
but did include quality control operations in proposed § 111.95 for
review and investigation of consumer complaints.  The final rule’s
product complaint requirements are now set forth in final subpart O. 
However, we have duplicated the requirements for quality control
operations for product complaints in subpart F to make clear that your
investigation of the product complaint has the potential to uncover a
problem with your production and process control system and, therefore,
the quality control personnelunit must exercise appropriate oversight of
your investigation of any product complaint.  

N.  What Records Must the YouQuality Control Unit

Make and Keep?

(Final § 111.140)

     Final § 111.140 sets forth the requirements for records that the
quality control personnelunit must make and keep.  

1.  Final § 111.140(a)

     Final § 111.140(a) requires the quality control personnelunit to
make and keep records required under subpart F in accordance with
subpart P.  Final § 111.140(a) derives from proposed § 111.37(d) with
editorial revisions associated with the reorganization.  

     Other than comments that generally opposed the requirements to make
and keep records, and to have records available for  inspection and
copying by FDA when requested (see the discussion in section V), we did
not receive comments specific to proposed § 111.37(d). 

2.  Final § 111.140(b)(1)

    The final rule (final § 111.103) requires you to establish and
follow written procedures for the responsibilities of the quality
control unit operations, including written procedures for conducting a
material review and making a disposition decision and for approving or
rejecting reprocessing.  The written procedures are records.  Therefore,
final § 111.140(b)(1) requires you to make and keep a record of the
written procedures for the responsibilities of the quality control unit
operations.

3.  Final § 111.140(b)(2)     

     Final § 111.140(b)(2) requires written documentation, at the time
of performance, that the quality control personnelunit performed theits
review, approval, or rejection requirements under subpart F.  Final §
111.140(b)(2)(i) requires the quality control personnelunit to record
the date that the review, approval, or rejection was performed.  Final
§ 111.140(b)(2)(ii) requires the quality control personnelunit to
record the signature of the person performing the review, approval, or
rejection.  Final § 111.140(b)(2) derives from proposed § 111.37(c)
with revisions associated with the reorganization.

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

4.  Final § 111.140(b)(3)

     Final § 111.140(b)(3) requires the quality control personnelunit
to document any material review and disposition decision and follow-up
and include the documentation in the batch record.  Final §
111.140(b)(3) derives from proposed § 111.35(j) with revisions
associated with the reorganization and a revision, associated with final
§ 111.87 which requires the quality control personnelunit to conduct
the material review and make the disposition decision.

     Final § 111.140(b)(3) details the type of information that must be
included as part of this documentation.  Five paragraphs derive from
proposed § 111.35(j)(1) through (j)(5), with editorial changes
associated with the reorganization.  One paragraph is associated with
final § 111.90(b) which requires that you not reprocess any component
or dietary supplement that is rejected or treat a component or make an
in-process adjustment to make it suitable for use in the manufacture of
a dietary supplement, unless your quality control personnelunit conducts
a material review and makes a disposition decision that is based on a
scientifically valid reason and approves the reprocessing, treatment, or
in-process adjustment.  Another paragraph derives, in part, from
proposed § 111.37(c)(2) which would requires the signature of the
quality control unit person performing the requirement.

     The documentation that must be included under final §
111.140(b)(3) is as follows:

•    § 111.140(b)(3)(i) - Identification of the specific deviation or
the unanticipated occurrence; 

•    § 111.140(b)(3)(ii) – A description of your investigation into
the cause of the deviation from the specification or the unanticipated
occurrence;

•    § 111.140(b)(3)(iii) – An evaluation of whether the deviation
or unanticipated occurrence has resulted in or could lead to a failure
to ensure the quality of the dietary supplement or a failure to package
and label the dietary supplement as specified in the master
manufacturing record;

•    § 111.140(b)(3)(iv) - Identification of the action(s) taken to
correct, and prevent a recurrence of, the deviation or the unanticipated
occurrence; 

•    § 111.140(b)(3)(v) – An explanation of what you did with the
component, dietary supplement, packaging, or label;

•    § 111.140(b)(3)(vi) - A scientifically valid reason for any
reprocessing of a dietary supplement that is rejected, or the treatment
or in-process adjustment of a component that is rejected;

•    § 111.140(b)(3)(vii) - The signature of the individual(s)
designated to performfrom the quality control operation,unit who
conducted the material review and made the disposition decision, and of
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page   PAGE  629