  SEQ CHAPTER \h \r 1 XIII.  Comments on the Production and Process
Control System: 

Requirements for the Master Manufacturing Record 

(Final Subpart H)

A.  Organization of Final Subpart H

     In the 2003 CGMP Proposal, the requirements for the master
manufacturing record were set forth in proposed § 111.45.  As shown in
table 9, we are setting forth the requirements for the master
manufacturing record in a distinct subpart (final Subpart H –
Production and Process Control System: Requirements for the Master
Manufacturing Record).  Table 9 lists the sections in final subpart H
and identifies the proposed provisions that form the basis for the final
rule.

Table 9. - Derivation of Sections in Final Subpart H

Final Rule	2003 CGMP Proposal

§ 111.205 What is the Requirement to Establish a Master Manufacturing
Record?	§ 111.45(a)(1), (a)(2), and

(d)

§ 111.210 What Must the Master Manufacturing Record Include?	§
111.45(b)



     The requirements in final subpart H are set forth from the
perspective of the manufacture of a batch of a dietary supplement.  You
must comply with all requirements that pertain to your activity. 
However, you must comply with the requirement to prepare and follow a
“master manufacturing record” regardless of whether you manufacture
a batch, or whether you package or label product you receive from a
supplier for packaging or labeling as a dietary supplement (and for
distribution rather than for return to the supplier).  If you are a
packager or labeler, you only need to include those parts relevant to
your process.  For example, if you are a labeler, under final §
111.210(c) you would not need to include an accurate statement of the
weight or measure of each component to be used because you would be
starting from packages already filled.

B.  Highlights of Changes to the Proposed Requirements 

for the Master Manufacturing Record

1.  Revisions

      The final rule:

•	Includes revisions that reflect that the final rule applies to
persons who manufacture, package, label, or hold dietary supplements
unless subject to an exclusion in § 111.1;  

•	Includes revisions so the requirements for the master manufacturing
record are consistent with final § 111.70(a) which requires you to
establish a specification for any point, step, or stage in the
manufacturing process where control is necessary to ensure the quality
of the dietary supplement and that the dietary supplement is packaged
and labeled as specified in the master manufacturing record; and

•	Includes a revision associated with final § 111.75(h), which
provides for the use of either tests or examinations for complying with
the requirements of part 111.

2. Changes Associated With the Reorganization

•	The proposed requirement (§ 111.45(c)) that the quality control
unit approve each master manufacturing record and any modifications to a
master manufacturing record is set forth as final § 111.123(a) in
subpart F, rather than in final subpart H, with the changes we made to
the definition of “quality control unit” to “quality control
personnel as explained in Section VI, Subpart A. 

3.  Changes After Considering Comments

	The final rule: 

•	Retains a requirement to state any intentional overage of a dietary
ingredient but does not require an explanation for such an overage;

•	Provides flexibility to include either a representative label, or a
cross-reference to the physical location of the actual or representative
label if an actual label is not provided; and

•	Provides flexibility for what must be included in written
instructions when operations are not conducted manually.

C.  General Comments on Proposed § 111.45 

(Final Subpart H)

1.  Comments on Written Procedures

We received many comments that recommended written procedures for
various provisions.  We address the need for written procedures
generally in section IV.  We also respond to individual comments on
specific provisions in the same section.  As discussed in section IV, we
do not require  you to establish and follow written procedures for
preparing a master manufacturing record. 

2.  Comments That Support Proposed § 111.45

     (Comment 249) A few comments support the proposed requirements for
the master manufacturing record.  One comment states that properly
recorded quality control measures, such as the batch production and
master manufacturing records, will aid manufacturers in producing
dietary supplements in a consistent and uniform manner, as well as serve
as tools to assess possible sources of contamination and flaws in the
production process.  Another comment asserts the master manufacturing
and batch production records probably have the second greatest impact on
overall product quality, surpassed only by the quality of the
“people” manufacturing the product.

 	(Response) We agree the master manufacturing record requirements in
the 2003 CGMP Proposal are important for reasons that include those
expressed in the comments.  Establishing a master manufacturing record
will help to ensure the quality of the dietary supplement.  The proposed
requirements for the master manufacturing record have been codified as
subpart H in this final rule. 

D.  What Is the Requirement to Establish 

a Master Manufacturing Record? 

(Final § 111.205)

     Final § 111.205 (proposed § 111.45(a) and (d)) sets forth the
requirement to prepare and follow a written master manufacturing record.


1.  Final § 111.205(a)

	Final § 111.205(a) requires you to prepare and follow a written master
manufacturing record for each unique formulation of dietary supplement
that you manufacture, and for each batch size, to ensure uniformity in
the finished batch from batch to batch.  Final § 111.205(a) is similar
to proposed § 111.45(a) which would require you to prepare and follow a
written master manufacturing record for each type of dietary supplement
you manufacture and for each batch size to ensure uniformity from batch
to batch. 

	(Comment 250) Some comments suggest the phrase “to ensure uniformity
from batch to batch” be changed to “to ensure that specifications
are met from batch to batch.”  One comment states the term
“uniformity” could be interpreted to mean that two batches would be
exactly the same, down to the minutest detail.  The comment expresses
concern about how batches of herbal products will meet this standard of
“uniformity” from batch to batch.

	(Response)  These comments may have misinterpreted the term
“uniformity” as we used it in proposed § 111.45(a).  Uniformity
means that the specifications you establish for identity, purity,
strength, and composition of the finished batch must be the same
throughout a given batch – e.g., at the beginning, middle, and end of
a production run.  To emphasize this, we have revised the requirement so
it is clear that the uniformity relates to “the finished batch.” 
Whether two batches must be exactly the same, down to the minutest level
would depend on the specifications the manufacturer establishes for the
finished batch under final § 111.70(e).  Although a finished batch must
meet those specifications “from batch to batch,” it is up to the
manufacturer to determine what those specifications will be.  We are
making no changes to the requirement. 

	(Comment 251) Some comments assert that the proposed requirement to
prepare a separate record “for each batch size” is burdensome,
particularly for smaller firms who specialize in custom blended
products.  These comments would revise the rule so the master
manufacturing record includes a master formula with instructions for how
to adjust the amount of ingredients to add depending on the batch size,
with the actual amounts included in the applicable batch record. 

	(Response) We disagree with these comments.  Requiring a separate
master manufacturing record for each batch size will lessen the
likelihood of mistakes that can happen when a formula is “multiplied
up” or “divided down,” particularly in light of the requirement
that the quality control personnelunit review and approve each master
manufacturing record (final § 111.123(a)).  Moreover, it is not clear
that the scenario described in the comments would lessen any burden,
because a new “formula,” based on the master formula, would still
need to be prepared for each batch.

	In essence, these comments suggest shifting the burden from a
requirement to prepare a master manufacturing record to a requirement to
prepare a batch record.  Under final § 111.123, the quality control
personnelunit reviews the master manufacturing record before that record
is used, but reviews the batch record only after the batch is prepared. 
Shifting the requirement in the manner suggested by these comments would
defeat the purpose of having the quality control personnelunit review
and approve each “formula.”  We are not making the suggested changes
to proposed § 111.45(a).  

	We are changing the word “type” to “unique formulation” to
clarify that the requirement for a master manufacturing record applies
to each different dietary supplement whether it is a different strength,
includes any different ingredients, is a capsule or tablet, or includes
minor variations.   

 2.  Final § 111.205(b)(1)

	Final § 111.205(b)(1) requires that the master manufacturing record
identify specifications for each 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 §
111.205(b)(1) derives from proposed § 111.45(a)(1).  We received no
comments specific to proposed § 111.45(a)(1).  We revised this section
to include changes that we made to § 111.70(a)

3.  Final § 111.205(b)(2)

	Final § 111.205(b)(2) requires that the master manufacturing record
establish controls and procedures to ensure that each batch of dietary
supplement you manufacture meets the specifications identified in
accordance with paragraph (b)(1) of this section.  Final §
111.205(b)(2) derives from proposed § 111.45(a)(2) with grammatical
changes and changes associated with the reorganization.  We did not
receive comments specific to proposed § 111.45(a)(2).

4.  Final § 111.205(c)

	Final § 111.205(c) requires you to make and keep master manufacturing
records in accordance with subpart P.  Final § 111.205(c) derives from
proposed § 111.45(a) and (d), and clarifies that you must prepare and
keep the master manufacturing records.  We did not receive comments
specific to proposed § 111.45(d), and comments relevant to § 111.45(a)
are discussed above in the response to comment 250.

E.  What Must the Master Manufacturing Record Include? 

(Final § 111.210)

	Final § 111.210 sets forth the requirements for what the master
manufacturing record must include.  Final § 111.210 derives from
proposed § 111.45(b).

1.  Final § 111.210(a)

	Final § 111.210(a) requires that the master manufacturing record
include the name of the dietary supplement to be manufactured and the
strength, concentration, weight, or measure of each dietary ingredient
for each batch size.  Final § 111.210(a) derives from proposed §
111.45(b)(1). 

	(Comment 252) One comment supports listing the weight or measure for
each ingredient but believes that including the strength and
concentration is unnecessary.  This comment also suggests that the
identity of each ingredient can be controlled using a unique item number
identifier, along with a brief description of the ingredient. 

	(Response) Proposed § 111.45(b)(1) would require the master
manufacturing record to include strength, concentration, weight, or
measure of each dietary ingredient for each batch size.  We did not
intend that all would be required.  The purpose of this requirement is
to ensure the correct dietary ingredient and amount are used in a given
batch.  To the extent that weight or measure best describes what that
dietary ingredient is and how much is to be used in a given batch, the
manufacturer could use weight or measure.  To the extent that a
manufacturer determines, for a particular dietary ingredient, strength,
or concentration would best describe what is to be used in a given
batch, the manufacturer could use those instead.  We are giving firms
the flexibility to use the measure that they determine best describes
the amount of dietary ingredient to use in their batch.  For example,
assume you are manufacturing a million tablets of a vitamin C product in
250 mg tablets and the only other ingredients in your product are
starch, microcrystalline cellulose, and dicalcium phosphate.  Under
proposed § 111.45(b)(1) (final § 111.210(a)) your master manufacturing
record would state: “Vitamin C 250 mg, 1,000,000 tablets.”  As
another example, if you are manufacturing 100 liters of a liquid dietary
supplement that provides tuna oil as a dietary ingredient, and the only
other ingredients are alpha-tocopherols for use as an antioxidant, then
your master manufacturing record would state: “Tuna oil, 100
liters.”  

	The unique identifier comment states “the identity of each dietary
ingredient can be controlled instead with the use of a unique item
identifier, along with a brief description of the ingredient.”  It is
not clear what the comment meant by “a brief description of the
ingredient.”  If the “brief description of the ingredient”
includes the identity, then it would comply with the final rule.  Firms
are free to use unique identifiers in addition to the identity.  If,
however, the comment means something other than identity, the comment
fails to explain how the identity will be controlled to prevent
manufacturing errors.  In the absence of such an explanation, we have no
basis to make the requested change.

Moreover, under final § 111.205(c) the master manufacturing record is a
record you must make and keep in accordance with final § 111.610 in
final subpart P.  Under final § 111.610, the master manufacturing
record must be available during the record retention period for
inspection and copying by us when we request that you do so.  A master
manufacturing record that does not identify the dietary ingredient and
the weight or measure of the dietary ingredient would not allow an FDA
investigator to determine, for example, how your master manufacturing
record relates to the finished dietary supplement and to the product
label of that dietary supplement.

     (Comment 253) One comment recommends the weight or measure be
expressed per unit or portion, or per unit of weight or measure of the
product, for each batch size.

    (Response) The final rule does not prescribe the units you must use.
 Thus, firms have the flexibility to include this information in the way
that best suits their product.

2.	Final § 111.210(b)

     Final § 111.210(b) requires that the master manufacturing record
include a complete list of components to be used.  Final § 111.210(b)
is identical to proposed § 111.45(b)(2).  We did not receive comments
specific to proposed § 111.45(b)(2). 

3.	Final § 111.210(c)

     Final § 111.210(c) requires that the master manufacturing record
include an accurate statement of the weight or measure of each component
to be used.  Final § 111.210(c) is identical to  proposed §
111.45(b)(3).  We did not receive comments specific to proposed §
111.45(b)(3). 

4.	Final § 111.210(d)

     Final § 111.210(d) requires that the master manufacturing record
include the identity and weight or measure of each dietary ingredient
that will be declared on the Supplement Facts label and the identity of
each ingredient that will be declared on the ingredients list of the
dietary supplement.  Final § 111.210(d) is similar to proposed §
111.45(b)(4).  We have removed the phrase “in compliance with section
403(s) of the act” as it is unnecessary in the context of compliance
with the dietary supplement CGMP requirements.  The manufacturer must
still comply with section 403(s) and failure to do so will result in a
misbranding violation, not a CGMP violation under this final rule.   

     (Comment 254) One comment supports having the identity and weight
or measure of each dietary ingredient as required by proposed §
111.45(b)(4), but asserts it is unnecessary for the verbiage to
identically match the corresponding label statements.  This comment also
asserts that the ingredients can be controlled in the master
manufacturing record by use of a unique identifier, instead of the
ingredient name, along with a brief description of the ingredient. 

	(Response) We disagree for the reasons stated above in response to
comment 252 and decline to revise the provision in this manner.  

5.  Final § 111.210(e)

	Final § 111.210(e) requires that the master manufacturing record
include a statement of any intentional overage amount of a dietary
ingredient.  Final § 111.210(e) derives from proposed § 111.45(b)(5)
which would require you to explain any intentional excess amount of a
dietary ingredient.

	(Comment 255)  Some comments request us to modify this requirement. 
Several comments note that a manufacturer may design products with
overage levels adjusted so the product always tests at least 100 percent
of the amount claimed on the label throughout the declared shelf life. 
One comment states it should be sufficient to identify any overage
amount, rather than having to explain it.

	(Response) We understand that some firms design products using an
additional amount of certain ingredients to ensure the product meets its
specifications for the amount of the ingredient during the expected
shelf life of the product.  We agree it is not necessary to include the
reason for adding the intentional excess amount.  	

	We also understand it would be more appropriate to refer to the
additional amount as an “overage” amount rather than an “excess”
amount, because “overage” is commonly used in the industry to convey
the practice that is now the subject of final § 111.260(e).  Therefore,
we have revised proposed § 111.45(b)(1) to use the term “overage”
rather than “excess” and to delete the proposed requirement to
include the reason for the intended overage.  As discussed in the
preamble to the 2003 CGMP Proposal (68 FR 12157 at 12203), the amount of
overage should be limited to the amount needed to meet the amounts
listed in accordance with final § 111.210(d).     

6.  Final § 111.210(f)

	Final § 111.210(f) requires that the master manufacturing record
include a statement of theoretical yield of a manufactured dietary
supplement expected at each point, step, or stage of the manufacturing
process where control is needed to ensure the quality of the dietary
supplement, and the expected yield when you finish manufacturing the
dietary supplement, including the maximum and minimum percentages of
theoretical yield beyond which a deviation investigation of a batch is
necessary and material review is conducted and disposition decision is
made.  Final § 111.210(f) derives from proposed § 111.45(b)(6).  We
revised the section to state “beyond which a deviation investigation
of a batch is necessary” rather than “beyond which a deviation is
performed” for clarity.

	(Comment 256) One comment suggests the term “maximum and minimum
percentages” in proposed § 111.45(b)(6) be replaced with the term
“normal range.”

	Another comment recommends proposed § 111.45(b)(6) be replaced with
“A statement of theoretical yield of a manufactured dietary ingredient
or dietary supplement expected at appropriate phases of
manufacturing.”  This comment states the detail in this proposed
requirement should be eliminated because the manufacturer should decide
where and when to include a statement about theoretical yield. 

	(Response) Final § 111.210(f) clearly communicates when it is
necessary to conduct a material review and make a disposition decision. 
The comment’s suggestions do not improve the communication or clarify
this point.  

	Final § 111.210(f) gives firms the flexibility to decide what steps,
in the manufacturing process, are points, steps, or stages where control
is needed to ensure the quality of the dietary supplement.  A statement
about theoretical yield is necessary at each such point, step, or stage
including at the finished batch stage so that you will know, when you
manufacture a batch, whether the process is proceeding as expected or
whether something is wrong.  For example, your master manufacturing
record could state the theoretical yield after mixing a series of
components is 100 percent, because nothing about the additional step
would remove any material from the production system.  When
manufacturing the batch, a yield of less than 100 percent would tell you
something was wrong – for example, if there was an obstruction that
prevented a component that was being delivered by automated equipment
from actually entering the production vessel.  For a process such as
recrystallization, knowing the theoretical yield is critical, because if
the expected yield is not achieved at a given step it may mean that the
process did not proceed as intended. 

	(Comment 257) One comment argues it is not possible for the majority of
supplement products, especially botanicals, to provide 100% of the
claimed amount of the botanical, because botanicals are inherently of
uneven consistency, density, and particle size.  This comment recommends
that we allow for variability in yield, especially for botanicals.

	(Response) Final § 111.210(f) does not specify what the yield must be,
so no revision is necessary.  It is the manufacturer’s responsibility
to manufacture the product in a way that will ensure that a product
contains what the manufacturer has established in its specifications and
its master manufacturing record.  The manufacturer must establish
specifications for the identity, purity, strength, and composition and
limits on contamination and other specifications the manufacturer
decides are necessary to ensure the quality of the dietary supplements
that it makes, and design and implement a production and process control
system that will ensure those specifications are met.  In the situation
described by the comment, it is the manufacturer’s responsibility to
design and implement a production and process control system that will
ensure the quality of the dietary supplement regardless of the problems
presented by the nature of the ingredients.

7.  Final § 111.210(g)

	Final § 111.210(g) requires that the master manufacturing record
include a description of packaging and a representative label, or a
cross-reference to the physical location of the actual or representative
label.  Final § 111.210(g) derives from proposed § 111.45(b)(7), which
would require a description of packaging and a copy of the label to be
used.

	(Comment 258) One comment supports the proposed requirement that the
master manufacturing record contain a copy of the dietary supplement
label.  Other comments contend that the proposed requirement to include
a copy of the label is neither appropriate nor necessary.  Some comments
state that companies often do not have a label available to include in
the master manufacturing record and believe that a description of the
packaging or label in the master manufacturing record should be
sufficient.  Another comment, by a company that produces many different
brands for each bulk product, asserts that updating labels in the record
would be burdensome and suggests wording similar to that used by USP,
for which a positive identification of all labeling used is permitted. 
One comment asks whether the packaging and label copy requirements can
be in separate documents cross-referenced in the master manufacturing
record, because some companies treat tablet manufacturing and packaging
as two separate and distinct operational elements.  This comment
explains that the master manufacturing record includes the specifics
required to manufacture the tablets, but the actual description of
packaging and label copy requirements are contained in separate
documents cross-referenced to the master manufacturing record by a
product part number.

	(Response) We understand there may be some circumstances where it would
be impractical to have actual copies of labels in the master
manufacturing record.  If an actual label is not available, you may
include a representative label in the master manufacturing record.  A
representative label could be a graphic representation of the label,
including the exact statements that would be on the product label, or a
detailed description of the statements and other information (such as
pictures or graphics) that will be on the actual label.  The
representative label must be an accurate representation of the label
that will be affixed to the dietary supplement distributed.  We also
agree that it would be acceptable to cross-reference the physical
location of the actual or representative label. 

	Finally, because the actual or representative label is a record that
you must make and keep in accordance with final § 111.610 in final
subpart P, it must be readily available during the retention period for
inspection or copying by FDA.  Thus, we are revising proposed §
111.45(b)(6) (final § 111.210(g)) as discussed above.

	(Comment 259) One comment states that a company that manufactures a
dietary supplement under contract to another company would not have
access to the product label.

(Response) Under final § 111.210(g) a company that manufactures a
dietary supplement under contract could comply with the requirement by,
for example, providing the name and address of the company who
contracted for the manufacture of the batch as the cross-reference to
the physical location of the label.

8.  Final § 111.210(h)(1)

	Final § 111.210(h)(1) requires that the master manufacturing record
include written instructions for specifications for each 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 § 111.210(h)(1) is similar to proposed § 111.45(b)(8)(i) which
would require that the master manufacturing record include written
instructions for specifications for each point, step, or stage in
manufacturing the dietary supplement necessary to prevent adulteration. 
Final § 111.210(h)(1) includes changes that we are making for
consistency with final § 111.70(a). 

	We did not receive comments specific to proposed § 111.45(b)(8)(i). 

9.  Final § 111.210(h)(2)

	Final § 111.210(h)(2) requires that the master manufacturing record
include written instructions for procedures for sampling, and a
cross-reference to procedures for tests or examinations.  Final §
111.210(h)(2) derives from proposed § 111.45(b)(8)(ii), which would
require that the master manufacturing record include written
instructions for sampling and testing.    

	(Comment 260) A few comments object to including certain written
instructions for sampling and testing procedures in the master
manufacturing record.  One comment states that this documentation, such
as laboratory testing procedures, would be a burdensome task and should
be maintained separate from the master manufacturing record and be
retrievable by appropriate cross-referencing information. 

	(Response) As we discussed in the preamble to the 2003 CGMP Proposal
(68 FR 12157 at 12204), the written instructions are similar to a
recipe.  As such, the written instructions must include instructions
related to procedures for sampling plans so you can collect appropriate
samples for tests or examinations.  We agree, however, that it is not
necessary for the master manufacturing record to include written
instructions for tests or examinations.  Accordingly, we have revised
the provision to permit the master manufacturing record to include a
cross-reference to the procedures for tests or examinations.  The final
rule includes a requirement that you establish and follow written
procedures for laboratory operations, including for tests and
examinations that you conduct to determine whether specifications are
met (final § 111.303).  In essence, these written procedures for tests
and examinations would constitute the written instructions that we
proposed under § 111.45(b)(8)(ii) for testing procedures.  This
requirement for written procedures is generally described in section IV.
 

10.  Final § 111.210(h)(3)

	Final § 111.210(h)(3) requires that the master manufacturing record
include written instructions for specific actions necessary to perform
and verify each 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 § 111.210(h)(3) derives from
proposed § 111.45(b)(8)(iii) which would require that the master
manufacturing record include written instructions for specific actions
necessary to perform and verify each point, step, or stage necessary to
meet specifications and otherwise prevent adulteration.  Final §
111.210(h)(3) includes changes for consistency with final § 111.70(a). 

	Final § 111.210(h)(3)(i) requires that the specific actions include
verifying the weight or measure of any component and verifying the
addition of any component.  Final § 111.210(h)(3)(ii) requires that,
for manual operations, the specific actions include: (1) One person
weighing or measuring a component and another person verifying the
weight or measure, and (2) one person adding a component and another
person verifying the addition.  Final § 111.210(h)(3)(i) and (h)(3)(ii)
derive from proposed § 111.45(b)(8))(iii).     

	(Comment 261)  Some comments suggest the requirement to have more than
one person involved in performing and verifying each point, step, or
stage in the manufacturing process is overly prescriptive and that
alternative, reliable methods for verifying the weighing and addition of
components should be permitted.  One comment explains many manufacturers
use bar code systems to identify the weight and identity of components
both before and after weighing.  In such cases, a computer generated
weight record and corresponding bar code can be created and affixed to
the container by one individual as reliable verification of the
material’s contents and weight.  Likewise, the addition of components
to a blender can be adequately controlled and verified by one person
through scanning technology that allows reliable verification of the
identity and weight of components added to a blender without the need
for a second person.

	(Response) These comments describe a system partially under the control
of automated equipment.  Final § 111.30 establishes a series of
requirements for automated equipment.  We agree that, with such
requirements in place for an automated system such as that described by
the comments, the requirement to verify the weight or measure of a
component, or to verify the addition of a component, can be achieved
without requiring that one person do the weighing or measuring and
another person verify the weighing or measuring and without requiring
that one person add the component and another person verify the
addition.  Therefore, final § 111.210(h)(3) provides both that the
written instructions must include verifying the weight or measure of any
component and verifying the addition of any component and that, for
manual operations, the written instructions must include: (1) One person
weighing or measuring a component and another person verifying the
weight or measure and (2) one person adding a component and another
person verifying the addition.  The final rule makes clear that there
must be a verification step and gives firms  flexibility, when the
weighing or addition is not done manually, to determine how they would
accomplish the verification. 

11.  Final § 111.210(h)(4)

	Final § 111.210(h)(4) requires that the master manufacturing record
include written instructions for special notations and precautions to be
followed.  Final § 111.210(h)(4) derives from proposed §
111.45(b)(8)(iv).  We did not receive comments specific to proposed §
111.45(b)(8)(iv).

12.  Final § 111.210(h)(5)

	Final § 111.210(h)(5) requires that the master manufacturing record
include written instructions for corrective action plans for use when a
specification is not met.  Final § 111.210(h)(5) derives from proposed
§ 111.45(b)(8)(v).  

	(Comment 262)  Several comments argue pre-established corrective action
plans are not useful for complex failure scenarios, and that the quality
control unit should instead approve corrective action procedures on a
case-by-case basis.  One comment suggests the rule should refer to
“procedures” rather than specifying “corrective action plans.”

	(Response)  We acknowledge that corrective action plans would be
focused on each point, step, or stage where control is necessary to
ensure the quality of the dietary supplement.  We also acknowledge that
it may not be practical to establish a corrective action plan for all
foreseeable circumstances.  In circumstances such as the complex failure
scenario described by the comments, the documentation of the material
review and disposition decision (rather than the corrective action plan)
would identify the action taken to correct, and prevent a recurrence of,
the deviation and discuss what you did with the batch (final §
111.140(b)(3)(iv) and (b)(3)(v)).  However, we disagree that the fact
that it may not be practical to establish a corrective action plan for
all foreseeable circumstances means you could not establish a corrective
action plan at each point, step, or stage where you can, in fact,
predict a scenario and provide a plan for action when that scenario
presents itself.  Therefore, for any circumstance you can predict, final
§ 111.210(h)(5) requires that you establish corrective action plan.

	F. Quality Control Responsibility 

(Proposed § 111.45(c))

     In proposed § 111.45(c) we would require the quality control unit
to review and approve each master manufacturing record and any
modifications to a master manufacturing record.  As part of the
reorganization, this requirement is set forth under final § 111.123(a)
in subpart F for quality control personnel.  There is no reason to
repeat the requirement in final subpart H and, thus, it does not appear
in final subpart H.  

FDA-Internal-Confidential-Deliberative

Final Subpart H 9-28-05, 6-26-06, 3-30-07, 5-04-07

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