XVI.  Comments on the Production and Process Control System: 

Requirements for Manufacturing Operations 

(Final Subpart K)

A.  Organization of Final Subpart K

     In the 2003 CGMP Proposal, the requirements for manufacturing
operations were set forth in § 111.65.  As shown in table 12, we are
establishing the requirements for manufacturing operations in a distinct
subpart (final Subpart K – Production and Process Control System:
Requirements for Manufacturing Operations).  In addition, we are
incorporating some requirements from proposed § 111.74 relating to
rejected components, dietary supplements, and packaging and labels into
final subpart K.  Table 12 lists the sections in final subpart K and
identifies the proposed sections that form the basis of the final rule. 

Table 12. - Derivation of Sections in Final subpart K

Final Rule	2003 CGMP Proposal

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

§ 111.355  What Are the Design Requirements for Manufacturing
Operations?	§ 111.65(a)

§ 111.360 What Are the Requirements for Sanitation?	§ 111.65(b)

§ 111.365 What Precautions Must You Take to Prevent Contamination? 	§
111.65(c)

§ 111.370 What Requirements Apply to Rejected Dietary Supplements?	§
111.74

§ 111.375 Under
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●	Applies to persons who manufacture, package, label, or hold dietary
supplements unless subject to an exclusion in § 111.1; and

● 	Reflects changes relevant to this subpart that we are making to
final subpart C concerning water standards.  

2. Changes Made After Considering Comments

● 	Requires written procedures for manufacturing operations.

3. Revisions Associated With the Reorganization

	The final rule: 

●	Sets forth in final § 111.90, rather than in subpart K, the
requirements for in-process adjustments or reprocessing.

C.  General Comments on 

Manufacturing Operations

     (Comment 286) Some comments support proposed § 111.65 as a “good
model” for an appropriate level of flexibility, noting that proposed
§ 111.65 clearly states the requirements and presents relevant factors
that must be considered when determining how to best meet the
requirements of the rule.

     (Response) We acknowledge these comments and utilize many elements
of proposed § 111.65 in final § 111.355. 

D. What Are the Requirements Under 

This Subpart for Written Procedures? 

(Final § 111.353)

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.

We are including a new provision, final § 111.353, to require that you
establish and follow written procedures for manufacturing operations. 

E. What Are the Design Requirements 

for Manufacturing Operations? 

(Final § 111.355) 

     Final § 111.355 requires you to design or select manufacturing
processes to ensure that product specifications  are consistently met. 
Final § 111.355 derives from proposed § 111.65(a) which would require
you to design or select manufacturing processes to ensure that dietary
supplement specifications are consistently achieved.  Final § 111.355
refers to “product specifications” rather than “dietary supplement
specifications” to conform with final § 111.70(e).  We have
substituted the word “met” for “achieved” to comply with plain
language initiatives and to be consistent with other provisions.

     We did not receive comments specific to proposed § 111.65(a).

F.  What Are the Requirements for Sanitation? 

(Final § 111.360) 

     Final § 111.360 requires you to conduct all manufacturing
operations in accordance with adequate sanitation principles.  Final §
111.360 derives from proposed § 111.65(b).  We did not receive comments
specific to proposed § 111.65(b).

G.  What Precautions Must You Take 

to Prevent Contamination? 

(Final § 111.365)

     Final § 111.365 requires you to take all necessary precautions
during the manufacture of a dietary supplement to prevent contamination
of components or dietary supplements.  Final § 111.365 derives from
proposed § 111.65(c)(1) through (c) (11).  

1.  Final § 111.365(a)

     Final § 111.365(a) requires that the necessary precautions include
performing manufacturing operations under conditions and controls that
protect against the potential for growth of microorganisms and the
potential for contamination.  Final § 111.365(a) derives from proposed
§ 111.65(c)(1).

     (Comment  287) One comment contends that the requirement in
proposed § 111.65(c)(1) to protect “against the potential for growth
of microorganisms,” does not take into account processes that have a
kill step.  The comment recommends that proposed § 111.65(c)(1) be
revised to be more consistent with § 110.80(b)(2) and state,
“performing manufacturing operations under such conditions and
controls as are necessary to minimize the potential for the growth of
undesirable microorganisms, or for the contamination of the product.”

     (Response) We decline to modify final § 111.365(a as requested by
the comment.  We defined “microorganism” in the 2003 CGMP Proposal
similar to how we describe “undesirable microorganisms” in §
110.3(i).  Further, we decline to use the words “minimize the
potential for growth” instead of “protect against the potential for
growth” because the word “minimize” suggests a lesser standard
than “protect against” the potential for growth of microorganisms.

We would consider that you are not complying with the final rule if you
do not perform manufacturing operations under conditions and controls
that protect against the potential for growth of microorganisms and the
potential for contamination, regardless of whether you use a kill step. 
Although a kill step may be necessary in some circumstances, it is not a
substitute for conditions and controls that protect against the
potential for growth of microorganisms and the potential for
contamination.  Therefore, we decline to make the change requested by
this comment.

2.  Final § 111.365(b) 

     Final § 111.365(b) requires that necessary precautions include
washing or cleaning components that contain soil or other contaminants. 
Final § 111.365(b) is identical to proposed § 111.65(c)(2).  We did
not receive comments specific to proposed § 111.65(c)(2).

3.  Final 111.365(c)

     Final § 111.365(c) requires that the necessary precautions
include using water that, at a minimum, complies with the applicable
Federal, State, and local requirements and does not contaminate the
dietary supplement when the water may become a component of the finished
batch of dietary supplement.

	The proposed requirements would set forth parallel requirements for
water that is used in the manufacture of a dietary supplement for both
your physical plant (proposed § 111.15(d)(2)) and for manufacturing
operations (proposed § 111.65(c)(3)).  Thus, proposed § 111.15(d)(2)
would require that water that contacts components, dietary ingredients,
dietary supplements, or any contact surface must, at a minimum, comply
with the NPDW regulations prescribed by the EPA under 40 CFR part 141
and any State and local requirements.   

	As discussed in subpart C, section VIII (final § 111.15(e)(2)), we
are revising proposed § 111.15(d)(2) to require in the final rule that
water, used in the manufacture of a dietary supplement in a manner such
that the water may become a component of the dietary supplement, e.g.,
when such water contacts components, dietary supplements, or any contact
surface, must, at a minimum, comply with applicable Federal, State, and
local requirements and not contaminate the dietary supplement.  Given
the parallel nature of proposed § 111.65(c)(3) and proposed
§ 111.15(d)(2), we are revising proposed § 111.65(c) to be
consistent with the revisions we are making to proposed § 111.15(d)(2)
(final § 111.15(e)(2)).  

	Final § 111.365(c) also includes grammatical changes consistent with
the structure of final § 111.365.

     (Comment 288) One comment asks that the words “or equivalent
quality water” be added to “water that meets the National Primary
Drinking Water regulations” in proposed § 111.65(c)(3) to allow for
ingredients manufactured in facilities outside the United States. 

     (Response)  As stated in response to comment 91, dietary
supplements manufactured in a foreign country would be subject to the
requirements of this final rule.  Although EPA NPDW regulations would
not apply to a foreign manufacturer, the foreign manufacturer would need
to use water that is of a standard required in this final rule and that
achieves the same level of performance required of domestic
manufacturers.  The water used by the foreign facility must not
contaminate the dietary supplement that is manufactured.  We decline to
add “or equivalent water quality” because that would suggest that
domestic firms would not need to follow whatever Federal, State, andor
local requirements are applicable.  

     (Comment 289) One comment recommends that proposed § 111.65(c)(3)
be revised to be consistent with proposed § 111.15(d)(1), which would
require you to provide water that is safe and of adequate sanitary
quality, at suitable temperatures, and under pressure as needed, in all
areas where water is necessary for: (1) Manufacturing dietary
ingredients or dietary supplements; (2) making ice that comes in contact
with components, dietary ingredients, dietary supplements, or contact
surfaces; (3) cleaning any surface; and (4) employee bathrooms and
hand-washing facilities.

     (Response) We do not agree with the comment that we should be
consistent in the water requirement related to proposed § 111.15(d)(1)
and the requirement in proposed § 111.65(c)(3).  The requirement in
proposed § 111.15(d)(1) describes a variety of manufacturing
operations where water is used.  For example, water that is safe and of
adequate sanitary quality, as described in the proposed rule, for
purposes of manufacturing dietary supplements or that comes into contact
with a dietary supplement would be water that would have been required
to  comply with the requirement in proposed § 111.15(d)(2).  Under the
proposed rule and under the final rule, if such water is subject to EPA
NPDW, then the water must meet EPA NPDW requirementsgulations at point
of use.  Proposed § 111.15(d)(1) has been revised and simplified in
final § 111.15(e)(1) to require you to provide water that is safe and
sanitary, at suitable temperatures, and under pressure as needed, for
all uses where water does not become a component of the dietary
supplement. Water that is safe and sanitary for cleaning the floor in a
facility would not need to meet standards for drinking water, but such
water could not be a source of contamination of the dietary supplement. 
The standard “safe and sanitary” in final § 111.15(e)(1) allows
some flexibility for the manufacturer in deciding what water it can use
in various operations for which no other requirements in this final rule
apply.  The requirements of final § 111.365(c) are consistent with the
changes in final § 111.15(e). 

4.  Final § 111.365(d)

     Final § 111.365(d) requires that the necessary precautions you
take during the manufacture of a dietary supplement to prevent
contamination of components or dietary supplements include performing
chemical, microbiological, or other testing, as necessary to prevent the
use of contaminated components.  Final § 111.365(d) derives from
proposed § 111.65(c)(4).

     (Comment 290) One comment asserts that requirements for testing
belong in proposed § 111.25 (proposed requirements for equipment and
utensils) rather than in proposed § 111.65 (proposed requirements for
manufacturing operations). 

     (Response) In our discussion of proposed § 111.65(c)(4) in the
2003 CGMP Proposal (68 FR 12157 at 12210), we stated that you consider
identifying those areas in the processing and production areas where
chemical, microbial, or other forms of contamination are most likely to
occur.  We also stated that chemical, microbial, or other testing is
necessary to identify areas where sanitation measures have not been
adequate or where products may become adulterated.  These remarks
reflect that the proposed requirement in proposed § 111.65(c)(4) is
directed to facilities rather than to equipment and utensils.  For
example, under proposed § 111.65(c)(4), we encouraged you to establish
a testing program that monitors levels of microorganisms at key places
in your physical plant where you process and produce your products. 
Thus, we disagree with the comment that the testing requirements belong
in proposed § 111.25 and are not making any changes in final §
111.365(d). 

5.  Final § 111.365(e)

     Final § 111.365(e) requires that the necessary precautions you
take during the manufacture of a dietary supplement to prevent
contamination of components or dietary supplements include sterilizing,
pasteurizing, freezing, refrigerating, controlling hydrogen-ion
concentration (pH), controlling humidity, controlling water activity
(aw), or using any other effective means to remove, destroy, or prevent
the growth of microorganisms, and prevent decomposition.  Final §
111.365(e) derives from proposed § 111.65(c)(5).

      (Comment 291) One comment asserts that only sanitary practices are
needed to prevent microbial contamination or decomposition, and,
therefore, requests that we clarify the processes listed in proposed §
111.65(c)(5) are optional.

     (Response) We disagree with this comment.  Good sanitary practices
are important, but they are not the only precaution to take to prevent a
component or dietary supplement from contamination with microorganisms. 
In the preamble to the 2003 CGMP Proposal, we gave the example of bovine
colostrum, which is the lacteal secretion that precedes milk after a cow
gives birth and is a substance that is used in dietary supplements.  We
also stated that we consider that bovine colostrum likely presents the
same potential health risks as bovine milk, which can contain pathogenic
organisms capable of causing diseases in man such as tuberculosis,
undulant fever, or gastrointestinal disease and, thus, must be
pasteurized (§ 1240.61).  Under final § 111.365(e) you must sterilize
or pasteurize bovine colostrums, or take other steps, to remove or
destroy microorganisms that could be present in bovine colostrum.  Under
final § 111.365(e) we list various ways that, depending upon the
particular situation, would be effective in removing, destroying, or
preventing the growth of microorganisms and preventing decomposition. 
You must decide for your given operation what means to use to remove,
destroy, or prevent the growth of microorganisms and prevent
deterioration of your components and dietary supplements so that you
ensure the quality of the dietary supplement. 

     (Comment 292) Some comments recommend adding “irradiating” to
the list of practices to prevent the growth of microorganisms in
proposed § 111.65(c)(5) as in the 1997 ANPRM.  

     (Response) We decline to revise the provision as suggested by these
comments.  We are not adding “irradiating” to the list of practices
because, at this time, irradiation of dietary ingredients and dietary
supplements, as a means to reduce or eliminate microbial loads, is not
permitted.  CFSAN is currently reviewing the use of irradiation for the
control of microbial contamination on dietary supplements and
ingredients (including dietary ingredients) used in the manufacture of
dietary supplements (68 FR 25048 May 9, 2003).  If we authorize this use
of irradiation you could then use irradiation in compliance with that
rule to comply with final § 111.365(e) as an “other effective
means.”  

6.  Final § 111.365(f)

     Final § 111.365(f) requires that the necessary precautions you
take during the manufacture of a dietary supplement to prevent
contamination of components or dietary supplements include holding
components and dietary supplements that can support the rapid growth of
microorganisms of public health significance in a manner that prevents
the components and dietary supplements from becoming adulterated.  Final
§ 111.365(f) derives from proposed § 111.65(c)(6).  We did not receive
comments specific to proposed § 111.65(c)(6). 

7.  Final § 111.365(g)

     Final § 111.365(g) requires that the necessary precautions you
take during the manufacture of a dietary supplement to prevent
contamination of components or dietary supplements include identifying
and holding any components or dietary supplements, for which a material
review and disposition decision is required, in a manner that protects
components or dietary supplements that are not under a material review
against contamination and mix-ups with those under a material review. 
Final § 111.365(g) is substantially similar to proposed §
111.65(c)(7).  We did not receive comments specific to proposed §
111.65(c)(7).

8.  Final § 111.365(h)

     Final § 111.365(h) requires that the necessary precautions you
take during the manufacture of a dietary supplement to prevent
contamination of components or dietary supplements include performing
mechanical manufacturing steps (such as cutting, sorting, inspecting,
shredding, drying, grinding, blending, and sifting) by any effective
means to protect the dietary supplements against contamination.  Final
§ 111.365(h) derives from proposed § 111.65(c)(8).  Such steps must
include consideration of: (1) Cleaning and sanitizing contact surfaces,
(2) using temperature controls, and (3) using time controls.

     (Comment 293) One comment suggests that the time controls required
in proposed § 111.65(c)(8)(iii) are not always necessary.

     (Response) As written, proposed § 111.65(c)(8) acknowledges that
time controls are not always necessary, because the provision requires
that you consider using time controls, and implement them if they are
necessary to prevent contamination of components or dietary supplements.
 Final § 111.65(h) retains this same language.

9.  Final § 111.365(i)

     Final § 111.365(i) requires that the necessary precautions you
take during the manufacture of a dietary supplement to prevent
contamination of components or dietary supplements include using
effective measures to protect against the inclusion of metal or other
foreign material in components or dietary supplements.  Compliance with
this requirement must include consideration of the use of: (1) Filters
or strainers, (2) traps, (3) magnets, or (4) electronic metal detectors.
 Final § 111.365(i) derives from proposed § 111.65(c)(9).

     (Comment 294) One comment contends it is sufficient to require in
proposed § 111.65(c)(9) that manufacturers inspect their equipment
before and after use to determine if any piece is missing, and if so,
the entire batch should be disposed of.  The comment states metal
detection devices are not 100 percent effective and that inspection of
equipment before and after use would be preferable. 

     (Response) We disagree with the comment.  As discussed in the 2003
CGMP Proposal, the purpose behind proposed § 111.65(c)(9) is to ensure
that no metal or foreign material becomes a source of possible
contamination and not to establish mechanisms to be used after
contamination has or is suspected to have occurred (68 FR 12157 at
12211).  The source of metal contamination is not limited to
manufacturing equipment.  For example, metal contamination could occur
through using utensils such as metal brushes during processing of
natural products.  It would be impractical to determine whether
contamination has occurred by examining the brush.

10.  Final § 111.365(j)

     Final § 111.365(j) requires that the necessary precautions you
take during the manufacture of a dietary supplement to prevent
contamination of components or dietary supplements include segregating
and identifying all containers for a specific batch of dietary
supplements to identify their contents and, when necessary, the phase of
manufacturing.  Final § 111.365(j) derives from proposed §
111.65(c)(10).  We did not receive comments specific to proposed §
111.65(c)(10).

11.  Final § 111.365(k)

     Final § 111.365(k) requires that the necessary precautions you
take during the manufacture of a dietary supplement to prevent
contamination of components or dietary supplements include identifying
all processing lines and major equipment used during manufacturing to
indicate their contents, including the name of the dietary supplement
and the specific batch or lot number and, when necessary, the phase of
manufacturing.  Final § 111.365(k) derives from proposed §
111.65(c)(11).

     (Comment 295) One comment suggests continuous processes should be
excluded from the requirement in proposed § 111.65(c)(11) to identify
specific batch or lot numbers.  The comment explains that in continuous
bulk operations for manufacturing dietary ingredients, the batch or lot
number often is not identified until after the materials have been
blended and moved into a storage bin. 

     (Response)  We are making no changes to proposed § 111.65(c)(11)
in final § 111.365(k) because the comment describes a situation where
the manufacturer is manufacturing a dietary ingredient, and the final
rule does not apply to the manufacture of a “dietary ingredient”
within the meaning of Section 201(ff) of the act.  

H.  What Requirements Apply to 

Rejected Dietary Supplements? 

(Final § 111.370) 

     Final § 111.370 requires you to clearly identify, hold, and
control under a quarantine system for appropriate disposition any
dietary supplement that is rejected and unsuitable for use in
manufacturing, packaging, or label operations.  Final § 111.370 derives
from proposed § 111.74 which would require that you clearly identify,
hold, and control under a quarantine system any component, dietary
ingredient, dietary supplement, packaging, and label that is rejected
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     We did not receive comments specific to proposed § 111.74.

I. Under This Subpart, What

Records Must You Make and Keep?

Final § 111.375

	In order to ensure that records are maintained as required under
subpart P, we are adding a new § 111.375.  This section requires that
you make and keep records of the written procedures you establish for
manufacturing operations.  These written procedures are required under
final § 111.353.

HHS/FDA-Internal-Deliberative-Confidential

Final Subpart K 9-28-05

page   PAGE  826 

