encompasses ``all aspects of physical growth and normal maturational
development, including maturation of organ systems and achievement of
normal functional development of motor, neurocognitive, and immune
systems. All of these growth and maturational processes are major
determinants of an infant's ability to achieve his/her biological
potential, and all can be affected by the nutritional status of an
infant.'' Thus, in the 1996 proposal, FDA recognized that the
nutritional status of an infant can affect the growth and developmental
process contemplated by the concept of ``healthy growth.'' Currently,
well-established reference data derived using non-invasive procedures
are not available to characterize body composition of infants, and
methods for establishing the requirements for other quality factors
discussed in the proposed rule that contribute to ``healthy growth''
are not available or are impracticable. For this reason, FDA did not
propose, and is not establishing in this interim final rule,
requirements for quality factors other than normal physical growth and
sufficient biological quality of protein. However, as new methodology
and appropriate reference criteria become available, FDA will consider
amending this regulation by identifying additional quality factors and
establishing appropriate requirements to meet the additional quality
factors.
    (Comment 24) Several comments also expressed confusion about the
need for quality factors for individual infant formula nutrients as
well as for the formula as a whole.
    (Response) As explained in section VIII.A, the 1986 Amendments
revised section 412(b)(1) of the FD&C Act by extending the requirements
for quality factors to the infant formula as a whole as well to the
nutrients required by section 412(i) of the FD&C Act (21 U.S.C.
350a(i)). Thus, by law, FDA must establish requirements for individual
nutrient quality factors and the formula as a whole to the extent
possible consistent with current scientific knowledge. To alleviate
confusion about ``healthy growth'' and ``quality factors,'' and to
clarify that quality factors apply both to the formula matrix and to
the

individual required nutrients, FDA has revised the definition of
``quality factors.'' Thus, in the interim final rule, ``quality
factors'' is defined as follows: ``Quality factors means those factors
necessary to demonstrate the bioavailability and safety of the infant
formula, as prepared for market and when fed as a sole source of
nutrition, including the bioavailability of individual nutrients in the
formula, to ensure healthy growth of infants.''
    In addition to revising the definition of ``quality factors,'' FDA
is revising the section of the proposed regulation specifying the
minimum quality factors for infant formulas to clarify the relationship
between ``healthy growth'' and ``normal physical growth.'' Proposed
Sec.  106.96 addressed the quality factors for infant formula and
stated in part: ``All infant formulas shall . . . be of sufficient
quality to meet the nutritional requirements for healthy growth.'' The
proposed rule appears to have created some confusion about how to
comply with such a requirement and how this provision differs from the
requirements that infant formula be capable of supporting normal
physical growth and be formulated and manufactured with protein that is
of sufficient biological quality. A demonstration of ``normal physical
growth'' is a factor that helps to ensure that the infant formula
supports ``healthy growth.'' Similarly, a demonstration of sufficient
biological quality of the protein is a factor that helps to ensure that
the protein in the infant formula (as opposed the entire formula
matrix) helps to support healthy growth.
    Consistent with the changes to the definition of ``quality
factors'' in Sec.  106.3 of the interim final rule, proposed Sec.
106.96 has been revised by reorganizing Sec.  106.96 to identify the
two specific quality factors of normal physical growth and sufficient
biological quality of the protein and to set forth the minimum
requirements for quality factors for each of the two quality factors.
Specifically, Sec.  106.96(a) of the interim final rule identifies the
quality factor of normal physical growth and Sec.  106.96(b) of the
interim final rule establishes the minimum requirements for that
quality factor, and Sec.  106.96(e) of the interim final rule
identifies the quality factor of sufficient biological quality of the
protein and Sec.  106.96(f) of the interim final rule establishes the
requirements for this second quality factor. Consistent with FDA's
original intent, Sec.  106.96 of the interim final rule does not
identify ``healthy growth'' as a separate quality factor.
    The comments FDA received on the specific quality factor
requirements of the proposed rule, FDA's responses to those comments,
and the quality factor requirements as established in this interim
final rule are addressed in detail in section VIII of this document.
    (Comment 25) One comment requested that FDA delete the reference to
safety in the definition of ``quality factors'' in proposed Sec.
106.3(o) to be consistent with the fact that the Infant Formula Act
does not deal with ``safety'' per se, but rather with nutritional
adequacy. The comment stated that the omission of a reference to safety
is consistent with the fact that the FD&C Act ensures safety in many
ways. Consequently, the comment stated, the additional regulation
dictated by the Infant Formula Act was only needed to focus on the
particular reliance of infants on the nutritional aspects of a food
that might substitute for breast milk as their sole source of
nutrition.
    (Response) FDA disagrees that the Infant Formula Act, and
specifically the term ``quality factors,'' does not have aspects
related to the safety of an infant formula. While it is true that each
ingredient in infant formula must be approved for use as a food
additive, be GRAS under the conditions of intended use, or be used in
accordance with a prior sanction, it is also true that the ingredients
and the combination of ingredients, i.e., the entire infant formula
matrix, must be able to support the growth and development of infants.
The concept of ``bioavailability'' is not separate and distinct from
the concept of safety. If an infant formula, which is the sole source
of nutrition for infants, could not support healthy growth of infants,
FDA would not consider the formula to be safe for use by infants.
Therefore, FDA disagrees with this comment's request to delete the
reference to safety in the definition of quality factors and is not
modifying proposed Sec.  106.3(o) in response to the request.
    (Comment 26) One comment recommended deletion of ``healthy growth''
as a quality factor. Another comment requested removal of any reference
to ``growth'' in the definition of quality factors, asserting that the
effort to establish ``healthy'' or ``normal'' growth as a quality
factor is flawed. This comment did not explain the basis for its
assertion that ``healthy'' or ``normal'' physical growth as a quality
factor is flawed.
    (Response) As is discussed previously in this document, FDA has
revised Sec.  106.96 to clarify that ``healthy growth'' is not itself a
quality factor. Instead, FDA has identified two quality factors,
``normal physical growth'' and ``sufficient biological quality of
protein'' and has established in Sec.  106.96 of the interim final rule
requirements to establish those quality factors. This change has been
made to clarify that all quality factors in combination help to ensure
that a formula and the individual nutrients in a formula support
``healthy growth.'' ``Normal physical growth'' is only one factor that
helps to ensure healthy growth. As noted previously in this document,
as science evolves, FDA will consider whether it is appropriate and
feasible to develop additional quality factors that will help to ensure
healthy growth and to establish requirements to demonstrate that a
formula satisfies those additional quality factors.
    FDA disagrees with the comment's claim that the effort to establish
``normal physical growth'' as a quality factor is flawed. Quality
factors pertain to the bioavailability of an infant formula and the
individual nutrients in that formula; demonstrating bioavailability
helps to ensure that infants will achieve healthy growth when fed the
formula as a sole source of nutrition. As discussed previously in this
document, and consistent with the 1996 proposal, FDA considers the
concept of ``healthy growth'' to be ``broad, encompassing all aspects
of physical growth and normal maturational development, including
maturation of organ systems and achievement of normal functional
development of motor, neurocognitive, and immune systems'' (61 FR 36154
at 36179). FDA further recognizes that ``all of these growth and
maturational development processes are major determinants of an
infant's ability to achieve his/her biological potential, and all can
be affected by the nutritional status of an infant'' (61 FR 36154 at
36179). The report of the House Committee on Interstate and Foreign
Commerce (the 1980 Committee Report) that accompanied the Infant
Formula Act stated that ``growth of infants during the first few months
of life is a determining factor for the pattern of development and
quality of health in adult life'' (Ref. 9). FDA interprets this
statement as evidence that the Committee recognized the vulnerable
nature of this period of life and the critical role of diet in
affecting long-term growth and development during this stage, and that
healthy growth involves integration of the myriad processes by which an
infant reaches his/her biological growth potential.
    The concept of ``healthy growth'' in the definition of quality
factors is not only consistent with the Committee's report, but is also
consistent with

discussions of diet and health by several authoritative bodies. For
example, the preamble to the Constitution of WHO states that ``health
is a state of complete physical, mental, and social well-being and not
merely the absence of disease or infirmity'' (http://www.who.int/governance/eb/constitution/en/index.html) (Ref. 10). While FDA's use of
the term ``healthy growth'' in this regulation does not extend to
measures of social well-being, it is otherwise consistent with the
concepts in the WHO definition in that normal development is
encompassed within the concept of complete physical and mental well-
being. The term ``healthy growth'' is also closely allied with the
conceptual framework adopted by the Food and Nutrition Board of the
IOM, which established a comprehensive set of reference values for
nutrient intakes consistent with the maintenance of good health. For
example, in revising the dietary reference intakes for the B vitamins,
the IOM considered risk of developmental abnormalities and chronic
degenerative disease as well as nutrient functions and their indicators
(Ref. 8).
    Therefore, FDA is retaining the reference to ``healthy growth'' in
the definition of ``quality factors'' in Sec.  106.3 of the interim
final rule, and is retaining normal physical growth as a quality
factor.
    (Comment 27) One comment agreed with the critical importance of
ensuring the bioavailability of infant formula and stated that growth
is clearly an indicator of bioavailability. However, the comment also
claimed that it would be inappropriate to establish ``healthy growth''
or ``normal growth'' as a quality factor and recommended that neither
be included as a quality factor in proposed Sec.  106.96. The comment
alleged that there are meaningful scientific weaknesses to establishing
growth as a quality factor but did not identify those weaknesses.
    The comment also argued that not enough is known about what
constitutes optimal growth to make it possible to choose the one
perfect standard against which ``normal'' or ``healthy'' growth should
be judged and that, as a matter of policy, it would be unwise to depend
on growth as an outcome. The comment also claimed that focusing on a
single outcome may cause FDA problems in being even-handed in its
treatment of manufacturers developing new infant formulas although the
comment did not explain this assertion.
    (Response) FDA agrees that it would be inappropriate to establish
``healthy growth'' as an individual quality factor but for reasons
other than those offered in the comment. As noted previously in this
document, all quality factors contribute to demonstrating the
bioavailability and safety of a formula and help to ensure ``healthy
growth.'' There are many factors that help to ensure ``healthy
growth,'' one of them being ``normal physical growth'' and another
being sufficient biological quality of protein. Therefore, because all
quality factors help to ensure healthy growth, it would be
inappropriate to establish ``healthy growth'' as a separate and
distinct quality factor.
    FDA disagrees, however, that it is inappropriate to establish
``normal physical growth'' as a quality factor. Importantly, FDA does
not consider ``optimal growth'' to be synonymous with ``normal physical
growth.'' Demonstrating that a formula supports ``normal physical
growth'' is a scientifically valid means to contribute to demonstrating
that the formula (in its entirety) is bioavailable to and safe for the
infant. Notably, the IOM committee strongly supported studies of normal
physical growth, recommending ``that growth studies should continue to
be a centerpiece of clinical evaluation of infant formulas and should
include precise and reliable measurements of weight and length
velocity, and head circumference'' (Ref. 4, p. 10).
    Even though there may always be debate in the scientific community
on what constitutes optimal growth, there is a sufficient knowledge
base to establish ``normal physical growth'' as a quality factor. It is
well-established that infants grow steadily and predictably, and there
are now data to identify what constitutes ``normal physical growth''
and how infants should grow. Using worldwide data of how infants grow
as well as improved statistical procedures, WHO developed new growth
standards, which are regarded as the most comprehensive standards for
how infants should grow. The Centers for Disease Control and Prevention
(CDC) has recommended the use of the WHO growth standards for birth to
2 years of age since 2009 and CDC's determination was formally
presented in 2010 (Ref. 11). The 2009 CDC growth charts, based on the
WHO Child Growth Standards, are available at http://www.cdc.gov/growthcharts/who_charts.htm, and are a valuable clinical tool for both
health professionals and clinical investigators. The 2009 CDC growth
charts are incorporated by reference in Sec.  106.160(e) of this
interim final rule.
    (Comment 28) Several comments addressed the use of ``healthy
growth'' as a general quality factor (proposed Sec.  106.96(a)). One
comment stated that it would not be possible to achieve a reasonable
scientific consensus on what additional functions (in addition to
anthropometric measurements of physical growth) might constitute
``healthy growth'' as it is related to nutrition, suggesting that
``healthy growth'' should not be a quality factor.
    (Response) FDA agrees that ``healthy growth'' should not itself be
a quality factor and accordingly, the Agency is revising both the
definition of quality factors in proposed Sec.  106.3(o) and the
requirements for quality factors in proposed Sec.  106.97 to clarify
this issue. As noted, ``healthy growth'' is a broad concept, and the
definition of ``quality factors'' in Sec.  106.3 of the interim final
rule identifies the achievement of healthy growth as the overall goal
of all specific quality factors. Importantly, however, FDA has not
established any requirements for demonstrating ``healthy growth.'' As
clarified previously in this document, the interim final rule
identifies two quality factors (``normal physical growth'' and
``sufficient biological quality of protein'') and establishes
requirements that relate specifically to those two quality factors. In
particular, Sec.  106.96(b) of the interim final rule establishes the
requirements for the quality factor of ``normal physical growth,'' and
Sec.  106.96(f) of the interim final rule establishes the requirements
for the quality factor of ``sufficient biological quality of protein.''
Meeting the quality factors that are delineated by the Agency, both now
and in the future, will help to ensure that the individual nutrients in
an infant formula and the infant formula as a whole support healthy
growth.
    (Comment 29) Several comments favored requiring normal physical
growth as a quality factor, and a related comment stated that the only
practical way of assessing growth is by physical measurement.
    (Response) The Agency agrees with this comment to the extent that
the comment asserts that the only practical way of measuring normal
physical growth is by physical measurement. Importantly, it is possible
that in the future, as science advances, other measures for assessing
normal physical growth may be identified, and FDA intends to consider
amending the regulations issued in this interim final rule to
establish, as appropriate, additional quality factors and associated
requirements.
    (Comment 30) One comment stated that because of the increasing
complexity of formula ingredients, it is more relevant to evaluate the
formula's overall nutrient quality and availability than merely
assessing selected

individual nutrients required by the FD&C Act.
    (Response) To the extent this comment asserts that quality factors
should be established for the complete infant formula, FDA agrees.
    FDA disagrees with the comment, however, to the extent that it
suggests that evaluation of the formula's overall nutritional quality
and overall nutrient availability is sufficient or more relevant than
evaluating the bioavailability of individual nutrients. As explained in
this document, it is scientifically appropriate to establish quality
factors both for the complete formula and certain individual formula
ingredients.
    The 1996 proposal noted that individual nutrient bioavailability is
especially critical for formula because, for some infants, it serves as
the sole source of nutrition at a life stage of particular
vulnerability to harm from nutritional insults (61 FR 36154 at 36179).
A nutrient is ``bioavailable'' to an infant if it is ``physiologically
available in sufficient quantities to perform its metabolic
functions;'' the factors affecting bioavailability are complex and can
be difficult to predict (61 FR 36154 at 36179). Given the documented
importance of individual nutrients, it is entirely appropriate that FDA
consider identifying quality factors for these nutrients.
    Protein is one of the nutrients required to be present in infant
formula, and the 1996 proposal discussed in detail the complexity of
protein and its central importance in the infant diet (61 FR 36154 at
36181). Therefore, at the present time, protein is the only individual
nutrient for which a quality factor should be established, and thus,
Sec.  106.96(e) of the interim final rule requires that a formula's
protein ingredient be of sufficient biological quality. FDA did not
propose, and is not including in this interim final rule, requirements
for quality factors for other required nutrients because, for example,
methods to determine whether such requirements are met are either not
available, or if available, are impractical because they are invasive,
technically difficult, or their results cannot be meaningfully
interpreted.
    A quality factor for the formula's overall nutritional sufficiency
(i.e., normal physical growth) and a quality factor for the biological
quality of the formula's protein component (i.e., sufficient biological
quality) are complementary. Although a growth study can provide an
assessment of a formula's overall nutritional sufficiency, such a study
has limitations. In particular, an infant may experience normal
physical growth in terms of height, weight, and head circumference but
nevertheless be malnourished because the protein does not contain all
of the essential amino acids at levels and relative proportions needed
for healthy growth and development. Said differently, the functional
outcome from an ingredient, such as protein, may not necessarily be
immediately reflected by anthropometric measures of physical growth.
Thus, FDA has concluded that it is scientifically appropriate to
establish quality factors both for the overall formula and the
individual formula ingredient, protein. See the discussion in section
VIII.
    Moreover, section 412(b)(1) of the FD&C Act requires FDA to
establish, to the extent possible consistent with current scientific
knowledge, requirements for quality factors for individual ingredients
and the formula as a whole. Thus, Sec.  106.96 of the interim final
rule establishes requirements for demonstrating two quality factors:
normal physical growth and sufficient biological quality of the protein
ingredient.
    (Comment 31) Several other comments indicated that quality factors
requirements for infant formulas should demonstrate not only normal
physical growth but also normal development and health of infants
during the study period.
    (Response) Physical growth and overall development are both aspects
of the term ``healthy growth.'' Currently, normal physical growth is a
readily available method for evaluating the bioavailability of the
infant formula matrix; however, as science evolves, FDA may add
additional quality factor requirements that demonstrate that the
formula ensures that infants achieve healthy growth. The Agency does
not consider it necessary at this time to include in the four-month
study period additional quality factors relating to the ``health of
infants'' or ``normal development,'' nor does the comment explain how
specifically these additional quality factors would be measured or why
four months would be a sufficient period of time within which to expect
measurable changes. Thus, the interim final rule does not identify
``normal development and health of the infant'' as an additional
quality factor.
    (Comment 32) One comment agreed with the Agency as to the
importance of assessing substantive changes in the manufacturing
process on nutrient bioavailability, but stated that a broad definition
of growth (healthy growth) would not achieve this objective. Another
comment requested that FDA put any mention of measurement of
``healthy'' or ``normal growth'' into a guidance document to identify
when a clinical demonstration of growth is the most appropriate way to
demonstrate bioavailability, and that the term ``healthy growth'' be
changed to ``expected physical growth'' in that guidance. The comment
also stated that ``expected'' is a more meaningful term and refers to
the population for whom the formula is intended and can be measured
objectively.
    (Response) As explained previously in this document, FDA has
revised proposed Sec.  106.3(o), the definition of ``quality factors,''
and is not identifying ``healthy growth'' as an individual quality
factor in this interim final rule. Further, FDA does not agree that the
term ``expected physical growth'' should replace the term ``healthy
growth.'' Unlike the broad concept of ``healthy growth,'' the term
``expected physical growth'' is too narrow to describe what a
manufacturer must ensure with respect to the bioavailability and safety
of the infant formula. The Agency is codifying ``normal physical
growth'' and ``sufficient biological quality of the protein
ingredient'' as the two quality factors in this interim final rule. As
science evolves, FDA will consider amending this regulation by
identifying additional quality factors.
8. Other Definitions Requested in Comments
    (Comment 33) One comment recommended that the Agency adopt a
definition of ``minor change,'' and suggested ``any new formulation, or
any change of ingredients or processes where experience or theory would
not predict a possible significant adverse impact on nutrient levels or
nutrient availability. Minor changes may or may not affect whether a
formula is adulterated under section 412(a) of the FD&C Act; changes
that affect whether a formula is adulterated under section 412(a) would
require the manufacturer to notify FDA prior to first processing.'' The
comment noted that the 1996 proposal did not mention ``minor change,''
and claimed that the failure to define ``minor change'' created
unnecessary confusion. The comment gave several examples of both minor
changes that would require notification prior to first processing, and
those that would not require such notification.
    (Response) FDA declines to add a definition for the term ``minor
change'' because such a definition is unnecessary. Although the comment
asserts that defining ``minor change'' is needed to dispel confusion,
the comment does not explain this statement. The pivotal concept for a

submission required by section 412(d) of the FD&C Act for a new infant
formula is whether the change is ``major,'' and, in Sec.  106.3, the
interim final rule includes a definition of ``major change.'' This
definition of ``major change'' makes clear that only certain changes
are of a type that require the submission under section 412(d) of the
FD&C Act; the definition in proposed Sec.  106.3(i) is derived from
section 412(c)(2)(B) of the FD&C Act, and, the definition of ``major
change'' in Sec.  106.3 of the interim final rule provides examples of
changes that would be considered ``major'' because they are changes
that cause a formula to differ fundamentally in processing or
composition. Moreover, elsewhere in this preamble, FDA has affirmed
that not every change to a formula is a ``major change.'' Thus, the
need for a definition of ``minor change'' has not been established.
Accordingly, FDA is not persuaded to add a definition for ``minor
change'' to this interim final rule.
    (Comment 34) A comment suggested adding a definition for the term
``critical'' in order to limit the scope of ``validation'' (e.g. Sec.
106.35) to those areas of manufacture that may truly have public health
significance. The comment suggested that the term ``critical'' be
defined when describing ``systems or equipment that has been designated
by the infant formula manufacturer as necessary to control to prevent
adulteration.'' The comment stated that this definition also emphasizes
the responsibility of the manufacturer to make a careful determination
of which areas of the production process may have public health
significance.
    (Response) FDA is not persuaded to include a definition of
``critical'' in the interim final rule. Throughout the interim final
rule, the Agency refers to points, steps, stages, equipment, and
systems ``where control is necessary to prevent adulteration.'' This is
the standard in section 412(b)(2)(A), the relevant statutory provision.
Therefore, it is not appropriate to limit or otherwise modify this
standard with the term ``critical.'' Accordingly, FDA declines to
include a definition of ``critical'' in the interim final rule.
    (Comment 35) One comment suggested defining the term
``specifications.'' The comment stated that FDA should define
``specifications'' as ``quality control limits or standards for raw
materials, in-process materials, and finished product, which are
established by the manufacturer for purposes of controlling quality and
consistency for infant formula. Failure to meet an established
specification requires a documented review and material disposition
decision.'' The comment suggests that in the drug industry, there is
common acceptance that the term ``specification'' means a predetermined
value or range for a given parameter, which must be met in order to
continue the manufacturing process or release the product for
distribution. Failure to meet a specification triggers special, non-
routine, documented review, not automatic rejection of the product. The
comment states that this procedure is appropriate because
specifications, like those in infant formula manufacture, are set well
within the outer limits that would cause adulteration. In view of this
definition, the comment suggests deleting the word ``standard''
throughout the proposed rule and replacing it with ``specifications.''
If FDA opts to define ``specifications'' as the outer acceptability
limits, the comment strongly recommends that manufacturers be allowed
to retain the current tighter control range approach and to determine
whether outer acceptability limits need to be established at each given
step in the manufacturing process, as opposed to making the
establishment of outer limits an absolute requirement in every case.
    (Response) FDA agrees that the term ``standards'' does not add
clarity to the interim final rule because any standard would be
considered a specification. Thus, the Agency is deleting the term
``standards'' when used and retaining the term ``specifications.''
    FDA disagrees, however, that the term ``specification'' needs to be
defined in this interim final rule. The term is commonly used and well-
understood in the context of CGMP. In proposed Sec.  106.6(c), a
manufacturer would have to establish standards or specifications at any
point, step, or stage in the production process where control is
necessary to prevent adulteration. Controls to ensure quality include
planning processes to determine desired product features or
characteristics, a system of controls to ensure that the desired
product will be consistently produced, and making necessary
improvements to the process (Ref. 12). Manufacturers must plan what
they intend to produce, institute adequate controls to achieve the
desired outcome, and ensure that the controls work so that the desired
outcome is consistently achieved. If the outcome is not consistently
achieved, one or more corrective actions must be implemented to reach
the desired outcome.
    This interim final rule embodies the basic concepts of ensuring
quality through planning, establishing controls, and providing feedback
to ensure necessary improvements are implemented. An infant formula
manufacturer must establish controls at all stages of manufacturing to
ensure that the finished product, as packaged and labeled, meets the
requirements of the FD&C Act. The controls chosen by a manufacturer may
include a specific limit (e.g., addition of 60 milligrams (mg) of
vitamin C) or a range (e.g., product must be held between 35-45 degrees
F). This interim final rule does not require that a manufacturer set
specifications at an outer acceptability limit or within a tighter
control range, as described by the comment. Instead, the manufacturer
has the flexibility to establish those specifications that are
necessary to meet the requirements of section 412 of the FD&C Act and
not adulterate the product under sections 402(a)(1), (a)(2), (a)(3), or
(a)(4) of the FD&C Act.
    (Comment 36) One comment suggested defining the term ``target
value.'' The comment also suggests defining the term ``target value''
as ``control limits or standards for raw materials, in-process
materials, and finished product which are established by the
manufacturer for purposes of targeting the manufacturing process to a
tight range within broader specifications. Failure to meet an
established target value shall result in an immediate review and
adjustment, if necessary, during the manufacturing process. No
documented review and material disposition is [sic] needed when a
target value is not met, provided that the established specifications
are met.'' The comment explained that infant formula manufacturers
sometimes establish ``target values'' within tight specifications so
that operators can adjust the process if the target value is exceeded.
The comment suggested that the term ``target value'' should be not
defined for purposes of establishing a requirement for them, but,
instead, to recognize that some infant formula manufacturers use them
for quality control purposes and to distinguish them from
specifications because failure to meet a target value should not
trigger the kind of detailed and documented review prompted by a
failure to meet specifications.
    (Response) FDA is not persuaded to define the term ``target value''
because FDA is not requiring manufacturers to establish target values
in this interim final rule. Manufacturers who establish ``target
values'' within their specifications are free to continue this
practice. Importantly, however, any target value established by a

manufacturer should be consistent with the manufacturer's
specifications. FDA agrees that although a failure to meet a
specification shall prompt a detailed and documented review, such
review would not be required by the failure to meet a target value that
does not also serve as a specification.

V. Subpart B--Current Good Manufacturing Practice

    In the 1996 proposed rule, FDA proposed to establish a new subpart
B in part 106 of title 21 of the CFR to implement section 412(b)(2) of
the FD&C Act. Section 412(b)(2) of the FD&C Act requires the Secretary
(and FDA by delegation) to issue regulations to ``establish good
manufacturing practices for infant formulas, including quality control
procedures that the Secretary determines are necessary to assure that
an infant formula provides nutrients in accordance with this subsection
and subsection (i) and is manufactured in a manner designed to prevent
adulteration of the infant formula.'' The system proposed by FDA was
intended to establish a framework in which manufacturing decisions are
left to the formula manufacturer, but also charges a manufacturer with
incorporating into its process measures designed to ensure the safety
and nutritional quality of the formula. The 2003 reopening requested
comments on all aspects of the 1996 proposal, including proposed
subpart B. Also, certain provisions of proposed subpart B were the
subject of FDA's 2006 request for comments.
    FDA received both general comments as well as specific comments on
proposed subpart B. These comments are summarized in this document
along with the Agency's responses. In addition to the substantive
revisions to subpart B noted in this document, FDA is also making minor
editorial revisions in this subpart.

A. General Comments

    (Comment 37) One comment suggested that the proposed production and
in-process control system should be called a Hazard Analysis and
Critical Control Point (HACCP) system because it contains the elements
of HACCP.
    (Response) The Agency disagrees. In this interim final rule, FDA is
adopting CGMP requirements for infant formula as mandated by section
412(b)(2) of the FD&C Act. That statutory provision expressly requires
that the Secretary establish by regulation good manufacturing practices
requirements.
    HACCP is a science-based, systematic approach to preventing food
safety problems through the identification and the assessment of risk
(likelihood of occurrence and severity), and control of the biological,
chemical, and physical hazards associated with a particular food
production process or practice. Application of HACCP requires the food
producer to develop a plan for the manufacturer's particular production
process that anticipates food safety hazards and identifies the points
(critical control points) in such a process where a failure would
likely result in a hazard being created or allowed to persist.
    HACCP and CGMP share the common goal of a systematic approach to
food safety. CGMP requires that a manufacturer take all necessary steps
both to prevent hazards and to ensure that the manufactured product is
what was established in the manufacturer's specifications. Although
some requirements of this interim final rule may be consistent with a
HACCP-based system, this interim final rule establishes CGMP in
accordance with section 412(b)(2)(A) of the FD&C Act.

B. Current Good Manufacturing Practices (Proposed Sec.  106.5)

    As proposed in 1996, Sec.  106.5(a) stated that the regulations in
subpart B defined the minimum current good manufacturing practices for
infant formula and that the provisions of part 113 (21 CFR part 113)
applied to liquid infant formulas. Under proposed Sec.  106.5(b), the
failure to comply with any provision of subpart B, or for a liquid
infant formula, any provision of part 113, would cause the formula to
be adulterated under section 412(a)(3) of the FD&C Act. The comments
FDA received on proposed Sec.  106.5 supported the language without
modification.
    The Agency has recently become aware of an infant formula product
that satisfies the definition of an ``acidified food'' under Sec.
114.3(b) (21 CFR 114.3(b)). As an acidified food, this infant formula
must comply with part 114 (21 CFR part 114). To make Sec.  106.5 a
comprehensive statement, FDA is, on its own initiative, revising
proposed Sec.  106.5 to clarify that an infant formula that is an
acidified food is subject to the requirements of part 114 and that, for
an infant formula that is an acidified food, the failure to comply with
any provision of part 114 will cause the formula to be adulterated
under section 412(a)(3) of the FD&C Act.

C. Production and In-Process Control System (Proposed Sec.  106.6)

    In the 1996 proposal, FDA proposed in Sec.  106.6 to require that
infant formula manufacturers implement a system of production and in-
process controls designed to ensure that all requirements of subpart B
are met and that the infant formula is not otherwise adulterated. This
system would be required to be set out in a written plan extending to
all stages of processing, from receipt and acceptance of raw materials,
ingredients, and components, through storage and distribution of
finished product. For each point at which control is necessary, a
manufacturer would be required to set specifications, monitor the
control point, establish a corrective action plan for use when a
specification is not met, have an individual qualified by education,
training, or experience evaluate the public health significance of any
deviation from specifications, and establish recordkeeping procedures.
    The Agency received comments on several aspects of Sec.  106.6,
which are addressed in this document.
1. Specifications and Failure To Conform to an Established
Specification
    FDA received comments that addressed ``specifications'' generally
and did not focus on particular requirements of the proposed rule.
These comments are relevant to several sections of the proposed rule
that require a manufacturer to establish, implement, and enforce
specifications. For purposes of clarity and consistency, FDA addresses
in this document, in the context of proposed Sec.  106.6, the general
comments concerning specifications.
    (Comment 38) One comment stated that infant formula manufacturers
currently establish very tight internal specifications and that, while
the objective during manufacturing is to produce a product that falls
within these tight internal specifications, the failure to do so does
not necessarily mean that the infant formula product is adulterated.
The comment asserted that a deviation that falls outside the tight
internal specifications should trigger a formal, documented review and
a material disposition decision and should not lead to automatic
rejection of the product. The comment explained that a documented
review and a material disposition decision is appropriate because
specifications are customarily well within the outer limits that would
cause adulteration.
    (Response) The requirement to establish, monitor, and otherwise
apply specifications was included in several places in the proposed
rule, including proposed Sec. Sec.  106.6(c), 106.40(d), 106.40(e), and
106.70. FDA is persuaded by this comment as well as other comments
received that it is appropriate to make certain revisions to the
proposed rule's specification requirements.

    First, FDA is revising proposed Sec.  106.40(d) by removing the
proposed requirement that an ingredient, container, or closure that
fails to conform to a specification be automatically rejected for use
in formula manufacturing and, instead, to provide that such ingredient,
container, or closure, as well as any affected infant formula, shall be
subject to a formal, documented review and material disposition
decision and shall be quarantined pending such review and disposition
decision. The disposition decision may be to reject the ingredient,
container, or closure or the affected formula; to reprocess or
otherwise recondition it; or to approve and release it for use. As
stated previously in this document, the CGMP procedures in this interim
final rule are designed to prevent the production of an adulterated
infant formula. FDA agrees that failure to meet a specification does
not necessarily mean that the infant formula manufactured using the
ingredient, container, or closure will be adulterated and thus, the
ingredient, container, or closure does not need to be automatically
rejected. Similarly, in such situations, the affected infant formula
need not be automatically rejected. In order for the revision of Sec.
106.40(d) to result in adequate public health protection, however, the
manufacturer must have in place a robust procedure to investigate any
deviation from its specifications for ingredients, containers, and
closures so that the manufacturer can credibly determine whether the
deviation from specifications could result in adulteration of infant
formula. Such procedure must consist of a documented review of the
deviation from a specification, records of such documented review,
including the corrective action taken and the disposition of the
affected materials, and control of the affected materials pending their
appropriate disposition. The failure to follow these procedures would
result in the formula being deemed adulterated under section 412(a)(3)
of the FD&C Act.
    Specifically, under Sec.  106.40(d) of the interim final rule, any
deviation from a specification must result in a documented,
comprehensive, and systematic examination of the affected ingredient,
container, closure, or of the in-process or finished infant formula in
which the suspect ingredient, container, or closure was used by an
individual qualified by education, training, or experience to perform
such examination. An adequate documented review includes: (1)
Identification of the specific deviation; (2) a determination of the
need for an investigation into the cause of the deviation; (3)
evaluation of the material or product that does not conform to the
specification to determine whether the deviation has resulted in or may
lead to adulteration of infant formula; (4) identification of the
action or actions taken to correct, and prevent a recurrence of, the
deviation; and (5) documentation of the disposition of the affected
material and infant formula products, if any.
    Adequate records of the documented review and disposition are
critical, and the rule requires a manufacturer to establish and
maintain such records. Specifically, under Sec.  106.100(e)(4) of the
interim final rule, required records include those showing the identity
and conclusions of, and followup by, the qualified individual who
investigated a deviation from a master manufacturing order, a failure
of a production aggregate or an ingredient of a production aggregate to
meet manufacturer's specifications, or a failure to meet any
specification applicable to a production process where control is
deemed necessary to prevent adulteration.
    Accordingly, proposed Sec.  106.40(d) is revised by deleting the
requirement to develop written specifications for acceptance or
rejection of ingredients, containers, and closures used in
manufacturing infant formula. In its place, FDA is establishing a
requirement that a manufacturer develop written specifications for
ingredients, containers, and closures and develop written procedures to
determine whether such specifications are met. The Agency is also
establishing a requirement for a documented review and material
disposition decision by an individual qualified by education, training,
or experience when an ingredient, container, or closure is determined
not to meet the manufacturer's specifications.
    Comments on other issues pertaining to proposed Sec.  106.40(d) are
discussed in section V.H.2.
    Adequate public health protection also requires a manufacturer to
ensure that any ingredient, container, or closure that does not meet
the manufacturer's specifications be controlled under a quarantine
system designed to prevent its use in the manufacturer of an infant
formula unless and until it is released for such use. Proposed Sec.
106.40(e) would have required that ingredients, containers, or closures
be stored in areas clearly designated as ``pending release for use,''
``released for use,'' or ``rejected for use.'' In addition, proposed
Sec.  106.40(e)(3) would have required ingredients, containers, or
closures that did not meet a manufacturer's specifications to be
rejected and controlled under a quarantine system to prevent their use
in the manufacture of infant formula. However, under this interim final
rule, a disposition decision based on a failure to meet a specification
is not limited to a decision to reject the material; a decision could
be made to release the ingredient, container, or closure, or the
affected infant formula, for use, or to reprocess or recondition it.
The need to control the ingredient, container, or closure, or the
affected formula, to prevent its use in the manufacture of infant
formula, pending a material review and disposition decision, applies
any time a manufacturer fails to meet a specification. Controlling the
material under a quarantine system will prevent potentially adulterated
material from being used, or from co-mingling it with other material,
in the manufacture of an infant formula. Comments discussed elsewhere
in this preamble requested clarification with respect to methods that
could be used to control and segregate material. Section 106.40(e)
describes the ways a manufacturer may quarantine material that has not
been released for use due to failure to meet a specification, or that
has been rejected for use in the manufacture of an infant formula.
    Comments on other issues pertaining to Sec.  106.40(e) are
discussed in section V.H.2. Consistent with the changes in Sec.
106.40(d) and (e) of the interim final rule, Sec.  106.40(f) requires a
manufacturer to quarantine an ingredient, container, or closure and to
conduct a documented review and make a material disposition decision if
the ingredient, container, or closure has been, or may have been,
exposed to conditions that may adversely affect it.
    Comments on other issues pertaining to Sec.  106.40(f) are
discussed in section V.H.3.
    Similarly, under Sec.  106.50(f) of the interim final rule, failure
to meet a specification does not result in automatic rejection. A
manufacturer must control, under a quarantine system, in-process
material that does not meet specifications pending a material review
and disposition decision by a qualified individual. In-process material
that does not meet a manufacturer's specifications could potentially
adulterate an infant formula, if used. If an affected in-process
material is reprocessed or otherwise reconditioned, it must be
controlled under a quarantine system, pending a documented review and
material disposition decision. Any in-process material that is rejected
must also be

controlled under quarantine system to prevent its use in infant formula
manufacturing and processing operations.
    Finally, at the final production stage, a manufacturer must
determine whether the production aggregate may be released for use or
distribution. Pending a decision by the manufacturer to release the
production aggregate for use or distribution, proposed Sec.  106.70(a)
would have required that the manufacturer ``hold, or maintain under its
control,'' each production aggregate until the manufacturer determines
certain criteria are met. This language was proposed in order to ensure
that adulterated formula would not be released (see 61 FR 36154 at
36174). For consistency with changes made to Sec. Sec.  106.40 and
106.50 related to the need to establish a quarantine system pending a
documented review and material disposition decision by a qualified
individual, and options to reject, reprocess or otherwise recondition,
or approve and release affected material, FDA is making corresponding
changes to Sec.  106.70 of the interim final rule.
    For purposes of consistency with the changes in Sec. Sec.
106.40(d), (e), and (f), 106.50(f), and 106.70(a), (b), and (c), FDA is
revising Sec.  106.6(c)(4) to state that the review conducted shall be
a documented review resulting in a material disposition to reject,
reprocess or otherwise recondition, or approve and release the affected
article. Likewise, FDA is inserting a new Sec.  106.6(d) that states
the requirement to establish a quarantine system pending a documented
review and material disposition decision for any article that fails to
meet a specification.
    These revisions reflect CGMP and are necessary to prevent
adulteration of an infant formula, provide consistency across
requirements, and clarify, in response to comments, that a failure to
meet a specification does not necessarily result in automatic rejection
at each stage of the manufacturing process, i.e., for an ingredient,
container or closure, for an in-process material, or for a finished
infant formula.
    FDA also received comments on specific aspects of proposed Sec.
106.6. These comments are discussed in this document.
    (Comment 39) One comment regarding specifications focused on
proposed Sec.  106.70. This comment expressed support for the intent of
this provision, which the comment characterized as preventing the sale
and consumption of a formula that is nutritionally or microbiologically
inadequate. The comment asserted, however, that the rejection or
reprocessing of a batch (production aggregate) of infant formula that
falls outside a manufacturer's specifications is an overly prescriptive
means of achieving this objective, and explained that a manufacturer
assesses deviations from specifications on a case by case basis and
that, once reported, all deviations are evaluated by suitably trained
personnel who consider the nutritional and public health significance
of the deviation. The comment proposed alternative language for
proposed Sec.  106.70(b).
    (Response) As noted, FDA has revised several provisions of the
interim final rule that concern specification deviations, including
proposed Sec.  106.70(b). Although FDA declines to adopt the
alternative language offered by this comment, the Agency believes that
the revisions to proposed Sec.  106.70(b), which clarify the
responsibilities of a manufacturer when a production aggregate does not
conform to its specifications, respond to the issues raised by the
comment.
2. Establishment and Implementation of a Control System (Proposed Sec.
106.6(a))
    (Comment 40) One comment suggested that instead of requiring in
proposed Sec.  106.6(a) a system to cover all stages of processing, the
production and in-process control system should extend to those stages
of processing, storage, and distribution that are under the
manufacturer's control because, the comment contended, a manufacturer
cannot be expected to be responsible for ensuring proper distribution
practices. In addition, the comment asserted that, for co-packers, the
scope of responsibility of the co-packer is necessarily limited to the
specific aspect of manufacturing, storage, or distribution that the co-
packer has agreed by contract to handle.
    (Response) FDA believes that this comment misunderstands the
responsibilities of manufacturers under the interim final rule. As
discussed in the response to Comment 17, there are two types of
responsibilities under the interim final rule: The obligation to
conduct certain activities according to the requirements of the CGMP
regulations and the obligation of certain persons to ensure compliance
with the rule's requirements even if such person is not engaged in the
specific activities covered by the rule. The degree to which a
manufacturer must adhere to the interim final rule's CGMP requirements
is determined by the specific activities in which such manufacturer is
engaged: Under the interim final rule, a manufacturer must comply with
all the CGMP requirements that cover activities in which such
manufacturer actually engages. Thus, a firm that packages an infant
formula is a ``manufacturer'' as defined in Sec.  106.3 and must comply
with all requirements applicable to the operations it performs. For
example, a firm that packages an infant formula is responsible for
having a production and in-process control plan for that operation.
Conversely, the firm that packages the formula is not responsible for
production and in-process control requirements that are not related to
packaging operations, such as those related to the receipt of raw
materials.
    For the foregoing reasons, FDA is not persuaded to change Sec.
106.6(a) in response to this comment and, with the exception of minor
editorial changes, Sec.  106.6(a) is included in this interim final
rule as proposed.
3. Elements of the Production and In-Process Control System (Proposed
Sec.  106.6(c))
    (Comment 41) Another comment objected to the requirement in
proposed Sec.  106.6(c) that the manufacturer take certain actions at
any point, step, or stage in the production process where control is
necessary to prevent adulteration. The comment argued that ``any point,
step, or stage'' could refer to every conceivable manufacturing
activity and there are few manufacturing activities that could not,
theoretically, give rise to a finding of ``technical'' adulteration.
The comment stated that it is impractical to fulfill the requirements
of proposed Sec.  106.6(c) for every conceivable manufacturing activity
and suggested that the regulation be revised to focus on the
manufacturing steps most important or critical to ensuring that a
product is free from actual adulteration. The comment claimed that this
would also make proposed Sec.  106.6(c) consistent with the
recordkeeping requirements in proposed Sec.  106.100(e)(3). The comment
also emphasized that it is the responsibility of the manufacturer to
identify the critical points.
    (Response) FDA does not intend that the control procedures
established under Sec.  106.6(c) would address every theoretical risk
of technical adulteration. Importantly, however, a manufacturer has a
responsibility, as part of CGMP, to ensure quality in the finished
product on a consistent basis. The way to ensure quality is to identify
controls needed at various steps in the production process so that, in
its final form, the formula complies with all requirements.

    FDA agrees with the comment to the extent that it asserts that
certain actions (e.g., the establishing of specifications) are not
required at every step in the manufacturer's process. Instead, it is
the responsibility of a manufacturer to identify those points at which
control is necessary to prevent adulteration of infant formula
products. A manufacturer must consider all possible risks likely to
occur with its products and determine how these risks will be
controlled. These risks include insanitary conditions that may
contaminate formula or may render a formula injurious to health, not
just conditions that do, in fact, contaminate the formula or render it
injurious to health. A formula product that has been held under
insanitary conditions whereby it may become contaminated with filth or
it may be rendered injurious to health is deemed adulterated under
section 402(a)(4) of the FD&C Act.
    In addition, a manufacturer must determine the controls that are
necessary to prevent adulteration during the production of each formula
based on the manufacturer's individual operations. Failure to establish
specifications under Sec.  106.6(c) at any point, step, or stage where
control is necessary to prevent adulteration would cause the product to
be adulterated under section 412(a)(3) of the FD&C Act for failure to
follow CGMP, including quality control procedures, required by FDA.
Accordingly, FDA is not persuaded to make the revisions requested in
this comment.
    (Comment 42) One comment requested that FDA consider the meaning of
the term ``specification'' in proposed Sec.  106.6(c)(1), which
requires that infant formula manufacturers establish standards or
specifications to be met at any point, step, or stage in the production
process where control is necessary to prevent adulteration.
    The comment presented several objections to setting specifications
at the outer limits. The comment stated that a manufacturer should be
encouraged to impose tight control over its manufacturing process to
produce infant formula of consistent quality and noted that infant
formula manufacturers set their specifications well within the outer
limits that would cause adulteration. The comment noted that, in most
cases, manufacturers have not identified every extreme outer limit for
every process and product parameter that would result in rejection.
    (Response) The Agency believes that this comment misreads the
proposed rule. The comment seems to suggest that proposed Sec.
106.6(c)(1) would require a manufacturer to establish a specification
at a particular level or range that, if not met, would cause the infant
formula to be adulterated. The Agency disagrees with this reading of
proposed Sec.  106.6(c)(1). The purpose of Sec.  106.6(c) is to ensure
that each manufacturer examines its infant formula production processes
and addresses those points, steps, and stages where control is needed
to ensure that the process will produce the formula the manufacturer
intends to produce. Proposed Sec.  106.6(c)(1) stated that a
specification must be established where control is necessary to prevent
adulteration but does not specify the range or magnitude of the
specification. Also, as discussed in section V.C.1, although proposed
Sec.  106.40(d) stated that specifications shall be set for the
acceptance or rejection of ingredients, containers, and closures; FDA
is revising proposed Sec.  106.40 so that when a formula ingredient,
container, or closure fails to conform to specifications, an individual
qualified by education, training, or experience must conduct a
documented review to determine whether such failure could result in an
adulterated infant formula, and thereafter, must make and document a
material disposition decision to reject, reprocess or otherwise
recondition, or approve and release the material or the affected infant
formula for use. Additionally, as discussed in section V.I, FDA is
revising Sec.  106.50 so that if any in-process material fails to meet
a specification established under Sec.  106.6(c)(1), an individual
qualified by education, training, or experience must conduct a
documented review and make a material disposition decision to reject,
reprocess or otherwise recondition, or approve and release the in-
process material. Therefore, a manufacturer may choose to establish a
level or range as a specification that must be met in order to produce
a formula that is not actually adulterated but is not compelled or
encouraged to set its specifications at the outer limits. In fact, a
manufacturer may establish a specification within a narrow range to
ensure a larger margin of error for some or all of its processes.
    In addition, FDA notes that, as discussed in section IV, the Agency
is revising, in response to a comment, proposed Sec.  106.6(c)(3) to
delete the words ``standard or'' (see subpart A).
    (Comment 43) Several comments suggested changes to proposed Sec.
106.6(c)(3), which would require a manufacturer to establish a
corrective action plan to use when a specification, established in
accordance with Sec.  106.6 (c)(1), is not met. One comment suggested
establishing standard operating procedures (SOPs) for use when a
specification is not met as an alternative to a corrective action plan.
The comment objected to the language in the preamble to the 1996
proposal that ``the best way to ensure that a corrective action is
appropriate is to determine the action in advance,'' asserting that
while it may often be feasible to establish corrective action plans in
advance, a manufacturer cannot be expected to foresee all future
circumstances that may require reliance on a corrective action plan and
to predict how it will operate and that many circumstances may have a
different set of elements to be considered, thus requiring a case-by-
case analysis. The comment stated that a manufacturer could include
potential corrective actions in an SOP, but a corrective action should
not be mandated when irrelevant to the facts of a given situation.
    (Response) FDA is not persuaded to change Sec.  106.6(c)(3) for the
following reasons. First, a corrective action plan is one type of SOP
that addresses corrective actions. Therefore, a manufacturer may use a
SOP as its corrective action plan. Second, although FDA acknowledges
that a manufacturer may not foresee all circumstances in which a
corrective action will be necessary, such a plan is needed only to
respond to the failure to meet a specification. Under Sec.
106.6(c)(1), a manufacturer must set specifications only for those
points, steps, or stages in the production process where the
manufacturer has determined that control is necessary to prevent
adulteration. Thus, the manufacturer should have some familiarity with
the circumstances in which a correction action would be required.
    Moreover, having in place a corrective action plan for those
situations that the manufacturer can anticipate will enable the
manufacturer to react more promptly when the anticipated control
failure occurs. Even if it is a general mechanism or policy, it is
appropriate for a manufacturer to establish a corrective action plan to
anticipate the response to a deviation from specifications; the plan
should identify what steps should be taken in response to a deviation
and by whom. For example, the manufacturer may decide that for certain
deviations from a specification, a designated person should stop the
production process until a documented review and material disposition
decision can be made. In addition, the corrective action plan should
include a procedure for the manufacturer's documented review and
material disposition decision for the

deviation, but does not need to specify in advance a decision for a set
of facts not yet known.
    (Comment 44) In response to the 2003 request for comments, one
comment stated that corrective actions are based on scientific judgment
and past experiences and that if each specification needs to be tested
to the point of failure, the cost would be huge and would prevent or
severely limit new product development. Given the complex and multi-
factorial aspects of infant formula production and the occasional
failure of finished products to meet specifications, the comment
questioned whether such speculative actions would provide applicable
guidance in a specific instance. Instead, if scientific judgment
supported by empirical evidence were allowed to determine which
specifications should be challenged, some corrective action procedures
might be identified in advance, but they would be limited to those
situations that manufacturers would reasonably expect to encounter.
    (Response) As discussed in response to the previous comment, a
corrective action plan is needed only to respond to the failure to meet
a specification, and such specifications are not unlimited. That is,
under Sec.  106.6(c)(1), a manufacturer is required to set
specifications only for those points, steps, or stages in the
production process where the manufacturer has determined that control
is necessary to prevent adulteration. Thus, FDA does not agree with the
comment that the costs of establishing corrective action plans will be
overwhelming.
    The Agency does agree that a manufacturer cannot predict in advance
the outcome of a documented review and material disposition decision
for every deviation. However, as the comment recognizes, a manufacturer
can anticipate certain corrective actions. For these anticipated
deviations, the corrective action plan required under Sec.  106.6(c)(3)
will provide a procedure in advance for what, if any, action is needed
when a specification is not met, who should take such action, and the
process for the documented review and material disposition decision. A
manufacturer is expected periodically to revise and include additional
relevant information, as appropriate, to a corrective action plan for
the identified specifications.
    (Comment 45) Several comments were received on proposed Sec.
106.6(c)(4), which requires review of the results of monitoring of
production and in-process control points, steps, or stages where
control is necessary to prevent adulteration and evaluation of the
public health significance of any deviations from established
specifications. These comments noted that not all deviations from
specifications involve concerns of public health significance; for
example, shipper cartons that are found with a printing color that
differs slightly when compared to the color standard would not justify
a public health significance evaluation. The comments agreed, however,
that if a deviation has potential public health significance, a
qualified individual must make a documented review and material
disposition decision.
    (Response) These comments appear to misunderstand the proposed
rule. Proposed Sec.  106.6(c)(1) would require a manufacturer to
establish specifications only at those points, steps, or stages in the
production process where control is necessary to prevent adulteration.
The Agency recognizes that a manufacturer may establish specifications
that are not related to preventing product adulteration, such as the
shade of ink on shipper cartons. Unless the manufacturer determines
that a particular specification is necessary to prevent product
adulteration, it would not be a specification established under Sec.
106.6(c)(1) and, thus, would not be subject to review under Sec.
106.6(c)(4). For this reason, FDA is not revising Sec.  106.6(c)(4) in
response to these comments.

D. Controls To Prevent Adulteration by Workers (Proposed Sec.  106.10)

    In the 1996 proposal, FDA proposed in Sec.  106.10 general
standards to help ensure that workers involved in the production of
infant formula do not cause the formula to become adulterated. The
proposed provisions address sufficiency and training of personnel,
personal hygiene of production personnel, and safeguarding formula from
microbial contamination from production personnel. The Agency received
comments on several aspects of proposed Sec.  106.10, which comments
are addressed in this document.
    (Comment 46) One comment suggested eliminating Sec.  106.10(a)
because it is overly prescriptive. The comment stated that the only
standard by which one can demonstrate that ``sufficient personnel
qualified by training and experience, to perform all operations'' have
been employed by the manufacturer is by demonstrating that an
unadulterated infant formula can be routinely manufactured. In
addition, the comment argued, because other provisions of the existing
and proposed regulations already require that unadulterated products be
routinely manufactured, compliance with CGMP requirements should be
adequate without the Agency's evaluation of internal staffing matters.
The same comment stated that if this section is not deleted, it should
be made clear that it is the manufacturer's responsibility to determine
what is meant by ``sufficient'' personnel.
    (Response) FDA disagrees with this comment and declines to delete
Sec.  106.10(a) from the interim final rule. It is critical that a
manufacturer of infant formula employ an adequate number of qualified
personnel to staff the manufacturing operation, and the requirement in
Sec.  106.10(a) ensures that a manufacturer will provide sufficient
trained personnel to achieve compliance with CGMP.
    FDA does not believe that Sec.  106.10(a) is overly prescriptive.
In fact, the Agency agrees that it is the manufacturer's responsibility
to determine what constitutes ``sufficient'' personnel to perform fully
all operations necessary to produce the infant formula in compliance
with CGMP. The proposal identified no specific number of workers that
must be employed, expressly noting that the Agency ``is proposing a
general standard for determining how many employees are necessary [but]
is leaving the determination of the actual number of employees
necessary to the manufacturer's discretion.'' (61 FR 36154 at 36159).
To clarify that the decision regarding sufficiency of personnel is both
within the manufacturer's authority as well as an obligation of the
manufacturer, FDA is revising proposed Sec.  106.10(a) to emphasize
that the ``A manufacturer shall employ sufficient personnel,'' rather
than retaining the somewhat ambiguous language of the proposal.
    (Comment 47) Another comment stated that it was unrealistic to
demand that all individuals be fully trained and experienced in infant
formula manufacturing because training must be carried out on the job.
The comment suggested that some form of licensing of infant formula
manufacturing may be appropriate and suggested that at least one
licensed person be present during each shift of infant formula
manufacture.
    (Response) FDA believes that this comment misinterprets proposed
Sec.  106.10(a). FDA proposed that production personnel be qualified by
training and experience to ensure that all operations are correctly and
fully performed. This provision would simply require an infant formula
manufacturer to have, at all times, sufficient numbers of employees in
both

supervisory positions and non-supervisory positions who are
knowledgeable and qualified to perform the functions necessary to
manufacture an infant formula so that the formula is not adulterated.
Employees may obtain the necessary knowledge and qualifications through
training (which may include formal training and on-the-job training),
experience, or a combination of these. FDA recognizes that a new
employee may be trained in the manufacture of infant formula on the
job, for example, when that new employee is under the supervision of a
person trained and experienced in the operation that the new employee
is asked to perform. FDA is revising proposed Sec.  106.10(a) to
clarify that training may include both education and on-the-job
training and to clarify that an employee may be qualified by any
combination of education, training, or experience.
    Finally, FDA does not currently require any type of licensure for
individuals involved in the manufacture of infant formula. The Agency
is not aware of any problems that have resulted from of the absence of
a licensure requirement and is not aware of the particular benefits
that would result from such requirement. The comment did not identify
either particular problems or specific benefits related to such
licensure. Therefore, FDA is not persuaded to modify Sec.  106.10(a) in
response to this comment.

E. Controls To Prevent Adulteration Caused by Facilities (Proposed
Sec.  106.20)

    In the 1996 proposal, FDA proposed in Sec.  106.20 to require that
an infant formula manufacturer implement a system of controls designed
to prevent adulteration caused by an infant formula facility. These
controls would cover buildings, storage areas, lighting, air filtration
systems, appropriate storage of certain chemicals, water quality,
plumbing and toilet and hand-washing facilities for employees. FDA
received no comments on proposed Sec.  106.20(a), (e), and (g), and
those provisions are included in the interim final rule as proposed.
The Agency did receive comments on several other aspects of proposed
Sec.  106.20, which are addressed in this section.
1. Systems of Separation (Proposed Sec.  106.20(b))
    (Comment 48) Several comments on the 1996 proposal objected to
proposed Sec. Sec.  106.20(b) and 106.40(e), which would require an
infant formula manufacturer to designate separate areas for holding or
storing raw materials (ingredients, containers, and closures), in-
process materials, and final infant formula product pending release for
use, after rejection for use and before disposition, and after release
for use. The comments agreed that each manufacturer must establish an
effective system to identify and control materials and finished product
before and after release for use, but argued that physical separation
of materials was not practical. The comments suggested that we allow
separation of materials by a means other than physical separation of
materials, including computerized inventory controls and adequately
marked pallets. As a result of these comments, in the 2003 reopening,
FDA specifically requested additional comment on this issue.
    (Response) Based on the comments, FDA is persuaded to revise Sec.
106.20(b) to allow materials to be segregated by means other than
physically separate storage areas. It may be desirable to have separate
storage areas for holding or storing raw materials, in-process
materials, and final infant formula product pending release for use,
after rejection for use and before disposition, and after release for
use. However, use of physically separate storage areas is not necessary
if other systems, such as computerized inventory controls or automated
systems of separation, can adequately segregate materials to prevent
accidental mixups or co-mingling of materials. A computerized inventory
system utilizes technical advances and allows tracking of materials
through the use of bar codes and radio frequency identification tags
that identify items in a firm's inventory. An inventory system could
also employ bar codes to identify and track the material in the
production facility; for example, a bar code could identify the
material, the item's storage location, when it arrived at its
designated storage location, and could be used to reorder the item.
    FDA disagrees, however, that marked pallets alone would be adequate
to prevent mix-ups of these materials because there is no assurance
that specific materials will stay associated with a particular pallet
without additional arrangements. For example, unless additional
measures are taken to avoid mixups such as physical attachment of the
material to the pallet (e.g., materials are shrink-wrapped in plastic
to the pallet), there is a risk that the separated materials will
accidentally become co-mingled with other materials. The objective of
this proposed CGMP requirement is to avoid the mix-up of different
materials (or different lots of the same material) and ensure the
continuing integrity of such materials through the use of systematic
storage methods. Use of shrink-wrapped pallets would be an acceptable
storage system so long as the integrity of a pallet's contents is
reestablished by rewrapping following penetration of the shrink-wrap.
2. Holding of Rejected Materials (Proposed Sec.  106.20(b)(2))
    (Comment 49) One comment objected to proposed Sec.  106.20(b)(2),
which would require separation of raw materials, in-process materials,
and final product infant formula after rejection for use in infant
formula and before disposition. The comment suggested removing the
phrase ``before disposition'' because once a decision is made
concerning disposition, the requirement for proper status designation
should not end. The comment also suggested that the need for separation
of rejected or released finished infant formula also should be
acknowledged in proposed Sec.  106.20(b)(2) and (b)(3).
    (Response) The Agency agrees that the phrase ``before disposition''
is not necessary. Any time such materials or formula are rejected, the
materials should remain segregated until disposition is completed to
avoid co-mingling of rejected and released materials.
    FDA also agrees with the comment that the interim final rule should
acknowledge that finished infant formula product should be segregated.
Therefore, FDA is revising proposed Sec.  106.20(b)(2) to state ``After
rejection for use in, or as, infant formula.'' However, FDA is not
adding the phrase ``or as'' to Sec.  106.20(b)(3) of the interim final
rule, because the need to segregate released final product is already
acknowledged in this provision.
    FDA is also making corresponding revisions to Sec.  106.40(e) of
the interim final rule.
3. Lighting (Proposed Sec.  106.20(c))
    (Comment 50) One comment objected to Sec.  106.20(c) and
recommended that this provision be deleted, asserting that it is
redundant with food CGMP, Sec.  110.35(b)(5).
    (Response) Although this comment refers to Sec.  110.35(b)(5), FDA
believes the correct reference to food CGMP is Sec.  110.20(b)(5). The
comment did not criticize the substance of proposed Sec.  106.20(c) and
did not claim that its more specific requirements were inappropriate
for infant formula manufacture. While FDA agrees that the requirements
in part 110 (the CGMP for manufacturing, packing and holding human
food) apply to infant formula manufacture, redundancy, in and of

itself, is not a reason to eliminate this provision. Indeed, given the
nature of infant formula, the manufacturing process is necessarily a
more specific and highly sophisticated operation, and all lighting must
be adequate for each specific area. Accordingly, Sec.  106.20(c) is
included in the interim final rule as proposed.
4. Air Filtration Systems (Proposed Sec.  106.20(d))
    (Comment 51) Several comments objected to the requirement of
proposed Sec.  106.20(d) that air filtration systems, including
prefilters and particulate matter air filters, be used on air supplies
to production areas where ingredients or infant formula are directly
exposed to the atmosphere and suggested that Sec.  106.20(d) be
deleted. One comment stated that proposed Sec.  106.20(d) was overly
prescriptive and that CGMP for foods in current Sec.  110.20(b)(6)
should be sufficient for infant formula manufacturing facilities.
Current Sec.  110.20(b)(6) requires the plant and facilities to
``provide adequate ventilation or control equipment to minimize odors
and vapors (including steam and noxious fumes) in areas where they may
contaminate food; and locate and operate fans and other air-blowing
equipment in a manner that minimizes the potential for contaminating
food, food-packaging materials, and food-contact surfaces.''
    (Response) FDA agrees that the requirements in current Sec.
110.20(b)(6) are appropriately applied to infant formula manufacturing
facilities. However, the Agency is not persuaded that the requirements
of current Sec.  110.20(b)(6) are completely sufficient because current
Sec.  110.20(b)(6) does not address air filtration. As stated in the
preamble to the 1996 proposal (61 FR 36154 at 36160-36161), proposed
Sec.  106.20(d) is designed to improve air quality in formula
production areas and thus reduce the potential for contamination by
air-borne sources such as spores, molds, and bacteria that may be
carried on dust or other air-borne contaminants. The presence of such
spores, molds, and bacteria may lead to severe illness, particularly in
the vulnerable population consuming infant formula.
    Importantly, however, because of differences in plant design,
location, and other unique features, the manufacturer can best
determine which air filtration system or systems are needed to prevent
contamination by air-borne sources in a specific plant. Therefore, FDA
is persuaded that the interim final rule does not need to require
specific types of filters or prescribe when filters are necessary to
prevent air-borne contamination. Accordingly, as revised, the interim
final rule requires a manufacturer to identify the parts of the
production facility in which there is potential for airborne
contamination of ingredients, in-process product, finished product,
packing materials, and infant formula contact surfaces, and use air
filtration as necessary to prevent contamination of these materials.
    (Comment 52) One comment noted that although the Agency referenced
the drug CGMP as a formative source for the 1996 proposal, the phrase
in the drug CGMP regulations, ``when appropriate,'' was not included in
the infant formula CGMP proposed rule. This comment suggested
alternative language for the CGMP provision, such as ``when there is
reason to believe that the air in a particular area of the plant might
result in adulteration of the product, measures should be taken to
prevent such adulteration, by air filtration or some other means.''
    (Response) FDA believes that the revision to proposed Sec.
106.20(d), which incorporates the concept of ``as appropriate,''
responds to this comment.
    (Comment 53) Another comment stated that proposed Sec.  106.20(d)
would require complete air filtration and cooling to be used for all
production rooms and maintenance of positive air pressure at all times
in these rooms. This comment recommended that air filtration should be
required only in areas where there is direct contact between the air
and formula, such as in dryers and dehumidifiers.
    (Response) FDA believes that this comment misunderstands proposed
Sec.  106.20(d). Proposed Sec.  106.20(d) would not have mandated air
cooling and positive air pressure in all production rooms; it would
have expressly limited prefilters and particulate matter air filters to
those production areas where ingredients and infant formula would be
directly exposed to the atmosphere. Moreover, as noted, the comments
have persuaded FDA to delete the proposed requirement for specific
types of filters or when filters are necessary to prevent
contamination. Accordingly, Sec.  106.20(d) of the interim final rule
requires a manufacturer to identify the parts of the production
facility in which there is potential for airborne contamination of
ingredients, in-process product, finished product, packing materials,
and infant formula contact surfaces and use air filtration as necessary
to prevent contamination of these materials.
    (Comment 54) In the 2003 reopening, FDA requested comments on types
and costs of air filtration systems used by infant formula
manufacturers and the costs of making changes to these systems. One
comment stated that manufacturers use different filters in different
areas of a facility and that prefilters and particulate matter air
filters are used on air supplies to production areas and areas where
formula may be exposed to the atmosphere. The comment stated that the
proposed provision would not result in the expenditure of any
additional funds and that a more detailed account of the types and
costs of air filtration systems would be wasteful and an undue burden
on industry when no public interest would be served by insisting on
specific changes in this arena.
    (Response) FDA considered the information provided in this comment
and, as noted previously in this document in response to Comment 51,
the requirement of proposed Sec.  106.20(d) that prefilters and
particulate matter filters be used in formula manufacturing facilities
is not included in Sec.  106.20(d) of the interim final rule. Thus, the
interim final rule will not necessarily result in specific changes to
the air filtration systems of infant formula manufacturing facilities.
    (Comment 55) Another comment stated that one manufacturer currently
has air filtration systems in all areas of the manufacturing plant
where infant formula or raw materials may be exposed to the atmosphere.
These mechanisms filter all incoming air using pleated filters or bag
filters to remove particulate matter. The comment states that FDA
should consider the prohibitive cost and level of disruption
encountered in changing air filtration systems to meet an increased
specification in comparison to systems currently performing to an
appropriate standard and posing no risk of contamination of infant
formula products.
    (Response) FDA believes that the revisions to the interim final
rule will avoid the costs and disruptions raised as a concern in this
comment. As noted, as revised, Sec.  106.20(d) does not require the use
of particular filtration measures (such as prefilters and particulate
matter air filters). Instead, the interim final rule requires a
manufacturer to employ ``appropriate measures'' to reach the goal of
minimizing the potential for contamination of materials in the
manufacturing facility. Such measures may, but are not required to,
include the use of air filtration or the location and operation of fans
and other air-blowing equipment.

5. Potable Water (Proposed Sec.  106.20(f))
    (Comment 56) Several comments objected to the requirement in
proposed Sec.  106.20(f)(1) that the fluoride level of the water used
in infant formula manufacturing be as low as possible. The comments
asserted that this requirement is vague, potentially prohibitively
costly, and not needed to address a public health concern. The comments
stated that manufacturers strive to produce infant formula products
with low fluoride levels utilizing a variety of technologies. One
comment suggested that the requirement that fluoride removal equipment
be used for fluoridated water would be sufficient. Another comment
suggested that the regulation be modified to state that the water used
in infant formula manufacturing must ``not be fluoridated or shall be
defluoridated prior to use.'' The comment stated that this change more
accurately reflects current technology and industry practice.
    (Response) In the 1996 proposed rule, the Agency noted that infant
formulas are currently manufactured without using fluoridated water and
recommended that manufacturers continue their practice of not using
fluoridated water in the manufacture of infant formula (61 FR 36154 at
36161). Also as noted in the proposed rule, the NAS recommends a safe
and adequate intake of 0.1 to 0.5 mg/day fluoride for infants from 0 to
6 months. Accordingly, the Agency is not persuaded that a requirement
that the water used in infant formula manufacturing must ``not be
fluoridated or shall be defluoridated prior to use'' is consistent with
the recommendations of the NAS/IOM. The purpose of this requirement is
to reduce fluoride levels in water used to produce infant formula and,
thereby, reduce the likelihood that fluoride intake of infants
consuming finished infant formula product will exceed the tolerable
upper intake level of 0.7 mg fluoride/day that has been established by
the IOM for infants 0 to 6 months of age (Ref. 8). The glossary of the
Environmental Protection Agency (EPA) includes a definition of
``defluoridation,'' which is ``The removal of excess fluoride in
drinking water to prevent the mottling (brown stains) of teeth'' (Ref.
13). Importantly, the EPA definition does not specify an upper fluoride
limit for ``defluoridated'' water. However, the requirement for the
fluoride level should better reflect industry practices and, therefore,
FDA is clarifying in Sec.  106.20(f) that water used in the manufacture
of infant formula shall either be free of fluoride or defluoridated to
a level as low as possible. FDA disagrees that requiring a manufacturer
to defluoridate water to achieve a level of fluoride ``as low as
possible'' is vague. The Agency is providing some flexibility for the
manufacturer to determine the level of fluoride the manufacturer can
achieve in its operations to keep such level ``as low as possible,''
should the manufacturer choose to defluoridate water rather than to use
water that is not fluoridated.
6. Steam (Proposed Sec.  106.20(h))
    (Comment 57) One comment suggested that proposed Sec.  106.20(h)
require that only culinary steam in compliance with 3-A Sanitary
Standards be used at infant formula product contact points.
    (Response) Proposed Sec.  106.20(h) would require that steam in
direct contact with infant formula be ``safe.'' FDA has considered this
comment and agrees that the interim final rule should require that only
culinary steam in compliance with 3-A Sanitary Standards should be used
for steam that comes in contact with infant formula product. The
interim final rule incorporates by reference at Sec.  106.160 the
current 3-A Sanitary Standard for culinary steam, 3-A Sanitary
Standards, No. 60903: Method of Producing Steam of Culinary Quality
(November 2004) (Ref. 14). The 3-A standard is more specific than the
standard of the proposed rule (``safe.''). The standard is a method for
producing steam of culinary quality that is accepted practice for
systems used to process perishable foods and it will ensure that the
steam that comes in contact with infant formula will not contaminate
the formula. Accordingly, the Agency is revising proposed Sec.
106.20(h) to include the 3-A Sanitary Standard as a requirement for
steam that comes into direct contact with infant formula.
7. Employee Toilet Facilities (Proposed Sec.  106.20(i))
    (Comment 58) One comment suggested that proposed Sec.  106.20(i)
should be deleted because it is redundant with the food CGMP, Sec.
110.37(d) and (e). The comment stated that if proposed Sec.  106.20(i)
were retained, it should be revised to include ``air dryers'' as an
alternative to single-service sanitary towels in the toilet facility.
    (Response) For the reasons discussed in the response to Comment 1,
FDA disagrees with the suggestion to delete proposed Sec.  106.20(i)
due to redundancy with the food CGMP regulation, Sec.  110.37(d) and
(e). FDA agrees that air dryers are an equally acceptable alternative
to single-service sanitary towels in the toilet facility. In the
preamble to the 1996 proposal, FDA stated its view that proposed Sec.
106.20(i) would be consistent with the Agency's food CGMP (Sec.
110.37(d)) and drug CGMP (Sec.  211.52). Importantly, under both the
food CGMP and the drug CGMP, air dryers are permitted as an alternative
to single service towels in employee toilet and hand washing
facilities. Thus, it is reasonable to include air dryers as an
alternative in infant formula manufacturing facilities, and Sec.
106.20(i) has been revised accordingly, along with several minor
editorial changes.

F. Controls To Prevent Adulteration Caused by Equipment or Utensils
(Proposed Sec.  106.30)

    In 1996, FDA proposed in Sec.  106.30 to require that an infant
formula manufacturer implement a system of controls designed to prevent
adulteration caused by equipment and utensils. The proposed provisions
addressed the design, installation, and maintenance of infant formula
manufacturing equipment. Specific proposed provisions addressed the
accuracy of instruments used in such manufacturing (including their
calibration), appropriate time and temperature for storage and
processing, and the use of compressed gases in infant formula
production operations. The Agency received comments on several aspects
of proposed Sec.  106.30, which are addressed in this section. In
addition to revisions made in response to comments, FDA has made minor
editorial revisions in proposed Sec.  106.30.
1. Design, Cleaning, and Sanitizing of Equipment and Utensils (Proposed
Sec.  106.30(b))
    (Comment 59) One comment suggested that this section be deleted
because it is redundant with FDA's CGMP for food (Sec.  110.35(d)). The
comment further stated that if Sec.  106.30(b) was not removed then a
clarification to proposed Sec.  106.30(b) was needed. Section 106.30(b)
would require that all surfaces that contact ingredients, in-process
materials, or infant formula be cleaned, sanitized, and maintained to
protect infant formula from being contaminated by any source. The
comment argued that there are some areas where wet cleaning is neither
practical nor desirable (e.g., in the infant formula powder
manufacturing process) because frequent exposures to moisture should be
avoided to reduce the likelihood of microbiological contamination. The
comment acknowledged that this proposed

regulation could be interpreted to allow for these unique
circumstances, but suggested that a statement, such as ``as
necessary,'' be added to this section.
    (Response) For the reasons discussed in the response to Comment 1,
FDA disagrees with the suggestion to delete proposed Sec.  106.30(b)
due to redundancy with the food CGMP regulations, Sec.  110.35(d).
Further, FDA did not intend that proposed Sec.  106.30(b) would be
interpreted to specify wet cleaning as the most appropriate cleaning
method for equipment or utensils used to manufacture infant formula. As
the comment notes, proposed Sec.  106.30(b) would permit cleaning and
sanitizing of powdered infant formula equipment or utensils by means
other than a wet cleaning method. However, FDA does recognize that it
may not be necessary to sanitize a contact surface for which wet
processing is not used. Therefore, FDA is modifying this provision to
require that surfaces be cleaned and sanitized, ``as necessary,'' and
be maintained to protect infant formula from being contaminated by any
source.
    In addition, FDA is deleting the last sentence of proposed Sec.
106.30(b), which states ``Sanitizing agents used on food-contact
surfaces must comply with Sec.  178.1010.'' The Food Quality Protection
Act of 1996 (Pub. L. 104-170) and the Antimicrobial Regulation
Technical Corrections Act of 1998 (Pub. L. 105-324) clarified which
sanitizing agents are under the jurisdiction of EPA and which are under
the jurisdiction of FDA. For example, a sanitizing agent that is used
on a semi-permanent or permanent food contact surface (excluding food
packaging) is a ``pesticide chemical'' subject to the regulatory
purview of EPA (section 201(q)(1)(B)(i)(III) of the FD&C Act (21 U.S.C.
321(q)(1)(B)(i)(III)). Most sanitizers used on equipment or utensils to
which Sec.  106.30(b) of the interim final rule applies would be
sanitizers under EPA's regulatory purview as ``pesticide chemicals.''
To the extent that a sanitizer that a manufacturer uses is a food
additive or a GRAS ingredient, such substance is subject to FDA's
regulatory purview and such use must comply with applicable FDA laws
and regulations. FDA modified proposed Sec.  106.30(b) in view of this
change in regulatory authority, in response to the foregoing comments,
and with the addition of several editorial changes.
2. Use of Lubricants and Coolants in Infant Formula Manufacture
(Proposed Sec.  106.30(c))
    (Comment 60) One comment requested that proposed Sec.  106.30(c) be
clarified to state that lubricants or coolants that would render the
infant formula adulterated if they came in contact with the formula
must not come in contact with closures prior to the closing/sealing
operation. The comment stated that the requirement is probably implied
in proposed Sec.  106.30(c), but requested an explicit statement that
the reference to containers and closures means prior to the closing/
sealing operation when the hermetic seal is formed. The comment also
suggested that the phrase ``in a manner not permitted by applicable
food additive regulations'' be added to the end of this proposed
requirement to make it consistent with applicable food additive
regulations.
    (Response) FDA agrees that lubricants and coolants that would
render the infant formula adulterated if they came in contact with the
formula must not be allowed to come in contact with containers and
closures before the closing/sealing operation. Additionally, such
lubricants and coolants must not be allowed to come in contact with
containers and closures even after sealing as this may lead to
contamination when the container is opened for use. Further, it is not
clear that all lubricants that may be used would be necessarily subject
to the food additive regulation in 21 CFR 178.3570 for lubricants with
incidental food contact. Consequently, FDA is replacing the phrase ``if
they contaminated the formula'' with ``if such substances were to come
in contact with the formula'' in Sec.  106.30(c). In this way, if a
particular lubricant is not subject to a food additive regulation,
e.g., it is GRAS under certain conditions of use, the requirement would
cover all such substances.
3. Controlling Parameters at Points Where Control Is Deemed Necessary
To Prevent Adulteration (Proposed Sec.  106.30(d)(1))
    (Comment 61) One comment requested that FDA clarify in proposed
Sec.  106.30(d)(1) that the infant formula manufacturer is responsible
for determining the points where control is deemed necessary to prevent
adulteration and the routine intervals necessary for calibration of
instruments. The comment did not object to the requirement for the
calibration of instruments, but noted that it could prove unduly
burdensome if the Agency applied ``drug'' type compliance standards.
The comment stated that including the qualification that infant formula
manufacturers bear the final responsibility for determining the
frequency and scope of testing would help assure that the standard
applied to infant formula is appropriate.
    (Response) FDA observes that the comment did not explain what would
constitute ``unduly burdensome, `drug' type compliance standards.''
Moreover, the Agency is not persuaded that the requested clarification
is necessary because proposed Sec.  106.30(d)(1) specifically states
that instruments and controls shall be calibrated at routine intervals,
as specified in writing by the manufacturer of the instrument or
control or as otherwise deemed necessary to ensure the accuracy of the
instrument (emphasis added). Thus, the Agency affirms that proposed
Sec.  106.30(d)(1) does provide a formula manufacturer with discretion
to determine the calibration frequency for controls and instruments
that is required to ensure that these instruments or controls are
operating within the correct parameters.
    (Comment 62) One comment explained that because of the number of
instruments to which this rule will apply, it is possible that certain
of the instruments requiring calibration may need to be in use while
they are being calibrated. Thus, the comment suggested adding the words
``on or before first use'' to describe the timing of the initial
certification (calibration).
    (Response) FDA agrees with this suggestion. Calibrating an
instrument against a known reference standard at the time the
instrument is first used will be sufficient to ensure the accuracy of
testing subsequently done with the instrument to establish that certain
specifications are met. Thus, FDA is revising Sec.  106.30(d)(1) in the
interim final rule by adding the phrase ``at the time of or.''
    (Comment 63) In response to FDA's 2003 comment period reopening and
request for comments on calibration, one comment stated that U.S.
formula manufacturers have established calibration and preventative
maintenance schedules for appropriate pieces of equipment, that
priorities for calibrations and preventative maintenance are linked to
``criticality in regard to product quality and safety,'' and that
procedures and schedules are aligned according to the criticality
assessments, which vary from company to company, and are often based on
the recommendations of the instrument supplier. The comment asserted
that the regulation should simply require that calibrations and
preventative maintenance be performed on pre-established schedules and
according to written procedures as the formula manufacturer determines,
based on information from the equipment

supplier where applicable and that a requirement that all instruments
need to be calibrated routinely, regardless of function, would result
in either the removal of all instruments that the manufacturer deems
not critical or the addition of significant new personnel and extensive
systems to coordinate and track the calibration program.
    (Response) FDA believes that this comments misunderstands the
calibration requirement in proposed Sec.  106.30(d)(1) in two important
ways. First, only certain instruments and controls used in an infant
formula manufacturing operation are subject to calibration under
proposed Sec.  106.30(d)(1); that is, not all instruments and controls
used in formula manufacturing are required to be calibrated.
Specifically, proposed Sec.  106.30(d)(1) requires only those
instruments and controls at points where ``control is deemed necessary
to prevent adulteration'' to be accurate and maintained, including by
calibration. Second, the proposed rule would require a calibration
schedule based on the written specifications of the instrument or
control manufacturer or that is otherwise necessary to ensure
instrument or control accuracy. Although the comment does not define
``criticality,'' FDA believes that ``criticality'' and the proposed
standard of Sec.  106.30(d)(1) (where ``control is deemed necessary to
prevent adulteration'') are comparable. Thus, the Agency believes that
proposed Sec.  106.30(d)(1) is consistent with the comment.
Accordingly, FDA is making no revisions in the interim final rule in
response to this comment.
    (Comment 64) Another comment in response to the 2003 reopening
stated that because more specificity is required and that infant
formula is the sole source of nutrition for a high risk population,
calibration needs to be high and frequent. The comment stated that this
frequency is necessitated by the ubiquity of microbes and formula's
status as an ideal medium for bacterial growth.
    (Response) FDA notes that this comment did not explain the
additional ``specificity'' required, or the relationship between
instrument calibration and microbial contamination.
    The requirement to calibrate is limited to those instruments and
controls used in the manufacture of an infant formula for measuring,
regulating, or controlling those parameters where control is deemed
necessary to prevent adulteration, such as mixing time and speed,
temperature, pressure, moisture, or water activity. To the extent that
this comment asserts that calibration should be performed as necessary
to prevent microbial contamination that would result in adulteration of
an infant formula, FDA agrees with the comment. However, this comment
does not require a revision of proposed Sec.  106.30(d)(1). Therefore,
in light of the foregoing Sec.  106.30(d) is included in the interim
final rule as proposed with minor editorial changes.
4. Areas of Cold Storage (Proposed Sec.  106.30(e)(2))
    Several comments questioned the across-the-board storage
temperature requirement of 40 [deg]F (4.4 [deg]C) in proposed Sec.
106.30(e)(2).
    (Comment 65) One comment argued that instead of requiring that cold
storage compartments be maintained at a temperature of 40 [deg]F (4.4
[deg]C) or below, FDA allow manufacturers to establish the appropriate
temperature for cold storage compartments that would assure the quality
and safety of in-process materials. The comment recommended that the
regulations simply state the end point to be achieved, e.g., ``cold
storage will be maintained at temperatures that prevent growth of
harmful microorganisms.'' The comment acknowledged that in some
situations (e.g., the long-term storage of aqueous solutions of
nutrients that might support microbial growth), the use of 40 [deg]F as
a storage temperature is well-established as appropriate. But, the
comment asserted, many materials stored at low temperatures in infant
formula plants do not require the use of 40 [deg]F to ensure stability.
    (Response) FDA disagrees with this comment. The Agency proposed 40
[deg]F as the maximum temperature for cold storage compartments because
a temperature of 40 [deg]F (4.4 [deg]C) is considered to be an
appropriate temperature to minimize the growth of pathogens (Ref. 15)
and the deterioration of liquid ingredients, nutrients, and the
formulated product. The comment did not provide any data, authoritative
research, or other material to contradict the information supporting
the proposed standard of 40 [deg]F (4.4 [deg]C). Thus, the proposed
temperature limit remains appropriate.
    (Comment 66) One comment stated that defining cold storage only as
40 [deg]F or lower is incompatible with the manufacture of quality
infant formula. Another comment argued that in some cases, the use of
temperatures this low may create quality problems for the infant
formula, such as mix destabilization and non-homogeneity, which could
theoretically result in the final product being adulterated.
    (Response) FDA agrees in part with this comment. The Agency is
aware that storing some in-process and final formulas at too low a
temperature may create quality problems that risk causing a formula to
be adulterated. Importantly, however, these problems of precipitation
and instability do not exist in all infant formula materials (such as
raw ingredients.) Indeed, as noted in Comment 65 there are certain
infant formula materials that must be stored at lower temperatures,
such as the 40 [deg]F storage temperature originally proposed, in order
to maintain quality and safety.
    Accordingly, FDA is revising proposed Sec.  106.30(e)(2) to provide
infant formula manufacturers with some flexibility in terms of cold
storage conditions. Specifically, Sec.  106.30(e)(2) of the interim
final rule permits a manufacturer to store in-process material and
final formula product (those items that, according to the comments, are
susceptible to destabilization or loss of homogeneity) for a limited
period of time at a temperature not greater than 45 [deg]F (7.2
[deg]C), provided that the manufacturer has data and other information
to demonstrate both that such materials cannot be stored at 40 [deg]F
(4.4 [deg]C) without risking an adverse effect on their quality and
that the storage conditions (i.e., the time and temperature) used by
the manufacturer are sufficient to ensure the safety of the stored
product.
    It is well-recognized that the microbial load of a substance, the
length of time a product is held at a particular temperature, and the
nature of the product (e.g., product pH) must be considered when
determining safe storage conditions. The maximum temperature of 45
[deg]F (7.2 [deg]C) for cold storage compartments will prevent
significant growth of microorganisms of public health significance
under certain conditions specific to the product composition and the
processing step. (Product composition is a factor in how well a
particular formulation will support microbial growth.) For this reason,
Sec.  106.30(e)(2)(ii) of the interim final rule requires a
manufacturer to have data and other information to demonstrate that the
time and temperature conditions are sufficient to ensure product
safety. That is, the manufacturer must determine whether a temperature
not greater than 45 [deg]F (7.2 [deg]C) will be sufficient for the cold
storage of an in-process formula or a final infant formula for the
storage period contemplated by the manufacturer. Because the nature of
the product will affect the extent of microbial growth, this
determination must be product-

specific. FDA will consider the conditions of cold storage (i.e., time
and temperature) to be sufficient for a particular product at a
particular product stage, provided that there is no significant growth
of microorganisms of public health significance during the period of
storage. Significant growth is considered to be growth of one or more
log colony forming units (CFUs) (Refs. 16 and 17).
    (Comment 67) Another comment maintained that the short period of
time the materials are held does not justify the use of a 40 [deg]F
storage temperature and thus, mandating an absolute maximum temperature
of 40 [deg]F for all purposes is not justifiable to protect public
health and would require additional capital investments for cooling
capacity that would not add value to the product.
    (Response) FDA believes that the revision of proposed Sec.
106.30(e)(2) is responsive to this comment. That revision is based in
part on the recognition that all infant formula materials do not
require identical cold storage conditions and thus, the revision
provides a manufacturer with some flexibility in terms of permissible
cold storage conditions. In addition, Sec.  106.30(e)(2) of the interim
final rule reflects the point made implicitly by the comment that
storage time, as well as temperature, is an important factor in
ensuring safety of formula materials.
    (Comment 68) One comment noted that if it were necessary to ensure
that the temperature never rose above 40 [deg]F, the materials would
have to be held at even lower temperatures most of the time in order to
allow a ``margin.''
    (Response) FDA disagrees with this comment. In addition to
specifying a maximum holding temperature and an alternative, proposed
Sec.  106.30(e) would require a manufacturer to have in place
safeguards to help ensure appropriate storage temperature, including
monitoring cold compartment temperatures at appropriate frequencies and
equipping such compartments with easily readable, accurate temperature-
indicating devices. These provisions are included in Sec.  106.30(e) of
the interim final rule. The comment did not explain why these
requirements would not be sufficient to ensure that the maximum holding
temperature of 40 [deg]F would be achieved without the use of a
``margin.'' Moreover, as discussed previously in this document, FDA
recognizes that, in certain circumstances, the 40 [deg]F (4.4 [deg]C)
holding temperature could adversely affect product quality. Thus, FDA
has revised proposed Sec.  106.30(e)(2) to provide some flexibility in
terms of the maximum holding temperature for certain in-process and
finished infant formulas.
    (Comment 69) Another comment suggested that the maximum temperature
of 45 [deg]F (7.2 [deg]C) for cold storage would be appropriate and
consistent with Sec.  110.80(b)(3)(i), the Grade ``A'' Pasteurized Milk
Ordinance, industry practice, and equipment design capabilities.
    (Response) FDA believes that the revision of proposed Sec.
106.30(e)(2) is responsive to this comment. That revision is based in
part on the recognition that all infant formula materials do not
require identical cold storage conditions and thus, the revision
provides a manufacturer with some flexibility in terms of permissible
cold storage conditions. In particular, Sec.  106.30(e)(2) of the
interim final rule will permit certain formula materials to be stored
at a temperature not greater than 45 [deg]F (7.2 [deg]C) as long as the
formula manufacturer has data and other information to demonstrate an
adverse effect on the quality of the product if held at 40 [deg]F or
below and to demonstrate that there is no significant growth of
microorganisms of public health significance during the period of
storage.
5. Thermal Processing and Temperature-Recording Devices (Proposed Sec.
106.30(e)(3))
    (Comment 70) One comment stated that the thermal processing
recording device requirement in proposed Sec.  106.30(e)(3)(ii) is
either redundant or in conflict with part 113 (Thermally Processed Low-
Acid Foods Packaged in Hermetically Sealed Containers). The comment
observed that proposed Sec.  106.30(e)(3)(ii) requires that a thermal
processing temperature-recording device reflect the true temperature,
and that Sec.  113.40(e)(2) requires a bias so that the temperature-
recording device reads ``as nearly as possible with, but to be in no
event higher than, the known accurate mercury-in-glass thermometer.''
The comment stated that part 113 more accurately reflects the needs of
a thermal processing system, and suggested that the infant formula CGMP
simply refer to the regulations in part 113.
    (Response) FDA agrees with these comments and is revising and
consolidating certain provisions of proposed Sec.  106.30(e), as
discussed in detail in this document.
    First, FDA is revising proposed Sec.  106.30(e)(1) to clarify that
the requirements in parts 108 and 113 (21 CFR parts 108 and 113) apply
to thermally-processed infant formula. This is simply restating an
existing requirement. In light of this revision, FDA is deleting the
language in proposed Sec.  106.30(e)(3)(ii) that ``Thermal processing
equipment shall be equipped with temperature-recording devices that
will reflect the true temperature on a continuing basis.'' Thus, Sec.
106.30(e)(1) of the interim final rule states: ``Equipment and
procedures for thermal processing of infant formula packaged in
hermetically sealed containers shall conform to the requirements in 21
CFR parts 108 and 113.''
    Second, FDA is revising the portion of proposed Sec.  106.30(e)(1)
that would require, among other things, that thermal processing
equipment used at points where temperature control is necessary to
prevent adulteration ``be monitored with such frequency as is necessary
to ensure that temperature control is maintained,'' and redesignating
it in the interim final rule as Sec.  106.30(e)(5). Under Sec.
108.35(c)(2), thermal processing monitoring frequency would be included
in the information required to be submitted in the process filing for
the scheduled process. Thus, Sec.  106.30(e)(5) of the interim final
rule states that ``Such monitoring shall be at such frequency as is
required by regulation or is necessary to ensure that temperature
control is maintained.''
    (Comment 71) A comment stated that it was unnecessary to require in
proposed Sec.  106.30(e)(3)(ii) that ``[c]old storage compartments must
be equipped with either temperature-recording devices that will reflect
the true temperature, on a continuing basis, within the compartment or,
in lieu of a temperature-recording device, a high temperature alarm or
a maximum-indicating thermometer that has been verified to function
properly'' because cold storage temperature monitoring can be
acceptably achieved through periodic manual recordings with sufficient
frequency to ensure proper temperature control. The comment explained
that the large volume liquid mixes in the infant formula manufacturing
process do not demonstrate significant temperature changes over time,
and therefore, do not warrant the increased capital investment of
recording devices and temperature alarms. The comment argued that
manual recordings at predetermined intervals are adequate to monitor
cold temperature storage conditions.
    (Response) FDA agrees that an appropriate method of ensuring that
cold storage temperature control is maintained is by manual monitoring
compartment temperature on a temperature-indicating device and

recording this temperature in a record with such frequency as is
necessary to ensure that temperature control is maintained. The goal of
proposed Sec.  106.30(e)(3)(ii) is to ensure adequate control of cold
temperatures. It is feasible to accomplish manually what can also be
achieved automatically; in this case, establishing a plan to monitor
cold temperatures, monitoring and recording the temperature, and doing
so at appropriate intervals, can provide the same assurance as an
automatic temperature monitoring system. Accordingly, FDA is adding
such manual monitoring to the options originally provided in proposed
Sec.  106.30(e)(3)(ii). Thus, an infant formula manufacturer will have
four choices for monitoring the temperature of a cold storage
compartment: (1) The temperature may be monitored manually using a
temperature-indicating device and manually recording the temperature at
an appropriate frequency; (2) the compartment may be equipped with a
temperature-recording device that will reflect the true temperature, on
a continuing basis, within the compartment; (3) the compartment may be
equipped with a high temperature alarm that has been verified to
function properly and the temperature may be manually recorded at an
appropriate frequency; or (4) the compartment may be equipped with a
maximum-indicating thermometer that has been verified to function
properly and the temperature may be manually recorded at an appropriate
frequency.
    Additionally, Sec.  106.30(e)(3)(ii) of the interim final rule
includes information about making and retaining records. Section
106.30(e)(3)(iii) of the interim final rule takes into account the
option to manually monitor temperatures, by stating that ``the
manufacturer shall, in accordance with Sec.  106.100(f)(3), make and
retain records of the temperatures recorded in compliance with Sec.
106.30(e)(3)(ii).'' Because Sec.  106.30(e)(3)(iii) of the interim
final rule contains the requirement that ``the manufacturer shall, in
accordance with Sec.  106.100(f)(3), make and retain records of the
temperatures recorded in compliance with Sec.  106.30(e)(3)(ii),'' FDA
is making conforming changes to proposed Sec.  106.100(f)(3). Section
106.100(f)(3) of the interim final rule includes ``records in
accordance with Sec.  106.30(e)(3)(iii).''
    (Comment 72) One comment suggested that proposed Sec.  106.30(e)(4)
be deleted because the requirement that thermal process recording
devices be biased to not read higher than the calibrated temperature-
indicating device is redundant with part 113. Another comment asserted
that proposed Sec.  106.30(e)(3)(ii) and proposed Sec.  106.30(e)(4)
conflict with one another.
    (Response) As noted, FDA is revising proposed Sec.  106.30(e)(1) to
clarify that the requirements in parts 108 and 113 apply to thermally-
processed infant formula. The requirement of proposed Sec.
106.30(e)(4) is incorporated into Sec.  106.30(e)(1) of the interim
final rule by virtue of the reference to the application of the
requirements in parts 108 and 113 to thermally-processed formula.
Accordingly, in Sec.  106.30(e)(4) of the interim final rule, FDA is
deleting the language referring to thermal process recording devices
not reading ``higher than the calibrated temperature-indicating device
for thermal processing equipment.''
    (Comment 73) A comment argued that the bias in proposed Sec.
106.30(e)(4) relating to cold storage temperature recorders was
inappropriate because a slight temperature deviation of the cold
storage compartment would have a very small impact on the growth of
microorganisms. The comment contended that the proposal appears to
equate the importance of a very slight temperature deviation for the
sterilization process with a very slight temperature deviation of the
cold storage compartment when the two situations are radically
different. The comment explained that a one degree Fahrenheit drop in
the sterilization temperature could have a significant effect on the
process lethality and could result in a failure to meet commercial
sterility, whereas a one degree Fahrenheit increase in the temperature
of a cold storage compartment would have a very small impact on the
growth of microorganisms.
    (Response) FDA disagrees with this comment. The purpose of proposed
Sec.  106.30(e)(4) is to ensure that a temperature-recording device for
a cold storage compartment reflects the actual temperature of the
compartment and will not overstate the conditions in the compartment.
The accuracy of a temperature-recording device is important given that
the record in this rulemaking establishes that a temperature of
40[deg]F (4.4[deg]C) in cold storage compartments will prevent the
growth of harmful microorganisms and will prevent spoilage and
deterioration of nutrients, all of which could lead to adulteration of
the infant formula. Moreover, as noted previously in this document, the
impact of temperature variation, including a one degree Fahrenheit
increase in temperature, will vary depending upon the initial microbial
load of the chilled product, the time the product is held at the
elevated temperature, and other product characteristics, such as
product hydrogen-ion concentration (pH) (Refs. 16 and 17).
    Accordingly, in light of the foregoing comments, Sec.  106.30(e)(4)
of the interim final rule provides that ``When a manufacturer uses a
temperature-recording device for a cold storage compartment, such
device shall not read lower than the reference temperature-indicating
device.''
    (Comment 74) One comment objected to the recommendation in the 1996
preamble that ``manufacturers should calibrate thermometers for cold
storage temperature measurements at least at the beginning and end of
each production day . . ..'' The comment argued that FDA is
recommending a calibration frequency that is far more stringent than
measurement devices for thermal food processing, which is a process of
critical importance. The comment asserted that the frequency for
calibration of cold storage temperature measurement devices should be
determined by the manufacturer based on the volume, hold time, and
location in the manufacturing process.
    (Response) FDA agrees with this comment to the extent that the
comment asserts that calibration frequency should be determined by the
manufacturer based on variables of the manufacturer's process. In
addition, in determining the appropriate calibration frequency, a
manufacturer should consider the calibration frequency recommended by
the manufacturer of the equipment in question.
6. Maintenance of Equipment and Utensils at Regular Intervals (Proposed
Sec.  106.30(f))
    A number of comments objected to the requirements in proposed Sec.
106.30(f) relating to cleaning, sanitizing, and maintaining equipment
and utensils. These comments indicate that there is confusion about
what would be required by proposed Sec.  106.30(f).
    FDA intended that the requirements of proposed Sec.  106.30(f)
would extend to all equipment and utensils used in the production of
infant formula, including storage tanks, equipment and utensils used in
the ingredient weighing area, in-process and processing equipment and
utensils, and container filling, closure, and container packaging
equipment. All of the equipment and utensils used in producing infant
formula have some potential to cause adulteration of the formula and
thus, all must be appropriately cleaned, sanitized, and maintained.
Although every piece of equipment and each utensil is not likely

to require the same cleaning, sanitizing, or maintenance, all must be
subject to such activities at intervals that will prevent such
adulteration.
    (Comment 75) One comment questioned whether the requirement of
``regular intervals of cleaning, sanitizing, and maintenance'' would
apply when a production line that ordinarily requires daily cleaning
and sanitizing is taken out of service. The comment requested that the
Agency clarify that it is the equipment and utensils used in an
operating production line for the manufacture of infant formula that
must be cleaned, sanitized, and maintained at regular intervals.
    (Response) FDA disagrees with this comment. Contrary to the
comment's suggestion, these requirements apply equally to the equipment
and utensils of an operating production line and to the equipment and
utensils of a production line that is taken out of service. FDA
recognizes that entire production lines, along with their associated
equipment and utensils, may be taken out of service, sometimes for
prolonged periods. However, manufacturers must establish cleaning,
sanitizing, and maintenance procedures that include a schedule for
cleaning and sanitizing, as necessary, and maintaining dormant
equipment, including production lines and utensils, prior to
reactivating their use.
    (Comment 76) Another comment requested that FDA clarify whether the
requirement in proposed Sec.  106.30(f) to maintain equipment and
utensils and to check and retain records on this maintenance would
apply only to major equipment or would include every minor action that
is taken to maintain equipment (e.g., changing an ``O'' ring). The
comment argued that if minor actions were included, the requirement
would be extensive. The comment also suggested that the terms
``maintained'' and ``maintenance'' be deleted from this section.
    (Response) As stated previously in this document, because all
equipment and utensils used in producing infant formula have the
potential to cause adulteration of the formula, all must be
appropriately cleaned, sanitized, and maintained. Although every piece
of equipment and each utensil is not likely to require the same degree
of cleaning, sanitizing, or maintenance, all must be subject to such
activities at intervals that will prevent such adulteration. Thus, FDA
disagrees with the comment suggesting that the requirement to maintain
equipment and utensils, to have a qualified individual check all
cleaning, sanitizing, and maintenance, and to make and retain records
of such activities should apply only to major equipment.
    The requirements of proposed Sec.  106.30(f) include both routine
and required maintenance of all equipment as well as any unplanned
correction or repair of equipment. Manufacturers generally document the
routine servicing of production equipment as part of a preventative
maintenance program that identifies the work to be performed and its
frequency. Changing an ``O'' ring, an example given in the comment, may
be documented in a preventative maintenance program simply by noting
the time, date, and employee involved if changing the ``O'' ring
represents routine, scheduled equipment maintenance. If, however, this
activity is an unplanned correction or equipment repair, more detailed