data collected during a growth monitoring study be compared to standard
measurements of infant physical growth as a means of assessing whether
the pattern of changes in weight and length of each individual infant
study participant (both on test and control formulas) was similar to
that observed for healthy infants of the same age, allowing for the
range of normal individual variation in body weight and length that the
2000 CDC growth chart percentiles would have provided. Importantly, FDA
does not intend that comparison with any growth chart be the sole
analysis of the anthropometric data collected during a growth
monitoring study. This comparison of the study data with growth charts
will complement the comparison of data from the two study groups and
will provide a context for interpreting the primary comparison of
growth data between test and control groups.
    In addition, by evaluating whether, over time, each infant study
subject follows the generally expected growth rate for infants,
deviations in individual growth rate may be identified, thereby
alerting study investigators and FDA to a possible problem with formula
sufficiency. The Agency expects that such deviations would be promptly
scrutinized by study investigators to determine whether the deviations
are likely to be formula-related. Thus, individual subjects' growth
during the study may provide an early indication to investigators that
the new formulation of an infant formula is not nutritionally
sufficient. Also, monitoring individual infant rate of growth and
comparing such growth rate to the 2009 CDC growth charts, which
establish a standard for how infants should grow, may alert the study
investigator to an individual infant who may be in distress or
otherwise has potential issues and thereby, ensures the safety and
well-being of the study subjects. Accordingly, for two separate
reasons, it is important to compare each individual infant's growth to
the 2009 CDC growth charts to monitor individual infant growth
patterns.
    (Comment 239) One comment challenged the use of individual growth
charts, asserting that such charts are not appropriate to establish
whether one group of infants differs from another group of infants in
terms of growth rates. The comment further asserted that the use of
curves to evaluate growth of infants could lead to inappropriate
conclusions concerning normal growth, and cited a 2002 paper by
Grummer-Strawn in support (Ref. 72).
    (Response) FDA regards growth monitoring as the single most useful
tool in describing health and nutritional status at both the individual
and group level. Plotting the mean group data on a growth chart permits
a comparison of how groups of infants grow. In contrast, as described
previously in this document, plotting the growth of individual infants
on growth charts provides an early indication of a possible problem
with formula composition because it allows the investigator to observe
disturbances in the growth of individual subjects.
    FDA agrees that growth charts based on reference data have
limitations, many of which have been addressed in the development of
the 2009 CDC growth charts. As discussed previously in this document,
the purpose of

plotting the anthropometric data of study subjects is to monitor
individual subjects' growth during the study. Under Sec.  106.96(b)(4)
of the interim final rule, the growth monitoring study must include a
concurrent control group, and the anthropometric data on the test and
control groups will be separately compared independent of the growth
chart activity to determine whether the new formula supports normal
physical growth. Comparing the anthropometric data to a growth chart is
intended to complement the use of concurrent controls and evaluation of
the data from such controls.
    The 2002 paper by Grummer-Strawn does not contradict the interim
final rule's use of the 2009 CDC growth charts as a complement to the
use of a concurrent control group (Ref. 72). The Grummer-Strawn paper
explained why the use of the 2009 CDC growth charts is preferred to the
use of the 2000 CDC growth charts. Unlike the 2000 CDC growth charts,
the 2009 CDC growth charts are based on data from a longitudinal study
of healthy infants growing optimally.
    (Comment 240) One comment asserted that the use of curves to
evaluate growth of infants could lead to inappropriate conclusions
concerning normal growth.
    (Response) FDA disagrees with this comment and notes that the
comment did not explain how the complementary use of growth charts
could result in inappropriate conclusions about growth. As noted, there
is a two-fold purpose for plotting study subjects' individual growth
data on a growth chart. FDA is requiring the plotting of these data as
a check on the nutrition provided to both the test and control subjects
and also to monitor the growth of individual study participants as part
of the controls for human subject protection. The growth monitoring
study must include a concurrent control group for which anthropometric
data will be collected, analyzed, and used as a comparison to similar
data collected from the infants on test formula.
    (Comment 241) One comment stated that because the NCHS growth
charts had been recently revised and published by the CDC in 2000, and
because new science is constantly accumulating, which may impact the
understanding of what constitutes ``expected'' physical growth, it
would be shortsighted to tie the assessment only to the currently
existing reference standards.
    (Response) As discussed previously in this document, the CDC now
recommends the use of the 2009 CDC growth charts that are based on the
WHO Child Growth Standards for infants and children from birth to 24
months. To the extent that the CDC growth charts are revised in the
future, and new growth charts are developed, FDA would consider the
need to revise the growth charts required by this interim final rule at
that time.
    (Comment 242) One comment stated that the Iowa reference data,
while excellent, may be less accessible than the NCHS growth charts,
and the growth charts do incorporate some mechanism for quantitative
assessment of growth patterns.
    (Response) Data quality and not data accessibility is the relevant
issue here. Although the Iowa reference data have some value (Refs. 68
and 73), the value of these reference data has been superseded by the
2009 CDC growth charts (Ref. 11). The Iowa data lack the ethnic and
racial diversity that underlie the 2009 CDC growth charts. Also, the
2009 CDC growth charts establish a standard for the quantitative
assessment of infant growth patterns. Given these strengths of the data
provided in the WHO Child Growth Standards, Sec.  106.96(b)(4) of the
interim final rule requires that the anthropometric data be plotted on
the 2009 CDC growth charts that are based on the WHO Child Growth
Standards. A manufacturer who wishes to compare such data to other
reference data, such as the Iowa reference data, must request and meet
the requirements for an exemption under Sec.  106.96(c)(2)(i) of the
interim final rule.
    (Comment 243) One comment stated that national data that reflect
the diversity of the U.S. population should be used instead of the Iowa
data, because Iowa has historically not represented diverse
populations.
    (Response) As discussed previously in this document, the 2009 CDC
growth charts reflect appropriate racial and ethnic diversity and thus,
are appropriate for plotting the growth of infants in the U.S.
population.
    (Comment 244) One comment recommended that for growth monitoring
studies conducted outside the United States, the comparisons of
anthropometric data should be plotted on growth charts that are
routinely used in the country in which the study is performed.
    (Response) Although the 1996 proposed rule did not specifically
address the conduct of growth monitoring studies outside the United
States, the Agency does not disagree that such studies may potentially
be used as assurances for the quality factor of normal physical growth.
Importantly, however, any such study would have to meet the
requirements of the interim final rule, including the human subject
protections for pediatric studies in 21 CFR part 50, subpart D, and 21
CFR part 56 to ensure that the infant study subjects are not
inappropriately exposed to risk. When assessing the adequacy of a
growth monitoring study conducted in a foreign country, FDA would
consider whether the study satisfies good clinical practice, whether
the investigators have recognized competence to conduct the study,
whether the scientific evidence is valid, and whether the results are
applicable to the U.S. infant population (Ref. 74). FDA would also
consider whether the formula studied is the formula to be marketed in
the United States. If the studied formula is not the formula to be
marketed in the United States, the manufacturer would be required to
request and meet the requirements for an exemption under Sec.
106.96(c)(2)(i) of the interim final rule, and would be expected to
explain why the formulation studied would be considered an appropriate
proxy for the formula to be marketed in the United States.
    In terms of the comment's specific concern, FDA notes that, as of
March 2012, more than 140 countries had adopted the WHO Child Growth
Standards. Thus, it is very likely that the WHO Child Growth Standards
would be used in the foreign country in which a growth monitoring study
is to be conducted, and such data would be consistent with the 2009 CDC
growth charts.
    (Comment 245) One comment urged that that studies conducted to
evaluate infant growth test a sufficient number of infants to provide
precise estimates of mean growth in weight, length, and head
circumference (with confidence intervals around the mean that exclude
rates of growth that are outside the bounds of accepted standards.)
    (Response) FDA notes that the comment did not identify ``accepted
standards'' or describe what would be considered ``outside the bounds''
of such standards.
    Nonetheless, FDA agrees that a growth study must include a sample
size sufficient to permit detection of differences in growth, between
the control and test formula groups, if such differences exist.
Confidence intervals are used in statistics to describe a range of
values in an attempt to quantify the uncertainty of a particular
statistical estimate. A narrow confidence interval suggests a highly
precise estimate, and a wide confidence interval implies poor
precision. The desired confidence interval can be used to estimate
needed sample size as can a ``power'' calculation, and a wide
confidence

interval is often an indication of inadequate sample size. Absent an
adequate sample size, a study cannot sufficiently test the question
under study. Although FDA is not codifying statistical requirements for
a growth monitoring study, the Agency notes that such study must be
appropriately designed and conducted so as to produce data that can be
meaningfully interpreted on the question of whether the formula
supports normal physical growth.
    (Comment 246) One comment noted that because sick infants may grow
at a slower rate and on lower percentiles due to their underlying
medical condition rather than any deficiency in the formula being
consumed, population reference standards are less useful for evaluating
growth of sick infants than that of healthy infants.
    (Response) FDA is uncertain as to what the comment meant by ``sick
infants.'' Although the Agency would agree that, generally speaking,
due to an underlying medical condition, a sick infant will grow at a
slower rate and on lower percentiles, FDA would not expect a
manufacturer to plan purposefully to conduct a growth monitoring study
in a population of ``sick infants.''
    It is possible that the comment had in mind a growth monitoring
study of a so-called ``exempt infant formula.'' Section 412(h)(1) of
the FD&C Act exempts certain infant formulas (those for infants with
inborn errors of metabolism, low birth weight, or other unusual medical
or dietary problems) from several statutory requirements, including the
requirement that a manufacturer provide assurances that a formula meets
the quality factor requirements established by the Secretary. Infants
for whom ``exempt infant formulas'' are developed could be considered
``sick.'' Importantly, however, as noted earlier in this preamble, this
interim final rule applies only to nonexempt infant formulas. Thus, the
manufacturer of an exempt infant formula is not required to comply with
the requirement to conduct a growth monitoring study. FDA's current
thinking on the application of the interim final rule to exempt infant
formula may be found in a draft FDA guidance document, a notice of
availability for which is published elsewhere in this issue of the
Federal Register. Accordingly, the comment about growth rates of ``sick
infants'' has no bearing on the interim final rule.

D. Exemptions From Quality Factor Requirements for Normal Physical
Growth

    In the 1996 proposed rule, FDA set forth in proposed Sec.
106.97(a)(2) exemptions from the growth monitoring study requirements
of proposed Sec.  106.97(a)(1). Specifically, proposed Sec.
106.97(a)(2) provided exemptions from the need for a study to evaluate
physical growth in the following three situations:
     The manufacturer has similar experience using an
ingredient, an ingredient mixture, or a processing method in the
production of an infant formula marketed in the United States and can
demonstrate that infant formula made with that ingredient, ingredient
mixture, or processing method meets quality factor requirements in
Sec.  106.96;
     The manufacturer markets a formulation in more than one
form (e.g., liquid and powdered forms) and can demonstrate that the
quality factor requirements are met by the form of the formula that is
processed using the method that has the greatest potential for
adversely affecting nutrient content and bioavailability; and
     The manufacturer can demonstrate that the requirements (of
Sec.  106.97(a)(1)) are not appropriate for the evaluation of a
specific infant formula, and that an alternative method or study design
for showing that the formula supports healthy growth in infants fed it
as their sole source of nutrition is available.
    Several comments expressed confusion about the proposed exemptions.
In response to these comments, FDA has significantly revised the
proposed exemptions, which are set out in Sec.  106.96(c) of the
interim final rule. FDA's responses to the comments and the Agency's
explanation for the revisions of the proposed exemptions are set out in
this document.
    (Comment 247) One comment recommended that a manufacturer be
responsible for demonstrating that a growth study is not needed rather
than exempting the manufacturer from conducting studies in a finite
number of circumstances.
    (Response) FDA agrees that, in general, a manufacturer should be
responsible for demonstrating, in appropriate circumstances, that a
growth study is not needed and that some ``major changes'' may not
require a growth monitoring study to demonstrate that the formula
supports normal physical growth. Thus, in the interim final rule, Sec.
106.96(c)(1) contains a narrowly defined circumstance in which FDA will
grant a manufacturer an exemption from the growth monitoring study
requirement upon the manufacturer's request. The interim final rule's
three additional exemptions from the requirement to meet the specific
growth monitoring study requirements under Sec.  106.96(b) clearly
place the responsibility on the manufacturer to demonstrate to the
Agency's satisfaction that the conditions of the exemption have been
satisfied.
    (Comment 248) Another comment stated that not every change in an
infant formula raises questions as to infant growth that cannot be
answered adequately by other scientific supportive data that may be
equally convincing and more appropriate.
    (Response) FDA agrees with this comment to the extent that it
asserts that not every change in an infant formula will require the
manufacturer to conduct a growth monitoring study of a new formulation
of an infant formula. As noted in the response to the previous comment,
the interim final rule provides separate exemptions from the growth
monitoring study requirement in Sec.  106.96(c)(2) of the interim final
rule, including an exemption for the situation in which a manufacturer
establishes that an alternative method or study design that is based on
sound scientific principles can show that the formula supports normal
physical growth when fed as the sole source of nutrition (Sec.
106.96(c)(2)(i) of the interim final rule). Thus, FDA believes that the
interim final rule responds to this comment.
    (Comment 249) One comment noted that the proposed rule contains a
broad definition of ``major change'' that would mandate the filing of a
premarket notification for numerous changes in processing or
formulation, and that, while the industry recognizes that a growth
study may be needed to assess some of these major changes (such as the
use of certain new ingredients with no prior history of use in infant
formula), there is no scientific basis to mandate a growth study for
other major changes (such as the manufacture of an infant formula on a
new processing line).
    (Response) FDA disagrees with this comment to the extent that it
asserts that the proposed definition of ``major change'' is too broad.
The definition of ``major change'' in this interim final rule is
discussed previously in this document in section IV.C.2.
    FDA agrees that a growth monitoring study may be needed to assess
some major changes (such as the use of certain new ingredients with no
prior history of use in infant formula). However, in the case of use of
a new processing line, some changes, such as

introduction of a new retort system with altered time and temperature
processing conditions, could potentially have an adverse effect on the
bioavailability of the formula, including the bioavailability of
nutrients in the formula. On the other hand, FDA also recognizes that
not all processing changes have the same potential to affect formula
bioavailability and bioavailability of nutrients. Thus, Sec.
106.96(c)(2)(ii) of the interim final rule provides an exemption from
the quality factor requirements for normal physical growth, Sec.
106.96(b) of the interim final rule, where the manufacturer provides
assurances, as required under Sec.  106.121 of the interim final rule,
that demonstrate that a ``major change'' to an existing formula does
not affect the bioavailability of the formula, including the
bioavailability of nutrients in such formula. In addition, the interim
final rule provides an exemption, upon the manufacturer's request, from
the requirements of Sec.  106.96(b) of the interim final rule, for a
change that is a ``major change,'' but is limited to altering the type
of packaging of an existing infant formula. For these reasons, FDA
declines to make revisions in response to this comment.
    (Comment 250) One comment requested deletion of proposed Sec.
106.97(a)(2)(i) because, the comment asserted, providing that an
exemption ``may be available'' based on a requirement to
``demonstrate'' that a manufacturer or responsible party has experience
with an ingredient, ingredient mixture, or a processing method
constitutes premarket approval, not notification.
    (Response) FDA disagrees with this comment to the extent that it
asserts that the structure of proposed Sec.  106.97(a)(2)(i)
constitutes premarket approval. The proposed exemption is part of FDA's
establishment of requirements for quality factors, an action expressly
required by section 412(b)(1) of the FD&C Act, and nothing in this
proposed exemption can or does alter the statutory process of premarket
notification established by section 412(c) of the FD&C Act. FDA is
deleting this specific exemption as unnecessary, however, because its
specific circumstances are covered by the broader exemption in Sec.
106.96(c)(2)(ii) of the interim final rule.
    (Comment 251) One comment suggested that ``similar experience''
with an ingredient, an ingredient mixture, or a processing method
should be relevant regardless of whether it occurred in the United
States or elsewhere.
    (Response) As noted, FDA is deleting the specific exemption in
proposed Sec.  106.97(a)(2)(i) because its circumstances will be
covered by the broader exemption in Sec.  106.96(c)(2)(ii) of the
interim final rule. As part of the showing required by Sec.
106.96(c)(2)(ii) of the interim final rule, a manufacturer may submit
data from marketing outside the United States. FDA expects that, in
such circumstances, the manufacturer will explain why such data are
both relevant to a change in an infant formula marketed in the United
States and why FDA should consider such data. Thus, under the interim
final rule, the information relating to a manufacturer's experience
outside the United States with an ingredient, ingredient mixture, or
processing method will not be categorically classified as irrelevant to
a change in a formula distributed in the United States.
    (Comment 252) One comment requested deletion of Sec.
106.97(a)(2)(ii) from the final rule but did not state why. Another
comment agreed with the concept of choosing the most stringent case for
conducting quality factor testing, whenever possible, but also stated
that the choice of the representative formula should not be based
solely on greatest adverse nutrient effect and provided the following
example: If a product has two forms, one a liquid, ready-to-feed
formula for hospital use only, and the other a powder formula for
retail use, it may be more appropriate to study the form that is
intended for long term use (i.e., the powder) as opposed to the very
short term formula (i.e., the liquid), where processing actually may
have the greatest adverse nutrient effect.
    (Response) FDA disagrees with this comment. All forms of infant
formula (ready-to-feed, concentrate, and powder) are marketed for
extended use and thus, all must be capable of supporting normal
physical growth of healthy term infants when used as the sole source of
nutrition. For this reason, FDA disputes the comment's suggestion that
powdered infant formula is the infant formula form intended for long-
term use and thus, is the form that should be used in a growth
monitoring study. The comment did not directly dispute FDA's view that
the infant formula form processed under the most severe conditions is
the form with the greatest likelihood of having adverse effects on its
nutrient content and, thus, on the formula's bioavailability to the
infant. In most cases, the most highly processed form of formula is the
liquid product that undergoes pasteurization plus a heat treatment
(typically, retorting to temperatures of 244[emsp14][deg]F) to ensure
commercial sterility. Such retorting is more severe than the heat
treatment applied during the production of powdered products, which
typically involves only pasteurization plus a relatively milder heat
treatment during spray drying (powder temperature reaching 110-175
[deg]F at the dryer outlet) (Ref. 75).
    For this reason, FDA concludes that, in all likelihood, it would be
appropriate to test in a growth monitoring study the liquid form of an
infant formula processed under the most severe conditions, which
results would be applicable to the less highly processed powdered form
of the formula. For companies producing only powdered infant formula,
the appropriate formula to test would, of course, be the powdered form.
Given the disparities in processing and the effects of processing,
however, the results of a growth monitoring study of powdered product
generally would not be evidence that more highly processed liquid forms
of the formulation satisfy the quality factor of normal physical growth
in healthy term infants.
    (Comment 253) One comment asserted that in applying the exemption
of proposed Sec.  106.97(a)(2)(ii), the manufacturer must be given
responsibility for determining the most representative form to test.
    (Response) FDA notes that the exemption in proposed Sec.
106.97(a)(2)(ii) has been recodified at Sec.  106.96(c)(2)(iii) of the
interim final rule.
    FDA disagrees in part with this comment to the extent that the
comment asserts that the manufacturer should be able to determine
unilaterally which form of a formulation to test in a growth monitoring
study. The provision in question is part of the assurances that a
formula satisfies the requirements for quality factors, which
requirements and assurances the statute authorizes FDA to establish.
Although the statutory scheme does not require the Agency to establish
exemptions from the assurances that such requirements are satisfied,
FDA has determined, in its discretion, to do so. Accordingly, it is
also within the Agency's discretion to establish the terms of such
exemptions, including the requirement that a manufacturer must satisfy
FDA that the conditions of an exemption exist.
    Moreover, in this case, it is reasonable that a manufacturer
establish, to the Agency's satisfaction, that the form of the formula
tested in a growth monitoring study is the form processed using the
method with the greatest potential for adverse effects on the nutrient
content and bioavailability. This standard will provide the greatest

certainty that all forms of a formula will be nutritionally sufficient
regardless of the means of processing. FDA does agree, however, that
under this exemption, the manufacturer may initially choose which form
of a formulation to test for such purposes, but when submitting its
assurances to the Agency, the manufacturer must demonstrate that the
form tested meets the standard in Sec.  106.96(c)(2)(iii) of the
interim final rule.
    (Comment 254) One comment argued that when studies have already
been carried out on a form of the product that meets neither criterion
(i.e., a formula with greatest potential for an adverse effect on
nutrients or a formula intended for long term use), but the new
formulation cannot reasonably be expected to differ significantly from
the formula in question in terms of nutrient levels or bioavailability,
those studies should also be able to provide the basis for exemption
from additional studies. The comment stated that to require duplicative
studies on different forms of a product that do not differ
significantly would be difficult to justify on an ethical basis.
    (Response) As noted previously in this document, FDA has added an
exemption to the interim final rule allowing manufacturers to request
an exemption and provide assurances that demonstrate that an
alternative method or study design that is based on sound scientific
principles is available to show that the formula supports normal
physical growth in infants when the formula is fed as the sole source
of nutrition. This would permit a manufacturer to submit data relating
to a particular formulation and to demonstrate that, even if the
formulation tested is not the most heavily processed, sound science
principles support reliance on such data to demonstrate that all forms
of the formulation satisfy the quality factor of normal physical
growth. Thus, there is an option in the interim final rule for the
manufacturer to request an exemption from the need for a growth
monitoring study under the circumstances identified in the comment.
    (Comment 255) One comment requested deletion of proposed Sec.
106.97(a)(2)(iii), but did not state why. Another comment noted FDA's
recognition of the flexibility necessary to accommodate evolution in
clinical study design and suggested that consideration should be given
to situations where formula is not intended as the sole source of
nutrition.
    (Response) The request to allow infant formulas to be tested other
than as the sole source of nutrition was addressed previously in this
document in section VIII.C.4.c. Consistent with this discussion, the
Agency does not agree that ``sole source of nutrition'' should be
removed from the language in the exemption.
    FDA acknowledged in proposed Sec.  106.97(a)(2)(iii) that it is
possible to assure the Agency that an alternative method or study
design may be appropriate for the evaluation of the ability of some
infant formulas to support normal physical growth. Therefore, FDA is
providing a mechanism whereby manufacturers may request an exemption
from the growth monitoring study requirement and use an alternate
method or study design to provide assurances of normal physical growth.
Because questions about the adequacy of a study design or method may be
varied and may raise unique questions about the ability of such method
or design to generate data to demonstrate normal physical growth, FDA
is requiring that the assurances, required under Sec.  106.121 of the
interim final rule for such an exemption, demonstrate that the
alternative method or study design be based on sound scientific
principles and show that the formula supports normal physical growth
when the formula is the sole source of nutrition (see section X for
further discussion on the assurances required by Sec.  106.121 of the
interim final rule). This exemption, as revised, is now Sec.
106.96(c)(2)(i) of the interim final rule.
    (Comment 256) One comment suggested that proposed Sec.
106.97(a)(2) be revised to allow a manufacturer to request an exemption
from the individual testing requirements of proposed Sec.  106.97(a)(1)
if the manufacturer has determined that a change in formulation or
processing does not cause the formula to be adulterated under section
412(a) of the FD&C Act and provides to FDA the basis for this
determination. The comment argued that without the suggested change,
the proposed rule provides no exemptions for changes such as minor
changes in ingredient levels, replacing one nutrient form with another,
or insignificant changes in processing conditions. The comment argued
that such changes would require a submission under proposed Sec.
106.140, which includes assurances under proposed Sec.  106.121. The
comment asserted that it was not the Agency's intent or a correct
interpretation of section 412(d)(3) of the FD&C Act to require clinical
testing and protein efficiency ratio (PER) data for such minor changes.
    (Response) FDA disagrees with this comment. The fact that the
proposed rule would have required a quality factors submission
complying with proposed Sec.  106.121 is clear evidence of FDA's
intent. This intent is consistent with the statute, which requires that
a manufacturer of a new infant formula provide assurance that the
formula meets quality factor requirements in a ``before first
processing'' (BFP) submission made under section 412(d)(3) of the FD&C
Act. In lieu of a growth monitoring study, the manufacturer may request
an exemption under Sec.  106.96(c)(2)(ii) of the interim final rule and
provide the scientific basis to explain why the changes in the formula
would not affect the bioavailability of the formula and its nutrients
and submit the results of the nutrient testing on finished product
required under Sec.  106.91(a) of the interim final rule.
    The comment misunderstood the intent of the requirements for growth
monitoring studies. FDA does not intend to require a growth monitoring
study for all changes to a formula. A BFP notification under section
412(d)(3) of the FD&C Act must be submitted when the manufacturer
determines that a change in the formulation of the formula or a change
in the processing of the formula ``may affect whether the formula is
adulterated'' under section 412(a) of the FD&C Act, e.g., when there
are questions about whether a formula provides nutrients required by
section 412(i) of the FD&C Act, meets quality factor requirements, or
is in compliance with CGMP and quality control procedures. The 1986
Guidelines Concerning Notification and Testing of Infant Formulas
listed several examples of types of changes for BFPs, such as replacing
certain nutrient forms with another form or adjustments in the quantity
of a nutrient in a premix or individually added nutrient that results
in a specification change for that nutrient in the finished product, or
changes in time-temperature conditions of preheating during handling of
bulk product that cannot reasonably be expected to cause an adverse
impact on nutrient levels or nutrient availability.

E. Quality Factor: Protein Quality

    In 1996, FDA proposed (Sec.  106.96(c)) protein of sufficient
biological quality as a second quality factor for infant formula and
stated that a formula must not only contain adequate amounts of protein
but also protein in a form that can be utilized by infants. At that
time, the Agency noted that protein quality depends on a number of
factors and complex interactions, including

differences in the digestibility of proteins from different sources and
on the processing method for the formula. FDA also observed that the
nutritive value of protein depends upon the presence of all essential
amino acids at levels and relative proportions that will support
healthy growth and stated that this quality factor would require an
evaluation of whether the formula contains the essential amino acids
and total nitrogen in the amount and proportion to permit normal tissue
and organ growth and development (61 FR 36154 at 36181). In proposed
Sec.  106.97(b)(1), FDA proposed to require that biological protein
quality be established using the Protein Efficiency Ratio (PER) rat
bioassay described in the Official Methods of AOAC International, which
the Agency proposed to incorporate by reference (61 FR at 36215). In
proposed Sec.  106.97(b)(2), the proposed rule identified two
situations in which the manufacturer could request an exemption from
the PER assay requirement.
    FDA received no general comments on the Agency's proposal to
establish protein of sufficient biological quality as a quality factor
for infant formula. As noted previously in this document, FDA is
reorganizing and consolidating into Sec.  106.96 of the interim final
rule most of the content of proposed Sec.  106.96 and proposed Sec.
106.97 related to requirements for infant formula quality factors.
Thus, in the absence of comments, Sec.  106.96(e) of the interim final
rule establishes a second infant formula quality factor, biological
quality of protein sufficient to meet the protein requirements of
infants. Accordingly, Sec.  106.96(e) states the following: ``An infant
formula manufacturer shall meet the quality factor of sufficient
biological quality of protein.''
1. Methods for Determining Biological Quality of Protein in Infant
Formulas
    (Comment 257) One comment objected that the proposal specified a
particular AOAC method for evaluating protein quality and stated that
the biological quality of the protein in infant formula could be
established with any AOAC approved method including the PER.
    (Response) FDA disagrees with this comment. As noted, protein will
be of sufficient quality only if it contains sufficient amounts of all
amino acids essential for infants, is present in adequate amounts, and
is present in a form that infants can utilize. In the 1996 proposed
rule, the Agency explained that ``A protein source may contain the
necessary amino acids, but they may be in a form that the infant cannot
digest and absorb. Furthermore, processing methods may alter the
chemical nature of the protein source, possibly making the protein more
resistant to digestion by the infant'' (61 FR 36154 at 36187). FDA
proposed the PER method because, unlike chemical measures of protein
composition, PER provides an estimate of the bioavailability of the
protein. The Agency notes that the comment did not offer specific
objections to the PER method. Nor did the comment identify other
official AOAC methods that could successfully evaluate the presence and
bioavailability of protein in an infant formula. Accordingly, FDA is
not modifying this provision in response to this comment.
    (Comment 258) Several comments questioned whether the PER is the
best method of determining the protein quality of an infant formula and
whether measurements of protein status in the infant would be more
appropriate.
    (Response) FDA disagrees with these comments to the extent that
they challenge the use of the PER method. The PER method uses an animal
model and thus, will allow a manufacturer to assess an infant formula's
protein quality before the formula is fed to infants in a growth
monitoring study or otherwise. High quality proteins are easily
digestible and contain all of the essential amino acids in amounts that
humans require. As stated in the previous response, evaluating protein
quality requires both measuring the amount present and the amount that
is bioavailable. The PER permits a comparison of different protein
sources (i.e., is the test protein better or worse than the control
protein?). FDA is aware that the PER, although sensitive, is not
specific. The PER method has limitations (as discussed in this
document); however, FDA is not aware of any other available method to
assess protein bioavailability, and no comment, including this one,
identified any such method.
    FDA notes that the Agency consulted with an expert panel
established by the Life Sciences Research Office (LSRO) of the
Federation of American Societies for Experimental Biology (FASEB). The
LSRO panel was asked about minimum and maximum levels of protein in
infant formula and considered methods that measured protein quality but
not protein bioavailability (Ref. 76). Although total protein
(measurement of nitrogen) as well as amino acid patterns can now be
measured and such measures may be appropriate for certain aspects of
protein quality, chemical measures of this type do not address the
protein's bioavailability. The ability to estimate protein
bioavailability is the advantage of a biological test system such as
the PER assay.
    FDA is well aware of the limitations of the PER as these
limitations have been known for many years (Refs. 77 and 78). A
principal criticism of the PER is that it is highly correlated to
weight gain but does not characterize the protein, rather it reflects
the rate of weight gain of the rat consuming the test substance with
the weight gain of a control group. The Agency acknowledges that body
weight gain does not necessarily correspond to gain in muscle related
to protein intake nor does body weight gain detect changes in body
composition (Refs. 77 and 78). The PER assay has also been criticized
because, even under standardized conditions, laboratories may obtain
variable results in terms of the ratio percentage. However, PER is a
simple test with an AOAC standardized method that has improved the
assay (Ref. 79). Appropriate modifications of the PER are described in
this document.
    For the foregoing reasons, FDA declines to delete the requirement
that infant formula protein be assayed using the PER method.
    (Comment 259) One comment stated that when a manufacturer proposes
to alter the protein source or composition of an infant formula, the
manufacturer should be required to demonstrate that the serum amino
acid levels of infants consuming the altered formula are comparable to
those of breast-fed infants or infants fed other standard infant
formulas.
    Another comment countered that universally requiring amino acid
determinations in infants consuming the altered infant formula would
add nothing to the assessment of new combinations of protein sources
and the potential for the use of additional invasive procedures to
collect these data would be considered unethical unless specifically
justified. The comment further stated that the need for such analyses
can only be determined on a case-by-case basis.
    (Response) Determining serum free amino acid levels in infants
consuming the test formula would not be an adequate means of assessing
protein quality. Importantly, the comment did not provide evidence to
support this recommendation, and there are at least two reasons that
such tests would have limited value, if any. First, serum free amino
acids reflect circulating amino acids, which may be present in an
infant's blood either from the diet (i.e., the infant formula being
consumed) or from endogenous sources, such as the breakdown of the
infant's muscles. In

addition, determining serum levels of free amino acids would require
blood draws, an invasive procedure. Given the limited usefulness of
serum free amino acid analyses, requiring such analyses and thus, an
invasive procedure, is not reasonable. Accordingly, FDA declines to
revise the interim final rule to require formula manufacturers to
demonstrate routinely that serum amino acid levels of study infants are
comparable to those of breast-fed infants or of infants fed other
appropriate infant formulas.
    (Comment 260) One comment disputed that PER measurements in young
rats would add anything to the data collected in human infants. The
comment asserted that anthropometric measures, nitrogen balance
studies, and biochemical markers required by FDA in the growth
monitoring study would provide an indication of the sufficiency of
protein quality and quantity and that these measures in human infants
would be sufficient to confirm that such quality and quantity are
adequate.
    (Response) FDA disagrees with this comment. Contrary to what some
comments have suggested, FDA did not propose to require nitrogen
balance studies or biochemical markers as requirements for infant
formula quality factors. (A balance study is a study that measures each
individual study subject's intake and excretion of one or more
particular substances, such as required nutrients.)
    Moreover, the PER analysis would contribute valuable information to
the assessment of an infant formula's nutritional adequacy, value not
provided by a growth monitoring study, for two reasons. First, as
noted, the PER analysis is conducted in an animal model and thus, will
permit determination of a formula's protein quality before infants are
exposed to the formula. This ensures that infants will not be fed a
formula with inadequate or biologically unavailable protein, which is
critical because when an infant formula is the sole source of
nutrition, any inadequacy in protein quality cannot be compensated for
by other dietary components, and such inadequacy may result in serious,
and in some cases, permanent, adverse effects on an infant's growth and
development (Ref. 80).
    Second, as discussed previously in this document, a growth
monitoring study that includes anthropometric measurements assesses
whether the complete infant formula matrix supports normal physical
growth and contributes to an assessment of healthy growth. However, it
is imperative that protein quality be established prior to its use in
an infant formula, particularly where there is an accepted means (the
PER) to do so. It is critical that the composition of the protein,
e.g., type and amounts of essential amino acids, in a formula be
adequate to support the needs of a developing infant, and that the
formula containing the protein support normal physical growth.
Importantly, the failure of a formula to support normal physical growth
could be the result of a number of shortcomings in the formula. Thus,
the growth monitoring study will not provide information specific to
protein quality and bioavailability.
2. Method for Assessing Protein Efficiency Ratio (PER)
    (Comment 261) One comment pointed out that the citation to the PER
method in proposed Sec.  106.97(b)(1) should be changed to Protein
Efficiency Ratio (PER) rat bioassay described in the ``Official Methods
of Analysis of AOAC INTERNATIONAL,'' 16th ed., AOAC[supreg] Official
Methods 960.48, Protein Efficiency Ratio Rat Bioassay and 982.30,
Protein Efficiency Ratio, Calculation Method.
    (Response) In Sec.  106.96(f) of the interim final rule, FDA has
updated the references to AOAC International and to the AOAC methods,
and has used the current name and address for AOAC International in
Sec.  106.160, ``Incorporation by reference.''
    (Comment 262) Another comment stated that proposed Sec.
106.97(b)(1) should be revised to recognize other AOAC methods as they
become available.
    (Response) FDA will evaluate any AOAC method that becomes available
that might serve as a substitute for, or alternative to, the PER assay
and, if appropriate, will consider amending Sec.  106.96(f) to include
such method or methods.
    Although FDA is not revising the requirement to use the PER assay
in response to comments, the Agency is making, in addition to several
minor editorial changes, three revisions to proposed Sec.  106.97(b)(1)
on its own initiative.
    First, at the time of the 1996 proposal, certain language was
inadvertently omitted from proposed Sec.  106.97(b). In particular, the
phrase by ``an appropriate modification of'' should have been included
so that the sentence, as proposed, would read ``The manufacturer shall
establish the biological quality of the protein in its infant formula
by demonstrating that the protein source supports adequate growth using
an appropriate modification of the Protein Efficiency Ratio (PER) rat
bioassay described in the ''Official Methods of Analysis of the
Association of Official Analytical Chemists . . . .'' The basis for
this change is explained in this document.
    The requirement to assess the quality of the protein component of
an infant formula was originally established in FDA's quality control
regulations for infant formula, 21 CFR 106.30(c)(2), which were issued
in 1982 (47 FR 17016 at 17026 (April 26, 1982)). Comments on the
proposed rule asserted that, without certain modifications, the
official AOAC assay for PER would not give valid test results for
infant formulas due to the type of fat and concentrations of lactose
and fat required in infant formula (47 FR 17016 at 17023). The Agency
agreed with this view and thus, Sec.  106.30(c)(2) of the final rule
provided that ``The biological quality of the protein shall be
determined by an appropriate modification of the AOAC bioassay method
of analysis.''
    The purpose of the PER rat bioassay is to compare the quality of
protein in a finished infant formula product to a protein of known high
biological quality (casein) to demonstrate that the protein in a
proposed formula is bioavailable (supports comparable growth of the
rats), as a decrease in the protein's biological value would not be
detected by chemical analysis. As noted previously in this document,
the PER rat bioassay is currently the only method that accounts for
protein digestibility and absorption in a living animal system.
Digestibility and absorption are critical elements to ensuring, prior
to marketing, that an infant formula has sufficient protein quality.
    The official AOAC method is based on weight gain in test animals
where one group of rats is fed a casein control diet and another group
is fed a diet containing the test product (infant formula) (Ref. 81),
and the animals' food intake and body weight are measured. The mean
protein efficiency ratio (PER) is calculated based on the protein
consumed by and weight gain of each animal group. Prior to study
initiation, the test product (finished infant formula) and the casein
control are subjected to a compositional assessment (proximate
analysis). The diets are then formulated to contain matching amounts of
protein, fat, minerals, fiber, and moisture. These diets are analyzed
for protein to confirm that they were formulated correctly, which
information is used to calculate the PER at completion of the trial.
    Although the method has limitations with respect to assessment of
the quality of protein sources for infant formulas, the limitations are
greatly reduced by modification of the test and control diets. Three
dietary adjustments

commonly required for evaluation of the protein quality of infant
formulas are:
     Adjustment of the fat content: In most cases, when the
infant formula is incorporated into the protein evaluation diet based
on the nitrogen content, the fat content will be above the limit (8
percent) specified by the AOAC Official Method. The fat content of the
reference control (casein) diet must be adjusted to match the fat
content of the infant formula test diet.
     Carbohydrate composition adjustments: Lactose is the
carbohydrate component of most milk-based infant formulas. Rats do not
tolerate lactose well and often develop diarrhea, which may lead to an
underestimation of protein quality of the formula. The casein reference
control diet(s) must contain levels of lactose comparable to the amount
in the infant formula test diet to adjust for possible confounding of
the estimation of protein quality. If an infant formula contains a
carbohydrate source other than lactose (e.g., sucrose, corn syrup
solids), the source of carbohydrate in the formula should be used in
the control diet as well.
     Removal of water from liquid infant formula: Infant
formula is incorporated into the protein evaluation diet based on its
nitrogen content. Because of the high water content of infant formulas
in liquid form, these products usually are below the lower limit of
total nitrogen (1.8 percent by weight) required for the PER bioassay.
Liquid infant formulas must be freeze-dried so that the test sample
contains more than 1.8 percent nitrogen before the infant formula test
diet is formulated.
    Second, in order to ensure that determination of the biological
quality of the protein of a new formulation precedes the initiation of
the growth monitoring study required by Sec.  106.96(b) of the interim
final rule, the Agency is adding the following sentence in Sec.
106.96(f) of the interim final rule: ``The PER rat bioassay shall be
conducted on a formula and the results evaluated prior to the
initiation of a growth monitoring study of the formula that is required
under paragraph (b).'' This will prevent the exposure of growth
monitoring study subjects to a protein of undetermined biological
quality and any unnecessary attendant risk of such exposure.
    Finally, proposed Sec.  106.97(b)(1) provided that ``[i]f the
manufacturer is unable to conduct a PER rat bioassay because of the
composition of the protein in the formula, then it shall demonstrate
that the amino acid composition of the protein meets the known amino
acid requirements of infants for whom the formula is intended.'' As an
example of a formula for which this proposed flexibility might be
necessary, the preamble cited the instance of an ``exempt infant
formula'' that contains an incomplete protein (61 FR 36154 at 36187).
As discussed previously in this document, this interim final rule only
applies to non-exempt infant formulas; the composition of the protein
of such non-exempt formulas would not preclude the use of the PER to
determine protein quality. Therefore, FDA is excluding as unnecessary
from Sec.  106.96(f) of the interim final rule the following
sentence:''If the manufacturer is unable to conduct a PER rat bioassay
because of the composition of the protein in the formula, then it shall
demonstrate that the amino acid composition of the protein meets the
known amino acid requirements of infants for whom the formula is
intended.''

F. Exemption From the Quality Factor of Protein Quality Sufficiency

    As noted, the 1996 proposed rule identified two situations in which
the manufacturer could request an exemption from the PER assay
requirement in proposed Sec.  106.97(b)(2). Specifically, an exemption
from the PER requirement would have been available where the
manufacturer was already using the same protein source produced by the
same processing method in another infant formula marketed in the United
States, and the manufacturer could demonstrate that current formula met
the quality factor requirements of the proposed rule, and where the
protein source, including any processing method used to produce the
protein, would not have been a major change from its predecessor
formula and the manufacturer could demonstrate that the predecessor
formula met the quality factor requirements of the proposed rule.
    As discussed previously in this document in section VIII.D. in this
interim final rule, FDA is revising the exemptions from conducting a
growth monitoring study under Sec.  106.96(b). Section 106.96(c)(1) of
the interim final rule provides that, in response to a manufacturer's
request, the Agency will exempt the manufacturer from the obligation to
conduct a growth monitoring study when the manufacturer requests an
exemption and provides assurances under Sec.  106.121 of the interim
final rule that the changes to the existing formula are limited to
changing the type of packaging for an existing infant formula.
    An assay of protein quality would also not be required in the
foregoing circumstance because the change would not be expected to have
an effect on protein quality or on any of the other nutrients in the
formula that could affect the bioavailability of the protein.
Accordingly, Sec.  106.96(g)(1) of the interim final rule provides that
FDA will exempt a manufacturer from the requirement to conduct a PER
assay where the manufacturer requests an exemption and provides
assurances that the change to an existing infant formula is limited to
changing the type of packaging for an existing formula.
    FDA also recognizes that not all changes to an infant formula have
the potential to affect the biological quality of the protein in the
formula. Accordingly, to provide flexibility in the interim final rule
for these types of circumstances, Sec.  106.96(g)(2) of the interim
final rule includes an additional exemption. FDA emphasizes that it is
the obligation of the manufacturer to establish that all the conditions
of the exemption are satisfied. Specifically, Sec.  106.96(g)(2) of the
interim final rule provides that a manufacturer may request an
exemption from the requirement to perform the PER assay if the
manufacturer demonstrates that a change made by the manufacturer to an
existing formula does not affect the quality or the bioavailability of
the protein.

G. Miscellaneous Comments on the Quality Factor for Sufficient
Biological Quality of Protein

    (Comment 263) In response to the 2003 reopening notice, one comment
stated that protein quality for infant formula is based on estimates,
extrapolations, and safety margins that have caused some products to
provide protein intakes to formula-fed babies at twice the rate of
breastfed infants. The comment stated that ``Heat-treated proteins have
lower digestibility with high amounts contributing to metabolic and
excretory stress in the infant.''
    (Response) This comment appears to raise issues related to the
quantity of protein in infant formulas rather than protein quality and
did not suggest changes to the proposed quality factor of protein
quality. The issue raised in this comment would be more appropriately
considered in any future revision of Sec.  107.100 and the maximum
protein levels for infant formulas, an issue that is outside the scope
of this interim final rule. Accordingly, no response to this comment is
required.

H. Application of Quality Factors to Currently Marketed and Previously
Marketed Formulas

    As noted in section VIII.C.1, in 1996, FDA proposed ``normal
physical

growth'' as a quality factor (proposed Sec.  106.96(b)) and proposed
requirements for the assurances for such quality factor (proposed Sec.
106.97(a)). At the same time, FDA proposed ``sufficient biological
quality'' of the formula's protein component as a second quality factor
(proposed Sec.  106.96(c)) and proposed requirements for the assurances
for this quality factor (proposed Sec.  106.97(b)). As proposed, the
quality factors described in proposed Sec.  106.96 and the assurance
provisions of proposed Sec.  106.97 would have applied to all infant
formulas distributed in U.S. commerce and not simply ``new infant
formulas.'' Subsequently, in the 2003 reopening, the Agency expressly
requested comment on the appropriateness of the two quality factors
proposed in 1996 (68 FR 22341 at 22342-22343).
    This interim final rule establishes two quality factors, the
quality factor of ``normal physical growth'' (Sec.  106.96(a) of the
interim final rule) and the quality factor of ``sufficient biological
quality of protein'' (Sec.  106.96(e)), and sets minimum requirements
for both quality factors (Sec.  106.96(b) and (f) of the interim final
rule, respectively). Under the interim final rule, for each quality
factor, the results of a single study, when conducted consistent with
the requirements of the interim final rule, are sufficient to establish
that the formula meets the quality factor. Thus, under the interim
final rule, a single study--a growth monitoring study conducted as
specified in Sec.  106.96(b) of the interim final rule--is sufficient
to demonstrate that an infant formula supports normal physical growth.
Similarly, a single study--a protein efficiency ratio (PER) study
conducted as specified in Sec.  106.96(f) of the interim final rule--is
sufficient to establish that a formula's protein component is of
sufficient biological quality.
    Like the proposed rule, the quality factors set forth in the
provisions of Sec.  106.96(a) and (e) of the interim final rule apply
to all infant formulas distributed in interstate commerce. This means
that a ``not new'' infant formula (i.e., an infant formula that
previously was the subject of a new infant formula submission made
under section 412(c)(1) of the FD&C Act) must satisfy the two quality
factors established by this interim final rule. These ``not new''
infant formulas may be formulas that are not currently distributed as
well as formulas that are currently distributed in the United States.
Any formula, including a ``not new'' formula, that does not satisfy the
quality factor requirements established under section 412(b)(1) of the
FD&C Act is deemed adulterated under section 412(a)(2) of the FD&C Act.
    As discussed in the introduction of this document, the 1986
amendments mandated that FDA establish by regulation requirements for
quality factors for infant formula. Section 412(b)(1) of the FD&C Act,
the quality factor requirements provision, is not self-executing and
thus, there have been no enforceable quality factor requirements
pending the issuance of this interim final rule. Prior to and since the
1986 amendments, a variety of infant formula products have been
distributed in the United States. Consistent with section 412(c) and
(d) of the FD&C Act, manufacturers of these products have been required
to notify FDA of their intent to market these infant formulas and to
make a new infant formula submission, and they have done so. In the
absence of implementing regulations, however, these notifications were
not required to provide assurances that the formula meets any quality
factor requirements.
    Nevertheless, many notifications made after publication of the 1996
proposed rule have included information about the ability of the infant
formula that is the subject of the notification to support normal
physical growth and about the protein quality. Several submissions have
included growth information on the formula, some of which was derived
from growth studies that conform, more or less, to the provisions in
proposed Sec.  106.97(a). Some submissions have also included evidence
on the biological quality of the formula's protein component. Over this
same period, as manufacturers have brought to market new products
containing new ingredients, they have often stopped distributing
previous versions of the newer products. Thus, there is an existing
body of data and information, both published and unpublished, on many
currently marketed and previously marketed formulas that may be
relevant to whether such formulas support normal physical growth and
whether the protein component of each such formula is of sufficient
biological quality.
    FDA evaluated the data and information available to the Agency that
is relevant to whether currently marketed infant formulas meet the two
quality factors established by the interim final rule. This information
includes material submitted to FDA and also published studies. The
Agency recognizes, however, that formula manufacturers may have
information on their products in addition to that available to FDA.
Importantly, none of the available evidence suggests that any currently
marketed infant formula fails to support normal physical growth or uses
a protein component that lacks sufficient biological quality. By the
same token, however, the available scientific record evaluated by FDA
did not include sufficient information to document that all currently
marketed infant formulas meet the quality factors of normal physical
growth and are composed of a protein of sufficient biological quality.
    Although the data and information available to FDA may not be
sufficient to demonstrate that every currently marketed formula meets
the two quality factors, the Agency acknowledges that removal of infant
formula from the market, based on limitations in the data and
information that is available to FDA to date, would likely be very
disruptive. Therefore, the Agency has developed separate provisions and
an orderly process for these formulas to transition to the newly
established requirements. There are two reasons that an orderly process
that minimizes disruption in the marketplace is essential for a product
like infant formula.
    First, as noted previously in this document, for many infants,
infant formula is the sole source or the primary source of nutrition in
the critical early months of growth and development, and formula often
continues to be an integral part of the diet of many infants through 12
months of age. Indeed, based on the CDC's study of breastfeeding rates
in the U.S., in 2010, one quarter of U.S. infants were formula-fed from
birth (approximately 1,027,000 infants) and by three months of age,
two-thirds of U.S. infants (approximately 2,700,000 infants) relied on
formula for some portion of their nutrition (http://www.cdc.gov/breastfeeding/data/reportcard.htm) (Ref. 82). Thus, it is essential
that an adequate supply of formula be maintained as infant formula
products transition to compliance with the requirements established by
the interim final rule.
    Disruption in the infant formula supply in the United States could
be especially problematic for the USDA's Special Supplemental Nutrition
Program for Woman, Infants, and Children (WIC). More than half of the
infant formula fed to U.S. infants is purchased through the WIC
program. This program provides Federal grants to states for
supplemental foods, health care referrals, and nutrition education to
low-income pregnant, breastfeeding, and non-breastfeeding postpartum
women, and to infants and children up to age five who are at
nutritional risk. Under the current WIC program, each state contracts
with a single formula

manufacturer to provide formula to the WIC participants in the state.
Although it is possible for a state to change its contractual
arrangements, it is nevertheless important to avoid market disruptions
that could have an impact on the availability of formulas distributed
through the WIC program.
    Second, maintaining sufficient availability of a variety of infant
formulas in the marketplace during this transition period is important.
Although all infant formula products must satisfy the nutrient
requirements of FDA's regulations in Sec.  107.100, these products
differ in their overall composition; such differences are not only in a
formula's protein source (cow milk protein or soy protein isolate) but
extend to other ingredients and components. The variations in formula
products may not be equally tolerated by every infant and, thus,
different infant formulas may not be interchangeable. For this reason,
pediatricians generally recommend that parents of a formula-fed infant
identify a single formula that their infant can tolerate and feed that
formula to their child. Thus, it is also important to maintain a
consistent supply of a variety of formula products.
    As noted, there is a considerable body of evidence relevant to
whether currently marketed and previously marketed infant formulas are
likely to satisfy the quality factors established by the interim final
rule. These data and information consist of a variety of different
studies and sources of information. The studies may not, strictly
speaking, fulfill the detailed requirements of the interim final rule
in that, for example, there is not likely to be a single growth
monitoring study that satisfies all of the requirements of Sec.
106.96(b) of the interim final rule. Importantly, however, this
existing body of evidence, when viewed collectively, may show that a
particular infant formula supports normal physical growth. FDA further
recognizes that if these existing data and this existing information
were not considered in assessing currently marketed and previously
marketed formulas, it would likely be necessary for formula
manufacturers to conduct new growth monitoring studies on such
formulas, which would require infant study subjects to be exposed to
the risks, however small, of the study protocol. In contrast,
considering the existing clinical evidence to assess whether a
currently marketed or previously marketed formula supports normal
physical growth may avoid exposing infants to these additional risks.
    Going forward, infant formula manufacturers will be aware of the
interim final rule's requirement for a growth monitoring study and the
design characteristics required for such a study. Thus, the Agency
fully expects that, in the future, the data and information used by a
manufacturer to demonstrate that a new infant formula supports normal
physical growth will conform to the specific requirements of Sec.
106.96(b) of the interim final rule unless the formula qualifies for an
exemption under Sec.  106.96(c) of the interim final rule.
    To minimize market disruption and its potential public health
impact, and to limit the exposure of infants to the risks of additional
clinical studies while ensuring that a formula meets the quality
factors established in this interim final rule, the interim final rule
includes specific provisions that apply to certain currently marketed
and previously marketed formulas. The interim final rule designates
these formulas as ``eligible'' infant formulas.
    The following discussion explains Sec.  106.96(i) of the interim
final rule and specifically addresses: (1) Which formulas are covered
by these provisions (2) the applicable standard for each quality factor
and its basis, (3) the voluntary petition process and the outcome of a
manufacturer's participation in the petition process, (4) records
maintenance requirements, (5) the consequences of engaging or not
engaging in the voluntary petition process, and (6) compliance dates.
    The provisions of Sec.  106.96(i) of the interim final rule apply
to any infant formula that satisfies the definition of ``eligible
infant formula.'' An ``eligible infant formula'' is defined in Sec.
106.3 of the interim final rule as an infant formula that ``could have
been or was lawfully distributed in the United States on May 12, 2014.
Thus, any formula that has been the subject of a properly submitted
infant formula notification under section 412(c) of the FD&C Act at
least 1 day before the publication date of the interim final rule is
eligible to utilize the provisions in Sec.  106.96(i) of the interim
final rule.
    All infant formulas, including eligible infant formulas, must
satisfy the two quality factors established by the interim final rule,
normal physical growth and sufficient biological quality of the protein
component of the formula. Section 106.96(i) of the interim final rule
establishes quality factor requirements for eligible infant formulas.
Although the requirements of Sec.  106.96(i) of the interim final rule
are somewhat more flexible than the interim final rule's quality factor
requirements for infant formulas that are not ``eligible'' infant
formulas, these requirements are substantial. In particular, each of
the three alternative means of demonstrating quality factor
satisfaction mandates that scientific evidence be used to demonstrate
that the formula meets the quality factors. Moreover, under Sec.
106.96(i)(4) of the interim final rule, the manufacturer of each
eligible infant formula is required to make and retain records to
substantiate the view that the formula meets the quality factors, and
such records must contain all relevant scientific data and information
relied upon by the manufacturer for such substantiation as well as a
narrative explanation of the manufacturer's conclusion.
    It is reasonable to extend the provisions in Sec.  106.96(i) and
its more flexible standards to formulas that are lawfully marketed by
the 89th day after the publication date of this interim final rule
because these are the formulas currently fulfilling the needs of
formula-fed infants. Establishing a mechanism to facilitate their
continued availability and thus, to minimize disruptions in the
availability of this essential source of infant nutrition, is
imperative. It is also sound to extend these provisions only to those
formulas that may be lawfully marketed by the 89th day after the
publication of this interim final rule. With the publication of this
interim final rule, infant formula manufacturers are now fully aware of
the standards that its products must satisfy and thereby, are
positioned to develop the required data and information for any new
infant formula that is the subject of a submission under section 412(c)
of the FD&C Act, including information that satisfies Sec.  106.96(b)
and (f) of the interim final rule. By comparison, a manufacturer of an
eligible infant formula could not reasonably have been expected to
develop the data and information to fulfill the specific requirements
of Sec.  106.96(b) and (f) of the interim final rule.
    Section 106.96(i)(1) of the interim final rule addresses the
quality factor of normal physical growth. Under this provision, an
``eligible infant formula'' that fulfills one or more of three criteria
meets the quality factor of normal physical growth. FDA recognizes that
there may be one or more eligible infant formulas for which no growth
monitoring studies may have been conducted. In such circumstances, FDA
recommends that the manufacturer conduct a growth monitoring study and
may choose to design and conduct the study in conformity with the
primary quality factor requirements of the interim final rule in Sec.
106.96(b). Thus, Sec.  106.96(i)(1)(i) of the interim final rule

provides that an eligible infant formula meets the quality factor of
normal physical growth if the scientific evidence on such formula
fulfills the requirements of Sec.  106.96(b) of the interim final rule.
Similarly, a manufacturer who previously chose to develop evidence of a
formula's ability to support normal physical growth may have, quite
reasonably, chosen to conduct a growth monitoring study, the design of
which conformed to the provisions proposed in 1996 as those proposed
provisions represented FDA's then-best judgment about the design and
conduct of a growth monitoring study. To provide for these
circumstances, the Agency has set forth in Sec.  106.96(i)(1)(ii) of
the interim final rule the requirements for a growth monitoring study
that were proposed in 1996, and Sec.  106.96(i)(1)(ii) of the interim
final rule states that an eligible infant formula meets the quality
factor of normal physical growth if the scientific evidence on such
formula meets the provisions of that paragraph. The growth charts that
the 1996 proposed rule stated should be used for plotting growth data
are incorporated by reference under Sec.  106.160 of the interim final
rule. Finally, there may be some eligible infant formulas for which
there is no single growth study satisfying Sec.  106.96(i)(1)(i) or
(i)(1)(ii) of the interim final rule but for which there is a body of
scientific evidence drawn from multiple sources that, taken as a whole,
demonstrates that the formula supports normal physical growth. Thus,
Sec.  106.96(i)(1)(iii) of the interim final rule provides that an
eligible infant formula meets the quality factor of normal physical
growth if the scientific evidence on such formula otherwise
demonstrates that the formula supports normal physical growth. This
third option will require FDA to exercise its scientific judgment about
the data and other information and whether that evidence demonstrates
that the formula supports normal physical growth.
    Section 106.96(i)(2) of the interim final rule addresses the
quality factor of sufficient biological quality of a formula's protein
component. Under this provision, an ``eligible infant formula'' that
fulfills one or more of three criteria meets the quality factor of
sufficient biological quality of the protein component. FDA recognizes
that there may be eligible infant formulas for which a protein
efficiency ratio (PER) study was not conducted. The manufacturer may
choose to conduct a PER study as specified in Sec.  106.96(f) of the
interim final rule. Thus, Sec.  106.96(i)(2)(i) of the interim final
rule provides that an eligible infant formula satisfies the quality
factor of sufficient biological quality of the protein component if the
scientific evidence on such formula fulfills the requirements of Sec.
106.96(f) of the interim final rule. Similarly, a manufacturer who
previously chose to develop evidence of the sufficient biological
quality of a formula's protein component may have, quite reasonably,
chosen to conduct a PER study according to the proposed rule's
provisions. To provide for these circumstances, the Agency has set
forth in Sec.  106.96(i)(2)(ii) of the interim final rule the
requirements for establishing sufficient biological quality of a
formula's protein component that were proposed in 1996, and Sec.
106.96(i)(2)(ii) of the interim final rule states that an eligible
infant formula meets the quality factor of sufficient biological
quality of the protein component if the scientific evidence on such
formula meets the provisions of that paragraph. The official method of
analysis of AOAC to conduct a PER study that was proposed in the 1996
proposed rule is incorporated by reference in Sec.  106.160 of the
interim final rule. Finally, there are some eligible infant formulas
for which there may be a body of scientific evidence drawn from
multiple sources that, taken collectively, demonstrates that the
formula's protein component is of sufficient biological quality. Thus,
Sec.  106.96(i)(2)(iii) of the interim final rule provides that an
eligible infant formula satisfies the quality factor of sufficient
biological quality of the protein component if the scientific evidence
on such formula otherwise demonstrates that the protein component of
the formula has sufficient biological quality. Like Sec.
106.96(i)(1)(iii) of the interim final rule, this third option will
require FDA to exercise its scientific judgment about the data and
other information and whether that evidence demonstrates that the
protein component of the formula is of sufficient biological quality.
    An infant formula, including a ``not new'' infant formula, that
does not comply with established quality factor requirements is deemed
adulterated under section 412(a)(2) of the FD&C Act. As an adulterated
food, this formula is subject to seizure, condemnation, and forfeiture
under section 304 of the FD&C Act. Similarly, those who ship the
formula in interstate commerce, cause its interstate shipment, or
commit another prohibited act related to an adulterated food may be
enjoined under sections 301 and 302 of the FD&C Act.
    FDA recognizes that to facilitate marketing and distribution plans,
a manufacturer of an eligible infant formula may wish to understand the
Agency's assessment of the quality factor evidence for that formula. To
permit the manufacturer of an eligible infant formula to be aware of
FDA's view of the manufacturer's determination that their formula meets
the quality factor requirements of Sec.  106.96 of the interim final
rule prior to the compliance date for meeting the requirements under
106.96(i), Sec.  106.96(i)(3) of the interim final rule includes a
time-limited petition process that allows a manufacturer to submit a
citizen petition to FDA that contains scientific data and information
to demonstrate that an eligible formula supports normal physical
growth, that the formula's protein component is of sufficient
biological quality, or both. FDA emphasizes that although participation
in the petition process established by Sec.  106.96(i)(3) of the
interim final rule is voluntary, satisfying the two quality factor
requirements of the interim final rule is required of all infant
formulas distributed in interstate commerce. The Agency encourages any
manufacturer planning to file a petition under Sec.  106.96(i)(3) of
the interim final rule to contact FDA to discuss any questions.
    The procedure in Sec.  106.96(i)(3) of the interim final rule uses
the FDA citizen petition process in 21 CFR 10.30, and allows such a
petition for an eligible formula to be submitted untilNovember 12,
2015. Although there is likely to be some existing scientific evidence
relating to quality factor status of many eligible formulas, some
manufacturers may need to design, conduct, and analyze the results of a
growth monitoring study before they can make a submission to FDA
through the voluntary petition process. Because the Agency recognizes
that one or more manufacturers of eligible infant formulas may need to
design, conduct, and analyze the results of a growth monitoring study
to develop evidence of the formula's ability to support normal physical
growth, the interim final rule establishes a separate compliance date
for certain quality factor provisions that apply to eligible infant
formulas. Specifically, Sec. Sec.  106.96(a), 106.96(e), 106.96(i)(5),
106.100(p)(2) and 106.100(q)(2) of the interim final rule are binding
as of November 12, 2015. This means that eligible infant formulas must
meet the quality factors, and keep records demonstrating that they meet
the quality factors, as of November 12, 2015. Postponing the compliance
date for these provisions for eligible infant formulas, combined with
the same nearly 2-year period to submit a

voluntary petition will provide manufacturers of eligible infant
formulas with sufficient time to develop the required data and
information to demonstrate that their products meet the quality
factors, and to submit such data and information to FDA through the
voluntary petition process.
    FDA notes that under current Agency regulations and practice, a
response to a citizen petition is publicly available and is routinely
posted on the Agency's Web site. The Agency intends to follow this
practice for infant formula quality factor citizen petitions and FDA's
responses to such petitions by establishing a Web page dedicated to
such petitions and responses. This practice will allow the public,
including competitors, purchasers for retailer stores, and individual
consumers, to know whether the manufacturer of an eligible infant
formula product has availed itself of the opportunity to demonstrate
that the formula meets the quality factors of normal physical growth
and sufficient quality of the protein and to be informed of FDA's
response to such submission.
    The petition process in Sec.  106.96(i)(3) of the interim final
rule is a voluntary process, one that will provide FDA with access to
important information relating to eligible infant formulas. For infant
formula manufacturers and other interested parties, this process has
the advantage of clarity and certainty in terms of whether FDA views a
formula to be in compliance with the relevant quality factor
requirements. Likewise, infant formula purchasers at all levels of the
supply chain will indirectly benefit from this process because they
will have access to scientific evidence and other information on the
quality factor status of eligible infant formulas as well as FDA's view
of that evidence.
    Accordingly, under Sec.  106.96(i)(3) of the interim final rule,
the manufacturer of an eligible infant formula may, not later than
November 12, 2015, submit a citizen petition to FDA under 21 CFR 10.30
that such formula fulfills one or more of the criteria in Sec.
106.96(i)(1) of the interim final rule relating to the quality factor
of normal physical growth, one or more of the criteria in Sec.
106.96(i)(2) of the interim final rule relating to the quality factor
of sufficient biological quality of the protein component, or both.
Consistent with the citizen petition regulation, Sec.  10.30(a), a
petition filed under Sec.  106.96(i)(3) of the interim final rule must
contain all data and information relied upon by the manufacturer to
demonstrate that the formula fulfills one or more of the quality factor
requirements in Sec.  106.96(i)(1) or (i)(2) of the interim final rule.
Also, to help enhance the clarity and focus of these quality factor
petitions, Sec.  106.96(i)(4) of the interim final rule provides that
each such petition shall address only a single infant formula
formulation. Importantly, however, a single petition may address both
Sec.  106.96(i)(3)(i) and (i)(3)(ii) of the interim final rule for the
same formulation.
    Additionally, as noted previously in this document, the
manufacturer of an infant formula, including an eligible infant
formula, is responsible for ensuring that the formula meets the two
quality factors established by the interim final rule. Regardless of
whether the formula is a new infant formula or a ``not new'' formula,
it is reasonable to expect the manufacturer to have scientific data and
information demonstrating that the quality factors are met because only
with such data and information can a manufacturer make an informed
decision to market and lawfully distribute a particular formula. Given
this responsibility and the means reasonably required to fulfill that
responsibility, an infant formula manufacturer must necessarily
establish and maintain records documenting that each eligible formula
meets the two quality factors. As noted, the provisions of the interim
final rule in Sec.  106.96(i) recognize this need for records of the
quality factor evidence for eligible infant formulas. Specifically,
Sec.  106.96(i)(5) of the interim final rule requires the manufacturer
of each eligible infant formula to make and retain records to
demonstrate that such formula supports normal physical growth in
infants when fed as the sole source of nutrition and to demonstrate
that the protein in such infant formula is of sufficient biological
quality. The records established under Sec.  106.96(i)(5) of the
interim final rule must contain all relevant scientific data and
information as well as a narrative explanation of why the data and
information demonstrate that the formula meets the two quality factors
established by the interim final rule. The requirement for a narrative
explanation is a logical extension of the responsibility for ensuring
that a formula meets the quality factors because without analyzing and
summarizing the relevant data and information, a manufacturer has
little or no basis to conclude that a particular formula supports
normal physical growth or that it contains protein of sufficient
biological quality. Additionally, this record requirement is
reasonable, because without records, FDA has no way of determining
whether a formula meets the quality factor requirements established
under section 412(b)(1) of the FD&C Act. As noted in sections III and
VIII.A, section 701(a) of the FD&C Act authorizes FDA to issue
regulations for the efficient enforcement of the FD&C Act in order to
effectuate an objective stated elsewhere in the FD&C Act. Thus, under
sections 701(a) and 412(b)(1) of the FD&C Act, FDA has the authority to
require a manufacturer of an eligible formula to maintain records
demonstrating that their formula meets the quality factor requirements
that apply to such formula. FDA emphasizes that this record-keeping
provision for quality factor data and information required by Sec.
106.96(i)(5) of the interim final rule applies to all eligible infant
formulas that a manufacturer distributes or intends to distribute in
interstate commerce and not simply to eligible formulas that are the
subject of a petition under Sec.  106.96(i)(3) of the interim final
rule.
    Although there are several distinct advantages to a manufacturer of
an eligible infant formula that submits a petition to FDA under Sec.
106.96(i)(3) of the interim final rule, the Agency recognizes that some
manufacturers of eligible formulas may choose not to submit such a
petition. Where no petition is submitted for an eligible infant
formula, FDA intends to conduct an inspection of the formula's
manufacturer and to review and evaluate the records for the formula
that are required under Sec.  106.96(i)(5) of the interim final rule.
If the data and information or the narrative explanation in the records
made and retained under Sec.  106.96(i)(5) of the interim final rule do
not demonstrate that the formula supports normal physical growth and
that the protein in such infant formula is of sufficient biological
quality, FDA will consider the formula to be adulterated under section
412(a)(2) of the FD&C Act and will pursue the Agency's customary
regulatory process, which may include official communication with the
firm such as a Warning Letter followed by appropriate legal remedies.
    FDA received several comments related to the issue of currently
marketed and previously marketed formulas. The Agency responds to these
comments in this document.
    (Comment 264) One comment stated that it did not believe that it is
FDA's intent to require all infant formulas currently on the market in
the United States to undergo the study required by proposed Sec.
106.97(a) and if this is the Agency's intent, the comment strongly
objects to this requirement as unnecessarily burdensome and without
cause.

    (Response) The commenter's statement of FDA's intent is not
correct. As discussed previously in this document, all currently
marketed formulas must be shown to meet the two quality factors
established by the interim final rule. The Agency's intent was clear in
that the 1996 proposed rule established quality factors for ``infant
formulas'' and did not describe any subset that would not be covered by
the requirements set forth in this interim final rule. Section
412(a)(2) of the FD&C Act states that infant formulas that do not meet
the quality factor requirements are deemed adulterated. Significantly,
this adulteration provision applies to all infant formulas (not just
``new infant formulas''). Thus, all infant formulas must meet the
quality factors established in this interim final rule. However, as
discussed in detail previously in this document, the interim final rule
includes in Sec.  106.96(i) specific quality factor requirements for a
formula that meets the definition of ``eligible infant formula.''
    (Comment 265) One comment noted that not all infant formula
products currently marketed in the United States have undergone a
clinical study as described in proposed Sec.  106.97(a). The comment
asserted that there is no reason to believe these currently marketed
products do not support normal physical growth and suggested that
proposed Sec.  106.97(a)(2)(i) be revised to reduce unnecessary
clinical studies, particularly where currently marketed formulas that
have not been the subject of a growth monitoring study have undergone
small changes in formulation or processing. The comment stated that if
proposed Sec.  106.97(a)(2)(i) is not changed, it may pose an
``unresolvable'' dilemma in the case of future modifications of some
currently marketed infant formulas.
    (Response) The comment did not provide data or other information to
explain the basis for its assertion that ``there is no reason to
believe these currently marketed products do not support ``normal
physical growth.'' FDA is a science-based Agency, and as such, must
rely on valid data and other sound scientific information to draw
conclusions about product safety, including the safety and nutritional
sufficiency of infant formula.
    FDA disagrees that the expectation that all currently marketed
formulas be demonstrated with valid scientific evidence to satisfy the
quality factor of normal physical growth will result in an
``unresolvable'' dilemma. The interim final rule provides specific
provisions for manufacturers of eligible infant formulas to demonstrate
that their products meet the quality factors of normal physical growth
and sufficiency biological quality of the protein component, and Sec.
106.96(i) of the interim final rule clearly contemplates that
previously conducted growth studies, as well as other scientific data
and information, may be used to demonstrate satisfaction of these
quality factors. FDA believes that the opportunity to utilize existing
data is certain to reduce the likelihood of requiring unnecessary
growth monitoring studies.
    Requirements to assure that quality factors have been met in the
case of small changes to formulations is discussed under Comment 256
regarding submissions made under section 412(d)(3) of the FD&C Act.
    (Comment 266) Another comment stated that the Agency has no way of
being assured that an infant formula that may have been marketed at
some time in the past, but which is not currently on the market, would
meet quality factor requirements. Therefore, the comment asserts, if a
manufacturer wanted to reintroduce such a formula into the market, the
manufacturer would need to submit a new infant formula notification.
    (Response) If a formula manufacturer wishes to reintroduce a
formula into the market place, the reintroduced formula would need to
meet the quality factors of normal physical growth and sufficient
biological quality of the protein component. The mechanism in Sec.
106.96(i) of the interim final rule contemplates this situation and
establishes quality factor requirements for eligible infant formulas,
which include certain previously marketed formulas. In addition, under
Sec.  106.96(i)(5) of the interim final rule, the manufacturer of an
eligible infant formula, including a previously marketed formula that
is reintroduced, is required to make and retain records that
demonstrate that such formula meets the two quality factors. FDA
disagrees, however, that a reintroduced formula must necessarily be the
subject of a new infant formula submission because the requirement to
make such a submission applies only to a formula that is a ``new infant
formula'' as defined by section 412(c) of the FD&C Act and Sec.  106.3
of the interim final rule. If a previously marketed formula is altered
such that the formula would be classified as a ``new infant formula,''
such formula would need to be the subject of a new infant formula
submission, and would not be eligible to meet the quality factors under
Sec.  106.96(i) of the interim final rule.
    (Comment 267) One comment requested that FDA confirm that the
protein quality factor pertains only to new situations that arise after
the effective date of the quality factor requirements. The comment
argued that this is reasonable because the assurance of quality factors
of all currently marketed formulas has been provided by the good health
of infants that have been raised on those formulas over the years.
    (Response) Under section 412(b)(1) of the FD&C Act, quality factor
requirements apply to all infant formulas; not only new infant
formulas. As such, currently marketed formulas must meet the quality
factors under this interim final rule, including the quality factor of
sufficient biological quality of protein. However, as is explained
previously in this document, currently marketed formulas that are
``eligible formulas'' under Sec.  106.96(i) of the interim final rule
have some flexibility in terms of how satisfaction of the two quality
factors may be demonstrated.

I. Records Demonstrating Compliance With the Quality Factor
Requirements for Infant Formulas That Are Not Eligible Infant Formulas

    For consistency with other records requirements, FDA is adding a
provision in the interim final rule (Sec.  106.96(d)) that requires a
manufacturer of a new infant formula that is not an eligible infant
formula to make and retain certain records demonstrating that such
formula meets the quality factor of normal physical growth. Likewise,
FDA is adding a provision in the interim final rule (Sec.  106.96(h))
that requires a manufacturer of a new infant formula that is not an
eligible infant formula to make and retain certain records
demonstrating that the formula meets the quality factor of sufficient
biological quality of protein. As noted previously in this document in
section VIII.A, it is reasonable and necessary for the efficient
enforcement of the FD&C Act for FDA to require a manufacturer of infant
formula to make and retain records demonstrating that the formula
satisfies the quality factors requirements. These records may assist
FDA in determining whether an infant formula meets the quality factor
requirements.
    As is discussed further in section IX.F, in order to comply with
this records requirement, a manufacturer of a new formula that is not
an eligible infant formula will be required to make and retain records
demonstrating compliance with the growth monitoring study requirements
under Sec.  106.96(b) of the interim final rule, or make and

retain records demonstrating satisfaction of an applicable exemption
under section Sec.  106.96(c) of the interim final rule.
    In the proposed rule, proposed Sec.  106.97(a)(i)(B) would have
required a manufacturer to collect and maintain, in the growth study,
anthropometric measures of physical growth. This interim final rule
expands and clarifies this collection and maintenance requirement, to
require that a manufacturer make and retain records demonstrating
compliance with the growth monitoring study requirements under Sec.
106.96(b) of the interim final rule, or in the alternative, records
demonstrating satisfaction of an applicable exemption under section
Sec.  106.96(c) of the interim final rule.
    Likewise, the interim final rule includes a provision (Sec.
106.96(h)) that requires a manufacturer of a new infant formula to make
and retain certain records demonstrating that the formula meets the
quality factor of sufficient biological quality of protein. With
respect to the quality factor of sufficient biological quality of
protein, the proposed rule would have required a manufacturer of an
infant formula to collect and maintain data establishing that the
biological quality of protein in the infant formulas is sufficient to
meet the protein requirements of infants proposed Sec.  106.97(b)(1) .
As is discussed in further detail in section IX.F, this interim final
rule clarifies that the requirement to make and retain records
demonstrating that the formula has sufficient biological quality of
protein includes, when applicable, records demonstrating satisfaction
of an applicable exemption under Sec.  106.96(g) of the interim final
rule. If the formula manufacturer is not seeking an exemption from the
requirements of Sec.  106.96(f) of the interim final rule, the formula
manufacturer would need to make and retain records demonstrating
compliance with the requirements under Sec.  106.96(f) of the interim
final rule.

J. Establishment of Other Quality Factors

1. General Comments
    Several comments agreed with FDA's tentative conclusion in the 2003
reopening notice that the quality factors of normal physical growth and
protein biological quality are sufficient at this time for assessing
the bioavailability of nutrients in an infant formula and that the
physical growth and protein quality would be considered reasonable
benchmarks, presuming the infant formula contains all nutrients
required by section 412 of the FD&C Act. Other comments recommended
that the Agency identify additional quality factors and establish
requirements for such factors.
    (Comment 268) One comment expressed concern about the Agency's
suggestion in the 1996 proposal (61 FR 36154 at 36181) that additional
quality factors may be identified on a case-by-case basis for specific
formula products, stating that this would create difficulties for
manufacturers without more explicit guidance as to what is required.
    (Response) FDA is not including in the interim final rule
requirements for quality factors other than those for normal physical
growth and biological quality of the protein. The Agency notes that, in
the future, it may propose requirements for additional quality factors
for infant formula, or nutrients in such formula, in general or for
specific types of formula or for specific nutrients. However, any
additional quality factors requirements will be established in a future
rulemaking or FDA will make recommendations in a future guidance
established under FDA's GGPs (21 CFR 10.115). Both of these processes
would include prior notice and the opportunity for public
participation.
    (Comment 269) One comment stated that, due to the increasing
complexity of infant formula ingredients, benchmarks such as growth and
protein quality do not evaluate the effect of new ingredients, such as
long-chain polyunsaturated fatty acids and probiotic microorganisms or
other complex ingredients. The comment suggested that instead, FDA
evaluate overall nutrient quality and availability, targeted vitamins,
minerals, and macronutrients.
    (Response) The quality factors of normal physical growth and
sufficient biological protein quality are necessary to demonstrate that
the required nutritional components of infant formula are bioavailable,
in order to help ensure that the formula supports healthy growth.
Evaluation of normal physical growth by a well-controlled growth
monitoring study and evaluation of the biological quality of the
protein by PER rat bioassay are not intended to, and do not, evaluate
other purported effects of new ingredients (e.g., effects of long-chain
polyunsaturated fatty acids on visual development or effects of
probiotic microorganisms on gut flora). Thus, the suggestion of this
comment is beyond the scope of this interim final rule.
2. Quality Factors for Fat, Calcium, and Phosphorus
    In the 1996 proposal (61 FR 36154 at 36182), FDA stated ``because
of the potential seriousness of the public health impact of not meeting
quality factors, FDA also believes that it is desirable to establish
additional quality factors, as soon as they are warranted by evolving
scientific knowledge, to ensure adequate nutrient bioavailability.''
The Agency notes that the CON/AAP Task Force (Ref. 67) recommended
metabolic balance studies to determine whether a formula meets quality
factors for fat, calcium, and phosphorus. FDA specifically requested
comment on whether the scientific evidence and usefulness of results
are sufficient to support establishing quality factor requirements for
nutrients other than protein, such as fat, calcium, and phosphorus, and
if so, what assurances should be established for such factors (61 FR
36154 at 36181). The Agency also requested comment on balance studies
or other methods that could be used to assess potential quality factor
requirements for these three nutrients. This opportunity was renewed
with the 2003 reopening of the comment period.
    Several comments responded to FDA's request for comment on whether
quality factor requirements should be established for fat, calcium, and
phosphorus.
    (Comment 270) One comment supported including quality factor
requirements for fat, calcium, and phosphorus in assessments of the
nutritional adequacy of formulas, and stated that manufacturers are
currently expected to include these measures in the clinical evaluation
of their formulas and the measurement of these quality factors should
not present difficulties to manufacturers or those involved in the
clinical study of infant formulas.
    (Response) FDA disagrees with this comment to the extent that it
asserts that manufacturers currently measure the bioavailability of
fat, calcium, and phosphorus in their clinical evaluations of infant
formulas. To date, FDA has not recommended that manufacturers include
metabolic balance studies to evaluate the adequacy of fat, calcium, and
phosphorus in new infant formulas. In fact, in the 1996 proposal, FDA
tentatively concluded that the clinical and nutritional sciences had
not reached a level of development such that specific tests were
available to establish that infant formulas could be demonstrated to
satisfy quality factors for each of the essential nutrients listed in
Sec.  107.100, except for protein. In particular, the Agency expressed

concern about the absence of meaningful measures for the assessment of
the bioavailability of calcium and phosphorus. At the same time, FDA
noted that studies of infant excretion of fat indicate that the fats in
formula are highly digestible, thus mitigating questions about fat
bioavailability. The comment did not provide any information to
contradict the Agency's tentative conclusion that quality factor
requirements should not be established for nutrients other than
protein. Accordingly, FDA declines to establish quality factor
requirements for fat, calcium, and phosphorus in this interim final
rule.
    (Comment 271) Some comments disagreed with FDA's statement in the
1996 proposal (61 FR 36154 at 36187) about the degree of technical
difficulty in performing fat balance studies, saying that metabolic
studies are difficult to perform well and are conducted at few research
centers (Ref. 67).
    (Response) FDA agrees in part with this comment. In the 1996
proposed rule, FDA stated that the current method for measuring fat
excretion is noninvasive, by which FDA meant that these studies
consisted of collecting feces and urine which are naturally excreted
from the body of infants. However, as noted in the comment, the
accurate collection of such specimens is technically very difficult
and, in some or all cases, would require hospitalization to ensure
accurate sampling and measurement. The limitations on such studies are
a second separate reason not to require metabolic balance studies of
infant formula.
    (Comment 272) With respect to fat balance studies, one comment
stated that the level of fat malabsorption that leads to clinical or
body composition effects is not well defined and may not be 15 percent
as stated in the 1996 proposal (61 FR 36154 at 36181). The comment
concluded that this factor adds to the limitations of fat balance
studies.
    (Response) FDA agrees with this comment that the level of fat
malabsorption that leads to clinical or body composition effects is not
well defined and that this fact would be a further limitation to fat
balance studies. The mean amount of fat not absorbed is approximately
15%, but the degree of malabsorption depends on the type of fat at
issue. One source shows that the range of fat excreted (Ref. 83,
pp.164-165) is between 0.66 to 9.3 percent of intake when vegetable
oils are the fat source in a milk-based infant formula, and that
infants excrete a higher proportion of fat when homogenized cow milk is
consumed; the latter level is related to the type of fat in cow milk
(butterfat), which young infants cannot readily digest because they
lack the necessary bile salts and enzyme. Thus, this comment supports
the Agency's decision not to establish quality factor requirements for
fat.
    (Comment 273) One comment opposed the establishment of quality
factor requirements for fat, calcium, and phosphorus because, the
comment asserted, the collection of formula intake and stool data by
untrained parents (which would be part of a metabolic balance study)
would result in extremely inaccurate data if studies were conducted on
term infants in the home.
    (Response) FDA agrees that the use of untrained parents to collect
study data is one very practical limitation of a balance study and
thus, is an additional reason to not identify, and establish
requirements for, quality factors for fat, calcium, and phosphorus at
this time.
    (Comment 274) Other comments noted that financial and, perhaps,
ethical difficulties may be associated with balance studies because
such studies may require hospitalization and restraint of infants. The
comment characterized hospitalization as ``invasive.''
    (Response) FDA does not agree with the comment that hospitalization
is conventionally considered ``invasive.'' However, the Agency agrees
that to ensure maximum accuracy in the collection of infant input and
output information in a balance study, it could be necessary to confine
the infant study subjects to a hospital and, in some cases, to restrain
the subjects. FDA agrees that these two possibilities are significant
negatives of establishing a quality factor for fat and requiring a
balance study of a new formulation of an infant formula to demonstrate
that the quality factor is satisfied.
    (Comment 275) Several comments suggested that fat, calcium, and
phosphorus balance studies should be performed on a voluntary basis
when the manufacturer believes they are necessary to assess specific
effects of a formula or ingredient.
    (Response) FDA does not disagree with this comment. To the extent
that a formula manufacturer believes that fat, calcium, or phosphorus
studies would be meaningful for evaluating a particular infant formula,
FDA would generally not object to the conduct of such a study.
Importantly, however, prior to conducting any such study, the
manufacturer should be certain that data from such study are necessary
and will be meaningful so as to avoid subjecting the infants study
subjects to unnecessary testing.
    (Comment 276) One comment stated that balance studies are more
useful for comparing formulas than for assessing adequacy of a
particular formula and suggested that the decision to include balance
studies should be made during development of a study protocol.
    (Response) FDA agrees with this comment to the extent that it
asserts that a balance study must be designed to answer the research
question at issue. However, the comment did not explain how adequacy of
a particular formula could be determined without comparing the test
formula to a control formula that has already been evaluated for
nutritional adequacy.
    Generally speaking, a balance study would be used to compare one
factor under investigation (e.g., the fat blend of a formula) while all
other factors are kept constant. Thus, in a study comparing the fat
blend of one formula to another, the study design would require that
the test and control formulas contain all the same nutrients except the
fat source, which would be different in the test and control formulas
(Refs. 83 and 84). As noted, however, FDA is affirming the Agency's
tentative 1996 decision that no metabolic balance studies will be
required of new formulations of infant formulas.
    Several comments addressed specific aspects of balance study design
and methodology.
    (Comment 277) One comment pointed out the desirability of using
comparable levels of minerals in both the test and control formulas
since mineral retention in balance studies tends to become more
positive with higher intakes.
    (Response) FDA agrees that mineral retention in balance studies
tends to become more positive with higher intakes and that, when
conducting a balance study, it is desirable to use comparable levels of
minerals in test and control formulas to reduce the potential for
confounding, which could result in misinterpretation of study results.
As noted, however, FDA is affirming the Agency's tentative 1996
decision that no balance studies will be required of new formulations
of infant formulas.
    (Comment 278) One comment asserted that serum alkaline phosphatase
determination would be of no value in calcium and phosphorus balance
studies as the time course of its response is slower than the brief
period of a balance study and there are age specific, gestational, and
nutrient effects that complicate its interpretation.
    (Response) FDA agrees with this comment that alkaline phosphatase

analysis in balance studies would be of limited value for the reasons
given. As noted, however, FDA is affirming the Agency's tentative 1996
decision that no balance studies will be required of new formulations
of infant formulas. Therefore, this comment has no bearing on the
interim final rule.
    (Comment 279) Another comment pointed out that preterm infants, who
have sometimes been used as subjects for balance studies, would not be
appropriate subjects for the studies of formulas for term infants.
    (Response) FDA agrees with this comment. Preterm infants would not
be appropriate participants for balance studies evaluating the
bioavailability of infant formulas intended for term infants because
each group has specific nutrient needs that are not identical. In
particular, preterm infants are at great risk for malnutrition and
require relatively greater amounts of energy, protein, calcium,
phosphorus, vitamin D, and vitamin A levels compared to the needs of
healthy term infants. Thus, extrapolation of data from preterm infants
to healthy term infants could result in erroneous conclusions about
necessary nutrients for healthy term infants. For a study of a formula
intended for use in term infants, the study population must be composed
of such infants. Because the Agency has confirmed its 1996 tentative
decision not to require balance studies of infant formula, however, no
change in the interim final rule is required in response to this
comment.
    (Comment 280) One comment indicated that sensitivity of balance
studies is greater with a crossover design (Ref. 67). Another comment
pointed out that crossover design would subject an infant to a longer
period of confinement and restraint and considered this unwarranted for
routine testing of all products.
    (Response) FDA agrees that a crossover design could be used in a
balance study to increase the power of a study using a small study
population because each participant would serve as his or her own
control. Importantly, however, balance studies require that the infant
be confined to a hospital for 72 hours for each study period,
immobilized in a ``papoose-like'' devise that permits all urine and
feces to be continuously collected. Given these necessary conditions of
a balance study, this type of study should only be performed when
absolutely necessary because of its extremely restrictive nature (Ref.
85). Given the lack of sound methods for measuring essential nutrients
and the lack of predictive outcomes from many of these of studies, FDA
has determined that balance studies should not be required by this
interim final rule for any nutrient in infant formula.
    Several comments addressed the use of methods other than balance
studies to evaluate bioavailability of total fat, calcium, and
phosphorus.
    (Comment 281) One comment concurred with FDA's tentative conclusion
in the 1996 proposal that there is no current practical and generally
accepted alternative to balance studies for assessing bioavailability
of these nutrients (61 FR 36154 at 36188). However, the comment noted
that newer measures of assessing bone mineralization directly hold
considerable promise for evaluating these nutrients in infant formulas,
suggesting that these methods could be useful when they become more
standardized and more normative data become available for infants.
    (Response) FDA agrees with this comment that, at the time of the
1996 proposal, new means of assessing bone mineralization directly,
such as dual-energy x-ray absorptiometry (DEXA) scans, appeared
promising. However, DEXA has not achieved sufficient reliability to be
considered a ``gold standard'' for body composition of infants and is
currently confined largely to use as a research tool. The Agency has
considered the data presented at the 2002 meeting of the FAC, as well
as recent studies (Refs. 86 and 87), and finds no basis to require DEXA
scans in growth monitoring studies. Accordingly, the Agency is not
persuaded at this time to add tests using these methods as a
requirement to demonstrate the bioavailability of an infant formula or
of calcium and phosphorus in infant formulas.
    (Comment 282) One comment stated that, when alterations in fat
source or composition are proposed, the manufacturer should be required
to demonstrate that study subjects' serum fatty acid levels are
comparable to those of breast-fed infants or infants fed other standard
infant formulas.
    (Response) FDA does not agree with this comment. The comment
provided no evidence or reasoning to support the recommendation that
the evaluation of serum fatty acid levels of infants consuming a new
infant formula formulation should be required to be measured and
determined to be equivalent to infants that are breast-fed or are
consuming a standard infant formula. Moreover, FDA is aware of no
scientific evidence that suggests that measurement of serum fatty acids
would be a means to assessing the ability of an infant formula to
ensure healthy growth. Although measuring serum fatty acids reflects,
to some extent, an infant's diet, serum fatty acids are also influenced
by other factors such as timing of the blood draw in relation to
formula consumption and hormonal responses. Finally, the fatty acids in
circulation do not predict growth. The levels of some fatty acids can
be used to determine whether there are adequate levels of essential
fatty acids (linoleic and linolenic) but these circulating levels are
not directly related to normal physical growth.
    For the reasons discussed previously in this document, the Agency
is not establishing in this interim final rule requirements for quality
factors related to fat, calcium, or phosphorus.
3. Quality Factor for Iron
    In the 1996 proposal (61 FR 36154 at 36182 and 36189), FDA
requested comment on whether a quality factor for iron should be
established and what data would be needed to establish that the iron in
an infant formula is sufficiently bioavailable and maintains the iron
status of infants that consume the formula. The Agency observed that
the data on iron bioavailability would need to demonstrate that an
infant formula provides enough iron to prevent iron deficiency and
anemia. The Agency expressed concern, however, that a growth monitoring
study of full-term infants aged zero to four to five months might not
be sensitive enough to detect significant differences in iron
bioavailability of a formula product because healthy, full-term infants
are usually born with adequate iron stores to maintain normal iron
status for the first three to four months of life--the time when the
growth monitoring study would be conducted. Without assurance that the
test results would be meaningful, the Agency tentatively decided not to
establish quality factor requirements for iron.
    A number of comments supported the inclusion of a quality factor
for iron for infant formulas and supported establishing requirements
for such quality factor. Other comments objected to a general quality
factor for iron.
    (Comment 283) One comment stated that manufacturers are currently
expected to include these measures in the clinical evaluation of their
formulas and thus, it is not anticipated that measurements of this
quality factor should present difficulties to manufacturers or those
involved in the clinical study of infant formulas.
    (Response) FDA disagrees with this comment to the extent that it
asserts that manufacturers currently measure the bioavailability of
iron in their clinical

evaluations of infant formulas. To date, FDA has not recommended that
manufacturers include metabolic balance studies to evaluate the
adequacy of iron in new infant formulas. In fact, in the 1996 proposal,
FDA tentatively concluded that the clinical and nutritional sciences
had not reached a level of development such that specific tests were
available to establish that infant formulas could be demonstrated to
satisfy quality factors for each of the essential nutrients listed in
Sec.  107.100, except for protein (61 FR 36154 at 36182). This comment
did not provide any information to contradict the Agency's tentative
conclusion that quality factor requirements should not be established
for nutrients other than protein. Accordingly, FDA declines to
establish a quality factor for iron in this interim final rule.
    (Comment 284) Another comment regarded the failure to include a
quality standard for iron as a problem, noting that iron deficiency
would not be detected by anthropometric (weight) measurements used to
evaluate the normal physical growth quality factor.
    (Response) FDA disagrees in part with this comment. The Agency
agrees that iron insufficiency will not be readily detected in a growth
study evaluating normal physical growth. Importantly, however, as noted
in the preamble to the proposed rule, infants are born with iron stores
sufficient until age three to four months. For this reason, the growth
monitoring study required by Sec.  106.96(b) of the interim final rule
to assess normal physical growth will be neither sensitive enough nor
long enough to show iron deficiency. Thus, FDA is not adding a
requirement to measure iron to the requirements for the growth
monitoring study.
    (Comment 285) Another comment strongly supported establishing a
quality factor for iron, concluding that implementation of the iron
status quality factor would go a long way toward providing the
scientific data to resolve the issue of what level of iron is correct
for infant formula.
    (Response) FDA agrees that iron status is important to infants'
nutritional well-being. Although there are some available methods for
evaluating iron status, the most sensitive of these methods require
invasive procedures. Balance studies also offer a means to assess
bioavailability of iron but the balance method is less sensitive and,
as noted previously in this document, requires hospitalization and
prolonged restraint of the infants.
    As noted in the 1996 proposed rule, term infants are generally born
with adequate iron stores to meet their needs for the first few months
of life. Even if suitably sensitive and noninvasive methods were
available to measure iron status in infants, it is questionable whether
such measurements made during early infancy would provide meaningful
information on the bioavailability of iron in infant formulas. For
these reasons, FDA does not agree that the Agency should establish a
quality factor for iron at this time.
    The purpose of establishing a quality factor for a nutrient is to
require a determination of whether the nutrient is bioavailable in the
infant formula, i.e., that the nutrient is digested and absorbed by the
infant as the product is formulated for market. The question of what
level of a nutrient is ``correct'' for infant formula is better
addressed by studies with outcome measures designed to answer that
question specifically.
    (Comment 286) One comment stated that a poorly available source of
iron would be a problem for an infant between the ages 4 and 12 months
fed only formula and noted that, while feeding only formula to healthy
infants from 4 to 12 months of age is not consistent with CON/AAP
recommendations, there are instances where a formula-only diet has been
fed for extended periods of time to infants 4 to 12 months of age.
    (Response) FDA agrees that there may be rare cases in which formula
is the exclusive nourishment provided to infants after age 4 months and
that it could be problematic if that formula is deficient in iron.
Importantly, however, the comment included no evidence to establish the
concern that currently marketed formulas are poor sources of iron.
Infants are usually seen by their pediatricians every 1 to 2 months
during the first year of life, and, consistent with AAP
recommendations, most but not all infants are starting complementary
foods by 4 months of age (Refs. 70 and 88). Thus, these rare instances
of formula-only diets in older infants do not require the Agency to
establish a quality factor for iron, particularly given the factors
weighing against such establishment.
    (Comment 287) One comment recommended that studies of iron status
in infants be performed only when the manufacturer believes that such
studies may help assess effects of a specific formula or ingredient.
    (Response) FDA does not disagree with this comment. To the extent
that a formula manufacturer believes that an iron status study would be
meaningful for evaluating a particular infant formula with a specific
ingredient, FDA would not object to the conduct of such a study.
Importantly, however, before conducting any such study, the
manufacturer should be certain that data from such study are necessary
and will be meaningful so as to avoid subjecting the infant study
subjects to unnecessary testing.
    (Comment 288) Several comments noted that the quality factor for
iron would be of little value in the first four months of life, when
the standard growth study would be conducted.
    (Response) FDA agrees with this comment. As noted in the 1996
proposed rule, full-term infants are generally born with adequate iron
stores to meet their iron needs for the first few months of life, a
fact that restricts the ability to conduct an accurate assessment of
iron bioavailability during the period of the growth monitoring study.
The Agency did not receive data or other information challenging FDA's
statement about newborn iron stores nor did any comment dispute that
these stores would interfere with the ability to measure iron
bioavailability during the growth monitoring study.
    (Comment 289) Other comments objected to establishment of a quality
factor for iron status because it would require an invasive procedure
of drawing blood. The comments further stated that when blood draws are
required in infants, physicians are more reluctant to conduct studies
on well babies and parents are much more likely to refuse enrollment or
drop out of the study.
    (Response) FDA agrees that establishing a quality factor for iron
and a requirement to show that this quality factor is satisfied by an
infant formula would likely require blood draws of study subjects,
which would be an invasive procedure not otherwise required in the
growth monitoring study. However, as noted previously in this document,
FDA is not establishing a quality factor for iron because it is not
possible to perform an accurate assessment of iron's bioavailability in
the early months of infancy, the period during which formula is
consumed as the sole source of nutrition. FDA concludes that the risk,
however small, of the invasive procedure of a blood draw is not
justified given that any resulting iron bioavailability data would be
of very limited, if any, value.
    (Comment 290) One comment noted that the creation of a quality
factor for iron is complicated by the presence in the U.S. market of
formulas with varying levels of iron fortification, some of which are
nutritionally adequate from the standpoint of iron and others which may
not be adequate, but still meet the

standards of the FD&C Act. The comment contended that it makes little
sense to develop a quality factor for a nutrient that is not required
by law in formulas for healthy infants in nutritionally adequate
amounts and that no quality factor recommendation would be appropriate
until and unless the FD&C Act is modified to establish a required level
of bioavailable iron.
    (Response) FDA disagrees with this comment. Although the comment is
correct that Sec.  107.100 permits a wide range of iron content in
infant formula (0.15 to 3 mg/100 kcal), the comment appears to confuse
the range of permitted iron levels in infant formulas with the need for
the iron in formulas to be bioavailable. The iron in infant formula
must be bioavailable, regardless of the amount present. As noted, FDA
is not establishing a quality factor for iron in this interim final
rule, but not for the reason given in this comment.
    (Comment 291) One comment recommended that FDA establish a quality
factor for iron and require animal assays to assess the iron's
bioavailability, rather than require additional assessment measures in
a standard growth study.
    (Response) As explained previously in this document, FDA is not
establishing a quality factor for iron because of constraints on the
use of available methods for measuring the iron status of healthy term
human infants. The comment did not identify any animal assay that could
potentially be used to demonstrate that a particular infant formula
satisfies an established quality factor for iron. The Agency is aware
that nonhuman primate and rodent models have been used in studies of
iron status and infant neurocognitive and neurobehavioral development
(Ref. 89), and newborn piglets have also been used in studies of
nutrient absorption from infant formulas, but the comment provided no
animal data on iron bioavailability that could readily be applied to