
[Federal Register Volume 79, Number 111 (Tuesday, June 10, 2014)]
[Rules and Regulations]
[Pages 33057-33072]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2014-13384]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 106 and 107

[Docket No. FDA-1995-N-0063 (formerly 95N-0309)]
RIN 0910-AF27


Current Good Manufacturing Practices, Quality Control Procedures, 
Quality Factors, Notification Requirements, and Records and Reports, 
for Infant Formula

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA or we) is issuing a 
final rule that adopts, with some modifications, the interim final rule 
(IFR) entitled ``Current Good Manufacturing Practices, Quality Control 
Procedures, Quality Factors, Notification Requirements, and Records and 
Reports, for Infant Formula'' (February 10, 2014). This final rule 
affirms the IFR's changes to FDA's regulations and provides additional 
modifications and clarifications. The final rule also responds to 
certain comments submitted in response to the request for comments in 
the IFR.

DATES: This final rule is effective July 10, 2014. The compliance date 
for manufacturers to meet the requirements of Sec. Sec.  106.96(a), 
106.96(e), 106.96(i)(5), 106.100(p)(2) and 106.100(q)(2) related to 
quality factors for eligible infant formulas is November 12, 2015. The 
compliance date for the remaining provisions of this final rule is 
September 8, 2014. Submit comments on information collection issues 
under the Paperwork Reduction Act of 1995 by July 10, 2014 (see section 
VII, the ``Paperwork Reduction Act of 1995'' section of this document).

ADDRESSES: To ensure that comments on the information collection are 
received, the Office of Management and Budget (OMB) recommends that 
written comments be faxed to the Office of Information and Regulatory 
Affairs, OMB, Attn: FDA Desk Officer, FAX: 202-395-7285, or emailed to 
oira_submission@omb.eop.gov. All comments should be identified with 
the OMB control number 0910-0256 and titled ``Infant Formula 
Requirements.'' Also include the FDA docket number found in brackets in 
the heading of this document.

FOR FURTHER INFORMATION CONTACT: Benson M. Silverman, Office of

[[Page 33058]]

Nutrition, Labeling, and Dietary Supplements (HFS-850), Center for Food 
Safety and Applied Nutrition, Food and Drug Administration, 5100 Paint 
Branch Pkwy., College Park, MD 20740, 240-402-1451.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
II. Summary of Changes Made to the Interim Final Rule
III. Comments on the Interim Final Rule
IV. Technical Amendments
V. Executive Order 12866 and Executive Order 13563: Cost Benefit 
Analysis
VI. Small Entity Analysis (or Final Regulatory Flexibility Analysis)
VII. Paperwork Reduction Act of 1995
VIII. Analysis of Environmental Impact
IX. Federalism
X. References

I. Background

    We are issuing this final rule to establish requirements for 
quality factors for infant formulas and good manufacturing practices, 
including quality control procedures, under section 412 of the Federal 
Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 350a). The final 
rule will help prevent the manufacture of adulterated infant formula, 
ensure the safety of infant formula, and ensure that the nutrients in 
infant formula are present in a form that is bioavailable.
    Congress passed the Infant Formula Act of 1980 (the Infant Formula 
Act) (Public Law 96-359), which created section 412 of the FD&C Act. In 
1986, Congress, as part of the Anti-Drug Abuse Act of 1986 (Pub. L. 99-
570) (the 1986 amendments), amended section 412 of the FD&C Act to 
address concerns related to the sufficiency of quality control testing, 
current good manufacturing practices (CGMP), recordkeeping, and recall 
requirements for infant formula. The requirements in the final rule 
improve protection of infants consuming infant formula products by 
establishing greater regulatory control over the formulation and 
production of infant formula.
    We previously implemented certain of the provisions in the Infant 
Formula Act and 1986 amendments. This final rule implements the 
remaining provisions of the 1986 amendments, including provisions for 
CGMPs and quality factor requirements.
    This final rule generally affirms the IFR's changes to FDA's 
regulations at parts 106 and 107 (21 CFR parts 106 and 107) and 
provides additional modifications and clarifications to part 106. The 
final rule also responds to certain comments submitted in response to 
the request for comments in the IFR (79 FR 7934, February 10, 2014).

II. Summary of Changes Made to the Interim Final Rule

A. Definitions (Sec.  106.3)

1. Eligible Infant Formula
    We are amending the definition of ``eligible infant formula'' in 
Sec.  106.3. Eligible infant formula means an infant formula that could 
be lawfully distributed in the United States on December 8, 2014.
2. Quality Factors
    We are clarifying the definition of ``quality factors'' in Sec.  
106.3. Under this final rule, quality factors means those factors 
necessary to demonstrate the safety of the infant formula and the 
bioavailability of its nutrients, as prepared for market and when fed 
as the sole source of nutrition, to ensure the healthy growth of 
infants.

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

    We are modifying the language in Sec.  106.20(i) to permit doors to 
toilet facilities to open into the plant facilities where infant 
formula, ingredients, containers, or closures are processed, handled, 
or stored if alternate means have been taken to protect against 
contamination.

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

    We are deleting Sec.  106.30(e)(2)(ii)(A) and combining Sec.  
106.30(e)(2)(ii) from the IFR with Sec.  106.30(e)(2)(ii)(B) from the 
IFR. The section is designated as Sec.  106.30(e)(2)(ii). In the final 
rule, Sec.  106.30(e)(2)(ii) states that ``A manufacturer may maintain 
a cold storage area for an in-process infant formula or for a final 
infant formula at a temperature not to exceed 45[emsp14][deg]F (7.2 
[deg]C) for a defined period of time provided that the manufacturer has 
scientific data and other information to demonstrate that the time and 
temperature conditions of such storage are sufficient to ensure that 
there is no significant growth of microorganisms of public health 
significance during the period of storage of the in-process or final 
infant formula product.''

D. Controls To Prevent Adulteration Due to Automatic (Mechanical or 
Electronic) Equipment (Sec.  106.35)

    We are amending Sec.  106.35(a)(4) to clarify that validation can 
be accomplished through any suitable means, such as verification 
studies or modeling. We are also amending Sec.  106.35(b)(1) to specify 
that requirements for the calibration, inspection, and checking of 
hardware apply at any point, step, or stage where control is necessary 
to prevent adulteration of infant formula.

E. Controls To Prevent Adulteration During Manufacturing (Sec.  106.50)

    We are deleting the word ``drafted'' from Sec.  106.50(a)(2) in the 
final rule in response to a comment noting that persons other than a 
responsible official could draft changes to a master manufacturing 
order.

F. General Quality Control (Sec.  106.91)

1. Section 106.91(b)(1)
    We are reducing the required frequency of stability testing for new 
infant formulas from every 3 months to every 4 months in Sec.  
106.91(b)(1)(i) of the final rule because we agree with a comment that 
explained that stability testing of new formulas every 3 months, as 
required by Sec.  106.91(b)(1) in the IFR, would not provide additional 
public health protection over testing every 4 months.
    We are modifying Sec.  106.91(b)(1) to provide an exemption from 
the testing required by Sec.  106.91(b)(1) of the IFR if the 
manufacturer of a new infant formula requests an exemption and provides 
analytical data that demonstrate that the stability of the new infant 
formula will likely not differ from the stability of formulas with 
similar composition, processing, and packaging for which there are 
extensive stability data. In doing so, we are renumbering Sec.  
106.91(b)(1) of the IFR as Sec.  106.91(b)(1)(i) and creating Sec.  
106.91(b)(1)(ii) in the final rule to provide the exemption. The 
manufacturer would request the exemption in the 90-day notification for 
the new infant formula as required by new Sec.  106.120(b)(7). If the 
manufacturer is exempted from the testing required by Sec.  
106.91(b)(1)(i), the manufacturer would then be required under Sec.  
106.91(b)(1)(ii) to test the first production aggregate of the new 
infant formula in accordance with the stability testing requirements 
for subsequent production aggregates in Sec.  106.91(b)(2).
2. Section 106.91(b)(2)
    We are deleting the requirement to conduct stability testing at the 
midpoint of the shelf life for infant formulas tested under Sec.  
106.91(b)(2) in response to a comment that questioned how measuring 
nutrients at the midpoint of shelf life would provide additional 
assurance for formulas for which stability data have been established. 
We

[[Page 33059]]

agree with the comment that the critical data are the nutrient levels 
present at the end of shelf life and that the midpoint data are not 
essential.
3. Section 106.91(b)(3) and (4)
    We are making a technical correction to Sec.  106.91(b)(3) of the 
final rule to clarify our intent that manufacturers have the option to 
adjust the ``Use by'' date on an infant formula container so that such 
date is substantiated if the stability data from the testing required 
by Sec.  106.91(b)(1) did not substantiate the anticipated shelf life 
of the formula. We are also changing Sec.  106.91(b)(3) to provide 
flexibility for manufacturers to take other appropriate actions, in 
addition to conducting the testing required by Sec.  106.91(b)(1) or 
adjusting the ``Use by'' date, when stability testing does not 
substantiate the shelf life of the formula. Further, we are clarifying 
that the manufacturer must address all production aggregates released 
and pending release for distribution that are implicated by the testing 
results.
    We are making conforming changes to Sec.  106.91(b)(4)(iii) to 
clarify that manufacturers also must address all production aggregates 
released and pending release for distribution that are implicated by 
testing results required by Sec.  106.91(b)(2) that show that any 
nutrient that is not present in the production aggregate of infant 
formula at the level intended by the manufacturer.
    We are making other conforming changes in Sec.  106.91(b)(3) and 
(4) as a result of changes made to these provisions in the final rule.

G. Requirements for Quality Factors for Infant Formulas (Sec.  106.96)

    We are revising the exemption in Sec.  106.96(c)(2)(ii) so that it 
applies when a change to a formula does not impact normal physical 
growth. We are also adding section 106.96(g)(3), which states that FDA 
will exempt a manufacturer from the requirements of conducting a 
protein efficiency ratio (PER) rat bioassay if the manufacturer 
requests an exemption and provides assurances, as required under Sec.  
106.121(i), that demonstrate that an alternative method to the PER that 
is based on sound scientific principles is available to show that the 
formula supports the quality factor for the biological quality of the 
protein.

H. Records (Sec.  106.100)

    We are revising Sec.  106.100(m) to require access to records 
``within 24 hours'' in response to a comment.

I. New Infant Formula Submission (Sec.  106.120)

    As stated earlier in section II.F.1 of this document, we are 
providing an exemption in Sec.  106.91(b)(1)(ii) from the testing 
required by Sec.  106.91(b)(1) if the manufacturer of a new infant 
formula requests an exemption and provides analytical data that 
demonstrate that the stability of the new infant formula will likely 
not differ from the stability of formulas with similar composition, 
processing, and packaging for which there are extensive stability data. 
In doing so, we added Sec.  106.120(b)(7), which states that if the 
manufacturer is requesting an exemption under Sec.  106.91(b)(1)(ii), 
the manufacturer shall include the scientific evidence that the 
manufacturer is relying on to demonstrate that the stability of the new 
infant formula will likely not differ from the stability of formulas 
with similar composition, processing, and packaging for which there are 
extensive stability data.

J. Quality Factor Assurances for Infant Formulas (Sec.  106.121)

    We are making a change to Sec.  106.121 by adding Sec.  106.121(i) 
to the final rule, which states that if the manufacturer is requesting 
an exemption under Sec.  106.96(g)(3), the manufacturer shall include a 
detailed explanation of the alternative method, an explanation of why 
the method is based on sound scientific principles, and the data that 
demonstrates that the quality factor for the biological quality of the 
protein has been met.

III. Comments on the Interim Final Rule

    We provided an opportunity for comment in the IFR but indicated 
that comments submitted in response to the IFR ``should be limited to 
those that present new issues or new information'' (79 FR 7934 at 
8056). The preamble to the IFR also stated that ``Comments previously 
submitted to the Division of Dockets Management have been considered 
and addressed in this IFR and should not be resubmitted'' (id).
    We received a number of comments to the IFR. The comments were 
generally supportive of the rule. After considering all the comments 
submitted to this docket number, we are making minor technical 
corrections, clarifications to some provisions in response to comments 
that indicate some confusion on the part of industry, and modifications 
that increase flexibility with respect to certain requirements included 
in the IFR. In addition, we summarize and respond to relevant portions 
of comments.
    To make it easier to identify comments and FDA's responses, the 
word ``Comment,'' in parentheses, appears before the comment's 
description, and the word ``Response,'' in parentheses, appears before 
FDA's response. Each comment is numbered to help distinguish between 
different comments. The number assigned to each comment is purely for 
organizational purposes and does not signify the comment's value or 
importance.

A. Subpart A--General Provisions

1. Definitions (Sec.  106.3)
    (Comment 1) One comment stated that FDA's definition of quality 
factors in the IFR introduced a novel concept, i.e., the 
``bioavailability . . . of the formula,'' that is inconsistent with 
FDA's definition of bioavailability in the IFR and with the scientific 
and common meaning of ``bioavailability,'' which refers to absorption 
of particular nutrients. The comment continued that the concept of the 
bioavailability of a food should be subjected to external nutritional 
science input before being given the force and effect of law and 
recommended that the definition of quality factors in the 1996 proposed 
rule be restored.
    (Response) We recognize that the wording of the definition of 
quality factors in the IFR inadvertently suggested a ``novel'' concept 
of ``bioavailability.'' To clarify and better align the wording in the 
definition of quality factors with the definition of bioavailability 
used by FDA and the scientific community, we are modifying the wording 
of the definition of ``quality factor'' in Sec.  106.3 in the final 
rule.
    The revised definition still speaks to the safety of the formula 
while clarifying that the term ``bioavailability'' refers to nutrients. 
We note, however, that the infant formula as a whole, i.e., the matrix 
that contains the nutrients, must be formulated, processed, and 
packaged such that the nutrients are bioavailable. Changes in an infant 
formula matrix can greatly influence nutrient bioavailability (see 79 
FR 7934 at 8007). Because infants are fed formula as the sole source of 
nutrients, it is imperative that formulas have characteristics that 
allow the nutrients to be bioavailable.
    We decline to restore the definition of quality factors from the 
1996 proposed rule. As discussed in response to comment 23 of the IFR, 
the definition of quality factors in the proposed rule caused some 
people to interpret

[[Page 33060]]

``healthy growth'' as a separate quality factor (79 FR 7934 at 7950-
7951).
    (Comment 2) One comment expressed concern with defining quality 
factors to apply to bioavailability of the infant formula as a whole, 
but did not explain the basis for its concern. Another comment asserted 
that our explanation for why quality factors apply to the 
``bioavailability . . . of the formula'' is inconsistent with the 
definition of ``bioavailability'' as understood by Congress and fails 
to consider other more plausible and well-precedented interpretations 
of Congressional intent. The comment stated that FDA's conclusion that 
quality factors pertain to the ``bioavailability . . . of the formula'' 
appears arbitrary in the context of the 1986 Amendments to the Infant 
Formula Act of 1980. The comment stated that the statutory language 
requiring that the Secretary of Health and Human Services (the 
Secretary) establish requirements for quality factors for infant 
formulas ``including'' quality factor requirements for the nutrients 
required to be contained in infant formula under section 412(i) of the 
FD&C Act demonstrates that Congress intended to grant FDA the authority 
to establish quality factor requirements for individual nutrients other 
than those specified in section 412(i) of the FD&C Act, as well as 
quality factor requirements relating to issues other than the 
quantitative levels of nutrients as prescribed in section 412(i) of the 
FD&C Act (e.g., the bioavailability of distinct forms of individual 
nutrients), but not the authority to establish quality factor 
requirements for the infant formula as a whole. The comment argued that 
the IFR's definition of ``quality factors'' fails the legal analysis 
provided by FDA in section VIII.A of the IFR because Congress was not 
silent about the meaning of the term quality factors.
    (Response) To the extent that either comment relates to the 
explanation of bioavailability as set forth in the IFR and the 
suggestion that bioavailability relates to the infant formula as a 
whole, rather than to the bioavailability of individual nutrients, we 
address this issue in our response to comment 1. To the extent these 
comments assert that we lack authority to establish a definition of 
quality factors that relates to the infant formula as a whole, we 
disagree. We also disagree with the assertion that the legal analysis 
provided in section VIII.A of the IFR failed to consider all the 
possible interpretations of the statutory language or otherwise 
provides an insufficient or inaccurate analysis of FDA's authority.
    Comment 195 in the preamble to the IFR explicitly challenged FDA's 
authority to establish the quality factor of normal physical growth, 
which relates to the formula as a whole rather than any individual 
nutrient (79 FR 7934 at 8003). In responding to comment 195, we 
provided a detailed interpretation of our authority based, in part, on 
section 412(b)(1) of the FD&C Act, and we summarize some of this 
argument below (79 FR 7934 at 8003 through 8006). We reaffirm our 
explanation of our authority as set forth in the response to comment 
195 in the preamble to the IFR.
    As discussed in the preamble to the IFR, section 412(b)(1) of the 
FD&C Act requires the Secretary to ``by regulation establish 
requirements for quality factors for infant formulas to the extent 
possible consistent with current scientific knowledge, including 
quality factor requirements for the nutrients required by [section 
412(i)].'' This statutory language indicates that the Secretary must 
establish quality factors for (1) the individual nutrient components 
required under subsection (i) and (2) the infant formula as a whole to 
the extent possible consistent with current scientific knowledge. The 
language is silent regarding what the exact quality factors should be. 
The 1986 Amendments to the 1980 Infant Formula Act are consistent with 
our interpretation that quality factors extend beyond requirements for 
individual nutrients. The original language from the Infant Formula Act 
of 1980 authorized the Secretary to, by regulation, ``establish 
requirements for quality factors for such nutrients [required by 
subsection (g)].'' Infant Formula Act of 1980, Public Law 96-359, 
section 2, 94 Stat. 1190 (1980). (Subsection (g) of section 412 of the 
FD&C Act was subsequently redesignated as subsection (i) of section 412 
of the FD&C Act as part of the 1986 Amendments. Anti-Drug Abuse Act of 
1986, Public Law 99-570, section 4014(a)(1), 100 Stat. 3207 (1986).) In 
1986, however, the infant formula provisions were amended to specify in 
revised section 412(b)(1) of the FD&C Act that the ``Secretary shall by 
regulation establish requirements for quality factors for infant 
formulas, . . . including quality factor requirements for the nutrients 
required by subsection (i).'' (Emphasis added). This amendment 
clarified that quality factor requirements apply to the ``infant 
formula'' as a whole as well as to the individual nutrients.
    Further, requiring that quality factors relate to the safety of the 
infant formula as a whole is reasonable when considering the statutory 
scheme as a whole. See FDA v. Brown & Williamson Tobacco Corp., 529 
U.S. 120, 133 (2000) (explaining that the words of a statute must be 
read in the context of the overall statutory scheme). Our explicit 
statutory mission is, in part, to protect the public health by ensuring 
that foods (including infant formula) are safe, wholesome, sanitary, 
and properly labeled (section 903(b)(2)(A) of the FD&C Act) (21 U.S.C. 
393(b)(2)(A)). Further, the FD&C Act touches ``phases of the lives and 
health of people which, in the circumstances of modern industrialism, 
are largely beyond self protection. Regard for these purposes should 
infuse construction of the legislation if it is to be treated as a 
working instrument of government and not merely as a collection of 
English words.'' United States v. Dotterweich, 320 U.S. 277, 281 
(1943); see also United States v. Park, 421 U.S. 658, 668 (1975). The 
Infant Formula Act and the 1986 amendments were meant to ensure the 
``safety and nutrition'' of infant formulas, and this purpose is 
achieved, in part, through the establishment of requirements for 
quality factors that help ensure the safety of the infant formula as a 
whole. See Public Law 96-359, 94 Stat. 1190, 1190 (1980).
    (Comment 3) One comment expressed concern that the IFR is silent on 
what changes, other than major changes, should be submitted to FDA 
before processing for FDA's concurrence in the manufacturer's 
assessment. The comment stated that because the guidelines issued under 
21 CFR 106.30(c)(2) (and incorporated by reference in the 1986 Infant 
Formula Act Amendments) discuss changes other than major changes and 
have the force and effect of law, we should honor those guidelines.
    (Response) We disagree that the IFR is silent on what changes, 
other than major changes, a manufacturer should submit to FDA before 
first processing (BFP). We addressed this issue in response to comments 
256 and 352 of the IFR (79 FR 7934 at 8021 and 8053). As discussed in 
the preamble to the IFR, a ``before first processing'' (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.

[[Page 33061]]

    As for the comment's assertion that we should honor the guidelines 
issued under 21 CFR 106.30(c)(2) with respect to changes other than 
major changes, the comment misinterprets the language in section 
412(c)(2) of the FD&C Act. Section 412(c)(2) of the FD&C Act only 
incorporates the definition of ``major change'' as found in 21 CFR 
106.30(c)(2) (as in effect on August 1, 1986) and the guidelines issued 
thereunder. Thus, FDA's decision not to codify portions of the 
guidelines related to changes other than major changes is not 
inconsistent with section 412(c)(2) of the FD&C Act.
    (Comment 4) One comment requested that we clarify the notification 
requirements of an infant formula submitted after February 10, 2014 (90 
days prior to May 12, 2014) under the current 90-day premarket 
notification requirements. The comment stated that the requirements for 
formulas submitted before July 10, 2014, and especially before May 12, 
2014, need to be clarified.
    (Response) We recognize the lack of clarity surrounding the 
notification requirements for infant formulas submitted after February 
10, 2014, based on the definition of eligible infant formula as set 
forth in the IFR. To address the issue, we are amending the definition 
of ``eligible infant formula'' to mean an infant formula that could be 
lawfully distributed in the United States on December 8, 2014. The 
change should eliminate the confusion surrounding notification 
requirements for new infant formula products that are the subject of a 
new infant formula notification submitted after the publication of the 
IFR. Under the revised definition, new infant formulas that are the 
subject of a notification submitted prior to the compliance date of 
September 8, 2014 will be considered eligible.

B. Subpart B--Current Good Manufacturing Practice

1. Production and In-Process Control System (Sec.  106.6)
    (Comment 5) One comment stated that FDA had declined to accept 
comments submitted on the proposed rule that would limit the areas of 
production requiring establishment of specifications to those deemed to 
be critical and requested that wording be inserted in Sec.  106.6(a) to 
align this section with other parts of the IFR (e.g., Sec.  
106.30(d)(1)).
    (Response) The comment's assertion that we declined to accept 
recommendations to limit the areas of production that require 
specifications to be established to those deemed to be critical is 
incorrect. This issue is addressed in Sec.  106.6(c), which limits the 
establishment of specifications to be met ``to any point, step, or 
stage in the production process where control is necessary to prevent 
adulteration.'' We indicated in the response to comment 41 in the 
preamble to the IFR (see 79 FR 7934 at 7957-7958) that ``FDA does not 
intend that the control procedures established under Sec.  106.6(c) 
would address every theoretical risk of technical adulteration'' and 
further stated that ``a manufacturer has a responsibility, as part of 
CGMP, to ensure quality in the finished product on a consistent basis. 
The way to ensure quality is to identify controls needed at various 
steps in the production process so that, in its final form, the formula 
complies with all requirements.'' The response continued that ``certain 
actions (e.g., the establishing of specifications) are not required at 
every step in the manufacturer's process . . . [and] it is the 
responsibility of the manufacturer to identify those points at which 
control is necessary to prevent adulteration of infant formula 
products.'' (79 FR 7934 at 7958).
    (Comment 6) One comment stated that specifications necessary to 
prevent adulteration during production are currently established and 
contended that additional controls such as warehousing conditions and 
trailer temperatures during distribution are not expected to cause 
adulteration and should be out of the scope of the IFR. The comment 
asked us to clarify whether additional non-process related 
specifications beyond what manufacturers currently do are required and, 
if so, which non-process related specifications, or the criteria to 
make this determination, are needed. The comment said that 
manufacturers need this information to assess their ability to comply 
and determine related costs. The comment further stated that compliance 
with Sec.  106.6 of the IFR would not be feasible by the effective date 
of the IFR because, if additional specifications need to be developed 
for areas the comment asserted are not critical to preventing product 
adulteration, much more time than 150 days will be required to draft, 
finalize, implement, and train employees. The comment requested that we 
provide relief through an announcement and exercise of enforcement 
discretion, a delayed compliance date, or a formal delay for this 
provision to align with the compliance date for eligible infant 
formulas.
    (Response) We do not agree that warehousing conditions and trailer 
temperatures during distribution can be dismissed as a potential cause 
of adulteration. For example, temperatures that are too cold during 
storage and distribution may result in breaking of the emulsion of an 
infant formula, causing separation of the fat and liquid portions of 
the products and rendering the products inappropriate/unfit for 
consumption by infants. Temperatures that are too hot may result in 
growth of thermophilic organisms (organisms that need high temperatures 
for proliferation or that thrive at high temperature) that render the 
products unpalatable and inappropriate/unfit for infant consumption. As 
another example, during storage and distribution, rats that may gain 
access to warehouses and/or trailers could gnaw through cardboard 
cartons and plastic containers containing infant formula, which would 
result in adulteration of the product under section 402(a) of the FD&C 
Act.
    The comment did not define non-process related specifications or 
provide additional examples of non-process related specifications 
beyond what manufacturers currently do. Therefore, we cannot respond to 
the comment's request for additional information. However, we remind 
manufacturers that Sec.  110.93 of Part 110--Current Good Manufacturing 
Practice in Manufacturing, Packing, or Holding Human Food requires that 
storage and transportation of finished food shall be under conditions 
that will protect food against physical, chemical, and microbiological 
contamination as well as deterioration of the food and the container. 
We expect that infant formula manufacturers have already instituted 
practices, whether or not they are currently identified as 
specifications, to prevent adulteration and maintain product integrity 
during storage and distribution as a necessary step in fulfilling their 
responsibility to ensure that their formulas reach the consumer in a 
condition that is safe and appropriate for consumption. Creating 
written specifications as required by Sec.  106.6(b) for such practices 
should not involve extensive effort or extra cost, and we see no basis 
for announcing the exercise of enforcement discretion or a formal delay 
for this provision to align with the compliance date for eligible 
infant formulas. Nonetheless, with the exception of the compliance date 
for certain requirements related to quality factors for eligible infant 
formulas, the final rule adopts a compliance date of September 8, 2014 
to facilitate manufacturer compliance with all requirements of this 
final rule.

[[Page 33062]]

2. Controls To Prevent Adulteration Caused by Facilities (Sec.  106.20)
    (Comment 7) One comment said that the requirements of Sec.  
106.20(i), which addresses controls to prevent adulteration from in-
plant toilet facilities, are more restrictive than the provisions for 
toilet facilities in the food GMPs (21 CFR 110.37(d)(4)), which allows 
for doors in in-plant toilet facilities to open into enumerated areas 
if alternate means have been taken to protect against contamination 
(such as double doors or positive air-flow systems). The comment 
continued that FDA did not establish a public health need for the more 
restrictive requirements and claimed that infant formula manufacturers 
will have to move or otherwise reconfigure their in-plant toilet 
facilities if the IFR is interpreted not to permit the alternate means 
in the food GMPs or exempt facilities in areas where product is not 
subject to airborne contamination. The comment further stated that 
compliance with Sec.  106.20 of the IFR would not be feasible by the 
effective date of the IFR if the comment's proposed changes to Sec.  
106.20 were not accepted and requested that we provide relief through 
an announcement and exercise of enforcement discretion, a delayed 
compliance date, or a formal delay for this provision to align with the 
compliance date for eligible infant formulas.
    (Response) We agree with the aspect of the comment that suggests 
that it should be permissible for doors in in-plant toilet facilities 
to open into certain areas if alternate means have been taken to 
protect against contamination. However, we disagree that airborne 
contamination is the only source of contamination from toilet 
facilities. Contamination can come from hands, clothing, and footwear 
of employees exiting the toilet facilities, and it is likely that 
measures such as foot baths and footwear and garment changes in 
addition to double doors and positive air-flow systems will be needed 
to prevent contamination from in-plant toilet facilities. We are 
revising Sec.  106.20(i) to permit doors to toilet facilities to open 
into the plant facilities if alternate means have been taken to protect 
against contamination. With this change to Sec.  106.20(i), we see no 
basis for announcing the exercise of enforcement discretion or a formal 
delay for this provision to align with the compliance date for eligible 
infant formulas. Nonetheless, with the exception of the compliance date 
for certain requirements related to quality factors for eligible infant 
formulas, the final rule adopts a compliance date of September 8, 2014 
to facilitate manufacturer compliance with all requirements of this 
final rule.
3. Controls To Prevent Adulteration Caused by Equipment or Utensils 
(Sec.  106.30)
    (Comment 8) One comment agreed with FDA that controlling the 
temperature of infant formula is important to prevent adulteration, 
requested clarification regarding the equipment covered by Sec.  
106.30(e)(2), and requested that we modify the provision to apply only 
to cold bulk liquid storage. The comment stated that, with this change, 
ingredient receipt through blending would not be classified as in-
process infant formula or finished infant formula until the components 
are mixed and introduced into the cold storage vessel. In support of 
the requested modification, the comment pointed to FDA's report 
``Analysis of Results for FDA Food Defense Vulnerability Assessments 
and Identification of Activity Types,'' in which we defined liquid 
storage as follows: ``Bulk liquid storage refers to any medium-long 
term storage silo or tank where liquid product may be stored prior to 
introduction into the product stream or to hold finished product prior 
to loading for outbound shipping.''
    (Response) We do not agree with the modification recommended in 
this comment. The report to which the comment refers, ``Analysis of 
Results for FDA Food Defense Vulnerability Assessments and 
Identification of Activity Types,'' identifies liquid storage/hold/
surge tanks as a key activity type found in most production 
environments. However, in addition to the category of bulk liquid 
storage described in the comment, the report describes a second 
category of non-bulk holding and surge tanks, which ``refer to any 
storage tanks used to hold product for a short period or surge tanks. 
Non-bulk tanks can be used to store non-bulk liquid ingredients, hold 
liquid product for sample testing and other QC activity, or to control 
flow rates of liquid ingredients/product through the production 
system.'' The report also specifies that liquid storage ``refers to any 
processing step where liquid ingredient (emphasis added) or 
intermediate/finished liquid product is stored in either bulk storage 
tanks or smaller secondary holding tanks or surge tanks.'' Thus, the 
report does not provide a basis for restricting cold storage in Sec.  
106.30(e)(2)(i) to cold bulk liquid storage, so we decline to revise 
Sec.  106.30(e)(2)(i) as suggested by the comment.
    (Comment 9) One comment asked us to allow a less restrictive 
approach to meet the showing required underSec.  106.30(e)(2)(ii) 
(i.e., meeting both of the conditions listed in Sec.  106.30(e)(2)(ii) 
of the IFR). Under Sec.  106.30(e)(2)(ii) in the IFR, a manufacturer 
may maintain a cold storage area for an in-process infant formula or 
for a final infant formula at a temperature not to exceed 
45[emsp14][deg]F (F) for a defined period of time if the manufacturer 
has scientific data and other information to demonstrate that (a) 
compliance with Sec.  106.30(e)(2)(i) (which established 
40[emsp14][deg]F or below as the temperature level for all areas of 
cold storage) would have an adverse effect on the quality of the in-
process or final infant formula and (b) the time and temperature 
conditions of such storage are sufficient to ensure that there is no 
significant growth of microorganisms of public health significance 
during the period of storage. The comment argued that the changes we 
made in the IFR do not fully encompass our stated rationale for the 
provision ``to minimize the growth of pathogens and the deterioration 
of liquid ingredients'' (79 FR 7934 at 7964).
    (Response) In response to the comment's concern, we have revised 
Sec.  106.30(e)(2)(ii) of the IFR. We are deleting Sec.  
106.30(e)(2)(ii)(A) and combining Sec.  106.30(e)(2)(ii) from the IFR 
with Sec.  106.30(e)(2)(ii)(B) from the IFR. The section will be 
designated as Sec.  106.30(e)(2)(ii) in the final rule. In the final 
rule, Sec.  106.30(e)(2)(ii) states that ``A manufacturer may maintain 
a cold storage area for an in-process infant formula or for a final 
infant formula at a temperature not to exceed 45[emsp14][deg]F (7.2 
[deg]C) for a defined period of time provided that the manufacturer has 
scientific data and other information to demonstrate that the time and 
temperature conditions of such storage are sufficient to ensure that 
there is no significant growth of microorganisms of public health 
significance during the period of storage of the in-process or final 
infant formula product.''
    (Comment 10) One comment requested that we align section Sec.  
106.30(e)(2)(ii) with the Pasteurized Milk Ordinance, which specifies 
45 [deg]F as the maximum storage temperature of pasteurized milk and 
milk products. The comment stated that any capital improvements to 
facilities needed to comply with Sec.  106.30(e)(2) will take 
considerably longer than the 150 days until the effective date.
    (Response) The language in Sec.  106.30(e)(2)(ii) of this final 
rule (see

[[Page 33063]]

response to comment 9) allows the 45 [deg]F temperature permitted for 
pasteurized milk and milk products for in-process or final infant 
formula for a defined period of time provided that the manufacturer has 
scientific information to demonstrate that the time and temperature 
conditions of such storage are sufficient to ensure that there is no 
significant growth of microorganisms of public health significance 
during the period of storage of the in-process or final infant formula 
product. We discussed in the responses to comments 65 and 66 in the IFR 
our reasons why the time and temperature conditions established in the 
IFR are sufficient to ensure product safety and the reasons for the 40 
[deg]F requirement. Furthermore, because infant formula is consumed by 
a vulnerable population, food safety and public health considerations 
do not justify further relaxing of the requirements of Sec.  
106.30(e)(2)(ii) of this final rule.
    With regard to the comment's concern that compliance will take 
considerably longer than 150 days, we disagree. Section 106.30(e)(2) of 
this final rule allows a manufacturer the flexibility to store in-
process and final product at temperatures up to and including 45 
[deg]F, provided that the manufacturer has scientific data and other 
information to demonstrate that the time and temperature conditions of 
such storage are sufficient to ensure that there is no significant 
growth of microorganisms of public health significance during the 
period of storage of the in-process or final infant formula product. 
The comment provided no information that would lead us to believe that 
compiling such scientific data would prove difficult or burdensome.
4. Controls To Prevent Adulteration Due to Automatic (Mechanical or 
Electronic) Equipment (Sec.  106.35)
    (Comment 11) One comment noted that the concept under Sec.  
106.30(d)(1), which requires only those instruments and controls at 
points where control is necessary to prevent adulteration to be 
accurate and maintained, including by calibration, should be applied to 
Sec.  106.35(b)(1).
    (Response) To the extent this comment requests consistency between 
the language in the two provisions, we agree that the use of consistent 
language would be beneficial, and we are amending Sec.  106.35(b)(1) to 
provide that a manufacturer shall ensure, at any point, step, or stage 
where control is necessary to prevent adulteration of infant formula, 
that all hardware is routinely inspected and checked according to 
written procedures and that hardware that is capable of being 
calibrated is routinely calibrated according to written procedures. We 
note, however, that we are not aware of hardware currently in use in 
the infant formula manufacturing process that is capable of calibration 
that is not used at a point, step, or stage where control is necessary 
to prevent adulteration of infant formula. Infant formula manufacturing 
plants contain many automatic measuring devices that are capable of 
being calibrated, and they must be calibrated at whatever frequency is 
necessary to ensure accurate measurement. No device should be providing 
inaccurate data that could lead to adulteration of the infant formula.
    (Comment 12) One comment stated that Sec.  106.35(b)(4) would 
require revalidation of any system that is modified and suggested an 
alternative definition of validation in Sec.  106.35(a)(4) to add the 
phrase ``either through validation or verification of all components or 
through the validation of the system.'' The comment stated that 
industry supports the requirement for full system validation. The 
comment acknowledged that our response to comments in the IFR contains 
references to ``appropriate regression testing'' and ``validation 
analysis'' but said that the IFR ultimately points to revalidation of 
the entire system. The comment suggested revising the final rule to 
clarify that verification is a sufficient method of ensuring control 
for some components in a system.
    (Response) The preamble to the IFR included an extensive discussion 
of validation of automatic equipment and FDA's reasons for establishing 
the definition of validation in Sec.  106.35(a)(4) in the IFR (79 FR 
7934 at 7968-7971). We do not agree with the alternative definition 
proposed because it would permit the initial validation of a system 
through verification of all components. Complete validation of an 
automatic system is required initially; however, FDA did not intend 
that a whole system would always need to be completely revalidated with 
every change. For example, there may be operations upstream from 
another part of a system that is being changed that are not affected 
when the part of the system that is downstream has changed. In such 
cases, it may be possible to revalidate those parts of the system that 
are being changed or impacted by the change by other means such as 
verification studies or modeling. In response to the comment, we are 
revising Sec.  106.35(a)(4) to clarify that validation can be 
accomplished through any suitable means, such as verification studies 
or modeling. However, we note that such verification studies differ 
from the nutrient testing of the final product, which is a form of 
verification of a system's proper operation. Finished product testing 
for nutrients does not eliminate the need for system validation.
    (Comment 13) One comment stated that 150 days is insufficient time 
to conduct all the validations required by Sec.  106.35(b)(3). The 
comment stated that automation, validation, and change control that is 
currently used would meet the requirements of ``consistently produces a 
product meeting predetermined specifications'' and that validation 
analyses are performed to determine the extent and impact of the change 
on the system. The comment stated that this is further augmented by the 
ongoing monitoring of critical control points. The comment requested 
that, with regard to the requirements of Sec.  106.35, we announce the 
exercise of enforcement discretion or a formal delay for this provision 
to align with the compliance date for eligible infant formulas. 
Nonetheless, with the exception of the compliance date for certain 
requirements related to quality factors for eligible infant formulas, 
the final rule adopts a compliance date of September 8, 2014 to 
facilitate manufacturer compliance with all requirements of this final 
rule.
    (Response) We note that the validation requirement in Sec.  
106.35(b)(3) applies to new infant formulas that have not yet been 
released. As such, manufacturers will not need to conduct a complete 
system validation for formulas that are already on the market when this 
rule becomes effective. However, we also note that manufacturers will 
still need to ensure that all systems are designed, installed, tested, 
and maintained in a manner that will ensure that they are capable of 
performing their intended function and of producing and analyzing 
infant formula in accordance with the CGMP and quality control 
procedures as required by Sec.  106.35(b). Given that the requirement 
in Sec.  106.35(b)(3) applies to new infant formulas, complying with 
the section by the effective date of the rule should not be an issue. 
We therefore decline the request to announce the exercise of 
enforcement discretion, a delayed compliance date, or a formal delay 
for this provision to align with the compliance date for eligible 
infant formulas.
5. Controls To Prevent Adulteration During Manufacturing (Sec.  106.50)
    (Comment 14) One comment noted that Sec.  106.50(a)(2) of the IFR 
could be

[[Page 33064]]

interpreted to require a ``responsible official'' to draft changes to 
the master manufacturing order and recommended that we delete the term 
``drafted.''
    (Response) Although a responsible official is required to review 
and approve changes in a master manufacturing order, we agree that 
persons other than a responsible official could draft changes to a 
master manufacturing order. Accordingly, we have deleted the word 
``drafted'' from Sec.  106.50(a)(2) in the final rule.
    (Comment 15) One comment recommended adding some examples (e.g., 
physical separation or another system of segregation) to Sec.  
106.50(f)(4) to make it consistent with Sec.  106.20(b)(2), which deals 
with facilities and separation of raw materials, in-process materials 
and final product. Section 106.50(f)(4) requires, in part, that 
rejected in-process materials be controlled under a quarantine system 
designed to prevent the use of the materials in manufacturing or 
processing operations.
    (Response) Section 106.20(b)(2) requires separate areas or another 
system of separation such as a computerized inventory control, a 
written card system, or an automated system of segregation for holding 
raw materials, in-process materials, and final infant formula product 
after rejection for use in, or as, infant formula. As noted in the IFR, 
``section 106.40(e) describes the ways a manufacturer may quarantine 
material that has not been released for use due to failure to meet a 
specification, or that has been rejected for use in the manufacture of 
an infant formula'' (79 FR 7934 at 7956). As such, we do not believe 
that adding examples is needed in Sec.  106.50(f)(4) and, therefore, 
are not making the change recommended in the comment.
6. Controls To Prevent Adulteration From Microorganisms (Sec.  106.55)
    (Comment 16) A comment stated that a 95% level of confidence 
interval means that up to approximately 5% of C. sakazakii-contaminated 
production aggregates may test negative with FDA's proposed testing 
scheme and be released to market. The comment said that because 
thousands of production aggregates are released to market each year, 
this risk is not inconsiderable. The comment further stated that 
contamination can occur as clumps and clusters, and this contamination 
could be missed when the production aggregate is tested. The comment 
expressed concern that powdered infant formula presents a potential 
risk to the health of infants of all ages.
    (Response) Although we consider the concerns expressed in this 
comment to be important, the comment appears to mischaracterize the 
meaning of confidence interval in the quantitative risk analysis. A 
confidence interval is a range of values in which there is a specified 
probability that the value of a parameter lies within it. The 
confidence level does not indicate the percentage of adulterated infant 
formula that will reach the market.
    For purposes of our response, we assume that this comment is 
referring to the finished product testing required under Sec.  
106.55(c). Finished product testing under Sec.  106.55(c) is but one 
means of assuring the safety of powdered infant formula. The purpose of 
CGMPs is to have a system that produces products that are consistent in 
quality and safety and to collectively provide additional safeguards. 
In the preamble to the IFR, we explained that the sampling plan is 
intended to help manufacturers identify unacceptable production 
aggregates at the finished product stage. The sampling plan is a 
statistical approach based on a quantitative risk analysis and was 
extensively discussed in the IFR (79 FR 7934 at 7984-7988).
    (Comment 17) One comment noted that peer-reviewed articles 
published after 2011 are not cited and discussed in the IFR and that no 
articles published after 2011 appear to have been taken into 
consideration in formulating the IFR. The comment also noted that 
significant progress has been made in clarifying sources of and risk 
groups for Cronobacter, particularly C. sakazakii. The comment noted a 
2012 publication in the American Association of Pediatrics to support 
this statement. The comment urged FDA to review publications after 
2011, in particular with regard to C. sakazakii.
    (Response) Although the IFR did not provide literature citations 
after 2011, we monitor the scientific literature closely with respect 
to data and studies that affect infant formula. The comment did not 
identify, and we are not aware of, any articles published after 2011, 
including the 2012 publication by Jason cited in the comment, that 
would have suggested a need to change the IFR's requirements or the 
requirements of this final rule.
    (Comment 18) One comment recommends that the rule clarify that 
technologies currently used by manufacturers cannot produce a sterile 
formula but that there are technologies capable of producing a sterile 
powdered infant formula without damaging the product's nutritional 
value, if these technologies were applied by manufacturers.
    (Response) We discussed in the preamble to the IFR (79 FR 7934 at 
7980-7981) the use of technology to eradicate Cronobacter spp. To the 
extent this comment suggests we mandate which production method to use, 
we disagree. To a large extent, the IFR, as well as this final rule, 
gives manufacturers the flexibility to establish controls, 
specifications, and other operations and does not require the use of 
specific technologies. Given the pace at which technological changes 
can occur, we believe this more flexible approach is more practical to 
address the use of changing technologies and best practices.
7. Audits of Current Good Manufacturing Practice (Sec.  106.90)
    (Comment 19) One comment agreed with FDA that audits should be 
performed by individuals who have as little bias as possible and who do 
not have a direct interest in the outcome of the audit. The comment 
also noted that the determination of who satisfies these criteria is 
largely subjective unless the audit is conducted by a third party, and 
the comment requested some examples of situations where an audit might 
be conducted by an individual that is not a third party (e.g., the Head 
of Quality Assurance auditing a facility) that would be acceptable to 
FDA.
    (Response) As the comment noted, the determination of the 
objectivity of an in-house employee for performing audits involves 
subjective as well as objective evaluation of the suitability of the 
individual for a particular audit. Such assessments must be made on a 
case-by-case basis. As explained in response to comment 166 in the IFR 
(79 FR 7934 at 7994), in evaluating whether an audit might be conducted 
by an individual that is not a third party, the manufacturer should 
consider factors such as the scope of the employee's previous 
responsibilities, the time elapsed between the reassignment of the 
former responsibilities and the audit, and whether the audit will be 
conducted by this single individual or a team. Therefore, we decline to 
give examples as requested by the comment.

C. Subpart C--Quality Control Procedures

1. General Quality Control (Sec.  106.91)
a. Premix Testing
    (Comment 20) One comment stated that infant formula manufacturers 
should be allowed to rely on a premix supplier's certificate of 
analysis to provide analytical information on all

[[Page 33065]]

nutrients in a premix. The comment continued that our proposed rules on 
Current Good Manufacturing Practice and Hazard Analysis and Risk-Based 
Preventive Controls for Human Food (78 FR 3646 (January 16, 2013)) and 
Foreign Supplier Verification Programs for Importers of Food for Humans 
and Animals (78 FR 45729 (July 29, 2013)) (part of our implementation 
of the Food Safety Modernization Act (FSMA)) would require food 
manufacturers to conduct supplier verification activities with respect 
to their premix suppliers. The comment predicted that the FSMA-mandated 
supplier verification requirements will adequately address any 
potential concerns related to whether nutrient premixes comply with an 
infant formula manufacturer's specifications and should be taken into 
account in determining the extent of premix testing that should be 
required in the IFR.
    (Response) We disagree that infant formula manufacturers should be 
allowed to rely on a premix supplier's certificate of analysis to 
provide information on the composition of a premix. Section 
412(b)(3)(B) of the FD&C Act stipulates that ``[e]ach nutrient premix 
used in the manufacture of an infant formula shall be tested for each 
relied upon nutrient required by subsection (i) which is contained in 
such premix to ensure that such premix is in compliance with its 
specifications or certifications by a premix supplier.'' (Emphasis 
added.) The statutory language makes it clear that a premix 
manufacturer's certification is not to be relied upon by the 
manufacturer of the infant formula to establish the analytical 
composition of a premix. Further, the statute does not allow other 
options as substitutes for the testing of premixes by infant formula 
manufacturers. Therefore, we decline to revise Sec.  106.91(a)(1) as 
suggested by the comment.
b. Stability Testing and Frequency
    (Comment 21) One comment stated that the recipe (the manufacturing 
order) should be the unit of production used for setting stability 
testing requirements rather than the production aggregate required by 
Sec.  106.91(b).
    (Response) Under section 412(a) of the FD&C Act, an infant formula 
that does not provide nutrients as required by section 412(i) is deemed 
to be adulterated. Section 106.91(b) of the IFR established the 
production aggregate as the quantity of formula to be used for setting 
stability testing requirements to provide direct evidence that nutrient 
levels are maintained throughout the shelf life of all of the product 
in the marketplace. A requirement to use the recipe (manufacturing 
order) as the unit of production for setting stability testing 
requirements, as requested in the comment, could be interpreted to mean 
that after stability testing was conducted one time on the quantity of 
formula produced from the recipe, no more stability testing would be 
required for that formula. Using such a basis for stability testing 
would not provide evidence that nutrient levels are maintained 
throughout the shelf life in all formula in the marketplace. Therefore, 
we are not revising the unit of production to be used for setting 
stability testing requirements in response to this comment. The 
production aggregate is the quantity of infant formula from which 
manufacturers must take a representative sample for the stability 
testing required by Sec.  106.91(b)(1) and (2) in the final rule.
    (Comment 22) One comment asked us to clarify the frequency of 
stability testing needed for batch processing operations.
    (Response) When manufacturers produce their formulas using batch 
production, they typically manufacture a ``batch'' during a single 
cycle of manufacture, which would correspond to what we have defined as 
the production unit in Sec.  106.3 of the IFR (i.e., a specific 
quantity of an infant formula produced during a single cycle of 
manufacture that has uniform composition, character, and quality, 
within specified limits). The individual ``batches'' (i.e., production 
units) are stored in containers (often referred to as totes) until the 
formula is packaged. Comingling of the individual ``batches'' 
(production units) occurs when the contents of the individual storage 
containers are combined during the packaging process, thereby resulting 
in a larger quantity of formula that is intended to have uniform 
composition, character, and quality, consistent with the definition of 
``production aggregate'' in the IFR. The larger quantity of the formula 
that is comingled and packaged in one packaging run would be considered 
the production aggregate for manufacturers using batch production. Each 
such production aggregate would be subject to the stability testing 
requirements as applicable under Sec.  106.91.
    (Comment 23) One comment stated that the requirement to conduct 
stability testing for every production aggregate of infant formula 
disregards extensive data from longstanding stability programs and 
treats each production aggregate as an independent sample.
    (Response) FDA appreciates that infant formula manufacturers have 
been conducting stability testing on their infant formulas since the 
passage of the Infant Formula Act of 1980 and recognizes that a 
manufacturer may have extensive stability data for existing products 
that may be applicable to new infant formulas. We realize the potential 
value of such data and consider that manufacturers may be able to rely 
on such data in some instances rather than always conducting the de 
novo stability testing of new infant formulas required by Sec.  
106.91(b)(1). For this reason, and in order to reduce the amount of 
comprehensive stability testing required for new products, we are 
providing an exemption in Sec.  106.91(b)(1)(ii) from the testing 
required by Sec.  106.91(b)(1)(i) in this final rule if the 
manufacturer of a new infant formula requests an exemption and provides 
analytical data that demonstrate that the stability of the new infant 
formula will likely not differ from the stability of non-new formulas 
with similar composition, processing, and packaging for which there are 
extensive stability data. Under Sec.  106.91(b)(1)(ii) of the final 
rule, the manufacturer would request the exemption in the 90-day 
notification for the new infant formula under Sec.  106.120(b)(7). If 
the manufacturer is exempted from the testing required by Sec.  
106.91(b)(1)(i), the manufacturer would then be required under Sec.  
106.91(b)(1)(ii) of the final rule to test the first production 
aggregate in accordance with the requirements for routine stability 
testing of all subsequent production aggregates of infant formula under 
Sec.  106.91(b)(2).
    (Comment 24) One comment stated that stability testing of new 
formulas every 3 months as required by Sec.  106.91(b)(1) of the IFR is 
unnecessary. The comment contended that an analytical value at an 
isolated point in time may misrepresent the shelf life of the product 
as determined through a manufacturer's existing stability programs. The 
comment also said that the rate of degradation early in shelf life is 
not relevant to product safety if the product meets nutrient 
specifications at the end of the shelf life period.
    (Response) We agree that an unexpected analytical value at one 
point in time may not necessarily be predictive of the shelf life of 
the product. We disagree, however, that the rate of nutrient 
degradation early in shelf life is irrelevant to product safety. If the 
product does not meet nutrient specifications at the end of the shelf 
life period, the knowledge that nutrient degradation is occurring more 
rapidly than predicted by previous data

[[Page 33066]]

provides a valuable early indicator that possible action may be 
required to avoid having an adulterated product in the marketplace. We 
have further considered the requirement that stability testing of new 
infant formulas be conducted every 3 months (four times a year) in 
Sec.  106.91(b)(1) of the IFR and conclude that satisfactory data could 
still be obtained if the frequency of testing is reduced to every 4 
months (3 times a year). Therefore, we have reduced the required 
frequency of stability testing for new infant formulas to every 4 
months in Sec.  106.91(b)(1)(i) of the final rule.
    (Comment 25) One comment questioned the benefit in requiring that 
every production aggregate after the first undergo stability testing, 
as such requirement would represent a large increase in the number of 
samples undergoing stability testing on a routine basis. The comment 
stated this testing requirement would have a significant impact on the 
industry and questioned the value of such testing. Another comment 
questioned how measuring nutrients at the midpoint of shelf life will 
provide additional assurance for formulas for which stability data have 
been established.
    (Response) The purpose of stability testing of subsequent 
production aggregates for nutrients as required by Sec.  106.91(b)(2) 
is to confirm that the nutrients present in an infant formula at the 
finished product stage do not degrade below minimum levels over the 
shelf life of the product. Every production aggregate must be at or 
above such minimum levels at the end of the shelf life of the product. 
The evidence that nutrient levels have been maintained at or above such 
minimum levels in each production aggregate is provided by the results 
of stability testing at the end of the shelf life of each production 
aggregate. This testing requirement will provide direct evidence that 
nutrient levels are maintained throughout the shelf life of infant 
formula products. We agree that the critical data are the nutrient 
levels present at the end of shelf life and that the midpoint data are 
not essential in subsequent production aggregates. Therefore, we have 
deleted the requirement to conduct stability testing at the midpoint of 
the shelf life for infant formulas tested under Sec.  106.91(b)(2).
    (Comment 26) One comment stated that routine stability testing 
should not include analysis of nutrients that are not labile (i.e., 
easily broken down). The comment recommended that we limit routine 
stability testing to reliable indicator nutrients and supplement such 
testing with periodic comprehensive testing.
    (Response) We do not agree that the routine stability testing 
required at the end of shelf life under Sec.  106.91(b)(2) should 
include only labile nutrients or that the purpose of stability testing 
would be met by the comment's suggested approach. It is essential to 
have proof that all nutrients, including those that deteriorate more 
slowly, are present at or above the minimum required levels at the end 
of shelf life to demonstrate that the product is not adulterated. We 
note, however, that Sec.  106.91(b)(5) waives evaluation of the levels 
of minerals from the testing required by Sec.  106.91(b)(1) and (2) 
because these nutrients do not degrade in infant formula. We decline to 
revise the final rule in response to this comment.
    (Comment 27) One comment stated that the requirements of Sec.  
106.91(b)(3) are too prescriptive and pointed out that market 
withdrawal of the product was another option. The comment further 
stated that the manufacturer should be allowed to determine the 
disposition of a product that does not maintain its required nutrient 
levels throughout shelf life and recommended that Sec.  106.91(b)(3) be 
deleted.
    (Response) We made an inadvertent error in the language of Sec.  
106.91(b)(3) by including the words ``shelf life label statement.'' We 
intended that manufacturers would have the option of making changes to 
the ``use by'' date, not the ``shelf life label statement,'' if the 
stability data from the testing required by Sec.  106.91(b)(1) did not 
substantiate the anticipated shelf life of the formula. We have revised 
Sec.  106.91(b)(3) accordingly.
    We realize that there may be some situations when manufacturers may 
find that actions other than those provided for in Sec.  106.91(b)(3) 
in the IFR may be appropriate when the stability testing of a new 
infant formula required by Sec.  106.91(b)(1) does not substantiate the 
shelf life of the formula. Consequently, we have revised Sec.  
106.91(b)(3) of the final rule to clarify our intent that manufacturers 
have the option to adjust the ``use by'' date so that such date is 
substantiated if the stability data from the testing required by Sec.  
106.91(b)(1) did not substantiate the anticipated shelf life of the 
formula. FDA also is providing flexibility for manufacturers to take 
other appropriate actions in Sec.  106.91(b)(3)--other than conducting 
the testing required by Sec.  106.91(b)(1) or adjusting the ``use by'' 
date--when stability testing does not substantiate the shelf life of 
the formula. We also are clarifying in Sec.  106.91(b)(3) that the 
manufacturer must address all production aggregates released and 
pending release for distribution that are implicated by the testing 
results.
    We also are making a conforming change to Sec.  106.91(b)(4)(iii) 
to clarify that manufacturers must address all production aggregates 
released and pending release for distribution that are implicated by 
testing results required by Sec.  106.91(b)(2) that show that any 
required nutrient is not present in the production aggregate of infant 
formula at the level required by Sec.  107.100 or that any nutrient 
added by the manufacturer is not present at the level declared on the 
labels for the finished products from the production aggregate of 
infant formula.
    (Comment 28) One comment stated that FDA should give further 
consideration to periodic testing as a complement to stability testing 
rather than requiring stability testing of each production aggregate. 
The comment also requested that we change the requirement of the IFR to 
require that the manufacturer collect representative samples of 
formulas every 3 months for stability testing.
    (Response) We considered whether to require periodic testing in 
establishing the requirements for quality control procedures in the 
IFR. However, we concluded that periodic testing was not necessary 
because the testing required by Sec.  106.91(a) of the IFR ``can serve 
as final product testing of each production aggregate and also fulfill 
the purpose of periodic testing by serving as a check on the proper 
operation of the controls used by a manufacturer to ensure the presence 
and proper concentration of all nutrients'' (79 FR 7934 at 7993). 
Adding a requirement for periodic testing would result in unnecessary 
testing. Further, periodic testing (e.g., testing representative 
samples of formula every 3 months) would not provide sufficient 
evidence that nutrient levels in each production aggregate are being 
maintained. As stated in the response to comment 25, the purpose of 
routine stability testing for nutrients is to confirm that the 
nutrients present in an infant formula at the finished product stage do 
not degrade below minimum levels over the shelf life of the product. 
Every production aggregate must be at or above such minimum levels at 
the end of the shelf life of the product. Implementation of the 
approach requested in the comment would not provide evidence that 
nutrient levels have been maintained at or above such minimum levels in 
each production aggregate. Therefore, we are not making either of the 
changes requested by this comment.

[[Page 33067]]

    (Comment 29) One comment stated that the requirement in Sec.  
106.91(b) to do stability testing on every production aggregate is 
overly burdensome and unnecessary. The comment stated that this 
requirement would generate redundant data and would add considerable 
costs for formulas.
    (Response) We note that under Sec.  106.91(a)(4), manufacturers 
must test every production aggregate of finished infant formula for all 
nutrients required by Sec.  107.100 and any other nutrient added by the 
manufacturer before distribution of the product. Testing at this point 
is already mandated by section 412(b)(2)(B)(i) of the FD&C Act, and the 
results of this testing can also serve as the initial stability data. 
Under the final rule, manufacturers must also conduct stability testing 
on each subsequent production aggregate only at the end of shelf life. 
In addition, we are providing for an exemption in Sec.  
106.91(b)(1)(ii) from the comprehensive stability testing required for 
new infant formulas by Sec.  106.91(b)(1)(i) if a manufacturer of a new 
infant formula requests an exemption and provides analytical data that 
demonstrate that the stability of the new infant formula will likely 
not differ from the stability of non-new formulas with similar 
composition, processing and packaging for which there exist extensive 
stability data.
    As such, we do not consider that a requirement for testing of every 
production aggregate generates redundant data. Each production 
aggregate is produced independently and verification is needed that an 
infant formula is not adulterated when it reaches the end of its shelf 
life as well as at the time of production. Because infant formula 
serves as the sole source of nutrition for infants, we disagree that 
such a requirement is overly burdensome or unnecessary.
    (Comment 30) One comment stated that the testing required in Sec.  
106.91(a)(4) and (b)(1) is limited to the nutrients in Sec.  107.100 
because section 412(b)(3)(D) of the FD&C Act specifies that if the 
Secretary adds a nutrient to the list of nutrients provided in section 
412(i) of the FD&C Act, the Secretary shall by regulation require that 
the manufacturer of an infant formula test each batch of such formula 
for such new nutrient in accordance with subparagraphs (A), (B), and 
(C) of section 412(b)(3) of the FD&C Act. The comment argued that 
section 412(b)(3)(D) of the FD&C Act means that if FDA has not deemed 
the nutrient to be essential by requiring its addition to infant 
formula, then testing for the nutrient is also not essential.
    (Response) To the extent this comment asserts that we intended to 
limit the testing required in Sec.  106.91(a)(4) and (b)(1) to those 
nutrients specified in Sec.  107.100, we disagree. We discuss this 
issue in detail in our response to comment 173 in the preamble to the 
IFR (79 FR 7934 at 7996). To the extent this comment suggests that we 
lack the authority to impose testing requirements on nutrients other 
than those specified in Sec.  107.100, we also disagree. The statutory 
language in section 412(b)(3)(D) of the FD&C Act is not our sole 
authority to establish requirements for nutrient testing. As explained 
in the IFR, testing for nutrients not required under Sec.  107.100 in 
each production aggregate of infant formula is consistent with CGMP and 
quality control procedures that must be established by section 
412(b)(2)(A) of the FD&C Act. The preamble to the 1996 proposal 
explained why testing for these added nutrients is necessary for proper 
formulation of a formula as follows: ``[I]t is important that the level 
of these added nutrients be controlled, and that the level of the added 
nutrient be consistent from batch to batch [production aggregate to 
production aggregate] and be uniform throughout the batch [production 
aggregate] of infant formula. The level of a nutrient needs to be 
controlled because some nutrients can be toxic to an infant if given at 
too high a level. Controlling the level of the added nutrient for 
consistency from batch to batch [production aggregate to production 
aggregate] and in a particular batch [production aggregate] of infant 
formula will ensure that the infant receives the essential nutrient on 
a consistent basis and will also ensure that the infant does not 
receive too high, or too low, a level of the nutrient because the 
nutrient was not uniform through the batch [production aggregate] of 
infant formula'' (61 FR 36154 at 36176).
    (Comment 31) One comment stated that compliance with Sec.  106.91 
by the effective date of the IFR cannot realistically be achieved and 
requested that we announce and exercise enforcement discretion, delay 
the compliance date, or formally delay the provisions of Sec.  106.91 
to align with the compliance date for eligible infant formula. The 
comment asserted that the requirements of Sec.  106.91 are burdensome 
but did not provide specific information about why compliance with 
Sec.  106.91 by the effective date of the IFR would be impractical.
    (Response) As discussed in our responses to other comments relating 
to Sec.  106.91, we are taking some steps in this final rule to 
increase flexibility and lessen the burden of some of the requirements 
in Sec.  106.91. This increased flexibility should address any concerns 
about complying with Sec.  106.91 by the effective date of this rule. 
Therefore, we are rejecting the request to announce and exercise 
enforcement discretion or formally delay the provisions of Sec.  106.91 
to align with the compliance date for eligible infant formula. 
Nonetheless, with the exception of the compliance date for certain 
requirements related to quality factors for eligible infant formulas, 
the final rule adopts a compliance date of September 8, 2014 to 
facilitate manufacturer compliance with all requirements of this final 
rule.

D. Subpart E--Quality Factors for Infant Formula

    (Comment 32) One comment stated that FDA's expansion of the 
definition of ``Quality Factors'' in the IFR to require a growth 
monitoring study on the ``bioavailability'' of an infant formula as a 
whole was not consistent with current scientific knowledge, as 
specified in section 412(b)(1) of the FD&C Act. The comment included an 
extended discussion of current scientific knowledge of the effects of 
specific nutrients on infant growth and alternative methods for 
evaluating infant formulas, such as animal studies.
    (Response) The preamble to the IFR (see 79 FR 7934 at 7951-7952) 
explored the concept of healthy growth and explained why normal 
physical growth as a quality factor is not flawed. As that discussion 
indicates, infant growth is steady and predicable, and physical growth 
and normal maturation should occur together. If the infant formula does 
not have all the nutrients needed by an infant in a form that is 
bioavailable, the infant will not grow. Monitoring of physical growth 
of infants has long been recognized as an indicator of healthy growth. 
For example, the 1980 report of the Committee on Nutrition of the 
American Academy of Pediatrics cited in the IFR stated that ``growth of 
infants during the first few months of life is a determining factor for 
the pattern of development and quality of health in adult life'' (79 FR 
7934 at 7951), thereby recognizing the critical nature of this period 
of unparalleled growth. More recently, the 2004 report of the Institute 
of Medicine of the National Academy of Sciences concluded that ``Growth 
is well recognized as a sensitive, but nonspecific indicator of the 
overall health and nutritional status of an infant'' (79 FR 7934 at 
8006).

[[Page 33068]]

    In the preamble to the IFR, we stated that ``the least invasive and 
most practical means to ensure that the formula, as a whole, delivers 
nutrients in a form that is bioavailable and safe is a growth 
monitoring study in which anthropometric measurements of infants fed a 
new infant formula are assessed (79 FR 7934 at 8008). Assessments 
described in the comment would require invasive procedures that would 
increase the level of risk associated with a human study of an infant 
formula applying such measures. The information provided in the comment 
also suggested that the evaluation of an infant formula should be 
accomplished by studying animals. We understand that animal studies can 
be very useful in determining the bioavailability of nutrients and 
establishing the safety of ingredients, as well as exploring metabolic 
pathways. However, as we concluded in the IFR, FDA is not aware of an 
animal model that is a suitable substitute for the infants in a growth 
monitoring study (79 FR 7934 at 8008), and the information provided in 
the comment did not discuss this issue. Therefore, we are maintaining 
the requirement to conduct a growth monitoring study in this final 
rule.
    (Comment 33) One comment noted that the IFR identified two quality 
factors, normal physical growth and sufficient biological quality of 
the formula's protein component. The comment interpreted the IFR to 
mean that of the many different functional requirements, the only one 
to be assessed for infant formula is its efficacy in leading to 
adequate physical growth in the short term, and if the infant leads to 
adequate growth over a period of fifteen weeks, the infant formula is 
of good quality. The comment also stated that it should not be 
suggested that quality on a single dimension is sufficient when an 
infant must perform well on many different dimensions, and it is 
misleading to suggest that a short-term measure of infants' physical 
growth can reasonably be viewed as a measure of the overall quality of 
infant formula.
    (Response) The quality factor requirements are meant to provide the 
assurance that, when fed as the sole source of nutrition, the infant 
formula in its entirety will support healthy growth. We understand that 
the quality factors of normal physical growth and sufficient biological 
quality of the formula's protein component have limitations and that 
there are other ``dimensions'' that are relevant to infant formula. The 
preamble to the IFR (79 FR 7934 at 7953) discussed the limitations of 
both quality factors, as demonstrated by the growth study and the PER. 
Although we are aware of these limitations, at this time other methods 
are not available or are impracticable. As discussed in the IFR, FDA 
will consider amending the quality factor regulations as new 
methodology and appropriate reference criteria become available (79 FR 
7934 at 7950).
    (Comment 34) One comment requested that we revise the designation 
of normal physical growth to limit the quality factor to changes in 
formulations that may have an effect on growth. The comment noted that 
Sec.  106.96(b) sets the default requirement of a growth monitoring 
study (GMS) for all new formulas. The comment continued that although 
Sec.  106.96(c) provides exemptions from the requirements of paragraph 
Sec.  106.96(b) under three conditions, the condition set forth in 
Sec.  106.96(c)(2)(ii)--that the change from the existing formula does 
not affect the bioavailability of the formula or bioavailability of 
nutrients in the formula--is circular because FDA defined the quality 
factor as normal physical growth, not as bioavailability of the 
nutrients in the formula. The comments stated that the exemption from 
the GMS requirement should be provided when there is evidence that a 
change to the infant formula would not affect physical growth. The 
comment stated that neither bioavailability of the infant formula nor 
the nutrients in the formula is directly measured in the GMS. The 
comment concluded that to require a GMS across all new formulas even 
when it is known that measurement of physical growth will not be able 
to detect inadequacies of many nutrients risks the institutionalization 
of an insensitive, unreliable measure of formula quality that does 
nothing to ensure the health of formula-fed infants.
    (Response) FDA agrees that the exemption from the GMS study should 
be provided when a change to an existing infant formula would not 
affect the ability of the formula to support physical growth 
specifically, instead of when the change to the formula does not affect 
bioavailability. We agree that bioavailability of individual nutrients 
is not directly measured in the GMS. We understand that every 
formulation change may not need a GMS and clearly indicated in the 
preamble to the IFR that a GMS ``may not be necessary to demonstrate 
normal physical growth for every new infant formula, including a change 
to a marketed formula that results in a new infant formula'' (79 FR 
7934 at 8005). We are revising the exemption in Sec.  106.96(c)(2)(ii) 
so that it applies when a change to an existing infant formula would 
not affect the ability of the formula to support normal physical 
growth, and are also making conforming changes to the notification 
requirements in Sec.  106.121(d).
    (Comment 35) Two comments urged us to provide greater detail for 
studies supporting quality factors, particularly in areas of the size 
and representativeness of the population of infants studied. The 
comments requested that we develop additional guidance beyond what was 
published in February 2014 regarding the structure and methodology that 
should be used in the studies.
    (Response) The preamble to the IFR provided a basis for structuring 
and conducting an adequate and well-controlled growth monitoring study 
to demonstrate that a new infant formula supports normal physical 
growth in infants when fed as the sole source of nutrition (79 FR 7934 
at 8007-8021). This information provided the scientific basis for how a 
growth monitoring study should be designed and methodological concerns 
that included sample size considerations. We would consider future 
development of additional guidance to expand upon the information in 
the preamble of the IFR regarding conduct of a growth monitoring study. 
We are satisfied, however, that the standards set forth in the preamble 
to the IFR provide sufficient guidance with which to conduct adequate 
and well-controlled growth monitoring studies.
    (Comment 36) One comment expressed concern regarding the voluntary 
citizen petition process by which manufacturers of eligible infant 
formula can provide to FDA the basis on which they have concluded that 
their eligible infant formulas satisfy the quality factors for physical 
growth and/or protein efficiency ratio (PER). The comment stated that 
the citizen petition option under Sec.  106.96(i)(3) for eligible 
infant formulas would make information public to competitors, 
consumers, and others. The comment continued that it would be difficult 
for a manufacturer not to submit a citizen petition because there would 
be a public expectation that the manufacturers do so. The comment 
further stated that formulas on the market have been through FDA review 
and have had to satisfy all the requirements of the Infant Formula Act 
and subsequent amendments. The comment stated that if there is any 
additional information that the Agency feels is needed from 
manufacturers, the Agency should include such details in the new 
notification requirements in the provisions of Sec.  106.120 and Sec.  
106.121,

[[Page 33069]]

consistent with good administrative procedures for notice and comment. 
The comment requested clarification of the reasons an additional 
process was created and how manufacturers would receive a response from 
FDA. The comment also expressed concern about the manufacturers' 
ability to submit petitions for each formula by the November 2015 
compliance date. The comment noted that because the citizen petition is 
a voluntary process, it provides no assurance that the Agency will 
obtain any outstanding information the Agency requires. The comment 
concluded that the citizen petition process is not necessary, is 
redundant, and provides no additional benefit to the Agency, the 
manufacturer, or the public, and that Sec.  106.96(i)(3) should be 
deleted.
    (Response) We disagree that Sec.  106.96(i)(3) should be removed. 
The preamble to the IFR described the basis for the voluntary citizen 
petition process and further explained that all formulas, new or not 
new (i.e., currently marketed products), must meet the quality factors 
requirements (79 FR 7934 at 8028). We reiterate that the citizen 
petition process under Sec.  106.96(i)(3) is voluntary and transparent; 
however, meeting the quality factor requirements is not voluntary. 
Meeting the quality factor requirements is mandatory under section 
412(a)(2) of the FD&C Act, and an infant formula that does not meet 
quality factor requirements is an adulterated product.
    We consider the citizen petition process to be a beneficial 
opportunity for the manufacturer of an eligible infant formula to 
describe how the quality factors have been met before the compliance 
date for eligible infant formulas (79 FR 7934 at 8005). We described in 
further detail in an accompanying draft guidance document how the 
process works, including information about how FDA will respond to 
petitioners. Additionally, we indicated that we are available to meet 
with manufacturers and discuss their particular concerns regarding the 
citizen petition process. We note that FDA will protect the 
confidentiality of information submitted through the citizen petition 
process in accordance with the Freedom of Information Act (5 U.S.C. 
552) and FDA's regulations (see, e.g., 21 CFR 20.61). In addition, we 
are providing more detailed information regarding the process for 
submitting a citizen petition to meet the quality factor requirements 
for eligible infant formulas in a guidance document posted on FDA's Web 
site at http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm400036.htm. However, we also 
note that because the citizen petition process is voluntary, we would 
not consider the absence of such a petition negatively. Finally, we 
note that new infant formula notifications submitted prior to the 
compliance date of September 8, 2014 would not necessarily have 
demonstrated satisfaction of the quality factor requirements in this 
final rule. As such, we disagree that providing this voluntary 
opportunity to describe how the quality factors have been met is 
redundant.
    (Comment 37) One comment requested that additional language be 
added to Sec.  106.96(f) regarding the methodology required to 
determine the biological protein quality. The comment suggested the 
addition of the phrase ``or by other appropriate method(s)'' be added 
to Sec.  106.96(f) and Sec.  106.96(i)(2)(ii). The comment continued 
that by incorporating this change of language into the final rule, 
there would be an opportunity for the use of other scientifically valid 
methods for determining protein quality beyond what exists currently 
and for the possibility of other methods that may be developed in the 
future.
    (Response) FDA acknowledges that currently and in the future there 
may be other methods that could be used for determining protein 
quality. To address this issue, we added an exemption to Sec.  
106.96(g)(3) to allow manufacturers of new infant formulas to use 
alternative methods based on sound scientific principles to demonstrate 
protein quality. FDA is also adding language to Sec.  106.121(i) of 
this final rule, consistent with this change, to explain the 
information that must be included in a new infant formula notification 
if the manufacturer is requesting this exemption.
    (Comment 38) Several comments understood the protein efficiency 
ratio (PER) to be a quality factor and indicated this was not an 
appropriate quality factor.
    (Response) We note that the comments have misidentified the quality 
factor as the PER. The quality factor is the biological quality of the 
protein, and the PER is a method used to assure such quality.

D. Subpart F--Records and Reports

    (Comment 39) One comment stated that the term ``immediate'' is 
unclear in Sec.  106.100(m). Section 106.100(m) of the IFR described 
various means of recordkeeping and stated, in relevant part, that the 
records are to be maintained in a manner that ensures that both the 
manufacturer and FDA can be provided with ``immediate access'' to the 
records. The comment would revise Sec.  106.100(m) by replacing 
``immediate'' with ``within 24 hours'' to be consistent with records 
access in Sec.  106.100(k)(5)(v).
    (Response) We agree that access to records within 24 hours is 
reasonable and have revised the wording in Sec.  106.100(m) in the 
final rule to require access within 24 hours.

IV. Technical Amendments

    In addition to the changes we are making in response to the 
comments, we are making minor technical corrections to Sec.  
106.96(c)(1) and (g) to provide more specific cross references to other 
provisions of the rule. Also, consistent with our discussion in the IFR 
explaining our decision to use the terms ``production unit'' and 
``production aggregate'' instead of ``batch'' and ``lot'' (79 FR 7934 
at 7942-7944), we are eliminating the use of the words ``batch'' and 
lot'' in Sec.  106.100(f)(4), (k)(5)(ii), and (o) to ensure consistency 
with the terminology used elsewhere in the IFR and final rule. Finally, 
we are deleting an unnecessary reference to Sec.  106.3 from what was 
Sec.  106.91(b)(1) in the IFR, which has been redesignated as Sec.  
106.91(b)(1)(i) in this final rule.

V. Executive Order 12866 and Executive Order 13563: Cost Benefit 
Analysis

    On February 10, 2014, FDA issued an IFR amending certain 
requirements in the regulation on the current good manufacturing 
practices, quality control procedures, quality factors, notification 
requirements, and records and reports, for infant formula (79 FR 7934). 
The Economic Impact Analysis in the IFR explained and further revised 
the analysis set forth in the proposed rule by addressing the economic 
impact of the changes to the regulations at parts 106 and 107. We did 
not receive any comments that would warrant further revising the 
economic analysis of the IFR.
    FDA has examined the impacts of this final rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct Agencies to assess all 
costs and benefits of available regulatory alternatives and, when 
regulation is necessary, to select regulatory approaches that maximize 
net benefits (including potential economic, environmental, public 
health and safety, and other advantages; distributive impacts; and 
equity). We

[[Page 33070]]

believe that the final rule is not a significant regulatory action 
under Executive Orders 12866 and 13563.
    The Regulatory Flexibility Act requires Agencies to determine 
whether a final rule will have a significant impact on small entities 
when an Agency issues a final rule ``after being required . . . to 
publish a general notice of proposed rulemaking.'' We certify that this 
final rule will not have a significant economic impact on a substantial 
number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that Agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $141 million, using the most current (2013) Implicit 
Price Deflator for the Gross Domestic Product. We do not expect this 
final rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    Thus, this economic analysis affirms the economic impact analysis 
of the IFR. For a full explanation of the economic impact analysis of 
this final rule, we direct interested persons to the text of the 
economic impact analyses in the IFR (79 FR 7934, February 10, 2014, 
Ref. 92). The analyses that we have performed to examine the impacts of 
this final rule under Executive Order 12866, Executive Order 13563, the 
Regulatory Flexibility Act, and the Unfunded Mandates Reform Act of 
1995 are included in the RIA for the final rule (Ref. 1).

VI. Small Entity Analysis (or Final Regulatory Flexibility Analysis)

    A regulatory flexibility analysis is required only when an Agency 
must publish a notice of proposed rulemaking (5 U.S.C. 603, 604). FDA 
published the IFR after publishing a notice of proposed rulemaking in 
1996 (61 FR 36154; July 9, 1996) and reopening of the comment period in 
2003 (68 FR 22341; April 28, 2003) and 2006 (71 FR 43392; August 1, 
2006). We have conducted such an analysis and examined the economic 
implications of this final rule on small entities. This final rule is 
not a significant regulatory action as defined by Executive Order 
12866. FDA also certifies that this final rule will not have a 
significant impact on a substantial number of small entities.

VII. Paperwork Reduction Act of 1995

    This final rule contains information collection provisions that are 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). A 
description of these provisions with estimates of the annual reporting, 
recordkeeping, and third-party disclosure burden are included in the 
RIA in section IV, entitled ``Paperwork Reduction Act of 1995'' (Ref. 
1). An Agency may not conduct or sponsor, and a person is not required 
to respond to, a collection of information unless it displays a 
currently valid OMB control number.
    We had included a section titled ``Paperwork Reduction Act of 
1995'' in the preamble to the IFR (79 FR 7934 at 8055-8056). Any 
comments on our analysis of the burdens presented in that section were 
submitted to OMB. We will not address these comments in this document. 
We are resubmitting the information collection provisions of this final 
rule to OMB because the final rule provides additional modifications 
and clarifications to 21 CFR part 106.
    In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C. 
3507(d)), we have submitted the information collection provisions of 
this final rule to OMB for review. Interested persons are requested to 
submit comments regarding information collection to OMB (see DATES and 
ADDRESSES).
    We will publish a notice in the Federal Register announcing OMB's 
decision to approve, modify, or disapprove the information collection 
provisions in this final rule. An Agency may not conduct or sponsor, 
and a person is not required to respond to, a collection of information 
unless it displays a currently valid OMB control number.

VIII. Analysis of Environmental Impact

    We have carefully considered the potential environmental effects of 
this action. FDA has concluded under 21 CFR 25.30(j) and 25.32(n) that 
this action is of a type that does not individually or cumulatively 
have a significant effect on the human environment. Therefore, neither 
an environmental assessment nor an environmental impact statement is 
required.

IX. Federalism

    We have analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, we conclude that the rule 
does not contain policies that have federalism implications as defined 
in the Executive order and, consequently, a federalism summary impact 
statement is not required.

X. Reference

    The following reference has been placed on display in the Division 
of Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 
20852, and may be seen by interested persons between 9 a.m. and 4 p.m., 
Monday through Friday.

1. FDA. Current Good Manufacturing Practices, Quality Control 
Procedures, Quality Factors, Notification Requirements, and Records 
and Reports, for Infant Formula. Regulatory Impact Analysis for 
Final Rule. FDA-1995-N-0063 (formerly 95N-0309), 2014.

List of Subjects

21 CFR Part 106

    Food grades and standards, Infants and children, Incorporation by 
reference, Nutrition, Reporting and recordkeeping requirements.

21 CFR Part 107

    Food labeling, Infants and children, Nutrition, Reporting and 
recordkeeping, Signs and symbols.

    Accordingly, the interim final rule amending 21 CFR parts 106 and 
107, which was published at 79 FR 7933 on February 10, 2014, is adopted 
as a final rule with the following changes:

PART 106--INFANT FORMULA REQUIREMENTS PERTAINING TO CURRENT GOOD 
MANUFACTURING PRACTICE, QUALITY CONTROL PROCEDURES, QUALITY 
FACTORS, RECORDS AND REPORTS, AND NOTIFICATIONS

0
1. The authority citation for 21 CFR part 106 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 342, 350a, 371.


0
2. In Sec.  106.3, revise the definitions for ``Eligible infant 
formula'' and ``Quality factors'' to read as follows:


Sec.  106.3  Definitions.

* * * * *
    Eligible infant formula means an infant formula that could be 
lawfully distributed in the United States on December 8, 2014.
* * * * *

[[Page 33071]]

    Quality factors means those factors necessary to demonstrate the 
safety of the infant formula and the bioavailability of its nutrients, 
as prepared for market and when fed as the sole source of nutrition, to 
ensure the healthy growth of infants.
* * * * *

0
3. In Sec.  106.20, revise paragraph (i) to read as follows:


Sec.  106.20  Controls to prevent adulteration caused by facilities.

* * * * *
    (i) Each infant formula manufacturing site shall provide its 
employees with readily accessible toilet facilities and hand washing 
facilities that include hot and cold water, soap or detergent, single-
service towels or air dryers in toilet facilities. These facilities 
shall be maintained in good repair and in a sanitary condition at all 
times. These facilities shall provide for proper disposal of the 
sewage. Doors to the toilet facility shall not open into areas where 
infant formula, ingredients, containers, or closures are processed, 
handled, or stored, except where alternate means have been taken to 
protect against contamination.

0
4. In Sec.  106.30, revise paragraph (e)(2)(ii) to read as follows:


Sec.  106.30  Controls to prevent adulteration caused by equipment or 
utensils.

* * * * *
    (e) * * *
    (2)(i) * * *
    (ii) A manufacturer may maintain a cold storage area for an in-
process infant formula or for a final infant formula at a temperature 
not to exceed 45[emsp14][deg]F (7.2 [deg]C) for a defined period of 
time provided that the manufacturer has scientific data and other 
information to demonstrate that the time and temperature conditions of 
such storage are sufficient to ensure that there is no significant 
growth of microorganisms of public health significance during the 
period of storage of the in-process or final infant formula product.
* * * * *

0
5. In Sec.  106.35, revise paragraphs (a)(4) and (b)(1) to read as 
follows:


Sec.  106.35  Controls to prevent adulteration due to automatic 
(mechanical or electronic) equipment.

    (a) * * *
    (4) ``Validation'' means establishing documented evidence that 
provides a high degree of assurance that a system will consistently 
produce a product meeting its predetermined specifications and quality 
characteristics. Validation can be accomplished through any suitable 
means, such as verification studies or modeling.
    (b) * * *
    (1) A manufacturer shall ensure, at any point, step, or stage where 
control is necessary to prevent adulteration of the infant formula, 
that all hardware is routinely inspected and checked according to 
written procedures and that hardware that is capable of being 
calibrated is routinely calibrated according to written procedures.
* * * * *

0
6. In Sec.  106.50, revise paragraph (a)(2) to read as follows:


Sec.  106.50  Controls to prevent adulteration during manufacturing.

    (a) * * *
    (2) Changes made to the master manufacturing order shall be 
reviewed and approved by a responsible official and include an 
evaluation of the effect of the change on the nutrient content and the 
suitability of the formula for infants.
* * * * *

0
7. In Sec.  106.91, revise paragraphs (b)(1), (b)(2), (b)(3), 
(b)(4)(ii), (b)(4)(iii), and (b)(4)(iv) to read as follows:


Sec.  106.91  General quality control.

* * * * *
    (b) * * *
    (1)(i) For an infant formula that is a new infant formula the 
manufacturer shall collect, from each manufacturing site and at the 
final product stage, a representative sample of the first production 
aggregate of packaged, finished formula in each physical form (powder, 
ready-to-feed, or concentrate) and evaluate the levels of all nutrients 
required under Sec.  107.100 of this chapter and all other nutrients 
added by the manufacturer. The manufacturer shall repeat such testing 
every 4 months thereafter throughout the shelf life of the product.
    (ii) The Food and Drug Administration will exempt the manufacturer 
from the requirements of paragraph (b)(1)(i) of this section if the 
manufacturer of a new infant formula requests an exemption and provides 
analytical data, as required under Sec.  106.120(b)(7), that 
demonstrates that the stability of the new infant formula will likely 
not differ from the stability of formulas with similar composition, 
processing, and packaging for which there are extensive stability data. 
A manufacturer exempt from the requirements of paragraph (b)(1)(i) of 
this section would be required to test the first production aggregate 
according to the requirements of Sec.  106.91(b)(2).
    (2) The manufacturer shall collect, from each manufacturing site 
and at the final product stage, a representative sample of each 
subsequent production aggregate of packaged, finished formula in each 
physical form (powder, ready-to-feed, or concentrate) and evaluate the 
levels of all nutrients required under Sec.  107.100 of this chapter 
and all other nutrients added by the manufacturer. The manufacturer 
shall repeat such testing at the end of the shelf life of the product.
    (3) If the results of the testing required by paragraph (b)(1) of 
this section do not substantiate the shelf life of the infant formula, 
the manufacturer shall address, as appropriate, all production 
aggregates of formula released and pending release for distribution 
that are implicated by the testing results, such as by conducting the 
testing required by paragraph (b)(1) of this section on a subsequently 
produced production aggregate to substantiate the shelf life of the 
infant formula or revising the use by date for such product so that 
such date is substantiated by the stability testing results.
    (4) * * *
    (ii) Evaluate the significance, if any, of the results for other 
production aggregates of the same formula that have been released for 
distribution;
    (iii) Address, as appropriate, all production aggregates of formula 
released and pending release for distribution that are implicated by 
the testing results; and
    (iv) Determine whether it is necessary to conduct the testing 
required by paragraph (b)(1) of this section.
* * * * *

0
8. In Sec.  106.96, revise paragraphs (c)(1), (c)(2)(ii), (g)(1), and 
(g)(2), and add paragraph (g)(3) to read as follows:


Sec.  106.96  Requirements for quality factors for infant formulas.

* * * * *
    (c) * * *
    (1) The manufacturer requests an exemption and provides assurances, 
as required under Sec.  106.121(b), that the changes made by the 
manufacturer to an existing infant formula are limited to changing the 
type of packaging of an existing infant formula (e.g., changing from 
metal cans to plastic pouches); or
    (2) * * *
    (ii) The change made by the manufacturer to an existing formula 
does not affect the ability of the formula to support normal physical 
growth; or
* * * * *
    (g) * * *
    (1) The manufacturer requests an exemption and provides assurances 
as required under Sec.  106.121(g) that the changes made by the 
manufacturer to an

[[Page 33072]]

existing infant formula are limited to changing the type of packaging 
of an existing infant formula (e.g., changing from metal cans to 
plastic pouches); or
    (2) The manufacturer requests an exemption and provides assurances, 
as required under Sec.  106.121(h), that demonstrate that the change 
made by the manufacturer to an existing formula does not affect the 
bioavailability of the protein.
    (3) The manufacturer requests an exemption and provides assurances, 
as required under Sec.  106.121(i), that demonstrate that an 
alternative method to the PER that is based on sound scientific 
principles is available to demonstrate that the formula supports the 
quality factor for the biological quality of the protein.
* * * * *

0
9. In Sec.  106.100, revise paragraphs (f)(4), (k)(5)(ii), (m), and (o) 
to read as follows:


Sec.  106.100  Records.

* * * * *
    (f) * * *
    (4) Records, in accordance with Sec.  106.30(f), on equipment 
cleaning, sanitizing, and maintenance that show the date and time of 
such cleaning, sanitizing, and maintenance and the production aggregate 
number of each infant formula processed between equipment startup and 
shutdown for cleaning, sanitizing, and maintenance. The person 
performing and checking the cleaning, sanitizing, and maintenance shall 
date and sign or initial the record indicating that the work was 
performed.
* * * * *
    (k) * * *
    (5) * * *
    (ii) The production aggregate number;
* * * * *
    (m) A manufacturer shall maintain all records required under this 
part in a manner that ensures that both the manufacturer and the Food 
and Drug Administration can be provided with access to such records 
within 24 hours. The manufacturer may maintain the records required 
under this part as original records, as true copies such as 
photocopies, microfilm, microfiche, or other accurate reproductions of 
the original records, or as electronic records. Where reduction 
techniques, such as microfilming, are used, suitable reader and 
photocopying equipment shall be readily available. All electronic 
records maintained under this part shall comply with part 11 of this 
chapter.
* * * * *
    (o) The manufacturer shall maintain quality control records that 
contain sufficient information to permit a public health evaluation of 
any production aggregate of infant formula.
* * * * *

0
10. In Sec.  106.120, add paragraph (b)(7) to read as follows:


Sec.  106.120  New infant formula submission.

* * * * *
    (b) * * *
* * * * *
    (7) If the manufacturer is requesting an exemption under Sec.  
106.91(b)(1)(ii), the manufacturer shall include the scientific 
evidence that the manufacturer is relying on to demonstrate that the 
stability of the new infant formula will likely not differ from the 
stability of formulas with similar composition, processing, and 
packaging for which there are extensive stability data.
* * * * *

0
11. In Sec.  106.121 revise paragraphs (d) and (i) and add paragraph 
(j) to read as follows:


Sec.  106.121  Quality factor assurances for infant formulas.

* * * * *
    (d) If the manufacturer is requesting an exemption under Sec.  
106.96(c)(2)(ii), the manufacturer shall include a detailed description 
of the change and an explanation of why the change made by the 
manufacturer to an existing infant formula does not the affect the 
ability of the formula to support normal physical growth.
* * * * *
    (i) If the manufacturer is requesting an exemption under Sec.  
106.96(g)(3), the manufacturer shall include a detailed explanation of 
the alternative method, an explanation of why the method is based on 
sound scientific principles, and the data that demonstrate that the 
quality factor for the biological quality of the protein has been met.
    (j) A statement certifying that the manufacturer has collected and 
considered all information and data concerning the ability of the 
infant formula to meet the requirements for quality factors and that 
the manufacturer is not aware of any information or data that would 
show that the formula does not meet the requirements for quality 
factors.

    Dated: June 4, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-13384 Filed 6-9-14; 8:45 am]
BILLING CODE 4160-01-P


