[Federal Register Volume 79, Number 27 (Monday, February 10, 2014)]
[Rules and Regulations]
[Pages 7933-8075]
[FR Doc No: 2014-02148]

Vol. 79

Monday,

No. 27

February 10, 2014

Part IV

Department of Health and Human Services

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Food and Drug Administration

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21 CFR Parts 106 and 107

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

Federal Register / Vol. 79 , No. 27 / Monday, February 10, 2014 /
Rules and Regulations

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 106 and 107

[Docket No. FDA-1995-N-0036 (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: Interim final rule; request for comments.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
revising our infant formula regulations to establish requirements for
current good manufacturing practices (CGMP), including audits; to
establish requirements for quality factors; and to amend FDA's quality
control procedures, notification, and record and reporting requirements
for infant formula. FDA is taking this action to improve the protection
of infants who consume infant formula products.

DATES: Effective date: This interim final rule is effective July 10,
2014.
    Comment date: Interested persons may submit either electronic or
written comments on this interim final rule by March 27, 2014.
    Paperwork Reduction Act date: Submit comments on information
collection issues under the Paperwork Reduction Act of 1995 by March
12, 2014, (see the ``Paperwork Reduction Act of 1995'' section of this
document). The incorporation by reference of certain publications
listed in the rule is approved by the Director of the Federal Register
as of July 10, 2014.

ADDRESSES: Submit either electronic or written comments on the interim
final rule to the addresses in this ADDRESSES section. To ensure that
comments on information collection are received, the Office of
Information and Regulatory Affairs, 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:
202-395-5806. All comments received must include the Agency name,
Docket No. FDA-1995-N-0036, and RIN number 0910-AF27 for this
rulemaking. You may submit comments, identified by Docket No. FDA-1995-
N-0036 (formerly 95N-0309) and/or RIN number RIN 0910-AF27, by any of
the following methods:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.
     Written Submissions
    Submit written submissions in the following ways:
     Mail/Hand delivery/Courier (for paper or CD-ROM
submissions): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Agency name
and Docket No. FDA-1995-N-0036 (formerly 95N-0309) and RIN 0910-AF27
for this rulemaking. All comments received may be posted without change
to http://www.regulations.gov, including any personal information
provided. For additional information on submitting comments, see the
``Comments'' heading of the SUPPLEMENTARY INFORMATION section of this
document.
    Docket: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov and insert the
docket number(s), found in brackets in the heading of this document,
into the ``Search'' box and follow the prompts and/or go to the
Division of Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville,
MD 20852.

FOR FURTHER INFORMATION CONTACT: Benson M. Silverman, Office of
Nutrition, Labeling, and Dietary Supplements (HFS-850), Center for Food
Safety and Applied Nutrition, Food and Drug Administration, 5100 Paint
Branch Parkway, College Park, MD 20740,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

Executive Summary

Purpose of the Interim Final Rule

    FDA is issuing this interim final rule to fulfill the statutory
mandate set forth in section 412 of the Federal Food, Drug, and
Cosmetic Act (the FD&C Act) (21 U.S.C. 350a) for the Secretary of
Health and Human Services (the Secretary), and by delegation FDA, to
establish requirements for quality factors for infant formulas and good
manufacturing practices, including quality control procedures. The
requirements in this interim final rule will prevent the manufacture of
adulterated infant formula and ensure that the nutrients in the infant
formula are present in a form that is bioavailable and safe. Congress
passed the Infant Formula Act of 1980 (the Infant Formula Act) (Pub. L.
96-359), which amended the FD&C Act to include section 412. 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 practice (CGMP), recordkeeping, and recall
requirements for infant formula. The requirements in this interim 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 interim final rule implements the
remaining provisions of the 1986 amendments, including provisions for
CGMPs and quality factor requirements.

Summary of Legal Authority

    Section 412 of the FD&C Act provides FDA with the authority to
establish requirements for quality factors, CGMPs, quality control
procedures, registration, submission, notification, and records and
reports. Specifically, FDA's authority to establish requirements for
quality factors is derived from section 412(b)(1) of the FD&C Act. The
authority to establish requirements for CGMPs and quality control
procedures derives from section 412(b)(2) and (b)(3) of the FD&C Act.
FDA also has authority to establish requirements for registration,
submission, and notification under section 412(c) and (d) of the FD&C
Act, respectively. Finally, a number of specific authorities in section
412 of the FD&C Act provide FDA with authority to establish
requirements for records and reports, e.g., section 412(b)(4)(A)
related to record retention for good manufacturing practices and
quality control procedures, audits and complaints. Moreover, section
701(a) of the FD&C Act (21 U.S.C. 371(a)), when coupled with other
provisions of section 412 of the FD&C Act, provides FDA with the
authority to issue records requirements that are necessary for the
efficient enforcement of section 412.
    Sections 701(a) and 402 of the FD&C Act (21 U.S.C. 371(a) and 342)
provide additional authority to establish requirements to prevent
adulteration.

Summary of the Major Provisions of the Interim Final Rule

Current Good Manufacturing Practice

    This interim final rule issues comprehensive CGMP requirements for

the manufacture of infant formula by establishing a framework in which
specific process and control decisions are assigned to the formula
manufacturer; i.e., it specifies the result to be achieved and does not
prescriptively mandate how the manufacturer must achieve the result.
    Under Sec.  106.6, the interim final rule requires manufacturers to
implement a system of production and in-process controls that covers
all stages of processing. The system must be set out in a written plan
or set of procedures that includes establishment of specifications and
corrective action plans, documented reviews and material disposition
decisions for articles not meeting a specification, and the quarantine
of any article that fails to meet a specification pending completion of
a documented review and material disposition decision.
    The interim final rule also includes specific controls to prevent
adulteration by workers (Sec.  106.10), facilities (Sec.  106.20),
equipment or utensils (Sec.  106.30), automatic (mechanical or
electronic) equipment (Sec.  106.35), and ingredients, containers, and
closures (Sec.  106.40). Under Sec.  106.50, manufacturers are required
to prepare and follow a written master manufacturing order that
establishes controls and procedures for the production of an infant
formula. In addition, controls are specified to prevent adulteration
during packaging and labeling (Sec.  106.60) and on the release of
finished infant formula (Sec.  106.70). The interim final rule also
requires that infant formula be coded with a sequential number that
permits identification of the product including the location where it
was packed and tracing of all stages of manufacture (Sec.  106.80).
    Controls are also required to prevent adulteration of infant
formula from microorganisms (Sec.  106.55). Because powdered infant
formulas are not sterile products, the interim final rule requires
testing of representative samples of powdered infant formula at the
final product stage, before distribution, and establishes values for
two microorganisms, Cronobacter spp. and Salmonella spp.

Quality Control Procedures

    The interim final rule revises FDA's existing infant formula
quality control procedures regulations to implement the 1986
amendments. Under Sec.  106.91, the revised regulations require in-
process and final product testing of infant formula to ensure that all
required and added nutrients are present at appropriate levels. The
revised regulations also require comprehensive stability testing for
new infant formula and routine stability for subsequently produced
infant formula.

Audits

    The interim final rule includes requirements for audits under
Sec. Sec.  106.90, 106.92, and 106.94. Regularly scheduled audits of
CGMP and quality control procedures must be conducted according to a
written audit plan at a frequency required to ensure compliance with
the provisions of the interim final rule.

Quality Factors

    The interim final rule identifies two infant formula quality
factors, normal physical growth and sufficient biological quality of
the formula's protein component, and establishes requirements for the
two quality factors in Sec.  106.96. Under the interim final rule,
quality factors are defined as those factors necessary to demonstrate
the bioavailability and safety of a formula, including the
bioavailability of individual nutrients, to ensure healthy growth
(Sec.  106.3).
    To establish that an infant formula supports normal physical
growth, the interim final rule requires under Sec.  106.96(b) that a
manufacturer conduct a growth monitoring study (GMS) of the formula
(unless the formula qualifies for an exemption). To establish
biological protein quality, the interim final rule requires under Sec.
106.96(f) that a manufacturer conduct a Protein Efficiency Ratio (PER)
rat bioassay.
    The interim final rule's quality factor requirements apply to all
infant formulas. Because, prior to this interim final rule, there were
no established quality factors and no quality factor requirements, a
formula manufacturer was not required to demonstrate to FDA that the
formula supports normal physical growth or that its protein was of
sufficient biological quality. Therefore, we provide a more flexible
means for a manufacturer of a formula that is ``not new'' (i.e., a
currently marketed or previously marketed formula) to demonstrate
satisfaction of the two quality factors (Sec.  106.96(i)). The more
flexible standards will allow manufacturers, as appropriate, to rely on
existing scientific data and information and to voluntarily submit
quality factor data and information on a specific infant formula
formulation to FDA for evaluation.

Records and Reports

    The majority of the interim final rule's records and reports
provisions are designed to support or otherwise help to actualize other
interim final rule requirements. Manufacturers of infant formula are
required to establish and maintain various records that help
demonstrate compliance with the quality factor, CGMP, quality control
procedure, registration, submission, and notification requirements. For
example, the interim final rule includes a requirement (Sec.
106.100(e)(5)(ii)) that a manufacturer establish and maintain records
of the microbiological testing of infant formula required under Sec.
106.55.

Registration, Submission, and Notification Requirements

    The registration requirements under Sec.  106.110 of the interim
final rule require infant formula manufacturers to provide FDA with up-
to-date information about firms producing infant formula for U.S.
distribution. Furthermore, the notification requirements under
Sec. Sec.  106.120 and 106.121 require an infant formula manufacturer
to submit scientific data and information to FDA to demonstrate that a
new infant formula contains all required nutrients, is produced
consistent with the interim final rule's CGMP and quality control
requirements, and meets established quality factors. The submission
provisions also permit a manufacturer of infant formula for export only
to make an alternative submission that provides assurances that the
relevant export provisions of the FD&C Act are satisfied and that the
manufacturer has established adequate controls to ensure that these
formulas are actually exported.

Costs and Benefits

    The estimated cost of the interim final rule is $7.29 million in
the first year and $4.06 million in subsequent years. The estimated
benefit to public health from this interim final rule is $10.00 million
annually, resulting in total net benefits of $2.71 million in the first
year and $5.94 million in subsequent years.

                                            Benefit and Cost Overview
                                                  [In millions]
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                                                                     Benefits          Costs       Net Benefits
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Total First Year................................................          $10.00           $7.29           $2.71
Annual Total After the First Year...............................          $10.00           $4.06           $5.94
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Table of Contents

I. Background
II. Highlights of the Interim Final Rule and Summary of Significant
Changes Made to the Proposed Rule
III. Legal Authority
IV. General Comments and Subpart A--General Provisions
    A. General Comments
    B. Status and Applicability of the Regulations (Proposed Sec.
106.1)
    C. Definitions (Proposed Sec.  106.3)
V. Subpart B--Current Good Manufacturing Practice
    A. General Comments
    B. Current Good Manufacturing Practices (Proposed Sec.  106.5)
    C. Production and In-Process Control System (Proposed Sec.
106.6)
    D. Controls to Prevent Adulteration by Workers (Proposed Sec.
106.10)
    E. Controls to Prevent Adulteration Caused by Facilities
(Proposed Sec.  106.20)
    F. Controls to Prevent Adulteration Caused by Equipment or
Utensils (Proposed Sec.  106.30)
    G. Controls to Prevent Adulteration Due to Automatic (Mechanical
or Electronic) Equipment (Proposed Sec.  106.35)
    H. Controls to Prevent Adulteration Caused by Ingredients,
Containers, and Closures (Proposed Sec.  106.40)
    I. Controls to Prevent Adulteration During Manufacturing
(Proposed Sec.  106.50)
    J. Controls to Prevent Adulteration From Microorganisms
(Proposed Sec.  106.55)
    K. Controls to Prevent Adulteration During Packaging and
Labeling (Proposed Sec.  106.60)
    L. Controls on the Release of Finished Infant Formula (Proposed
Sec.  106.70)
    M. Traceability (Proposed Sec.  106.80)
    N. Audits of Current Good Manufacturing Practice (Proposed Sec.
106.90)
VI. Subpart C--Quality Control Procedures
    A. General Quality Control (Proposed Sec.  106.91)
    B. Audits of Quality Control Procedures (Proposed Sec.  106.92)
VII. Subpart D--Conduct of Audits
VIII. Subpart E--Quality Factors
    A. Quality Factors: Legal Authority
    B. Quality Factors for Infant Formulas
    C. Quality Factor: Normal Physical Growth
    D. Exemptions From Quality Factor Requirements for Normal
Physical Growth
    E. Quality Factor: Protein Quality
    F. Exemption From the Quality Factor of Protein Quality
Sufficiency
    G. Miscellaneous Comments on the Quality Factor for Sufficient
Biological Quality of Protein
    H. Application of Quality Factors to Currently Marketed and
Previously Marketed Formulas
    I. Records Demonstrating Compliance with the Quality Factor
Requirements for Infant Formulas That Are Not Eligible Infant
Formulas
    J. Establishment of Other Quality Factors
    K. Miscellaneous Comments on Quality Factors
IX. Subpart F--Records and Reports
    A. General Comments on Records (Proposed Sec.  106.100)
    B. Production Aggregate Production and Control Records (Proposed
Sec.  106.100(e))
    C. Records of CGMP (Proposed Sec.  106.100(f))
    D. Records on Infant Formula for Export Only (Proposed Sec.
106.100(g))
    E. Means of Recordkeeping (Sec.  106.100(m))
    F. Records of Quality Factors (Sec.  106.100(p) and (q))
    G. Adulteration as a Consequence of the Failure to Keep Records
(Sec.  106.100(r))
X. Subpart G--Registration, Submission, and Notification
Requirements
    A. General Comments
    B. New Infant Formula Registration (Proposed Sec.  106.110)
    C. New Infant Formula Notifications (Proposed Sec.  106.120)
    D. Quality Factor Submissions for Infant Formula (Proposed Sec.
106.121)
    E. Verification Submissions (Proposed Sec.  106.130)
    F. Submission Concerning a Change in Infant Formula That May
Adulterate the Product (Proposed Sec.  106.140)
    G. Notification of an Adulterated or Misbranded Infant Formula
(Proposed Sec.  106.150)
    H. Incorporation by Reference
XI. Conforming Amendments to Part 107
XII. Environmental Impact
XIII. Federalism
XIV. Regulatory Impact Analysis for Interim Final Rule
XV. Paperwork Reduction Act of 1995
XVI. Comments
XVII. References

I. Background

    The Infant Formula Act amended the FD&C Act to include section 412.
This law was intended to improve protection of infants consuming infant
formula products by establishing greater regulatory control over the
formulation and production of infant formula. In 1982, FDA adopted
infant formula recall procedures in subpart D of part 107 (21 CFR part
107, subpart D) of its regulations (47 FR 18832, April 30, 1982), and
infant formula quality control procedures in subpart B of part 106 (21
CFR part 106, subpart B) (47 FR 17016, April 20, 1982). In 1985, FDA
further implemented the Infant Formula Act by establishing subparts B,
C, and D in part 107 regarding the labeling of infant formula, exempt
infant formulas, and nutrient requirements for infant formula,
respectively (50 FR 1833, January 14, 1985; 50 FR 48183, November 22,
1985; and 50 FR 45106, October 30, 1985).
    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 that had been expressed by Congress and consumers
about the Infant Formula Act and its implementation related to the
sufficiency of quality control testing, CGMP, recordkeeping, and recall
requirements. The 1986 amendments: (1) Provide that an infant formula
is deemed to be adulterated if it fails to provide certain required
nutrients, fails to meet quality factor requirements established by the
Secretary (and, by delegation, FDA), or if it is not processed in
compliance with the CGMP and quality control procedures established by
the Secretary; (2) require the Secretary to issue regulations
establishing requirements for quality factors and CGMP, including
quality control procedures; (3) require infant formula manufacturers to
audit their operations regularly to ensure that those operations comply
with CGMP and quality control procedure regulations; (4) require a
manufacturer to make a submission to FDA when there is a major change
in an infant formula or a change that may affect whether the formula is
adulterated; (5) specify the required nutrient quality control testing
for each batch of infant formula; (6) modify the infant formula recall
requirements; and (7) authorize the Secretary to establish requirements
for records retention, including records necessary to demonstrate
compliance with CGMP and quality control procedures. In 1989, the
Agency implemented the provisions on recalls (sections 412(f) and (g)
of the FD&C Act) by establishing subpart E in part 107 (54 FR 4006,
January 27, 1989). In 1991, the Agency implemented the provisions on
records and record retention requirements by revising Sec.  106.100 (56
FR 66566, December 24, 1991).

    On July 9, 1996, FDA published a notice of proposed rulemaking (the
1996 proposal) to implement the remaining provisions of the 1986
amendments (61 FR 36154). Specifically, FDA proposed to amend the
infant formula regulations in parts 106 and 107 to: (1) Establish good
manufacturing practices, including microbiological testing, to minimize
production of adulterated infant formula; (2) revise the quality
control procedures in part 106 to ensure that an infant formula
contains the level of nutrients necessary to support infant growth and
development, both when the formula enters commerce and throughout its
shelf life; (3) specify the audit procedures necessary to ensure that
operations comply with CGMP and quality control procedure regulations;
(4) establish requirements for quality factors to ensure that the
required nutrients will be in a bioavailable form; (5) establish batch
and good manufacturing recordkeeping requirements; (6) specify the
submission requirements for registration and notification to the Agency
before the introduction of an infant formula into interstate commerce;
and (7) update part 107 to reflect the 1986 amendments and the November
1992 reorganization of the Center for Food Safety and Applied Nutrition
(CFSAN).
    FDA initially opened the comment period for the 1996 proposal for
90 days and subsequently extended it upon request for another 60 days
(61 FR 49714, September 23, 1996).
    Following publication of the proposed rule in September 1996, FDA
convened three meetings of FDA's Food Advisory Committee (FAC) or
subcommittees of the FAC to address issues related to the regulation of
infant formula. On April 4 and 5, 2002, the FAC met to discuss general
scientific principles related to quality factors for infant formula.
The FAC also discussed the scientific issues related to the
generalization of findings from a clinical study using preterm infant
formula consumed by preterm infants to a different formula in a
different population (a term infant formula intended for use by term
infants). At a meeting on November 18 and 19, 2002, the Infant Formula
Subcommittee (IFS) of the FAC discussed the scientific issues and
principles involved in assessing and evaluating whether a ``new''
infant formula supports normal physical growth in infants when consumed
as a sole source of nutrition. Finally, the Contaminants and Natural
Toxicants Subcommittee (CNTS) of the FAC met on March 18 and 19, 2003,
and discussed the scientific issues and principles involved in
assessing and evaluating Enterobacter sakazakii contamination in
powdered infant formula, risk reduction strategies based on available
data, and research questions and priorities. (The organism E. sakazakii
was reclassified in 2008 to a new genus, Cronobacter spp.) (Ref. 1).
    In the Federal Register of April 28, 2003 (68 FR 22341) (the 2003
reopening), FDA reopened the comment period for the proposed rule to
update comments generally and to receive new information based on the
three FAC meetings held in 2002 and 2003. FDA specifically requested
comment on the following issues related to these meetings: (1) Whether
there is a need for a microbiological requirement for E. sakazakii, and
if so, what requirement the Agency should consider to ensure safety and
whether a stricter standard was needed for powdered infant formula to
be consumed by premature and newborn infants; (2) what changes, if any,
in the proposed microbiological requirements would be needed to ensure
the safety of powdered infant formula to which microorganisms are
intentionally added; (3) which provisions in the proposed rule would
require changes to manufacturers' current activities, and a request for
information on the types of control systems used to separate materials
and types of air filtration systems and associated costs of making
changes in each case; (4) current quality control activities by
manufacturers related to validation of automated systems and FDA's
proposed validation requirements; (5) current frequency and conditions
of calibration of instruments and controls by manufacturers and the
adequacy of such procedures; (6) quality factor issues, including
sufficiency of protein quality and normal physical growth as quality
factors, and when clinical growth studies are required for a new or
reformulated infant formula; which growth reference should be the
standard of comparison for infant growth; and duration of study and
enrollment age; and (7) removal of the reference to Institutional
Review Board (IRB) review and informed consent from the proposed rule
as the requirements are now codified in 21 CFR parts 50 and 56, and
removal of the other clinical study protocol provisions from the
proposed rule for consideration in a future guidance document.
    Interested persons were originally given until June 27, 2003, to
comment on these issues and the 1996 proposal. However, in response to
a request, the comment period was extended to August 26, 2003 (68 FR
38247, June 27, 2003).
    Based on three reports published after the 2003 reopening, FDA
again reopened the comment period on August 1, 2006 (71 FR 43392) (the
2006 reopening), for 45 days to accept comment on a limited set of
issues related to these reports. Two reports address microbiological
standards for E. sakazakii and other microbes; the third report
addresses, in part, clinical studies as a means to assess the growth
and development of infants. The reports addressing microbiological
standards are products of a series of expert consultations related to
the efforts of the Codex Committee on Food Hygiene (CCFH) of the Codex
Alimentarius Commission to update the 1979 Recommended International
Code of Hygienic Practice for Foods for Infants and Children (the 1979
Code). These reports (``Enterobacter sakazakii and Salmonella in
Powdered Infant Formula: Meeting Report'' (the 2004 FAO/WHO Report)
(Ref. 2) and ``E. sakazakii and Salmonella spp. in Powdered Infant
Formula'' (the 2006 FAO/WHO Report) (Ref. 3)) were issued by the Food
and Agriculture Organization of the United Nations, World Health
Organization (WHO), in 2004 and 2006 and provide scientific advice
concerning E. sakazakii, Salmonella spp, and other microorganisms in
powdered infant formula. The third report is from the Committee on the
Evaluation of the Addition of Ingredients New to Infant Formula, which
the Institute of Medicine (IOM) of the National Academy of Sciences
(NAS) convened at the request of FDA and Health Canada, FDA's Canadian
counterpart. The purpose of the report was, in part, to evaluate the
performance of a new infant formula. The committee made several
recommendations regarding growth studies, including the recommendation
that ``Growth studies should include precise and reliable measurements
of weight and length velocity and head circumference. Duration of
measurements should cover at least the period when infant formula
remains the sole source of nutrients in the infant diet.'' (Ref. 4, p.
108).
    In reopening the comment period in August 2006, FDA requested
comment on the following issues:
     Whether FDA should require a microbiological standard for
E. sakazakii for powdered infant formula of negative in 30 x 10 gram
(g) samples;
     Whether FDA should require microbiological standards for
aerobic plate count, coliforms, fecal coliforms, Listeria
monocytogenes, Bacillus cereus, and Staphylococcus aureus;

     Whether FDA should require measurements of healthy growth
beyond the two proposed quality factors of normal physical growth (as
measured by body weight, recumbent length, head circumference, and
average daily weight increment) and protein quality;
     Whether FDA should require a measure for body composition
as an indicator of normal physical growth, and if so, what measure; and
     Whether FDA should require that the duration for a
clinical study, if required, be no less than 15 weeks, and commence
when infants are no older than 2 weeks of age.

II. Highlights of the Interim Final Rule and Summary of Significant
Changes Made to the Proposed Rule

    The highlights of this interim final rule are as follows:
     FDA is establishing CGMP requirements for the production
of nonexempt infant formula. FDA is also clarifying the current
requirements related to the validation of manufacturing systems and the
establishment of specifications in the manufacture of infant formula.
     FDA is establishing requirements for microbiological
quality to prevent adulteration of powdered infant formula.
     FDA is establishing requirements for quality factors to
provide assurance that, as a sole source of nutrition, an infant
formula supports infants' healthy growth. These provisions include a
requirement to conduct an adequate and well-controlled growth
monitoring study to measure physical growth and exemptions from the
requirement to conduct such a study.
     FDA is establishing requirements for recordkeeping and
reports that, where possible, reduce redundancy.

III. Legal Authority

    FDA's authority to issue regulations that establish requirements
for quality factors, current good manufacturing practices, quality
control procedures, registration, submission, notification, and records
and reports is derived from section 412 of the FD&C Act. FDA also
relies on other sections of the FD&C Act, including sections 701(a) and
402 (21 U.S.C. 371(a) and 342). The regulations in this interim final
rule are consistent with FDA's explicit statutory mission, which 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))). The
regulations are also consistent with the overall purpose of section 412
of the FD&C Act (see Pub. L. 96-359, 94 Stat. 1190, 1190 (1980)
(stating the purpose of the Infant Formula Act is to provide for the
``safety and nutrition'' of infant formula)).
    FDA's authority to establish requirements for quality factors is
explicit in section 412(b)(1) of the FD&C Act, which states that the
``Secretary shall by regulation establish requirements for quality
factors.'' Infant formulas that are not in compliance with the quality
factor requirements are adulterated under section 412(a)(2) of the FD&C
Act. In section IV of this interim final rule FDA defines ``quality
factors,'' and in section VIII FDA establishes specific quality factor
requirements.
    Similarly, FDA's authority to establish current good manufacturing
practices and quality control procedure requirements is explicit in
section 412(b)(2) of the FD&C Act. Section 412(b)(2) of the FD&C Act
specifies certain overarching requirements that must be included as
part of CGMP and quality control procedure requirements. Specifically,
the section states that the ``Secretary shall by regulation establish
good manufacturing practices for infant formulas, including quality
control procedures that the Secretary determines are necessary to
assure that an infant formula . . . is manufactured in a manner
designed to prevent adulteration of the infant formula.'' Infant
formulas that are not in compliance with the CGMP and quality control
procedure requirements are adulterated under section 412(a)(3) of the
FD&C Act. In addition, the failure to comply with certain CGMP
requirements will result in the infant formula being adulterated under
sections 402(a)(1), (a)(2), (a)(3), or (a)(4) of the FD&C Act. Although
Congress has identified specific provisions that must be included as
CGMP and quality control procedure requirements (see section 412(b)(2)
and (b)(3) of the FD&C Act), it did not prescribe all such
requirements. Rather, Congress left a gap for FDA to prescribe, by
regulation, such other practices and procedures necessary to ensure the
nutrient content of infant formula and prevent adulteration under
section 412(b)(2) of the FD&C Act.
    In addition, FDA has explicit authority under sections 412(c), (d),
and (e) of the FD&C Act to establish registration, submission, and
notification requirements, respectively. Section 412(c)(1)(A) of the
FD&C Act states that no person may introduce a new infant formula into
interstate commerce, unless the person has ``registered with the
Secretary the name of such person, the place of business of such
person, and all establishments at which such person intends to
manufacturer such infant formula.'' The registration requirements in
the interim final rule set forth the information that must be included
in a new infant formula registration sent to FDA.
    Further, the interim final rule sets forth the information that
must be included in a new infant formula submission to FDA. Section
412(d) of the FD&C Act requires that a manufacturer make an infant
formula submission and describes the type of information that must be
included in such submission. For example, section 412(d)(1)(A) of the
FD&C Act requires that the submission include the quantitative
formulation of the formula. Additionally, section 412(d)(1)(C) of the
FD&C Act requires, in part, assurances that the infant formula will not
be marketed unless it meets the requirements of section 412(b)(1) of
the FD&C Act (quality factor requirements). Section 412(d)(1)(D) of the
FD&C Act requires assurances that the formula will not be marketed
unless the processing of the formula complies with section 412(b)(2) of
the FD&C Act (the CGMP and quality control procedure requirements). The
interim final rule prescribes requirements for the assurances required
by these sections of the FD&C Act.
    The notification requirements in the interim final rule describe
when a notification must be provided to FDA, as required by section
412(e) of the FD&C Act. Section 412(e) of the FD&C Act sets forth the
circumstances in which a manufacturer must notify FDA that an infant
formula processed by the manufacturer has left an establishment under
the manufacturer's control and may be adulterated or misbranded.
    FDA also has authority to establish requirements for records under
section 412(b)(4)(A) of the FD&C Act. This interim final rule includes
record requirements for CGMP and quality control procedures and for the
conduct of audits. For example, under section 412(b)(4)(A)(i) of the
FD&C Act, FDA has authority to establish recordkeeping requirements
necessary to demonstrate compliance with CGMP and quality control
procedure requirements, including records containing the results of all
testing designed to prevent the adulteration of infant formula. Thus,
FDA is establishing requirements in this interim final rule for
manufacturers to make and retain records that include complete
information relating to the production and control of each production
aggregate (for discussion of this term see section IV.C.1 of this
document) of infant formula to ensure

compliance with the CGMP and quality control procedure requirements
related to the production aggregate. Specifically, Sec.  106.100(e)
requires manufacturers to make and retain records that include complete
information relating to the production and control of the production
aggregate. Information about the processing of the production aggregate
is important to the manufacturer, which must ensure that it is
producing the formula it intends to produce under the master
manufacturing order. In addition, if a problem arises from a particular
production aggregate of formula, such records will assist the
manufacturer and FDA in identifying the source of the problem and what
action may be necessary to correct it. For example, Sec.  106.100(e)(3)
requires documentation of the monitoring at any point, step, or stage
in the production process where control is deemed necessary to prevent
adulteration.
    Moreover, FDA has authority to establish record requirements under
other provisions of section 412 of the FD&C Act, as well as section
701(a) of the FD&C Act. For example, as is discussed in greater detail
in section VIII, it is necessary for manufacturers to create records
pertaining to a growth monitoring study in order to determine whether
their infant formula meets the quality factor requirement of normal
physical growth established under section 412(b)(1) of the FD&C Act. It
is also necessary for the enforcement of section 412(a)(2) of the FD&C
Act, with respect to meeting quality factor requirements, for FDA to
require records pertaining to a growth monitoring study, when such a
study is required. Without such records, FDA cannot determine whether
the quality factor requirements have been met. Additionally, FDA has
authority under section 701(a) of the FD&C Act, when coupled with the
specific authorities granted to FDA under section 412 of the FD&C Act,
to establish record requirements that are necessary for the efficient
enforcement of the FD&C Act.

IV. General Comments and Subpart A--General Provisions

    During the three periods provided for comments, FDA received a
number of comments in response to the proposed rule. Some of the
comments supported the proposal generally or supported aspects of the
proposal. Other comments objected to specific provisions and requested
revisions. A few comments addressed issues outside the scope of the
proposal and will not be discussed in this document. To make it easier
to identify comments and FDA's responses to the comments, the word
``Comment'' will appear in parentheses before the description of the
comment, and the word, ``Response'' will appear in parentheses before
FDA's response. FDA has also numbered each comment to make it easier to
identify a particular comment. The number assigned to each comment is
for organizational purposes only and does not signify the comment's
value, importance, or the order in which it was submitted. Comments
generally are not distinguished by year of receipt.

A. General Comments

    The general comments discussed in this section are those that
addressed the rule in its entirety.
    (Comment 1) One comment stated that many provisions of the infant
formula proposal are ``overly redundant'' with other FDA laws and
regulations, such as the food CGMP and food additive regulations. These
redundancies include personnel requirements and the permitted use of
food ingredients and food contact materials. The comment claims that
these redundancies do not provide the public with greater protection,
but serve only to create unnecessary confusion in those plants
manufacturing both infant formulas and similar products not intended
for use by infants. The comment noted that FDA's stated intent in
promulgating the food CGMP regulations was to have those regulations
function as ``umbrella'' regulations, to which FDA would add additional
regulations targeted at specific industries.
    (Response) As stated in the proposed rule, the CGMP requirements
for infant formula are based, in part, on FDA's existing regulations
concerning CGMP for foods (61 FR 36154 at 36157). Infant formulas are
food, and thus, the Agency would expect that certain CGMP requirements
for infant formula would parallel the CGMP provisions in part 110 (21
CFR part 110).
    FDA disagrees, however, that many provisions of the infant formula
rule are overly redundant with other FDA laws and regulations. The food
CGMP regulations (part 110) predate the 1986 amendments. Thus, Congress
was aware of these regulations at the time of the 1986 amendments when
it established an explicit mandate for infant formula CGMP. By
mandating that FDA establish good manufacturing practices, including
quality control procedures, Congress recognized that requirements in
addition to the food CGMP were necessary for infant formula. The CGMP
regulations established by this interim final rule implement Congress'
express mandate. As noted, section 412(b)(2)(A) of the FD&C Act
specifically mandates that FDA establish CGMP for infant formula: ``The
Secretary shall, by regulation, establish good manufacturing practices
for infant formulas, including quality control procedures that the
Secretary determines are necessary to assure that an infant formula
provides nutrients in accordance with [section 412] and is manufactured
in a manner designed to prevent adulteration of the infant formula.''
In addition, section 412(a)(3) of the FD&C Act provides that an infant
formula is deemed to be adulterated if ``the processing of such infant
formula is not in compliance with the good manufacturing practices and
the quality control procedures prescribed by the Secretary'' under
section 412(b)(2). This provision of section 412 of the FD&C Act
underscores the Congressional determination that product-specific CGMP
requirements are necessary for infant formula.
    Moreover, the purpose of section 412 of the FD&C Act is to ensure
product safety for the vulnerable population that consumes infant
formula. To this end, FDA may include CGMP requirements in this interim
final rule that are the same or similar to those found in 21 CFR part
110 for foods in general. FDA has included in this interim final rule
the part 110 requirements that are common to most or all infant formula
manufacturing. The Agency recognizes that there may be aspects of
infant formula manufacturing operations for which certain provisions in
part 110 apply, but that FDA did not determine to be common to most
infant formula manufacturing operations. Infant formula manufacturers
are responsible for understanding and following all of the regulations
that govern their products even if the regulations are not in parts 106
and 107.\1\ Thus, a manufacturer is subject to the regulations in part
110 in addition to the regulations in part 106. To the extent that the
regulations conflict, the infant formula manufacturer must comply with
part 106.
---------------------------------------------------------------------------

    \1\ FDA notes that the FDA Food Safety Modernization Act (FSMA)
creates new requirements with respect to food safety and requires
FDA to issue certain regulations. For example, section 103 of FSMA
requires FDA to issue regulations establishing science-based minimum
standards for certain food facilities to conduct a hazard analysis,
document hazards, implement preventive controls, and document
implementation of such preventive controls (Pub. L. 111-353, 124
Stat. 3885 (2011)). The purpose of this interim final rule is not to
implement the requirements of FSMA. Any additional requirements in
the rulemakings implementing FSMA that may apply to infant formula
will be addressed in those rulemakings.

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

    In addition, FDA may include CGMP requirements in this interim
final rule concerning the use of lawful ingredients and food packaging
materials. Section 106.40(a) states that only substances that are safe
and suitable under the applicable food safety provisions of the FD&C
Act may be used in infant formulas. Section 106.40(b) requires that
packaging material that comes in contact with infant formula be
composed of substances that are safe and lawful for such use. FDA
disagrees such requirements are ``overly redundant.'' The statute
contains express authority to establish by regulation CGMP requirements
for infant formula to prevent adulteration, in general (see section
412(b)(2)(A) of the FD&C Act) and to prevent adulteration of each
production aggregate of infant formula, specifically (see section
412(b)(2)(B)(iii) of the FD&C Act). The use of ingredients in the
formula, and of substances in food packaging materials that would come
into contact with the formula, that are safe and lawful is important to
ensuring that each production aggregate of infant formula is not
adulterated. Sections 106.40(a) and (b) help to ensure that appropriate
manufacturing processes are in place such that only safe and lawful
food ingredients and food packaging materials are used to manufacture
infant formula, a food intended for consumption by a vulnerable
population. These requirements are necessary to ensure the safety of
all of the formula's ingredients and food packaging materials used in
the manufacture of an infant formula to prevent adulteration of the
infant formula. A failure to do so would result in the infant formula
being deemed adulterated under section 412 of the FD&C Act.
    For the reasons set forth previously in this document, the Agency
is making no changes to the language set forth in the proposed rule in
response to this comment.
    (Comment 2) One comment stated that since the proposed rule was
published, FDA's Center for Drug Evaluation and Research (CDER)
announced a new initiative on August 21, 2002, ``Pharmaceutical CGMP
for the 21st Century: A Risk Based Approach'' (Ref. 5) that involves
significant examination and reevaluation of FDA's drug CGMP. The
comment suggested that the infant formula CGMP may benefit from using
this risk-based drug CGMP initiative as a model and that the infant
formula industry partner with CFSAN in the same way that CDER and other
FDA Centers are partnering with the industries they regulate.
    (Response) In developing this interim final rule, FDA did consider
the drug CGMPs and those for other FDA-regulated products. FDA has on
many occasions held discussions with, solicited comments from, and
partnered with the infant formula industry to work toward a risk-based
philosophy that provides for process control that is scientifically
validated, rather than on a system that is overly reliant on testing.
In addition to the three FAC meetings described previously in this
document, the Agency and the infant formula industry have worked
collaboratively to provide input for the WHO expert consultation on
testing for microorganisms of public health significance in powdered
infant formula, and to provide input on the revision of the Codex
hygienic practices for production of powdered infant formula. In
addition, the Agency has provided opportunities for the public,
including the infant formula industry, to communicate with FDA by
reopening the comment period on the proposed rule on two occasions, and
again by accepting comments upon publication of this interim final
rule. Thus, this rulemaking has been a collaborative process that has
resulted in a sound, risk-based approach to process control for infant
formula manufacture.
    An example of the Agency's risk-based approach is the resolution in
the interim final rule of the requirements for microbiological testing.
As discussed in more detail in section V, in the 1996 proposed rule,
FDA proposed broad microbiological testing requirements for powdered
formula. Upon further evaluation, the Agency determined that most of
the pathogens originally proposed for testing have not been associated
with infant formula. Instead, relying on the WHO risk assessment model
set out in the 2006 FAO/WHO Report (Ref. 3), FDA determined that
Cronobacter spp. (formerly classified as E sakazakii) and Salmonella
spp. are the only two pathogens of concern for powdered infant formula.
Thus, the interim final rule replaces the broad microbiological testing
mandate in the proposal with more narrow, risk-based requirements.
    (Comment 3) One comment asked FDA to acknowledge in the preamble to
the final rule that under the FD&C Act and Sec.  107.50(c) of the
regulations, exempt infant formulas are not subject to the CGMP,
quality control, and quality factor requirements of part 106. The
comment identified some logistical issues associated with the
application of quality factor requirements to exempt infant formulas.
The comment also requested that FDA state in the preamble that during
inspections of special infant formula manufacturing plants (referring
to plants that manufacture exempt infant formula), the Agency will
accept quality control activities other than those articulated in part
106 provided that the manufacturer documents those activities,
demonstrates that the product meets the nutrient requirements of the
FD&C Act, and manufactures the product in a manner designed to prevent
adulteration. The comment stated that FDA should encourage
manufacturers of exempt infant formula to comply voluntarily with part
106, where practical, because exempt formulas should be manufactured to
a high standard of quality.
    (Response) The regulations in Sec.  107.50 pertaining to exempt
infant formula were finalized in 1985 (50 FR 48183) prior to the 1986
amendments. As FDA explained in the 1996 proposal, the Agency intends
to address, in a separate rulemaking, the exempt infant formula
regulations and the effect of the 1986 amendments on exempt infant
formulas (61 FR 36154 at 36201-36202). In the interim, FDA encourages
exempt infant formula manufacturers to use the requirements in this
interim final rule as guidance because infant formulas for use by
infants with inborn errors of metabolism, low birth weight, or other
unusual medical or dietary problems should conform to the same
standards set forth in the requirements of this interim final rule
applicable to formulas for healthy term infants, unless there is a
medical, nutritional, scientific, or technological rationale for a
deviation from such requirements. Elsewhere in this issue of the
Federal Register, FDA is issuing a notice of availability for a draft
guidance document that addresses the application of new part 106 to
exempt infant formulas. Manufacturers are encouraged to consult with
CFSAN prior to the submission of an exempt infant formula submission to
the extent a manufacturer believes there is such a rationale for a
deviation from the provisions of this interim final rule.
    (Comment 4) One comment stated that its review of the authorities
cited in support of the 1996 proposed requirements calls into question
the existence of concrete bases for a number of the proposed
``requirements'' and thus, appears to reflect ``administrative''
expertise and thinking as opposed to practical hands-on experience that
the industry possesses. Another comment emphasized that the real GMP
expertise rests with the infant formula industry, and further argues
that reliance by FDA on Agency administrative expertise in response to
comments, if unsupported

by additional data, outside expert recommendations, or detailed
explanation, may be neither good nor reasonable administrative
practice.
    (Response) FDA disagrees that real GMP ``expertise'' rests only
with industry and disagrees with the comment's suggestion that the
Agency does not have the expertise it needs to establish requirements.
Such assertions are unfounded because FDA does have staff with ``real
GMP expertise'' and, in addition, has consulted with experts outside
the Agency through the FAC process. Moreover, FDA field and compliance
personnel regularly interact with industry staff during inspections and
other compliance activities. FDA has also achieved greater insight into
the industry's concerns by virtue of the extensive comments submitted
by the industry during this lengthy rule-making process. Further, the
comment identifies no specific proposed requirement for which it
questions the underlying support. Accordingly, FDA is making no changes
in response to this comment.
    (Comment 5) One comment stated that many of the provisions in the
proposed regulation are inflexible and overly prescriptive. The comment
requested that FDA establish the results to be achieved in the infant
formula manufacturing process, but not prescribe or limit the ways in
which the required results can be achieved.
    (Response) FDA agrees in part with this comment. To the extent
feasible, FDA is establishing requirements for the manufacturing
process in a way that describes the result to be achieved and does not
specifically mandate how to achieve that result. For example, as noted
in this document, Sec.  106.50(d)(3) mandates that the manufacturer
establish controls for the removal of air from the finished product,
because such controls are necessary to ensure that nutrient
deterioration does not occur. The method used and extent of air removal
are left to the discretion of the manufacturer. In other cases, the
statutory language mandates how to achieve a result, e.g., the vitamins
that must be tested at the final product stage for each batch
(production aggregate) of infant formula to ensure compliance with
required nutrient levels (section 412(b)(3) of the FD&C Act). Specific
statutory mandates are reflected in the interim final rule.
    (Comment 6) One comment submitted in 2003 states that instead of
responding to comments submitted in response to the 1996 proposed rule,
the 2003 comment period reopening merely requests comment again without
giving any indication of FDA's current views on the rule's major
issues. The comment further stated that the 2003 reopening raises new
issues not covered in the proposed rule and fails to provide guidance
on how FDA proposes to address these issues. The comment argued that
the 2003 reopening is at odds with FDA's obligation under the
Administrative Procedure Act (APA) to make its views known to the
public in a concrete and focused form in order to make criticism or
formulation of alternatives possible, and that this format forces
industry to comment on a rule that the public does not see until it is
in final form. Accordingly, this comment requests that FDA permit an
additional round of notice and comment, especially to the extent that
FDA intends to draft regulations addressing new substantive issues not
in the proposed rule.
    (Response) FDA disagrees with the comment's criticism of the 2003
reopening and suggestion that an additional round of notice and comment
on the proposed rule is needed. The 2003 reopening provided a 60-day
comment period that ended on June 27, 2003. FDA extended the reopened
comment period for an additional 60 days to allow interested persons
additional time to comment, as requested in a comment. With this
extension, the public was provided with a total of 120 days to submit
comments during the 2003 reopening.
    As noted previously in this document, in 2003, FDA reopened the
comment period to receive comments on all issues presented by the 1996
proposed rule. Thus, at the time of the 2003 reopening, the 1996
proposal identified FDA's views on the issues in the rulemaking. This
interim final rule only addresses issues that are within the scope of
the original proposal. In light of three meetings that occurred between
the issuance of the 1996 proposal and the 2003 reopening, FDA also
specifically requested in the 2003 reopening comments on a discrete set
of issues that were within the scope of the original proposal. These
issues were explained clearly, and opportunity to provide comments on
these discrete issues, as well as the rule generally, was provided. In
2006, FDA again reopened the comment period on a specific
microbiological standard it was considering for E. sakazakii (now
classified as Cronobacter spp.), in addition to other specific issues.
    Under the APA, in order to provide adequate notice, a proposed
rulemaking, unless a specific exception applies, must include ``either
the terms or substance of the proposed rule or a description of the
subjects and issues involved'' (5 U.S.C. 553(b)(3).) In other words,
the notice must be sufficient to fairly apprise interested parties of
issues involved, but it does not need to specify every precise proposal
which the Agency may ultimately adopt as a rule. Action for Children's
Television v. FCC, 564 F.2d 458, 470 (D.C. Cir. 1977). The notice given
by FDA in the original 1996 proposal, the 2003 reopening, and later in
the 2006 reopening, was sufficient to fairly apprise all interested
parties of the issues involved in the rulemaking. Thus, sufficient
notice has been given and additional opportunity for comment is not
required. Notwithstanding the adequacy of the prior comment periods, we
are accepting comments on this interim final rule. For more details on
the comment period, see part XVI of this document.
    (Comment 7) One 2006 comment objected to the Agency's limiting the
additional 2006 comment period to certain issues and expressed concern
that the effect of this limitation would be to prevent the submission
of information that could have a negative impact on the resolution of
important issues. The comment stated that the limited 2006 reopening
may result in the promulgation of a GMP regulation that does not
reflect current good manufacturing practices and requested that the
entire proposed regulation be reopened and that the public be given the
opportunity to respond to FDA's reactions to the voluminous comments
submitted since 1996.
    (Response) FDA disagrees with this comment. First, the 1996
proposal provided sufficient notice of all issues in this interim final
rule. Further, the 2003 reopening provided the public with a lengthy
opportunity to comment on all issues raised by the 1996 proposal, and
this 2006 comment does not specifically address why an opportunity in
addition to that provided in 2003 is needed to comment on all issues.
Finally, the 2006 reopening provided sufficient notice of the matters
at issue in the reopening. In particular, FDA described the significant
expert consultations held since the 2003 reopening and provided the
Agency's tentative conclusions, including the basis for such
conclusions, relying on the information added to the administrative
record and comments received on such information from the 2003
reopening. Therefore, ample notice and opportunity for comment has been
provided on all aspects of this interim final rule. As noted previously
in this document, however, notwithstanding the adequacy of the prior
comment periods, we are accepting comments on

this interim final rule (see part XVI of this document).

B. Status and Applicability of the Regulations (Proposed Sec.  106.1)

    Proposed Sec.  106.1 described the authority for each subpart of
the proposal and the consequences under the FD&C Act of a failure to
comply with any of the proposed regulations. FDA is including Sec.
106.1 because it is important for those in the infant formula industry
to be aware of the legal consequences of failing to comply with these
regulations, which are being issued to implement specific sections of
the FD&C Act.
    FDA did receive comments supporting Sec.  106.1 as proposed but did
not receive any adverse comments. On its own initiative, however, FDA
is revising Sec.  106.1 to clarify all of the requirements in subparts
F and G of this interim final rule, and also to clarify the legal
consequences of failing to comply with certain requirements in subparts
F and G of the interim final rule.
    Proposed Sec.  106.1(a) stated that subparts B, C, and D prescribe
the steps that shall be taken under section 412(b)(2) and (b)(3) of the
FD&C Act (i.e., CGMP and quality control procedures requirements,
including audit requirements) in processing infant formula, and that
the failure to comply with any regulation under these subparts would
adulterate the formula under section 412(a)(3) of the FD&C Act. While
it is true that subparts B, C, and D describe CGMP and quality control
procedures requirements issued under section 412(b)(2) and (b)(3) of
the FD&C Act, these are not the only subparts of the interim final rule
that contain CGMP and quality control procedures requirements. Subpart
F of this interim final rule prescribes records requirements, some of
which are part of the requirements for CGMP and quality control
procedures issued under the authority of section 412(b)(2) of the FD&C
Act. Additionally, some of the CGMP and quality control procedures
requirements are codified in subpart G of this interim final rule.
Subpart G describes, in part, the content of submissions. Some of the
records that make up the content of these submissions are records made
as part of requirements for CGMP and quality control procedures issued
under the authority of section 412(b)(2).
    Because subparts F and G also contain requirements that are
properly classified as CGMP and quality control procedures requirements
issued under the authority of section 412(b)(2) of the FD&C Act, FDA is
revising proposed Sec.  106.1(c) and (d) to include these requirements
and the authority under which they are issued. FDA is also revising
proposed Sec.  106.1(c) and (d) to explain that the failure to follow
these requirements issued under section 412(b)(2) of the FD&C Act will
result in an infant formula that is deemed to be adulterated under
section 412(a)(3) of the FD&C Act.
    Furthermore, FDA is revising proposed Sec.  106.1(c) and (d) to
describe requirements in subparts F and G that are issued under the
authority of section 412(b)(1) of the FD&C Act, which requires FDA to
establish requirements for quality factors. Proposed Sec.  106.1(b)
stated that subpart E prescribed the quality factor requirements issued
under section 412(b)(1) of the Act. As with CGMP and quality control
procedures requirements, however, quality factor requirements are also
contained in subparts F and G. Some of the records requirements that
are codified in subpart F are records required under the authority to
issue quality factor requirements in section 412(b)(1) of the FD&C Act.
Likewise, some of the records that make up the content of the
submissions required under subpart G of this interim final rule are
required under the authority to issue quality factor requirements under
section 412(b)(1) of the FD&C Act. Therefore, because subparts F and G
contain records requirements that are part of the quality factor
requirements, FDA is also revising proposed Sec.  106.1(c) and (d) to
explain that the failure to follow any quality factor requirements
issued under section 412(b)(1) of the FD&C Act will result in an infant
formula that is deemed adulterated under section 412(a)(2) of the FD&C
Act.

C. Definitions (Proposed Sec.  106.3)

    Section 106.3 of the 1996 proposed rule provided definitions for
the following terms: Batch; final-product-stage; indicator nutrient;
infant; infant formula; in-process batch; lot; lot number, control
number or batch number; major change; manufacturer; microorganism; new
infant formula; nutrient; nutrient premix; quality factors;
representative sample; shall; and should. In the 1996 proposed rule,
each definition in proposed Sec.  106.3 was designated as a
subparagraph of the section using letters (for example, the definition
of ``batch'' was proposed Sec.  106.3(a)). Individual designation of
definitions in a regulation is no longer standard in Federal
regulations. Accordingly, these individual designations have been
removed in the interim final rule and are not used in the discussion in
this document. Consistent with the 1996 proposed rule, the definitions
continue to be listed in alphabetical order.
    No comments suggest modification of the definition of proposed
Sec.  106.3(q) for ``shall'' and thus, it is included, as proposed, in
Sec.  106.3 of the interim final rule. Because all of the provisions in
this interim final rule are mandatory, there is no need for the
definition ``should'' (proposed Sec.  106.3(r)) and accordingly, this
definition is deleted in this interim final rule.
    The comments FDA received on the definitions of final-product-
stage; indicator nutrient; infant; infant formula; nutrient premix; and
representative sample supported the proposed definitions. Thus, these
definitions are included, as proposed, in the interim final rule.
    FDA received comments that suggested revisions to the definitions
of the following terms in the proposed rule: Batch; lot; major change;
manufacturer; microorganism; new infant formula; nutrient; and quality
factors. Based on changes to the proposed definitions of ``lot'' and
``batch,'' FDA has made conforming changes to the proposed definitions
of ``in-process batch'' and ``lot number, control number, or batch
number.'' FDA also received comments that recommended that FDA include
additional definitions of the following terms: Minor change;
responsible party; specifications; target values; and critical. FDA
responds to these comments in this interim final rule.
    In addition, FDA is adding a definition for ``eligible infant
formula'' on its own initiative. As discussed in section VIII, FDA is
adding provisions to the quality factor requirements in Sec.  106.96
that relate to a formula that could have been or was lawfully
distributed in the United States on the 89th day after the publication
of this interim final rule. FDA is describing these formulas as
``eligible infant formulas,'' and for clarity, FDA is adding a
definition in Sec.  106.3 to describe these formulas.
1. Batch (Proposed Sec.  106.3(a) and Lot (Proposed Sec.  106.3(g))
    As described in more detail in this document, FDA believes that
during the course of this rulemaking, two related terms, ``batch'' and
``lot,'' have been used in different ways, potentially causing
confusion. These terms describe two volumes of formula that have
significance in the production of infant formula. At the same time, FDA
has come to understand that the food industry and the drug industry
generally do not use these terms in the same way. This is particularly
relevant because the

definitions originally proposed were based on FDA's drug manufacturing
CGMP regulations in part 210 (21 CFR part 210) and because some formula
manufacturers are part of a larger drug manufacturing firm and others
are part of a larger food manufacturing firm. Accordingly, in order to
achieve necessary clarity, the interim final rule establishes and
defines two new terms, ``production unit'' and ``production
aggregate,'' which are substituted for the terms ``batch'' and ``lot''
used in the earlier stages of this rulemaking.
    The discussion that follows recounts the background and history of
the use of the terms ``batch'' and ``lot'' in this rulemaking.
    In current industry practice, two volumes of formula have
significance during the infant formula manufacturing phase: the
quantity of formula that can be mixed in the production equipment at
one time (the relatively smaller volume) and the amount of formula
manufactured during a single production run (the relatively larger
volume.) With a continuous production process (which is used by all
formula manufacturers), the larger volume is necessarily somewhat co-
mingled because there is no cleaning between production of each smaller
volume, and in fact, may be purposefully co-mingled through the
combination of several smaller volumes to create a single larger
volume. Generally speaking, the larger volume is the production volume
of particular interest to the formula manufacturer. At certain times,
the quantity produced during a single production run may be a much
smaller amount. In most cases, the production of two different larger
volumes of formula (two different production runs) will be separated by
an intervening cleaning of the production equipment. Manufacturers
currently sample from the final volume produced from a single
production run, which may include co-mingled volumes, for testing both
for nutrients and for microbial contamination.
    Although section 412 uses the term ``batch,'' the term is not
defined. Specifically, section 412(b)(2)(B)(i) of the FD&C Act (21
U.S.C. 350a(b)(2)(B)(i)) requires testing of ``each batch of infant
formula'' for nutrients prior to distribution of the ``batch;'' section
412(b)(3)(A) of the FD&C Act (21 U.S.C. 350a(b)(3)(A)) requires that
``at the final product stage, each batch of infant formula'' shall be
tested for certain vitamins; and section 412(b)(3)(C) of the FD&C Act
(21 U.S.C. 350a(b)(3)(C)) requires that ``during the manufacturing
process or at the final product stage and before distribution,''
(emphasis added) the formula shall be tested for all nutrients; and
section 412(b)(3)(D) (21 U.S.C. 350a(b)(3)(D)) requires that if a
nutrient is added to the list in section 412(i) of the FD&C Act (21
U.S.C. (350a(i)), the Secretary shall require that the manufacturer
test ``each batch.'' Section 412(b)(2)(E) of the FD&C Act (21 U.S.C.
350a(b)(2)(E)) defines ``final product stage'' as ``the point in the
manufacturing process, before distribution of an infant formula, at
which an infant formula is homogenous and not subject to further
degradation.'' The fact that section 412 of the FD&C Act either
requires or permits testing of each ``batch'' of a formula at the
``final product stage'' illustrates that Congress used the term
``batch'' to mean the relatively larger, often co-mingled portion of
formula in which individually mixed portions of formula are combined.
    Unlike ``batch,'' the term ``lot'' is not used in section 412 of
the FD&C Act. The 1996 proposed rule included definitions for ``batch''
and ``lot'' (proposed Sec.  106.3(a) and (g), respectively.) These
definitions were derived from FDA's drug CGMP regulations in part 210.
The proposed rule defined ``batch'' to mean ``a specific quantity of an
infant formula or other material that is intended to have uniform
character and quality, within specified limits, and is produced
according to a single manufacturing order during the same cycle of
manufacture.'' The proposed rule defined ``lot'' to mean ``a batch, or
a specifically identified portion of a batch, having uniform character
and quality within specified limits; or, in the case of an infant
formula produced by continuous process, it is a specific identified
amount produced in a unit of time or quantity in a manner that assures
its having uniform character and quality within specified limits.''
    The proposed rule stated that it was important to maintain
consistency throughout FDA's regulations. Therefore, where possible and
appropriate, the proposed definitions relied on FDA's regulations in
part 210, the CGMP for drugs. Specifically, the definitions in the
proposed rule for ``batch,'' ``lot,'' ``lot number, control number, or
batch number,'' and ``representative sample'' were based on the
definitions in part 210.
    The proposed definitions of ``batch'' and ``lot'' contemplated that
infant formula would be produced in bulk, that ``batch'' was considered
the relatively larger volume, that ``lot'' was the relatively smaller
volume, and that more than one ``lot'' could comprise a ``batch.'' The
1996 proposed rule (Sec.  106.55) used the term ``batch'' when
describing the requirements for evaluating the microbiological quality
of powdered formula at the final product stage.
    In 2006, following the emergence of Enterobacter sakazakii as a
contaminant in powdered infant formula, FDA reopened the comment period
on the 1996 proposal to receive comments on the microbiological testing
scheme. (The organism E. sakazakii was reclassified in 2008 to new
genus, Cronobacter spp. (Ref. 1).) In that reopening, FDA proposed a
new microbiological testing scheme for powdered infant formula. The
revised testing requirement proposed in the 2006 reopening was confined
to testing for E. sakazakii and Salmonella ssp. This change was based
on the findings of the 2006 FAO/WHO Report (Ref. 3) which provided, for
the first time, a risk assessment model to describe the factors leading
to E. sakazakii infection in infants and identified potential risk
mitigation strategies. The 2006 FAO/WHO Report also described a
microbiological standard sampling plan for E. sakazakii, of negative
for E. sakazakii in 30 x 10 gram samples from each lot of powdered
infant formula. The microbiological standard for Salmonella spp. of
negative in 60 x 25 gram samples is well established and was not
changed. Details concerning the microbiological testing required for
powdered infant formula by this interim final rule are discussed in
section V of this document.
    In proposing to adopt this microbiological standard, FDA also
proposed that the definition of ``lot'' be modified to be consistent
with the statistical basis for the proposed microbiological testing
requirements and the agreed upon international terminology.
Specifically, FDA stated that the Agency was considering modifying the
definition of ``lot'' to mean ``a quantity of product, having uniform
character or quality, within specified limits, or, in the case of an
infant formula produced by continuous process, it is a specific
identified amount produced in a unit of time or quantity in a manner
that assures its having uniform character and quality within specified
limits'' (71 FR 43392 at 43395).
    Unfortunately, the terms ``batch'' and ``lot'' were used without
adequate distinction in the 2006 FAO/WHO Report and in the 2006
reopening. As noted, the 2006 reopening proposed a revised definition
of ``lot'' (71 FR 43392 at 44395; August 1, 2006.) Under this
definition, ``lot'' would have been the relatively larger quantity of
formula, a definition inconsistent with both the

1996 proposal and FDA's drug CGMP definition. Also, at the time of the
2006 reopening, the Agency did not propose a comparable modification of
the definition of ``batch.'' As a result of this oversight, the most
recently proposed definitions for ``lot'' and ``batch'' both refer to
the relatively larger quantity of infant formula. Elsewhere in the 2006
reopening notice, the Agency referred to ``batch testing'' of
microorganisms (71 FR 43392 at 43396), a reference intended to identify
the relatively larger quantity of formula.
    The confusion surrounding ``lot'' and ``batch'' is further
illustrated by the comments FDA received on the definitions of
``batch'' and ``lot'' in response to the 1996 proposal. Specifically,
comments reflected that these terms are used inconsistently and that
the terms are not used in the same way in formula manufacturing and in
drug manufacturing. As a result of the foregoing, FDA believes that
there is significant confusion about the meaning of ``batch'' and
``lot,'' about the relationship between ``batch'' and ``lot,'' and,
most significantly, about the quantity of formula under discussion for
the microbial testing requirements of the interim final rule.
    FDA has considered the need to resolve this confusion as well as
the importance of clarifying the volume of formula associated with the
master manufacturing order and the requirements for nutrient and
microbiological testing and has concluded that the terms ``batch'' and
``lot'' should be replaced in the interim final rule with two new
terms, ``production aggregate'' and ``production unit.'' The interim
final rule defines ``production aggregate'' and ``production unit'' in
a manner that clarifies the volume of formula and stage of production
contemplated by each term as well as the relationship between the two
volumes of formula. In addition, the definitions of the two terms
reflect changes made in response to comments on ``batch'' and ``lot.''
By incorporating ``production unit'' and ``production aggregate'' into
the interim final rule, however, FDA does not intend to introduce new
concepts or to make significant changes. Rather, the Agency is using
new descriptors to clarify the quantity of formula associated with the
master manufacturing order and with the requirements for
microbiological and nutrient testing.
    ``Production unit'' represents the individually mixed portion of
formula and is defined in Sec.  106.3 as ``a specific quantity of an
infant formula produced during a single cycle of manufacture that has
uniform composition, character, and quality, within specified limits.''
``Production aggregate'' is frequently a co-mingled portion of formula
composed of one or more production units; it is defined in Sec.  106.3
as ``a quantity of product, or, in the case of an infant formula
produced by continuous process, a specific identified amount produced
in a unit of time, that is intended to have uniform composition,
character, and quality, within specified limits, and is produced
according to a master manufacturing order.'' Thus, under this interim
final rule, as a result of the revision of these definitions and the
addition of these new terms:
     ``Production aggregate'' represents the relatively larger
volume of formula and thus, effectively replaces ``batch'' (the 1996
proposal) and ``lot'' (the 2006 reopening).
     ``Production unit'' represents the relatively smaller
volume of formula and effectively replaces ``lot'' (the 1996 proposal).
(The 2006 reopening did not specifically propose a term or definition
for the relatively smaller volume.)
     A ``production aggregate'' may consist of one or more
``production units.'' This is consistent with the definition of lot
proposed in 1996. (``Lot means a batch or a specifically identified
portion of a batch. . . .'')
     As with ``batch'' (the 1996 proposal) and ``lot'' (the
2006 reopening), the term ``production aggregate,'' the term
representing the relatively larger volume of formula, incorporates the
concept of being produced according to a master manufacturing order.
     The term ``production aggregate'' (Sec.  106.3), which
refers to the relatively larger volume of formula, is defined both for
purposes of conventional manufacturing and continuous process
manufacturing. The comparable term from the 1996 proposal did not
address the application of the concept to continuous processing.
     As discussed in section V, the requirements for controls
to prevent adulteration from microorganisms (Sec.  106.55) stipulate
that testing be conducted on each ``production aggregate'' of formula.
Imposing the testing requirement on the relatively larger volume of
formula is consistent with the FAO/WHO report and is also necessitated
by the formula industry's use of continuous processing, a production
method that generally does not always result in identifiable smaller
volumes. Testing the relatively larger volume is consistent with the
proposed rule (which would have required each ``batch'' to be tested),
the 2006 reopening (which would have required each ``lot'' to be
tested), and the language in section 412 (which uses the term ``batch''
to mean the relatively larger, often co-mingled portion of formula in
which individually mixed portions of formula are combined.)
    In the remainder of this preamble, FDA uses the terms ``production
unit'' and ``production aggregate,'' as appropriate, to minimize
confusion and misunderstanding.
    (Comment 8) One comment requested that the term ``composition'' be
added to the definition of ``batch'' in proposed Sec.  106.3, so that
the definition would read ``uniform composition, character, and
quality.'' The comment stated that the word ``composition'' adds to the
accepted concept of the characteristics of a batch.
    (Response) FDA agrees with this comment, and has added the word
``composition'' to the definition of ``production aggregate'' in Sec.
106.3. The ordinary meaning of the word ``composition'' is ``a product
of mixing or combining various elements or ingredients.'' (Ref. 6,
p.236) A formula with uniform composition will have the various formula
components evenly distributed throughout the quantity of formula
manufactured; uniform composition directly contributes to the uniform
character and quality of a formula, the two other elements in the
definition of ``production aggregate.''
    (Comment 9) One comment requested that the Agency strike the term
``single'' from, and substitute the word ``master'' in, the proposed
definition of ``batch.'' In the proposed definition, ``single''
modified ``manufacturing order.'' The comment suggested that modifying
``manufacturing order'' with the word ``master'' would ensure that in-
process adjustments, undertaken so that the batch meets nutritional
requirements, would not contravene the definition.
    (Response) FDA does not disagree with this comment and thus, has
replaced the term ``single'' with ``master'' to describe a
manufacturing order. ``Master manufacturing order'' is a term commonly
used in the infant formula industry and is used to describe the
``recipe'' the manufacturer uses to prepare the production aggregate.
The Agency understands the comment's underlying concern to be that the
proposed definition, which referred to a ``single manufacturing
order,'' could be interpreted to mean that a manufacturer is precluded
from making in-process adjustments in what this interim final rule
refers to as the ``production aggregate'' as defined in Sec.  106.3.
FDA recognizes that a formula manufacturer may be required to make in-
process adjustments to ensure that established specifications for the
in-process or final product are met. Given the potential

confusion, FDA is making the change requested in this comment.
    (Comment 10) One comment stated that the meaning of the phrase ``or
other material'' in the proposed definition of batch was unclear and
recommended that it be removed.
    (Response) FDA agrees that the phrase ``or other material'' is not
clear. Also, this phrase is not necessary and thus, it is being deleted
from the definition of ``production aggregate'' in Sec.  106.3.
    (Comment 11) A comment requested that FDA delete the phrase
``within specified limits'' from the definition of ``batch'' asserting
that the phrase creates a substantive requirement that could cause
confusion. The comment also claimed that manufacturers determine some
of the specifications related to the disposition of a batch on a case-
by-case basis. The comment further stated that manufacturers have not
identified every outer limit for every process and product parameter
that would result in rejection and determination of these limits would
require an overwhelming amount of technical and administrative
resources.
    (Response) FDA disagrees that the phrase ``within specified
limits'' creates a substantive requirement for the identification of
every outer limit for every process and product parameter that would
result in product rejection. The purpose of the ``within specified
limits'' language in this definition is to ensure that the manufactured
infant formula is what the manufacturer intends, and reflects both
customary practice in the formula industry as well as the requirements
in Sec.  106.6(c)(1) to establish specifications. The manufacturer
establishes specifications for each production aggregate of formula,
which ensures that the manufactured formula meets the nutrient
requirements and applicable microbial contamination standards. Thus,
the term ``within specified limits'' ensures that a production
aggregate has the uniform composition, character, and quality intended.
    As noted, the comment also requested deletion of ``within specified
limits'' because, the comment asserted, specifications are established
on a case-by-case basis. FDA disagrees with this justification because
manufacturers should not be determining specifications on a case-by-
case basis during production of a formula, as the comment seems to
suggest. It is crucial that a manufacturer establish appropriate
specifications at any point, step, or stage where control is necessary
to prevent adulteration prior to manufacturing formula so that the
manufacturer can ensure that its process is under control and is able
to produce what is intended. Failure to meet predetermined
specifications, or failure to perform necessary in-process adjustments
to ensure such specifications are met, suggests that the manufacturing
process is not adequately controlled to prevent adulteration.
    For all of the foregoing reasons, the Agency declines to delete the
phrase ``within specified limits'' and is retaining such phrase in the
definition of ``production aggregate'' in Sec.  106.3.
    (Comment 12) FDA received comments on the definition of ``lot'' (as
proposed in 1996) that were similar to comments on the definition of
``batch.'' In particular, these comments suggested removing the phrase
``within specified limits'' from the definition of ``lot,'' and also
recommended that the definition of ``lot'' include the term
``composition.'' The comments also requested that the definition of
``lot'' be clarified in terms of production of infant formula by
continuous process.
    (Response) As explained previously in this document, the concepts
of ``production aggregate'' and ``production unit'' are closely related
and thus, the definitions of these terms should be consistent with one
another. Accordingly, FDA agrees that the term ``composition'' should
be added to the definition of ``production unit.'' In addition, in
continuous processing manufacture, each production unit needs to have
uniform composition, which will help to ensure that the composition of
the production aggregate will be uniform and within the specified
limits. Accordingly, for the reasons stated in the responses to comment
11, FDA has also added the term ``composition'' to the definition of
``production unit'' in Sec.  106.3.
    Similarly, for the reasons stated in the response to comment 11,
FDA is also retaining the phrase ``within specified limits'' in the
definition of ``production unit'' in Sec.  106.3.
    Finally, the definition of ``production aggregate'' refers to the
production of infant formula by continuous process. FDA recognizes that
a single production unit may also be a production aggregate where, for
example, only smaller volumes of infant formula are produced.
    (Comment 13) One comment stated that the phrase ``or other
material'' is more appropriate in the definition of ``lot'' than in the
definition of ``batch'' because the definition of ``lot'' ``encompasses
raw material lots better than does the definition of batch'.''
    (Response) FDA disagrees with this comment. The comment is a
reflection of the problem resulting from the variety of ways in which
the term ``lot'' is used in manufacturing and also was used in the
earlier stages of this rulemaking. The concept of ``lots'' of raw
materials is separate from the concept of ``lot,'' which was used in
the 1996 proposed rule, and ``production unit,'' which is the term used
in this interim final rule and is defined in Sec.  106.3. The addition
of the phrase ``or other material'' to the definition of production
unit is not appropriate because the production unit does not refer to
``lots'' of raw materials. Therefore, FDA has not added the phrase ``or
other material'' to the definition for ``production unit'' in Sec.
106.3.
    As a result of establishing the new terms ``production aggregate''
and ``production unit'' and their definitions, FDA is also making
technical revisions to two related definitions that the Agency proposed
in 1996. First, FDA is revising proposed Sec.  106.3(f), the definition
of ``in-process batch'' and codifying the new term and definition in
Sec.  106.3 of the interim final rule as follows: ``In-process
production aggregate means a combination of ingredients at any point in
the manufacturing process before packaging.'' Similarly, the Agency is
revising proposed Sec.  106.3(h), the definition of ``lot number,
control number, batch number,'' and codifying the new term and
definition in Sec.  106.3 of the interim final rule as follows:
``Production unit number or production aggregate number means any
distinctive combination of letters, numbers, symbols, or any
combination of them, from which the complete history of the
manufacture, processing, packing, holding, and distribution of a
production aggregate or a production unit of infant formula can be
determined.''
2. Major Change (Proposed Sec.  106.3(i))
    The proposed rule defined ``major change in an infant formula'' to
mean ``any new formulation, or any change of ingredients or processes
where experience or theory would predict a possible significant adverse
impact on levels of nutrients or bioavailability \2\ of

nutrients, or any change that causes an infant formula to differ
fundamentally in processing or in composition from any previous
formulation produced by the manufacturer.'' The proposed definition
provided seven examples of changes resulting in an infant formula that
would be deemed to differ ``fundamentally in processing or in
composition.''
---------------------------------------------------------------------------

    \2\ For the purposes of this interim final rule,
``bioavailability'' (the noun) refers to the degree to which a
nutrient is absorbed or otherwise becomes available to the body.
Bioavailability may affect the choice of an ingredient; for example,
vegetable oil has been substituted for butterfat in infant formulas
because the latter is not well absorbed by infants. Bioavailability
may also affect the amount of a substance that must be added to a
product to ensure adequate delivery of the substance; for example,
soy-based formula must contain relatively more calcium than a cow
milk formula because the phytate (a phosphorus compound in soy)
interferes with the absorption of calcium. ``Bioavailable'' is an
adjectival form of ``bioavailability.''
---------------------------------------------------------------------------

    (Comment 14) One comment agreed with the proposed definition of
``major change'' in proposed Sec.  106.3(i) but suggested revised
language for the example in proposed Sec.  106.3(i)(5). The comment
suggested that the phrase ``containing a new constituent'' in proposed
Sec.  106.3(i)(5) should be changed to ``containing a new nutrient''
because, the comment asserted, the purpose of the Infant Formula Act is
to ensure proper nutrition and the term ``nutrient'' is more consistent
with that purpose. The comment asserted that the term ``constituent''
is overbroad, that its use could result in designating as a major
change the addition of a wholly innocuous new constituent added at
nominal levels, and that such a result is beyond the basic scope of
section 412 of the FD&C Act. The comment further argued that this
interpretation would require formula manufacturers to submit 90 day
notifications for each of these constituents, which would require both
the manufacturer and FDA to expend additional resources with no added
benefit to the consumer.
    (Response) FDA disagrees with this comment and, for two reasons,
declines to make the suggested revision to the definition of ``major
change'' in Sec.  106.3 of the interim final rule. First, the use of
the term ``constituent'' is required by the applicable statute. The
definition of ``major change'' in proposed Sec.  106.3(i) was based on
the directive in section 412(c)(2) of the FD&C Act, which states that
``the term `major change' '' has the meaning given to such term in
Sec.  106.30(c)(2) of title 21, Code of Federal Regulations (as in
effect on August 1, 1986), and guidelines issued thereunder.'' The
guidelines referred to in section 412(c)(2) of the FD&C Act are the
Guidelines Concerning Notification and Testing of Infant Formulas
(``the Guidelines'') (Ref. 7). The Guidelines list seven examples of
changes that cause an infant formula ``to differ fundamentally in
processing or in composition from any previous formulation produced by
the manufacturer.'' Accordingly, in proposed Sec.  106.3(i), FDA listed
the seven examples set out in the Guidelines, including, in proposed
Sec.  106.3(i)(5), ``Any infant formula manufactured containing a new
constituent not listed in section 412(i) of the FD&C Act, such as
taurine or L-carnitine.'' Thus, the language in proposed Sec.
106.3(i)(5) was drawn directly from the definitional source identified
in the applicable statute.
    Second, sound policy reasons support use of the term
``constituent'' in the definition of ``major change'' in Sec.  106.3.
Constituents other than the nutrients listed in section 412(i) of the
FD&C Act (``required nutrients'') are added to infant formula (e.g.,
intentionally added microorganisms), and a new constituent other than a
required nutrient could potentially affect the bioavailability of a
formula and such nutrients. The Guidelines recognize, and the
definition of ``major change'' incorporates the recognition, that a new
constituent other than a required nutrient can potentially affect the
bioavailability of nutrients in the formula and the formula as a whole.
Thus, from the standpoint of ensuring the bioavailability of the
formula matrix as a whole, in addition to the bioavailability of
individual required nutrients, use of the term ``constituent'' in the
definition of ``major change'' is appropriate as a matter of policy.
Therefore, FDA is not revising the definition of ``major change'' in
response to this comment.
    (Comment 15) Another comment suggested that the conjunction ``and''
after proposed Sec.  106.3(i)(6) be changed to ``or.'' The comment
argued that this revision is appropriate because each of the examples
in this section is intended to stand alone and, although more than one
example could be applicable in a given situation, all seven are
unlikely to occur at the same time.
    (Response) The Agency agrees with this comment. Proposed Sec.
106.3(i) includes a list of examples of infant formulas, each of which
differs fundamentally in processing or in composition and thus, each is
a separate example of a ``major change in an infant formula.''
Accordingly, FDA is revising proposed Sec.  106.3(i) by changing the
conjunction ``and'' to ``or'' before the last example in the definition
of ``major change'' in Sec.  106.3.
    On its own initiative FDA is removing the words ``for commercial or
charitable distribution'' from proposed Sec.  106.3(i)(2). This change
is consistent with the definition of ``manufacturer'' as discussed in
this document, in which the Agency declined to include the phrase ``for
commercial or charitable distribution.''
3. Manufacturer (Proposed Sec.  106.3(j))
    The proposed rule (Sec.  106.3(j)) defined ``manufacturer'' as ``a
person who prepares, reconstitutes, or otherwise changes the physical
or chemical characteristics of an infant formula or packages or labels
the product in a container for distribution.''
    (Comment 16) One comment suggested that the definition of
``manufacturer'' be revised so that ``manufacturer'' means ``a person
who prepares, reconstitutes, or otherwise changes the physical or
chemical characteristics of an infant formula or packages or labels the
product in a container for commercial or charitable distribution
(emphasis added)'' and asserted that, by including the phrase
``commercial or charitable,'' parents, child care providers, hospitals,
and other institutions who prepare formula for infants under their
direct care would not be considered a ``manufacturer.''
    (Response) FDA believes that this comment raises an important issue
about the breadth of the proposed definition of ``manufacturer.'' The
Agency disagrees, however, that including the phrase ``commercial or
charitable'' as a modifier of the word ``distribution'' would
sufficiently clarify that those who prepare infant formula for infants
under their direct care are not ``manufacturers.''
    The Agency recognizes that there are several groups of persons who
reconstitute powdered or concentrated liquid infant formula or
otherwise mix formula and provide that formula to an infant for whom
these persons are providing direct care. These persons include parents,
daycare providers and other caregivers, and nurses and other healthcare
personnel. In addition, in some healthcare settings, there is a
designated institutional unit that performs the formula mixing in place
of a nurse or other healthcare provider, such as a hospital formula
room; these staff mix or reconstitute formula for infants under the
direct care of the hospital or healthcare institution. Whether the
reconstitution is done by an individual, such as a daycare provider or
staff in a hospital formula room, the preparation of the infant formula
is an extension of the care-giving function. FDA does not believe that
Congress intended that a person who or institution that mixes formula
for a child as an extension of the care-giving function be considered a
``manufacturer'' subject to the requirements established under section
412. Instead, the provisions of section 412 are intended to regulate
entities that prepare or reconstitute formula for further distribution
because a manufacturing error by one of these entities has greater
potential to cause harm by virtue of the broad distribution of its
products. Also, the activities of a

hospital formula room or comparable unit are subject to the oversight
and standards of the hospital or other institution of which it is a
part. Moreover, as a policy matter, FDA does not believe that it is
appropriate to interfere with these care-giving relationships by
requiring a person who mixes formula for an infant under his/her direct
care to adhere to the types of controls the Agency is establishing in
this interim final rule.
    FDA affirms, however, that a person or institution that
reconstitutes formula for subsequent distribution to infants not under
the direct care of that person or institution is a ``manufacturer'' for
purposes of the interim final rule. In this situation, the mixing or
reconstitution and subsequent distribution are separate activities and
are not simply an extension of the care-giving function.
    Accordingly, FDA is revising proposed Sec.  106.3(j) to clarify
that the term ``manufacturer'' does not include a person or institution
employing such person that prepares, reconstitutes, or mixes infant
formula exclusively for an infant under his/her direct care or the
direct care of the institution employing such person.
    (Comment 17) One comment suggested that a definition for
``responsible party'' be added to Sec.  106.3 because the proposed
definition of ``manufacturer'' would result in overlapping
responsibilities whenever co-packers are involved in the manufacturing
of infant formula. This comment suggested defining ``responsible
party'' as ``the manufacturer of an infant formula when all
manufacturing steps are performed by a single entity; however, when
several entities are involved in the manufacture of a given formula, it
means the manufacturer or other entity that has agreed to assume
responsibility for ensuring that all requirements for notification and
assurance under these regulations are satisfied.'' The comment stated
that for certain requirements, the responsible party would replace the
manufacturer completely, to avoid duplication and to attribute
appropriately actual responsibility for other requirements. The comment
asserted that that duplicate responsibilities for the same activity do
not serve any purpose in the majority of proposed requirements, and
therefore, suggested that the concept of ``responsible party'' be
introduced to eliminate duplication. The comment stated that only for
``registration'' (see proposed Sec.  106.110) would duplicate
responsibilities serve FDA's purpose (e.g., for inspections and
counterfeit formula surveillance).
    (Response) FDA disagrees that a definition for ``responsible
party'' is needed in the interim final rule because, properly
understood, the interim final rule will require no duplication of
effort.
    The Agency believes that the comment did not understand the
responsibilities under the proposed rule. These obligations are of two
types: The obligation to conduct certain activities according to the
requirements of the CGMP regulation and the obligation of certain
persons to ensure that there is compliance with the rule's requirements
even if such person is not engaged in the specific activities covered
by the rule.
    In terms of activities, under the interim final rule, any person
who satisfies the definition of ``manufacturer'' in Sec.  106.3 must
comply with all the CGMP requirements that cover activities in which
such person engages. Thus, if a person conducts all the activities
necessary to produce an infant formula in its final packaged form
(i.e., prepares, reconstitutes, or otherwise changes the physical or
chemical characteristics of a formula, packages the formula, and labels
the product for distribution), that person must comply with all CGMP
requirements established by this interim final rule.
    FDA recognizes, however, that in the infant formula industry, a
person may contract with another to perform some portion of the formula
production process, such as the packaging and labeling phases of
manufacture, and there is no legal prohibition to such arrangements. To
the extent that a contractor performs any of the activities identified
in the definition of manufacturer in Sec.  106.3, the contractor is a
``manufacturer'' for purposes of those activities under this interim
final rule. However, where a person (such as a contractor) performs
only a part of the complete infant formula manufacturing operation,
that person is obligated to adhere only to the specific parts of the
CGMP rule that are relevant to such person's activities. For example,
if an entity has contracted to act as a spray dryer for a powdered
infant formula, the spray dryer is an infant formula manufacturer under
Sec.  106.3 and is responsible for complying with the applicable
sections of subpart B (CGMPs), subpart D (Conduct of Audits), and
Subpart F (Records and Reports). The specific responsibilities of a
given contractor would depend on the terms of the contract. For
example, a contactor whose duties under the contract are limited to
spray drying infant formula generally would not be responsible for the
nutrient testing required under subpart C (Quality Control Procedures),
subpart E (Quality Factors), or subpart G (Registration, Submission,
and Notification Requirements).
    Importantly, in addition to the obligation to comply with the parts
of the CGMP rule that apply to the activities of a particular person's
operation, the entity who causes the infant formula to be introduced
into interstate commerce in its final form for distribution to
consumers has an overarching and ultimate responsibility to ensure that
all phases of the production of that formula are in compliance with the
final CGMP regulations and that the formula is lawful in all respects.
Generally, the person who submits the notification required by section
412(c)(1)(B) of the FD&C Act is the person with this ultimate
responsibility. (Under section 201(e) of the FD&C Act (21 U.S.C.
321(e)), ``person'' includes an individual, partnership, corporation,
or association.) That is, although a firm can contract out certain
parts of formula production, the firm cannot, by the same token,
contract out its ultimate responsibility to ensure that the formula
that such firm places into commerce (or causes to be placed into
commerce) is not adulterated and is otherwise lawful. See U.S. v.
Dotterweich, 320 U.S. 277, 284 (1943) (explaining that an offense can
be committed under the FD&C Act by anyone who has ``a responsible share
in the furtherance of the transaction which the statute outlaws'');
United States v. Park, 421 U.S. 658, 672 (1975) (holding that criminal
liability under the FD&C Act does not turn on awareness of wrongdoing,
and that ``agents vested with the responsibility, and power
commensurate with that responsibility, to devise whatever measures are
necessary to ensure compliance with the Act'' can be held accountable
for violations of the FD&C Act). This overarching responsibility flows
from the FD&C Act's structure. In particular, the FD&C Act prohibits a
person from introducing or delivering for introduction, or causing the
delivery or introduction, into interstate commerce an adulterated
infant formula, 21 U.S.C. 350a(a) and 331(a). Thus, the firm that
causes an infant formula to be introduced into interstate commerce is
responsible for ensuring that such formula complies with all the
requirements under section 412 of the FD&C Act and the interim final
rule and thus, is not adulterated, regardless of

who actually carries out the activities covered by the rule.
    In terms of an infant formula firm's obligations relating to the
use of contractors, FDA notes, as discussed in section X.B, that under
Sec.  106.110(b)(4), the manufacturer of a new infant formula must
register with FDA and the registration must list all establishments at
which the manufacturer intends to manufacture the new formula. FDA
advises that the list of establishments required by Sec.  106.110(b)(4)
must include the establishments of all contractors involved in the
production of the new formula.
4. Microorganisms (Proposed Sec.  106.3(k))
    The proposed rule defined ``microorganisms'' to mean ``yeasts,
molds, bacteria, and viruses and includes, but is not limited to,
species having public health significance.''
    (Comment 18) One comment stated that this definition of
``microorganisms'' is identical to the definition in the food CGMPs (21
CFR 110.3(i)), which are also applicable to the manufacture of infant
formulas. Thus, the comment asserted, the definition of
``microorganism'' should be deleted as it represents a redundancy.
    (Response) The Agency disagrees with this comment. As discussed
earlier in this preamble, Congress specifically mandated in section
412(b)(2)(A) of the FD&C Act that the Secretary (and by delegation,
FDA) establish regulations for ``good manufacturing practices for
infant formulas, including quality control procedures that the
Secretary determines are necessary'' to assure that an infant formula
provides nutrients in accordance with the FD&C Act and is
``manufactured in a manner designed to prevent adulteration of the
infant formula.'' Section 412(a)(3) of the FD&C Act provides that an
infant formula is deemed to be adulterated if the ``processing of such
infant formula is not in compliance with the good manufacturing
practices and the quality control procedures prescribed by the
Secretary'' under section 412(b)(2) of the FD&C Act. FDA is
establishing a definition of ``microorganisms'' in this interim final
rule for use with the specific requirements related to such term that
have been issued under section 412 of the FD&C Act. Therefore, FDA is
not deleting proposed Sec.  106.3(k) in response to this comment, and
the definition of ``microorganisms'' is included in Sec.  106.3.
5. New Infant Formula (Proposed Sec.  106.3(l))
    The proposed rule defined ``new infant formula'' to mean ``(1) An
infant formula manufactured by a person that has not previously
manufactured an infant formula for the U.S. market, and (2) An infant
formula manufactured by a person that has previously manufactured
infant formula and in which there is a major change in processing or
formulation from a current or any previous formulation produced by such
manufacturer.''
    (Comment 19) One comment suggested that the definition of ``new
infant formula'' in proposed Sec.  106.3(l) be changed by replacing the
word ``means'' with the word ``includes.'' The comment stated that this
change would make the definition consistent with the FD&C Act and would
allow for situations not described in this definition. In addition, the
comment suggested removing the phrase ``for the U.S. market'' from the
first part of this definition in proposed Sec.  106.3(l). The comment
argued that the phrase ``for the U.S. market'' does not appear in the
FD&C Act's definition of new infant formula. Also, the comment asserted
that, for purposes of proposed Sec.  106.110 (New infant formula
registration), the phrase would exclude from the definition of ``new
infant formula'' formulas intended for export only.
    (Response) FDA disagrees with the comment that the term ``means''
should be replaced with the term ``includes'' in the definition of
``new infant formula.'' Although the language in section 412(c)(2) of
the FD&C Act allows for situations not described in the definition of
``new infant formula,'' the definition of ``new infant formula'' in
this rule is limited to the situations described in the definition. An
infant formula manufacturer must determine whether its formula is a
``new infant formula'' in order to comply with FD&C Act and its
implementing regulations. A precise definition of ``new infant
formula'' will provide these manufacturers with clarity in this area.
Therefore, FDA is not revising proposed Sec.  106.3(l) to incorporate
this change.
    However, FDA is removing the phrase ``for the U.S. market,'' from
the first clause of the definition of ``new infant formula'' as
suggested in the comment. As the comment suggests, the definition of
``new infant formula'' in the proposed rule could be interpreted to
exclude formulas for export only from certain requirements under the
FD&C Act, e.g. the registration requirements under section 412(c) of
the FD&C Act. Therefore, FDA is revising proposed Sec.  106.3(l) to
remove the phrase ``for the U.S. market'' from the first clause of such
definition.
    In addition, FDA recognizes that a definition of ``new infant
formula'' without the phrase ``for the U.S. market'' in the first
clause of the definition could be interpreted to permit a manufacturer
who has been manufacturing and marketing formula abroad to market the
same formula that they have been marketing abroad in the United States
without registering with FDA under section 412(c) of the FD&C Act or
making a submission under section 412(d) of the FD&C Act, provided that
the manufacturer made no ``major change'' to the formula. This is
because the formula would not be a ``formula manufactured by a person
that has not previously manufactured an infant formula'' in the
proposed definition of ``new infant formula.'' Even without the removal
of the phrase ``for the U.S. market'' from the proposed definition,
such definition could be interpreted to permit certain manufacturers
who are marketing infant formula abroad to market that formula in the
United States without making a submission under section 412(c) of the
FD&C Act. For example, a formula could be considered to be excluded
from the ``new infant formula'' definition if made by a manufacturer
that has been marketing that formula abroad, but has also previously
marketed a different formula in the United States. To avoid any
ambiguity and to ensure that an infant formula that is being marketed
in the United States for the first time is classified as a ``new infant
formula,'' FDA is revising the definition of ``new infant formula''
(proposed Sec.  106.3(l)) by inserting at the end of the definition
``or which has not previously been the subject of a submission under
section 412(c) of the FD&C Act for the U.S. market.'' With the addition
of this language, any manufacturer that produces a formula that has not
been the subject of such a submission will be considered a ``new infant
formula,'' even if that manufacturer has been continuously
manufacturing and marketing that formula abroad without making a major
change. In addition, as explained in response to comment 328, this
change is consistent with the notification requirements for a
manufacturer of an infant formula for export only. Although a
manufacturer of infant formula for export only must still submit a
notification under section 412(c) of the FD&C Act, the formula is not
for the U.S. market and the submission requirements in this interim
final rule for such a formula differ from those required for an infant
formula intended for the U.S. market. Therefore, the addition of the
phrase ``for the U.S. market'' in the second clause of the definition
of ``new infant formula''

makes it clear that the submission described in section 412(c) of the
FD&C Act is that which is submitted for infant formula marketed in
domestic commerce.
    Although the phrase ``or which has not previously been the subject
of a submission under section 412(c) of the FD&C Act for the U.S.
market'' does not appear in the definition of ``new infant formula''
under the FD&C Act, the inclusion of such a phrase in the definition of
``new infant formula'' is well within FDA's authority. If the FD&C Act
is silent or ambiguous with respect to the meaning of ``new infant
formula,'' the Agency may interpret the term based on a reasonable
construction of the statute. See Chevron U.S.A. Inc. v. Natural
Resources Defense Council, 467 U.S. 837, 842-843; FDA v. Brown &
Williamson Tobacco Corp., 529 U.S. 120, 132 (2000). There is ambiguity
in the definition of ``new infant formula'' under section 412(c)(2) of
the FD&C Act. As noted previously in this document, the word
``includes'' in the definition of new infant formula in section
412(c)(2) of the FD&C Act indicates that the term ``new infant
formula'' was meant to encompass situations not described in the
definition. See NORMAN J. SINGER & J.D. SHAMBIE SINGER, 2A SUTHERLAND
STATUTORY CONSTRUCTION Sec.  47:7 (7th ed. 2009) (explaining that when
a statutory definition declares what it ``includes,'' it ``conveys the
conclusion that there are other items includable, though not
specifically enumerated''). The situations described in the FD&C Act's
definition of ``new infant formula'' do not encompass, for example, a
situation where an infant formula manufacturer who has been
manufacturing and marketing formula abroad decides to market that
formula in the United States.
    Because the FD&C Act's definition of ``new infant formula'' is
ambiguous, the Agency may establish a regulation to fill any gaps in
that definition so long as it is not ``arbitrary, capricious, or
manifestly contrary to the statute.'' See Chevron, 467 U.S. at 844.
Adding to the definition of ``new infant formula'' to account for a
situation where an infant formula manufacturer who has been
manufacturing and marketing formula abroad decides to market that
formula in the United States is clearly consistent with the overall
purpose of the Infant Formula Act. The Infant Formula Act and the 1986
Amendments were intended to ensure the ``safety and nutrition'' of
infant formulas. See Public Law 96-359, 94 Stat. 1190, 1190 (1980).
Without defining ``new infant formula'' as described previously in this
document, however, FDA would not be able to ensure the safety and
nutrition of all infant formulas imported into the United States,
because a firm that had already been manufacturing and marketing a
formula abroad would not need to register with FDA or make a submission
to FDA demonstrating compliance with the applicable U.S. laws.
6. Nutrient (Proposed Sec.  106.3(m))
    The proposed rule defined ``nutrient'' to mean ``any vitamin,
mineral, or other substance or ingredient that is required in
accordance with the table set out in section 412(i)(1) of the FD&C Act
or by regulations issued under section 412(i)(2) or that is identified
as essential for infants by the Food and Nutrition Board of the
National Research Counsel through its development of a Recommended
Dietary Allowance or an Estimated Safe and Adequate Daily Dietary
Intake range, or that has been identified as essential for infants by
the Food and Drug Administration through a Federal Register
publication.''
    (Comment 20) One comment suggested limiting the definition of
``nutrient'' to ``any vitamin, mineral, or other substance or
ingredient in infant formula that is required by the act or by
regulations issued pursuant to the act.'' The comment asserted that the
intent of the proposed definition is to describe the ways in which
nutrients can be added to the list of those already required in Sec.
107.100. The comment stated that it interpreted both the proposed
language and the suggested revision as applying to ``essential''
nutrients, and not to other potential or current ingredients in infant
formula. On this basis, the comment stated that the regulations should
not create restrictions on the ability of a manufacturer to include new
ingredients that are in compliance with existing regulations, nor
should the regulations affect substances that are being added currently
in compliance with existing regulations.
    (Response) The proposed definition of ``nutrient'' included ``any
vitamin or mineral'' or ``other substance or ingredient'' that is (1)
Required in accordance with the table in section 412(i)(1) of the FD&C
Act; (2) required by FDA under section 412(i)(2) of the FD&C Act; or
(3) identified as ``essential'' consistent with the regulations in
Sec.  107.10(b)(5). FDA believes that the comment confuses the
declaration of ``required nutrients'' and the declaration of
``essential nutrients,'' with the use of ``other substances or
ingredients'' that a manufacturer may add when producing an infant
formula that are not declared as either ``required'' or ``essential''
nutrients. Thus, the Agency provides the following clarification.
    The definition of ``nutrient'' in proposed Sec.  106.3(m) included
not only vitamins and minerals that may be considered required or
essential nutrients, but includes the potential for another ``substance
or ingredient'' that is not a vitamin or mineral to be a required or
essential nutrient. In the preamble to the 1996 proposal, the Agency
stated that ``nutrients that are required to be in infant formula under
Sec.  107.100 will be referred to as 'required nutrients'''(61 FR 36154
at 36155). Such nutrients include those listed in the table in section
412(i) of the FD&C Act and those that FDA may require, if FDA revises
such table by regulation. Importantly, there are currently several
vitamins and minerals (i.e., selenium, chromium, and molybdenum) that
are considered ``essential'' nutrients (not ``required'' nutrients)
based on one of the following: (1) Identified as essential by NAS
through its development of a recommended dietary allowance or an
estimated safe and adequate daily dietary intake range; (2) identified
as essential by the FDA through a Federal Register publication; or (3)
identified as essential under the 10th edition of the Food and
Nutrition Board's Recommended Dietary Allowances (RDA), 21 CFR
107.10(b)(5). Under the proposed definition of ``nutrient,'' a vitamin,
or mineral, or other substance or ingredient that is ``essential'' may
be declared on the infant formula label when provided at a level
considered in the publications as having biological significance, when
this level is known (Sec.  107.10(b)(5)(ii)). Section 107.10(b)(5)
limits the label declaration of vitamins and minerals added to in an
infant formula that are not otherwise required to those that are
``essential.'' Thus, FDA included, in the proposed definition of
``nutrient,'' those substances ``determined to be essential by the Food
and Nutrition Board of the National Research Council or by the FDA'' to
be consistent with Sec.  107.10(b)(5) on labeling information (61 FR
36154 at 36157). In the preamble to the final rule implementing section
Sec.  107.10(b)(5), FDA stated that the ``declaration of nutrients that
are not required by the Infant Formula Act, not considered to be
essential by the NAS or FDA, and not at levels considered to have
biological significance is considered to be a misbranding violation
under section 403(a)(1) of the FD&C Act . . . because including such
nutrients in the nutrient table or declaring a nutrient at a level

that may not have biological significance implies a level of
significance or usefulness in human nutrition that has not been
established'' (50 FR 1833 at 1836 (January 14, 1985)). Therefore, under
the proposed definition of ``nutrient,'' any vitamin, mineral, and
other substance or ingredient that is not a ``required nutrient'' or an
``essential nutrient,'' as those terms are used in Sec.  107.10, cannot
be part of the nutrient declaration of an infant formula. Ingredients
that may be considered ``nutrients'' but that are not ``required
nutrients'' or ``essential nutrients'' may be added to infant formula
provided that the use of the specific chemical form of the ingredient
is in accordance with the 'Agency's food additive regulations, is
generally recognized as safe (GRAS), or is authorized by a prior
sanction. Thus, for these reasons, limiting the definition of
``nutrient'' to include only substances required under section 412(i)
of the FD&C Act, or regulations issued under such section is not
warranted. Accordingly, FDA is not changing the definition for
``nutrient'' in proposed Sec.  106.3(m) in response to this comment.
    (Comment 21) One comment questioned FDA's authority to ``sub-
delegate'' to the Food and Nutrition Board of the National Research
Council the 'Agency's authority to establish required nutrients and
levels for infant formulas.
    (Response) The comment asserting that the Agency is ``sub-
delegating'' its responsibility for establishing required nutrients and
levels for infant formulas is beyond the scope of this rulemaking
because current Sec.  107.10(b)(5) establishes the role of the NAS in
designating nutrients essential for infants, and the Food and Nutrition
Board is a part of NAS. FDA notes that the NAS Food and Nutrition Board
is now part of the IOM and that the Food and Nutrition Board has
replaced ``Recommended Dietary Allowances'' and ``Estimated Safe and
Adequate Dietary Intake Range'' with ``Dietary Reference Intakes''
(Ref. 8). Thus, the Agency is making technical changes to the
definition of ``nutrient'' in Sec.  106.3 of the interim final rule so
that ``Institute of Medicine'' replaces ``National Research Council''
and ``Dietary Reference Intake (DRI)'' replaces ``Recommended Dietary
Allowance'' and ``Estimated Safe and Adequate Daily Dietary Intake
range.''
    Because these same out-of-date references are currently used in
Sec.  107.10(b)(5), FDA is also making technical revisions to that
regulation that identify the role of the Food and Nutrition Board of
the IOM for identifying essential nutrients, and that replace
``recommended dietary allowance'' and ``estimated safe and adequate
daily dietary intake range'' with ``Dietary Reference Intake.''
    (Comment 22) One comment requested that the Agency clarify what is
meant by the phrase ``has been identified as essential for infants by
the Food and Drug Administration through a Federal Register
publication,'' and questioned whether nutrients could be identified as
essential in Federal Register publications that do not constitute
rulemaking. The comment recommended broadening the definition to
encompass all FDA rulemaking activities related to infant formula and
eliminating the last part of the proposed definition (i.e., deleting
``through a Federal Register publication'').
    (Response) With respect to whether nutrients may be identified as
essential in Federal Register publications that do not constitute
rulemaking, this comment is beyond the scope of this rulemaking because
the process for establishing a nutrient as ``essential'' is set out in
Sec.  107.10(b)(5) of FDA's regulations. FDA advises that the Agency
will consider, on a case-by-case basis, the administrative process,
including Federal Register publication, needed to identify a nutrient
as ``essential.'' FDA declines to broaden the definition as requested
by the comment.
7. Quality Factors (Proposed Sec.  106.3(o)) and Requirements for
Quality Factors (Proposed Sec.  106.96)
    In this portion of the preamble, FDA addresses comments regarding
the definition of ``quality factors'' in proposed Sec.  106.3(o).
Because the requirements for quality factors identified in proposed
Sec.  106.96 are related to the definition of ``quality factors'' in
proposed Sec.  106.3(o), this portion of the preamble also addresses
certain comments on proposed Sec.  106.96 that are related to comments
received on the definition of quality factors.
    The proposed rule defined ``quality factors'' as ``those factors
necessary to demonstrate that the infant formula, as prepared for
market, provides nutrients in a form that is bioavailable and safe as
shown by evidence that demonstrates that the formula supports healthy
growth when fed as a sole source of nutrition.''
    (Comment 23) Several comments expressed confusion about the role of
``healthy growth'' as a quality factor compared to a quality factor of
``normal physical growth.'' ``Normal physical growth'' was identified
as a quality factor in proposed Sec.  106.96(b).
    (Response) In the 1996 proposal, FDA did not intend to establish
``healthy growth'' as an individual or separate quality factor
requirement. Rather, the proposed rule used the broad concept of
``healthy growth'' to describe what would be achieved when the
requirements for all quality factors are met. The Agency noted in the
proposed rule (61 FR 36154 at 36179) that ``healthy growth''