[Federal Register Volume 79, Number 27 (Monday, February 10, 2014)]
[Rules and Regulations]
[Pages 7934-8075]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-02148]
[[Page 7933]]
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
[[Page 7934]]
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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, 240-402-1450.
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
[[Page 7935]]
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.
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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).
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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;
[[Page 7938]]
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
[[Page 7939]]
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.
---------------------------------------------------------------------------
[[Page 7940]]
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
[[Page 7941]]
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
[[Page 7942]]
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
[[Page 7943]]
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
[[Page 7944]]
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
[[Page 7945]]
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
[[Page 7946]]
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
[[Page 7947]]
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
[[Page 7948]]
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''
[[Page 7949]]
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
[[Page 7950]]
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''
encompasses ``all aspects of physical growth and normal maturational
development, including maturation of organ systems and achievement of
normal functional development of motor, neurocognitive, and immune
systems. All of these growth and maturational processes are major
determinants of an infant's ability to achieve his/her biological
potential, and all can be affected by the nutritional status of an
infant.'' Thus, in the 1996 proposal, FDA recognized that the
nutritional status of an infant can affect the growth and developmental
process contemplated by the concept of ``healthy growth.'' Currently,
well-established reference data derived using non-invasive procedures
are not available to characterize body composition of infants, and
methods for establishing the requirements for other quality factors
discussed in the proposed rule that contribute to ``healthy growth''
are not available or are impracticable. For this reason, FDA did not
propose, and is not establishing in this interim final rule,
requirements for quality factors other than normal physical growth and
sufficient biological quality of protein. However, as new methodology
and appropriate reference criteria become available, FDA will consider
amending this regulation by identifying additional quality factors and
establishing appropriate requirements to meet the additional quality
factors.
(Comment 24) Several comments also expressed confusion about the
need for quality factors for individual infant formula nutrients as
well as for the formula as a whole.
(Response) As explained in section VIII.A, the 1986 Amendments
revised section 412(b)(1) of the FD&C Act by extending the requirements
for quality factors to the infant formula as a whole as well to the
nutrients required by section 412(i) of the FD&C Act (21 U.S.C.
350a(i)). Thus, by law, FDA must establish requirements for individual
nutrient quality factors and the formula as a whole to the extent
possible consistent with current scientific knowledge. To alleviate
confusion about ``healthy growth'' and ``quality factors,'' and to
clarify that quality factors apply both to the formula matrix and to
the
[[Page 7951]]
individual required nutrients, FDA has revised the definition of
``quality factors.'' Thus, in the interim final rule, ``quality
factors'' is defined as follows: ``Quality factors means those factors
necessary to demonstrate the bioavailability and safety of the infant
formula, as prepared for market and when fed as a sole source of
nutrition, including the bioavailability of individual nutrients in the
formula, to ensure healthy growth of infants.''
In addition to revising the definition of ``quality factors,'' FDA
is revising the section of the proposed regulation specifying the
minimum quality factors for infant formulas to clarify the relationship
between ``healthy growth'' and ``normal physical growth.'' Proposed
Sec. 106.96 addressed the quality factors for infant formula and
stated in part: ``All infant formulas shall . . . be of sufficient
quality to meet the nutritional requirements for healthy growth.'' The
proposed rule appears to have created some confusion about how to
comply with such a requirement and how this provision differs from the
requirements that infant formula be capable of supporting normal
physical growth and be formulated and manufactured with protein that is
of sufficient biological quality. A demonstration of ``normal physical
growth'' is a factor that helps to ensure that the infant formula
supports ``healthy growth.'' Similarly, a demonstration of sufficient
biological quality of the protein is a factor that helps to ensure that
the protein in the infant formula (as opposed the entire formula
matrix) helps to support healthy growth.
Consistent with the changes to the definition of ``quality
factors'' in Sec. 106.3 of the interim final rule, proposed Sec.
106.96 has been revised by reorganizing Sec. 106.96 to identify the
two specific quality factors of normal physical growth and sufficient
biological quality of the protein and to set forth the minimum
requirements for quality factors for each of the two quality factors.
Specifically, Sec. 106.96(a) of the interim final rule identifies the
quality factor of normal physical growth and Sec. 106.96(b) of the
interim final rule establishes the minimum requirements for that
quality factor, and Sec. 106.96(e) of the interim final rule
identifies the quality factor of sufficient biological quality of the
protein and Sec. 106.96(f) of the interim final rule establishes the
requirements for this second quality factor. Consistent with FDA's
original intent, Sec. 106.96 of the interim final rule does not
identify ``healthy growth'' as a separate quality factor.
The comments FDA received on the specific quality factor
requirements of the proposed rule, FDA's responses to those comments,
and the quality factor requirements as established in this interim
final rule are addressed in detail in section VIII of this document.
(Comment 25) One comment requested that FDA delete the reference to
safety in the definition of ``quality factors'' in proposed Sec.
106.3(o) to be consistent with the fact that the Infant Formula Act
does not deal with ``safety'' per se, but rather with nutritional
adequacy. The comment stated that the omission of a reference to safety
is consistent with the fact that the FD&C Act ensures safety in many
ways. Consequently, the comment stated, the additional regulation
dictated by the Infant Formula Act was only needed to focus on the
particular reliance of infants on the nutritional aspects of a food
that might substitute for breast milk as their sole source of
nutrition.
(Response) FDA disagrees that the Infant Formula Act, and
specifically the term ``quality factors,'' does not have aspects
related to the safety of an infant formula. While it is true that each
ingredient in infant formula must be approved for use as a food
additive, be GRAS under the conditions of intended use, or be used in
accordance with a prior sanction, it is also true that the ingredients
and the combination of ingredients, i.e., the entire infant formula
matrix, must be able to support the growth and development of infants.
The concept of ``bioavailability'' is not separate and distinct from
the concept of safety. If an infant formula, which is the sole source
of nutrition for infants, could not support healthy growth of infants,
FDA would not consider the formula to be safe for use by infants.
Therefore, FDA disagrees with this comment's request to delete the
reference to safety in the definition of quality factors and is not
modifying proposed Sec. 106.3(o) in response to the request.
(Comment 26) One comment recommended deletion of ``healthy growth''
as a quality factor. Another comment requested removal of any reference
to ``growth'' in the definition of quality factors, asserting that the
effort to establish ``healthy'' or ``normal'' growth as a quality
factor is flawed. This comment did not explain the basis for its
assertion that ``healthy'' or ``normal'' physical growth as a quality
factor is flawed.
(Response) As is discussed previously in this document, FDA has
revised Sec. 106.96 to clarify that ``healthy growth'' is not itself a
quality factor. Instead, FDA has identified two quality factors,
``normal physical growth'' and ``sufficient biological quality of
protein'' and has established in Sec. 106.96 of the interim final rule
requirements to establish those quality factors. This change has been
made to clarify that all quality factors in combination help to ensure
that a formula and the individual nutrients in a formula support
``healthy growth.'' ``Normal physical growth'' is only one factor that
helps to ensure healthy growth. As noted previously in this document,
as science evolves, FDA will consider whether it is appropriate and
feasible to develop additional quality factors that will help to ensure
healthy growth and to establish requirements to demonstrate that a
formula satisfies those additional quality factors.
FDA disagrees with the comment's claim that the effort to establish
``normal physical growth'' as a quality factor is flawed. Quality
factors pertain to the bioavailability of an infant formula and the
individual nutrients in that formula; demonstrating bioavailability
helps to ensure that infants will achieve healthy growth when fed the
formula as a sole source of nutrition. As discussed previously in this
document, and consistent with the 1996 proposal, FDA considers the
concept of ``healthy growth'' to be ``broad, encompassing all aspects
of physical growth and normal maturational development, including
maturation of organ systems and achievement of normal functional
development of motor, neurocognitive, and immune systems'' (61 FR 36154
at 36179). FDA further recognizes that ``all of these growth and
maturational development processes are major determinants of an
infant's ability to achieve his/her biological potential, and all can
be affected by the nutritional status of an infant'' (61 FR 36154 at
36179). The report of the House Committee on Interstate and Foreign
Commerce (the 1980 Committee Report) that accompanied the Infant
Formula Act stated that ``growth of infants during the first few months
of life is a determining factor for the pattern of development and
quality of health in adult life'' (Ref. 9). FDA interprets this
statement as evidence that the Committee recognized the vulnerable
nature of this period of life and the critical role of diet in
affecting long-term growth and development during this stage, and that
healthy growth involves integration of the myriad processes by which an
infant reaches his/her biological growth potential.
The concept of ``healthy growth'' in the definition of quality
factors is not only consistent with the Committee's report, but is also
consistent with
[[Page 7952]]
discussions of diet and health by several authoritative bodies. For
example, the preamble to the Constitution of WHO states that ``health
is a state of complete physical, mental, and social well-being and not
merely the absence of disease or infirmity'' (http://www.who.int/governance/eb/constitution/en/index.html) (Ref. 10). While FDA's use of
the term ``healthy growth'' in this regulation does not extend to
measures of social well-being, it is otherwise consistent with the
concepts in the WHO definition in that normal development is
encompassed within the concept of complete physical and mental well-
being. The term ``healthy growth'' is also closely allied with the
conceptual framework adopted by the Food and Nutrition Board of the
IOM, which established a comprehensive set of reference values for
nutrient intakes consistent with the maintenance of good health. For
example, in revising the dietary reference intakes for the B vitamins,
the IOM considered risk of developmental abnormalities and chronic
degenerative disease as well as nutrient functions and their indicators
(Ref. 8).
Therefore, FDA is retaining the reference to ``healthy growth'' in
the definition of ``quality factors'' in Sec. 106.3 of the interim
final rule, and is retaining normal physical growth as a quality
factor.
(Comment 27) One comment agreed with the critical importance of
ensuring the bioavailability of infant formula and stated that growth
is clearly an indicator of bioavailability. However, the comment also
claimed that it would be inappropriate to establish ``healthy growth''
or ``normal growth'' as a quality factor and recommended that neither
be included as a quality factor in proposed Sec. 106.96. The comment
alleged that there are meaningful scientific weaknesses to establishing
growth as a quality factor but did not identify those weaknesses.
The comment also argued that not enough is known about what
constitutes optimal growth to make it possible to choose the one
perfect standard against which ``normal'' or ``healthy'' growth should
be judged and that, as a matter of policy, it would be unwise to depend
on growth as an outcome. The comment also claimed that focusing on a
single outcome may cause FDA problems in being even-handed in its
treatment of manufacturers developing new infant formulas although the
comment did not explain this assertion.
(Response) FDA agrees that it would be inappropriate to establish
``healthy growth'' as an individual quality factor but for reasons
other than those offered in the comment. As noted previously in this
document, all quality factors contribute to demonstrating the
bioavailability and safety of a formula and help to ensure ``healthy
growth.'' There are many factors that help to ensure ``healthy
growth,'' one of them being ``normal physical growth'' and another
being sufficient biological quality of protein. Therefore, because all
quality factors help to ensure healthy growth, it would be
inappropriate to establish ``healthy growth'' as a separate and
distinct quality factor.
FDA disagrees, however, that it is inappropriate to establish
``normal physical growth'' as a quality factor. Importantly, FDA does
not consider ``optimal growth'' to be synonymous with ``normal physical
growth.'' Demonstrating that a formula supports ``normal physical
growth'' is a scientifically valid means to contribute to demonstrating
that the formula (in its entirety) is bioavailable to and safe for the
infant. Notably, the IOM committee strongly supported studies of normal
physical growth, recommending ``that growth studies should continue to
be a centerpiece of clinical evaluation of infant formulas and should
include precise and reliable measurements of weight and length
velocity, and head circumference'' (Ref. 4, p. 10).
Even though there may always be debate in the scientific community
on what constitutes optimal growth, there is a sufficient knowledge
base to establish ``normal physical growth'' as a quality factor. It is
well-established that infants grow steadily and predictably, and there
are now data to identify what constitutes ``normal physical growth''
and how infants should grow. Using worldwide data of how infants grow
as well as improved statistical procedures, WHO developed new growth
standards, which are regarded as the most comprehensive standards for
how infants should grow. The Centers for Disease Control and Prevention
(CDC) has recommended the use of the WHO growth standards for birth to
2 years of age since 2009 and CDC's determination was formally
presented in 2010 (Ref. 11). The 2009 CDC growth charts, based on the
WHO Child Growth Standards, are available at http://www.cdc.gov/growthcharts/who_charts.htm, and are a valuable clinical tool for both
health professionals and clinical investigators. The 2009 CDC growth
charts are incorporated by reference in Sec. 106.160(e) of this
interim final rule.
(Comment 28) Several comments addressed the use of ``healthy
growth'' as a general quality factor (proposed Sec. 106.96(a)). One
comment stated that it would not be possible to achieve a reasonable
scientific consensus on what additional functions (in addition to
anthropometric measurements of physical growth) might constitute
``healthy growth'' as it is related to nutrition, suggesting that
``healthy growth'' should not be a quality factor.
(Response) FDA agrees that ``healthy growth'' should not itself be
a quality factor and accordingly, the Agency is revising both the
definition of quality factors in proposed Sec. 106.3(o) and the
requirements for quality factors in proposed Sec. 106.97 to clarify
this issue. As noted, ``healthy growth'' is a broad concept, and the
definition of ``quality factors'' in Sec. 106.3 of the interim final
rule identifies the achievement of healthy growth as the overall goal
of all specific quality factors. Importantly, however, FDA has not
established any requirements for demonstrating ``healthy growth.'' As
clarified previously in this document, the interim final rule
identifies two quality factors (``normal physical growth'' and
``sufficient biological quality of protein'') and establishes
requirements that relate specifically to those two quality factors. In
particular, Sec. 106.96(b) of the interim final rule establishes the
requirements for the quality factor of ``normal physical growth,'' and
Sec. 106.96(f) of the interim final rule establishes the requirements
for the quality factor of ``sufficient biological quality of protein.''
Meeting the quality factors that are delineated by the Agency, both now
and in the future, will help to ensure that the individual nutrients in
an infant formula and the infant formula as a whole support healthy
growth.
(Comment 29) Several comments favored requiring normal physical
growth as a quality factor, and a related comment stated that the only
practical way of assessing growth is by physical measurement.
(Response) The Agency agrees with this comment to the extent that
the comment asserts that the only practical way of measuring normal
physical growth is by physical measurement. Importantly, it is possible
that in the future, as science advances, other measures for assessing
normal physical growth may be identified, and FDA intends to consider
amending the regulations issued in this interim final rule to
establish, as appropriate, additional quality factors and associated
requirements.
(Comment 30) One comment stated that because of the increasing
complexity of formula ingredients, it is more relevant to evaluate the
formula's overall nutrient quality and availability than merely
assessing selected
[[Page 7953]]
individual nutrients required by the FD&C Act.
(Response) To the extent this comment asserts that quality factors
should be established for the complete infant formula, FDA agrees.
FDA disagrees with the comment, however, to the extent that it
suggests that evaluation of the formula's overall nutritional quality
and overall nutrient availability is sufficient or more relevant than
evaluating the bioavailability of individual nutrients. As explained in
this document, it is scientifically appropriate to establish quality
factors both for the complete formula and certain individual formula
ingredients.
The 1996 proposal noted that individual nutrient bioavailability is
especially critical for formula because, for some infants, it serves as
the sole source of nutrition at a life stage of particular
vulnerability to harm from nutritional insults (61 FR 36154 at 36179).
A nutrient is ``bioavailable'' to an infant if it is ``physiologically
available in sufficient quantities to perform its metabolic
functions;'' the factors affecting bioavailability are complex and can
be difficult to predict (61 FR 36154 at 36179). Given the documented
importance of individual nutrients, it is entirely appropriate that FDA
consider identifying quality factors for these nutrients.
Protein is one of the nutrients required to be present in infant
formula, and the 1996 proposal discussed in detail the complexity of
protein and its central importance in the infant diet (61 FR 36154 at
36181). Therefore, at the present time, protein is the only individual
nutrient for which a quality factor should be established, and thus,
Sec. 106.96(e) of the interim final rule requires that a formula's
protein ingredient be of sufficient biological quality. FDA did not
propose, and is not including in this interim final rule, requirements
for quality factors for other required nutrients because, for example,
methods to determine whether such requirements are met are either not
available, or if available, are impractical because they are invasive,
technically difficult, or their results cannot be meaningfully
interpreted.
A quality factor for the formula's overall nutritional sufficiency
(i.e., normal physical growth) and a quality factor for the biological
quality of the formula's protein component (i.e., sufficient biological
quality) are complementary. Although a growth study can provide an
assessment of a formula's overall nutritional sufficiency, such a study
has limitations. In particular, an infant may experience normal
physical growth in terms of height, weight, and head circumference but
nevertheless be malnourished because the protein does not contain all
of the essential amino acids at levels and relative proportions needed
for healthy growth and development. Said differently, the functional
outcome from an ingredient, such as protein, may not necessarily be
immediately reflected by anthropometric measures of physical growth.
Thus, FDA has concluded that it is scientifically appropriate to
establish quality factors both for the overall formula and the
individual formula ingredient, protein. See the discussion in section
VIII.
Moreover, section 412(b)(1) of the FD&C Act requires FDA to
establish, to the extent possible consistent with current scientific
knowledge, requirements for quality factors for individual ingredients
and the formula as a whole. Thus, Sec. 106.96 of the interim final
rule establishes requirements for demonstrating two quality factors:
normal physical growth and sufficient biological quality of the protein
ingredient.
(Comment 31) Several other comments indicated that quality factors
requirements for infant formulas should demonstrate not only normal
physical growth but also normal development and health of infants
during the study period.
(Response) Physical growth and overall development are both aspects
of the term ``healthy growth.'' Currently, normal physical growth is a
readily available method for evaluating the bioavailability of the
infant formula matrix; however, as science evolves, FDA may add
additional quality factor requirements that demonstrate that the
formula ensures that infants achieve healthy growth. The Agency does
not consider it necessary at this time to include in the four-month
study period additional quality factors relating to the ``health of
infants'' or ``normal development,'' nor does the comment explain how
specifically these additional quality factors would be measured or why
four months would be a sufficient period of time within which to expect
measurable changes. Thus, the interim final rule does not identify
``normal development and health of the infant'' as an additional
quality factor.
(Comment 32) One comment agreed with the Agency as to the
importance of assessing substantive changes in the manufacturing
process on nutrient bioavailability, but stated that a broad definition
of growth (healthy growth) would not achieve this objective. Another
comment requested that FDA put any mention of measurement of
``healthy'' or ``normal growth'' into a guidance document to identify
when a clinical demonstration of growth is the most appropriate way to
demonstrate bioavailability, and that the term ``healthy growth'' be
changed to ``expected physical growth'' in that guidance. The comment
also stated that ``expected'' is a more meaningful term and refers to
the population for whom the formula is intended and can be measured
objectively.
(Response) As explained previously in this document, FDA has
revised proposed Sec. 106.3(o), the definition of ``quality factors,''
and is not identifying ``healthy growth'' as an individual quality
factor in this interim final rule. Further, FDA does not agree that the
term ``expected physical growth'' should replace the term ``healthy
growth.'' Unlike the broad concept of ``healthy growth,'' the term
``expected physical growth'' is too narrow to describe what a
manufacturer must ensure with respect to the bioavailability and safety
of the infant formula. The Agency is codifying ``normal physical
growth'' and ``sufficient biological quality of the protein
ingredient'' as the two quality factors in this interim final rule. As
science evolves, FDA will consider amending this regulation by
identifying additional quality factors.
8. Other Definitions Requested in Comments
(Comment 33) One comment recommended that the Agency adopt a
definition of ``minor change,'' and suggested ``any new formulation, or
any change of ingredients or processes where experience or theory would
not predict a possible significant adverse impact on nutrient levels or
nutrient availability. Minor changes may or may not affect whether a
formula is adulterated under section 412(a) of the FD&C Act; changes
that affect whether a formula is adulterated under section 412(a) would
require the manufacturer to notify FDA prior to first processing.'' The
comment noted that the 1996 proposal did not mention ``minor change,''
and claimed that the failure to define ``minor change'' created
unnecessary confusion. The comment gave several examples of both minor
changes that would require notification prior to first processing, and
those that would not require such notification.
(Response) FDA declines to add a definition for the term ``minor
change'' because such a definition is unnecessary. Although the comment
asserts that defining ``minor change'' is needed to dispel confusion,
the comment does not explain this statement. The pivotal concept for a
[[Page 7954]]
submission required by section 412(d) of the FD&C Act for a new infant
formula is whether the change is ``major,'' and, in Sec. 106.3, the
interim final rule includes a definition of ``major change.'' This
definition of ``major change'' makes clear that only certain changes
are of a type that require the submission under section 412(d) of the
FD&C Act; the definition in proposed Sec. 106.3(i) is derived from
section 412(c)(2)(B) of the FD&C Act, and, the definition of ``major
change'' in Sec. 106.3 of the interim final rule provides examples of
changes that would be considered ``major'' because they are changes
that cause a formula to differ fundamentally in processing or
composition. Moreover, elsewhere in this preamble, FDA has affirmed
that not every change to a formula is a ``major change.'' Thus, the
need for a definition of ``minor change'' has not been established.
Accordingly, FDA is not persuaded to add a definition for ``minor
change'' to this interim final rule.
(Comment 34) A comment suggested adding a definition for the term
``critical'' in order to limit the scope of ``validation'' (e.g. Sec.
106.35) to those areas of manufacture that may truly have public health
significance. The comment suggested that the term ``critical'' be
defined when describing ``systems or equipment that has been designated
by the infant formula manufacturer as necessary to control to prevent
adulteration.'' The comment stated that this definition also emphasizes
the responsibility of the manufacturer to make a careful determination
of which areas of the production process may have public health
significance.
(Response) FDA is not persuaded to include a definition of
``critical'' in the interim final rule. Throughout the interim final
rule, the Agency refers to points, steps, stages, equipment, and
systems ``where control is necessary to prevent adulteration.'' This is
the standard in section 412(b)(2)(A), the relevant statutory provision.
Therefore, it is not appropriate to limit or otherwise modify this
standard with the term ``critical.'' Accordingly, FDA declines to
include a definition of ``critical'' in the interim final rule.
(Comment 35) One comment suggested defining the term
``specifications.'' The comment stated that FDA should define
``specifications'' as ``quality control limits or standards for raw
materials, in-process materials, and finished product, which are
established by the manufacturer for purposes of controlling quality and
consistency for infant formula. Failure to meet an established
specification requires a documented review and material disposition
decision.'' The comment suggests that in the drug industry, there is
common acceptance that the term ``specification'' means a predetermined
value or range for a given parameter, which must be met in order to
continue the manufacturing process or release the product for
distribution. Failure to meet a specification triggers special, non-
routine, documented review, not automatic rejection of the product. The
comment states that this procedure is appropriate because
specifications, like those in infant formula manufacture, are set well
within the outer limits that would cause adulteration. In view of this
definition, the comment suggests deleting the word ``standard''
throughout the proposed rule and replacing it with ``specifications.''
If FDA opts to define ``specifications'' as the outer acceptability
limits, the comment strongly recommends that manufacturers be allowed
to retain the current tighter control range approach and to determine
whether outer acceptability limits need to be established at each given
step in the manufacturing process, as opposed to making the
establishment of outer limits an absolute requirement in every case.
(Response) FDA agrees that the term ``standards'' does not add
clarity to the interim final rule because any standard would be
considered a specification. Thus, the Agency is deleting the term
``standards'' when used and retaining the term ``specifications.''
FDA disagrees, however, that the term ``specification'' needs to be
defined in this interim final rule. The term is commonly used and well-
understood in the context of CGMP. In proposed Sec. 106.6(c), a
manufacturer would have to establish standards or specifications at any
point, step, or stage in the production process where control is
necessary to prevent adulteration. Controls to ensure quality include
planning processes to determine desired product features or
characteristics, a system of controls to ensure that the desired
product will be consistently produced, and making necessary
improvements to the process (Ref. 12). Manufacturers must plan what
they intend to produce, institute adequate controls to achieve the
desired outcome, and ensure that the controls work so that the desired
outcome is consistently achieved. If the outcome is not consistently
achieved, one or more corrective actions must be implemented to reach
the desired outcome.
This interim final rule embodies the basic concepts of ensuring
quality through planning, establishing controls, and providing feedback
to ensure necessary improvements are implemented. An infant formula
manufacturer must establish controls at all stages of manufacturing to
ensure that the finished product, as packaged and labeled, meets the
requirements of the FD&C Act. The controls chosen by a manufacturer may
include a specific limit (e.g., addition of 60 milligrams (mg) of
vitamin C) or a range (e.g., product must be held between 35-45 degrees
F). This interim final rule does not require that a manufacturer set
specifications at an outer acceptability limit or within a tighter
control range, as described by the comment. Instead, the manufacturer
has the flexibility to establish those specifications that are
necessary to meet the requirements of section 412 of the FD&C Act and
not adulterate the product under sections 402(a)(1), (a)(2), (a)(3), or
(a)(4) of the FD&C Act.
(Comment 36) One comment suggested defining the term ``target
value.'' The comment also suggests defining the term ``target value''
as ``control limits or standards for raw materials, in-process
materials, and finished product which are established by the
manufacturer for purposes of targeting the manufacturing process to a
tight range within broader specifications. Failure to meet an
established target value shall result in an immediate review and
adjustment, if necessary, during the manufacturing process. No
documented review and material disposition is [sic] needed when a
target value is not met, provided that the established specifications
are met.'' The comment explained that infant formula manufacturers
sometimes establish ``target values'' within tight specifications so
that operators can adjust the process if the target value is exceeded.
The comment suggested that the term ``target value'' should be not
defined for purposes of establishing a requirement for them, but,
instead, to recognize that some infant formula manufacturers use them
for quality control purposes and to distinguish them from
specifications because failure to meet a target value should not
trigger the kind of detailed and documented review prompted by a
failure to meet specifications.
(Response) FDA is not persuaded to define the term ``target value''
because FDA is not requiring manufacturers to establish target values
in this interim final rule. Manufacturers who establish ``target
values'' within their specifications are free to continue this
practice. Importantly, however, any target value established by a
[[Page 7955]]
manufacturer should be consistent with the manufacturer's
specifications. FDA agrees that although a failure to meet a
specification shall prompt a detailed and documented review, such
review would not be required by the failure to meet a target value that
does not also serve as a specification.
V. Subpart B--Current Good Manufacturing Practice
In the 1996 proposed rule, FDA proposed to establish a new subpart
B in part 106 of title 21 of the CFR to implement section 412(b)(2) of
the FD&C Act. Section 412(b)(2) of the FD&C Act requires the Secretary
(and FDA by delegation) to issue regulations to ``establish good
manufacturing practices for infant formulas, including quality control
procedures that the Secretary determines are necessary to assure that
an infant formula provides nutrients in accordance with this subsection
and subsection (i) and is manufactured in a manner designed to prevent
adulteration of the infant formula.'' The system proposed by FDA was
intended to establish a framework in which manufacturing decisions are
left to the formula manufacturer, but also charges a manufacturer with
incorporating into its process measures designed to ensure the safety
and nutritional quality of the formula. The 2003 reopening requested
comments on all aspects of the 1996 proposal, including proposed
subpart B. Also, certain provisions of proposed subpart B were the
subject of FDA's 2006 request for comments.
FDA received both general comments as well as specific comments on
proposed subpart B. These comments are summarized in this document
along with the Agency's responses. In addition to the substantive
revisions to subpart B noted in this document, FDA is also making minor
editorial revisions in this subpart.
A. General Comments
(Comment 37) One comment suggested that the proposed production and
in-process control system should be called a Hazard Analysis and
Critical Control Point (HACCP) system because it contains the elements
of HACCP.
(Response) The Agency disagrees. In this interim final rule, FDA is
adopting CGMP requirements for infant formula as mandated by section
412(b)(2) of the FD&C Act. That statutory provision expressly requires
that the Secretary establish by regulation good manufacturing practices
requirements.
HACCP is a science-based, systematic approach to preventing food
safety problems through the identification and the assessment of risk
(likelihood of occurrence and severity), and control of the biological,
chemical, and physical hazards associated with a particular food
production process or practice. Application of HACCP requires the food
producer to develop a plan for the manufacturer's particular production
process that anticipates food safety hazards and identifies the points
(critical control points) in such a process where a failure would
likely result in a hazard being created or allowed to persist.
HACCP and CGMP share the common goal of a systematic approach to
food safety. CGMP requires that a manufacturer take all necessary steps
both to prevent hazards and to ensure that the manufactured product is
what was established in the manufacturer's specifications. Although
some requirements of this interim final rule may be consistent with a
HACCP-based system, this interim final rule establishes CGMP in
accordance with section 412(b)(2)(A) of the FD&C Act.
B. Current Good Manufacturing Practices (Proposed Sec. 106.5)
As proposed in 1996, Sec. 106.5(a) stated that the regulations in
subpart B defined the minimum current good manufacturing practices for
infant formula and that the provisions of part 113 (21 CFR part 113)
applied to liquid infant formulas. Under proposed Sec. 106.5(b), the
failure to comply with any provision of subpart B, or for a liquid
infant formula, any provision of part 113, would cause the formula to
be adulterated under section 412(a)(3) of the FD&C Act. The comments
FDA received on proposed Sec. 106.5 supported the language without
modification.
The Agency has recently become aware of an infant formula product
that satisfies the definition of an ``acidified food'' under Sec.
114.3(b) (21 CFR 114.3(b)). As an acidified food, this infant formula
must comply with part 114 (21 CFR part 114). To make Sec. 106.5 a
comprehensive statement, FDA is, on its own initiative, revising
proposed Sec. 106.5 to clarify that an infant formula that is an
acidified food is subject to the requirements of part 114 and that, for
an infant formula that is an acidified food, the failure to comply with
any provision of part 114 will cause the formula to be adulterated
under section 412(a)(3) of the FD&C Act.
C. Production and In-Process Control System (Proposed Sec. 106.6)
In the 1996 proposal, FDA proposed in Sec. 106.6 to require that
infant formula manufacturers implement a system of production and in-
process controls designed to ensure that all requirements of subpart B
are met and that the infant formula is not otherwise adulterated. This
system would be required to be set out in a written plan extending to
all stages of processing, from receipt and acceptance of raw materials,
ingredients, and components, through storage and distribution of
finished product. For each point at which control is necessary, a
manufacturer would be required to set specifications, monitor the
control point, establish a corrective action plan for use when a
specification is not met, have an individual qualified by education,
training, or experience evaluate the public health significance of any
deviation from specifications, and establish recordkeeping procedures.
The Agency received comments on several aspects of Sec. 106.6,
which are addressed in this document.
1. Specifications and Failure To Conform to an Established
Specification
FDA received comments that addressed ``specifications'' generally
and did not focus on particular requirements of the proposed rule.
These comments are relevant to several sections of the proposed rule
that require a manufacturer to establish, implement, and enforce
specifications. For purposes of clarity and consistency, FDA addresses
in this document, in the context of proposed Sec. 106.6, the general
comments concerning specifications.
(Comment 38) One comment stated that infant formula manufacturers
currently establish very tight internal specifications and that, while
the objective during manufacturing is to produce a product that falls
within these tight internal specifications, the failure to do so does
not necessarily mean that the infant formula product is adulterated.
The comment asserted that a deviation that falls outside the tight
internal specifications should trigger a formal, documented review and
a material disposition decision and should not lead to automatic
rejection of the product. The comment explained that a documented
review and a material disposition decision is appropriate because
specifications are customarily well within the outer limits that would
cause adulteration.
(Response) The requirement to establish, monitor, and otherwise
apply specifications was included in several places in the proposed
rule, including proposed Sec. Sec. 106.6(c), 106.40(d), 106.40(e), and
106.70. FDA is persuaded by this comment as well as other comments
received that it is appropriate to make certain revisions to the
proposed rule's specification requirements.
[[Page 7956]]
First, FDA is revising proposed Sec. 106.40(d) by removing the
proposed requirement that an ingredient, container, or closure that
fails to conform to a specification be automatically rejected for use
in formula manufacturing and, instead, to provide that such ingredient,
container, or closure, as well as any affected infant formula, shall be
subject to a formal, documented review and material disposition
decision and shall be quarantined pending such review and disposition
decision. The disposition decision may be to reject the ingredient,
container, or closure or the affected formula; to reprocess or
otherwise recondition it; or to approve and release it for use. As
stated previously in this document, the CGMP procedures in this interim
final rule are designed to prevent the production of an adulterated
infant formula. FDA agrees that failure to meet a specification does
not necessarily mean that the infant formula manufactured using the
ingredient, container, or closure will be adulterated and thus, the
ingredient, container, or closure does not need to be automatically
rejected. Similarly, in such situations, the affected infant formula
need not be automatically rejected. In order for the revision of Sec.
106.40(d) to result in adequate public health protection, however, the
manufacturer must have in place a robust procedure to investigate any
deviation from its specifications for ingredients, containers, and
closures so that the manufacturer can credibly determine whether the
deviation from specifications could result in adulteration of infant
formula. Such procedure must consist of a documented review of the
deviation from a specification, records of such documented review,
including the corrective action taken and the disposition of the
affected materials, and control of the affected materials pending their
appropriate disposition. The failure to follow these procedures would
result in the formula being deemed adulterated under section 412(a)(3)
of the FD&C Act.
Specifically, under Sec. 106.40(d) of the interim final rule, any
deviation from a specification must result in a documented,
comprehensive, and systematic examination of the affected ingredient,
container, closure, or of the in-process or finished infant formula in
which the suspect ingredient, container, or closure was used by an
individual qualified by education, training, or experience to perform
such examination. An adequate documented review includes: (1)
Identification of the specific deviation; (2) a determination of the
need for an investigation into the cause of the deviation; (3)
evaluation of the material or product that does not conform to the
specification to determine whether the deviation has resulted in or may
lead to adulteration of infant formula; (4) identification of the
action or actions taken to correct, and prevent a recurrence of, the
deviation; and (5) documentation of the disposition of the affected
material and infant formula products, if any.
Adequate records of the documented review and disposition are
critical, and the rule requires a manufacturer to establish and
maintain such records. Specifically, under Sec. 106.100(e)(4) of the
interim final rule, required records include those showing the identity
and conclusions of, and followup by, the qualified individual who
investigated a deviation from a master manufacturing order, a failure
of a production aggregate or an ingredient of a production aggregate to
meet manufacturer's specifications, or a failure to meet any
specification applicable to a production process where control is
deemed necessary to prevent adulteration.
Accordingly, proposed Sec. 106.40(d) is revised by deleting the
requirement to develop written specifications for acceptance or
rejection of ingredients, containers, and closures used in
manufacturing infant formula. In its place, FDA is establishing a
requirement that a manufacturer develop written specifications for
ingredients, containers, and closures and develop written procedures to
determine whether such specifications are met. The Agency is also
establishing a requirement for a documented review and material
disposition decision by an individual qualified by education, training,
or experience when an ingredient, container, or closure is determined
not to meet the manufacturer's specifications.
Comments on other issues pertaining to proposed Sec. 106.40(d) are
discussed in section V.H.2.
Adequate public health protection also requires a manufacturer to
ensure that any ingredient, container, or closure that does not meet
the manufacturer's specifications be controlled under a quarantine
system designed to prevent its use in the manufacturer of an infant
formula unless and until it is released for such use. Proposed Sec.
106.40(e) would have required that ingredients, containers, or closures
be stored in areas clearly designated as ``pending release for use,''
``released for use,'' or ``rejected for use.'' In addition, proposed
Sec. 106.40(e)(3) would have required ingredients, containers, or
closures that did not meet a manufacturer's specifications to be
rejected and controlled under a quarantine system to prevent their use
in the manufacture of infant formula. However, under this interim final
rule, a disposition decision based on a failure to meet a specification
is not limited to a decision to reject the material; a decision could
be made to release the ingredient, container, or closure, or the
affected infant formula, for use, or to reprocess or recondition it.
The need to control the ingredient, container, or closure, or the
affected formula, to prevent its use in the manufacture of infant
formula, pending a material review and disposition decision, applies
any time a manufacturer fails to meet a specification. Controlling the
material under a quarantine system will prevent potentially adulterated
material from being used, or from co-mingling it with other material,
in the manufacture of an infant formula. Comments discussed elsewhere
in this preamble requested clarification with respect to methods that
could be used to control and segregate material. Section 106.40(e)
describes the ways a manufacturer may quarantine material that has not
been released for use due to failure to meet a specification, or that
has been rejected for use in the manufacture of an infant formula.
Comments on other issues pertaining to Sec. 106.40(e) are
discussed in section V.H.2. Consistent with the changes in Sec.
106.40(d) and (e) of the interim final rule, Sec. 106.40(f) requires a
manufacturer to quarantine an ingredient, container, or closure and to
conduct a documented review and make a material disposition decision if
the ingredient, container, or closure has been, or may have been,
exposed to conditions that may adversely affect it.
Comments on other issues pertaining to Sec. 106.40(f) are
discussed in section V.H.3.
Similarly, under Sec. 106.50(f) of the interim final rule, failure
to meet a specification does not result in automatic rejection. A
manufacturer must control, under a quarantine system, in-process
material that does not meet specifications pending a material review
and disposition decision by a qualified individual. In-process material
that does not meet a manufacturer's specifications could potentially
adulterate an infant formula, if used. If an affected in-process
material is reprocessed or otherwise reconditioned, it must be
controlled under a quarantine system, pending a documented review and
material disposition decision. Any in-process material that is rejected
must also be
[[Page 7957]]
controlled under quarantine system to prevent its use in infant formula
manufacturing and processing operations.
Finally, at the final production stage, a manufacturer must
determine whether the production aggregate may be released for use or
distribution. Pending a decision by the manufacturer to release the
production aggregate for use or distribution, proposed Sec. 106.70(a)
would have required that the manufacturer ``hold, or maintain under its
control,'' each production aggregate until the manufacturer determines
certain criteria are met. This language was proposed in order to ensure
that adulterated formula would not be released (see 61 FR 36154 at
36174). For consistency with changes made to Sec. Sec. 106.40 and
106.50 related to the need to establish a quarantine system pending a
documented review and material disposition decision by a qualified
individual, and options to reject, reprocess or otherwise recondition,
or approve and release affected material, FDA is making corresponding
changes to Sec. 106.70 of the interim final rule.
For purposes of consistency with the changes in Sec. Sec.
106.40(d), (e), and (f), 106.50(f), and 106.70(a), (b), and (c), FDA is
revising Sec. 106.6(c)(4) to state that the review conducted shall be
a documented review resulting in a material disposition to reject,
reprocess or otherwise recondition, or approve and release the affected
article. Likewise, FDA is inserting a new Sec. 106.6(d) that states
the requirement to establish a quarantine system pending a documented
review and material disposition decision for any article that fails to
meet a specification.
These revisions reflect CGMP and are necessary to prevent
adulteration of an infant formula, provide consistency across
requirements, and clarify, in response to comments, that a failure to
meet a specification does not necessarily result in automatic rejection
at each stage of the manufacturing process, i.e., for an ingredient,
container or closure, for an in-process material, or for a finished
infant formula.
FDA also received comments on specific aspects of proposed Sec.
106.6. These comments are discussed in this document.
(Comment 39) One comment regarding specifications focused on
proposed Sec. 106.70. This comment expressed support for the intent of
this provision, which the comment characterized as preventing the sale
and consumption of a formula that is nutritionally or microbiologically
inadequate. The comment asserted, however, that the rejection or
reprocessing of a batch (production aggregate) of infant formula that
falls outside a manufacturer's specifications is an overly prescriptive
means of achieving this objective, and explained that a manufacturer
assesses deviations from specifications on a case by case basis and
that, once reported, all deviations are evaluated by suitably trained
personnel who consider the nutritional and public health significance
of the deviation. The comment proposed alternative language for
proposed Sec. 106.70(b).
(Response) As noted, FDA has revised several provisions of the
interim final rule that concern specification deviations, including
proposed Sec. 106.70(b). Although FDA declines to adopt the
alternative language offered by this comment, the Agency believes that
the revisions to proposed Sec. 106.70(b), which clarify the
responsibilities of a manufacturer when a production aggregate does not
conform to its specifications, respond to the issues raised by the
comment.
2. Establishment and Implementation of a Control System (Proposed Sec.
106.6(a))
(Comment 40) One comment suggested that instead of requiring in
proposed Sec. 106.6(a) a system to cover all stages of processing, the
production and in-process control system should extend to those stages
of processing, storage, and distribution that are under the
manufacturer's control because, the comment contended, a manufacturer
cannot be expected to be responsible for ensuring proper distribution
practices. In addition, the comment asserted that, for co-packers, the
scope of responsibility of the co-packer is necessarily limited to the
specific aspect of manufacturing, storage, or distribution that the co-
packer has agreed by contract to handle.
(Response) FDA believes that this comment misunderstands the
responsibilities of manufacturers under the interim final rule. As
discussed in the response to Comment 17, there are two types of
responsibilities under the interim final rule: The obligation to
conduct certain activities according to the requirements of the CGMP
regulations and the obligation of certain persons to ensure compliance
with the rule's requirements even if such person is not engaged in the
specific activities covered by the rule. The degree to which a
manufacturer must adhere to the interim final rule's CGMP requirements
is determined by the specific activities in which such manufacturer is
engaged: Under the interim final rule, a manufacturer must comply with
all the CGMP requirements that cover activities in which such
manufacturer actually engages. Thus, a firm that packages an infant
formula is a ``manufacturer'' as defined in Sec. 106.3 and must comply
with all requirements applicable to the operations it performs. For
example, a firm that packages an infant formula is responsible for
having a production and in-process control plan for that operation.
Conversely, the firm that packages the formula is not responsible for
production and in-process control requirements that are not related to
packaging operations, such as those related to the receipt of raw
materials.
For the foregoing reasons, FDA is not persuaded to change Sec.
106.6(a) in response to this comment and, with the exception of minor
editorial changes, Sec. 106.6(a) is included in this interim final
rule as proposed.
3. Elements of the Production and In-Process Control System (Proposed
Sec. 106.6(c))
(Comment 41) Another comment objected to the requirement in
proposed Sec. 106.6(c) that the manufacturer take certain actions at
any point, step, or stage in the production process where control is
necessary to prevent adulteration. The comment argued that ``any point,
step, or stage'' could refer to every conceivable manufacturing
activity and there are few manufacturing activities that could not,
theoretically, give rise to a finding of ``technical'' adulteration.
The comment stated that it is impractical to fulfill the requirements
of proposed Sec. 106.6(c) for every conceivable manufacturing activity
and suggested that the regulation be revised to focus on the
manufacturing steps most important or critical to ensuring that a
product is free from actual adulteration. The comment claimed that this
would also make proposed Sec. 106.6(c) consistent with the
recordkeeping requirements in proposed Sec. 106.100(e)(3). The comment
also emphasized that it is the responsibility of the manufacturer to
identify the critical points.
(Response) FDA does not intend that the control procedures
established under Sec. 106.6(c) would address every theoretical risk
of technical adulteration. Importantly, however, a manufacturer has a
responsibility, as part of CGMP, to ensure quality in the finished
product on a consistent basis. The way to ensure quality is to identify
controls needed at various steps in the production process so that, in
its final form, the formula complies with all requirements.
[[Page 7958]]
FDA agrees with the comment to the extent that it asserts that
certain actions (e.g., the establishing of specifications) are not
required at every step in the manufacturer's process. Instead, it is
the responsibility of a manufacturer to identify those points at which
control is necessary to prevent adulteration of infant formula
products. A manufacturer must consider all possible risks likely to
occur with its products and determine how these risks will be
controlled. These risks include insanitary conditions that may
contaminate formula or may render a formula injurious to health, not
just conditions that do, in fact, contaminate the formula or render it
injurious to health. A formula product that has been held under
insanitary conditions whereby it may become contaminated with filth or
it may be rendered injurious to health is deemed adulterated under
section 402(a)(4) of the FD&C Act.
In addition, a manufacturer must determine the controls that are
necessary to prevent adulteration during the production of each formula
based on the manufacturer's individual operations. Failure to establish
specifications under Sec. 106.6(c) at any point, step, or stage where
control is necessary to prevent adulteration would cause the product to
be adulterated under section 412(a)(3) of the FD&C Act for failure to
follow CGMP, including quality control procedures, required by FDA.
Accordingly, FDA is not persuaded to make the revisions requested in
this comment.
(Comment 42) One comment requested that FDA consider the meaning of
the term ``specification'' in proposed Sec. 106.6(c)(1), which
requires that infant formula manufacturers establish standards or
specifications to be met at any point, step, or stage in the production
process where control is necessary to prevent adulteration.
The comment presented several objections to setting specifications
at the outer limits. The comment stated that a manufacturer should be
encouraged to impose tight control over its manufacturing process to
produce infant formula of consistent quality and noted that infant
formula manufacturers set their specifications well within the outer
limits that would cause adulteration. The comment noted that, in most
cases, manufacturers have not identified every extreme outer limit for
every process and product parameter that would result in rejection.
(Response) The Agency believes that this comment misreads the
proposed rule. The comment seems to suggest that proposed Sec.
106.6(c)(1) would require a manufacturer to establish a specification
at a particular level or range that, if not met, would cause the infant
formula to be adulterated. The Agency disagrees with this reading of
proposed Sec. 106.6(c)(1). The purpose of Sec. 106.6(c) is to ensure
that each manufacturer examines its infant formula production processes
and addresses those points, steps, and stages where control is needed
to ensure that the process will produce the formula the manufacturer
intends to produce. Proposed Sec. 106.6(c)(1) stated that a
specification must be established where control is necessary to prevent
adulteration but does not specify the range or magnitude of the
specification. Also, as discussed in section V.C.1, although proposed
Sec. 106.40(d) stated that specifications shall be set for the
acceptance or rejection of ingredients, containers, and closures; FDA
is revising proposed Sec. 106.40 so that when a formula ingredient,
container, or closure fails to conform to specifications, an individual
qualified by education, training, or experience must conduct a
documented review to determine whether such failure could result in an
adulterated infant formula, and thereafter, must make and document a
material disposition decision to reject, reprocess or otherwise
recondition, or approve and release the material or the affected infant
formula for use. Additionally, as discussed in section V.I, FDA is
revising Sec. 106.50 so that if any in-process material fails to meet
a specification established under Sec. 106.6(c)(1), an individual
qualified by education, training, or experience must conduct a
documented review and make a material disposition decision to reject,
reprocess or otherwise recondition, or approve and release the in-
process material. Therefore, a manufacturer may choose to establish a
level or range as a specification that must be met in order to produce
a formula that is not actually adulterated but is not compelled or
encouraged to set its specifications at the outer limits. In fact, a
manufacturer may establish a specification within a narrow range to
ensure a larger margin of error for some or all of its processes.
In addition, FDA notes that, as discussed in section IV, the Agency
is revising, in response to a comment, proposed Sec. 106.6(c)(3) to
delete the words ``standard or'' (see subpart A).
(Comment 43) Several comments suggested changes to proposed Sec.
106.6(c)(3), which would require a manufacturer to establish a
corrective action plan to use when a specification, established in
accordance with Sec. 106.6 (c)(1), is not met. One comment suggested
establishing standard operating procedures (SOPs) for use when a
specification is not met as an alternative to a corrective action plan.
The comment objected to the language in the preamble to the 1996
proposal that ``the best way to ensure that a corrective action is
appropriate is to determine the action in advance,'' asserting that
while it may often be feasible to establish corrective action plans in
advance, a manufacturer cannot be expected to foresee all future
circumstances that may require reliance on a corrective action plan and
to predict how it will operate and that many circumstances may have a
different set of elements to be considered, thus requiring a case-by-
case analysis. The comment stated that a manufacturer could include
potential corrective actions in an SOP, but a corrective action should
not be mandated when irrelevant to the facts of a given situation.
(Response) FDA is not persuaded to change Sec. 106.6(c)(3) for the
following reasons. First, a corrective action plan is one type of SOP
that addresses corrective actions. Therefore, a manufacturer may use a
SOP as its corrective action plan. Second, although FDA acknowledges
that a manufacturer may not foresee all circumstances in which a
corrective action will be necessary, such a plan is needed only to
respond to the failure to meet a specification. Under Sec.
106.6(c)(1), a manufacturer must set specifications only for those
points, steps, or stages in the production process where the
manufacturer has determined that control is necessary to prevent
adulteration. Thus, the manufacturer should have some familiarity with
the circumstances in which a correction action would be required.
Moreover, having in place a corrective action plan for those
situations that the manufacturer can anticipate will enable the
manufacturer to react more promptly when the anticipated control
failure occurs. Even if it is a general mechanism or policy, it is
appropriate for a manufacturer to establish a corrective action plan to
anticipate the response to a deviation from specifications; the plan
should identify what steps should be taken in response to a deviation
and by whom. For example, the manufacturer may decide that for certain
deviations from a specification, a designated person should stop the
production process until a documented review and material disposition
decision can be made. In addition, the corrective action plan should
include a procedure for the manufacturer's documented review and
material disposition decision for the
[[Page 7959]]
deviation, but does not need to specify in advance a decision for a set
of facts not yet known.
(Comment 44) In response to the 2003 request for comments, one
comment stated that corrective actions are based on scientific judgment
and past experiences and that if each specification needs to be tested
to the point of failure, the cost would be huge and would prevent or
severely limit new product development. Given the complex and multi-
factorial aspects of infant formula production and the occasional
failure of finished products to meet specifications, the comment
questioned whether such speculative actions would provide applicable
guidance in a specific instance. Instead, if scientific judgment
supported by empirical evidence were allowed to determine which
specifications should be challenged, some corrective action procedures
might be identified in advance, but they would be limited to those
situations that manufacturers would reasonably expect to encounter.
(Response) As discussed in response to the previous comment, a
corrective action plan is needed only to respond to the failure to meet
a specification, and such specifications are not unlimited. That is,
under Sec. 106.6(c)(1), a manufacturer is required to set
specifications only for those points, steps, or stages in the
production process where the manufacturer has determined that control
is necessary to prevent adulteration. Thus, FDA does not agree with the
comment that the costs of establishing corrective action plans will be
overwhelming.
The Agency does agree that a manufacturer cannot predict in advance
the outcome of a documented review and material disposition decision
for every deviation. However, as the comment recognizes, a manufacturer
can anticipate certain corrective actions. For these anticipated
deviations, the corrective action plan required under Sec. 106.6(c)(3)
will provide a procedure in advance for what, if any, action is needed
when a specification is not met, who should take such action, and the
process for the documented review and material disposition decision. A
manufacturer is expected periodically to revise and include additional
relevant information, as appropriate, to a corrective action plan for
the identified specifications.
(Comment 45) Several comments were received on proposed Sec.
106.6(c)(4), which requires review of the results of monitoring of
production and in-process control points, steps, or stages where
control is necessary to prevent adulteration and evaluation of the
public health significance of any deviations from established
specifications. These comments noted that not all deviations from
specifications involve concerns of public health significance; for
example, shipper cartons that are found with a printing color that
differs slightly when compared to the color standard would not justify
a public health significance evaluation. The comments agreed, however,
that if a deviation has potential public health significance, a
qualified individual must make a documented review and material
disposition decision.
(Response) These comments appear to misunderstand the proposed
rule. Proposed Sec. 106.6(c)(1) would require a manufacturer to
establish specifications only at those points, steps, or stages in the
production process where control is necessary to prevent adulteration.
The Agency recognizes that a manufacturer may establish specifications
that are not related to preventing product adulteration, such as the
shade of ink on shipper cartons. Unless the manufacturer determines
that a particular specification is necessary to prevent product
adulteration, it would not be a specification established under Sec.
106.6(c)(1) and, thus, would not be subject to review under Sec.
106.6(c)(4). For this reason, FDA is not revising Sec. 106.6(c)(4) in
response to these comments.
D. Controls To Prevent Adulteration by Workers (Proposed Sec. 106.10)
In the 1996 proposal, FDA proposed in Sec. 106.10 general
standards to help ensure that workers involved in the production of
infant formula do not cause the formula to become adulterated. The
proposed provisions address sufficiency and training of personnel,
personal hygiene of production personnel, and safeguarding formula from
microbial contamination from production personnel. The Agency received
comments on several aspects of proposed Sec. 106.10, which comments
are addressed in this document.
(Comment 46) One comment suggested eliminating Sec. 106.10(a)
because it is overly prescriptive. The comment stated that the only
standard by which one can demonstrate that ``sufficient personnel
qualified by training and experience, to perform all operations'' have
been employed by the manufacturer is by demonstrating that an
unadulterated infant formula can be routinely manufactured. In
addition, the comment argued, because other provisions of the existing
and proposed regulations already require that unadulterated products be
routinely manufactured, compliance with CGMP requirements should be
adequate without the Agency's evaluation of internal staffing matters.
The same comment stated that if this section is not deleted, it should
be made clear that it is the manufacturer's responsibility to determine
what is meant by ``sufficient'' personnel.
(Response) FDA disagrees with this comment and declines to delete
Sec. 106.10(a) from the interim final rule. It is critical that a
manufacturer of infant formula employ an adequate number of qualified
personnel to staff the manufacturing operation, and the requirement in
Sec. 106.10(a) ensures that a manufacturer will provide sufficient
trained personnel to achieve compliance with CGMP.
FDA does not believe that Sec. 106.10(a) is overly prescriptive.
In fact, the Agency agrees that it is the manufacturer's responsibility
to determine what constitutes ``sufficient'' personnel to perform fully
all operations necessary to produce the infant formula in compliance
with CGMP. The proposal identified no specific number of workers that
must be employed, expressly noting that the Agency ``is proposing a
general standard for determining how many employees are necessary [but]
is leaving the determination of the actual number of employees
necessary to the manufacturer's discretion.'' (61 FR 36154 at 36159).
To clarify that the decision regarding sufficiency of personnel is both
within the manufacturer's authority as well as an obligation of the
manufacturer, FDA is revising proposed Sec. 106.10(a) to emphasize
that the ``A manufacturer shall employ sufficient personnel,'' rather
than retaining the somewhat ambiguous language of the proposal.
(Comment 47) Another comment stated that it was unrealistic to
demand that all individuals be fully trained and experienced in infant
formula manufacturing because training must be carried out on the job.
The comment suggested that some form of licensing of infant formula
manufacturing may be appropriate and suggested that at least one
licensed person be present during each shift of infant formula
manufacture.
(Response) FDA believes that this comment misinterprets proposed
Sec. 106.10(a). FDA proposed that production personnel be qualified by
training and experience to ensure that all operations are correctly and
fully performed. This provision would simply require an infant formula
manufacturer to have, at all times, sufficient numbers of employees in
both
[[Page 7960]]
supervisory positions and non-supervisory positions who are
knowledgeable and qualified to perform the functions necessary to
manufacture an infant formula so that the formula is not adulterated.
Employees may obtain the necessary knowledge and qualifications through
training (which may include formal training and on-the-job training),
experience, or a combination of these. FDA recognizes that a new
employee may be trained in the manufacture of infant formula on the
job, for example, when that new employee is under the supervision of a
person trained and experienced in the operation that the new employee
is asked to perform. FDA is revising proposed Sec. 106.10(a) to
clarify that training may include both education and on-the-job
training and to clarify that an employee may be qualified by any
combination of education, training, or experience.
Finally, FDA does not currently require any type of licensure for
individuals involved in the manufacture of infant formula. The Agency
is not aware of any problems that have resulted from of the absence of
a licensure requirement and is not aware of the particular benefits
that would result from such requirement. The comment did not identify
either particular problems or specific benefits related to such
licensure. Therefore, FDA is not persuaded to modify Sec. 106.10(a) in
response to this comment.
E. Controls To Prevent Adulteration Caused by Facilities (Proposed
Sec. 106.20)
In the 1996 proposal, FDA proposed in Sec. 106.20 to require that
an infant formula manufacturer implement a system of controls designed
to prevent adulteration caused by an infant formula facility. These
controls would cover buildings, storage areas, lighting, air filtration
systems, appropriate storage of certain chemicals, water quality,
plumbing and toilet and hand-washing facilities for employees. FDA
received no comments on proposed Sec. 106.20(a), (e), and (g), and
those provisions are included in the interim final rule as proposed.
The Agency did receive comments on several other aspects of proposed
Sec. 106.20, which are addressed in this section.
1. Systems of Separation (Proposed Sec. 106.20(b))
(Comment 48) Several comments on the 1996 proposal objected to
proposed Sec. Sec. 106.20(b) and 106.40(e), which would require an
infant formula manufacturer to designate separate areas for holding or
storing raw materials (ingredients, containers, and closures), in-
process materials, and final infant formula product pending release for
use, after rejection for use and before disposition, and after release
for use. The comments agreed that each manufacturer must establish an
effective system to identify and control materials and finished product
before and after release for use, but argued that physical separation
of materials was not practical. The comments suggested that we allow
separation of materials by a means other than physical separation of
materials, including computerized inventory controls and adequately
marked pallets. As a result of these comments, in the 2003 reopening,
FDA specifically requested additional comment on this issue.
(Response) Based on the comments, FDA is persuaded to revise Sec.
106.20(b) to allow materials to be segregated by means other than
physically separate storage areas. It may be desirable to have separate
storage areas for holding or storing raw materials, in-process
materials, and final infant formula product pending release for use,
after rejection for use and before disposition, and after release for
use. However, use of physically separate storage areas is not necessary
if other systems, such as computerized inventory controls or automated
systems of separation, can adequately segregate materials to prevent
accidental mixups or co-mingling of materials. A computerized inventory
system utilizes technical advances and allows tracking of materials
through the use of bar codes and radio frequency identification tags
that identify items in a firm's inventory. An inventory system could
also employ bar codes to identify and track the material in the
production facility; for example, a bar code could identify the
material, the item's storage location, when it arrived at its
designated storage location, and could be used to reorder the item.
FDA disagrees, however, that marked pallets alone would be adequate
to prevent mix-ups of these materials because there is no assurance
that specific materials will stay associated with a particular pallet
without additional arrangements. For example, unless additional
measures are taken to avoid mixups such as physical attachment of the
material to the pallet (e.g., materials are shrink-wrapped in plastic
to the pallet), there is a risk that the separated materials will
accidentally become co-mingled with other materials. The objective of
this proposed CGMP requirement is to avoid the mix-up of different
materials (or different lots of the same material) and ensure the
continuing integrity of such materials through the use of systematic
storage methods. Use of shrink-wrapped pallets would be an acceptable
storage system so long as the integrity of a pallet's contents is
reestablished by rewrapping following penetration of the shrink-wrap.
2. Holding of Rejected Materials (Proposed Sec. 106.20(b)(2))
(Comment 49) One comment objected to proposed Sec. 106.20(b)(2),
which would require separation of raw materials, in-process materials,
and final product infant formula after rejection for use in infant
formula and before disposition. The comment suggested removing the
phrase ``before disposition'' because once a decision is made
concerning disposition, the requirement for proper status designation
should not end. The comment also suggested that the need for separation
of rejected or released finished infant formula also should be
acknowledged in proposed Sec. 106.20(b)(2) and (b)(3).
(Response) The Agency agrees that the phrase ``before disposition''
is not necessary. Any time such materials or formula are rejected, the
materials should remain segregated until disposition is completed to
avoid co-mingling of rejected and released materials.
FDA also agrees with the comment that the interim final rule should
acknowledge that finished infant formula product should be segregated.
Therefore, FDA is revising proposed Sec. 106.20(b)(2) to state ``After
rejection for use in, or as, infant formula.'' However, FDA is not
adding the phrase ``or as'' to Sec. 106.20(b)(3) of the interim final
rule, because the need to segregate released final product is already
acknowledged in this provision.
FDA is also making corresponding revisions to Sec. 106.40(e) of
the interim final rule.
3. Lighting (Proposed Sec. 106.20(c))
(Comment 50) One comment objected to Sec. 106.20(c) and
recommended that this provision be deleted, asserting that it is
redundant with food CGMP, Sec. 110.35(b)(5).
(Response) Although this comment refers to Sec. 110.35(b)(5), FDA
believes the correct reference to food CGMP is Sec. 110.20(b)(5). The
comment did not criticize the substance of proposed Sec. 106.20(c) and
did not claim that its more specific requirements were inappropriate
for infant formula manufacture. While FDA agrees that the requirements
in part 110 (the CGMP for manufacturing, packing and holding human
food) apply to infant formula manufacture, redundancy, in and of
[[Page 7961]]
itself, is not a reason to eliminate this provision. Indeed, given the
nature of infant formula, the manufacturing process is necessarily a
more specific and highly sophisticated operation, and all lighting must
be adequate for each specific area. Accordingly, Sec. 106.20(c) is
included in the interim final rule as proposed.
4. Air Filtration Systems (Proposed Sec. 106.20(d))
(Comment 51) Several comments objected to the requirement of
proposed Sec. 106.20(d) that air filtration systems, including
prefilters and particulate matter air filters, be used on air supplies
to production areas where ingredients or infant formula are directly
exposed to the atmosphere and suggested that Sec. 106.20(d) be
deleted. One comment stated that proposed Sec. 106.20(d) was overly
prescriptive and that CGMP for foods in current Sec. 110.20(b)(6)
should be sufficient for infant formula manufacturing facilities.
Current Sec. 110.20(b)(6) requires the plant and facilities to
``provide adequate ventilation or control equipment to minimize odors
and vapors (including steam and noxious fumes) in areas where they may
contaminate food; and locate and operate fans and other air-blowing
equipment in a manner that minimizes the potential for contaminating
food, food-packaging materials, and food-contact surfaces.''
(Response) FDA agrees that the requirements in current Sec.
110.20(b)(6) are appropriately applied to infant formula manufacturing
facilities. However, the Agency is not persuaded that the requirements
of current Sec. 110.20(b)(6) are completely sufficient because current
Sec. 110.20(b)(6) does not address air filtration. As stated in the
preamble to the 1996 proposal (61 FR 36154 at 36160-36161), proposed
Sec. 106.20(d) is designed to improve air quality in formula
production areas and thus reduce the potential for contamination by
air-borne sources such as spores, molds, and bacteria that may be
carried on dust or other air-borne contaminants. The presence of such
spores, molds, and bacteria may lead to severe illness, particularly in
the vulnerable population consuming infant formula.
Importantly, however, because of differences in plant design,
location, and other unique features, the manufacturer can best
determine which air filtration system or systems are needed to prevent
contamination by air-borne sources in a specific plant. Therefore, FDA
is persuaded that the interim final rule does not need to require
specific types of filters or prescribe when filters are necessary to
prevent air-borne contamination. Accordingly, as revised, the interim
final rule requires a manufacturer to identify the parts of the
production facility in which there is potential for airborne
contamination of ingredients, in-process product, finished product,
packing materials, and infant formula contact surfaces, and use air
filtration as necessary to prevent contamination of these materials.
(Comment 52) One comment noted that although the Agency referenced
the drug CGMP as a formative source for the 1996 proposal, the phrase
in the drug CGMP regulations, ``when appropriate,'' was not included in
the infant formula CGMP proposed rule. This comment suggested
alternative language for the CGMP provision, such as ``when there is
reason to believe that the air in a particular area of the plant might
result in adulteration of the product, measures should be taken to
prevent such adulteration, by air filtration or some other means.''
(Response) FDA believes that the revision to proposed Sec.
106.20(d), which incorporates the concept of ``as appropriate,''
responds to this comment.
(Comment 53) Another comment stated that proposed Sec. 106.20(d)
would require complete air filtration and cooling to be used for all
production rooms and maintenance of positive air pressure at all times
in these rooms. This comment recommended that air filtration should be
required only in areas where there is direct contact between the air
and formula, such as in dryers and dehumidifiers.
(Response) FDA believes that this comment misunderstands proposed
Sec. 106.20(d). Proposed Sec. 106.20(d) would not have mandated air
cooling and positive air pressure in all production rooms; it would
have expressly limited prefilters and particulate matter air filters to
those production areas where ingredients and infant formula would be
directly exposed to the atmosphere. Moreover, as noted, the comments
have persuaded FDA to delete the proposed requirement for specific
types of filters or when filters are necessary to prevent
contamination. Accordingly, Sec. 106.20(d) of the interim final rule
requires a manufacturer to identify the parts of the production
facility in which there is potential for airborne contamination of
ingredients, in-process product, finished product, packing materials,
and infant formula contact surfaces and use air filtration as necessary
to prevent contamination of these materials.
(Comment 54) In the 2003 reopening, FDA requested comments on types
and costs of air filtration systems used by infant formula
manufacturers and the costs of making changes to these systems. One
comment stated that manufacturers use different filters in different
areas of a facility and that prefilters and particulate matter air
filters are used on air supplies to production areas and areas where
formula may be exposed to the atmosphere. The comment stated that the
proposed provision would not result in the expenditure of any
additional funds and that a more detailed account of the types and
costs of air filtration systems would be wasteful and an undue burden
on industry when no public interest would be served by insisting on
specific changes in this arena.
(Response) FDA considered the information provided in this comment
and, as noted previously in this document in response to Comment 51,
the requirement of proposed Sec. 106.20(d) that prefilters and
particulate matter filters be used in formula manufacturing facilities
is not included in Sec. 106.20(d) of the interim final rule. Thus, the
interim final rule will not necessarily result in specific changes to
the air filtration systems of infant formula manufacturing facilities.
(Comment 55) Another comment stated that one manufacturer currently
has air filtration systems in all areas of the manufacturing plant
where infant formula or raw materials may be exposed to the atmosphere.
These mechanisms filter all incoming air using pleated filters or bag
filters to remove particulate matter. The comment states that FDA
should consider the prohibitive cost and level of disruption
encountered in changing air filtration systems to meet an increased
specification in comparison to systems currently performing to an
appropriate standard and posing no risk of contamination of infant
formula products.
(Response) FDA believes that the revisions to the interim final
rule will avoid the costs and disruptions raised as a concern in this
comment. As noted, as revised, Sec. 106.20(d) does not require the use
of particular filtration measures (such as prefilters and particulate
matter air filters). Instead, the interim final rule requires a
manufacturer to employ ``appropriate measures'' to reach the goal of
minimizing the potential for contamination of materials in the
manufacturing facility. Such measures may, but are not required to,
include the use of air filtration or the location and operation of fans
and other air-blowing equipment.
[[Page 7962]]
5. Potable Water (Proposed Sec. 106.20(f))
(Comment 56) Several comments objected to the requirement in
proposed Sec. 106.20(f)(1) that the fluoride level of the water used
in infant formula manufacturing be as low as possible. The comments
asserted that this requirement is vague, potentially prohibitively
costly, and not needed to address a public health concern. The comments
stated that manufacturers strive to produce infant formula products
with low fluoride levels utilizing a variety of technologies. One
comment suggested that the requirement that fluoride removal equipment
be used for fluoridated water would be sufficient. Another comment
suggested that the regulation be modified to state that the water used
in infant formula manufacturing must ``not be fluoridated or shall be
defluoridated prior to use.'' The comment stated that this change more
accurately reflects current technology and industry practice.
(Response) In the 1996 proposed rule, the Agency noted that infant
formulas are currently manufactured without using fluoridated water and
recommended that manufacturers continue their practice of not using
fluoridated water in the manufacture of infant formula (61 FR 36154 at
36161). Also as noted in the proposed rule, the NAS recommends a safe
and adequate intake of 0.1 to 0.5 mg/day fluoride for infants from 0 to
6 months. Accordingly, the Agency is not persuaded that a requirement
that the water used in infant formula manufacturing must ``not be
fluoridated or shall be defluoridated prior to use'' is consistent with
the recommendations of the NAS/IOM. The purpose of this requirement is
to reduce fluoride levels in water used to produce infant formula and,
thereby, reduce the likelihood that fluoride intake of infants
consuming finished infant formula product will exceed the tolerable
upper intake level of 0.7 mg fluoride/day that has been established by
the IOM for infants 0 to 6 months of age (Ref. 8). The glossary of the
Environmental Protection Agency (EPA) includes a definition of
``defluoridation,'' which is ``The removal of excess fluoride in
drinking water to prevent the mottling (brown stains) of teeth'' (Ref.
13). Importantly, the EPA definition does not specify an upper fluoride
limit for ``defluoridated'' water. However, the requirement for the
fluoride level should better reflect industry practices and, therefore,
FDA is clarifying in Sec. 106.20(f) that water used in the manufacture
of infant formula shall either be free of fluoride or defluoridated to
a level as low as possible. FDA disagrees that requiring a manufacturer
to defluoridate water to achieve a level of fluoride ``as low as
possible'' is vague. The Agency is providing some flexibility for the
manufacturer to determine the level of fluoride the manufacturer can
achieve in its operations to keep such level ``as low as possible,''
should the manufacturer choose to defluoridate water rather than to use
water that is not fluoridated.
6. Steam (Proposed Sec. 106.20(h))
(Comment 57) One comment suggested that proposed Sec. 106.20(h)
require that only culinary steam in compliance with 3-A Sanitary
Standards be used at infant formula product contact points.
(Response) Proposed Sec. 106.20(h) would require that steam in
direct contact with infant formula be ``safe.'' FDA has considered this
comment and agrees that the interim final rule should require that only
culinary steam in compliance with 3-A Sanitary Standards should be used
for steam that comes in contact with infant formula product. The
interim final rule incorporates by reference at Sec. 106.160 the
current 3-A Sanitary Standard for culinary steam, 3-A Sanitary
Standards, No. 60903: Method of Producing Steam of Culinary Quality
(November 2004) (Ref. 14). The 3-A standard is more specific than the
standard of the proposed rule (``safe.''). The standard is a method for
producing steam of culinary quality that is accepted practice for
systems used to process perishable foods and it will ensure that the
steam that comes in contact with infant formula will not contaminate
the formula. Accordingly, the Agency is revising proposed Sec.
106.20(h) to include the 3-A Sanitary Standard as a requirement for
steam that comes into direct contact with infant formula.
7. Employee Toilet Facilities (Proposed Sec. 106.20(i))
(Comment 58) One comment suggested that proposed Sec. 106.20(i)
should be deleted because it is redundant with the food CGMP, Sec.
110.37(d) and (e). The comment stated that if proposed Sec. 106.20(i)
were retained, it should be revised to include ``air dryers'' as an
alternative to single-service sanitary towels in the toilet facility.
(Response) For the reasons discussed in the response to Comment 1,
FDA disagrees with the suggestion to delete proposed Sec. 106.20(i)
due to redundancy with the food CGMP regulation, Sec. 110.37(d) and
(e). FDA agrees that air dryers are an equally acceptable alternative
to single-service sanitary towels in the toilet facility. In the
preamble to the 1996 proposal, FDA stated its view that proposed Sec.
106.20(i) would be consistent with the Agency's food CGMP (Sec.
110.37(d)) and drug CGMP (Sec. 211.52). Importantly, under both the
food CGMP and the drug CGMP, air dryers are permitted as an alternative
to single service towels in employee toilet and hand washing
facilities. Thus, it is reasonable to include air dryers as an
alternative in infant formula manufacturing facilities, and Sec.
106.20(i) has been revised accordingly, along with several minor
editorial changes.
F. Controls To Prevent Adulteration Caused by Equipment or Utensils
(Proposed Sec. 106.30)
In 1996, FDA proposed in Sec. 106.30 to require that an infant
formula manufacturer implement a system of controls designed to prevent
adulteration caused by equipment and utensils. The proposed provisions
addressed the design, installation, and maintenance of infant formula
manufacturing equipment. Specific proposed provisions addressed the
accuracy of instruments used in such manufacturing (including their
calibration), appropriate time and temperature for storage and
processing, and the use of compressed gases in infant formula
production operations. The Agency received comments on several aspects
of proposed Sec. 106.30, which are addressed in this section. In
addition to revisions made in response to comments, FDA has made minor
editorial revisions in proposed Sec. 106.30.
1. Design, Cleaning, and Sanitizing of Equipment and Utensils (Proposed
Sec. 106.30(b))
(Comment 59) One comment suggested that this section be deleted
because it is redundant with FDA's CGMP for food (Sec. 110.35(d)). The
comment further stated that if Sec. 106.30(b) was not removed then a
clarification to proposed Sec. 106.30(b) was needed. Section 106.30(b)
would require that all surfaces that contact ingredients, in-process
materials, or infant formula be cleaned, sanitized, and maintained to
protect infant formula from being contaminated by any source. The
comment argued that there are some areas where wet cleaning is neither
practical nor desirable (e.g., in the infant formula powder
manufacturing process) because frequent exposures to moisture should be
avoided to reduce the likelihood of microbiological contamination. The
comment acknowledged that this proposed
[[Page 7963]]
regulation could be interpreted to allow for these unique
circumstances, but suggested that a statement, such as ``as
necessary,'' be added to this section.
(Response) For the reasons discussed in the response to Comment 1,
FDA disagrees with the suggestion to delete proposed Sec. 106.30(b)
due to redundancy with the food CGMP regulations, Sec. 110.35(d).
Further, FDA did not intend that proposed Sec. 106.30(b) would be
interpreted to specify wet cleaning as the most appropriate cleaning
method for equipment or utensils used to manufacture infant formula. As
the comment notes, proposed Sec. 106.30(b) would permit cleaning and
sanitizing of powdered infant formula equipment or utensils by means
other than a wet cleaning method. However, FDA does recognize that it
may not be necessary to sanitize a contact surface for which wet
processing is not used. Therefore, FDA is modifying this provision to
require that surfaces be cleaned and sanitized, ``as necessary,'' and
be maintained to protect infant formula from being contaminated by any
source.
In addition, FDA is deleting the last sentence of proposed Sec.
106.30(b), which states ``Sanitizing agents used on food-contact
surfaces must comply with Sec. 178.1010.'' The Food Quality Protection
Act of 1996 (Pub. L. 104-170) and the Antimicrobial Regulation
Technical Corrections Act of 1998 (Pub. L. 105-324) clarified which
sanitizing agents are under the jurisdiction of EPA and which are under
the jurisdiction of FDA. For example, a sanitizing agent that is used
on a semi-permanent or permanent food contact surface (excluding food
packaging) is a ``pesticide chemical'' subject to the regulatory
purview of EPA (section 201(q)(1)(B)(i)(III) of the FD&C Act (21 U.S.C.
321(q)(1)(B)(i)(III)). Most sanitizers used on equipment or utensils to
which Sec. 106.30(b) of the interim final rule applies would be
sanitizers under EPA's regulatory purview as ``pesticide chemicals.''
To the extent that a sanitizer that a manufacturer uses is a food
additive or a GRAS ingredient, such substance is subject to FDA's
regulatory purview and such use must comply with applicable FDA laws
and regulations. FDA modified proposed Sec. 106.30(b) in view of this
change in regulatory authority, in response to the foregoing comments,
and with the addition of several editorial changes.
2. Use of Lubricants and Coolants in Infant Formula Manufacture
(Proposed Sec. 106.30(c))
(Comment 60) One comment requested that proposed Sec. 106.30(c) be
clarified to state that lubricants or coolants that would render the
infant formula adulterated if they came in contact with the formula
must not come in contact with closures prior to the closing/sealing
operation. The comment stated that the requirement is probably implied
in proposed Sec. 106.30(c), but requested an explicit statement that
the reference to containers and closures means prior to the closing/
sealing operation when the hermetic seal is formed. The comment also
suggested that the phrase ``in a manner not permitted by applicable
food additive regulations'' be added to the end of this proposed
requirement to make it consistent with applicable food additive
regulations.
(Response) FDA agrees that lubricants and coolants that would
render the infant formula adulterated if they came in contact with the
formula must not be allowed to come in contact with containers and
closures before the closing/sealing operation. Additionally, such
lubricants and coolants must not be allowed to come in contact with
containers and closures even after sealing as this may lead to
contamination when the container is opened for use. Further, it is not
clear that all lubricants that may be used would be necessarily subject
to the food additive regulation in 21 CFR 178.3570 for lubricants with
incidental food contact. Consequently, FDA is replacing the phrase ``if
they contaminated the formula'' with ``if such substances were to come
in contact with the formula'' in Sec. 106.30(c). In this way, if a
particular lubricant is not subject to a food additive regulation,
e.g., it is GRAS under certain conditions of use, the requirement would
cover all such substances.
3. Controlling Parameters at Points Where Control Is Deemed Necessary
To Prevent Adulteration (Proposed Sec. 106.30(d)(1))
(Comment 61) One comment requested that FDA clarify in proposed
Sec. 106.30(d)(1) that the infant formula manufacturer is responsible
for determining the points where control is deemed necessary to prevent
adulteration and the routine intervals necessary for calibration of
instruments. The comment did not object to the requirement for the
calibration of instruments, but noted that it could prove unduly
burdensome if the Agency applied ``drug'' type compliance standards.
The comment stated that including the qualification that infant formula
manufacturers bear the final responsibility for determining the
frequency and scope of testing would help assure that the standard
applied to infant formula is appropriate.
(Response) FDA observes that the comment did not explain what would
constitute ``unduly burdensome, `drug' type compliance standards.''
Moreover, the Agency is not persuaded that the requested clarification
is necessary because proposed Sec. 106.30(d)(1) specifically states
that instruments and controls shall be calibrated at routine intervals,
as specified in writing by the manufacturer of the instrument or
control or as otherwise deemed necessary to ensure the accuracy of the
instrument (emphasis added). Thus, the Agency affirms that proposed
Sec. 106.30(d)(1) does provide a formula manufacturer with discretion
to determine the calibration frequency for controls and instruments
that is required to ensure that these instruments or controls are
operating within the correct parameters.
(Comment 62) One comment explained that because of the number of
instruments to which this rule will apply, it is possible that certain
of the instruments requiring calibration may need to be in use while
they are being calibrated. Thus, the comment suggested adding the words
``on or before first use'' to describe the timing of the initial
certification (calibration).
(Response) FDA agrees with this suggestion. Calibrating an
instrument against a known reference standard at the time the
instrument is first used will be sufficient to ensure the accuracy of
testing subsequently done with the instrument to establish that certain
specifications are met. Thus, FDA is revising Sec. 106.30(d)(1) in the
interim final rule by adding the phrase ``at the time of or.''
(Comment 63) In response to FDA's 2003 comment period reopening and
request for comments on calibration, one comment stated that U.S.
formula manufacturers have established calibration and preventative
maintenance schedules for appropriate pieces of equipment, that
priorities for calibrations and preventative maintenance are linked to
``criticality in regard to product quality and safety,'' and that
procedures and schedules are aligned according to the criticality
assessments, which vary from company to company, and are often based on
the recommendations of the instrument supplier. The comment asserted
that the regulation should simply require that calibrations and
preventative maintenance be performed on pre-established schedules and
according to written procedures as the formula manufacturer determines,
based on information from the equipment
[[Page 7964]]
supplier where applicable and that a requirement that all instruments
need to be calibrated routinely, regardless of function, would result
in either the removal of all instruments that the manufacturer deems
not critical or the addition of significant new personnel and extensive
systems to coordinate and track the calibration program.
(Response) FDA believes that this comments misunderstands the
calibration requirement in proposed Sec. 106.30(d)(1) in two important
ways. First, only certain instruments and controls used in an infant
formula manufacturing operation are subject to calibration under
proposed Sec. 106.30(d)(1); that is, not all instruments and controls
used in formula manufacturing are required to be calibrated.
Specifically, proposed Sec. 106.30(d)(1) requires only those
instruments and controls at points where ``control is deemed necessary
to prevent adulteration'' to be accurate and maintained, including by
calibration. Second, the proposed rule would require a calibration
schedule based on the written specifications of the instrument or
control manufacturer or that is otherwise necessary to ensure
instrument or control accuracy. Although the comment does not define
``criticality,'' FDA believes that ``criticality'' and the proposed
standard of Sec. 106.30(d)(1) (where ``control is deemed necessary to
prevent adulteration'') are comparable. Thus, the Agency believes that
proposed Sec. 106.30(d)(1) is consistent with the comment.
Accordingly, FDA is making no revisions in the interim final rule in
response to this comment.
(Comment 64) Another comment in response to the 2003 reopening
stated that because more specificity is required and that infant
formula is the sole source of nutrition for a high risk population,
calibration needs to be high and frequent. The comment stated that this
frequency is necessitated by the ubiquity of microbes and formula's
status as an ideal medium for bacterial growth.
(Response) FDA notes that this comment did not explain the
additional ``specificity'' required, or the relationship between
instrument calibration and microbial contamination.
The requirement to calibrate is limited to those instruments and
controls used in the manufacture of an infant formula for measuring,
regulating, or controlling those parameters where control is deemed
necessary to prevent adulteration, such as mixing time and speed,
temperature, pressure, moisture, or water activity. To the extent that
this comment asserts that calibration should be performed as necessary
to prevent microbial contamination that would result in adulteration of
an infant formula, FDA agrees with the comment. However, this comment
does not require a revision of proposed Sec. 106.30(d)(1). Therefore,
in light of the foregoing Sec. 106.30(d) is included in the interim
final rule as proposed with minor editorial changes.
4. Areas of Cold Storage (Proposed Sec. 106.30(e)(2))
Several comments questioned the across-the-board storage
temperature requirement of 40 [deg]F (4.4 [deg]C) in proposed Sec.
106.30(e)(2).
(Comment 65) One comment argued that instead of requiring that cold
storage compartments be maintained at a temperature of 40 [deg]F (4.4
[deg]C) or below, FDA allow manufacturers to establish the appropriate
temperature for cold storage compartments that would assure the quality
and safety of in-process materials. The comment recommended that the
regulations simply state the end point to be achieved, e.g., ``cold
storage will be maintained at temperatures that prevent growth of
harmful microorganisms.'' The comment acknowledged that in some
situations (e.g., the long-term storage of aqueous solutions of
nutrients that might support microbial growth), the use of 40 [deg]F as
a storage temperature is well-established as appropriate. But, the
comment asserted, many materials stored at low temperatures in infant
formula plants do not require the use of 40 [deg]F to ensure stability.
(Response) FDA disagrees with this comment. The Agency proposed 40
[deg]F as the maximum temperature for cold storage compartments because
a temperature of 40 [deg]F (4.4 [deg]C) is considered to be an
appropriate temperature to minimize the growth of pathogens (Ref. 15)
and the deterioration of liquid ingredients, nutrients, and the
formulated product. The comment did not provide any data, authoritative
research, or other material to contradict the information supporting
the proposed standard of 40 [deg]F (4.4 [deg]C). Thus, the proposed
temperature limit remains appropriate.
(Comment 66) One comment stated that defining cold storage only as
40 [deg]F or lower is incompatible with the manufacture of quality
infant formula. Another comment argued that in some cases, the use of
temperatures this low may create quality problems for the infant
formula, such as mix destabilization and non-homogeneity, which could
theoretically result in the final product being adulterated.
(Response) FDA agrees in part with this comment. The Agency is
aware that storing some in-process and final formulas at too low a
temperature may create quality problems that risk causing a formula to
be adulterated. Importantly, however, these problems of precipitation
and instability do not exist in all infant formula materials (such as
raw ingredients.) Indeed, as noted in Comment 65 there are certain
infant formula materials that must be stored at lower temperatures,
such as the 40 [deg]F storage temperature originally proposed, in order
to maintain quality and safety.
Accordingly, FDA is revising proposed Sec. 106.30(e)(2) to provide
infant formula manufacturers with some flexibility in terms of cold
storage conditions. Specifically, Sec. 106.30(e)(2) of the interim
final rule permits a manufacturer to store in-process material and
final formula product (those items that, according to the comments, are
susceptible to destabilization or loss of homogeneity) for a limited
period of time at a temperature not greater than 45 [deg]F (7.2
[deg]C), provided that the manufacturer has data and other information
to demonstrate both that such materials cannot be stored at 40 [deg]F
(4.4 [deg]C) without risking an adverse effect on their quality and
that the storage conditions (i.e., the time and temperature) used by
the manufacturer are sufficient to ensure the safety of the stored
product.
It is well-recognized that the microbial load of a substance, the
length of time a product is held at a particular temperature, and the
nature of the product (e.g., product pH) must be considered when
determining safe storage conditions. The maximum temperature of 45
[deg]F (7.2 [deg]C) for cold storage compartments will prevent
significant growth of microorganisms of public health significance
under certain conditions specific to the product composition and the
processing step. (Product composition is a factor in how well a
particular formulation will support microbial growth.) For this reason,
Sec. 106.30(e)(2)(ii) of the interim final rule requires a
manufacturer to have data and other information to demonstrate that the
time and temperature conditions are sufficient to ensure product
safety. That is, the manufacturer must determine whether a temperature
not greater than 45 [deg]F (7.2 [deg]C) will be sufficient for the cold
storage of an in-process formula or a final infant formula for the
storage period contemplated by the manufacturer. Because the nature of
the product will affect the extent of microbial growth, this
determination must be product-
[[Page 7965]]
specific. FDA will consider the conditions of cold storage (i.e., time
and temperature) to be sufficient for a particular product at a
particular product stage, provided that there is no significant growth
of microorganisms of public health significance during the period of
storage. Significant growth is considered to be growth of one or more
log colony forming units (CFUs) (Refs. 16 and 17).
(Comment 67) Another comment maintained that the short period of
time the materials are held does not justify the use of a 40 [deg]F
storage temperature and thus, mandating an absolute maximum temperature
of 40 [deg]F for all purposes is not justifiable to protect public
health and would require additional capital investments for cooling
capacity that would not add value to the product.
(Response) FDA believes that the revision of proposed Sec.
106.30(e)(2) is responsive to this comment. That revision is based in
part on the recognition that all infant formula materials do not
require identical cold storage conditions and thus, the revision
provides a manufacturer with some flexibility in terms of permissible
cold storage conditions. In addition, Sec. 106.30(e)(2) of the interim
final rule reflects the point made implicitly by the comment that
storage time, as well as temperature, is an important factor in
ensuring safety of formula materials.
(Comment 68) One comment noted that if it were necessary to ensure
that the temperature never rose above 40 [deg]F, the materials would
have to be held at even lower temperatures most of the time in order to
allow a ``margin.''
(Response) FDA disagrees with this comment. In addition to
specifying a maximum holding temperature and an alternative, proposed
Sec. 106.30(e) would require a manufacturer to have in place
safeguards to help ensure appropriate storage temperature, including
monitoring cold compartment temperatures at appropriate frequencies and
equipping such compartments with easily readable, accurate temperature-
indicating devices. These provisions are included in Sec. 106.30(e) of
the interim final rule. The comment did not explain why these
requirements would not be sufficient to ensure that the maximum holding
temperature of 40 [deg]F would be achieved without the use of a
``margin.'' Moreover, as discussed previously in this document, FDA
recognizes that, in certain circumstances, the 40 [deg]F (4.4 [deg]C)
holding temperature could adversely affect product quality. Thus, FDA
has revised proposed Sec. 106.30(e)(2) to provide some flexibility in
terms of the maximum holding temperature for certain in-process and
finished infant formulas.
(Comment 69) Another comment suggested that the maximum temperature
of 45 [deg]F (7.2 [deg]C) for cold storage would be appropriate and
consistent with Sec. 110.80(b)(3)(i), the Grade ``A'' Pasteurized Milk
Ordinance, industry practice, and equipment design capabilities.
(Response) FDA believes that the revision of proposed Sec.
106.30(e)(2) is responsive to this comment. That revision is based in
part on the recognition that all infant formula materials do not
require identical cold storage conditions and thus, the revision
provides a manufacturer with some flexibility in terms of permissible
cold storage conditions. In particular, Sec. 106.30(e)(2) of the
interim final rule will permit certain formula materials to be stored
at a temperature not greater than 45 [deg]F (7.2 [deg]C) as long as the
formula manufacturer has data and other information to demonstrate an
adverse effect on the quality of the product if held at 40 [deg]F or
below and to demonstrate that there is no significant growth of
microorganisms of public health significance during the period of
storage.
5. Thermal Processing and Temperature-Recording Devices (Proposed Sec.
106.30(e)(3))
(Comment 70) One comment stated that the thermal processing
recording device requirement in proposed Sec. 106.30(e)(3)(ii) is
either redundant or in conflict with part 113 (Thermally Processed Low-
Acid Foods Packaged in Hermetically Sealed Containers). The comment
observed that proposed Sec. 106.30(e)(3)(ii) requires that a thermal
processing temperature-recording device reflect the true temperature,
and that Sec. 113.40(e)(2) requires a bias so that the temperature-
recording device reads ``as nearly as possible with, but to be in no
event higher than, the known accurate mercury-in-glass thermometer.''
The comment stated that part 113 more accurately reflects the needs of
a thermal processing system, and suggested that the infant formula CGMP
simply refer to the regulations in part 113.
(Response) FDA agrees with these comments and is revising and
consolidating certain provisions of proposed Sec. 106.30(e), as
discussed in detail in this document.
First, FDA is revising proposed Sec. 106.30(e)(1) to clarify that
the requirements in parts 108 and 113 (21 CFR parts 108 and 113) apply
to thermally-processed infant formula. This is simply restating an
existing requirement. In light of this revision, FDA is deleting the
language in proposed Sec. 106.30(e)(3)(ii) that ``Thermal processing
equipment shall be equipped with temperature-recording devices that
will reflect the true temperature on a continuing basis.'' Thus, Sec.
106.30(e)(1) of the interim final rule states: ``Equipment and
procedures for thermal processing of infant formula packaged in
hermetically sealed containers shall conform to the requirements in 21
CFR parts 108 and 113.''
Second, FDA is revising the portion of proposed Sec. 106.30(e)(1)
that would require, among other things, that thermal processing
equipment used at points where temperature control is necessary to
prevent adulteration ``be monitored with such frequency as is necessary
to ensure that temperature control is maintained,'' and redesignating
it in the interim final rule as Sec. 106.30(e)(5). Under Sec.
108.35(c)(2), thermal processing monitoring frequency would be included
in the information required to be submitted in the process filing for
the scheduled process. Thus, Sec. 106.30(e)(5) of the interim final
rule states that ``Such monitoring shall be at such frequency as is
required by regulation or is necessary to ensure that temperature
control is maintained.''
(Comment 71) A comment stated that it was unnecessary to require in
proposed Sec. 106.30(e)(3)(ii) that ``[c]old storage compartments must
be equipped with either temperature-recording devices that will reflect
the true temperature, on a continuing basis, within the compartment or,
in lieu of a temperature-recording device, a high temperature alarm or
a maximum-indicating thermometer that has been verified to function
properly'' because cold storage temperature monitoring can be
acceptably achieved through periodic manual recordings with sufficient
frequency to ensure proper temperature control. The comment explained
that the large volume liquid mixes in the infant formula manufacturing
process do not demonstrate significant temperature changes over time,
and therefore, do not warrant the increased capital investment of
recording devices and temperature alarms. The comment argued that
manual recordings at predetermined intervals are adequate to monitor
cold temperature storage conditions.
(Response) FDA agrees that an appropriate method of ensuring that
cold storage temperature control is maintained is by manual monitoring
compartment temperature on a temperature-indicating device and
[[Page 7966]]
recording this temperature in a record with such frequency as is
necessary to ensure that temperature control is maintained. The goal of
proposed Sec. 106.30(e)(3)(ii) is to ensure adequate control of cold
temperatures. It is feasible to accomplish manually what can also be
achieved automatically; in this case, establishing a plan to monitor
cold temperatures, monitoring and recording the temperature, and doing
so at appropriate intervals, can provide the same assurance as an
automatic temperature monitoring system. Accordingly, FDA is adding
such manual monitoring to the options originally provided in proposed
Sec. 106.30(e)(3)(ii). Thus, an infant formula manufacturer will have
four choices for monitoring the temperature of a cold storage
compartment: (1) The temperature may be monitored manually using a
temperature-indicating device and manually recording the temperature at
an appropriate frequency; (2) the compartment may be equipped with a
temperature-recording device that will reflect the true temperature, on
a continuing basis, within the compartment; (3) the compartment may be
equipped with a high temperature alarm that has been verified to
function properly and the temperature may be manually recorded at an
appropriate frequency; or (4) the compartment may be equipped with a
maximum-indicating thermometer that has been verified to function
properly and the temperature may be manually recorded at an appropriate
frequency.
Additionally, Sec. 106.30(e)(3)(ii) of the interim final rule
includes information about making and retaining records. Section
106.30(e)(3)(iii) of the interim final rule takes into account the
option to manually monitor temperatures, by stating that ``the
manufacturer shall, in accordance with Sec. 106.100(f)(3), make and
retain records of the temperatures recorded in compliance with Sec.
106.30(e)(3)(ii).'' Because Sec. 106.30(e)(3)(iii) of the interim
final rule contains the requirement that ``the manufacturer shall, in
accordance with Sec. 106.100(f)(3), make and retain records of the
temperatures recorded in compliance with Sec. 106.30(e)(3)(ii),'' FDA
is making conforming changes to proposed Sec. 106.100(f)(3). Section
106.100(f)(3) of the interim final rule includes ``records in
accordance with Sec. 106.30(e)(3)(iii).''
(Comment 72) One comment suggested that proposed Sec. 106.30(e)(4)
be deleted because the requirement that thermal process recording
devices be biased to not read higher than the calibrated temperature-
indicating device is redundant with part 113. Another comment asserted
that proposed Sec. 106.30(e)(3)(ii) and proposed Sec. 106.30(e)(4)
conflict with one another.
(Response) As noted, FDA is revising proposed Sec. 106.30(e)(1) to
clarify that the requirements in parts 108 and 113 apply to thermally-
processed infant formula. The requirement of proposed Sec.
106.30(e)(4) is incorporated into Sec. 106.30(e)(1) of the interim
final rule by virtue of the reference to the application of the
requirements in parts 108 and 113 to thermally-processed formula.
Accordingly, in Sec. 106.30(e)(4) of the interim final rule, FDA is
deleting the language referring to thermal process recording devices
not reading ``higher than the calibrated temperature-indicating device
for thermal processing equipment.''
(Comment 73) A comment argued that the bias in proposed Sec.
106.30(e)(4) relating to cold storage temperature recorders was
inappropriate because a slight temperature deviation of the cold
storage compartment would have a very small impact on the growth of
microorganisms. The comment contended that the proposal appears to
equate the importance of a very slight temperature deviation for the
sterilization process with a very slight temperature deviation of the
cold storage compartment when the two situations are radically
different. The comment explained that a one degree Fahrenheit drop in
the sterilization temperature could have a significant effect on the
process lethality and could result in a failure to meet commercial
sterility, whereas a one degree Fahrenheit increase in the temperature
of a cold storage compartment would have a very small impact on the
growth of microorganisms.
(Response) FDA disagrees with this comment. The purpose of proposed
Sec. 106.30(e)(4) is to ensure that a temperature-recording device for
a cold storage compartment reflects the actual temperature of the
compartment and will not overstate the conditions in the compartment.
The accuracy of a temperature-recording device is important given that
the record in this rulemaking establishes that a temperature of
40[deg]F (4.4[deg]C) in cold storage compartments will prevent the
growth of harmful microorganisms and will prevent spoilage and
deterioration of nutrients, all of which could lead to adulteration of
the infant formula. Moreover, as noted previously in this document, the
impact of temperature variation, including a one degree Fahrenheit
increase in temperature, will vary depending upon the initial microbial
load of the chilled product, the time the product is held at the
elevated temperature, and other product characteristics, such as
product hydrogen-ion concentration (pH) (Refs. 16 and 17).
Accordingly, in light of the foregoing comments, Sec. 106.30(e)(4)
of the interim final rule provides that ``When a manufacturer uses a
temperature-recording device for a cold storage compartment, such
device shall not read lower than the reference temperature-indicating
device.''
(Comment 74) One comment objected to the recommendation in the 1996
preamble that ``manufacturers should calibrate thermometers for cold
storage temperature measurements at least at the beginning and end of
each production day . . ..'' The comment argued that FDA is
recommending a calibration frequency that is far more stringent than
measurement devices for thermal food processing, which is a process of
critical importance. The comment asserted that the frequency for
calibration of cold storage temperature measurement devices should be
determined by the manufacturer based on the volume, hold time, and
location in the manufacturing process.
(Response) FDA agrees with this comment to the extent that the
comment asserts that calibration frequency should be determined by the
manufacturer based on variables of the manufacturer's process. In
addition, in determining the appropriate calibration frequency, a
manufacturer should consider the calibration frequency recommended by
the manufacturer of the equipment in question.
6. Maintenance of Equipment and Utensils at Regular Intervals (Proposed
Sec. 106.30(f))
A number of comments objected to the requirements in proposed Sec.
106.30(f) relating to cleaning, sanitizing, and maintaining equipment
and utensils. These comments indicate that there is confusion about
what would be required by proposed Sec. 106.30(f).
FDA intended that the requirements of proposed Sec. 106.30(f)
would extend to all equipment and utensils used in the production of
infant formula, including storage tanks, equipment and utensils used in
the ingredient weighing area, in-process and processing equipment and
utensils, and container filling, closure, and container packaging
equipment. All of the equipment and utensils used in producing infant
formula have some potential to cause adulteration of the formula and
thus, all must be appropriately cleaned, sanitized, and maintained.
Although every piece of equipment and each utensil is not likely
[[Page 7967]]
to require the same cleaning, sanitizing, or maintenance, all must be
subject to such activities at intervals that will prevent such
adulteration.
(Comment 75) One comment questioned whether the requirement of
``regular intervals of cleaning, sanitizing, and maintenance'' would
apply when a production line that ordinarily requires daily cleaning
and sanitizing is taken out of service. The comment requested that the
Agency clarify that it is the equipment and utensils used in an
operating production line for the manufacture of infant formula that
must be cleaned, sanitized, and maintained at regular intervals.
(Response) FDA disagrees with this comment. Contrary to the
comment's suggestion, these requirements apply equally to the equipment
and utensils of an operating production line and to the equipment and
utensils of a production line that is taken out of service. FDA
recognizes that entire production lines, along with their associated
equipment and utensils, may be taken out of service, sometimes for
prolonged periods. However, manufacturers must establish cleaning,
sanitizing, and maintenance procedures that include a schedule for
cleaning and sanitizing, as necessary, and maintaining dormant
equipment, including production lines and utensils, prior to
reactivating their use.
(Comment 76) Another comment requested that FDA clarify whether the
requirement in proposed Sec. 106.30(f) to maintain equipment and
utensils and to check and retain records on this maintenance would
apply only to major equipment or would include every minor action that
is taken to maintain equipment (e.g., changing an ``O'' ring). The
comment argued that if minor actions were included, the requirement
would be extensive. The comment also suggested that the terms
``maintained'' and ``maintenance'' be deleted from this section.
(Response) As stated previously in this document, because all
equipment and utensils used in producing infant formula have the
potential to cause adulteration of the formula, all must be
appropriately cleaned, sanitized, and maintained. Although every piece
of equipment and each utensil is not likely to require the same degree
of cleaning, sanitizing, or maintenance, all must be subject to such
activities at intervals that will prevent such adulteration. Thus, FDA
disagrees with the comment suggesting that the requirement to maintain
equipment and utensils, to have a qualified individual check all
cleaning, sanitizing, and maintenance, and to make and retain records
of such activities should apply only to major equipment.
The requirements of proposed Sec. 106.30(f) include both routine
and required maintenance of all equipment as well as any unplanned
correction or repair of equipment. Manufacturers generally document the
routine servicing of production equipment as part of a preventative
maintenance program that identifies the work to be performed and its
frequency. Changing an ``O'' ring, an example given in the comment, may
be documented in a preventative maintenance program simply by noting
the time, date, and employee involved if changing the ``O'' ring
represents routine, scheduled equipment maintenance. If, however, this
activity is an unplanned correction or equipment repair, more detailed
documentation would likely be required, including an evaluation of
whether the ``O'' ring failure may have resulted in product
adulteration.
The comment did not explain why the words ``maintain'' and
``maintenance'' should be deleted from proposed Sec. 106.30(f).
Maintaining production equipment and utensils is, like cleaning and
sanitizing, an essential part of ensuring that formula does not become
adulterated due to equipment and utensils. In fact, changing an ``O''
ring, an example of ``minor'' maintenance mentioned in the comment, may
be critically important if, for example, the ``O'' ring is used in pipe
connections of the processing system where a defective ring could
result in a loss of sterility or allow contaminants to enter the
product stream and thus, cause a formula to be adulterated. For these
reasons, FDA declines to delete ``maintain'' and ``maintenance'' from
Sec. 106.30(f) of the interim final rule.
(Comment 77) One comment requested that FDA clarify the meaning of
``regular intervals'' in the requirement that equipment and utensils
used in the manufacture of infant formula be cleaned, sanitized, and
maintained ``at regular intervals.'' This comment also requested that
FDA clarify that the manufacturer determines the appropriate ``regular
interval'' for cleaning, sanitizing, and maintaining equipment and
utensils to prevent adulteration of the infant formula.
(Response) FDA agrees that under proposed Sec. 106.30(f), the
manufacturer would determine the intervals between cleaning,
sanitation, and maintenance activities that are needed to prevent
adulteration of the infant formula. Specifically, a manufacturer is
responsible for identifying the ``regular interval'' for cleaning,
sanitizing, and maintaining equipment and utensils that is appropriate
to prevent adulteration of the formula. In the preamble to the 1996
proposal, FDA acknowledged that equipment cleaning, sanitizing, and
maintenance will vary from plant to plant, concluding that ``[e]ach
manufacturer should study its own plant and develop a procedure that is
tailored to that plant's needs and circumstances.'' (61 FR 36154 at
36165).
In determining the appropriate interval for these activities, a
manufacturer should consider the type and nature of the product being
manufactured (e.g., soy-based, milk-based, liquid, powder), the length
of production runs, the length of time between equipment and utensil
use and their cleaning, and the period of time between cleaning and
subsequent use of the equipment and utensils. Because a ``regular
interval'' will generally be plant-specific or operation-specific, FDA
declines to specify further the meaning of ``regular intervals'' in
proposed Sec. 106.30(f).
(Comment 78) Another comment objected to the requirement in
proposed Sec. 106.30(f) that all cleaning, sanitizing, and maintenance
be checked by a qualified individual to ensure that such activities
have been satisfactorily completed. The comment asserted that utensils
should be cleaned and maintained on an ``as needed'' basis and that a
requirement to check the satisfactory completion would be overly
burdensome. Thus, the comment suggested changing proposed Sec.
106.30(f) to only require checking of the cleaning, sanitizing, and
maintenance of equipment (not utensils). Another comment suggested that
records should be required to document equipment cleaning but not
cleaning of utensils.
(Response) FDA disagrees that the requirement that a qualified
individual confirm proper cleaning, sanitizing, and maintenance should
apply only to equipment and not to production utensils. This
requirement is designed to confirm that cleaning, sanitizing, and
maintenance have been properly executed. Unless properly cleaned,
sanitized, and maintained, utensils, like equipment, can be a source of
adulteration. For example, a utensil that is not properly cleaned,
sanitized and dried can be a source of microbial contamination.
FDA notes that this review of utensils is not required to be
performed immediately after cleaning or sanitizing, as this is left to
the manufacturer to address in its procedures. For example, a
manufacturer could conclude that, in its operation, it would be
sufficient for a qualified individual to check utensils for cleanliness
immediately before use.
[[Page 7968]]
The Agency agrees that a manufacturer does not need to maintain records
of utensil cleaning, sanitizing, and maintenance; proposed Sec.
106.100(f)(4) did not require such records for utensils.
(Comment 79) Another comment proposed that this section be revised
to state that only documentation relating to equipment cleaning,
sanitizing, and maintenance would need to be reviewed to ensure that
those activities have been completed satisfactorily rather than include
microbial or other testing required for this verification.
(Response) FDA is not persuaded to revise proposed Sec. 106.30(f)
as requested to clarify that a review of records of equipment cleaning,
sanitizing, and maintenance alone is sufficient to verify that these
activities have been properly completed. Although review of
documentation relating to such activities provides some assurance that
the activities occurred, such records do not provide evidence that such
efforts have been adequately performed. Only physical examination of
the equipment and utensils by a qualified individual will provide the
necessary level of assurance that cleaning, sanitizing, and maintenance
have been satisfactorily completed. This assessment may or may not
include the need for microbial or other testing. FDA advises that it is
the manufacturer's responsibility to determine the specific means
needed to verify that production equipment and utensils have been
properly cleaned, sanitized, and maintained in accordance with
established procedures.
For all of the foregoing reasons, FDA is not revising proposed
Sec. 106.30(f) in response to these comments and is making only minor
editorial changes to this requirement.
7. Use of Compressed Gases in the Manufacture of Infant Formula
(Proposed Sec. 106.30(g))
(Comment 80) One comment suggested that proposed Sec. 106.30(g) be
deleted because it was redundant and is already unlawful under existing
regulations to introduce indirect additives or adulterants into infant
formulas by way of gases or by any other means.
(Response) For the reasons discussed in section IV.A (response to
Comment 1), FDA disagrees with the suggestion to delete proposed Sec.
106.30(g) due to redundancy with other existing regulations. The
purpose of this rule is to establish CGMP and quality control
requirements designed to prevent the adulteration of infant formula,
including controls to prevent adulteration under section 402(a)(1),
(a)(2), (a)(3), and (a)(4) of the FD&C Act. In the preamble to the 1996
proposal, the Agency explained that compressed gases may be
contaminated with oil, filth, or microbes, and the comment did not
dispute that explanation. Accordingly, FDA is not persuaded that this
requirement relating to compressed gases is unnecessary, and is making
only minor editorial changes in Sec. 106.30(g) of the interim final
rule.
G. Controls To Prevent Adulteration Due to Automatic (Mechanical or
Electronic) Equipment (Proposed Sec. 106.35)
In 1996, FDA proposed in Sec. 106.35 to require that an infant
formula manufacturer implement a system of controls designed to prevent
adulteration due to automatic (mechanical or electronic) equipment. The
proposal defined the terms ``hardware,'' ``software,'' ``system,'' and
``validation'' for purposes of proposed Sec. 106.35, and proposed
requirements for the design, installation (including validation),
testing, and maintenance of such automatic equipment. The Agency
received comments on several aspects of proposed Sec. 106.35, which
are addressed in this document.
Several comments suggested that the proposed definition of
validation and the validation requirements be stricken from the rule.
(Comment 81) One comment requested that proposed Sec. 106.35 be
deleted and recommended that FDA and members of the infant formula
industry form a task force to define the scope and content of
validation of automated systems used in the production or quality
control of infant formula. The comment stated that through such a task
force, FDA would be able to assess the cost impact, the degree of
industry resources, and time necessary to attain compliance with
proposed Sec. 106.35. The comment further recommended that, until this
task force has completed these tasks, Sec. 106.35 be removed from part
106.
(Response) FDA is not persuaded to remove proposed Sec. 106.35
from part 106, nor is the Agency persuaded to delay finalizing Sec.
106.35 until a joint FDA-industry task force can discuss the details of
systems validation for production and quality control of infant
formulas. The comment asserted that the purpose of a joint task force
would be to allow FDA to acquire information to assess the cost impact,
the degree of industry resources, and time necessary to attain
compliance with proposed Sec. 106.35. In FDA's view, the comment
periods in this rulemaking serve the same purpose: they have provided
an opportunity for interested persons (including the infant formula
industry) to submit to FDA relevant information about the provisions of
the proposed rule, including details about the effect of the validation
provisions of proposed Sec. 106.35. Thus, the infant formula industry
had opportunities to submit such information in comments both at the
time of the 1996 proposal and in response to the 2003 reopening. In
fact, in the notice reopening the comment period in 2003, the Agency
expressly requested information on validation practices in the infant
formula industry. Accordingly, a joint task force is not necessary and
the implementation of Sec. 106.35 need not be delayed. For these
reasons, FDA is not removing Sec. 106.35 from the interim final rule
in response to this comment.
(Comment 82) Another comment suggested that FDA merely require that
processing equipment be ``designed, installed, tested, and maintained
in a manner that will ensure that it is capable of performing its
intended function and of producing or analyzing infant formula.''
(Response) Systems validation is critical to ensuring that
manufacturing processes for infant formula do not result in the
production of adulterated formula and thus, FDA disagrees with this
comment. The comment does not dispute that validation of systems and
revalidation of modified systems is a basic tenant of CGMP nor does the
comment explain why system validation is not necessary either generally
or specifically in the case of infant formula manufacture (Ref. 18). In
fact, systems validation is broadly recognized as essential to ensuring
that a product meeting established specifications can be consistently
produced under a manufacturer's system. Thus, FDA declines to adopt the
suggestion of this comment.
(Comment 83) One comment asserted that it is unnecessary to rely on
validation because the Infant Formula Act requires finished product
testing for specific nutrients in each batch of infant formula.
(Response) FDA believes that this comment confuses system
validation and system verification. System validation is the process by
which a manufacturer ensures that a system, if operating properly, is
capable of producing, on a consistent basis, a product (e.g., an infant
formula) that meets the manufacturer's specifications. In contrast,
verification is an on-going determination that the validated system is
performing as necessary to produce a product that conforms to
specifications. Nutrient testing is a form of verification of a
system's proper operation. To the
[[Page 7969]]
extent that such testing shows that a particular production aggregate
of infant formula does not meet specifications, the operation of the
manufacturing system is not verified and the validation of the system
is called into question. Given this distinction between validation and
verification, FDA disagrees that finished product testing for nutrients
eliminates the need for system validation.
(Comment 84) One comment claimed that FDA has proposed an all-
encompassing definition of ``validation'' that is well beyond the scope
applied even in the drug industry. The comment explained that drug
validation must be precise because it is imperative that drugs contain
the precise amount of active ingredient to achieve efficacy in treating
illness. Because the margin of safety for drugs can be so critical,
their manufacture requires far more critical tolerances than do infant
formulas. The comment stated that requiring strict ``drug-like''
validation and revalidation of systems for infant formula would be
extremely costly, unnecessarily burdensome, and a disincentive for
process improvements.
(Response) FDA disagrees that the proposed definition of
``validation'' is overly broad. In the 1996 preamble (61 FR 36154 at
36166), FDA explained the basis of the definition of ``validation'' in
proposed Sec. 106.35(a)(4) as follows: The proposed definition is
derived from the ISO International Guideline ISO-9000-3, (which defines
``validation'' as ``the process of evaluating software to ensure
compliance with specified requirements''); the IEEE Standard 610.12-
1990, which (defines it as ``the process of evaluating a system or
component during or at the end of the development process to determine
whether it satisfies specified requirements'''); and FDA's ``Glossary
of Computerized System and Software Development Terminology,'' which
defines it as ``establishing documented evidence which provides a high
degree of assurance that a specific process will consistently produce a
product meeting its predetermined specifications and quality
characteristics'' (Ref. 19).
All three sources of the proposed definition have in common the
concept that ``validation'' involves the evaluation of a system or a
system component to ensure that it meets established specifications or
requirements. The ISO definition was revised shortly after FDA issued
the 1996 proposal. The current ISO definition of validation (ISO
8402:1994) is ``a step beyond verification to ensure the user needs and
intended uses can be fulfilled on a consistent basis.'' The other two
sources of the proposed definition of validation, IEEE Standard 610.12-
1990 (Ref. 19) and FDA's ``Glossary of Computerized System and Software
Development Terminology'' (Ref. 20), are unchanged.
The proposed definition of ``validation'' is largely derived from
FDA's guidance, ``Glossary of Computerized System and Software
Development Terminology.'' This document is intended to serve as a
glossary applicable to software development and computerized systems in
all FDA regulated industries. As such, the guidance document's
definition of ``validation'' applies equally to all product areas
regulated by FDA, including human drugs. Thus, FDA disagrees with the
comment's claim that the proposed definition of ``validation'' is
``well beyond the scope applied even in the drug industry.''
Moreover, the comment does not dispute the importance of systems
validation. As noted, validation of systems and revalidation of
modified systems is a basic principle of CGMP, one that is essential to
ensuring that a consistent product can be produced under the
manufacturer's system. Like drug manufacturing systems, the system used
to produce infant formula must be able to produce a product that meets
the manufacturer's specifications and all applicable regulatory
requirements.
Finally, although the comment claims that validating all systems
used to manufacture infant formula before first use would be extremely
costly, unnecessarily burdensome, and create a disincentive for process
improvements, the comment does not explain the basis of these
assertions. Indeed, the comment merely asserted that the proposed
validation requirements would be costly but did not provide any data or
other information to support these assertions. FDA notes that in the
2003 reopening, the Agency expressly requested cost information
relating to systems validation but no such data were submitted in
response to that request.
Accordingly, FDA is not revising the definition of ``validation''
in proposed Sec. 106.35(a)(4), and thus, Sec. 106.35(a)(4) is
included in this interim final rule as proposed.
FDA received a number of comments addressing the scope of the
validation requirements.
(Comment 85) Several comments asserted that FDA's validation
requirements are overly burdensome, and other comments suggested
specific changes to the scope of validation. One comment suggested that
the requirements of proposed Sec. 106.35 be limited to the validation
of ``critical'' systems (i.e., proposed Sec. 106.35(b)(1), (b)(3),
(b)(4), and (b)(5)) and ``critical'' hardware and software (i.e.,
proposed Sec. 106.35(b)(2) and (b)(5)). Another comment stated that
although an indiscriminate and across-the-board validation requirement
is unnecessarily burdensome, validation of critical systems can be a
valuable quality assurance tool for the infant formula manufacturer and
that infant formula manufacturers are already validating systems and
procedures based upon a risk-based criticality assessment. The comment
requested that FDA consider a tiered approach to validation, including
such other concepts as verification, qualification, capability studies,
challenge testing, and operational testing. For example, HACCP involves
both a risk-based criticality assessment and other documented levels of
control. The comment suggested that each company should be permitted to
decide the levels of validation required, based upon the degree of
criticality of each system to assuring the safety and quality of the
infant formula produced.
(Response) FDA disagrees that the proposed validation requirements
are overly burdensome and declines to limit the scope of these
requirements by adding ``critical'' to the description of systems and
of hardware and software.
Although FDA agrees that the process for validation is necessarily
related to the level of risk that each component of the system
presents, the Agency does not agree that validation should be limited
to ``critical'' systems. A ``system'' is composed of multiple,
interdependent parts, and the proper functioning of the system requires
that all system elements are working as intended. Importantly, the
comment did not explain how to distinguish ``critical'' from
``noncritical'' systems used in the manufacture of infant formula.
Infant formula is a sophisticated mixture of ingredients that is
intended for use by a vulnerable population as the sole source of
nutrition during critically important developmental stages. Given the
nature of the product and its intended consumers, it is difficult, if
not impossible, to identify a part of the system that is not critical.
Accordingly, all parts of the ``system'' must be validated-- not
simply the ``critical'' pieces--to ensure that the system as a whole
operates properly. This approach is consistent with the Agency's
position as described in its Guide to Inspections of Computerized
Systems in the Food Processing Industry (http://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074955.htm), which states that ``as
long as the
[[Page 7970]]
computerized system controls or records are part of or the entirety of
a manufacturing process, the manufacturer is responsible for
establishing that the computerized system functions as it was intended
to function'' (Ref. 21).
FDA agrees that a manufacturer must determine how to validate its
systems to ensure that the system will consistently produce a product
meeting predetermined specifications and quality characteristics. The
Agency recognizes that the validation process may be more complex for
systems that are integral to controlling or affecting those points,
steps, or stages where control is necessary to prevent adulteration.
Thus, FDA is not specifying how each manufacturer must validate its
systems. It is, however, appropriate to require that a manufacturer
ensure that any system used to manufacture infant formula is validated
by having documented evidence that provides a high level of assurance
that the system will produce infant formula that meets applicable
specifications and requirements.
(Comment 86) One comment suggested that proposed Sec. 106.35(b)(5)
be changed to require revalidation only after a major functional change
to a system. The comment explained that this change will avoid
unnecessary revalidation as a result of documented operator interface
changes that do not change the functionality of the control system.
(Response) FDA disagrees with this comment that seeks to limit the
circumstances in which a manufacturer must revalidate a system used to
manufacture infant formula. By revalidation, FDA means that the
manufacturer must re-establish that, following a modification to a
system, the system is functioning as intended. Validation and
revalidation of a manufacturer's systems are both fundamental concepts
of CGMP applicable to many different types of products, and both are
essential to ensuring consistent production of the intended product.
Thus, a manufacturer must conduct a validation analysis to determine
the extent and impact of the change on the system in response to any
change to the system. In fact, a ``major functional change'' requires
more extensive revalidation than a change that does not change the
functionality of the control system. Nevertheless, revalidation after a
change other than a ``major functional change'' is necessary to provide
assurance that the system, as changed, will continue to produce
consistently a product that satisfies established specifications and
quality characteristics. Moreover, FDA advises that the manufacturer
must not only analyze the need to validate the individual change but
also the validation status of the entire system to ensure that the
change did not affect other parts of the system. Based on the
validation analysis, the manufacturer should conduct an appropriate
level of regression testing to demonstrate that unchanged but
vulnerable portions of the system have not been adversely affected.
For these reasons, FDA is not revising proposed Sec. 106.35(b)(5)
(recodified as Sec. 106.35(b)(4) in the interim final rule) in
response to this comment, and is making only minor editorial changes to
this requirement.
(Comment 87) Another comment requested that if FDA intends to
require validation of all mechanical and electronic processes used in
the manufacture of infant formula, this requirement should not apply
retrospectively to processes that have been used successfully for many
years. Instead, the comment asserted, validation should apply only to
significant changes to equipment or processes that are critical to
manufacturing formula in the future. The comment also stated that the
manufacturer is in the best position to determine what testing is
appropriate for specific pieces of equipment and whether this equipment
is critical to infant formula manufacture.
(Response) FDA's response to the previous comment explains why the
Agency declines to limit the validation requirement to critical
equipment. Similarly, FDA disagrees with the suggestion that validation
should not apply retrospectively to systems and processes in place for
many years. Although this comment claimed that certain systems have
been ``used successfully for many years,'' the comment provided no data
or other information to support this assertion. Validation requires a
systematic evaluation of a process or system and the development of
evidence to show that a system will consistently produce a product
within predetermined specifications. The mere operation of a system for
a lengthy period without apparent problems is neither systematic nor
``documented evidence'' of adequate function. The manufacturer must
ensure that the system it creates (including software and hardware)
functions in the way intended and therefore is capable of producing
what the manufacturer intends according to required specifications. As
noted, FDA is not specifying in the interim final rule how each
manufacturer must validate its systems, but is requiring that such
systems be validated. This requirement applies to all systems, whether
such systems were in place prior to the interim final rule or are
established after the effective date of the interim final rule.
(Comment 88) One comment suggested that proposed Sec. 106.35(b)(4)
be revised to require that only software-controlled equipment be
validated. The comment further stated that this requirement should be
changed to require only that the equipment be designed, installed,
tested, and maintained in a manner that will ensure that it is capable
of performing its intended function and of producing or analyzing
infant formula.
(Response) FDA disagrees with this comment. Although various
components of a system may, and should, be tested separately, the
entire ``system'' (i.e., collection of components, including software
and hardware, organized to accomplish a specific function or set of
functions in a specified environment) must be validated to ensure that
the system, as it is configured and used in the production of infant
formula, consistently performs within the pre-established operational
limits and consistently produces formula that meets established
specifications and quality characteristics. FDA notes that, as defined
in proposed Sec. 106.35(a)(3), a ``system'' is the collection of all
mechanical and electronic components, as well as all other components,
including manual components (such as a manually operated crank), and
the operation of such manual components would be evaluated as part of
the required validation of the system. The ability of a system to
produce the intended product on a consistent basis depends upon the
proper functioning of all system components. Thus, system validation
encompasses all equipment, including mechanical and electronic
equipment (which includes computer software.) Therefore, FDA is not
revising proposed Sec. 106.35(b)(4) in response to this comment.
(Comment 89) Several comments objected to proposed Sec.
106.35(b)(4) and (b)(5), which would require that all systems be
validated before their first use to manufacture commercial product or,
in the case of a modified system, before use of the modified system to
manufacture commercial product. The comments noted that while most
system validation work is conducted prior to the production of infant
formula, the first commercial batch should be produced as part of the
validation process.
[[Page 7971]]
(Response) FDA agrees that a production aggregate of infant formula
that is produced as part of the initial validation process of a system
may be commercially distributed, provided that the manufacturer
determines before release that the production aggregate meets the
manufacturer's specifications and otherwise complies with the FD&C Act
and FDA's regulations. Similarly, FDA agrees that a production
aggregate of infant formula that is produced as part of the
revalidation of a system may be commercially distributed, provided that
the manufacturer determines before release that the production
aggregate meets the manufacturer's specifications and otherwise
complies with the FD&C Act and FDA's regulations. Accordingly, FDA is
revising proposed Sec. 106.35(b)(4) and (b)(5), which are recodified
as Sec. 106.35(b)(3) and (b)(4) in the interim final rule and include
minor editorial revisions, to require that infant formula be produced
as part of the validation process.
In addition to the comments relating to validation, FDA received
comments on several other aspects of proposed Sec. 106.35.
(Comment 90) One comment suggested that the Agency delete the
requirement in proposed Sec. 106.35(b)(2) that hardware be routinely
calibrated. The comment argued that calibration applies to
instrumentation, not hardware.
(Response) FDA disagrees with this comment. The word ``hardware''
was defined in proposed Sec. 106.35(a)(1) as ``all automatic
equipment, including mechanical and electronic equipment (including
computers) that is used in the production or quality control of a
infant formula.'' As defined, hardware would include any automated
instrumentation that can be calibrated. Thus, it is appropriate that
proposed Sec. 106.35(b)(2) would require the calibration of hardware.
Accordingly, FDA is not deleting the requirement from proposed Sec.
106.35(b)(2) that hardware be routinely calibrated, but is clarifying
that calibration applies to hardware that is capable of being
calibrated. Thus, Sec. 106.35(b)(1) of the interim final rule reads
``A manufacturer shall ensure that hardware that is capable of being
calibrated is routinely calibrated according to written procedures, and
that all hardware is routinely inspected and checked according to such
procedures.''
(Comment 91) One comment suggested that the statement ``nutrient
test results should be used to substantiate the adequacy of the checks
required by this section'' be added to proposed Sec. 106.35(b)(3).
(Response) FDA is not persuaded to add this statement to proposed
Sec. 106.35(b)(3). Nutrient test results alone may not be sufficient
to substantiate the adequacy of all checks required by this provision.
Although meeting specifications for nutrients may be a part of input/
output verification, other factors, such as levels of microorganisms or
other contaminants and achieving adequate temperature, may also be a
part of verification of the production system.
Assessing the adequacy of can seam measurements illustrates the
limitations of nutrient test results for this purpose. A formula
manufacturer may use a computerized system to measure and determine the
adequacy of container seams. If the system is not confirmed as
accurate, errors could be generated by this system and the product
could become adulterated due to inadequate container seams.
Importantly, nutrient testing could not determine the accuracy of
results from this seam measurement system because such testing
evaluates the nutritional adequacy of the formula and does not address
the adequacy of a formula's packaging. Further, the systems covered by
proposed Sec. 106.35 are the automated systems used in the quality
control testing of an infant formula. Automated systems used in quality
control of an infant formula must also be validated before accurate
nutrient test results can be obtained. Thus, FDA declines to add
``nutrient test results should be used to substantiate the adequacy of
the checks required by this section'' to Sec. 106.35(b)(3) in the
interim final rule because this would erroneously suggest that nutrient
testing is all that is necessary to substantiate the adequacy of the
validation required by Sec. 106.35(b)(3).
(Comment 92) One comment suggested that FDA revise the part of
proposed Sec. 106.35(b)(3) that states ``the degree and frequency of
input/output verification shall be based on the complexity and
reliability of the system and the level of risk associated with the
safe operation of the system.'' The comment stated that the
verification must be based on the manufacturer's assessment of the
complexity and reliability of the system and the level of risk
associated with the safe operation of the system.
(Response) FDA disagrees with this comment because inserting the
phrase, ``based on the manufacturer's assessment,'' does not further
clarify what is being required. The ultimate purpose of the
verification required by proposed Sec. 106.35 is to confirm that
formula manufacturing systems will produce a formula that is not
adulterated. Although the verification process for more complex systems
and systems that operate to control potentially high levels of risk are
likely to require more diligence by the manufacturer to ensure the safe
operation of the system, the degree and frequency of verification that
the manufacturer employs must be sufficient to ensure that the final
product is not adulterated. Therefore, FDA is revising proposed Sec.
106.35(b)(3) to clarify the level of effort required. Section
106.35(b)(2) of the interim final rule states ``A manufacturer shall
check and document the accuracy of input into, and output generated by,
any system used in the production or quality control of an infant
formula to ensure that the infant formula is not adulterated.'' Adding
this phrase clarifies that the manufacturer must ensure that the system
is able to meet established specifications for any point, step, or
stage in the production process where control is necessary to prevent
adulteration.
(Comment 93) Regarding proposed Sec. 106.35(c), one comment
requested that FDA limit the recordkeeping requirements to critical
automatic equipment, as opposed to all automatic equipment.
(Response) As stated in response to Comment 85, FDA declines to
limit the validation requirements of the interim final rule to
``critical'' systems, hardware, and software.
In addition to the revisions to proposed Sec. 106.35 in response
to comments, the Agency has made minor editorial revisions in Sec.
106.35 of the interim final rule.
H. Controls To Prevent Adulteration Caused by Ingredients, Containers,
and Closures (Proposed Sec. 106.40)
In 1996, FDA proposed in Sec. 106.40 to require that an infant
formula manufacturer implement a system of controls designed to prevent
adulteration caused by ingredients, containers, and closures. The
proposed provisions included standards for ingredients, containers, and
closures used for infant formulas, as well as requirements for
identification, rejection and acceptance, and storage of these
materials.
The Agency received comments on several aspects of proposed Sec.
106.40, which are addressed in this document. In addition to the
revisions made in response to comments that are discussed in this
document, FDA has made minor editorial revisions in Sec. 106.40 of the
interim final rule.
[[Page 7972]]
1. Food Ingredients and Food Contact Substances (Proposed Sec.
106.40(a) and (b))
(Comment 94) One comment asserted that proposed Sec. 106.40(a)
should be deleted as redundant because, under current law and
regulations, it is illegal to use an ingredient in an infant formula
that is not GRAS, an approved food additive, or prior-sanctioned for
such use.
(Response) As discussed in the response to Comment 1, the Agency is
not making changes to Sec. 106.40(a) in response to this comment, and
has only made minor editorial changes in Sec. 106.40(a) of the interim
final rule.
(Comment 95) Several comments asserted that proposed Sec.
106.40(b) was unnecessarily restrictive in terms of the substances that
would be permitted for use in infant formula packaging, including
containers and closures. One comment expressed concern that proposed
Sec. 106.40(b) would appear to exclude the use of substances in infant
formula packaging that are not ``food additives'' within the meaning of
section 201(s) of the FD&C Act (i.e., substances that are not
reasonably expected to become a component of food when used as
intended). In addition, the comment expressed concern that proposed
Sec. 106.40(b) would prohibit the use of substances reviewed under 21
CFR 170.39 for use in food-contact material and exempted from the
requirement of a food additive regulation. This comment also contended
that all packaging materials authorized by a prior sanction issued by
the U.S. Department of Agriculture (USDA) should be allowed in infant
formula packaging.
(Response) FDA did not intend to limit permissible infant formula
packaging to substances regulated as food additives. To the extent that
use of a food packaging material for infant formula packaging is exempt
under Sec. 170.39, FDA agrees such substance would be permissible in
infant formula packaging. Similarly, although FDA is not aware of any
prior sanction issued by USDA for a substance that could be used in
infant formula packaging, if a prior sanction exists, a substance used
in accordance with such prior sanction would be lawful. Also, to the
extent that a substance in food packaging is not reasonably expected to
become a component of food, the substance is not a food additive under
section 201(s) of the FD&C Act and thus, could be lawfully used in
infant formula packaging without prior approval. Finally, proposed
Sec. 106.40(b) recognized that a substance authorized for use as an
``indirect food additive'' could be lawfully used in infant formula
packaging. As a result of amendments made to section 409 of the FD&C
Act by the Food and Drug Administration Modernization Act (FDAMA) (Pub.
L. 105-115), food packaging materials are generally now regulated as
``food contact substances.'' Thus, FDA agrees that the rule should
recognize that a food contact substance that is the subject of an
effective notification under section 409(h) of the FD&C Act may be
lawfully used in packaging for infant formula.
Thus, in response to these comments and the FDAMA amendments, FDA
is clarifying proposed Sec. 106.40(b) to identify all substances that
may lawfully be used for infant formula containers, closures, and
packaging. Section 106.40(b) of the interim final rule lists all
substances that may lawfully be used in food packaging for infant
formula.
(Comment 96) One comment suggested that FDA list in Sec. 106.40(b)
substances that are exempted from the requirement of a food additive
listing regulation under Sec. 170.39.
(Response) FDA does not agree that the Agency should list in Sec.
106.40(b) of the interim final rule those substances that FDA has
exempted from the requirement of a food additive listing regulation
under Sec. 170.39. This information is continually changing, and FDA's
Web site has current lists of the substances exempted under Sec.
170.39, http://www.fda.gov/Food/FoodIngredientsPackaging/FoodContactSubstancesFCS/ucm093685.htm, and the food contact substances
that are the subject of an effective notification, http://www.fda.gov/Food/FoodIngredientsPackaging/FoodContactSubstancesFCS/ucm116567.htm.
2. Written Specification for Ingredients, Containers, and Closures
(Proposed Sec. 106.40(d))
Several comments objected to proposed Sec. 106.40(d), which would
require an infant formula manufacturer to develop written
specifications for the acceptance or rejection of ingredients,
containers, and closures (``the materials'') to be used in infant
formula manufacturing.
(Comment 97) One comment objected to several statements in the 1996
proposal, including FDA's statement that ``indigenous'' nutrients
should be included in ingredient specifications and standards for
acceptance or rejection (61 FR 36154 at 36167). The comment argued that
testing for endogenous nutrients in these cases is not for acceptance
or rejection of the ingredient, but to determine the actual nutrient
levels that can be factored into specific batch formulations.
(Response) As discussed previously in this document in section
V.C.1, FDA is persuaded by the comments to revise Sec. 106.40(d) in
the interim final rule to delete the requirement that any ingredient,
container, or closure that does not conform to specifications must
automatically be rejected. The Agency believes that this change
responds, at least in part, to the comment objecting to statements in
the 1996 preamble that manufacturers must establish, and test for,
levels of endogenous nutrients in formula ingredients.
FDA disagrees with this comment to the extent that it objects to
the requirement that the proposed rule would require a formula
manufacturer to establish specifications for the nutrient content of
formula ingredients and a process to assess whether such specifications
have been met. These procedures may include reliance on a supplier's
guarantee or certification that an article conforms to specifications
or a laboratory analysis by the formula manufacturer that demonstrates
that the article conforms to established specifications. Even where a
formula manufacturer relies on a guarantee, FDA expects that the
ingredient will conform to the specifications set by the manufacturer
and that the manufacturer has a means to evaluate the guarantee or
certification, such as periodic chemical analysis of the ingredient.
A manufacturer's specifications should include specifications for
endogenous nutrients in formula ingredients because such specifications
are one method of ensuring both that the required nutrients will be
present in the infant formula at or above the established minimum level
and that any nutrient for which there is an established maximum level
is not present in the formula at a level that would cause the product
to be adulterated. Chemical analysis for such endogenous nutrients is
the means by which a manufacturer is able to determine the nutrient
levels actually present, which information may be factored into a
specific production aggregate's formulation.
Although there is no requirement that the manufacturer test every
ingredient for all nutrients as suggested in the comment, section
412(b)(3)(B) of the FD&C Act requires that manufacturers test each
nutrient premix for each nutrient that the manufacturer expects to be
supplied by the premix to ensure that the premix complies with its
specifications or the certification by the
[[Page 7973]]
premix supplier. Accordingly, the FD&C Act requires that a manufacturer
test each nutrient premix, but the FD&C Act does not require testing
the premix for nutrients not intended to be supplied by the premix.
(Comment 98) One comment asserted that infant formula manufacturers
have an extensive history in the use of condensed skim milk such that
they can predict endogenous nutrient levels within a narrow range. The
comment argued that because of this experience with this ingredient and
the fact that the condensed skim milk can provide 100 percent of
several of the final product's nutrients, there is no need to assay the
ingredients for specific batch formulations. The comment also argued
that because all nutrients required to be present in infant formula are
tested and assured in each batch as required by the Infant Formula Act,
any problems would be detected through routine, legally mandated in-
process and finished product testing.
(Response) Section 106.40(d) of the interim final rule does not
specify which nutrients in which formula ingredients must be the
subject of manufacturer specifications and does not require that
ingredients be tested for endogenous nutrients. FDA agrees with the
comment that an infant formula manufacturer's history of use of an
ingredient may help determine what endogenous nutrients should be
included as an ingredient specification and when testing is necessary
to confirm a supplier's assurance that the manufacturer's ingredient
specifications are met. FDA views endogenous nutrient specifications as
one method of ensuring both that the required nutrients will be present
in the infant formula at the appropriate level and that nutrients that
have maximum levels under Sec. 107.100 will not be present in the
formula at levels that would cause the product to be adulterated.
Testing of endogenous nutrients can serve to confirm that the nutrients
are in the ingredient in the amount anticipated by the manufacturer and
to ensure that the infant formula will have the required levels of
nutrients. The example given in the preamble to the 1996 proposal (61
FR 36154 at 36167) was the level of sodium determined in the protein
ingredient, sodium caseinate. The maximum level of sodium that can
legally be in an infant formula is 60 mg/100 kilocalorie (kcal). The
level of sodium in the sodium caseinate will affect how much sodium can
be added to the formula from other sources before this legally mandated
sodium limit is violated.
Although the interim final rule does not require testing
ingredients for endogenous nutrient levels, it is very useful for
manufacturers to know the endogenous nutrient content of the
ingredients so that the infant formula is manufactured with all the
required nutrients within required ranges and adjustments that may be
needed during processing may be better anticipated. Use of routine in-
process and finished product testing is valuable because it can help
detect problems with the levels of required nutrients prior to
distribution. Testing for endogenous ingredients may reduce the need
for adjustments during processing, which can provide the manufacturer
with added efficiency, reduced costs, and more robust adherence to
CGMP. Indeed, a manufacturer may find through experience that the best
way to ensure that the final product will meet all specifications is to
measure certain nutrients in ingredients before using them in the
production of infant formula.
(Comment 99) One comment stated requiring that ingredients be
tested for all endogenous nutrients would have a significant impact on
laboratory space, manpower, operating costs, and potentially quality,
with no increased assurance of benefit to infants consuming the final
product.
(Response) As noted previously in this document, FDA is requiring
under Sec. 106.40(d) of the interim final rule that any failure to
meet specifications be investigated to ensure that the failure does not
lead to the release into the marketplace of an adulterated infant
formula. FDA is not requiring that the manufacturer test all formula
ingredients for all endogenous nutrients. Importantly, however,
endogenous nutrient testing is one means to limit final product
rejection, reformulation, or reprocessing and thus, the costs of such
testing must be balanced by potential costs of rejection,
reformulation, or reprocessing. That is, a manufacturer should consider
that the costs of formula adjustments during or at the end of
processing might be avoided by chemical analysis of ingredients because
such an approach may offset possible costs related to testing the
endogenous nutrient content.
(Comment 100) One comment also objected to the suggestion in the
preamble to the 1996 proposal that included testing for contaminants in
the ingredient specifications and standards for acceptance or rejection
of the material except as provided in compendial standards such as
United States Pharmacopeia (USP) (http://www.usp.org). The comment
argued that this suggestion is inappropriate and unworkable and that
there are significant questions to be considered, such as the selection
of contaminants to test for in each ingredient, the determination of
acceptable/unacceptable levels, and detection versus quantification
scenarios. The comment further argued that even if one were to address
these questions, the inclusion of routine contaminant testing would be
grossly impractical due to the sophistication of the testing involved
and the exorbitantly high costs associated with compliance. The comment
stated that the testing requirements for ingredients, containers, and
closures should be determined by the manufacturer.
(Response) As explained in section V.C.1 of this document, FDA has
revised proposed Sec. 106.40(d) by removing the proposed requirement
that an ingredient, container, or closure that fails specifications
shall be automatically rejected for use in formula manufacturing and,
instead, to provide that an ingredient, container, or closure that
fails to meet a specification, as well as any formula that could be
affected by the deviation, shall be quarantined pending a formal,
documented review and material disposition decision. The Agency
recognizes that a failure to conform to a specification does not
necessarily mean that the infant formula manufactured using the
ingredient, container, or closure will be adulterated and thus, should
not be automatically rejected for use in formula manufacturing. In the
interim final rule, FDA has made additional revisions to the proposed
provisions to ensure that deleting the automatic rejection provision
will nevertheless result in adequate public health protection by
requiring that each manufacturer establish a robust procedure to
investigate any deviation from specifications so that the manufacturer
can credibly determine whether the deviation from specifications will
result in adulteration of infant formula. The revisions to the proposed
requirements will ensure that there is a documented review of the
deviation, that records of such documented review are established and
maintained, and that affected materials are quarantined pending a
decision about their appropriate disposition. Therefore, this comment
has been addressed to the extent that it relates to the need for a
specification to determine ``acceptance or rejection'' of ingredients,
containers, and closures.
FDA agrees with the comment that the infant formula manufacturer is
responsible for determining whether contaminant testing of formula
[[Page 7974]]
ingredients is warranted and if so, for which contaminants. In the 1996
proposal, FDA did not specify the contaminants for which a manufacturer
must test or when such testing must occur because the Agency believes
that formula manufacturers are likely to be more aware of which
contaminants may be present in their particular ingredients and that
may adulterate or lead to adulteration of formula.
(Comment 101) One comment suggested that FDA add the phrase ``as
components'' and the phrase ``and packaging'' to proposed Sec.
106.40(d) to require manufacturers to develop written specifications
for ingredients, containers, and closures used as components in infant
formula manufacturing and packaging.
(Response) FDA declines to adopt the suggestion in this comment
because the Agency considers that it is understood that the
ingredients, containers, and closures referred to in proposed Sec.
106.40 for which the manufacturer must develop written specifications
are those used by such manufacturer in its formula production
operation. Indeed, this is a reasonable interpretation because these
are the ingredients, containers, and closures over which the
manufacturer exercises control, including the authority and obligation
to establish and apply specifications for such materials.
(Comment 102) One comment suggested that proposed Sec.
106.40(e)(3) should be revised to permit the reconditioning, under
certain conditions, of materials that have been rejected for use in
infant formula production. The comment did not specify under what
conditions it thought reconditioning should be allowed.
(Response) As discussed previously in this document in response to
Comment 38, Sec. 106.40(d) of the interim final rule establishes
reconditioning of an ingredient, container, or closure that fails to
meet a specification as one of the three alternative dispositions that
may result from the documented review that is required when any such
material does not conform to a manufacturer's specifications.
3. Option To Reject Ingredients, Containers, or Closures (Proposed
Sec. 106.40(f))
(Comment 103) One comment requested that proposed Sec. 106.40(f)
be modified to permit rejection of ingredients, containers, or closures
that fail to meet a specification as well as for the retesting or
reexamination of such deviant materials.
(Response) As discussed in response to comment 38, Sec. 106.40(f)
of the interim final rule requires a documented review and material
disposition decision and such decision may be to reject an ingredient,
container, or closure that does not conform to the manufacturer's
specifications, to reprocess or otherwise recondition and then test or
reexamine such material to determine whether it should be approved and
released for use, or simply to approve and release for use without
reconditioning.
(Comment 104) Another comment agreed that the requirement to retest
or reexamine any ingredient, container, or closure, if it is found by
the infant formula manufacturer to have been exposed to adverse storage
conditions, is reasonable. However, the comment contended that this
requirement should only apply when the manufacturer has knowledge of
the potentially adverse conditions. The comment suggested that to
document control of all storage areas, additional recording charts
might be needed to provide continuous monitoring.
(Response) Consistent with changes elsewhere in the interim final
rule and discussed in section V.C.1, FDA has revised proposed Sec.
106.40(f) to provide for a documented review and material disposition
decision in the circumstances covered by this provision. Also, the
Agency is not persuaded that the requirement of proposed Sec.
106.40(f) should only apply when the manufacturer has actual knowledge
of potentially adverse conditions affecting an ingredient, container,
or closure. A manufacturer has a responsibility, as part of CGMP, to
quarantine an ingredient, container, or closure when that manufacturer
has a reasonable basis to believe that the ingredient, container, or
closure may have been exposed to adverse conditions. For example, a
manufacturer must quarantine and conduct a documented review and make a
material disposition decision when the manufacturer has information
relating to where and when such materials were held, which information
reasonably suggests that the integrity of the materials may have been
compromised. A formula manufacturer has the overarching responsibility
to ensure that its infant formula is not adulterated, which
responsibility includes ensuring that ingredients, containers, or
closures are not exposed to conditions that may result in the
production of an adulterated formula product. After a documented review
and material disposition decision to release, these ingredients,
containers, and closures must remain suitable for use in the
manufacture of infant formula so that when such materials are used in
formula production, the materials continue to conform to the
manufacturer's specifications. In response to this comment, the Agency
is revising proposed Sec. 106.40(f) to clarify that an ingredient,
container, or closure must also be quarantined when a manufacturer
reasonably believes that an ingredient, container, or closure may have
been exposed to adverse conditions.
I. Controls To Prevent Adulteration During Manufacturing (Proposed
Sec. 106.50)
In 1996, FDA proposed to require in Sec. 106.50 that an infant
formula manufacturer implement a system of controls designed to prevent
adulteration during the production of infant formula. The proposed
provisions included requirements for use of a written master
manufacturing order; for control and examination of raw and in-process
ingredients; for identification of the contents of compounding and
storage containers; processing lines and major equipment; for controls
to ensure required nutrient levels and to prevent contamination of
formula; for equipment monitoring; and for control of rejected in-
process materials.
The Agency received comments on several aspects of proposed Sec.
106.50, which are addressed in this document. In addition to the
changes discussed in this document made in response to comments, Sec.
106.50 of the interim final rule includes minor editorial revisions.
1. Identification of the Contents of Storage Containers, Processing
Lines, and Major Equipment (Proposed Sec. 106.50(c))
Several comments requested clarification of proposed Sec.
106.50(c), which would require a manufacturer to identify the contents,
including the processing stage and the lot or batch number of a batch
of infant formula, of all compounding and storage containers,
processing lines, and major equipment used during the production of a
batch (production aggregate) of an infant formula.
(Comment 105) One comment requested clarification of the meaning of
``identify'' in proposed Sec. 106.50(c). The comment objected to
physically labeling these items because, the comment asserted, infant
formula manufacturers use multitudes of equipment and lines in the
production of infant formula and physical labeling would require a
significant increase in manpower to apply and remove labels several
times
[[Page 7975]]
daily to accomplish this task with no benefit to the operation.
However, the comment stated that it would be reasonable to require a
system that would permit determination of the location and movement of
each batch of infant formula. The comment suggested alternative
language that would require a manufacturer to establish a system that
permits the manufacturer to determine the major equipment systems used
during the production of a batch of infant formula.
(Response) FDA considers that it is necessary to clarify the
purpose of proposed Sec. 106.50(c). The Agency did not intend the term
``identify'' in proposed Sec. 106.50 to require that a manufacturer
physically place a label identifying the contents, processing stage,
and production aggregate number on each piece of equipment used to
manufacture a particular production unit of infant formula. Although
FDA agrees that this method would satisfy the requirements of proposed
Sec. 106.50(c), it is not the only means by which a manufacturer could
comply with proposed Sec. 106.50(c). To clarify this requirement, the
Agency has revised Sec. 106.50(c) in the interim final rule to require
that a manufacturer establish a system (i.e., a collection of
components organized to accomplish a specific function or set of
functions in a specified environment) of identification for the
contents of all compounding and storage containers, processing lines,
and major equipment used during the manufacture of a production unit or
a production aggregate of an infant formula. As such, this provision
gives a manufacturer flexibility to design its production tracking
system. Thus, the requirement in Sec. 106.50(c) could be met, for
example, by establishing a computerized system that makes it possible
to track a particular production unit or production aggregate of infant
formula throughout all stages of the manufacturing process, permitting
the identification of the contents of all compounding and storage
containers, processing lines, and major equipment used during the
manufacturing of a specific production aggregate of infant formula. As
noted, the comment agreed that it is reasonable to require
establishment of a system that permits determination of the location
and movement of each production aggregate.
FDA declines to adopt the alternative language proposed by this
comment because it does not accurately capture the purpose of the
proposed requirement. The purpose of proposed Sec. 106.50(c) is to
require a manufacturer to establish a system to identify the contents
of compounding and storage containers, processing lines, and various
pieces of equipment used during the manufacture of a particular
production aggregate of infant formula and not to identify the major
equipment systems used during a particular production run. This purpose
was recognized in the preamble of the 1996 proposal: ``[Proposed Sec.
106.50(c)] will enable the manufacturer to accurately determine the
status of all batches of infant formula during all stages of the
manufacturing process, will help to prevent mix-ups in the addition of
ingredients to the formula, and will facilitate prompt action by the
manufacturer if any problems in processing are identified. For example,
identifying that a particular storage container contains a batch of
formula that has not yet had all ingredients added to it will prevent a
manufacturer from inadvertently final-stage packaging the product and
thus will help to ensure that adulterated product is not introduced
into interstate commerce'' (61 FR 36154 at 36169).
(Comment 106) One comment stated that it should be necessary to
identify the processing lines used in the manufacture of infant formula
only if the manufacturing facility is processing different types of
infant formula or non-infant formula products simultaneously because
there is increased potential for cross-contamination or comingling of
different products. In such circumstances, the comment argued,
processing lines should be identified.
(Response) FDA disagrees with the comment that the requirement of
proposed Sec. 106.50(c) should apply only when a firm is
simultaneously manufacturing more than one type of infant formula
product or a formula product and a non-formula product. The purpose of
the requirement to establish an identification system is to ensure that
both finished product and in-process material can be fully identified,
including by the unique number associated with its production
aggregate. This will ensure that if a problem develops with a formula
product necessitating a recall, the affected product can be
specifically identified and the recall structured as narrowly as
possible. A narrowly targeted recall is more readily managed by a
formula company and overseen by FDA and also reduces the likelihood of
a product shortage from an overly broad recall.
Moreover, as noted in the preceding comment, infant formula
processing facilities often contain a multitude of equipment, storage
tanks, and processing lines; those processing lines may include liquid
component lines, in-process lines, and finished product lines, as well
as ancillary lines such as cleaning solution lines, steam lines, and
water lines. Regardless of whether a facility processes different types
of infant formulas, processes non-formula products simultaneously with
infant formula, or processes only one type of infant formula, the
content of these lines, tanks, and equipment must be identified in some
way to ensure that such contents are not mishandled or misused. The
example from the 1996 preamble cited in the response to the preceding
comment illustrates clearly why content identification is essential
even when a facility produces only a single type of formula.
Importantly, under Sec. 106.50(c) of the interim final rule, a
manufacturer has the discretion to select its content identification
system.
2. Controls To Ensure the Nutrient Levels and Lack of Contaminants in
Formulas (Proposed Sec. 106.50(d))
(Comment 107) One comment agreed that the intent of proposed Sec.
106.50(d) is sound and is rightfully a part of the CGMP regulations for
infant formula but objected to what it characterized as the
prescriptive nature of proposed Sec. 106.50(d)(1) through (d)(4) and
requested that these specific paragraphs be deleted. The comment argued
that FDA should allow individual manufacturers to determine the best
and most economical approach to producing high quality infant formulas
that meet the nutrient requirements of Sec. 107.100 and do not contain
contaminants. The comment contended that FDA only needs to define the
goal and general intent of this section and not specify exact
parameters that a manufacturer must follow. The comment expressed
concern that defining exact parameters could unintentionally prevent
manufacturers from using other production methods that could result in
an acceptable product. The comment suggested that the manufacturer
should document its intended approach, as well as compliance with its
own designated control systems.
(Response) FDA disagrees that the requirements in proposed Sec.
106.50(d)(1) through (d)(4) are overly prescriptive. Indeed, one
benefit of this interim final rule is that it informs new infant
formula manufacturers of the controls that must be established in a
proper infant formula manufacturing operation. The points identified in
proposed Sec. 106.50(d)(1), (d)(2), (d)(3), and (d)(4) are those at
which control is necessary to produce a formula that is homogeneous,
that is not contaminated, that will not undergo nutritional
[[Page 7976]]
deterioration, and the containers of which will remain properly sealed.
Controls at these points are essential to the production of any formula
to ensure that it is not adulterated, a conclusion not disputed by the
comment. Importantly, however, the manufacturer has the authority,
responsibility, and flexibility to determine the parameters for each
control point, and these parameters are, in part, based on the
manufacturer's knowledge and experience. Thus, the manufacturer has the
flexibility to determine the specific time, temperature, and speed for
mixing; the steps needed in a spray-drying process to prevent microbial
and other contamination; the extent of air removal needed from finished
product to prevent nutrient deterioration; and procedures for ensuring
proper seal of containers. Because the comment did not explain why
control is not necessary at the points identified in proposed Sec.
106.50(d)(1) through (d)(4), FDA is not revising proposed Sec.
106.50(d) in response to this comment.
3. Removal of All Air From Containers of Infant Formula (Proposed Sec.
106.50(d)(3))
(Comment 108) One comment objected to proposed Sec. 106.50(d)(3),
which requires ``the removal of air from the finished product to ensure
that nutrient deterioration does not occur.'' The comment explained
that it is not technically feasible to remove all ``oxygen'' to ensure
that nutrient deterioration does not occur, and suggested that this
provision be revised to require ``the removal of oxygen from the
finished product to a level that will avoid deterioration below an
acceptable level of nutrients throughout the shelf life of the
product.'' Another comment stated that if a manufacturer could package
an infant formula without the removal of air and still meet the
nutritional and quality factors throughout the shelf-life of the
product, FDA should permit this approach.
(Response) The Agency recognizes that it may not be possible to
remove all of the air from finished product containers. Importantly,
however, the manufacturer must remove or control the amount of air in
the container to prevent deterioration of nutrients. When the
requirement of proposed Sec. 106.50(d)(3) is read in conjunction with
the stability testing requirements of proposed Sec. 106.91(b), air
removal must be sufficient to ensure that the nutrients continue to
meet the levels required by section 412(i) of the FD&C Act throughout
the shelf life of the product. Each manufacturer must decide the extent
to which air must be removed from its finished product containers to
ensure nutrient stability. Further, proposed Sec. 106.50(d)(3) is
consistent with the regulations on thermally processed low-acid foods
packaged in hermetically sealed containers (part 113), which require
that the ``exhausting of containers for the removal of air shall be
controlled so as to meet the conditions for which the process was
designed'' (Sec. 113.81(d)). Liquid infant formulas that are low-acid
canned foods must comply with part 113; one purpose of the process for
such liquid formulas is to ensure stability of a formula's nutrients
throughout the shelf-life of the formula. Accordingly, FDA is not
modifying proposed Sec. 106.50(d)(3) in response to these comments,
and Sec. 106.50(d)(3) is included in this interim final rule as
proposed.
4. Controls on Rejected In-Process Materials (Proposed Sec. 106.50(f))
(Comment 109) One comment suggested deleting or revising proposed
Sec. 106.50(f)(3), which would require a manufacturer to establish
controls to ensure that rejected in-process materials meet the
appropriate specifications, if reprocessed, before being released for
use in infant formula. The comment argued that this section could be
deleted if the definition of specifications suggested in the comment
were adopted by the Agency because the proposed definition of
specifications addresses the situation described in proposed Sec.
106.50(f)(3). The comment recommended the following definition of
``specifications:'' ``Specifications means quality control limits or
standards for raw materials, in-process materials, and finished
product, which are established by the manufacturer for purposes of
controlling quality and consistency for infant formula. Failure to meet
an established specification requires a documented review and material
disposition decision.''
(Response) The response to Comment 35 addresses the request that
the rule include a definition of ``specifications.'' For the reasons
stated in that response, FDA declines to add a definition of
``specifications'' to the interim final rule. Because the request to
delete proposed Sec. 106.50(f)(3) relies on a separate suggested
change that FDA declines to make, Comment 109 has been addressed.
(Comment 110) One comment asserted that proposed Sec. 106.50(f)(3)
could be interpreted as requiring that all out-of-specification in-
process materials be rejected.
(Response) As discussed previously in this document, FDA did not
intend all out-of-specification in-process materials to be rejected and
has revised proposed Sec. 106.50(f) to be consistent with revisions
made elsewhere in the interim final rule, including Sec. Sec.
106.6(c), 106.40(d), 106.40(e), 106.40(f), and 106.70, related to a
failure to meet a specification.
The distinction between ``out-of-specification material'' and
``rejected material'' is clear in light of the revisions made elsewhere
in the interim final rule. As noted previously in this document, the
interim final rule revises Sec. 106.6(c)(4) to require that, where
there is a failure to meet any specification established under Sec.
106.6(c)(1), an individual qualified by education, training, or
experience conduct a documented review and make a material disposition
decision to reject the affected article (i.e., material or product),
reprocess or otherwise recondition the affected article, or approve and
release the article for use or distribution. Thus, one possible outcome
is that the out-of-specification in-process material is not rejected
and is released for use in formula without the need for reprocessing or
other reconditioning. Another possible outcome of the documented review
and material disposition decision is that the non-conforming article is
rejected. Additionally, if appropriate, the out-of-specification
material may be reprocessed, and if successfully reprocessed, could be
used in an infant formula. Thus, under the terms of the interim final
rule, out-of-specification material is not necessarily required to be
rejected. However, if in-process material is rejected following the
documented review and material disposition decision required by Sec.
106.6(c), Sec. 106.50(f)(4) requires that any such material be clearly
identified as rejected and be quarantined. Likewise, under Sec.
106.50(f)(2) of the interim final rule, in-process materials that are
pending a documented review and disposition decision must be clearly
identified as such and be controlled under a quarantine system to
prevent their use prior to any disposition decision. Additionally, if
an in-process material is reprocessed, it must undergo another
documented review and material disposition decision to determine
whether the in-process material that has been reprocessed may be
released for use in infant formula.
Accordingly, to clarify the required controls for in-process
material that fails to meet specifications, including controls for
rejected in-process material, FDA is revising proposed Sec. 106.50(f)
as discussed previously in this document in section V.C.1.
[[Page 7977]]
J. Controls To Prevent Adulteration From Microorganisms (Proposed Sec.
106.55)
In 1996, FDA proposed to require that infant formula manufacturers
establish controls to prevent the adulteration of formula from
microorganisms. Specifically, proposed Sec. 106.55(a) would have
required that a manufacturer of liquid infant formula comply with the
procedures in part 113 (Thermally Processed Low-Acid Foods Packaged in
Hermetically Sealed Containers). Proposed Sec. 106.55(b) would have
required that a manufacturer of powdered infant formula test
representative samples of every batch (production aggregate) at the
final product stage and before distribution to ensure that the formula
meets microbiological quality standards, which standards were set out
in proposed Sec. 106.55(c). Proposed Sec. 106.55(c) would have
established seven microbiological standards: aerobic plate count (APC),
coliforms, fecal coliforms, Salmonella, Listeria monocytogenes,
Staphylococcus aureus, and Bacillus cereus. Under proposed Sec.
106.55(c), if the M value (defined as the maximum allowable number of
organisms present in 1 g of dry formula, expressed as ``colony forming
unit per gram'' (CFU/g) or ``most probable number'' (MPN/g)), for the
microbe was exceeded, the infant formula would have been considered
adulterated under sections 402 and 412 of the FD&C Act. Proposed Sec.
106.55(d) would have required a manufacturer to make and retain records
relating to the testing of infant formulas for microbial contamination.
Thereafter, in 2003, FDA reopened the comment period to receive new
information based on the 2002 and 2003 meetings of the FAC and two of
its subcommittees that considered, among other issues, microbiological
standards for E. sakazakii (Cronobacter spp.) \3\ and other
microorganisms in powdered infant formula (68 FR 22341). At that time,
the Agency requested comments on whether the final rule should include
a microbiological standard for E. sakazakii (Cronobacter spp.) and if
so, what that standard should be. Concerns about Cronobacter spp.
stemmed from the 2001 death of one of ten infants made ill from
consuming formula consisting of sterile water and contaminated powdered
infant formula (68 FR 22341 at 22342). The Agency also requested
comments on additional changes to the microbiological standards
proposed in 1996 and on whether formula for preterm and newborn infants
should be subject to more strict microbiological requirements.
---------------------------------------------------------------------------
\3\ As noted previously in the document, in 2008, the taxonomy
of Enterobacter sakazakii was reclassified to include all the
species that were pathogenic into a new genus named Cronobacter spp.
(Ref. 1).
---------------------------------------------------------------------------
FDA subsequently reopened the comment period in 2006 to consider
the recommendations from an FAO/WHO expert consultation, the report of
which included a risk assessment model and data used for that model
that became available after the 2003 reopening. The Agency announced
that, based on its review of the expert reports, it had tentatively
determined to establish a standard for Cronobacter spp.; that the
appropriate standard for Cronobacter spp. would be negative in 30 x 10
g samples and, for Salmonella spp., negative in 60 x 25 g samples; that
manufacturers would be required to test representative samples of each
production aggregate (batch) of powdered infant formula for the two
pathogens; and that testing for aerobic plate count (APC) and the five
remaining microorganisms identified in the 1996 proposal (coliforms,
fecal coliforms, Listeria monocytogenes, Staphylococcus aureus, and
Bacillus cereus) would not be required. The Agency specifically
requested comments on two issues related to the microbiological quality
of powdered infant formula: whether FDA should establish a standard for
Cronobacter spp. in powdered infant formula of negative in 30 x 10 g
samples and whether FDA should finalize microbiological standards for
APC, coliforms, fecal coliforms, Listeria monocytogenes, Staphylococcus
aureus, and Bacillus cereus.
The Agency received comments on microbiological controls in
response to the 1996 proposal and in response to the 2003 and 2006
reopenings. This section addresses those comments.
1. Microbiological Requirements for Liquid Infant Formula (Proposed
Sec. 106.55(a))
FDA received no comments opposing this proposed provision. On its
own initiative, FDA is revising proposed Sec. 106.55(a) to clarify
that liquid infant formulas that are acidified foods are required to
comply with the regulations in part 114 (``Acidified foods''). In
addition, for clarity and consistency with the remainder of the interim
final rule, FDA is making minor editorial changes and is redesignating
proposed Sec. 106.55(a) in this interim final rule as Sec. 106.55(b)
to state: ``A manufacturer of liquid infant formula shall comply, as
appropriate, with procedures specified in part 113 of this chapter for
thermally processed low-acid foods packaged in hermetically sealed
containers and part 114 of this chapter for acidified foods.''
FDA notes that Sec. 106.55(a) of the interim final rule is
discussed in section J.2.a.ii.
2. Microbiological Requirements for Powdered Infant Formula (Proposed
Sec. 106.55(b) and (c))
As a result of the reopening of the comment period in 2003 and
2006, the Agency's tentative conclusions about appropriate
microbiological testing requirements (proposed Sec. 106.55(b) and (c))
have been substantially revised and are discussed in this document.
a. General comments.
i. Final product stage testing.
(Comment 111) Several comments suggested that FDA re-evaluate the
need for finished product microbiological testing of all lots
(production aggregates) of infant formula to determine whether such
testing will provide significantly enhanced safety when an effective
in-process control system is in place.
(Response) FDA disagrees with the suggestion of this comment.
First, the comment appears to misunderstand the proposed
requirements for microbiological testing of finished product at the
final product stage. In particular, liquid infant formulas
(concentrates and ready-to-feed formulas) must comply with the
requirements for thermally processed, low-acid foods packaged in
hermetically sealed containers (in part 113) or with requirements for
acidified foods (in part 114), which do not require final product stage
microbiological testing. Part 113 focuses on ensuring that commercial
sterility \4\ is achieved in thermal processing and packaging; part 114
ensures that commercial sterility is achieved through acidification,
thermal processing, and packaging. Processing an infant formula
consistent with part 113 or part 114 ensures the destruction of
vegetative pathogens, including Cronobacter spp. and Salmonella spp.
---------------------------------------------------------------------------
\4\ FDA's regulations on acidified foods, 21 CFR 114.80 states
that ``acidified foods shall be thermally processed to an extent
that is sufficient to destroy the vegetative cells of microorganisms
of public health significance and those of non-health significance
capable of reproducing in the food under the conditions in which the
food is stored, distributed, retailed and held by the user.'' As
used in this interim final rule, the term ``commercial sterility''
includes an acidified food that has been thermally processed to an
extent that is sufficient to destroy the vegetative cells of
microorganisms of public health significance and those of non-health
significance capable of reproducing in the food under the conditions
in which the food is stored, distributed, retailed and held by the
user.
---------------------------------------------------------------------------
Second, FDA acknowledges that proposed Sec. 106.55(b) would have
[[Page 7978]]
established microbiological standards for powdered infant formulas and
would have required representative samples from every production
aggregate of powdered infant formula to be tested, at the final product
stage and before distribution, to ensure that the production aggregate
meets the established standards. The comment included no data or
information to support its suggestion that an effective in-process
control system would eliminate the need for end-product testing. The
purpose of final product stage testing is to ensure the microbiological
safety of each production aggregate of infant formula. In addition,
however, final product stage testing serves to verify that the
manufacturer's food safety control system is operating effectively to
prevent microbial contamination of formula during processing because,
to the extent that such testing shows finished product contamination,
the manufacturer is put on notice that its system of controls is not
functioning effectively.
(Comment 112) One comment stated that based on knowledge of factors
associated with E. sakazakii (Cronobacter spp.) infections (such as
abusive temperatures and poor storage conditions), relying on end-
product microbiological testing as a control strategy for this
microorganism is not a dependable approach to preventing illness.
Several other comments suggested that education concerning formula
preparation and handling, or additional labeling, is more likely to
reduce the risk of infection than finished product testing. One comment
suggested that FDA issue guidelines on the correct preparation of
formula.
(Response) FDA disagrees with these comments to the extent that
they suggest that education concerning formula preparation and handling
should replace final product stage testing. First, the comment does not
dispute that powdered infant formula itself can be a source of
Cronobacter spp. contamination. Although the data on surveys of
Cronobacter spp. in powdered infant formula show that the percent of
samples found positive for the pathogen have decreased over the past
years as manufacturers have implemented stricter controls in the
processing environment (Ref. 3, Table 4), the risk that the organism
will be present in finished formula still exists.
Cronobacter spp. have been described as ``a severe hazard for
restricted populations, [resulting in] life threatening or substantial
chronic sequelae of long duration'' by the International Commission for
Microbiological Specifications for Foods (ICMSF 2002) (Ref. 22).
Cronobacter spp. have been identified as the etiological agent in
neonatal meningitis, septicemia, and necrotizing enterocolitis, and are
considered emerging opportunistic pathogens (Ref. 23 and 24).
Cronobacter spp. have caused meningitis resulting in brain abscess and
ventriculitis (inflammation of the cerebral ventricles) with a very
high associated mortality rate in neonates and infants (Refs. 23 and
25). Survivors of Cronobacter-induced meningitis suffer life-long
mental and physical developmental delays (Ref. 23). Although there has
been continued study of this pathogen and further characterization, the
dose required to cause infection has yet to be determined (Ref. 24).
Given the absence of a documented infectious dose and the severity of
Cronobacter spp. infections in infants, even a low risk of such
contamination of infant formula from the production environment must
not be tolerated.
An important objective of CGMP is to identify points in product
processing where there is a risk of adulteration and implementing
controls to prevent contamination that adulterates the product. This
objective is captured generally in Sec. 106.6(b) of the interim final
rule and specifically in Sec. 106.55(a), which, as discussed in this
document, has been added to Sec. 106.55 of the interim final rule.
Implementing a standard for Cronobacter spp., which includes testing of
the final production aggregate, complements these efforts directed at
system control by providing a separate mechanism to verify that food
safety measures and system process controls are producing an infant
formula that is not adulterated.
It is also important to note that there have been multiple efforts
by various external groups to alert consumers and health professionals
about the risk of illness from Cronobacter spp. and powdered infant
formulas contaminated with this pathogen. For example, in 2011, the
American Dietetic Association (ADA) published an updated book titled
``Infant Feedings: Guidelines for Preparation of Formula and Breastmilk
in Health Care Facilities'' (Ref. 26). The International Formula
Council (IFC) published a pamphlet for health professionals, which was
based on the ADA book; the IFC guidelines are available at
www.infantformula.org/for-health-professionals (Ref. 27). The American
Academy of Pediatrics (AAP) also published an article on infant formula
safety that provides recommendations on food safety practices for
powdered infant formula (Ref. 28). Manufacturers of powdered infant
formula have developed educational materials for consumers and made
changes to their labels to include directions for the safe preparation
and storage of infant formula. In addition, the USDA provides guidance
to participants in the USDA Women, Infants, and Children (WIC) program
on safe preparation and storage of infant formula www.nal.usda.gov/wicworks/Topics/FG/Chapter4_Infantformulafeeding.pdf (Ref. 29, p.
91).\5\ All of these programs contribute to the overall food safety
efforts to prevent foodborne illness from contaminated powdered infant
formula.
---------------------------------------------------------------------------
\5\ Significantly, according to the USDA, Economic Research
Service, WIC participants now account for over half of all infant
formula sold in the United States (Ref. 30), and WIC participants
use powdered infant formula almost exclusively.
---------------------------------------------------------------------------
(Comment 113) Some comments suggested that point-of-use
contamination from poor preparation practices represents the most
significant risk of E. sakazakii (Cronobacter spp.) infection for
infants consuming formula.
(Response) FDA is not aware of data that would refute or
corroborate this point. Moreover, the comment did not provide any data
to support this assertion. There is always a potential risk that
microbial contamination may occur during food handling. However, that
possibility does not mean that there is no need to ensure that a
packaged infant formula product does not exceed microbial limits before
distribution from the processing plant. The responsibility for food
safety falls at every point along the food chain, which begins with
manufacturing. Better controls used by the manufacturer to minimize
contamination during processing contribute substantially to reducing
the risk of illness at point of use.
(Comment 114) One comment stated that the need for end-product
microorganism testing should be determined by the manufacturer.
(Response) FDA disagrees with this comment. Infant formula is
intended for consumption by a vulnerable population and, as discussed
previously in this document, infants are at risk of significant
morbidity or mortality from an infection caused by Cronobacter. Illness
caused by Salmonella spp. (salmonellosis) has long been associated with
contaminated dried milk products. Non-typhoidal serovars (NTS) of
Salmonella, such as Salmonella enterica, have also been found in infant
formulas and are capable of causing invasive disease. In the reported
outbreaks of Salmonella infection associated with powdered infant
formula, the organism was found at low
[[Page 7979]]
levels in the unreconstituted powdered formula. The incidence of
salmonellosis among infants is higher than in all other age groups and
is considered a public health problem (Ref. 31). Infants younger than 1
year of age are reported to have an infection rate of 120/100,000
population in the United States (Ref. 32). The symptoms associated with
salmonellosis range from dehydration to bloody diarrhea requiring
hospitalization, sepsis, and death. Complications from NTS include
bacteremia (bacterial bloodstream infection), enterocolitis
(inflammation of the mucus membrane of the small intestine or colon),
meningitis (inflammation of the membranes covering the brain or spinal
cord), and osteomyelitis (inflammation of bone due to an infection).
Indeed, the threat to the health of infants from consuming powdered
infant formula contaminated with these pathogens has been recognized
not only by the FDA, but by the international community as well.
Accordingly, due to the severity of illness associated with
contamination, FDA has concluded that the frequency and degree of end-
product testing must be prescribed by the Agency in the interim final
rule and not simply left to the discretion of each formula
manufacturer. However, because the testing specified in Sec. 106.55 of
the interim final rule is the minimum necessary, a formula manufacturer
is free to conduct additional microbiological testing. FDA notes that,
if such additional testing is conducted, the Agency expects that the
manufacturer would monitor such testing and act appropriately on the
results.
(Comment 115) Some comments stated that the proposed regulations
encompass a HACCP-type approach but the requirement for routine end
product testing for certain micro-organisms is contradictory to the
HACCP concept. However, these comments suggested that if end-product
testing is required, FDA should issue guidelines on the number and size
of samples to be tested to ensure that lots (production aggregates) of
powdered infant formula do not contain pathogens.
(Response) FDA disagrees with this comment. The purpose of this
interim final rule is to establish CGMP for infant formula. Thus, the
premise of the comment is erroneous.
Moreover, FDA does not agree that end-product testing is
contradictory to the HACCP concept. Although the HACCP concept may
emphasize process controls, finished product testing at the final
product stage, before distribution, is an important means of verifying
that process controls are being continuously applied and effective. As
discussed in response to Comment 116, testing representative samples of
final production aggregates can serve as a final check on both the food
safety controls and process designed to prevent microbial contamination
during processing and on the microbiological safety of the infant
formula prior to distribution.
The Agency is not issuing guidance on a sampling plan for microbial
testing, as requested in the comment, because the number and size of
formula samples for testing from each production aggregate are
specified in Sec. 106.55(e) of the interim final rule. As discussed in
section V.J.2.c., by specifying the number and size of the samples for
testing finished product, FDA ensures that there is sufficient
statistical confidence to support the validity of results showing that
the finished product meets the specified microbiological standards.
(Comment 116) Some comments asserted that there is no need to
establish a standard for E. sakazakii (Cronobacter spp.) because the
safety of infant formula would be better assured by hazard analysis
critical control plans (HACCP), environmental monitoring, labeling, and
education.
(Response) FDA disagrees with these comments. In the 2006
reopening, FDA noted that comments in response to the 1996 proposal
suggesting that alternatives to end-product testing would provide
sufficient assurance of safety (e.g., HACCP plans and environmental
monitoring, labeling, and education on formula preparation and
handling) had not submitted any data or other information to support
such assertions with respect to Cronobacter spp. All of the approaches
mentioned in these comments may contribute to a total food safety plan,
but essential to the plan is verifying the effectiveness of the process
control established to ensure the microbial safety of the finished food
product. Testing final production aggregates for Cronobacter spp. is
one way that the manufacturer can verify the production process and the
safety of the product prior to distribution and marketing. Further, FDA
did not receive any information or data in response to the 2006
reopening that contradicts its tentative conclusion regarding
microbiological testing of powdered infant formula for Cronobacter spp.
ii. Microbiological specifications and powdered infant formula.
(Comment 117) One comment questioned the practicality of including
specific microbiological specifications in the CGMP given the length of
time required to pass or change such regulations. The comment suggested
that, in the future, when FDA encounters emerging pathogens of concern,
it could establish interim requirements through such mechanism as a
guidance document, which would be less burdensome than establishing the
CGMP regulations.
(Response) FDA disagrees with the comment to the extent that it
suggests that the Agency issue guidance instead of establishing
standards for microbiological contamination for any future emerging
pathogens of concern. In many cases, guidance is not a long-term
substitute for a binding regulation. FDA's Good Guidance Practices
(GGPs) (21 CFR 10.115) state that guidance represents the Agency's
current thinking on a topic and does not create or confer any rights
for or on any person and does not operate to bind FDA or, more
importantly in this case, the public, including infant formula
manufacturers. As discussed in response to Comment 116, the population
for whom infant formula is manufactured and the risks for that
population from microbial contamination require that FDA establish
legally binding requirements. Because the process for issuing guidance
is somewhat simpler than the process for promulgating a regulation, the
Agency acknowledges that it may be appropriate, in some circumstances,
to use guidance to communicate FDA's current thinking on specifications
for an emerging pathogen of concern.
(Comment 118) One comment asserted that although manufacturers can
take proactive measures to reduce the level, frequency, and incidence
of E. sakazakii (Cronobacter spp.) in powdered infant formula, total
eradication of the microorganism from powdered infant formula is not
currently technologically possible given the nature of food powder
manufacturing. The comment stated that manufacturers are currently
attempting to further define and reduce, to the extent possible, any
potential risk posed by contaminated powdered infant formula.
(Response) Even if the total eradication of Cronobacter spp. may
not be technologically feasible, that limitation does not alter the
Agency's conclusion that a strict microbiological standard, such as
that required by the interim final rule (less than one organism in 300
grams of powdered formula) is necessary to reduce the risk of illness
associated with Cronobacter spp. in infants. Powdered infant formula
cannot undergo a post-packaging thermal process that is required for
liquid ready-to-feed or concentrated
[[Page 7980]]
products. This fact supports the need for a microbiological standard
for powder formula to ensure that the safest product possible is
available to infants. Under Sec. 106.6(b) of the interim final rule, a
manufacturer must take responsibility to establish appropriate controls
and monitor those manufacturing processes where adulteration could
occur, and Sec. 106.55(a) of the interim final rule requires a
manufacturer specifically to establish a system of process and controls
to ensure that infant formula does not become adulterated due to the
presence of microorganisms in the formula or in the processing
environment.
b. Need for a Cronobacter spp. (E. sakazakii) microbiological
standard for powdered infant formula.
i. Need for a standard for formula for term infants.
(Comment 119) One comment asserted that, given infant formula's
excellent safety record since the passage of the Infant Formula Act,
there is no need for additional microbiological requirements.
(Response) FDA disagrees with this comment. Cronobacter spp. have
been documented as responsible for infant illnesses such as bacteremia,
sepsis, and meningitis, with a reported mortality rate as high as 40 to
80 percent (Ref. 33). These cases of Cronobacter spp. infections have
been associated both directly with powdered infant formula and
epidemiologically (Refs. 33, 34, and 35). The existence of outbreaks
associated with powdered infant formula contaminated with Cronobacter
spp., such as the one that occurred in Tennessee (Ref. 34), attests to
the ability of this pathogen to cause significant illness and death.
Accordingly, the safety record for infant formula does not obviate the
need for the microbiological requirements of this interim final rule.
(Comment 120) Several comments noted that there are data
demonstrating that the industry has taken measures to achieve increased
control over potential contamination of powdered infant formula overall
and that since July 2003, there has been a reduction in the level of E.
sakazakii (Cronobacter spp.) found in powdered infant formula.
(Response) FDA agrees that available data appear to suggest that
the risk of Cronobacter spp. contamination of powdered infant formula
has decreased. One of the earliest surveys of powdered infant formula
samples for Cronobacter spp. was conducted in 1988 by Muytjens and co-
workers (Ref. 36). The investigators reported that 14 percent of
samples of powdered infant formula that had been collected from 13
countries contained the pathogen at levels that ranged from 0.36 to 66
CFU/100 g. A more recent analysis of 82 powdered infant formulas by
Iversen and Forsythe (2004) documented Cronobacter spp. in
approximately 2.4 percent of samples (Ref. 37). Although these two
investigations appear to reflect a reduction in the percent of formula
contaminated with Cronobacter spp., the risk of potentially fatal
illness will persist as long as the pathogen can survive in the
environment and in powdered formula. To the extent the comment is
suggesting that there is no need to establish a standard for this
organism given the reduction in the percent of formula contaminated
with Cronobacter spp., the Agency disagrees. Given the severe
consequences of a Cronobacter spp. infection in an infant, protection
of the public health requires that the Agency establish a standard for
this organism in powdered infant formula and require sampling and
testing to achieve that standard.
(Comment 121) One comment asserted that there have been no reported
cases linking powdered infant formula to illness caused by E. sakazakii
(Cronobacter spp.) in healthy term infants except when there was
positive evidence of external contamination or abuse of reconstituted
formula. Another comment argued that, based on the lack of evidence
linking Cronobacter spp. to outbreaks in term infants, FDA's current de
facto standard of zero tolerance of Cronobacter spp. in term infant
formulas is not warranted.
(Response) FDA disagrees with these comments because the available
scientific evidence demonstrates that term infants are at risk of
foodborne illness associated with powdered infant formula contaminated
with Cronobacter spp., including the risk of severe morbidity and
mortality. FDA notes that powdered infant formula is not intended to
be, nor is it, a sterile product. Because term infants are more likely
to receive powdered formula rather than liquid formula that is
commercially sterile, they risk being exposed to Cronobacter spp.
Reports in the published literature document the existence of this
risk for term infants. For example, in 1989, Biering et al. reported
three cases of neonatal meningitis associated with Cronobacter spp. in
three infants fed powdered milk formula where two of the three infants
were term infants (Ref. 38). The Cronobacter spp. isolated from the
term neonates was indistinguishable from the 22 strains grown from the
powdered infant formula. Muytjens et al. (1983) reported on one term
infant infected with Cronobacter spp. infection who died from
bacteremia (Ref. 39).
Additionally, FDA and CDC have both received reports through the
agencies' electronic adverse event reporting systems or otherwise of
several cases of healthy term infants becoming ill from Cronobacter
spp. infection (Ref. 40). In each case, contaminated powdered infant
formula was the suspect vehicle. Although followup investigations of
these cases were unable to determine the source of contamination that
caused the illness, these reports demonstrate nonetheless that healthy
term infants continue to be at risk of life-threatening illness from
Cronobacter spp. infections. Importantly, illnesses from Cronobacter
spp. are not required to be reported to the CDC (Ref. 41). Detection of
the pathogen and the disorders has been identified through surveillance
surveys. This suggests that the actual number of cases of Cronobacter
spp. infection in infants is under-reported.
Although infant age is not protective, infant age may be associated
with particular presentations of Cronobacter spp. illness. That is, CDC
data suggest that infants who develop meningitis tend to be near term
in gestational age and birth weight (Ref. 33). Consistent with this
observation are conclusions from the FAO/WHO expert consultation that
identified the two risk groups as ``preterm infants who develop
bacteraemia outside of the neonatal period, with most, but not all,
cases occurring in infants under two months, and term infants who
develop meningitis during the neonatal period.'' (Ref. 3) Importantly,
the FAO/WHO report further notes that ``any infant may develop either
syndrome at any age.''
FDA also notes that the comment incorrectly asserted that the
Cronobacter spp. standard is a zero tolerance standard. In fact, this
is not the case, as explained in the discussion of the standard and the
sampling plan (section V.J.2.c).
(Comment 122) One comment argued that the low risk among healthy
term infants is supported by the low number of reported cases among
healthy term infants in comparison with the estimated 100,000 infants
who have been exposed to contaminated formula in the past 15 years.
(Response) FDA agrees that the number of reported cases of illness
in term infants with Cronobacter spp. infection is less than those of
preterm infants but notes that the comment does not dispute the
Agency's conclusion that term infants have been afflicted with serious
illness caused by Cronobacter spp. infections. Term infants have been
reported ill from contaminated powdered infant formula
[[Page 7981]]
(Refs. 35 and 38), and several cases of term infants seriously affected
by Cronobacter spp. infections, without a clear association to powdered
infant formula, have been reported to FDA and CDC (Refs. 40 and 41). As
described in the response to Comment 112, extremely serious health
conditions, such as meningitis, bacteremia, seizures, brain abscess,
hydrocephalus, developmental delay, and death associated with infection
from Cronobacter spp. have been reported in the scientific literature
(Refs. 33 and 42) and directly to FDA or the CDC (Ref. 40). Thus, in
light of the consequences of an infection from Cronobacter spp., even a
``low risk'' of such infection in healthy infants is unacceptable and
is appropriately compared to what is essentially a zero risk of a
Cronobacter spp. infection in breast-fed infants.
(Comment 123) One comment suggested that products clearly labeled
for infants six months of age or older should be exempt from the E.
sakazakii (Cronobacter spp.) microbiological standard because there is
no evidence powered infant formula has caused any cases of E. sakazakii
(Cronobacter spp.) infection in older infants.
(Response) FDA disagrees with this comment for several reasons.
First, although Cronobacter spp. infections are less frequently
reported in infants six months of age and older than in younger
infants, older infants are nevertheless at risk of Cronobacter spp.
infections and the scientific literature includes reports of such
infections in older infants. In 2003, a case of Cronobacter spp.
infection in a healthy eight month old infant was reported directly to
the FDA and CDC (Ref. 40). The patient was healthy prior to consuming
powdered infant formula a few hours before the onset of symptoms of
illness. Likewise, in its expert review of multi-country data on the
risk of illness from Cronobacter spp., FAO/WHO reported that of 120
individually documented cases among infants and young children up to 3
years of age, six occurred in infants aged 6 to 11 months and two cases
in children 12 to 36 months (Ref. 43). Importantly, the FAO/WHO report
also noted that there are few data available on the prevalence of the
Cronobacter spp. pathogen in formulas specifically intended for infants
ages 6 to 11 months (so-called ``follow-up formula''), a situation
attributed to the absence of mandatory testing for Cronobacter spp.
(Ref. 43).
Second, a food that is capable of causing severe illness is
adulterated within the meaning of section 402(a)(1) of the FD&C Act
because the presence of a microorganism, and labeling to restrict the
food's use to certain subpopulations cannot make that unlawful food
lawful.
Third, section 201(z) of the FD&C Act defines ``infant formula'' as
``a food that purports to be or is represented for special dietary use
solely as a food for infants.'' FDA's regulations (21 CFR 105.3(3))
define ``infant'' as a person not more than 12 months of age.
Accordingly, the U.S. regulatory system does not distinguish between
formula for infants less than 6 months of age and formula intended for
infants older than 6 months. (The latter is often referred to as
``followup'' formula.) Thus, all infant formula for infants ages 0 to
12 months must meet the same microbiological standards and requirements
under this interim final rule.
For these reasons, FDA declines to adopt the suggestion of this
comment.
(Comment 124) One comment asserted that formula labeled for infants
6 months of age and older should be exempt from the E. sakazakii
(Cronobacter spp.) standard. The comment noted that in 2003, the FAC
defined the at-risk population as preterm infants born at less than 36
weeks gestational age up to a post term age of 4-6 weeks,
immunocompromised infants at any age, and term infants. The comment
asserted that the FAC did not identify healthy-term infants as at risk.
(Response) FDA does not disagree that preterm and immunocompromised
infants are at greater risk of infection from Cronobacter spp. compared
to term infants and infants six months of age and older. However, as
demonstrated by the evidence discussed in the previous responses, term
infants are still at risk of infection from Cronobacter spp.; these
infections are very serious and can lead to life-long disability or
death. The FAO/WHO 2008 report on the risk of illness from this
pathogen in powdered follow-up formula made several significant
observations: (1) Six cases of illness from Cronobacter spp. were
identified in infants between the ages of 6 and 11 months; (2)
globally, there are few surveillance data for Cronobacter spp. related
illness; (3) because there is no universal mandate for testing followup
formula for this pathogen, there are few data available on the
prevalence of the pathogen in these products intended for older
infants; and (4) there are data to demonstrate that followup formula is
consumed by infants less than 6 months of age and sometimes consumed by
infants less than 1 month (Ref. 43). To exempt followup formula from
the CGMP microbiological standards in this interim final rule would be
to ignore the very real potential for serious illness in this older
group of infants consuming these formulas, as well as infants less than
six months of age that may be consuming these formulas.
Accordingly, FDA declines to exempt ``follow-up formula'' from the
interim final rule's standard for Cronobacter spp.
(Comment 125) One comment asserted that although the available
scientific evidence does not permit a comprehensive risk assessment,
the available evidence does permit the rather straightforward
conclusion, such as that reached by the Food Advisory Committee, that
whatever the risk powdered infant formula may pose to term infants by
virtue of the presence of Cronobacter spp., that risk is not only lower
than that which is associated with premature infants, but also is
unquantifiable.
(Response) FDA disagrees in part and agrees in part with this
comment. Importantly, as discussed in detail in this document, a
scientifically sound quantitative risk assessment can be, and has been,
conducted of the potential for Cronobacter spp. infection in infants.
As noted in its response to Comment 114, FDA does agree that the
incidence of illness from Cronobacter spp. infection is lower in term
infants than in premature infants. Nonetheless, as also explained
previously in this document, it is appropriate to establish a
Cronobacter spp. standard for all infant formula, including formula for
older infants. Accordingly, FDA is not revising Sec. 106.55 in
response to this comment.
ii. Issues related to the standards for Cronobacter spp.
(Comment 126) One comment, which questioned the proposed standard,
stated that a research study by Health Canada, in which a suckling
mouse was used as a model to study E. sakazakii, found that this
organism has low infectivity, and that large numbers of organisms are
needed to cause infection, even with the most virulent strains.
(Response) As discussed in this document, this study does not
demonstrate that the Cronobacter spp. organism has low infectivity.
The research by Health Canada identified in the comment was
designed to study virulence factors and pathogenesis of E. sakazakii
(Cronobacter) using the suckling mouse assay (Ref. 44). The animals
were challenged both by oral and intraperitoneal routes with clinical
and food isolates of the pathogen. The investigators reported that one
strain of the pathogen (MNW2), which was administered orally, was
lethal to suckling mice at 10\8\ CFU per mouse,
[[Page 7982]]
while others were lethal at doses greater than 10\8\ CFU per mouse. In
a more recent animal study, Richardson et al. (2009) evaluated the
infectivity and lethality of the MNW2 strain of Cronobacter spp. in
three different strains of neonatal mice to determine whether neonatal
mice could be used as a model for Cronobacter spp. infection in
premature infants (Ref. 45). The investigators found that one of the
three mouse strains was the most susceptible to the pathogen and had
the lowest infectious dose (10\2\ CFU) and the lowest lethal dose
(10\2\ CFU) (Ref. 45). The investigators noted that there was not a
clear dose-dependent response after treatment with the pathogen.
FDA finds that the contradictory results of these two studies
demonstrate that more research is needed to identify an appropriate
animal model, or specific strain of animal, for Cronobacter spp.
research. Neither study clearly established the relationship between
growth of the pathogen in mice and growth of the pathogen in an infant.
The results of these studies do show that Cronobacter spp. is an
infectious and lethal pathogen. As noted, this organism has a 40-80
percent lethality in infant illness (Ref. 45).
(Comment 127) One comment argued that infections are primarily
associated with foods in which the pathogen has significantly
multiplied, but there is scant to no evidence to suggest that ingestion
of small numbers (<100 CFU) of E. sakazakii (Cronobacter spp.) or
Listeria monocytogenes causes illness in high risk populations. The
comment added that because of the presence of both pathogens in the
environment, there is the potential for contamination of foods during
at-point-of-use preparation as well as the potential for growth during
subsequent storage. Thus, the comment asserted that high-risk processed
foods initially free of the pathogens can become contaminated and
abused by the food preparer resulting in a dangerously unsafe product.
The comment stated that establishing a zero tolerance for these
pathogens in high-risk foods will not address the issue.
(Response) As discussed in section V.J.2.e, FDA has determined that
the interim final rule will not include a standard for Listeria
monocytogenes. Thus, the Agency's response to this comment addresses
the issues in the comment only from the perspective of Cronobacter spp.
FDA disagrees with this comment for several reasons. First, the
Agency is aware that the available data are not adequate to identify
with certainty the infectious dose for Cronobacter spp. Importantly,
however, FDA disagrees that the absence of information on the
infectious dose supports the conclusion that these organisms pose
little or no risk of illness in high risk populations when ingested in
small numbers.
Second, the available evidence demonstrates that post-processing
contamination is not required for there to be an illness outbreak as
illustrated by the investigation of the 2001 Tennessee outbreak of
Cronobacter spp. infection. As part of the follow-up investigation,
hospital personnel reviewed Neonatal Intensive Care Unit (NICU)
infection-control practices, policies, and procedures for preparation,
storage, and administration of powdered infant formula (Ref. 34), and
no breaches in infection control were identified. The investigation
determined that the formula was prepared in the NICU according to
manufacturer's instructions and that the powdered formula was mixed
with sterile water, immediately refrigerated, and used within 24 hours
of preparation. The infant that developed Cronobacter spp. meningitis
was given formula by continuous administration; administration or
``hang'' time (i.e., the amount of time the contents of a formula bag
are fed to a patient) did not exceed 8 hours. A second outbreak in a
Belgian hospital NICU also documented that infections associated with
powdered infant formula may occur in high-risk infants despite proper
formula preparation. In this instance, formula powder that was
apparently contaminated was prepared and administered according to NICU
protocol, and resulted in serious illnesses (including two deaths) of
12 premature infants (Ref. 46).
Finally, although there is potential for contamination of foods
during preparation and subsequent storage, that fact does not negate
the need to establish a tolerance. FDA disagrees that establishing a
tolerance (claimed by the comment to be a zero tolerance) for these
pathogens in high-risk foods will not address the illness issue. One
purpose of the CGMPs in this interim final rule is to focus on
manufacturing controls to help eliminate the potential for microbial
contamination of formula during processing and thus reduce the risk of
potential illness from powdered infant formula contaminated, even at
low levels, with harmful microorganisms. The Agency also disagrees that
the microbial standard for Cronobacter spp. established in Sec. 106.55
of the interim final rule is a ``zero tolerance'' standard, and we
respond to this comment in section V.J.2.c.
iii. Issues related to alternatives to testing for Cronobacter spp.
(Comment 128) One comment suggested that the addition of E.
sakazakii (Cronobacter spp.) inhibitors to formula, such as
antimicrobials inhibitory to E. sakazakii (Cronobacter spp.) that are
presently approved for use in foods, provide a more effective means of
preventing the growth of E. sakazakii (Cronobacter spp.) that may occur
under conditions of abuse. Importantly, however, the comment stated
that use of such antimicrobials would require that the formula not have
an initial level of contamination that would be considered unsafe.
(Response) FDA disagrees with the suggestion of this comment for
two reasons. First, the use of antimicrobials was not suggested as an
alternative to finished product testing. Rather, the comment proposed
that such inhibitors be used to manage the risk of post-rehydration
abuse. Thus, the comment does not provide a basis for rejecting the
Agency's tentative conclusion that testing finished powdered infant
formula is necessary to control contamination from Cronobacter spp.
before rehydration. Second, as noted in the 2006 reopening, the comment
suggesting the use of inhibitors to Cronobacter spp. in powdered
formula did not provide data to demonstrate the effectiveness of such
ingredients to control this pathogen in a powdered infant formula
matrix. For these reasons, FDA concludes that the use of antimicrobials
is not an alternative to establishing a standard for Cronobacter in
finished infant formula products.
(Comment 129) Several comments suggested that instead of requiring
testing for E. sakazakii (Cronobacter spp.), FDA should instead require
stricter testing for indicator organisms, such as Enterobacteriaceae
(which include E. sakazakii (Cronobacter spp.)). A second comment
recommended testing for the presence or absence of Enterobacteriaceae,
rather than requiring a quantitative analysis. The second comment
further suggested that a standard for Enterobacteriaceae of zero
organisms in a ten gram sample would provide an appropriate level of
assurance and that this criterion should be applied to all formulas,
including exempt formulas.
(Response) FDA disagrees with the comments that support testing
powdered infant formula for the presence or absence of an indicator
organism, specifically Enterobacteriaceae, as an alternative to testing
directly for Cronobacter spp. The Agency also notes that this interim
final rule does not extend to exempt infant
[[Page 7983]]
formulas. Thus, this response does not address the comment regarding
the appropriateness of testing exempt formula.
Cronobacter spp. is a member of the Enterobacteriaceae family.
Detection and identification of the organism have presented
methodological difficulties, which difficulties were considered when
determining the finished product standard. Baumgartner et al., (2009)
reported that some methods for the detection of Enterobacteriaceae may
not effectively identify or otherwise be used to determine the presence
of Cronobacter spp. (Ref. 47). The standard methods of isolation for
Enterobacteriaceae are not specific for Cronobacter spp., and detection
of the Cronobacter organism is further complicated by the sensitivity
of a number of Cronobacter spp. strains to certain chemicals used in
isolation and detection media for Enterobacteriaceae (Refs. 37, 48, and
49). Studies have shown that specially modified enrichment media are
needed for the detection of this pathogen (Refs. 48, 50, and 51) and
are described on the FDA Web site (http://www.fda.gov/Food/ScienceResearch/LaboratoryMethods/ucm114665.htm). In addition, the
primary microbial populations found in powdered infant formula are
Bacillus species and other gram-positive bacteria, which bacteria may
have an adverse affect on the enrichment and isolation of
Enterobacteriaceae (Ref. 52).
Detection, identification, and specificity of Cronobacter spp. are
critical to effective management of this pathogen. Enterobacteriaceae
may not function effectively as in indicator of the presence of
Cronobacter spp. because testing for Enterobacteriaceae may produce a
negative result for Enterobacteriaceae even though Cronobacter spp. is
present. Because powdered infant formula is not a sterile product, any
post-heat treatment contamination with Cronobacter spp. may be from a
source where Enterobacteriaceae are not present but Cronobacter are.
These same observations and conclusions were reported by Paoli and
Hartnett (2006) in their article ``Overview of a risk assessment model
for Enterobacter sakazakii in powdered infant formula'' (Ref. 53).
Following a statistical evaluation of the relationship between
Enterobacteriaceae and Cronobacter spp., the investigators concluded
the data indicated that a strong positive relationship between the
concentrations of the pathogens could not be inferred and that the
absence of Enterobacteriaceae in a powdered infant formula sample did
not necessarily mean that Cronobacter spp. were not present. Thus,
relying on testing for Enterobacteriaceae to identify Cronobacter spp.
could produce a false negative finding, resulting in the release of
product for distribution that is contaminated with Cronobacter spp.
For these reasons, FDA declines to require the use of
Enterobacteriaceae as an indicator organism to identify the presence of
Cronobacter spp. in powdered infant formula as an alternative to a
specific standard for Cronobacter spp. The interim final rule's
standard for Cronobacter spp. is discussed in detail in section
V.J.2.c.
iv. The microbial risk assessment.
(Comment 130) One comment requested that FDA make available to the
public a risk assessment or risk profile analysis to support its
Cronobacter spp. standard.
(Response) The comment requesting public disclosure of a risk
assessment or risk profile analysis was submitted prior to several
important actions related to microbial contamination of powdered infant
formula. These subsequent activities have effectively responded to the
comment's request.
In particular, as discussed previously in this document, FAO/WHO
organized two expert consultations (2004 and 2006) on Cronobacter spp.
contamination of powdered infant formula. The second consultation
culminated in the 2006 FAO/WHO report, Enterobacter sakazakii and
Salmonella in Powdered Infant Formula, which report included a
quantitative risk assessment of Cronobacter spp. contamination of such
formula (Ref. 3). In the 2006 reopening, FDA summarized the FAO/WHO
risk assessment model and announced the Agency's tentative decision to
rely on that assessment to support the Agency's risk management
decision as reflected in the proposed Cronobacter spp. standard. At the
time of the 2006 reopening, a pre-publication copy of the 2006 FAO/WHO
report was made available for review at FDA's Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
rm. 1061, Rockville, MD 20852 (Ref. 3). The final FAO/WHO report is
also available at FDA's Division of Dockets Management and also at the
following Web site: http://www.who.int/foodsafety/publications/micro/mra10.pdf. FDA notes that another document providing additional insight
into the 2006 risk assessment is ``Overview of a Risk Assessment Model
for Enterobacter sakazakii in Powdered Infant Formula'' (Ref. 53). This
document is likewise available at the Division of Dockets Management
and on the FAO/WHO Web site at www.who.int/foodsafety/micro/jemra/r_a_overview.pdf.
The Agency's review of the data and quantitative risk assessment
model as applied to Cronobacter spp. led to its tentative conclusions
to establish a standard for this pathogen. Since the 2006 reopening,
there have been no further scientific data made available to cause the
Agency to change its tentative conclusions.
Accordingly, FDA has responded to this comment.
(Comment 131) One comment expressed concern that the risk
assessment model relied upon by the Agency to propose a standard for E.
sakazakii (Cronobacter spp.) lacks sufficient supporting evidence,
particularly dose-response data.
(Response) FDA disagrees with this comment for several reasons.
First, one reason that quantitative risk assessment methodology has
been developed is to allow assessment of risk even where data are
limited; such methodology generally anticipates further refinements as
more data become available. The FAO/WHO Guidelines on ``Exposure
assessment of microbiological hazards in foods'' (Ref. 54) discuss the
characteristics of data used in an exposure assessment and note that
the iterative nature of an exposure assessment is ``concerned with the
fact that initial attempts to model a process are likely to utilize
data with a high degree of uncertainty. This process can be used to
identify where the greatest uncertainty lies, allowing targeted data
collection for subsequent model updating'' (Ref. 54).
Second, the Agency acknowledges that there are no complete dose-
response data for infants who consumed powdered infant formula and
developed Cronobacter infections. Similarly, as discussed previously in
this document, there are as well insufficient data in animals to
characterize a dose-response relationship. It is unlikely that
sufficient empirical data in infants will be developed even to
establish an infectious dose, i.e., the lowest dose of the pathogen
required to cause illness, for Cronobacter, because the illness is
relatively rare and such research would present significant ethical
problems. If and when an appropriate animal model is identified, more
research can perhaps be done to try to develop data on an infectious
dose and a dose-response curve in order to gain a better understanding
of the infectivity of Cronobacter spp. in infants.
Even in the face of limited data (Refs. 33, 34, and 46), the
severity of the public health risk from Cronobacter spp.
[[Page 7984]]
infections requires action by FDA. In this instance, the available tool
is a risk assessment grounded in well-considered, conservative
estimates; as more data become available and are applied to the model,
the levels of uncertainty will be reduced. Although the FAO/WHO risk
assessment was based on several estimates, the expert committee was
fortunate to receive data on the initial levels of Cronobacter spp.
contamination of infant formula from formula manufacturers worldwide.
It is also important to note that the technical experts at the 2006
FAO/WHO meeting in Rome, including representatives from FDA and CDC,
reviewed and endorsed the risk assessment, finding it to be ``accurate
and valid, based on the approach taken, the assumptions made and the
interpretation of data'' (Ref. 2, p. xvi) (see http://www.who.int/foodsafety/publications/micro/mra10.pdf).
For these reasons, FDA concludes that the FAO/WHO risk assessment
model is sound and an extremely valuable tool for managing the risk
presented by Cronobacter contamination of infant formula in the United
States.
(Comment 132) One comment asserted that there is no ``nominated
dose-response'' used to support the arguments, that a risk model is a
measure of relative rather than actual risk, and that caution is needed
when determining criteria to use to support a standard.
(Response) It is not clear what this comment means by ``nominated
dose-response.'' In the absence of an appropriate animal model, it is
not possible to establish a level of Cronobacter spp. in powdered
infant formula that, when consumed by infants, will result in illness.
It is reasonable, therefore, for FDA to employ a well-considered,
conservative estimate of the probable level of pathogen required to
cause illness.
In the absence of specific dose-response information, the exposure
assessment model used by the FAO/WHO expert group assumed that one
colony-forming unit of Cronobacter spp. per gram (1 CFU/g) powdered
infant formula was capable of causing illness (Ref. 53). In the
application of the model, this level was adjusted to take into account
any growth or decline that may occur due to the conditions of use.
The hazard characterization portion of the 2006 FAO/WHO risk
assessment model was used to evaluate the probability that illness
would result from powdered infant formula contaminated with Cronobacter
spp.; this probability of illness was assessed using an exponential
dose-response model in which an initial contamination level of 1 CFU/g
of Cronobacter spp. was assumed to cause illness (Ref. 53). The risk
assessors explained that this initial level of 1 CFU/g per serving was
``adjusted to take into account any growth or decline that may occur
due to the conditions of preparation, holding and feeding to give an
estimate of the dose ingested'' (Ref. 53). Because there were no data
available at the time of the risk assessment to estimate the value of
the model's dose-response parameter, six options were presented to
represent the baseline dose-response parameter. It was assumed that the
dose-response parameter would likely be specific for each of the infant
groups considered in the model. The risk assessment used a value of 1
for the dose-response multiplier, which enables a direct comparison of
the impact of the assumptions regarding the value of the dose-response
parameter and the relative susceptibility of the infant groups in terms
of the estimates of risk (Ref. 53).
For these reasons, the absence of an empirical dose-response does
not preclude managing the risk presented by Cronobacter ssp. in
powdered infant formula by relying on the FAO/WHO quantitative risk
assessment.
(Comment 133) One comment argued that the risk assessment used an
incorrect premise that healthy newborns should be grouped with
premature infants.
(Response) FDA disagrees with this comment. The risk assessment
appropriately grouped together healthy terms infants and preterm
infants. The report of the 2006 risk assessment explains this approach,
which FDA endorses. Specifically, the expert consultants reviewed the
available outbreak data and noted that the cases could be grouped into
two risk groups in terms of age at which the illness occurred:
``premature infants who developed bacteraemia outside of the neonatal
period, with more, but not all, cases occurring in infants under 2
months; and term infants who develop meningitis during the neonatal
period.'' http://www.who.int/foodsafety/publications/micro/mra10.pdf,
(Ref. 54, p. 14). These experts further observed, however, that the
differences in timing of infection onset may have been related to
differences in timing of exposure to the pathogen rather than to
differences in susceptibility. They concluded that any infant may
develop either syndrome (i.e., bacteraemia or meningitis) at any age
(Ref. 54, p. 14).
FDA agrees with the FAO/WHO expert consultants that the outbreak
data support the observation that both preterm and term infants are at
risk of illness from consuming powdered infant formula contaminated
with Cronobacter spp. and that the impact of illness from this pathogen
is significant for the term infant and the premature infant alike.
Because both premature and term infants are susceptible, at different
times in their lives, to illness from this pathogen and may be fed
powdered formula, it was reasonable and appropriate for the two cohorts
to be grouped together in the risk assessment.
c. Microbiological standards for powdered infant formula for
Cronobacter spp. and Salmonella spp.
In the 2006 reopening, FDA tentatively concluded that it was
appropriate to establish a standard for E. sakazakii (Cronobacter spp.)
of negative in 30 x 10 g samples (71 FR 43392 at 43395). The Agency
suggested no change to the proposed standard for Salmonella spp. of
negative in 60 x 25 g samples.
i. The sampling plan--Cronobacter spp.
(Comment 134) Several comments agreed with the need to establish a
microbiological standard for E. sakazakii (Cronobacter spp.), but did
not suggest a specific standard. Several other comments agreed with FDA
regarding the proposed microbiological standard and the proposed
sampling plan for Cronobacter spp. (negative in 30 x 10 g samples.)
Other comments requested that FDA provide an explanation of the number
and sample sizes required to test finished formula product for
contamination.
(Response) To place in context FDA's tentative decision to
establish a standard of negative in 30 x 10 g samples for Cronobacter,
it is useful to understand the outlines of the risk assessment and risk
management processes both generally and specifically with respect to
Cronobacter contamination of powdered infant formula.
Risk assessment and risk management are two separate, though
related, parts of the process to address a hazard. At the risk
assessment stage, the nature and probability of an adverse event is
calculated. Often, this calculation is an estimate based on a less than
complete set of empirical data. At the risk management stage, the risk
manager determines the tolerable level of risk (or the level of
protection) and the desirable level of confidence that the level of
protection will be achieved.
In the case of Cronobacter contamination of powdered infant
formula, a quantitative risk assessment model was developed as part of
the FAO/WHO expert consultation (Ref. 3).
[[Page 7985]]
This model estimates the risk of Cronobacter illness to infants
consuming powdered infant formula and ``provides the means to evaluate
microbiological criteria and sampling plans in terms of the risk
reductions achieved and the percentage of product [production
aggregates] rejected.'' (Ref. 3, p. xii). All told, the model was used
to project risk reduction and product rejection rates for 162 different
scenarios (Ref. 3, pp. 46-47). Importantly, the FAO/WHO expert group
did not select a specific approach to managing the Cronobacter hazard;
instead, the 2006 Rome Report recommended that each country manage this
risk using the risk assessment model (Ref. 3, p. xiv-xv).
Accordingly, using the information from and applying the FAO/WHO
risk assessment model, FDA subsequently engaged in the risk management
phase of addressing the Cronobacter hazard. Specifically, the Agency
identified both the appropriate level of protection (i.e., the level of
contamination below which we would not expect in a Cronobacter
infection to occur) and the level of desired certainty that such level
of protection would be achieved (i.e., the confidence level). In making
these determinations, FDA sought to balance the risk of illness and the
likely percentage of production aggregates of formula that would be
rejected due to a finding of the presence of Cronobacter spp., and
tentatively determined that a sampling plan of 30 samples of 10 g each
per production aggregate would appropriately manage the risk of
Cronobacter infections from powdered infant formula. According to the
FAO/WHO risk assessment model, the 30 x 10 g sampling plan (that is,
negative for Cronobacter in 30 x 10 g or 300 g total) would result in
approximately 20 percent fewer cases of Cronobacter illness each year
and the rejection of 1.4 percent of production aggregates of powdered
infant formula.
(Comment 135) One comment stated that FDA's regulatory sample size
of 30 x 10 g samples would not provide a high level of assurance that
the lot (production aggregate) was not contaminated because unlike
chemicals which may be uniformly dispersed throughout a powdered
formula, bacteriological contamination is likely to be unevenly
distributed in the final lot (production aggregate). The comment
asserted that because microbiological contamination present in finished
powdered infant formulations produced in inadequately controlled
systems are likely to be uneven and at low levels, sample size would
have to reach excessive levels (at a minimum ten percent of the lot
(production aggregate)) to ensure meaningful results.
(Response) FDA disagrees with this comment. The Agency notes that
the comment did not provide any data to support its assertion that, to
ensure meaningful results, the proposed sample size would have to reach
a minimum of 10 percent of the production aggregate. FDA agrees that
microbiological contamination of powdered infant formula may be
unevenly dispersed in the production aggregate, particularly when there
is low level contamination. However, even where the pathogen is
unevenly dispersed, an appropriately designed and executed sampling
plan can help to address the variability and uncertainty created by
such conditions. In addition to establishing a limit for the pathogens
of concern, microbiological criteria include the testing method
employed, the sampling plan (size and number of samples to be
examined), and the actions to be taken when the microbiological limits
are exceeded (Ref. 54, p. 62).
The sampling plan for Cronobacter spp. is intended to help
manufacturers identify unacceptable production aggregates at the
finished product stage, i.e., those production aggregates not complying
with the established limits, before release for distribution. To
establish an appropriate sampling plan, it is necessary to consider,
for any production aggregate, the likely level of contamination and the
variability within the production aggregate in order to evaluate the
likelihood that a sample will be positive for the pathogen (Ref. 55).
Because there will be variability between and among production
aggregates, the true concentration of the pathogen in a production
aggregate cannot be determined with 100 percent accuracy. Thus, the
average of the concentrations of the pathogen across all production
aggregates and the ``between production aggregate variability'' among
production aggregates is used to determine the percentage of production
aggregates likely to be rejected by a particular sampling plan. This
statistical approach is commonly used to establish microbiological and
chemical contaminant sampling plans for regulatory purposes.
With any sampling plan in which there is variability in the
concentration and dispersion of the contaminant, there is the
likelihood that some ``good'' production aggregates may be rejected by
the sampling plan (false positives) and that some ``bad'' production
aggregates (false negatives) may be deemed acceptable. In a public
health environment, FDA is most concerned about the risk to infants by
the acceptance of false negative (``bad'') production aggregates by the
sampling plan.
As noted previously in this document in response to Comment 134,
the FAO/WHO risk utilized a large body of data on the initial levels of
Cronobacter spp. contamination of infant formula from formula
manufacturers worldwide. Relying on these data, the proposed sampling
plan for Cronobacter spp. of 30 x 10 g samples took into consideration
the low levels of contamination and variability of contamination
between and among production aggregates. The statistical design of the
proposed sampling plan seeks to minimize false positives and false
negatives and to maximize true findings of positive and negative,
within a 95 percent confidence interval. As discussed in the 2006
reopening, based on the FAO/WHO risk assessment, the 30 x 10 g sample
plan is expected to provide a relative annual risk reduction of 20
percent fewer cases (assuming a mean log 10 concentration of
pathogen of -5 CFU/g) and 37 percent (assuming a mean log 10
concentration of -3 CFU/g) of illness from Cronobacter spp. than would
be the case if there were no powdered infant formula sampling plan in
place (71 FR 43392 at 43394-43395). Thus, the greater the contamination
of the powdered infant formula, the greater the sampling can reduce the
risk of illness, because as the level of contamination increases, the
rejection rate of production aggregates increases and the relative risk
reduction increases. If manufacturers focus on ensuring that the
overall mean log concentration of the pathogen is low and that
variation between lots (production aggregates) is controlled, the
potential for rejection of the lot (production aggregate), and the risk
of illness, are both reduced (71 FR 43392 at 43395).
(Comment 136) One comment argued that based on a lack of evidence
linking Cronobacter spp. to outbreaks in term infants, FDA's de facto
standard of zero tolerance for this pathogen in term infants is not
warranted. Another comment contended that because high risk foods
initially free of E. sakazakii (Cronobacter spp.) can become
contaminated and abused by the food preparer resulting in a dangerously
unsafe product, establishing a zero tolerance for the pathogen in high
risk foods will not address the issue.
(Response) FDA notes that the Agency's response to the comment
about term infants is addressed in Comment 121 (section V.J.2.b.i) and
the comment regarding post-processing
[[Page 7986]]
contamination is addressed in Comment 127 (section V.J.2.b.ii).
For two reasons, FDA disagrees with the comment that the standard
for Cronobacter spp. is zero. First, the sampling plan for Cronobacter
spp. proposed in the 2006 reopening and established in this interim
final rule is not zero; rather it is negative in a composite sample of
300 g (30 x 10 g samples) taken from a single production aggregate of
finished product. In other words, the standard is the absence of the
organism in a defined volume of powdered infant formula sampled from
the production aggregate, which is not the same as the absence of the
organism from the entirety of the production aggregate. This means that
when the production aggregate is sampled and the composite is tested,
if the pathogen is not detected, the manufacturer has a 95 percent
level of confidence that there would be <1 CFU Cronobacter spp. in 100
g powder. The statistical validity of the sampling plan, based on an
analysis of industry data, is discussed in detail in response to
Comment 134 in this section. Not finding Cronobacter spp. analytically
does not mean that the pathogen may not be present in the production
aggregate; it could be present but at an extremely low level (<1 CFU/
100 g). When the pathogen is present in the powdered formula, the
sampling plan approach accounts for a widely dispersed and, typically,
low level of contamination. For manufacturers who adhere to strict food
safety controls during processing, the standard will have little impact
on the number of production aggregates that would be rejected because
of a positive finding for the organism.
Second, the limit of detection of FDA's Cronobacter spp. analytical
method in the Agency's Bacteriological Analytical Manual (BAM) is 1
CFU/100 g (Ref. 56). This means that the lowest level of the pathogen
that can be detected is 1 CFU; not zero.
For these reasons, FDA disagrees that the standard in Sec.
106.55(e) of the interim final rule for Cronobacter spp. is a zero
tolerance.
(Comment 137) One comment stated that it has been well documented
in the literature that using small sample sizes of finished product
will provide no assurance of product safety. The comment contended
that, in the case of infant formula, to achieve ninety-nine percent
assurance that the finished product does not contain a pathogen (e.g.,
Salmonella spp., Listeria monocytogenes) that is subject to a ``zero''
tolerance level, the manufacturer would have to randomly select
hundreds of sample throughout the production aggregate, which would
require significant financial resources.
(Response) FDA notes that in the 2006 reopening, the Agency
tentatively decided to eliminate the proposed standard for Listeria
monocytogenes (71 FR 43392 at 43396), and this interim final rule
affirms that tentative decision. Thus, this response addresses the
comment only to the extent that it concerns Salmonella spp.
The Agency disagrees that the proposed standard for Salmonella is
zero tolerance for reasons that parallel those presented in response to
comments regarding the standard for Cronobacter spp (see the response
to Comment 135). In general, the sampling plan for Salmonella is based
on the category of food in which it may be present. FDA's BAM describes
three categories of foods (http://www.fda.gov/Food/ScienceResearch/LaboratoryMethods/BacteriologicalAnalyticalManualBAM/default.htm). Of
these, Category I Foods (defined as ``foods that would not normally be
subjected to a process lethal to Salmonella between the time of
sampling and consumption and are intended for consumption by the aged,
the infirm, and infants'') includes powdered infant formula. The
current standard for Category I foods is negative in 60 x 25 g samples
(i.e., a total composite sample of 1500 g). When FDA tests a sample for
the presence of Salmonella following the BAM method, four 375 g
subsamples are removed from the 1500 g composite and tested for the
pathogen as specified in the method. If no Salmonella are detected
using the 60 X 25 g sampling, there is a 95 percent level of confidence
that the pathogen, if present in the production aggregate, is < 1 CFU/
500g of product. This sampling plan has been validated statistically
and has been used to analyze many foods similar to powdered infant
formula where the pathogen of interest is likely to be widely dispersed
and at low concentration. This same sampling plan would provide the
same level of confidence when used by a formula manufacturer to test
final production aggregates. A finding of no Salmonella spp. in a 60 X
25 g composite of the manufacturer's powdered infant formula
demonstrates, with 95 percent confidence, that the pathogen is present
in the production aggregate at <1 CFU/500 g of product.
FDA notes that manufacturers may choose to do more intensive
testing, such as testing using larger sample sizes or more samples, to
enhance the confidence of the testing results. Further, the BAM
analytical method for Salmonella has a limit of detection of 1 CFU/25 g
and, for some products, 1 CFU/375 g; it cannot establish a total
absence of the pathogen (``zero'').
Based on the foregoing comments, Sec. 106.55(b) of the interim
final rule requires that manufacturers test representative samples of
each production aggregate of powdered infant formula at the final
product stage, before distribution, to ensure that each production
aggregate meets the microbiological quality standard of negative in 30
x 10 g samples for Cronobacter spp. and negative in 60 x 25 g samples
for Salmonella spp.
(Comment 138) One comment suggested that the level of 0.36 CFU/100
g should be considered safe for the term infant population, a level
that the comment characterized as the limit of detection.
(Response) FDA notes that the limit of detection of the analytical
method the Agency uses to detect the presence of Cronobacter spp. is 1
CFU/100 g of powdered infant formula. The Agency will consider an
infant formula to be adulterated under sections 402(a)(1), 402(a)(4),
and 412(a)(3) of the FD&C Act if the pathogen is detected at this level
or higher using the analytical method required by this interim final
rule for determining compliance with the M value in Sec. 106.55(e).
For the following reasons, FDA declines to adopt the suggestion of
this comment. First, this comment predates FDA's announcement of its
tentative decision in the 2006 reopening to establish a microbiological
standard for Cronobacter spp. of negative (i.e., no organisms) in 30 X
10 g. As discussed previously in this document, this standard should
protect both premature and term infants. Although it proposes a
slightly different standard, the comment does not directly challenge
the interim final rule's standard of 30 X 10 g. Second, on a 100 g
basis, FDA's final microbiological standard for Cronobacter spp.
(negative in 30 X 10 g) is slightly higher than the standard suggested
in this comment (0.36/100 g). FDA has determined that a standard of 30
X 10 g is adequate to protect all infants.
ii. Other issues regarding the sampling plan.
(Comment 139) Several comments asked for clarification about
whether the ``30 x 10 g'' refers only to the sampling plan, and that
the testing required would consist of one test of a composited sample.
(Response) FDA is clarifying that the 30 individual samples of 10 g
each are to be combined, for purposes of testing, into one 300 g sample
composite. FDA emphasizes that that when sampling, a
[[Page 7987]]
manufacturers must collect 30 individual samples of 10 g each randomly
from each production aggregate of finished product and may not take a
single sample of 300 g because a single sample consisting of 300 g
would not be considered representative of the production aggregate.
(Comment 140) One comment stated that while sampling large batches
of product can be problematic, and product sterility cannot be
absolutely assured, all powdered formula should be E. sakazakii
(Cronobacter spp.) free.
(Response) FDA believes that this comment does not fully understand
the standard proposed for Cronobacter spp. The standard that FDA
proposed in the 2006 reopening is negative for Cronobacter in 300 g (30
x 10 g samples) of composited formula. This means that there must be
less than one CFU in the 300 g sample. Said differently, a sample will
be considered positive (and the production aggregate of infant formula
will be considered adulterated) if one or more CFUs of Cronobacter are
found in the 300 g sample.
The Agency agrees that, based on current technologies, it is not
possible to produce a sterile powdered infant formula. For this reason,
the interim final rule does not establish a zero tolerance for
Cronobacter spp. However, by sampling and testing final production
aggregates, as required in this interim final rule, product
contamination with this pathogen will be minimized and public health
protection maximized.
(Comment 141) One comment stated that the sampling plan proposed in
the 2006 reopening is designed for use on large batches in continuous
process manufacturing, that, in contrast, exempt infant formulas are
often produced in small distinct batches, and that select sampling and
testing programs that are relevant to exempt infant formulas to ensure
the safety of the finished exempt formulas are preferable.
(Response) FDA notes that the requirements in this interim final
rule, including the microbiological testing and sampling requirements,
do not govern the manufacturing of exempt infant formulas. Elsewhere in
this issue of the Federal Register, FDA is publishing a notice of
availability of a draft guidance that addresses recommendations
concerning how these CGMP should be applied to the exempt infant
formulas.
d. A microbiological standard for Cronobacter spp. for powdered
infant formula consumed by premature and newborn infants.
Some of the following comments were addressed in the 2006 reopening
(71 FR 43392 at 43394).
(Comment 142) Some comments urged FDA to adopt the same standard
for formulas intended for term infants and formulas intended for
premature infants because a risk of E. sakazakii (Cronobacter spp.)
infection exists in both populations.
(Response) FDA agrees with the comments that, with respect to non-
exempt infant formula, consumption of powdered infant formula by
infants of any age poses a risk of illness from Cronobacter spp. and
therefore, all such formula should be subject to the same
microbiological standards.
(Comment 143) Some comments addressed the need for a
microbiological standard for exempt infant formulas, as defined in
Sec. 107.3, and asserted that, due to FDA's statutory authority under
section 412(h)(2) of the FD&C Act to establish terms and conditions for
the exemption of formulas intended for infants who are low birth weight
or who have unusual medical problems, any effort to establish stricter
microbiological requirements for these formulas should be done with a
separate notice and comment rulemaking.
(Response) FDA notes that exempt infant formulas are not required
to comply with this interim final rule. The Agency further notes that
many exempt formulas are liquids and are already required to comply
with part 113 because they are thermally processed low-acid foods
packaged in hermetically sealed containers or part 114 because they are
acidified foods. As such, these liquid formulas are commercially
sterile products. However, there are a few exempt infant formulas that
are powdered products, such as those for inborn errors of metabolism,
which are not sterile. Because the risk of contaminated powder exists
with these products, elsewhere in this issue of the Federal Register,
FDA is publishing a notice of availability of a draft guidance that
addresses recommendations concerning how these CGMP should be applied
to the exempt infant formulas.
(Comment 144) One comment stated that there is no need to establish
a more stringent standard for formula intended for premature or newborn
infants as it would be impractical to differentiate between formulas as
many of them are consumed by both full term and premature infants.
Another comment recommended that the standards regarding powdered
formula be the same for premature and term infants. The comment
contended that the absolute risk of serious illness, even to term
infants, is not zero. The comment also asserted that powdered formula
products should not be consumed by premature infants before 44 weeks
gestational age, or by any immunocompromised child, and that, with few
exceptions (amino acid and metabolic formulas), ``commercially''
sterile liquid products are available for these populations. The
comment noted, however, that it is not possible to eliminate completely
powdered human milk fortifiers fed to premature infants, because many
premature infants are unable to tolerate the added volume of liquid
fortifier.
(Response) To the extent that the comment is referring to non-
exempt infant formulas, FDA agrees that, as a practical matter, it
would be difficult to limit formula consumption by certain infant
subgroups to a specific type of formula unless the infants are directly
under medical supervision because powdered infant formula intended for
newborns and term infants may also be fed to premature infants. Thus,
it is essential that non-exempt powdered formulas, whether fed to
newborns, term infants, or premature infants, meet the same
microbiological standards. As noted, the data clearly implicate
powdered infant formula, a potential source of contamination from
Cronobacter spp. and Salmonella spp. for all infant groups (see
discussions in section V.J.2.b). The standard established by this
interim final rule will be protective of infants consuming non-exempt
infant formulas, regardless of gestational age.
The Agency notes, however, that infant formulas, including human
milk fortifiers, that are represented and labeled as being for infants
with inborn errors of metabolism, low birth weight, or infants with
other unusual medical or dietary problems are exempt infant formulas
and, as such, are not subject to the CGMP in this interim final rule.
Although many of the exempt infant formulas are commercially sterile
liquids, some are, as noted in the comment, powdered formulas and are
not commercially sterile. As noted, elsewhere in this issue of the
Federal Register, FDA is publishing a notice of availability of a draft
guidance that addresses how these CGMP should be applied to exempt
infant formulas.
(Comment 145) Some comments contended there should be a heightened
standard for formulas intended for certain sub-populations of infants,
including infants who are premature, of low birth weight, ill, or among
a group described as vulnerable hospitalized infants. Several of these
comments argued that there should either be no
[[Page 7988]]
standard or a lower standard for formulas intended for other infants.
(Response) To the extent that this comment is referring to
standards for exempt infant formulas (i.e., formulas represented and
labeled for use by infants who have an inborn error of metabolism, low
birth weight, or unusual medical or dietary problems), such products
are not, as noted previously in this document, subject to the
requirements of these CGMP FDA is publishing a notice of availability
of a draft guidance that addresses how to apply these CGMP, including
microbial testing standards, to such formulas. FDA notes that it is
possible that a number of subgroups of infants, including those term
infants who are ill or hospitalized, may be fed a non-exempt infant
formula, and that the microbiological standards in this interim final
rule are sufficiently protective of such subgroups of infants.
FDA disagrees with the comment that suggested no standard or a
lower standard for formulas intended for ``other infants,'' to the
extent that ``other infants'' refers to ``term infants,'' for the
reasons discussed in section V.J.2.b.i.
(Comment 146) One comment asserted that formulas for premature
infants or infants with gastrointestinal medical conditions should
receive specific and elevated testing. The comment argued that although
microbiological testing by formula manufacturers has generally been
sufficient for such infant populations in the past, there have been
changes in the infant population consuming powdered formula. In
particular, the comment claimed that premature infants are now viable
at ``micro weights'' and extreme prematurity of less than 23 weeks
gestation; these infants are more susceptible to microbial infection.
The comment asserted that a more rigorous standard may be needed for
powdered products designed for feeding low birth weight infants or some
vulnerable hospitalized infants, although even in these cases,
mishandling of formula during reconstitution, feeding, and storage may
increase the risk of disease.
(Response) FDA notes that this comment preceded the 2006 reopening
and the Agency's tentative determination to establish a standard for
Cronobacter spp. in powdered infant formula. Thus, the comment was not
directly challenging the adequacy of the microbiological standards
proposed at that time.
The Agency acknowledges the comment's concerns about the safety of
formula fed to very low weight premature infants but, as explained in
Comment 143, the formulas that are subject to this rulemaking are the
non-exempt infant formulas (i.e., formulas that are not represented and
labeled for infants that have an inborn error of metabolism, low birth
weight, or other unusual medical or dietary problem.) FDA is aware that
some premature infants may be fed the same powdered infant formulas
that are consumed by term infants and thus, are vulnerable to infection
from Cronobacter spp. and Salmonella spp., if these organisms are
present in the formula. The microbiological standards established in
Sec. 106.55(e) of the interim final rule for non-exempt infant
formulas are designed to provide and will provide adequate protection
for both premature and term infants who consume them. To the extent
that this comment concerns exempt infant formulas, FDA notes that such
powdered exempt formulas are not subject to the standards of this
interim final rule. While it may be appropriate at some future date to
propose a separate standard for some or all exempt infant formulas, the
Agency declines to do so at this time. As noted, the agency is
concurrently issuing draft guidance on how the CGMPs should apply to
exempt infant formulas.
FDA has carefully considered all of the comments that support two
standards for non-exempt infant formulas--one standard for formula
intended for premature and newborn infants and one for formula intended
for infants beyond the newborn period and finds that it is neither
necessary nor feasible to establish a more stringent Cronobacter spp.
standard or a more stringent Salmonella spp. standard for non-exempt
powdered infant formula consumed by premature and newborn infants. For
the reasons cited previously in this document, FDA concludes that the
standards established in Sec. 106.55(e) of the interim final rule for
Cronobacter spp. and for Salmonella spp. apply to all non-exempt
powdered formulas intended for infants from birth to 12 months of age
and that both such standards are sufficiently protective of such
infants.
(Comment 147) A few comments asserted that formulas for premature
infants or infants with gastrointestinal medical conditions should be
labeled to inform families and practitioners that the product is not
sterile. One comment added that the label should state that the product
should not be given to immunocompromised babies.
(Response) Comments regarding the labeling of formula for premature
or immunocompromised infants are beyond the scope of this interim final
rule. Importantly, however, FDA notes that a variety of educational and
other outreach programs have been established to communicate the proper
use, preparation, and handling of powdered infant formula, including
outreach by the AAP and ADA to their members.
e. Elimination of microbiological standards for Aerobic Plate
Count, Coliforms, Fecal Coliforms, Listeria monocytogenes,
Staphylococcus aureus, and Bacillus cereus.
In the original 1996 proposal, FDA proposed to establish seven
microbiological quality standards for powdered infant formula: APC,
coliforms, fecal coliforms, Listeria monocytogenes, Staphylococcus
aureus, Bacillus cereus, and Salmonella spp. At the time of the
proposal, the microorganisms for which FDA proposed standards were
those of known public health significance or were viewed as indicators
that a formula was prepared, packed, or held under insanitary
conditions (62 FR 36154 at 36170).
Subsequently, in the 2003 reopening, the Agency requested comment
on the need for a standard for Cronobacter spp., an emerging pathogen
associated with severe illness in certain formula-fed infants.
Thereafter, in the 2006 reopening, FDA announced the Agency's tentative
conclusion not to finalize the microbiological testing regime proposed
in 1996 and to limit required final product testing of powdered infant
formula to only two microorganisms, Cronobacter spp. and Salmonella
spp. Based on the available evidence, including the 2004 and 2006 FAO/
WHO expert consultations, the Agency tentatively concluded that only
Cronobacter spp. and Salmonella spp. had been associated with infant
illness related to microbiological contamination of powdered infant
formula (Ref. 2). In the 2006 reopening, FDA also explained that
testing for an indicator organism, such as Enterobacteriaceae, can be
beneficial to manufacturers in monitoring their overall process and
production sanitation (71 FR 43392 at 43396) but the Agency's tentative
decision was not to require such testing.
Several comments supported the Agency's tentative determination to
establish microbiological standards only for Cronobacter spp. and
Salmonella spp. in finished powdered infant formula product. One
comment noted that Listeria monocytogenes and Staphylococcus aureus
have not been problems for the U.S. formula industry. In addition,
several comments made in response to the 1996 proposal challenged the
proposed requirement to test each batch (production aggregate) of
[[Page 7989]]
powdered infant formula at the final product stage for the
microorganisms listed in proposed Sec. 106.55(c) and thus, indirectly
supported FDA's tentative determination not to finalize certain of the
proposed standards. Other comments objected to FDA's tentative plans to
revise proposed Sec. 106.55.
(Comment 148) One comment questioned FDA's tentative conclusion in
the 2006 reopening that only E. sakazakii (Cronobacter spp.) and
Salmonella spp. are of concern in infant formula.
(Response) FDA is confirming its tentative decision announced in
the September 2006 reopening not to finalize the proposed
microbiological standards for APC, coliforms, fecal coliforms, Listeria
monocytogenes, Staphylococcus aureus, and Bacillus cereus. FDA notes
that this comment provided no data or other information to contradict
the Agency's tentative conclusion that protection of the public health
does not require establishing microbiological standards and testing for
organisms other than Cronobacter spp. and Salmonella spp. The basis for
the decision not to finalize all of the proposed requirements is
discussed in detail in this document.
Aerobic Plate Count, Coliforms, and Fecal Coliforms: The 1996
proposed rule would have required infant formula manufacturers to
conduct tests for APC, coliforms, and fecal coliforms. In the proposal,
FDA noted that these three microbiological standards had a specific
purpose: an M value exceeding the proposed standard would imply that
the formula was produced under insanitary conditions whereby the
formula may have been rendered injurious to health and thus, the
formula could be adulterated under section 402(a)(4) of the FD&C Act.
(Such use of microbiological testing is often referred to as
``indicator organism'' testing.) The Agency acknowledged that all three
tests were capable of identifying both pathogenic and non-pathogenic
microorganisms, and the proposal did not specifically identify any
evidence that pathogenic organisms that would be identified by these
three tests had previously been linked to formula-borne illness in
infants.
FDA has concluded that, on balance, it is not necessary or
appropriate to finalize standards for APC, coliforms, and fecal
coliforms because in the context of the complete interim final rule,
including the required microbiological testing scheme, these tests are
not essential and the proper interpretation of the results of such
testing is not at all clear.
As discussed in section V.C. 2, Sec. 106.6 of the interim final
rule requires a manufacturer to implement a system of production and
in-process controls designed to prevent adulteration, including
adulteration due to insanitary conditions. The decision to conduct
``indicator organism'' testing (such as APC and testing for coliforms
and fecal coliforms) is best made on a facility-by-facility basis and
in the context of a manufacturer's entire production and in-process
control system. Thus, to the extent that a particular manufacturing
process requires or would otherwise benefit from the application of
indicator organism testing, such as APC or testing for coliforms or
fecal coliforms, as a means to control adulteration from insanitary
conditions, the manufacturer's plan may, and should, include such
testing. Accordingly, FDA declines to finalize standards for APC,
coliforms, and fecal coliforms that would apply to all manufacturers
regardless of the process control systems. Not finalizing the
requirements for APC and coliforms and fecal coliforms testing will not
increase the risk of illness to infants. As noted, the three tests do
not distinguish between pathogenic and non-pathogenic microorganisms so
they cannot be used to identify organisms that theoretically could
contaminate powdered infant formula with pathogens.
Moreover, as discussed in detail previously in this document, the
interim final rule mandates that each production aggregate of finished
infant formula be analyzed for the two pathogenic organisms that have a
documented association with powdered infant formula, Cronobacter spp.
and Salmonella spp. Thus, the interim final rule requires specific
controls to prevent the direct microbiological contamination of formula
with these pathogens. Although a variety of Enterobacteriaceae have
been isolated from powdered infant formula, including Citrobacter
koseri, Klebsiella pneumoniae, Klebsiella oxytoca, Pantoea agglomerans,
and Enterobacter cloacae, and are capable of causing illness, none have
been demonstrated to have done so (Ref. 2). In contrast, Salmonella
enterica (Ref. 57), Salmonella virchow (Ref. 58), and Cronobacter spp.
are associated with illness in infants (Refs. 24, 34, 59). Also, to the
extent that testing for Cronobacter spp. or Salmonella spp. documents
contamination of a production aggregate of finished formula, as
discussed in this document, other provisions of the interim final rule
require controls to prevent microbial contamination that would
adulterate the infant formula.
Section 106.6(c) of the interim final rule requires that a
manufacturer establish specifications at any point, step, or stage in
the production process where control is necessary to prevent
adulteration. Therefore, a manufacturer that determines that a
specification for indicator organism testing results is a necessary as
part of its system of production and in-process controls in order to
prevent adulteration is required to establish such a specification. If
a manufacturer's testing of its facility documents levels of APC,
coliforms, or fecal coliforms under circumstances that establish the
presence of insanitary conditions in the facility that would adulterate
the infant formula, and the manufacturer has either not included
indicator organism testing in its plan under Sec. 106.6(a) of the
interim final rule or has not established specifications for such
indicator organisms, the presence of such organisms at such levels and
the absence of established specifications for such organisms would be a
violation of Sec. 106.55(a) of the interim final rule.
Moreover, the interim final rule requires investigation and
evaluation of the circumstances that result in a failure to meet
specifications, including the microbiological standards of the interim
final rule. Specifically, Sec. 106.70(b) of the interim final rule
requires quarantine of the contaminated formula and a documented review
and a material disposition decision for the formula. Similarly, Sec.
106.100(e)(4)(iii) of the interim final rule requires a manufacturer to
maintain a record of the investigation and follow-up of such failure.
FDA expects that part of a manufacturer's investigation and follow-up
to a finding of actual contamination of formula will be the evaluation
of the manufacturing environment to determine whether insanitary
conditions may have contributed to the microbiological contamination of
the production aggregate and the identification and implementation of
appropriate corrective actions.
For these reasons, FDA declines to finalize the proposed
requirements for APC and for coliforms and fecal coliforms testing in
proposed Sec. 106.55(c).
Listeria monocytogenes, Staphylococcus aureus, and Bacillus cereus:
Proposed Sec. 106.55(c) would have required infant formula
manufacturers to conduct tests of finished powdered infant formula for
Listeria monocytogenes, Staphylococcus aureus, and Bacillus cereus. In
the proposal, FDA noted that ``health concerns may arise due to the
presence of any
[[Page 7990]]
detectable . . . Listeria or S. aureus bacteria in infant formula or
due to levels of B. cereus that exceed 1,000 `colony-forming units'
(CFU's) per gram (g) of a powdered formula.'' (61 FR at 36170). In
making this statement, the Agency did not cite specific data or other
information documenting the contamination of powdered infant formula
with any of these microorganisms.
More recently, in the 2006 reopening, FDA tentatively concluded,
based on the data developed during the FAO/WHO expert consultations,
that testing for these three organisms was not warranted to ensure
microbiological safety of powdered infant formula (Ref. 3). The report
of the 2004 FAO/WHO expert consultation sorted the microorganisms of
possible concern in infant formula into three categories; Listeria
monocytogenes, Staphylococcus aureus, and Bacillus cereus were placed
in the category ``causality less plausible or not yet demonstrated''
because the organisms had not been identified in powdered formula
(Listeria monocytogenes, Staphylococcus aureus) or because no causal
association between the organism and illness from powdered formula had
been demonstrated (Bacillus cereus) (Ref. 2). The report of the 2006
expert consultation affirmed this categorization (Ref. 3). Moreover,
FDA is not aware of any data or other information showing that these
organisms are present in powdered infant formula or, if present, have
been associated with infant illness.
Several comments supported FDA's tentative determination to not
finalize the microbiological standards for Listeria monocytogenes,
Staphylococcus aureus, and Bacillus cereus, with one comment noting
that Listeria monocytogenes and Staphylococcus aureus, have not been
problems for the U.S. formula industry. However, as noted, one comment
objected to FDA's proposal to delete microbiological standards for
Listeria monocytogenes, Staphylococcus aureus, and Bacillus cereus
although no data were submitted to support this objection.
(Comment 149) Several 1996 comments argued that testing for
Listeria monocytogenes was unnecessary because this organism does not
pose a significant health concern in infant formula.
(Response) FDA agrees with this comment and, as noted, is not
finalizing the proposed Listeria monocytogenes microbiological standard
for powdered infant formula. The Agency's decision on this point is
supported by the conclusions of the recent FAO/WHO expert consultation.
(Comment 150) One 1996 comment requested that FDA change the M
value for Bacillus cereus to 1,000 most probable number/g (MPN/g)
because there is no health concern associated with the proposed level
of 100 MPN/g.
(Response) FDA is not finalizing the proposed microbiological
standard for Bacillus cereus in powdered infant formula. As noted, the
recent FAO/WHO expert consultation concluded that there is no
documented association between Bacillus cereus and illness from
consumption of powdered infant formula, a conclusion with which the
Agency agrees. Thus, the suggestion that the M value for Bacillus
cereus be revised is moot.
(Comment 151) One comment requested that FDA replace the standards
for coliforms and fecal coliforms with one for E. coli due to the
possibility of improper interpretation of coliform and fecal coliform
tests.
(Response) As noted, FDA is not finalizing the proposed
microbiological standard for coliforms and fecal coliforms in powdered
infant formula because the Agency has determined that the decision to
use certain organisms as indicators of insanitary conditions, including
coliforms and fecal coliforms, should be made on a case-by-case basis
by each manufacturer in the context of the manufacturer's overall plan
to control adulteration and baseline data developed for the facility.
Thus, the suggestion that a test for E. coli be substituted for the
coliforms and fecal coliforms testing is moot.
(Comment 152) One comment recommended an Enterobacteriaceae
standard of 3.0 MPN/g as a substitute for coliforms.
(Response) FDA notes that the comment did not provide the reasoning
to support the use of this standard. The Agency is not finalizing the
proposed microbiological standard for coliforms in powdered infant
formula. Thus, the suggestion that a standard for Enterobacteriaceae of
3.0 MPN be substituted for the coliforms standard is moot.
(Comment 153) Several comments expressed concern about the Agency's
interpretation of ``unhygienic conditions'' and adulteration with
respect to a positive finding for a microorganism other than
Cronobacter spp. and Salmonella spp. The comments asserted that
language in the 2006 reopening (71 FR 43392 at 43397) advised that the
presence of any level of the identified organism would be sufficient to
conclude that a formula is adulterated. Thus, one comment suggested
that ``unhygienic conditions'' be defined through guidance criteria.
Another comment asserted that, in the absence of any standard for these
other microorganisms, FDA was establishing a zero tolerance for these
microorganisms and that elimination of all organisms is not be feasible
at this time.
(Response) FDA is restating its views on microbiological test
results and conclusions about insanitary conditions that lead to
adulteration of food.
As noted in the comment, in the 2006 reopening, FDA stated that
``the presence of these microorganisms in an infant formula reflects
that the formula was prepared, packed, or held under insanitary
conditions whereby it may have been rendered injurious to health and
therefore is adulterated under section 402(a)(4) of the FD&C Act.''
This statement appears to suggest that the violation of one of the
proposed microbiological standards (i.e., APC, coliform, fecal coliform
test, Listeria monocytogenes, Staphylococcus aureus, Bacillus cereus,
or Enterobacteriaceae) would categorically establish adulteration under
section 402(a)(4) of the FD&C Act.
In fact, FDA generally considers any microbiological test results
as well as any other CGMP observations when considering whether a food
has been processed under insanitary conditions. Moreover, as noted in
the 2006 reopening, the tests for several of these organisms (APC,
coliforms, fecal coliforms, and Enterobacteriaceae) do not distinguish
between pathogenic and non-pathogenic organisms (71 FR 43392 at 43396)
so it is difficult to interpret the meaning of any positive results in
the absence of baseline data, either for the infant formula industry
generally or specific to individual infant formula production
facilities. Accordingly, FDA has no current plans to define
``unhygienic conditions'' in an Agency guidance document.
Finally, for reasons comparable to those stated in the response to
Comment 121, FDA does not agree that the Agency is setting a zero
tolerance for any microorganism either in infant formula or in the
formula processing environment. Accordingly, FDA has no current plans
to define ``unhygienic conditions'' in an Agency guidance document.
(Comment 154) One comment suggested that FDA not repeat the
statement regarding adulteration as written in the 2006 reopening (71
FR 43392 at 43397), which referred to adulteration in the context of
finding any of the other pathogens present, and suggested the following
statement ``the presence of certain food borne pathogens in an infant
formula at levels (concentrations) known to be of public
[[Page 7991]]
health significance establishes that the formula may have been
prepared, packed or held under insanitary conditions whereby it may
have been rendered injurious to health and therefore is adulterated.''
(Response) In responding to Comment 148, FDA has clarified its
views on the significance of the presence of microorganisms other than
Cronobacter spp. and Salmonella spp. in powdered infant formula and the
infant formula processing environment and adulteration under section
402(a)(4) of the FD&C Act. Accordingly, it is unnecessary to adopt the
statement suggested in the comment and FDA declines to do so.
f. Comments on testing methodology.
(Comment 155) One comment expressed concern with the provision in
proposed Sec. 106.55(c) that states that the Agency will determine
compliance based on the methods cited in the Bacteriological Analytical
Manual. The comment stated that a comparison of the BAM and a method
used by the USDA for the determination of Listeria monocytogenes
concluded that neither method provided a greater detection of
efficiency for isolating Listeria monocytogenes from all types of
foods. However, the comment recommended that FDA consider the use of
other official, recognized methods, such as the USDA method, to reduce
the testing time and consequent costs without detriment to compliance.
(Response) As discussed previously in this document, FDA has
determined that the interim final rule need not contain a
microbiological standard for Listeria monocytogenes in final product
powdered infant formula. Thus, this comment no longer requires a
response.
(Comment 156) One comment pointed out that AOAC International
Association of Official Analytical Chemists should be changed to AOAC
International, in proposed Sec. 106.55(c).
(Response) Section 106.55 of the interim final rule does not refer
to the AOAC and thus, there is no need to update the organization's
name as requested.
g. Microbiological standard to ensure the safety of powdered infant
formula if microorganisms are intentionally added to the formula.
(Comment 157) Several comments discussed the effect of
intentionally added microorganisms (``probiotics'') on the testing for
compliance with microbiological standards. One comment asserted that it
is not clear that the addition of beneficial organisms would have any
negative impact on the proposed microbiological requirements and that
while it is possible that some infant formulas supplemented with
probiotics might exceed the APC, others, such as those containing
anaerobic bacteria, would not. Thus, the comment suggested that FDA
exempt formulas containing these organisms from the APC limit as long
as the manufacturer employed sanitation indicative testing, such as
testing for Enterobacteriaceae. Other comments suggested that for these
probiotic-containing formulas, FDA require automatic testing for
organisms such as B. cereus that is usually only required when the
formula exceeds the APC. One comment claimed that this additional
testing would be similar to the currently recommended evaluation of
cultured dairy products. Another comment requested that any final
regulation acknowledge that probiotic formulas would require exemption
for APC limits or any other proposed criteria for assessing insanitary
conditions. One comment suggested that, to ensure that a high APC is
caused by the added probiotic organism and not by contamination of the
formula, there would need to be a two-stage testing procedure: Prior to
addition of the probiotic organism, the bulk product would have to be
sampled and the APC measured, and then selective microbiological test
regimes would have to be carried out on final packaged product.
(Response) In the 2006 reopening, FDA stated it was not aware of
any marketed infant formula in the United States that contained
intentionally added microorganisms and tentatively decided not to
consider requirements related to such formula (71 FR 43392 at 43396).
Since that time, powdered infant formulas containing intentionally
added microorganisms have entered the U.S. market.
As discussed earlier in this section, FDA has decided not to
finalize the requirement for an APC count in proposed Sec. 106.55(c).
Under Sec. 106.55(a) of the interim final rule, a manufacturer of a
formula to which microorganisms have been intentionally added must
ensure that the formula does not become adulterated due to the presence
of microorganisms or in the processing environment. In addition, as
discussed previously in this document, under Sec. 106.6(c) of the
interim final rule, a manufacturer must establish specifications where
control is necessary to prevent adulteration, including a specification
for intentionally added microorganisms. Thus, a manufacturer would need
to evaluate the potential for any intentionally added organisms to
interfere with the ability to detect Cronobacter spp. and Salmonella
spp., and should have data to demonstrate the absence of such
interference in order to establish that the formula meets the
microbiological standards in Sec. 106.55 of the interim final rule.
Moreover, manufacturers would have to ensure that the presence of
microorganisms is due to the intentional addition of such
microorganisms, based on the master manufacturing order, and not to
contamination.
(Comment 158) One comment stated that manufacturers should do
specific culturing and identification of the intentionally added
bacteria, not just plate counts.
(Response) Although FDA is not finalizing the requirements for APC
testing, FDA emphasizes that a manufacturer needs to know the identity
and quantity of any microorganism that it is adding to a formula. FDA
agrees that any microorganism intentionally added to an infant formula
should be identified by genus, species, and strain through testing of
the final production aggregate to confirm that the organism present is
the organism added and is present in the intended amounts. For example,
if Bifidobacterium lactis strain Bb12 is added during production,
testing must demonstrate that the final production aggregate contains
the microorganism in the intended amount.
(Comment 159) One comment stated that testing would need to be
specific for the type of organism added and requested that ``any final
regulation acknowledge that validated methods for testing probiotic
formulas will need to be decided between the manufacturer and FDA as
part of the pre-market review process.''
(Response) As stated in the response to Comment 158, FDA agrees
that testing needs to be specific to the type of microorganism
intentionally added to a formula. In subpart C (see section VI.A.1 of
this preamble), FDA addresses the use of ``validated'' test methods for
nutrient testing. It is appropriate to apply a similar construct to the
use of microbiological test methods used to confirm the identity and
amount of intentionally added microorganisms. A manufacturer may use
any method that is accurate, precise, and specific for its intended
purpose, and thus, methods for intentionally added microorganisms
should not be restricted to FDA official BAM methods or other methods
formally validated in a multi-laboratory collaborative study.
(Comment 160) One comment suggested that because sampling and
testing for microbiological endpoints continue to lead to variability,
and thus
[[Page 7992]]
uncertainty of results, FDA should define sampling and testing methods
in association with establishing microbiological specifications as
proposed by International Commission on Microbiological Specifications
for Foods (ICMFS), and recognized by Codex, as an option.
(Response) FDA disagrees with this comment. First, the comment did
not explain how testing for microbiological endpoints would continue to
lead to variability and uncertainty of results. Second, the Agency does
expect that a manufacturer's sampling plan for an intentionally added
microorganism will have an appropriate statistical basis and will take
into account any variability in distribution of the microorganism in
the production aggregate. FDA has no objection to the use by a
manufacturer of a testing method proposed by ICMFS for intentionally
added microorganisms as long as the method is valid, that is, the
methods are scientifically sound, accurate, precise, and specific for
its intended use. Accordingly, FDA is not defining in this interim
final rule the specific sampling and analytical method(s) that should
be used for intentionally added microorganisms. Intentionally added
microorganisms have to meet the specifications set by manufacturers for
such ingredients, as would any ingredient added to an infant formula.
As discussed earlier in this preamble, manufacturers must characterize
the formula that they intend to produce, institute adequate controls to
produce that formula, and ensure that the controls work so that the
desired formula is consistently produced and is not adulterated.
(Comment 161) Several comments questioned the safety of
intentionally added microorganisms. One comment expressed concern
particularly with the use of these substances in formula intended for
preterm infants with underdeveloped gastrointestinal barriers. Another
comment suggested the need for a large clinical trial on both term and
preterm infants to uncover unwanted side effects. One comment expressed
opposition to the addition of Bifidobacterium and Streptococcus
intended for use in infant formulas for infants over the age of four
months because of concern about the GRAS status of these
microorganisms, the risk-benefits, and the unknown biological effects
of these organisms on the microflora in the infants' intestines. This
comment also expressed concern regarding the unknown effects of
manipulation of the infants' intestines and how these organisms might
affect the infants' developmental processes. The comment further stated
that although there have been reported beneficial effects of these
microorganisms, the mechanisms of these effects are not known nor have
long-term adverse effects been entirely excluded. The comment also
stated that there is a risk that infants not in the intended use group
would receive this formula as there is presently no formula on the
market that is only intended for infants over four months of age.
(Response) Comments relating to the safety of microorganisms added
to infant formula are beyond the scope of this rule. As discussed
previously in this document, the safety of ingredients of all
substances added to food, including microorganisms intentionally added
to infant formula, is governed by sections 409 and 201(s) of the FD&C
Act, and FDA expects that a formula manufacturer will ensure that the
safety of any formula ingredient is appropriately established prior to
using the ingredient in a formula product. FDA emphasizes that it is
the manufacturer's responsibility to ensure the safety of the all food
ingredients, including microorganisms added to infant formula.
K. Controls To Prevent Adulteration During Packaging and Labeling
(Proposed Sec. 106.60)
In 1996, FDA proposed in Sec. 106.60 to require that an infant
formula manufacturer implement specific controls designed to prevent
adulteration during the packaging and labeling of infant formula. The
proposed provisions included requirements for the examination of
packaged and labeled formula, label design and application, and
packaging of multiple container units of formula.
The Agency received comments on several aspects of proposed Sec.
106.60, which are addressed in this document. Section 106.60 of the
interim final rule includes minor editorial revisions as well as the
changes discussed in this document that are made in response to
comments.
1. Labels Designed To Remain Legible and Attached During Use (Proposed
Sec. 106.60(b))
(Comment 162) Several comments requested that the phrase ``and
use'' be deleted from proposed Sec. 106.60(b), which would require
that labels be designed, printed, and applied so that the labels remain
legible and attached during the conditions of processing, storage,
handling, distribution, and use. These comments noted that some infant
formula product labels are designed to be removed by the end user
because the backs of the labels are printed with use information (such
as use instructions in a foreign language) or coupons. One comment
contended that this proposed requirement would prohibit providing
useful information to the consumer.
(Response) The purpose of proposed Sec. 106.60(b) is to ensure
that a formula label is designed and applied so that the label cannot
easily become detached during processing, storage, handling,
distribution, and use. Importantly, however, FDA would not object to a
label that is designed and applied to a formula product so that a
consumer could purposefully remove the label, so long as the label is
otherwise designed and applied to remain attached to the infant formula
container under reasonably expected conditions of use. FDA is concerned
that removing the phrase ``and use'' from proposed Sec. 106.60(b)
would permit a manufacturer to design and apply a label that would not
remain attached or legible under reasonably expected conditions of use.
For example, with the suggested revision, a manufacturer could use a
label adhesive that dissolves when dampened. For this reason and in
light of the foregoing clarification, FDA declines to modify Sec.
106.60(b) in the interim final rule in response to these comments.
2. Multiple Container Packages (Proposed Sec. 106.60(c))
Several comments objected to proposed Sec. 106.60(c), which would
require that all infant formula held in a single package be the same
product bearing the same code. In the preamble to the proposal, FDA
explained how these proposed packaging requirements would make it more
difficult for counterfeit formulas, or formula with counterfeit labels,
to be shipped in interstate commerce (61 FR 36154 at 36173).
(Comment 163) One comment requested that FDA make a distinction in
the preamble to the final rule between counterfeiters and diverters.
The comment explained that diverters are part of the normal
distribution channel for infant formula and are not counterfeiters. The
comment stated that diverters generally purchase formula products in a
geographic area where a special allowance or deal is being offered and
then resell the products in an area where the deal is not offered. In
such circumstances, the comment explained, the immediate formula
containers retain the original manufacturer labels but several lots of
the same product may be consolidated to fill a single shipping
container. The comment requested that FDA remove all references to
diverters in the proposal.
[[Page 7993]]
(Response) FDA did not intend to stymie distribution of formula or
prohibit wholesaling or other legitimate marketing practices, including
those of legitimate diverters as described in the comment. However, to
ensure that, in the event of a product recall, all affected formula can
be readily identified, it is imperative that all infant formula
packaged in a single shipping container be completely and accurately
identified. Only with such identification will recalled formula be
traceable. As discussed in response to Comment 164, FDA is revising
proposed Sec. 106.60(c) to permit, in certain limited circumstances,
mixed lot packages of infant formula.
(Comment 164) Several comments asserted that proposed Sec.
106.60(c) would prohibit manufacturers from making discharge packages
or ``kits'' that contain samples of different products with different
codes. One comment explained that these packages, which are commonly
used by the infant formula industry to familiarize new parents with
infant formula prior to an infant's discharge from the hospital, are
designed to hold samples of different products and thus, necessarily
contain products with different manufacturing codes. According to this
comment, individual discharge packages are assigned a unique lot number
for traceability purposes. The comment concluded by asserting that
FDA's intention is not to eliminate discharge kits, which would be a
disservice to consumers and hospitals and would have a substantial
impact on the marketing programs of formula manufacturers.
(Response) In proposing Sec. 106.60(c), FDA did not intend to
prohibit manufacturers from preparing and distributing hospital
discharge packages of infant formula. The comments state that these
discharge kits are labeled with a unique identification number. Under
certain limited conditions, traceability can be assured even with a
mixed-lot container of formula, such as a discharge kit. Therefore, FDA
is revising proposed Sec. 106.60(c) to allow infant formula to be
packaged, in certain limited circumstances, in mixed-lot shipping
packages and in hospital discharge packages. Importantly, however,
these mixed-lot container packages will be required to bear complete
and accurate identification about all infant formulas in the package or
be labeled with a unique identification number that is linked to a
record that identifies the product code required under Sec. 106.80 for
each container of infant formula product in the multiple container
package.
L. Controls on the Release of Finished Infant Formula (Proposed Sec.
106.70)
In 1996, FDA proposed to require in Sec. 106.70 that infant
formula manufacturers establish controls on the release of finished
infant formula. In particular, the controls would require the
manufacturer to hold or otherwise maintain control of finished formula
until it was determined to conform to all specifications of the
manufacturer. In addition, proposed Sec. 106.70(b) would require any
out-of-specification formula to be rejected, and any rejected formula
that was reprocessed would be required to conform to all specifications
before release. Finally, proposed Sec. 106.70(c) would require an
individual qualified by training or experience to investigate any out-
of-specification finding.
FDA received comments on proposed Sec. 106.70, specifically on
Sec. 106.70(b). The Agency has addressed these comments in section
V.C.2, and proposed Sec. 106.70 has been revised as described
previously in this document.
M. Traceability (Proposed Sec. 106.80)
In 1996, FDA proposed to require that infant formula manufacturers
ensure traceability of their products by coding the finished products.
Adequate coding will ensure product recovery in case of a formula
recall. The Agency received no comments specifically on proposed Sec.
106.80, and to the extent other comments (such as those on proposed
Sec. 106.60) indirectly raised concerns about proposed Sec. 106.80,
the Agency has addressed those comments earlier in this preamble.
Since publication of the proposed rule in 1996, FDA has acquired
additional information about the production of infant formula. For
example, the Agency has learned that liquid formula may be produced
over more than a single day and that many formula manufacturers use a
``continuous process'' manufacturing approach for their formula
products regardless of the final form of the product (e.g., liquid or
powered). Thus, some parts of proposed Sec. 106.80 are no longer
appropriate. Accordingly, FDA has revised Sec. 106.80 in the interim
final rule to update this provision in light of current manufacturing
methods in the formula industry. The provisions of Sec. 106.80 of the
interim final rule do not distinguish between infant formula that has
been produced during a single day, and infant formula that has been
produced over more than a single day. In addition to being more
current, these changes will have the advantage of requiring the
application of the same coding protocol to all forms of a
manufacturer's products, resulting in more consistent coding for all
products of the same brand or line.
N. Audits of Current Good Manufacturing Practice (Proposed Sec.
106.90)
In 1996, FDA proposed to require that infant formula manufacturers
conduct regularly scheduled audits of a firm's compliance with CGMP and
stipulated that such audits be performed by a person with knowledge of
all aspects of infant formula production and FDA's CGMP regulations but
who has no direct responsibility for the matters being audited. The
Agency received several comments on proposed Sec. 106.90, which are
addressed in this document.
(Comment 165) One comment stated that requiring that the auditor be
knowledgeable in ``all'' aspects of infant formula production is a
lofty expectation given the complexities of an infant formula
production environment. The comment suggested that the auditor should
possess a general knowledge of the areas being audited, but not the
depth and extent implied by the word ``all.''
(Response) This comment does not fully understand the personnel
qualification requirement of proposed Sec. 106.90. The objective of an
audit required under proposed Sec. 106.90 would be to determine
whether the manufacturer has complied with current good manufacturing
practice. As with any audit, to be valid and effective, the auditor
must have well-developed knowledge of the focus of his audit. In this
case, this means that the individual conducting the audit must have in-
depth knowledge of infant formula production as well as the regulations
governing that process. FDA disagrees that this is a ``lofty''
expectation.
Importantly, however, the CGMP audit of a firm's infant formula
production would not be required to be conducted by a single
individual. Thus, a manufacturer may choose to utilize a team of
auditors, each of whom has general knowledge of the formula production
process as well as more detailed knowledge of a specific facet or
facets of that process so that, collectively, the auditing team is
knowledgeable in ``all'' aspects of infant formula production. Where a
team of auditors is used to conduct a CGMP audit, the team member
assigned to audit a specific facet or facets of the process must
possess specialized, detailed knowledge of both that aspect of the
process and the Agency regulations that apply to such facet or facets.
Importantly, however, where one person conducts a manufacturer's
[[Page 7994]]
CGMP audits, that individual must possess comprehensive knowledge of
all aspects of infant formula production and of the applicable CGMP
regulations. The Agency is revising Sec. 106.90 in the interim final
rule to expressly allow a team of individuals to conduct an audit. In
addition, the Agency is changing ``education, training, and
experience'' to ``education, training, or experience'' because the
Agency considers that each of these can independently provide an
adequate basis for an auditor have the necessary knowledge and skills
to perform an audit.
(Comment 166) Another comment agreed with the proposed requirement
that an auditor must not have direct responsibility for the matters
being audited, but took exception to the preamble statement that the
auditor must have no ``past involvement in the activities being
audited.'' The comment contended that this requirement presents a
dilemma if the auditor must have knowledge of infant formula
production, but could have no past involvement where knowledge might
have been gained. The comment recommended that a reasonable time (1
year) be established after which any concern about potential bias would
dissipate and an auditor could evaluate an area of previous employment.
(Response) As explained in this document, FDA agrees in part with
this comment. In order to be meaningful and function as an appropriate
oversight tool for CGMP compliance, any audit, including an audit
conducted under proposed Sec. 106.90, must be as objective as
possible. Thus, FDA proposed to require in Sec. 106.90 that the
individual conducting an audit (including an auditor who is an employee
of the company) have no direct responsibility for the matters being
audited. As FDA noted in the preamble to the 1996 proposal, ``The
requirement that the audit be performed by an individual who has no
direct responsibility for the matters being audited is one way to
ensure the objectiveness of the audit process. The person should be
free of any past involvement in the activities being audited because
the audit is intended to uncover any problems or shortcomings in the
manufacturer's procedures. A person who has been involved may feel that
finding problems will reflect poorly on his or her work'' (61 FR 36154
at 36175).
FDA is persuaded, however, that there may be certain circumstances
in which an auditor with prior involvement in the activities being
audited could still perform an unbiased audit. Each situation must be
evaluated on a case-by-case basis by the formula manufacturer to ensure
that that the audit will be objective and free from bias. A
manufacturer should determine that a proposed auditor is able to be
objective and to exercise independent judgment and thus, should
consider such factors as the scope of the employee's previous
responsibilities, the time elapsed between the reassignment of the
former responsibilities and the audit, and whether the audit will be
conducted by this single individual or a team. Evaluating these types
of factors can provide a manufacturer with reasonable assurance that an
audit conducted by this individual will be independent of bias.
(Comment 167) One comment contended that firms would have to hire
auditors from outside their company to perform audits since an
individual could not audit his or her own area and it would be unlikely
that one person would be knowledgeable in all areas of plant
operations. The comment points out that hiring an outside auditor would
be an added expense and suggests that auditing could be conducted as
effectively by in-house auditors trained in auditing practices.
(Response) FDA disagrees that a firm would have to hire auditors
from outside its company to perform audits. First, section
412(b)(2)(B)(iv) of the FD&C Act, which requires that audits ``be
conducted by appropriately trained individuals who do not have any
direct responsibility for the manufacture or production of infant
formula,'' would not preclude an auditor being an employee of the
manufacturer. Moreover, as noted in the responses to Comments 165 and
166, a manufacturer may employ a team approach to ensure that an audit
is staffed by individuals with comprehensive knowledge of the infant
formula production process and also, in certain circumstances, a
manufacturer may utilize an individual to audit an area of his/her
prior responsibility so long as the manufacturer determines that an
audit by such individual would be objective and free of bias.
The Agency notes that proposed Sec. 106.90 addressed both audit
scheduling and audit personnel requirements. For clarity, FDA is
dividing Sec. 106.90 of the interim final rule into two sections.
Section 106.90(a) of the interim final rule establishes the regularly
scheduled audit requirement, and Sec. 106.90(b) of the interim final
rule establishes the requirements for auditing personnel. The Agency is
also clarifying that audits must be performed frequently enough to
ensure compliance with the regulations in subpart B.
VI. Subpart C--Quality Control Procedures
As noted in the introductory section of this preamble, in 1982, FDA
established subpart B of part 106, Infant Formula Quality Control
Procedures (47 FR 17016 April 20, 1982). These regulations were
authorized by section 412 of the FD&C Act as it existed at that time.
Section 412 of the FD&C Act was subsequently amended in 1986 (Pub. L.
99-570). Thereafter, in 1996, the Agency proposed to redesignate,
revise, or remove parts of the current quality control procedures
regulations. The proposed requirements related to nutrient testing,
stability testing, quality control records, and quality control audits.
In proposing these changes, the Agency sought to establish the minimum
practices that infant formula manufacturers must implement to ensure
that all batches (production aggregates) of infant formula that they
produce contain the required nutrients at the required levels
throughout the shelf life of the product.
FDA received several comments on proposed subpart C. These comments
are summarized in this document along with the Agency's responses. In
addition to the revisions to subpart C, FDA is making minor editorial
revisions in this subpart. These editorial revisions include deleting
the titles from the paragraphs in Sec. 106.91, a change that will make
Sec. 106.91 of the interim final rule consistent with the rest of part
106.
A. General Quality Control (Proposed Sec. 106.91)
1. Nutrient Testing on Each Production Aggregate of Infant Formula
(Proposed Sec. 106.91(a)) \6\
---------------------------------------------------------------------------
\6\ In the following discussion, FDA uses the term ``nutrient''
as defined in Sec. 106.3(k) of the interim final rule (i.e., as
``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 Institute of Medicine through its development
of a Dietary Reference Intake (DRI), or that has been identified as
essential for infants by FDA through a Federal Register
publication.'') This was also the proposed rule's definition of
``nutrient'' with a few minor editorial revisions.
---------------------------------------------------------------------------
In 1996, the Agency proposed to require nutrient testing at four
separate stages during the production of formula. Specifically, FDA
proposed to require the following testing: (1) Testing of any nutrient
premix used by a manufacturer to ensure compliance with specifications;
(2) testing of each production aggregate of the infant formula product
for an indicator nutrient (as defined in proposed Sec. 106.3) either
during the manufacturing
[[Page 7995]]
process, after addition of the premix, or at the final product stage
and before distribution; (3) testing of the final product stage and
before distribution for vitamins A, E, C, and thiamin; and (4) testing
during manufacturing or at the final product stage and before
distribution for all required nutrients as well as for any added
nutrient for which the manufacturer has not previously tested.
(Comment 168) One comment requested that FDA delete proposed Sec.
106.91(a)(1), which would require the testing of any nutrient premix
used by a manufacturer. The comment contended that FDA should eliminate
the requirement for premix testing and require only end-product testing
for infant formula.
(Response) FDA disagrees with the suggestion to eliminate premix
testing because such revision would be inconsistent with section
412(b)(3)(B) of the FD&C Act. Section 412(b)(3)(B) of the FD&C Act
requires that each nutrient premix used in the manufacture of an infant
formula be tested for each nutrient required by section 412(i) of the
FD&C Act that is contained in such premix and that the manufacturer
relies on the premix to supply to ensure that such premix is in
compliance with its specifications or any certification by a premix
supplier. Moreover, ``nutrient'' is defined in Sec. 106.3 as any
vitamin, mineral, or other substance or ingredient that is set out in
the table of required nutrients in section 412(i) of the FD&C Act, that
is set out in such table as revised by FDA by regulation, or that is
identified as ``essential'' for infants by FDA or the Food and
Nutrition Board of the IOM. Thus, a manufacturer that adds a
``nutrient'' not otherwise required under section 412(i) of the FD&C
Act would have been required to test for such nutrient under proposed
Sec. 106.91(a), if the nutrient is added as part of a nutrient premix
and the manufacturer is relying on the premix to provide that nutrient.
Accordingly, the Agency declines to revise proposed Sec. 106.91(a)(1)
in response to the comment. For increased clarity regarding the
nutrients that must be tested, however, FDA is making a minor revision
as reflected in Sec. 106.91(a)(1) in the interim final rule by adding
the parenthetical phrase ``(required under Sec. 107.100 or otherwise
added by the manufacturer)'' after the words ``shall be tested'' in
Sec. 106.91(a)(1). The Agency is also deleting the title in proposed
Sec. 106.91(a) to make this section consistent with the rest of part
106.
(Comment 169) One comment also objected to proposed Sec.
106.91(a)(3), which would require that, because they are susceptible to
degradation, vitamins A, C, E, and thiamin be tested at the final batch
(production aggregate) stage. The comment asserted that these vitamins
are not always susceptible to degradation because susceptibility of a
particular vitamin to degradation is affected by formula pH and
processing techniques and that when using an aseptic or dry mix
process, vitamins A, E, and thiamin also degrade very slowly. The
comment contended that use of a premix with appropriate levels of
vitamins A, C, E, and thiamin, and analytical verification at final
product stage by a premix tracer (i.e., an indicator nutrient) is
sufficient to ensure compliance with required nutrient levels without
analyzing for these vitamins at the final product stage. The comment
further asserted that requiring 100 percent analytical testing at the
batch (production aggregate) stage is burdensome because of the
increased paperwork, the additional time required for analysis, and the
need to hold the finished product pending the analytical results and
that such testing will be extremely expensive, the cost of which will
need to be passed on to the consumer.
(Response) FDA is not persuaded by this comment to revise proposed
Sec. 106.91(a)(3) because such revision would be inconsistent with
section 412(b)(3)(A) of the FD&C Act. Section 412(b)(3)(A) of the FD&C
Act requires that at the final product stage, each production aggregate
(batch) of infant formula be tested for four specific vitamins
(vitamins A, C, E, and B1 (thiamin)) to ensure that the formula is in
compliance with section 412(b) and (i) of the FD&C Act. There are no
exceptions for this testing requirement for formulas that arguably
degrade more slowly due to product pH or the means by which the product
is manufactured. Moreover, the comment did not assert that the testing
required for vitamin C be stricken, apparently because the comment
could not credibly argue that vitamin C degrades slowly. Accordingly,
the Agency declines to revise proposed Sec. 106.91(a)(3) in response
to the comment, and proposed Sec. 106.91(a)(3) is included in this
interim final rule as proposed.
(Comment 170) One comment stated that the proposed regulation
requires that all nutrients required to be in infant formula by Sec.
107.100 must be tested at the final batch (production aggregate) stage,
even though the nutrient premixes already would have been analyzed for
all the nutrients that the manufacturer is relying on the premix to
supply.
(Response) This comment appears to relate to proposed Sec.
106.91(a)(4) and seems to suggest that this proposed provision should
be modified. FDA is not persuaded by this comment to revise the
proposed provision. Proposed Sec. 106.91(a)(4) is directly authorized
by section 412(b)(3)(C) of the FD&C Act (21 U.S.C. 350a(b)(3)(C)).
Section 412(b)(3)(C) of the FD&C Act requires that during the
manufacturing process or at the final product stage and before
distribution, an infant formula be tested for all nutrients required by
section 412(i) of the FD&C Act to be in the formula for which testing
has not been done under section 412(b)(3)(A) or (b)(3)(B) of the FD&C
Act. There are no exceptions from this testing requirement. A nutrient
that is not otherwise tested as part of testing the premix or is
required to be tested at the final product stage under Sec.
106.91(a)(3) of the interim final rule is required to be assayed either
during the manufacturing process or during the final product stage.
Accordingly, the Agency declines to revise proposed Sec. 106.91(a)(4)
in response to this comment.
(Comment 171) One comment suggested that FDA modify proposed Sec.
106.91(a)(4) to require that quality control testing be conducted using
validated nutrient test methods to ensure the accuracy and precision of
test results to determine compliance with the FD&C Act.
(Response) It is important to distinguish between ``validated''
test methods and ``valid'' test methods. The process of method
validation is a formal process for demonstrating that an analytical
procedure is suitable for its intended use. In contrast, a ``valid''
method is a method that is suitable for or capable of consistently
achieving the intended results.
Typical validation characteristics include accuracy, precision,
specificity, detection limit, quantitation limit, linearity, range, and
robustness. Methods, such as AOAC International methods, are validated
in collaborative studies using several laboratories under identical
conditions; these methods are often described as ``official [validated]
methods.'' Method validation may also be conducted in a single
laboratory by repeating the same test multiple times. Many analytical
methods have been formally validated. However, other scientifically
valid methods have not been subject to the formal validation process.
For example, a test method not validated by a collaborative study using
multiple laboratories may nonetheless be scientifically valid because
it is, in fact, suitable for its intended purpose
[[Page 7996]]
and capable of consistently producing accurate results.
FDA disagrees with the comment's specific recommendation that
proposed Sec. 106.91(a)(4) be revised to require that quality control
testing be conducted using validated nutrient test methods. It is
scientifically sound to permit nutrient tests to use any method that is
accurate, precise, and specific for its intended purpose and thus,
permitted methods should not be restricted to official AOAC methods or
other methods formally validated in a multi-laboratory, collaborative
study.
Although FDA does not agree with the comment's specific
recommendation, in light of the foregoing comment, it is appropriate to
stipulate in the interim final rule a standard for nutrient testing
methods. Accordingly, in this interim final rule, FDA is redesignating
proposed Sec. 106.91(c) ``Quality control records'' as Sec.
106.91(d), and adding a new Sec. 106.91(c) ``Use of scientifically
valid nutrient test methods.'' Section 106.91(c) of the interim final
rule states that ``All quality control testing shall be conducted using
appropriate, scientifically valid test methods.''
(Comment 172) One comment suggested revising proposed Sec.
106.91(a)(4) to require that during the manufacturing process or at the
final product stage, before distribution, each batch (production
aggregate) be tested for ``each nutrient'' instead of for ``all
nutrients'' required to be included in such formula under Sec.
107.100.
(Response) FDA declines to make the revision proposed by this
comment because the Agency is not persuaded that there is a sound
reason to replace the reference to ``all nutrients'' by the phrase
``each nutrient'' in proposed Sec. 106.91(a)(4). The comment provides
no reason for this suggested change. The proposed requirement is
consistent with the language in the statute in that section
412(b)(3)(C) of the FD&C Act requires testing for ``all nutrients''
required to be included in an infant formula for which testing had not
been completed earlier in the manufacturing process. On this basis, FDA
is not revising Sec. 106.91(a)(4) in response to this comment.
(Comment 173) One comment requested that FDA delete the requirement
in proposed Sec. 106.91(a)(4) and (b) that the manufacturer test ``for
any nutrient added by the manufacturer'' in addition to testing for the
nutrients required by Sec. 107.100. The comment contended that this
testing requirement is without added benefit.
(Response) FDA disagrees. Nutrients are unique compounds and are
needed at certain levels by the body for normal health. If an infant
formula contains too little of a nutrient, a deficiency may occur in
infants consuming the formula. Conversely, if an infant formula
contains too much of a nutrient, toxic effects may occur.
Testing for nutrients not required under Sec. 107.100 in each
production aggregate of infant formula is consistent with CGMP and
quality control procedures that are required to be established by
section 412(b)(2)(A) of the FD&C Act. The preamble to the 1996 proposal
explained why testing for these added nutrients is necessary for proper
formulation of a formula as follows: ``[I]t is important that the level
of these added nutrients be controlled, and that the level of the added
nutrient be consistent from batch to batch [production aggregate to
production aggregate] and be uniform throughout the batch [production
aggregate] of infant formula. The level of a nutrient needs to be
controlled because some nutrients can be toxic to an infant if given at
too high a level. Controlling the level of the added nutrient for
consistency from batch to batch [production aggregate to production
aggregate] and in a particular batch [production aggregate] of infant
formula will ensure that the infant receives the essential nutrient on
a consistent basis and will also ensure that the infant does not
receive too high, or too low, a level of the nutrient because the
nutrient was not uniform through the batch [production aggregate] of
infant formula'' (61 FR 36154 at 36176).
The comment does not dispute the reasoning of the 1996 preamble
that supports the need to test formula at the final product stage to
confirm the presence and level of a nutrient that is not legally
required in but added to formula by the manufacturer. Furthermore, if
health professionals or parents are selecting a particular infant
formula because it contains a particular nutrient that is declared in
the statement of nutrient amounts in the labeling and not currently
required by Sec. 107.100, it is important that the nutrient is present
in the infant formula at the level stated in the product's labeling.
The concern about the testing for nutrients added but not required
under Sec. 107.100 is not simply theoretical. Infant formula
manufacturers have voluntarily added the nutrient, selenium, to their
infant formulas even though this nutrient is not currently required by
Sec. 107.100. Selenium has been identified by the IOM of the NAS as an
essential nutrient for infants (61 FR 36154 at 36176) and, if added,
may be declared in the statement of nutrient amounts in the formula
labeling (Sec. 107.10(b)(5)). Selenium is necessary for health but is
toxic at high doses (Ref. 60). Characteristics of morbidity resulting
from both deficient and excess intakes were summarized in 2000 by the
IOM (Ref. 60). Keshan disease, a cardiomyopathy that occurs almost
exclusively in children, has been linked to selenium deficiency.
Chronic selenium toxicity (selenosis) has also been observed in humans.
Reported characteristics of such toxicity include gastrointestinal
upsets, hair and nail brittleness and loss, skin rash, garlic breath
odor, fatigue, irritability, and nervous system abnormalities. Although
acute selenium toxicity is rare, the literature contains a few reports
of acute fatal or near fatal selenium poisoning resulting from
accidental or suicidal ingestion of selenium (Ref. 60). Given the
adverse effects of too little or too much selenium, the IOM has
established an adequate intake level and a tolerable upper intake level
of selenium for infants.
As the sole source of nutrition for many infants, infant formula
must provide appropriate amounts of all nutrients in the formula.
Testing each production aggregate of infant formula for each nutrient
at the final product stage will help to ensure that an infant formula
consistently contains an appropriate amount of each nutrient.
For additional consideration of selenium in infant formula, see
Comment 295 in section VIII.
For these reasons, FDA is not revising Sec. 106.91(a)(4) in the
interim final rule in response to this comment.
Similarly, FDA is not persuaded to make the requested change in
proposed Sec. 106.91(b). Proposed Sec. 106.91(b) would establish
testing requirements to ensure that the nutrients in infant formula
products remain stable throughout the shelf-life of the products. The
provisions of proposed Sec. 106.91(b) implement section
412(b)(2)(B)(ii) of the FD&C Act. The reasons to conduct in-process and
finished product testing to confirm the presence and levels of all
nutrients apply to stability testing as well, a point not disputed by
the comment. Thus, FDA is not revising Sec. 106.91(b) in the interim
final rule in response to this comment. Additional comments on proposed
Sec. 106.91(b) are addressed in this document.
(Comment 174) One comment suggested that proposed Sec.
106.91(a)(4) be revised to state that each batch (production aggregate)
of infant formula must be tested for all nutrients required to be
included in such formula under Sec. 107.100 ``if the presence of that
nutrient in the batch (production
[[Page 7997]]
aggregate) has not been confirmed pursuant to testing'' conducted for
compliance with Sec. 106.91(a)(1) (premix testing) or (a)(3). The
comment suggested substituting this language for that in the proposal
to convey better that a manufacturer may rely on testing under Sec.
106.91(a)(1) instead of requiring that finished product be retested for
nutrients confirmed to be a part of a premix used in the infant
formula. This comment also suggested that Sec. 106.91(a)(2) (testing
for an indicator nutrient for each nutrient premix) be added as another
means of testing that would exclude the need to test for a nutrient
under proposed Sec. 106.91(a)(4). The comment stated that testing
under Sec. 106.91(a)(2) should be included in the list of prior
testing recognized as a substitute for finished product testing because
testing under proposed Sec. 106.91(a)(1) would only confirm that a
nutrient is present at the appropriate level in the premix and not
establish that the nutrient is present at the appropriate level in the
infant formula.
(Response) FDA is not persuaded by this comment to revise proposed
Sec. 106.91(a)(4). Section 106.91(a)(4) of the interim final rule
parallels the statutory language of section 412(b)(3)(C) of the FD&C
Act, which requires that each batch (production aggregate) of infant
formula be tested for all required nutrients for which testing has not
been conducted under sections 412(b)(3)(A) (final product stage
testing) and 412(b)(3)(B) (premix testing) of the FD&C Act. Under
proposed Sec. 106.91(a)(4), a manufacturer is permitted to rely on
testing under Sec. 106.91(a)(1) (premix testing for relied upon
nutrients) and thus, would not be required to test a production
aggregate of finished infant formula for each relied upon nutrient that
has been evaluated under Sec. 106.91(a)(1), unless testing of the
nutrient is also required at the final product stage by section
412(b)(3)(B) of the FD&C Act (i.e., vitamins A, C, E, and thiamin).
In addition, proposed Sec. 106.91(a)(4) would already provide for
an exemption for nutrients tested as indicator nutrients under proposed
Sec. 106.91(a)(2). Specifically, any indicator nutrient testing under
proposed Sec. 106.91(a)(2) would be conducted during the manufacturing
process after the addition of the premix, or at the final product
stage. If so tested, the manufacturer would have satisfied, for that
indicator nutrient, the requirement in proposed Sec. 106.91(a)(4).
Therefore, if the nutrient used as the indicator nutrient in tests
conducted under proposed Sec. 106.91(a)(2) is a required or added
nutrient, the manufacturer would have met testing requirements
established for the nutrient under proposed Sec. 106.91(a)(4). If the
indicator nutrient is tested under proposed Sec. 106.91(a)(2) and is
also a nutrient that is required to be tested under proposed Sec.
106.91(a)(1), the nutrient would need to be tested twice during
manufacturing. However, as the comment recognizes, the nutrient testing
under proposed Sec. 106.91(a)(1) and (a)(2) have separate and distinct
purposes and both types of testing are necessary to ensure that the
infant formula contains the nutrients it is intended to contain.
On its own initiative, FDA is making minor editorial changes in
Sec. 106.91(a)(4) of the interim final rule and is also clarifying
that the phrase ``for which testing is not conducted for compliance
with paragraphs (a)(1) or (a)(3) of this section'' applies both to
required nutrients and any nutrient not required but added by the
manufacturer, except that the latter would not have been tested under
Sec. 106.91(a)(3) of the interim final rule.
2. Testing of Packaged Finished Product To Confirm the Presence of the
Nutrients Required Under Sec. 107.100 and Any Nutrients Added by the
Manufacturer (Proposed Sec. 106.91(b))
The Agency received a number of comments objecting to the stability
testing requirements in proposed Sec. 106.91(b). This proposed
provision would implement section 412(b)(2)(B)(ii) of the FD&C Act,
which was part of the 1986 amendments, and would revise and replace
current Sec. 106.30(b)(3). Proposed Sec. 106.91(b) differs from the
current stability analysis requirements in three principal ways: it
would require the collection of representative samples every three
months; it would require that stability testing of a formula assess all
nutrients (both required and those added by the manufacturer); and it
would expressly require that stability testing be performed on the
collected samples at the beginning, the midpoint, and the end of the
shelf life of the product. The 1996 preamble noted that quarterly
testing of infant formulas for nutrient stability was the current
practice of the industry and that FDA was not aware of any problems
resulting from this frequency of testing. In addition, the Agency
expressly requested comment on the appropriateness of the 3-month
frequency for stability testing sample collection.
(Comment 175) One comment argued that proposed Sec. 106.91(b)
inappropriately combines requirements for periodic analyses and
stability testing. The comment suggested establishing separate
requirements for periodic analyses and stability testing because these
two testing regimens serve different purposes. The comment explained
that periodic analysis confirms on a quarterly basis the proper
operation of the controls used by a manufacturer to ensure the presence
of all required nutrients within required ranges in the finished infant
formula. In contrast, the comment further explained, stability testing
serves as a check that labeled nutrients present in the infant formula
at the finished product stage do not, over the shelf life of the
formula, degrade below minimum levels.
(Response) FDA believes that the comment results in part from the
lack of clarity in proposed Sec. 106.91, which did not separately
identify requirements for periodic testing and stability testing. The
Agency does, however, agree with the comment's description of the
nature and purpose of stability testing and also agrees that one
purpose of periodic testing can be to confirm the proper operation of
the controls used by a manufacturer.
FDA has considered this comment and has carefully analyzed the
various quality control testing requirements in proposed Sec. 106.91.
The Agency has concluded that the testing required by Sec. 106.91(a)
of the interim final rule can serve as final product testing of each
production aggregate and also fulfill the purpose of periodic testing
by serving as a check on the proper operation of the controls used by a
manufacturer to ensure the presence and proper concentration of all
nutrients. As discussed previously in this document, Sec. 106.91(a)(1)
of the interim final rule requires the manufacturer to test each premix
before manufacture of an infant formula to ensure that each premix
meets its specifications; Sec. 106.91(a)(2) of the interim final rule
requires the manufacturer to test, during the manufacture of the infant
formula, after addition of the premix, or at the final product stage,
for at least one indicator nutrient for each nutrient premix used in
the infant formula to confirm that the appropriate amount of each
premix is present in the production aggregate of infant formula; Sec.
106.91(a)(3) of the interim final rule requires the manufacturer to
test each production aggregate for the labile vitamins (vitamins A, C,
E, and thiamin) at the final product stage, before distribution; and
Sec. 106.91(a)(4) of the interim final rule requires the manufacturer
to test during the manufacturing process, or at the final product
stage, each production aggregate for all nutrients required to be in
the formula under Sec. 107.100 of this
[[Page 7998]]
chapter and for any nutrient added by the manufacturer, for which
testing was not conducted for compliance with paragraphs (a)(1) or
(a)(3). When the manufacturer conducts these tests as required by Sec.
106.91(a) of the interim final rule, the results will show whether all
nutrients required under 21 CFR 107.100 and any other nutrient added by
the manufacturer are present and at the proper concentration. These
collective results can also be used to evaluate whether the
manufacturer's production controls are functioning properly because any
nutrient not identified in the production aggregate or not found at the
correct concentration would be evidence that the production controls
may not be functioning properly. In such circumstances, the
manufacturer would need to address the production aggregate shown to be
out of compliance and would also need to evaluate the production
controls to determine where the error occurred. Because the testing in
Sec. 106.91(a) of the interim final rule not only confirms the
presence and concentration of the nutrients in the particular
production aggregate, but can also serve to demonstrate the proper
functioning of the manufacturing controls, FDA concludes that specific
requirements for periodic testing in Sec. 106.91 of the interim final
rule are not necessary.
(Comment 176) One comment suggested that periodic analysis requires
that quarterly, a manufacturer test a finished batch (production
aggregate) of each form of infant formula (from each facility) for all
nutrients not analyzed directly in the immediate analysis of that batch
(production aggregate).
(Response) As discussed in the response to the preceding comment,
the Agency has determined that the testing requirements of Sec.
106.91(a) of the interim final rule will satisfy the requirement in
section 412(b)(2)(B)(iii) of the FD&C Act, which requires that the
manufacturer test finished products to confirm that in-process controls
(i.e., CGMP) are operating properly and thereby, are preventing the
production of adulterated infant formula. That is, because Sec.
106.91(a) of the interim final rule requires each production aggregate
to be tested for the presence and level of all nutrients in the final
formula product, testing conducted to satisfy Sec. 106.91(a) of the
interim final rule can also be used to determine whether a
manufacturer's production controls are operating properly.
(Comment 177) One comment suggested permitting an appropriate
sampling and testing program for infant formulas produced less
frequently than every three months.
(Response) Because the interim final rule will not require periodic
testing, no response to this comment is required. Importantly, however,
an infant formula that is produced infrequently must still comply with
the nutrient testing requirements of Sec. 106.91(a) of the interim
final rule and the stability testing requirements of Sec. 106.91(b) of
the interim final rule.
(Comment 178) Several comments argued that the stability testing
requirements in proposed Sec. 106.91(b) are excessive. One comment
asserted that the proposed stability testing requirements require an
excessive number of infant formulas and nutrients to be routinely
analyzed and proposed that infant formula manufacturers continue to
follow the requirements of the current Sec. 106.30(b)(3), which
requires a manufacturer to conduct a stability analysis, using
representative samples collected from finished product batches
(production aggregates), for selected nutrients with sufficient
frequency to substantiate the maintenance of nutrient content
throughout the shelf life of the product.
(Response) The Agency disagrees that proposed Sec. 106.91(b) would
require an excessive number of infant formulas to be routinely tested.
It is well-recognized that nutrient stability is affected by several
factors, including the form of the infant formula (powder, ready-to-
feed, or concentrate), the matrix of the formulation, processing
techniques, and packaging (Ref. 61). Given the impact of these
variables, it is scientifically sound to require that stability testing
be performed on each production aggregate of each physical form
(powder, ready-to-feed, or concentrate) of each infant formula from
each manufacturing facility because different forms of the product may
contain different ingredients, and the various forms of infant formula
are subjected to manufacturing conditions and processing procedures
that are specific to the product and to the manufacturing facility. As
noted, each of these factors could affect the stability of the product.
The stability analysis required by the current regulation (21 CFR
106.30(b)(3)) is not adequate given the range of factors that are known
to affect nutrient stability. For example, Sec. 106.30(b)(3) requires
analysis only for selected nutrients and does not specify the frequency
of such testing to substantiate the maintenance of nutrient content
throughout the shelf life of the product.
Therefore, it is entirely reasonable to require that stability
testing include the analyses stipulated in proposed Sec. 106.91(b). As
explained in this document, the Agency is revising the proposed
stability testing provisions to distinguish between the comprehensive
stability testing of the first production aggregate of a new infant
formula (Sec. 106.91(b)(1) of the interim final rule) and the routine
stability testing of subsequent production aggregates of the same
formula (Sec. 106.91(b)(2) of the interim final rule).
Specifically, under Sec. 106.91(b)(1) of the interim final rule,
the manufacturer must demonstrate the appropriateness of the proposed
shelf life by completing the comprehensive testing of the first
production aggregate of the new infant formula every three months
during the proposed shelf-life and such testing must substantiate the
shelf life established for the product. If the testing conducted under
Sec. 106.91(b)(1) of the interim final rule does not substantiate the
chosen stability date, the manufacturer is required by Sec.
106.91(b)(3) of the interim final rule to repeat the comprehensive
stability testing under Sec. 106.91(b)(1) of the interim final rule to
confirm that the infant formula provides, throughout the shelf life of
the infant formula, appropriate levels of both required nutrients and
any nutrients added by the manufacturer. Alternatively, the
manufacturer may choose to revise the shelf life date for the formula
so that it is substantiated by the results of the comprehensive
stability testing. Additionally, where the testing under Sec.
106.91(b)(1) of the interim final rule fails to support the shelf life
date, the manufacturer must take appropriate action with regard to any
distributed formula bearing such unsubstantiated shelf life date.
In addition to comprehensive stability testing, the manufacturer is
required by Sec. 106.91(b)(2) of the interim final rule to conduct
routine stability testing of each production aggregate of a formula at
the beginning, midpoint, and end of its shelf life. If the results of
this routine testing show that any required nutrient is not present in
a production aggregate at the level required by Sec. 107.100 or that
any nutrient added by the manufacturer is not present at the level
declared on the formula's label, the manufacturer must take steps to
understand these results. Specifically, Sec. 106.91(b)(4) of the
interim final rule requires the manufacturer to investigate the cause
of a variance in the level of any nutrient; to evaluate the
significance of the results for other production aggregates of the same
formula that have been released for distribution; to determine which
production aggregates are implicated by the results and address those
production aggregates as appropriate; and to determine whether
[[Page 7999]]
it is necessary to repeat the comprehensive stability testing required
by Sec. 106.91(b)(1) of the interim final rule.
(Comment 179) One comment suggested that stability ``testing every
three months for vitamins and minerals should be used only when a new
product is introduced and until a history for that product is
established. After 2 years of experience is acquired, then stability
testing should be only at the beginning, middle, and end of shelf
life.''
(Response) FDA agrees in part with this comment. As such, Sec.
106.91(b) of the interim final rule focuses on stability testing and
differentiates between the initial comprehensive stability testing
required for the first production aggregate of a new infant formula
(Sec. 106.91(b)(1) of the interim final rule) and the routine
stability testing of subsequent production aggregates of that new
formula (Sec. 106.91(b)(2) of the interim final rule). For example, as
applied to a new infant formula in liquid form first produced in
January and initially labeled with a 1-year shelf life, the
requirements of Sec. 106.91(b) of the interim final rule would require
testing in the following months: ``First production aggregate: January,
April, July, October, and December. Subsequent production aggregates:
January, July, and December.''
Thus, routine stability testing at the beginning, midpoint, and end
of a product's shelf life should be retained for all formula products
after the completion of the comprehensive stability testing of the
initial production aggregate; these are the formulas with which the
manufacturer has had previous experience. Stability testing at the
beginning of the shelf life shows that the formula is in compliance
with the nutrient requirements of the FD&C Act when it is released for
distribution. (FDA notes that in some circumstances, the results from
the testing required under Sec. 106.91(a)(4) of the interim final rule
could also be used to meet the requirements for initial stability
testing of a particular production aggregate at the beginning of the
shelf-life and thereby reduce duplicative analyses.) Testing at the end
of the shelf life confirms that the formula contains all the nutrients
needed to comply with the FD&C Act throughout its shelf life and will
provide continued justification for the predicted shelf life. Testing
at the midpoint of the shelf-life will provide an early indicator when
nutrient concentrations are decreasing more rapidly than anticipated,
based on previous experience.
(Comment 180) Another comment argued that the proposed level of
quality control testing is appropriate for new infant formulas to guard
against unexpected changes in the formula, but is inappropriate for an
experienced infant formula manufacturer.
(Response) The Agency agrees with the comment to the extent that
the comment suggests that a new infant formula, as defined in Sec.
106.3 of the interim final rule, requires more frequent testing than
products with which the manufacturer has experience, and Sec.
106.91(b)(1) of the interim final rule reflects this principle. The
1986 amendments refer to ``regularly scheduled testing.'' With respect
to what constitutes ``regularly scheduled testing'' for each nutrient
in the infant formula, the Agency agrees that the stability testing of
the initial production aggregate of a ``new infant formula'' needs to
be more frequent because the infant formula manufacturer will have had
very limited or no experience with the stability of all nutrients in
the particular formula matrix.
FDA emphasizes that it is important that the stability testing be
conducted on the new infant formula product manufactured for the
marketplace, i.e., the formulation, processing, and packaging of the
marketed product. In the past, some infant formula manufacturers have
used pilot production aggregates that differed from the marketed
product in formulation, processing, or packaging to assess the
stability of the product and to assign the shelf-life. For these
reasons, the Agency is requiring that the first production aggregate of
a ``new infant formula,'' as defined in Sec. 106.3 of the interim
final rule, for distribution be tested every three months during its
predicted shelf-life.
(Comment 181) Several comments objected to the stability testing
requirements proposed in Sec. 106.91(b)(2), which would require
quality control testing of an infant formula that has been changed in
formulation or in processing in a way that does not make it a new
infant formula but that may affect whether it is adulterated under
section 412(a) of the FD&C Act. These comments suggested that the
manufacturers should determine whether stability testing needs to be
conducted for such a change. One comment contended that quality control
testing on changed infant formulas only needs to be conducted for each
nutrient that has been or may have been significantly and adversely
affected by the change.
(Response) FDA has considered these comments and has significantly
revised proposed Sec. 106.91(b)(2). Under Sec. 106.91(b) of the
interim final rule, a reformulated infant formula is subject to the
comprehensive stability testing of Sec. 106.91(b)(1) of the interim
final rule only if the change in the formula causes the formula to be a
``new infant formula'' within the meaning of Sec. 106.3 of the interim
final rule. Utilizing the concept of a ``new infant formula'' is a
reasonable basis for distinguishing when the comprehensive testing of
Sec. 106.91(b)(1) of the interim final rule and the routine testing of
Sec. 106.91(b)(2) of the interim final rule would be required. The
Agency believes that this revision responds to the concern expressed by
the comment.
(Comment 182) One comment stated that confirming the presence of a
mineral throughout the formula product's shelf life is not necessary
because minerals do not degrade.
(Response) FDA agrees that minerals do not undergo degradation and
will remain stable throughout the shelf-life of an infant formula.
Although it is critical to test for the presence and level of minerals
in the finished product, as required by Sec. 106.91(a) of the interim
final rule, the Agency agrees that subsequent analysis as a part of
stability testing for the presence and level of minerals is not needed
because these ingredients do not degrade. Therefore, Sec. 106.91(b)(5)
of the interim final rule exempts all required minerals (calcium,
phosphorus, magnesium, iron, iodine, zinc, copper, manganese, sodium,
potassium, and chloride), as well as any mineral added to the formula
by the manufacturer, from the requirements for stability testing in
Sec. 106.91(b)(1) and(b)(2) of the interim final rule.
(Comment 183) One comment suggested that the proposal be revised to
require stability testing of only labile nutrients. (A labile nutrient
is one that readily or frequently undergoes chemical or physical
change.)
(Response) FDA does not agree that only labile nutrients should be
the subject of stability testing as such approach would not address the
concerns that resulted in the 1986 amendments.
Although section 412(b)(2)(B)(ii) of the FD&C Act, added by the
1986 amendments, does not specify which nutrients must be tested to
ensure stability of the infant formula, the Agency proposed to require,
under its authority to establish quality control procedures, that all
nutrients be tested in a stability testing program. Infant formula is
very often the sole source of nutrition for infants during a critical
developmental period. As noted previously in this document, it is well
[[Page 8000]]
established that the absence or inappropriate amount of any of the
nutrients listed in Sec. 107.100 may cause adverse effects, many of
which may be life-threatening or result in life-long impairments (Refs.
62, 63, 64, 65, and 66). Without testing for the stability of all
nutrients, a manufacturer cannot know whether the level of a particular
nutrient has declined. (As noted in the preceding comment, FDA
recognizes that because minerals do not degrade, it is entirely
reasonable that stability testing not extend to such substances.) Thus,
it is both essential and reasonable to require stability testing of all
nutrients, both required and added (except minerals), in an infant
formula.
(Comment 184) One comment suggested that the title of proposed
Sec. 106.91(b) be changed from ``Stability testing'' to ``Testing of
packaged, finished product to confirm that the infant formula provides
nutrients in accordance with sec. 107.100.''
(Response) As noted, to make Sec. 106.91 of the interim final rule
consistent with the rest of part 106, FDA is deleting the titles from
the paragraphs in this section, including Sec. 106.91(b).
(Comment 185) Several comments stated that the manufacturer should
determine the frequency of stability testing, if deemed necessary.
(Response) The Agency agrees in part with the comment that
recommended that the manufacturer determine the frequency of stability
testing. The Agency disagrees that the manufacturer should be allowed
to test less frequently than required under Sec. 106.91(b)(1) or
(b)(2) of the interim final rule. The Agency views this testing
frequency as the minimum required to ensure nutrient stability over the
shelf-life of the product. However, if a manufacturer wishes to test
more frequently than required under Sec. 106.91(b)(1) or (b)(2) of the
interim final rule, FDA would not object to additional testing by the
manufacturer.
B. Audits of Quality Control Procedures (Proposed Sec. 106.92)
In 1996, FDA proposed to require in Sec. 106.92 that infant
formula manufacturers conduct regularly scheduled audits of a firm's
compliance with those quality control procedures that are necessary to
ensure that a formula provides nutrients in accordance with section
412(b) and (i) of the FD&C Act, and is manufactured in a manner
designed to prevent adulteration of the infant formula. Proposed Sec.
106.92 would also have required that such audits be performed by a
person with knowledge of all aspects of infant formula production and
FDA's quality control regulations but who had no direct responsibility
for the matters being audited. The Agency received several comments on
proposed Sec. 106.92, which are addressed in this document.
FDA notes that proposed Sec. 106.90 (Audits of current good
manufacturing practice) and proposed Sec. 106.92 (Audits of quality
control procedures) would have imposed similar requirements for the two
types of audits. As a result, several comments FDA received addressed
both proposed Sec. 106.90 and proposed Sec. 106.92. For this reason,
the discussion that follows references the responses to certain
comments on proposed Sec. 106.90 (section V.N).
(Comment 186) One comment stated that requiring that the auditor be
knowledgeable in ``all'' aspects of infant formula production is a
lofty expectation given the complexities of an infant formula
production environment. The comment suggested that the auditor should
possess a general knowledge of the areas being audited, but not the
depth and extent implied by the word ``all.''
(Response) As noted previously in this document in section V.N
(Comment 165), FDA disagrees that the standard in proposed Sec.
106.92(b) is a ``lofty'' expectation. As with any audit, to be valid
and effective, the auditor must have well-developed knowledge of the
focus of his audit. In this case, this means that the individual
conducting the audit must have in-depth knowledge of infant formula
production as well as the regulations governing that process. In
responding to Comment 165, the Agency explained that using a team of
individuals is a permissible approach to audits of infant formula
manufacturing, and is one way that the necessary breadth of expertise
can be assembled for an audit.
(Comment 187) Another comment agreed with the Agency that an
auditor must not have direct responsibility for the matters being
audited, but took exception to the preamble statement that the auditor
must have no ``past involvement in the activities being audited.'' The
comment contended that this requirement presents a dilemma if the
auditor must have knowledge of infant formula production, but could
have no past involvement where knowledge might have been gained. The
comment recommended that a reasonable time (1 year) be established
after which any concern about potential bias would dissipate and an
auditor could evaluate an area of previous employment.
(Response) As noted previously in this document in section V.N, in
order to be meaningful and function as an appropriate oversight tool
for quality control compliance, an audit, including one conducted under
proposed Sec. 106.92, must be as objective as possible although, as
noted, the Agency is persuaded that there may be certain circumstances
in which an auditor with prior involvement in the activities being
audited could still perform an unbiased audit. In designating an
individual to conduct an audit under Sec. 106.92(b), the manufacturer
should consider the factors identified in the response to Comment 166
and determine that the proposed auditor is able to be objective and to
exercise independent judgment.
(Comment 188) One comment contended that firms would have to hire
auditors from outside their company to perform audits since an
individual could not audit his or her own area and it would be unlikely
that one person would be knowledgeable in all areas of plant
operations. The comment pointed out that hiring an outside auditor
would be an added expense and suggested that auditing could be
conducted as effectively by in-house auditors trained in auditing
practices.
(Response) As discussed previously in this document in section V.N,
FDA disagrees that a firm would have to hire auditors from outside its
company to perform audits regardless of whether the audits are CGMP or
quality control audits. First, section 412(b)(2)(B)(iv) of the FD&C Act
would not preclude an auditor being an employee of the manufacturer. In
addition, as noted, a manufacturer may utilize a team approach to
ensure an audit is conducted by individuals, whether employees of the
manufacturer or otherwise, with comprehensive knowledge of the infant
formula production process and may also utilize an individual to audit
an area of his/her prior responsibility so long as the manufacturer
determines that an audit by such individual would be objective and free
of bias. Thus, FDA disagrees that the audit provisions of proposed
Sec. 106.92 would require a manufacturer to hire individuals from
outside the firm to conduct audits.
(Comment 189) One comment suggested that the language of proposed
Sec. 106.92 be changed to clarify that it is the manufacturer's
responsibility to determine what will constitute ``regularly scheduled
audits'' and to establish SOPs for that purpose. To achieve this goal,
the comment suggested that proposed Sec. 106.92 be revised to state
that the manufacturer must conduct audits ``according to its
established practice.''
[[Page 8001]]
(Response) FDA disagrees that proposed Sec. 106.92 should be
revised to make the established practice of the manufacturer the only
basis for the conduct of ``regularly scheduled'' audits.
The 1986 amendments to section 412 of the FD&C Act reflect a
Congressional determination that greater control over the formulation
and production of infant formula was needed. A total quality control
program for the manufacture of infant formula is necessary to ensure
that each production aggregate of formula is uniform in composition and
conforms to the nutrient requirements for infants. Under section
412(b)(2)(B)(iv) of the FD&C Act, a manufacturer is required to conduct
audits at regularly scheduled intervals. Thus, in response to this
comment, FDA advises that ``regularly scheduled'' means that a
manufacturer shall conduct, at each manufacturing facility, audits at a
frequency that is required to ensure compliance with such regulations,
with additional audits as needed, to determine whether the manufacturer
has complied with the quality control procedures regulations.
For clarity, FDA is dividing proposed Sec. 106.92 into two
sections. Section 106.92(a) of the interim final rule establishes the
regularly scheduled audit requirement, and Sec. 106.92(b) of the
interim final rule establishes the audit personnel requirement.
VII. Subpart D--Conduct of Audits
Audit Plans and Procedures (Proposed Sec. 106.94)
Three separate sections of the interim final rule address audits.
Section 106.90 of the interim final rule establishes the requirement to
conduct audits of compliance with CGMP, and Sec. 106.92 of the interim
final rule establishes the requirement to conduct audits of compliance
with quality control procedures. These provisions both implement
section 412(b)(2)(B)(iv) of the FD&C Act. Subpart D (Sec. 106.94 of
the interim final rule) establishes requirements for audit plans and
procedures.
In the 1996 proposal, FDA proposed in Sec. 106.94 to require that
infant formula manufacturers develop and follow a written audit plan.
The audit plan would be required to set out the method used to
determine whether the firm is operating in compliance with CGMP,
including quality control procedures, and would include evaluation of
the firm's production and in-process controls, a comparison of the
written plan to the observed process, and review of certain records,
including monitoring records, specification deviation investigations,
and a representative sample of all records maintained under proposed
Sec. 106.100(e) and (f).
The Agency received comments on several aspects of Sec. 106.94,
which are addressed in this document. Although FDA declines to make any
of the revisions to subpart D in response to the comments received, the
Agency is making minor editorial revisions in this subpart.
(Comment 190) One comment objected to proposed Sec.
106.94(c)(1)(i) which would require observation of the production of
infant formula and comparison of the observed process to the written
production and in-process control plan. The comment stated that this
proposal could be interpreted as requiring observation of every single
manufacturing operation, from ingredient receipt through manufacturing,
holding, and distribution, and that such detail during an audit would
make the auditing process an extremely tedious and unwieldy endeavor
and would result in overly prolonged audits. The comment proposed that
the actual observation portion of the audit be devoted to the critical,
product/line specific steps of the process as defined by the
manufacturer.
(Response) FDA disagrees with this comment. The requirement that a
manufacturer conduct regularly scheduled audits to assess compliance
with CGMP, including quality control procedures, derives from section
412(b)(2)(B)(iv) of the FD&C Act, which mandates that CGMP and quality
control procedures regulations include requirements for regularly
scheduled audits by a formula manufacturer to determine whether the
manufacturer has complied with such regulations. Thus, the scope of a
manufacturer's audits, and the audit plans and procedures established
under proposed Sec. 106.94(c)(1)(i), is determined by the breadth of
the CGMP and quality control procedure requirements. Section 106.6(a)
of the interim final rule requires a manufacturer to establish a system
of production and in-process controls that covers all stages of
processing, from the receipt and acceptance of the raw materials,
ingredients, and components through the storage and distribution of the
finished product, and Sec. 106.6(b) of the interim final rule requires
a written plan of such system. To assess compliance adequately, an
audit must extend to all of these areas of production. Thus, it is
appropriate that the audit plan required under proposed Sec.
106.94(c)(1)(i) include observation of each element of the
manufacturing operation, from ingredient receipt through manufacturing,
holding, and distribution. Accordingly, FDA is not revising Sec.
106.94(c)(1)(i) in the interim final rule in response to this comment.
(Comment 191) One comment claimed that proposed Sec.
106.94(c)(1)(i) would require additional trained personnel to complete
this type of audit, and that this requirement would interfere
unnecessarily with the focus on high quality production.
(Response) FDA notes that this comment did not explain its
assertion that additional personnel would be required to complete an
audit under proposed Sec. 106.94(c)(1)(i). Nor did the comment explain
how this proposed requirement would interfere with high quality
production. Without such details, FDA cannot respond to the comment.
Moreover, in its response to comments on the requirement to conduct
audits of compliance with CGMP and compliance with quality control
procedures, FDA addressed similar comments about the need for
additional trained personnel to conduct the audits that would be
required by proposed Sec. Sec. 106.90 and 106.92. In short, the audit
provisions (proposed Sec. Sec. 106.90. 106.92, and 106.94) provide
ample flexibility in terms of audit personnel.
For the foregoing reasons, Sec. 106.94(c)(1)(i) is included in
this interim final rule as proposed.
(Comment 192) One comment suggested revising proposed Sec.
106.94(c)(1)(ii), which requires that the audit procedures include
reviewing records of the monitoring of points, steps, or stages where
control is necessary to prevent adulteration. The comment noted that
the 1996 preamble to this proposed section stated that the review of
``production and in-process control records'' contemplated by this
section must involve ``all batches produced in a given period of time''
(61 FR 36154 at 36178). The comment recommended that the required audit
procedures be revised to include a review of records of representative
batches, over multiple days of production, of the monitoring of points,
steps, or stages where control is critical to prevent adulteration,
asserting that such audits would be more thorough and beneficial if the
records reviewed covered a wider span of time (i.e., months), but
extended only to ``representative'' batches, not ``all'' batches, and
to ``representative'' records of only the most important control points
(i.e., ``critical points'').
[[Page 8002]]
(Response) As discussed in this document, FDA declines to make the
revisions requested in this comment.
The purpose of an audit is to identify conditions related to
production and in-process controls that may result in the manufacture
of an adulterated infant formula. The Agency agrees with the comment
that an effective production and in-process control system audit may be
based on a ``representative sample'' (as defined in Sec. 106.3), of
production aggregates covering several months, and proposed Sec.
106.94 provides flexibility to the manufacturer as to the period of
production specified for review in the manufacturer's audit plan.
Importantly, however, the audit plan developed by the manufacturer
under proposed Sec. 106.94 must ensure that the audit covers a
sufficient number of products over a sufficient period of time so that
the manufacturer is able to determine whether its operations are in
compliance with CGMP, including quality control procedures required by
this interim final rule, to ensure that its infant formula provides the
required and added nutrients at the appropriate levels and is
manufactured in a manner designed to prevent adulteration. The audit
plan should provide a reasonable probability that any discrepancies in
the process can be identified. The audit plan must also provide a
mechanism whereby the manufacturer can identify any production
practices or in-process controls that require revision to ensure
compliance with all requirements for infant formula. FDA disagrees,
however, with the comment to the extent that it asserts that an audit
should be limited to ``representative records of the most important
control points.'' As discussed in the response to Comment 190, an
effective audit must be co-extensive with the production and in-process
controls established under Sec. 106.6 of the interim final rule.
Similarly, in order for such audit to be effective, an audit must
extend to the records of all points, steps, or stages where control is
necessary to prevent adulteration for each production aggregate in the
representative sample of an infant formula audited.
Importantly, under Sec. 106.6 of the interim final rule, a
manufacturer has both the responsibility and the flexibility to
identify in its own production process those points, steps, or stages
in the process where control is necessary to prevent adulteration of
formula. Any point, step, or stage identified by the manufacturer as a
focus for control under Sec. 106.6 of the interim final rule is, by
definition, ``critical'' to producing an infant formula that is not
adulterated. Thus, it is essential that all of these points, steps, or
production stages be audited, including through a review of the records
related to such points, steps, or production stages, to confirm that
the relevant controls are functioning properly and ensuring that no
adulterated formula is produced. Moreover, as noted previously in this
document, audits by infant formula manufacturers are required by
section 412(b)(2)(B)(iv) of the FD&C Act, and a requirement that a
manufacturer's audits be limited to a review of the ``most important
control points'' would not allow a manufacturer to determine whether it
has complied with the CGMP, including quality control procedures,
regulations as mandated by section 412(b)(2)(B)(iv) of the FD&C Act.
Thus, it is entirely appropriate that the audit plan established under
Sec. 106.94(c) of the interim final rule require the review of the
records relating to all of the points, steps, or stages of the
production process where control is deemed necessary to prevent
adulteration.
For these reasons, FDA declines to revise proposed Sec.
106.94(c)(1)(ii), and this provision is included in this interim final
rule as proposed.
(Comment 193) One comment suggested that proposed Sec.
106.94(c)(1)(iii), which would require reviewing records of the
handling of deviations from any standard or specification at points,
steps, or stages where control is deemed necessary to prevent
adulteration should be revised by adding the phrase ``to assure that
the review was complete.'' The comment noted that the 1996 preamble
states that the auditor must review these records to determine
``whether the conclusions and follow-up of these investigations are
appropriate for each failure to meet the specification or standard''
(61 FR 36154 at 36178), and asserted that it is unrealistic to expect
an auditor to have the background and breadth of technical knowledge to
assess whether the dispositions were ``appropriate.'' The comment
claimed that such disposition decisions may involve multiple
disciplines in a company, and it would be more reasonable to expect the
auditor's review to confirm the completeness and sufficiency of such
investigations, rather than to expect the auditor to determine whether
the conclusions and follow-up were appropriate.
(Response) Although FDA agrees that an audit should confirm the
completeness and sufficiency of the review of deviations from any
standard or specification, this action would not fulfill all of the
purposes of an audit. Because an audit serves as a manufacturer's
follow-up mechanism to provide independent evaluation of a firm's
management of deviations from specifications, a comprehensive audit
must also include an evaluation of how the manufacturer responded to
any deviation and whether the disposition decision was appropriate.
In terms of the comment's concern that an auditor may not have the
requisite expertise to evaluate the response and disposition to a
deviation, the Agency clarified in the response to Comment 165 that
audits may be conducted by a single individual or by a team of
individuals, each qualified to evaluate a particular portion or
portions of the production process. In fact, the use of a team for
audits is one way to ensure that an audit is comprehensive. Thus,
proposed Sec. 106.94(c)(iii) is not unrealistic and FDA is not
persuaded to make the revision suggested by this comment.
(Comment 194) One comment objected to the requirement in proposed
Sec. 106.94(c)(1)(iii) that the review of all deviations from the
manufacturer's standards or specifications at points, steps, or stages
where control is necessary to prevent adulteration be a part of
regularly scheduled audits. The comment suggested that instead of
requiring the auditor to review all deviations, review of a random
sample of deviations should be sufficient.
(Response) FDA disagrees that review of a ``random sample'' of
deviations from a manufacturer's specifications would constitute a
sufficient audit. The purpose of a quality control audit is to identify
recurring problems and detect any weaknesses or flaws in the system. In
order to maximize the likelihood of identifying a pattern of repeated
failures, an audit must include the review of all deviations from
specifications. As discussed previously in this document, the fact that
a manufacturer fails to meet a specification requires prompt
investigation to determine whether the manufacturing process is under
control. A subsequent audit evaluates the handling of all such
occurrences and assesses whether the appropriate material disposition
decisions were made. Thus, a review of all deviations as a part of the
audit will identify failures that occur and show how these failures are
handled by the manufacturer.
For these reasons, FDA is not revising proposed Sec.
106.94(c)(1)(iii) in response to this comment, and, with the exception
of minor editorial revisions, Sec. 106.94(c)(i)(iii) is included in
this interim final rule as proposed.
[[Page 8003]]
VIII. Subpart E--Quality Factors
In Subpart E, ``Quality Factors,'' comments often referred to both
proposed Sec. 106.96 and proposed Sec. 106.97 because the subjects of
these two proposed provisions are closely related. The interim final
rule reorganizes and consolidates into a single section (Sec. 106.96
of the interim final rule) most of the content of proposed Sec. 106.96
and proposed Sec. 106.97 related to requirements for infant formula
quality factors. In addition, Sec. 106.121 of the interim final rule,
which is discussed in section X.D., specifies the assurances for the
established quality factors that a manufacturer is required to submit
in a new infant formula submission or in a submission made under
section 412(d)(3) of the FD&C Act. For these reasons, this portion of
the preamble is generally organized by topic rather than by section of
the proposed codified.
FDA notes that the Agency received several comments in response to
proposed Sec. 106.96 and Sec. 106.97 that raised issues beyond the
scope of this rulemaking. In particular, FDA received comments
expressing concern about the safety of particular ingredients used in
infant formula. Because the safety of particular infant formula
ingredients is not at issue in this rulemaking, FDA is not responding
to these comments.
A. Quality Factors: Legal Authority
Section 412(b)(1) of the FD&C Act, which was added to the statute
by the 1986 amendments, requires that the Secretary ``. . . establish
requirements for quality factors for infant formulas to the extent
possible consistent with current scientific knowledge, including
quality factor requirements for the nutrients required by subsection
(i).''
Section 412(a)(2) of the FD&C Act deems an infant formula that does
not meet the quality factors requirements established by the Secretary
to be adulterated.
(Comment 195) One comment asserted that there is no basis in the
plain language of the statute or in its legislative history to support
an interpretation of ``normal growth'' as a quality factor, which would
establish a requirement that applies to the infant formula as a whole.
The comment cited to legislative statements and FDA testimony
concerning the Infant Formula Act or the 1986 amendments to the Infant
Formula Act as support for its assertion that Congress intended quality
factors to be limited to individual components in the infant formula,
and that the Infant Formula Act does not authorize FDA to require
clinical studies for new infant formulas, including those that have
undergone a major change.\7\
---------------------------------------------------------------------------
\7\ The comment cites to floor statements in the Senate Record
that describe the 1986 amendments as providing testing for ``each
essential nutrient'' and as further describing ``the quality factor
of nutrient content requirements of the law, as demonstrated by the
testing called for in the amendments.'' 132 Cong. Rec. S26775, 26777
(daily ed. Sept. 27, 1986). The comment also cites to a statement by
then Commissioner of Food and Drugs Jere E. Goyan stating that the
proposed legislation required ``tests, including clinical tests,
where appropriate.'' See Nutritional Quality of Infant Formula:
Hearings on H.R. 6590, H.R. 6608, H.R. 5836, and H.R. 5839 Before
the Subcomm. on Health and the Environment of the H. Comm. on
Interstate and Foreign Commerce, 96 Cong. 132, 74 (1980). The
comment notes that this statement by Commissioner Goyan was
responded to by Representative Mottl, who replied that ``I am
speaking of analysis in the chemical and nutritional laboratories,
and I am not referring to clinical trials.'' Id. at 120.
---------------------------------------------------------------------------
(Response) FDA disagrees with the suggestion that the Infant
Formula Act does not support an interpretation of ``normal growth'' as
a quality factor, or does not provide authority to require a well-
controlled growth monitoring study to ensure that a formula will
support normal physical growth. Such reasoning is flawed. Legislative
silence on an issue is not persuasive when determining the meaning of a
statute. Central Bank v. First Interstate Bank, 511 U.S. 164, 187
(1994) (stating that ``Congressional inaction lacks persuasive
significance''). Clearly, just as Congress is not expected to express
``every single evil sought to be corrected'' in a grant of authority to
issue a rule, it cannot be expected to articulate every requirement
that is within an Agency's delegated authority. American Trucking
Assoc. v. United States, 344 U.S. 298, 309-10 (1953).
In addition, the various legislative statements and Agency
testimony that the comment cites to support its assertion as to the
meaning of ``quality factors'' are not on point. First, the
congressional statements the comment cites to support its assertion
that FDA lacks the authority to require testing of the infant formula
as a whole (see footnote 1) discuss testing in the context of
laboratory analysis of required nutrients; the statements in question
do not relate to quality factors. Additionally, the Agency testimony
cited by the comment, stating that Congress did not intend the use of
clinical testing, comes from a discussion of the Infant Formula Act's
recall provisions. Second, even if these congressional statements and
FDA testimony were relevant, such isolated statements are not
sufficient evidence of congressional intent. See Weinberger v. Rossi,
456 U.S. 25, 34-35 (U.S. 1982) (rejecting the argument that a single
statement of a sponsor taken out of context should be determinative of
congressional intent); Regan v. Wald, 468 U.S. 222, 237 (1984)
(explaining that testimony of Senators and Representatives and
witnesses can seldom be expected to be as precise as the language of
the enacted bill, and should not later be permitted to undermine the
bill).
FDA disagrees that there is no basis under the infant formula
provisions of the FD&C Act to require a well-controlled growth
monitoring study that demonstrates normal physical growth. Under
section 412(a) of the FD&C Act, Congress stipulated that infant formula
``shall be deemed to be adulterated if . . . such infant formula does
not meet the quality factor requirements prescribed by the Secretary .
. . .'' Section 412(b)(1) of the FD&C Act further provides that ``[t]he
Secretary shall by regulation establish requirements for quality
factors for infant formulas to the extent possible consistent with
current scientific knowledge, including quality factor requirements for
the nutrients required by subsection (i).''
In construing the meaning of the term ``quality factors,'' FDA is
confronted with two questions. First, has Congress directly and
unambiguously spoken to the precise question at issue (``Chevron step
one'') Chevron U.S.A. Inc. v.Natural Resources Defense Council, 467
U.S. 837, 842 (1984)? To find no ambiguity, Congress must have clearly
manifested its intention with respect to the particular issue. See
Young v. Community Nutrition Institute, 476 U.S. 974, 980 (1986). If
Congress has spoken directly and plainly, the Agency must implement
Congress's unambiguously expressed intent. Chevron, 467 U.S. at 842-
843.
Second, if the FD&C Act is silent or ambiguous with respect to the
meaning of ``quality factors'' in section 412(b)(1) of the FD&C Act, is
the Agency's interpretation based on a permissible construction of the
statute (``Chevron step two'') Chevron, 467 U.S. at 842-843; FDA v.
Brown & Williamson Tobacco Corp., 529 U.S. 120, 132 (2000)? When, as is
the case here, Congress leaves a gap for the Agency to fill by
regulation, the regulation will pass muster so long as it is not
``arbitrary, capricious, or manifestly contrary to the statute.''
Chevron, 467 U.S. at 844.
The language in section 412(b)(1) of the FD&C Act provides an
express delegation of authority to ``by regulation establish
requirements for quality factors for infant formulas to the extent
[[Page 8004]]
possible consistent with current scientific knowledge.'' This language
necessarily contemplates broad Agency discretion to define the
requirements for ``quality factors,'' limited by current scientific
knowledge.
Congress also spoke to the precise question of whether ``quality
factors requirements'' were limited in application to the individual
nutrients required to be in the formula under section 412(i) of the
FD&C Act. Congress did not expressly limit quality factors in this way.
Rather, the statutory language describing what requirements for quality
factors are to be established states that the Secretary shall by
regulation establish ``quality factors for infant formulas . . .
including quality factor requirements for the nutrients required by
subsection (i).'' The use of the word ``including'' demonstrates that
Congress did not intend to limit quality factors for infant formulas to
the nutrients in subsection (i). 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''); Eric C. Surrette et.
al., American Jurisprudence Sec. 130 (2nd ed. 2008) (explaining that
``a statutory definition of a term as 'including' certain things does
not necessarily put a meaning thereon limited to the inclusion''); Gray
v. Powell, 314 U.S. 402 (1941) (explaining that ``[t]he definition of
disposal as including 'consumption or use by a producer, and any
transfer of title by the producer other than by sale' cannot be said to
put a meaning on disposal limited to the inclusion.''); Herb's Welding
v. Gray, 470 U.S. 414, 415, n. 9 (1985) (noting that by use of the term
``including,'' Congress indicated that the occupations specifically
mentioned in the law are not exhaustive). In sum, the infant formula
provisions of the FD&C Act direct the Agency to establish quality
factor requirements for infant formulas to the extent possible
consistent with current scientific knowledge, without limitation to
requirements relating only to the nutrients specified by statute to be
included in all infant formulas. Congress did not, however, define the
term ``quality factors,'' nor did it describe what such quality factors
might be. Instead Congress left a gap for the Agency to fill by
regulation.
Because Congress left a gap for the Agency to define the term
``quality factors'' and determine what quality factor requirements are
consistent with current scientific knowledge, under Chevron step two,
FDA may define the term and determine what quality factor requirements
may be imposed, provided that FDA's interpretation is not arbitrary,
capricious, or manifestly contrary to the statute. Chevron, 467 U.S. at
844. Accordingly, when defining quality factors, FDA should consider
the language itself, the placement of the language in the infant
formula provisions of the FD&C Act, and other tools of statutory
construction, including the purpose and the legislative history of the
Infant Formula Act and the 1986 Amendments, as well as the FD&C Act.
See Barnhart v. Peabody Coal Co., 537 U.S. 149, 160 (2003) (looking to
structure, purpose, and legislative history to interpret the Coal Act);
see also Chevron, 467 U.S. at 843 (noting that if a statute is silent
with respect to an issue the Agency's answer to the issue should be
based on a permissible interpretation of the statute).
The language in the infant formula provisions of the FD&C Act does
not define ``quality factors,'' but it does define the scope of
authority that Congress left FDA to establish quality factor
requirements. As noted previously in this document, according to the
language in section 412(b)(1) of the FD&C Act, quality factors include
requirements related to nutrients in section 412(i) of the FD&C Act,
but are not limited to such nutrients. This statutory language
indicates that the Secretary must establish quality factors for (1) the
individual nutrient components required under subsection (i), and, (2)
the infant formula as a whole to the extent possible consistent with
current scientific knowledge. If Congress had intended quality factors
to be limited to individual nutrient components of the formula, such as
protein and other nutrients that are added to the formula, Congress
would not have needed to incorporate the ``including'' language
referencing nutrients required by subsection (i).
The organization of section 412 of the FD&C Act aids in
interpreting the intended meaning of quality factors. The statutory
provisions for quality factor requirements are separate and distinct
from the provisions for requirements related to CGMP and quality
control procedures in section 412(b)(2)(A) and (b)(2)(B) of the FD&C
Act. The placement of quality factor requirements in a separate
statutory provision means that such requirements pertain to something
other than the CGMP and quality control provisions that, in part,
ensure that particular nutrients are present at particular levels in
each production aggregate of infant formula. The preamble to the
proposed rule recognized that quality control procedures and quality
factor requirements are separate and distinct: ``While quality control
procedures are intended to ensure that the safety and nutritional
potency of a formula is built into the manufacturing process,'' quality
factors are ``intended to ensure that an infant formula contains an
adequate amount of each nutrient in a form that can be digested,
absorbed, and utilized so that the infant's physiological needs for
these nutrients will be met'' (61 FR 36154 at 36179). Thus, the quality
factors pertain not to a measurement of the amount of each nutrient in
the formula, but to a broader concept of bioavailability; an infant
formula as a whole and the individual nutrients in the infant formula
must meet the physiological needs of infants when fed the formula as a
sole source of nutrition to foster normal growth and development. As
noted previously in this document, under the language of section 412 of
the FD&C Act, Congress required the Secretary to establish quality
factors for the infant formula as a whole as well as for individual
nutrients to the extent that is consistent with current scientific
knowledge. Thus, interpreting the infant formula provisions of the FD&C
Act to mean that quality factor requirements that apply to the infant
formula as a whole would pertain to the ability of the formula (i.e.,
all the nutrients in combination) to meet an infant's physiological
needs, is reasonable. The quality factor of ``normal physical growth''
is designed to demonstrate the ability of the infant formula as a whole
to meet such physiological needs.
Establishing normal physical growth as a quality factor requirement
is consistent with the overall purpose of the Infant Formula Act. The
need for an Infant Formula Act was discussed in the wake of the
marketing of two infant formulas that ``were critically deficient in
chloride, a life sustaining nutrient.'' S. Rep. No. 96-359, at 3
(1980). The Infant Formula Act was meant to provide the Secretary with
the means to ensure that formula ``will promote healthy growth'' in
infants. H.R. Rep. No. 96-936, at 3 (1980). ``Normal physical growth''
is an essential component of ``healthy growth,'' thus a quality factor
requirement for the demonstration of normal physical growth is
consistent with the overall purpose of the Infant Formula Act.
Additionally, a report from the House Committee on Interstate Commerce
that accompanied the Infant Formula Act supports the view that, as
originally
[[Page 8005]]
enacted, the Infant Formula Act authorizes the establishment of quality
factor requirements for normal physical growth. The report states:
``Quality factors pertain to the bioavailability of the nutrient . . .
.'' H.R. 96-936, at 6 (1980).
In the 1986 amendments to the Infant Formula Act Congress clarified
that quality factor requirements demonstrating the ``bioavailability of
the nutrient'' referred to all nutrients combined in a formula as well
as to individual nutrients. See 21 U.S.C. 350a(b)(1). The Infant
Formula Act stated that the Secretary may by regulation ``establish
requirements for quality factors for such nutrients [required by
subsection (g)].'' Infant Formula Act of 1980, Public Law 96-359, Sec.
2, 94 Stat. 1190 (1980). In 1986, however, the infant formula
provisions were amended to specify in revised section 412(b)(1) of the
FD&C Act that the ``Secretary shall by regulation establish
requirements for quality factors for infant formulas, . . . including
quality factor requirements for the nutrients required by subsection
(i).'' (Emphasis added). This amendment clarified that quality factor
requirements applied to the ``infant formula'' as a whole as well as to
the individual nutrients required by subsection (i), and also made the
establishment of requirements for quality factors mandatory.
Additionally, normal physical growth is an appropriate means to
assess whether the infant formula as a whole meets the physiological
needs of infants. Infants frequently consume formula as the sole or
primary source of nutrition at a time when the requirements for
nutrients are higher per kilogram body weight than at any other time
during the life cycle. The net effect for an infant who consumes an
infant formula that provides required nutrients in a bioavailable form
is the ability of the infant to achieve normal physical growth. Normal
physical growth is an indicator that an infant is thriving and is
inextricably linked to the bioavailability of nutrients in an infant
formula as a whole. Normal physical growth is an ``integrative
indicator of the net effect of the overall nutritional quality of the
formula'' (61 FR 36154 at 36180). Additionally, anthropometric
measurements of length, weight, and head circumference are easily made,
familiar to health care professionals, and are the same measurements as
those done during routine office visits and for which standardized
growth charts are available for comparison. Also, there is a very large
amount of data available on what constitutes ``normal physical
growth.'' Thus, it is reasonable for the Agency to require the conduct
of a well-controlled growth monitoring study, when necessary, to
determine whether an infant formula meets the quality factor of normal
physical growth.
Further, requiring such a study is reasonable when considering the
statutory scheme as a whole. See Brown & Williamson, 529 U.S. at 133
(explaining that the words of a statute must be read in the context of
the overall statutory scheme). FDA's explicit statutory mission is, in
part, to protect the public health by ensuring that foods (including
infant formula) are safe, wholesome, sanitary, and properly labeled
(section 903(b)(2)(A) of the FD&C Act) (21 U.S.C. 393(b)(2)(A)).
Further, the FD&C Act touches ``phases of the lives and health of
people which, in the circumstances of modern industrialism, are largely
beyond self-protection. Regard for these purposes should infuse
construction of the legislation if it is to be treated as a working
instrument of government and not merely as a collection of English
words.'' United States v. Dotterweich, 320 U.S. 277, 281 (1943); see
also United States v. Park, 421 U.S. 658, 668 (1975). The Infant
Formula Act and the 1986 amendments were meant to ensure the ``safety
and nutrition'' of infant formulas, a purpose achieved, in part, by
growth monitoring studies. See Infant Formula Act of 1980, Public Law
96-359, 94 Stat. 1190, 1190 (1980) (prior to 1986 amendment).
Section 701(a) of the FD&C Act authorizes FDA to issue regulations
for the efficient enforcement of the FD&C Act in order to ``effectuate
a congressional objective expressed elsewhere in the Act'' (Association
of American, Physicians and Surgeons, Inc. v. FDA, 226 F. Supp. 2d 204,
213 (D.D.C. 2002) (citing Pharm. Mfrs. Ass'n. v. FDA, 484 F. Supp.
1179, 1183 (D. Del. 1980)). The validity of such regulations issued
under section 701(a) of the FD&C Act is determined by a consideration
of the ``statutory purpose'' of the FD&C Act, as well as an
``understanding of what types of enforcement problems are encountered
by the FDA [and] the need for various sorts of supervision to
effectuate the goals of the Act.'' National Confectioners Assoc. v.
Califano, 569 F.2d 690, 693 (D.C. Cir 1978) (citing Toilet Goods Ass'n
v. Gardner, 387 U.S. 158, 163-64); see also Association of American
Physicians and Surgeons, Inc., 226 F. Supp. 2d at 213; NVE Inc. v. HHS,
436 F.3d 182, 186-190 (3d Cir. 2006) (noting that section 701(a) of the
FD&C Act grants FDA broad discretion to issue regulations for the
efficient enforcement of the FD&C Act within the scope of the authority
granted to it by Congress).
The interim final rule falls within FDA's discretion to issue
regulations for the efficient enforcement of the FD&C Act. The interim
final rule is designed, in part, to help ensure that infant formulas,
when fed as a sole source of nutrition, will support normal physical
growth in infants consuming the formula. The requirement to conduct a
well-controlled growth monitoring study is designed to determine
whether normal physical growth may be achieved using a particular
infant formula. Such a study is consistent with the purpose of the
Infant Formula Act, because it provides a mechanism by which FDA can
determine whether the formula promotes one of the factors contributing
to healthy growth (i.e., normal physical growth). See H.R. Rep. No. 96-
936, at 3 (1980). The requirement to conduct such a study is written to
facilitate efficient and effective action to enforce the FD&C Act's
terms when necessary. The requirement to conduct a well-controlled
growth monitoring study is also consistent with FDA's overall mission,
because the study helps to ensure that the formula is safe and
wholesome. (See section 903(b)(2)(A) of the FD&C Act (21 U.S.C.
393(b)(2)(A))).
FDA acknowledges that a well-controlled growth monitoring study may
not be necessary to demonstrate normal physical growth for every new
infant formula, including a change to a marketed formula that results
in a new infant formula. Thus, FDA has included in the interim final
rule exemptions from the requirement to conduct a well-controlled
growth monitoring study for certain changes in processing or methods
and, in addition, an opportunity for a manufacturer to demonstrate that
an alternative study design or method would provide assurances that an
infant formula supports normal physical growth or that a change to a
formula that has already been shown to meet the quality factor
requirements does not affect the bioavailability of the new formula,
including its nutrients. In addition, it is reasonable and necessary
for efficient enforcement of the FD&C Act for FDA to require that a
manufacturer make and retain records demonstrating that the formula
meets the quality factor of normal physical growth, and that certain
records related to the requirement to conduct a growth monitoring study
be included in the submission required in section 412(c)(1)(B) of the
FD&C Act (21 U.S.C. 350a(c)(1)(B)). Under section 412(d)(1)(C) of the
FD&C Act (21 U.S.C.
[[Page 8006]]
350(d)(1)(C)), assurances that the requirements for quality factors
have been met must be provided in a submission. FDA is requiring that
the assurances related to the quality factor requirements in the
submission be included in the form of a record that FDA can review
prior to the marketing of the infant formula to determine whether the
infant formula is adulterated under section 412(a)(2) of the FD&C Act.
Without records, FDA would not be able to evaluate whether an infant
formula meets the quality factor requirements, such as normal physical
growth.
For example, when a growth monitoring study is required, FDA needs
certain data and information to evaluate the growth of the study
participants (infants) who have been fed the infant formula under
study. As discussed in this document, Sec. 106.96(d) of the interim
final rule requires manufacturers to make records demonstrating that
the formula meets the quality factor of normal physical growth.
Additionally, Sec. 106.121 of the interim final rule requires a
manufacturer to submit certain data and information that are required
to be collected during the growth monitoring study and that are
necessary to assess whether the infant formula supports normal physical
growth. These data include all measurements for each feeding group at
the beginning of the study, and at every point where measurements were
made throughout the study. Without these data, and other data and
information, FDA would not be able to assess whether the formula
supports normal physical growth.
For the reasons stated previously in this document, it is
reasonable and appropriate under Chevron for the FDA to establish
normal physical growth as a quality factor requirement for infant
formula. Further, it is reasonable to include a requirement to conduct
a well-controlled growth monitoring study to evaluate whether an infant
formula complies with the quality factor requirement of normal physical
growth, and to require records related to such requirement.
B. Quality Factors for Infant Formulas
Section 106.96 of the 1996 proposed rule identified two infant
formula quality factors: All infant formulas must be capable of
supporting infants' normal physical growth and all infant formulas must
be formulated and manufactured to ensure that the protein is of
sufficient biological quality to satisfy infants' protein requirements.
The term ``quality factors'' was defined in proposed Sec. 106.3(o) 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.'' In the preamble to the 1996 proposed rule (61 FR at
36179), FDA explained that ``healthy growth'' is a broad concept,
encompassing all aspects of physical growth and normal maturational
development, including maturation of organ systems and achievement of
normal functional development of motor, neurocognitive, and immune
systems. All of these growth and maturational developmental processes
are major determinants of an infant's ability to achieve his/her
biological potential, and all can be affected by the nutritional status
of an infant.
To determine whether a formula supports normal physical growth in
infants when fed as the sole source of nutrition, proposed Sec.
106.97(a) would have required a formula manufacturer to conduct an
``adequate and well-controlled clinical study.'' Proposed Sec.
106.97(b) would also have required a formula manufacturer to collect
and maintain data to demonstrate that the biological quality of a
formula's protein is sufficient to meet the needs of infants.
As discussed in more detail in this document, in both the 2003 and
2006 reopenings, several issues related to requirements for quality
factors were identified for additional comment. In response to comments
and on its own initiative, FDA is reorganizing and consolidating into
Sec. 106.96 of the interim final rule most of the content of proposed
Sec. Sec. 106.96 and 106.97 related to requirements for infant formula
quality factors.
C. Quality Factor: Normal Physical Growth
In 1996, FDA proposed (Sec. 106.96(b)) ``normal physical growth''
as a quality factor for infant formula and stated that such growth is a
necessary indicator of the overall nutritional quality of a formula.
The Agency's proposal was consistent with the view of the Committee on
Nutrition of the American Academy of Pediatrics (CON/AAP) that the
determination of physical growth is the most valuable component of the
clinical evaluation of an infant formula (Ref. 67). FDA noted that
physical measures of growth (e.g., weight gain) are a widely accepted
measure of an infant's overall ability to utilize a formula's
nutrients, are familiar to practitioners and parents, are readily made,
and are not invasive.
In the 2003 reopening, the Agency expressly requested comment on
the two quality factors that it had tentatively identified in the 1996
proposal: Normal physical growth and protein biological quality. In
particular, FDA requested comment on the appropriateness of these
quality factors and any information on other quality factors that could
be implemented consistent with current scientific knowledge, as
required under section 412(b)(1) of the FD&C Act.
This interim final rule establishes as part of Sec. 106.96(a) the
general quality factor of ``normal physical growth.'' (As discussed in
section IV. C., the proposed definition of ``quality factors'' has been
slightly revised in Sec. 106.3.) FDA considered comments received from
the public, as discussed in this document, when including ``normal
physical growth'' as one quality factor.
(Comment 196) Several comments supported FDA's proposal to
designate ``normal physical growth'' as a quality factor for all non-
exempt infant formulas. One comment stated that overall physical growth
and protein quality are reasonable benchmarks, assuming that the
formula contains all nutrients required by law.
(Response) FDA agrees with the comments that support the
establishment of ``normal physical growth'' and ``protein quality'' as
infant formula quality factors. In considering the provision for
``normal physical growth,'' the Agency notes the IOM's conclusion (Ref.
4, p. 105): ``Growth is well recognized as a sensitive, but
nonspecific, indicator of the overall health and nutritional status of
an infant. Monitoring infant growth has always been an integral part of
pediatric care and is particularly important for young infants.''
(Comment 197) Another comment agreed that growth is clearly an
indicator of bioavailability but nonetheless challenged the Agency's
proposal to define ``normal physical growth'' as a quality factor,
asserting that few changes in an infant formula raise bioavailability
questions and objecting to the routine demonstration of growth relative
to most changes in an infant formula.
(Response) FDA disagrees with this comment for two reasons. First,
the comment does not dispute--indeed, agrees--that growth is a clear
indicator of formula bioavailability. Thus, the comment does not erode
or otherwise undermine FDA's rationale for defining ``normal physical
growth'' as a quality factor for infant formula. Second, although the
comment asserts that few changes in infant formulas create
[[Page 8007]]
bioavailability issues, the comment provided no data or other
information to support this assertion. The Agency notes that, among
others, the IOM has recognized that infant formula matrix changes can
highly influence nutrient bioavailability (Ref. 4, p. 45). In addition,
the interim final rule provides an exemption for new infant formulas
from the requirements for a growth monitoring study in Sec. 106.96(b),
if the formula manufacturer provides assurances that demonstrate that
the change made to the existing formula does not affect the
bioavailability of the formula, including the nutrients in such
formula.
Accordingly, the interim final rule establishes ``normal physical
growth'' as a quality factor for infant formula.
1. Appropriateness of a Growth Monitoring Study (GMS)
In the 1996 proposal, FDA proposed to require (Sec. 106.97(a)(1))
that a manufacturer conduct an adequate and well-controlled clinical
study, in accordance with good clinical practice, to determine whether
an infant formula supports normal physical growth when fed as the sole
source of nutrition. Proposed Sec. 106.97(a)(1)(i) would have required
that the manufacturer conduct a clinical study of at least four months
with study participants enrolled at no more than one month in age; that
the manufacturer collect, maintain, and plot on a growth chart certain
anthropometric measurements; and that these data be collected at
specified times. In addition, proposed Sec. 106.97(a)(1)(ii) included
nine proposed recommendations for the protocol of the clinical study.
FDA addressed the proposed clinical study requirement in the 2003
reopening. At that time, the Agency requested comment on three specific
issues related to the clinical study requirement (requirements for
determining when a clinical study should be required; appropriate
reference data; and the appropriate infant enrollment age). In
addition, the Agency announced its intention to remove the proposed
provision addressing Institutional Review Board (IRB) review and
approval (proposed Sec. 106.97(a)(1)(ii)(C)) as a result of Agency
rulemaking since the 1996 proposal and its plan to remove the remaining
protocol recommendations from the proposed rule and to develop a
guidance document containing recommendations for the protocol for an
infant formula clinical growth study (68 FR at 22342-22343).
Thereafter, in the 2006 reopening, the Agency requested comment on
several recommendations of the 2004 IOM report, including the need for
assessments of normal physical growth in addition to a clinical growth
study, the need for body composition measurements, and the appropriate
duration of and enrollment age for a clinical growth study.
This interim final rule includes a growth monitoring study
requirement in Sec. 106.96(b). This provision requires that a
manufacturer of infant formula satisfy the quality factor of ``normal
physical growth'' by conducting an adequate and well-controlled growth
monitoring study to demonstrate that the formula supports normal
physical growth in infants when fed as the sole source of nutrition.
The interim final rule substitutes the descriptor ``growth monitoring
study'' for ``clinical study,'' the term used in the proposed rule,
because the new term more accurately describes the nature and purpose
of the study. Section106.96(b) of the interim final rule establishes
requirements for the growth monitoring study, which address study
duration; subject age at enrollment; data collection and maintenance;
and comparison of data for study subjects and controls. In addition,
parts 50 and 56 require IRB review and approval and human subject
protection.
As discussed in more detail in this document, Sec. 106.96(c) of
the interim final rule provides certain exemptions from the growth
monitoring study requirements under Sec. 106.96(b).
(Comment 198) One comment recommended that a clinical growth study
be required for any new infant formula, change in the infant formula,
or change in the packaging of infant formula. To justify this
recommendation, the comment explained that infant formula is unique in
that it can be the sole source of nutrition for an infant for an
extended period and during a most vulnerable time.
(Response) FDA recognizes that infant formula often serves as the
sole source of nutrition for a vulnerable population during a
critically important developmental period, a consideration that broadly
underlies the interim final rule. To the extent that the comment
suggests that a growth monitoring study be required for all formulas,
including formulas that have undergone a ``major change'' in processing
or in composition, the Agency concludes that the requirements of the
interim final rule effectively achieve the outcome recommended by this
comment. Specifically, Sec. 106.96(b) of the interim final rule
requires a manufacturer to conduct a growth monitoring study of each
``infant formula,'' and Sec. 106.96(c) of the interim final rule
includes provisions for specific exemptions from that requirement where
a manufacturer can establish that the formula is entitled to the
exemption.
(Comment 199) One comment stated that while the future introduction
of novel ingredients in infant formula (such as components of human
milk not presently in infant formulas) may present new challenges to
the regulatory process, safety concerns about an ingredient new to
infant formula are better handled under the regulatory rubrics
specifically designed for ingredient evaluation, and that FDA's
Generally Recognized As Safe (GRAS) notification process provides the
Agency with a context in which to raise any safety concerns, including
concerns about matrix issues, processing issues, or nutrient
interactions.
(Response) As discussed in detail in this document, FDA agrees in
part with this comment. Ingredient safety is a basic principle of food
safety, for both food generally and for infant formula specifically. As
is the case with all foods, a manufacturer has an on-going
responsibility to ensure the safety of each ingredient in its products
and each substance produced for addition to food and to ensure that
such ingredients and substances are otherwise in compliance with all
applicable legal and regulatory requirements.
An ingredient newly intended for use in infant formula is
appropriately evaluated under section 409 of the FD&C Act as a food
additive or may be an ingredient that the manufacturer has determined
to be generally recognized as safe (GRAS) under section 201(s) of the
FD&C Act. For ingredients believed to be GRAS, FDA strongly encourages
the formula manufacturer or the ingredient supplier to submit the self-
determination of GRAS to FDA under the Agency's GRAS notification
program (see 62 FR 18937, April 17, 1997) well before the submission of
a new infant formula notification under section 412(c) of the FD&C Act.
Importantly, however, the review of a food additive petition under
section 409 of the FD&C Act or the evaluation of a GRAS notice for an
ingredient new to infant formula is separate and distinct from the
provision that a formula meet the quality factor requirements under
section 412(b)(1) of the FD&C Act. That is, FDA's evaluation and
determination of an ingredient's safety in response to a food additive
petition or FDA's response to a GRAS notice does not address the
scientific issue to be addressed by the quality factors, which is
whether the formula matrix and
[[Page 8008]]
individual nutrients in the formula support normal physical growth. In
section IV.C.7. FDA explained in the discussion of the ``quality
factors'' definition the criticality of ensuring the bioavailability of
the formula's nutrients in a particular formula matrix, including the
nutrients in the formula, and ensuring that an infant formula
containing the new ingredient is capable of supporting normal physical
growth.
Similarly, the ingredient safety review does not eliminate the
responsibility of an infant formula manufacturer to make the submission
required by section 412(d)(1) of the FD&C Act for each new infant
formula that the manufacturer wishes to market. Under section 412 of
the FD&C Act, any new formula ingredient is evaluated as part of a
complete formulation, and, as noted, under section 412(d)(1)(C) of the
FD&C Act, the new infant formula manufacturer must provide assurances
that the formula satisfies the requirements for quality factors for
specific nutrients and for the formula as a whole.
For these reasons, FDA is making no changes in response to this
comment.
(Comment 200) One comment suggested that the assurances under all
paragraphs of proposed Sec. 106.97(a) be deleted from the final rule
citing general legal, scientific, and policy grounds to these
provisions.
(Response) As explained previously in this document, proposed Sec.
106.97(a) has been removed from the interim final rule, and much of its
content is retained in Sec. 106.96(b) of the interim final rule.
Despite this revision, FDA responds to the substance of this comment.
Infant formulas must be able to serve as the sole source of
nutrition for a period of unparalleled growth and development of
infants in a form that will meet all of the known nutritional needs of
infants and to ensure that healthy growth and nutritional well-being
will be achieved by an infant consuming the infant formula as the sole
source of nutrition (61 FR 36154 at 36180). The least invasive and most
practical means to ensure that the formula, as a whole, delivers
nutrients in a form that is bioavailable and safe is a growth
monitoring study in which anthropometric measurements of infants fed a
new infant formula are assessed, and comparison of these data to a
concurrent control group, in addition to comparison of both test and
controls groups to a scientifically appropriate reference, is made.
Anthropometric measurements are easily made, are familiar to parents
and health care professionals, can be measured during outpatient study
visits, and are the same measurements as those done during routine
office visits.
As discussed in more detail in this document, the requirement for a
growth monitoring study in Sec. 106.96(b) of the interim final rule
applies to all infant formulas that are introduced or delivered for
introduction into interstate commerce. This means that a manufacturer
of an infant formula for distribution in the U.S. is required to
conduct a growth monitoring study under Sec. 106.96(b) of the interim
final rule, unless the manufacturer qualifies for an exemption under
Sec. 106.96(c) of the interim final rule from the growth monitoring
study requirements of Sec. 106.96(b) of the interim final rule, as
explained in section VIII.C and D, respectively. A manufacturer of a
``new'' infant formula is required to submit such study to FDA in a 90-
day submission, consistent with Sec. 106.120 of the interim final rule
and section 412(c)(1)(B) and (d)(1)(C) of the FD&C Act. As is discussed
in further detail in this document, a manufacturer of an ``eligible
infant formula'' (as defined in Sec. 106.3 of the interim final rule)
would not be required to make the submission required by Sec. 106.120
of the interim final rule and sections 412(c)(1)(B) and (d)(1)(C) of
the FD&C Act, but would be required under Sec. 106.96(d) of the
interim final rule to make and retain records demonstrating that the
formula meets the quality factor of normal physical growth. The need
for a growth monitoring study of an infant formula for export only is
addressed in section VIII. D.
FDA recognizes that not every change in an infant formula or change
in the packaging of infant formula will require a growth monitoring
study. In recognition of this fact, Sec. 106.96(c) of the interim
final rule includes several exemptions from the growth monitoring study
requirement, which are discussed in section VIII.D, ``Exemptions From
Quality Factor Requirements for Normal Physical Growth.''
(Comment 201) One comment on proposed Sec. 106.97 stated that FDA
is correct to insist that new substances themselves added to formula be
GRAS.
(Response) FDA believes that it is important to clarify FDA's
conclusions regarding the GRAS status of substances in formula. As
discussed previously in this document, all food manufacturers,
including infant formula manufacturers, have a duty to ensure that the
ingredients in their products satisfy the applicable statutory
standard. Under section 409 of the FD&C Act, a substance added to food
must be either an approved food additive or exempt from the definition
of food additive because it is GRAS.
(Comment 202) One comment argued that safety issues, including the
potential impact on infant growth, need to be raised and resolved, and
that in order to prevent unnecessary and invasive clinical studies,
animal studies should be relied upon as much as possible.
(Response) FDA disagrees with this comment for two reasons. First,
the study required by Sec. 106.96(b) of the interim final rule is a
growth monitoring study and is entirely non-invasive. Indeed, the
anthropometric measurements required of study participants are the same
measurements that are typically taken by a health care provider at
``well baby'' visits. Second, FDA is not aware of an animal model that
is a suitable substitute for the infants in a growth monitoring study,
and the comment provided no information about such a model.
(Comment 203) One comment acknowledged that the methodology to
conduct an adequate and well-controlled clinical study is
scientifically ideal to answer the question of whether a new substance
added to an existing formula has an effect on the bioavailability of a
nutrient required for infant growth. The comment also noted that not
every change in an infant formula raises questions about infant growth
that cannot be answered adequately by other supporting scientific data,
and provided references to sources of information that might be used
for this purpose.
(Response) FDA agrees with the comment's assessment of the value of
clinical study methodology to evaluate the ability of an infant formula
to support the normal physical growth of infants. FDA also agrees with
the comment that not every change in an infant formula would require a
growth monitoring study. This issue is discussed in detail in section
VIII.D.
(Comment 204) Another comment stated that routine growth studies
are not designed and generally not powered to detect rarely occurring
adverse events and therefore, are not comprehensive safety studies. The
comment argues that new ingredients are often substances identified in
human milk as having a nutritional function and that a case-by-case
review of available evidence can identify when there is a need for
safety endpoints in clinical studies.
(Response) Normal physical growth and protein quality are very
basic benchmarks for evaluating healthy growth of infants when fed an
infant formula as the sole source of nutrition. FDA agrees that growth
studies are not
[[Page 8009]]
designed and do not have sufficient statistical power to detect rarely
occurring adverse events. Importantly, however, the purpose of the
growth monitoring study is to assess the ability of an infant formula,
including the nutrients in the formula, to support normal physical
growth. To the extent that the ingredients may present safety concerns,
those issues are primarily addressed as part of the review under
sections 409 and 201(s) of the FD&C Act.
2. Clinical Study Protocols
In proposed Sec. 106.97(a)(1)(ii), FDA listed provisions that it
recommended manufacturers include in a clinical study protocol. In the
notice to reopen the comment period in 2003 (68 FR 22341 at 22343), FDA
stated its intent to remove the clinical study protocol provisions in
proposed Sec. 106.97(a)(1)(ii) and develop a guidance document
detailing the Agency's recommendations for what should be included in
the protocol for a clinical study that will be submitted to FDA as
``assurance'' that the formula satisfies the quality factor of normal
physical growth. Comments received in response to the 2003 reopening
agreed with FDA's view that detailed directions for the clinical study
protocols would be better addressed as guidance from the Agency. No
comments were received that suggested retaining the proposed clinical
study protocol provisions in the final rule. Therefore, the Agency has
deleted the specific study protocol recommendations of proposed Sec.
106.97(a)(1)(ii).
However, as discussed in section VIII. C., Sec. Sec. 106.96 and
106.121 of the interim final rule incorporate some of the proposed
study protocol recommendations as requirements in the interim final
rule. To the extent that proposed recommendations have become
requirements, FDA will address the comments received on those specific
recommendations. Otherwise, the Agency is not individually addressing
the comments submitted on those recommendations not incorporated into
the interim final rule. FDA will consider developing guidance in the
future on the protocol for a growth monitoring study of infant formula
and will consider relevant comments during the development of such
guidance.
As stated previously in this interim final rule, FDA has not
included all of the clinical study protocol recommendations that were
included in the 1996 proposal. The Agency has concluded, however, that
certain basic elements of study design, data collection, and evaluation
are necessary to ensure that a growth monitoring study provides the
quality and type of data needed to evaluate whether an infant formula
supports normal physical growth when fed as the sole source of
nutrition. Therefore, those elements have been codified in Sec. Sec.
106.96(b) and 106.121 of the interim final rule. In the responses to
the comments that follow, FDA explains the reasons for including these
elements.
3. Design of a Growth Monitoring Study
a. Appropriate study design. Several comments addressed the design
of growth monitoring studies of infant formulas.
(Comment 205) One comment stated that the requirement in proposed
Sec. 106.97(a)(1) that the study be ``well-controlled'' was too vague
to be meaningful and suggested that acceptable controls should be
specified.
(Response) For several reasons, FDA disagrees with this comment and
declines to specify acceptable controls for infant formula growth
monitoring studies. First, the concept of ``well-controlled'' is
generally well understood in the scientific community. The primary
purpose of conducting a well-controlled study is to distinguish the
effect of the treatment (here, feeding of the infant formula being
evaluated) from other influences, such as chance occurrences, normal
growth, or biased observation. A well-controlled study methodically
examines sameness and differences in outcomes across cohorts and
permits an organized comparison and the delineation of sameness and
difference.
Further, it would be unnecessarily restrictive to identify in a
regulation the specific type or types of controls that, if used in a
growth monitoring study, would make the study ``well-controlled.'' The
appropriateness of a particular control group or of other controls is
determined in part by the nature of the study and of the group being
studied. Accordingly, it is not possible for FDA to specify a priori
the controls relevant and appropriate to a particular growth monitoring
study. Thus, FDA is not revising this provision in the interim final
rule to elaborate on the controls needed to make an infant formula
growth monitoring study ``well-controlled.''
To the extent that the interim final rule addresses the specific
requirements of a growth monitoring study, FDA has clarified, by adding
Sec. 106.96(b)(4) and (b)(5) to the interim final rule, that the
protocol of a well-controlled growth monitoring study would require
information on infant formula intake for both the test and control
groups. A study that lacks formula intake data would be difficult to
interpret and could lead to erroneous conclusions regarding the
formulas being fed. Clearly, the relationship between formula intake
and growth is basic to the evaluation of an infant formula's capacity
to support normal physical growth. Therefore, any study of infants in
which normal physical growth is being assessed would include the
collection of formula intake data as part of the design of the study.
These data are needed to provide fair and meaningful interpretation of
the study results and to demonstrate whether the new formula is able to
support normal physical growth. To clarify the specific controls
expected in a study designed to evaluate whether an infant formula
supports normal physical growth when fed as the sole source of
nutrition, FDA is adding Sec. 106.96(b)(2) to the interim final rule
to require the growth study to include collection and maintenance of
data on infant formula intake and Sec. 106.96(b)(5) to require
comparison of the data on formula intake of the test group(s) and
control group(s), with each other and with a scientifically appropriate
reference to determine whether both groups had consumed age appropriate
volumes.
(Comment 206) Another comment stated that the design of the study
should address the specific objectives of the study.
(Response) FDA agrees with this comment. One characteristic of an
adequate and well-controlled study is that the protocol for the study
includes a clear statement of the study objective(s). Likewise, a
report of study results should also contain a clear statement of the
objective of the investigation. See, e.g., 21 CFR 314.126(b)(1) and
514.117(b)(1).
(Comment 207) One comment stated that a randomized clinical study,
with or without reference to an outside standard, is the best method to
assess whether infants receiving different feeding regimens differ in
terms of a primary outcome parameter. The comment also stated that this
research methodology is recognized as the most definitive method of
determining whether an intervention has the postulated effect.
(Response) FDA agrees that a randomized study design is generally
regarded as the strongest experimental design to determine whether an
intervention (i.e., feeding a new formulation of an infant formula) has
the postulated effect because this study design requires a concurrent
control group. For this reason, the interim final rule requires that
the growth monitoring study of an infant formula be an
[[Page 8010]]
adequate and well-controlled study, which would include randomizing
study participants into the treated and control groups.
Indeed, the purpose of a growth monitoring study is to evaluate
whether an infant formula supports normal physical growth by comparing
the growth of infants consuming the test formula with the growth of
infants consuming a baseline formula. Although weight is the most
sensitive indicator of infant growth, no single anthropometric
measurement provides all the information needed to assess growth.
Measures of length and head circumference provide additional
information on whether the formula supports normal physical growth.
Plotting these measures on growth charts for each infant in the test
and control groups provides information about how the infants in both
groups are growing compared to a reference population of infants.
Plotting weight and length on the weight for length charts is an
additional safety check that the infant is growing proportionally (not
too thin or too heavy for the measured length) relative to the norms
represented by the charts.
FDA received several comments on the proposal to require concurrent
control groups.
(Comment 208) One comment disagreed with the Agency on the value of
a concurrent control group in studies conducted in accordance with
proposed Sec. 106.97(a)(1). The comment asserted that historical
control data based on normal infants are available from Fomon and
Nelson (Ref. 68) and Guo et al. (Ref. 69) and that these data are
generally more appropriate than concurrent controls because the data
are based on a large number of normal infants studied under well-
defined conditions.
(Response) FDA disagrees in part with this comment. The optimal
comparator for infants consuming a new formulation of an infant formula
is a concurrent control group of infants fed a base formula. For this
reason, Sec. 106.96(b)(4) and (b)(5) of the interim final rule require
that a growth monitoring study of an infant formula use a concurrent
control group.
FDA acknowledged in the 1996 proposal that historical controls have
been used by some investigators to evaluate infant growth while being
fed a new formulation of a formula. Importantly, however, the Agency
noted that historical controls have inherent limitations, and the
differences and similarities in growth between the study infants and
the population reference standard cannot be meaningfully compared (61
FR 36154 at 36183). For example, difficulties in interpretation may
arise when the sample of infants receiving the test formula differs
significantly from the population in the historical controls; when the
variability in measures of growth in test subjects is large; when
attrition rates differ greatly between the population in the historical
controls and the infants on test; and when events occurring in the
study cannot be explained in the absence of concurrent controls.
FDA recognizes that historical control data may be useful in
certain limited situations in which a manufacturer has access to
extensive reference data, such as a database on many similarly
conducted studies in which infants were selected on the basis of nearly
identical criteria, and the results are available for all important
measurements, including formula intake and attrition rates. FDA notes
that the manufacturer is responsible for demonstrating that a new
formulation of an infant formula satisfies the quality factor of normal
physical growth. Thus, when designing a study protocol, the
manufacturer should carefully consider whether historical control data
permit a meaningful comparison to the infants consuming the new
formulation.
Because the use of historical control data may be appropriate in
certain narrow circumstances, the interim final rule provides
manufacturers with an opportunity to justify reliance on such data.
Specifically, a manufacturer may request an exemption under Sec.
106.96(c)(2)(i) of the interim final rule to conduct a growth
monitoring study using an alternative study method or design, provided
that the manufacturer provides assurances that demonstrate that the
alternative study design is based on sound scientific principles. In
such a situation, FDA expects that detailed study results from the
historical control data would be available to FDA for review.
(Comment 209) One comment stated that because growth may or may not
be the crucial outcome measured in future formula studies and
``optimal'' growth and development have yet to be defined, a concurrent
control group is the optimal comparator.
(Response) FDA agrees with this comment. As noted, in the 1996
proposal, the Agency acknowledged that although historical controls
have been used in some infant formula investigations, these historical
data have inherent limitations. Accordingly, Sec. 106.96(b)(4) and
(b)(5) of the interim final rule require that a growth monitoring study
of an infant formula use a concurrent control group. Importantly, if a
manufacturer wishes to utilize historical control data in a growth
monitoring study, the manufacturer may request an exemption under Sec.
106.96(c)(2)(i) of the interim final rule.
(Comment 210) One comment recommended a concurrent breastfeeding
control group, while another comment opined that the universally agreed
reference population that defines healthy growth as infants breastfed
by well-nourished mothers cannot be included in a randomized trial.
(Response) A growth monitoring study need not include a concurrent
control group of breast-fed infants because comparing the growth of
infants consuming the new formulation to that of a concurrent control
group consuming the control formula and to the appropriate reference
data is sufficient to assess whether the new formula supports normal
physical growth. Also, infants cannot be randomly assigned to be
formula-fed or breastfed so there are scientific limitations on the use
of a concurrent breast-fed control group. In addition, there may be
significant non-nutritional confounding factors with using breastfed
infants as a control group, such as the health and nutrition of the
mothers who choose to breastfeed. The Agency would not object, however,
if breastfed infants from the same population as the infants consuming
the infant formula under evaluation were included as a concurrent
cohort group. In such circumstances, the growth of breast-fed infants
could also be compared to the group of infants consuming formula as a
model or reference for growth.
(Comment 211) Another comment indicated that it may be necessary to
have a concurrent control from the same population if infants believed
to have different growth characteristics (e.g., infants from different
ethnic groups) are used as the study population.
(Response) FDA agrees in part with this comment. The Agency
acknowledges that the optimal comparator for a particular growth
monitoring study is a concurrent control group composed of infants that
mirror the study infants as closely as possible, including ethnic or
racial background. Importantly, however, the Agency is aware that the
pool of infants for study subjects and controls is limited and thus,
FDA is concerned that to require precise ethnic or racial comparability
between study and control group members could inhibit the ability to
recruit subjects and fulfill the growth monitoring study requirement.
[[Page 8011]]
Accordingly, FDA encourages manufacturers to consider factors such as
ethnic or racial background in developing test and control groups, but
the Agency declines to specify that such comparability is a necessary
characteristic of an adequate and well-controlled investigation.
(Comment 212) One comment stated that infant formulas should be
clinically tested in randomized trials and conducted in at least two
centers.
(Response) FDA agrees with this comment to the extent that it
asserts that a new formulation of an infant formula should be evaluated
in a randomized, well-controlled growth monitoring study to demonstrate
satisfaction of the quality factor of normal physical growth. Like all
study designs, studies conducted at multiple centers have advantages
and disadvantages. For example, the use of multiple centers may be
advantageous because it may make it easier to recruit sufficient
numbers of infants as study subjects. However, the failure to follow
the study protocol carefully at all centers may jeopardize the utility
of the combined data and thus, is a potential disadvantage to a multi-
center study. Such factors as an appropriate study design (including
suitable control groups and treatments, blinding of all caregivers and
study evaluators, and selection of appropriate outcome measures),
strict adherence to protocol requirements, adequately trained and
experienced study personnel, and appropriate management and analysis of
study data are critical determinants of the quality and thus, ultimate
value of a growth monitoring study. Therefore, FDA declines to require
that a growth monitoring study be conducted in at least two centers.
(Comment 213) One comment stated that clinical trials of infant
formula should have a low attrition rate of subjects in each feeding
group (preferably below 10 percent) as well as effective blinding of
the study subjects' caregivers and study evaluators to the feeding
group, whenever feasible.
(Response) FDA acknowledges that minimizing attrition in a growth
monitoring study is highly desirable because a high dropout rate may
introduce bias or otherwise compromise interpretation of the study
data. However, the comment did not provide a basis for the Agency to
require an attrition rate below 10 percent in an infant formula growth
monitoring study, and the Agency declines to do so. It is often
difficult to ensure a low attrition rate (e.g., below 10 percent) in
investigations, especially with infant subjects. Importantly, FDA
expects that study investigators and the manufacturer/sponsor will
thoroughly investigate and explain all dropouts. FDA intends to monitor
closely attrition rates in infant formulas growth monitoring studies
and will consider that higher than anticipated attrition rates may
signal cause for concern about the use of a particular formulation.
Thus, FDA is not making changes to the rule in response to this
comment.
(Comment 214) One comment asserted that as the changes in formulas
become more subtle, such as through the addition of long chain
polyunsaturated fatty acids (LCPUFAs), outcome measures must include
other relevant effects such as those on visual acuity and intelligence,
which may only become measurable months to years after formula
consumption. For this reason, the comment observed that this will
require manufacturers to conduct post-marketing surveillance as a part
of every formula study.
(Response) This comment is not relevant to the issues in this
rulemaking. The interim final rule requires a single type of study in
infants: a growth monitoring study. The purpose of a growth monitoring
study is very narrow and specific: to evaluate the bioavailability of
the infant formula, including its nutrients, that are required to be in
infant formula by section 412 of the FD&C Act to ensure that, during
the period that such formula serves as the sole source of nutrition for
infants, such infants experience normal physical growth. Contrary to
suggestion of the comment, a growth monitoring study is not designed to
evaluate whether there is a benefit of added ingredients such as
LCPUFAs like arachidonic acid (ARA) and docosahexanoic acid (DHA).
Accordingly, FDA is not responding to the comment's recommendation for
post-marketing surveillance for such purpose.
b. Age of enrollment for a growth monitoring study.
In 1996, FDA proposed in Sec. 106.97(a)(1)(i)(A) that
manufacturers shall ``conduct a clinical study that is no less than 4
months in duration, enrolling infants no more than 1 month old at time
of entry into the study'' (61 FR 36154 at 36215). In 2002, the Infant
Formula Subcommittee of the FDA Food Advisory Committee recommended
that infants be enrolled into clinical growth studies by 14 days of age
(http://www.fda.gov/ohrms/dockets/ac/cfsan02.htm0), and in 2004, the
IOM recommended a duration of 6 months (180 days) for growth studies of
infants (Ref. 4, p. 10). In the 2003 reopening (68 FR 22343) and in the
2006 reopening (71 FR 43392 at 43397-43398), the Agency expressly
requested comment on the appropriate age for enrollment of infants into
growth monitoring studies.
FDA received several comments regarding the age of subject
enrollment for growth monitoring studies.
(Comment 215) One comment stated that there is a rationale for
including infants not older than 14 days because this early period is
the time of greatest nutrient requirement and greatest sensitivity to
nutrient adequacy. Another comment suggested enrollment by 14 days of
age in order to ensure a 4 month observation period before other foods
are introduced into the infant's diet.
(Response) FDA agrees with the recommendations of these two
comments and thus, Sec. 106.96(b)(1) of the interim final rule
requires that subjects in a growth monitoring study be no more than 2
weeks of age at the time of enrollment. FDA included this age
requirement in the interim final rule for both data quality and
practical reasons.
There are three data quality reasons for establishing 14 days as
the maximum age of enrollment in a growth monitoring study. First,
early infancy is the period of greatest nutritional risk and the period
during which infants experience the most rapid growth. Thus, testing a
new formulation of a formula during this time period means that the
infant formula will be evaluated under the most demanding conditions of
use. Second, the earliest days of an infant's life are the most
sensitive in that this phase includes the most dramatic (and thus most
readily measurable) growth. Thus, a study including this period would
be most likely to detect deficiencies in normal physical growth.
Finally, by enrolling study participants at age 2 weeks or less, it
will be possible to conduct a growth monitoring study of an appropriate
length before an infant begins to consume a mixed diet. Health care
professionals currently recommend adding other foods (such as cereal,
strained vegetables, pureed fruits) to an infant's diet between the
ages of 4 to 6 months. (http://www.fns.usda.gov/tn/Resources/feddinginfants-ch2.pdf). When an infant is consuming such a mixed diet,
study data are likely to be difficult to interpret because dietary
intake is less controlled.
There is also a practical reason for establishing 14 days as the
maximum enrollment age for growth monitoring study participants. Most
health care professionals recommend that a newborn have his/her first
well-child visit at 3 to 5 days of age (Ref. 70) and another during the
second week after birth. Thus, the period of study enrollment coincides
with infant age
[[Page 8012]]
range for an early well-child visit which will likely enhance
recruitment of study participants and thereby, support the quality of
the growth monitoring studies conducted on new formulations of infant
formulas.
(Comment 216) One comment stated that for routine growth studies,
infants would ideally be enrolled by approximately 14 days of age.
However, the comment further stated that there is no biological reason
why any enrollment age short of one month should disqualify an infant
from such a study and noted that in 1993, the European Commission
Scientific Committee on Food recommended subjects be entered into a
study within the first month of life.
(Response) FDA agrees with this comment to the extent that it
suggests that subjects be enrolled in growth monitoring studies at no
more than 14 days of age. Importantly, the comment did not provide data
to support the assertion that there is no biological reason that
enrollment up to one month of age should disqualify an infant from a
growth monitoring study. In fact, as discussed previously in this
document, early infancy is the period of greatest nutritional risk and
also most rapid growth; both of these biological factors have the
potential to enhance the quality of the data generated in a growth
study.
(Comment 217) Two comments agreed with FDA's 1996 proposal to
require study subjects to be enrolled during the first month of life.
(Response) For the reasons outlined previously in this document,
FDA has revised the required enrollment age for the growth monitoring
study to 14 days or less, a decision based on the fact that 14 days is
the optimal age for enrollment because this age will capture the period
of subjects' greatest nutritional demand and greatest growth.
(Comment 218) One comment stated that a study to assess the
nutritional adequacy of a formula to be fed during the first year of
life by measuring weight gain (Ref. 67) should be initiated within the
first month of life. However, if the formula is for a different age
range, the design of the study should reflect this difference.
(Response) FDA does not agree with this comment. As explained
previously in this document, in Sec. 106.96(b)(1) of the interim final
rule, the Agency is establishing 2 weeks as the maximum age at time of
enrollment for subjects in a growth monitoring study because this age
will capture the most sensitive period of infant growth and the period
of greatest nutritional need.
In addition, the Agency does not agree that the interim final rule
should establish a different enrollment age for a study of a formula
intended for a ``different age range.'' First, even if a product is
marketed for use in older infants, e.g. those older than 6 months of
age, the product is an ``infant formula'' within the meaning of section
201(z) of the FD&C Act and 21 CFR 105.3(e). As such, the formula must
satisfy the nutrient requirements of section 412(i) of the FD&C Act and
Sec. 107.100 and the quality factor requirements established in Sec.
106.96 of the interim final rule under section 412(b)(1) of the FD&C
Act. As noted, the appropriate age of enrollment for a study of an
``infant formula'' is 14 days or less. Second, even if a particular
product is marketed for ``older'' infants, there is a possibility that
it will be fed to neonates. For this reason, it is essential that the
formula be nutritionally adequate for these younger infants. Testing
the formula in very young infants will maximize the certainty that such
formula will be nutritionally sufficient for all infants, including
neonates. Third, as noted previously in this document, data from
studies conducted in older babies may be difficult to interpret because
such infants are likely to be consuming a mixed diet. Finally, if a
manufacturer believes that the growth monitoring study of a particular
formula should have an enrollment age other than that established in
Sec. 106.96(b)(1) of the interim final rule, the manufacturer may
request an exemption under Sec. 106.96(c)(2)(i) of the interim final
rule.
(Comment 219) One comment asserted that the final requirement
should be more stringent than the proposed, and suggested that infants
should be enrolled in clinical studies before the end of the first
postnatal week. Another comment made a similar suggestion, stating that
the growth monitoring study should enroll infants at 8 days of age.
(Response) FDA acknowledges that early infancy is the period of
greatest nutritional risk and the age at which the most rapid growth
occurs, both of which make this time period the most demanding
conditions for use of a formula. Although initiating a growth
monitoring study by the end of the first postnatal week or at 8 days of
age would capture a greater portion of this period, FDA is concerned
that this limit on enrollment age could unduly restrict recruitment and
participation in the required growth monitoring studies. Establishing
14 days as the maximum age of enrollment strikes a reasonable balance
between acquiring high quality data and providing flexibility to foster
recruitment of study subjects.
c. Duration of a growth monitoring study. As noted, proposed Sec.
106.97(a)(1)(i)(A) would have required that a manufacturer ``conduct a
clinical study that is no less than 4 months in duration'' (61 FR 36154
at 36215). In its 2004 report, the IOM recommended that a growth study
should cover at least the period when infant formula serves as the sole
source of nutrients in the infant diet (Ref. 4, p. 108). Accordingly,
at that time, the Committee recommended a study of 6 months (180 days)
because such duration would mirror the recommended length of time an
infant should consume human milk exclusively. However, because current
infant feeding recommendations are to begin solid foods between the
ages of 4 and 6 months, the IOM acknowledged that it would be
difficult, as a practical matter, to convince parents of study subjects
to postpone such introduction until age 6 months. In the 2003 reopening
(68 FR 22343) and in the 2006 reopening (71 FR 43392 at 43397-43398),
the Agency expressly requested comment on the appropriate duration of a
growth monitoring study.
In addition to the IOM recommendation, FDA received several
comments regarding the appropriate duration of growth monitoring
studies.
(Comment 220) One comment noted that the IOM report recommended
that a growth monitoring study of an infant formula containing a new
ingredient be at least 6 months (180 days) in duration, and that this
recommendation was based on the use of formula as a substitute for
human breast milk and the current advice of the AAP that infants be
exclusively breastfed for at least 4 and, preferably, 6 months. The
comment expressed concern that the data from a 6-month study would be
confounded by the introduction and inclusion of complementary foods in
the diets of study subjects.
(Response) FDA agrees with this comment for several reasons. First,
current recommendations are to begin solid food between the ages of 4
and 6 months. The comment noted, the IOM report acknowledged, and FDA
agrees that feeding complementary foods to study subjects could
confound the study results of a 6-month study. The IOM report also
acknowledged that it would be difficult, as a practical matter, to
convince parents of study subjects to postpone such introduction until
age 6 months. Second, the IOM report noted that it would be unlikely
that adverse effects would appear only between 4 and 6 months if none
appeared between birth and 4 months, suggesting that no
[[Page 8013]]
significant information on adverse effects would be lost from a shorter
study. FDA agrees with these observations and concludes that a study of
4 months duration would provide the data and information necessary for
a manufacturer to evaluate the ability of an infant formula to support
normal physical growth. Importantly, however, FDA would not discourage
an infant formula manufacturer from conducting a growth monitoring
study of 6 months' duration if the manufacturer is able to address the
potentially confounding effect of complementary food consumption during
the study period.
(Comment 221) One comment recommended that the growth studies of
infants be conducted from 8 to 112 days of age (a time interval of 15
weeks). The comment noted that a study period of 8 to 112 days of age
would permit young infants to participate, and noted that such infants
may be the most sensitive subjects for demonstrating inadequacies of
infant formulas. The comment also observed that the period of 8 to 112
days of age has been used extensively in clinical studies of growth of
formula-fed infants and that the data from these studies have been used
to generate historical control data on gains in weight and length
during infancy (Refs. 68 and 69).
(Response) Although enrollment at age 8 days may provide an
additional week to evaluate growth during the most sensitive growth
period, FDA finds that some flexibility is needed for the enrollment
timeframe. Section 106.96(b)(1) of the interim final rule permits
infants to be enrolled in the growth monitoring study up to age 14
days. FDA has explained its reasons for selecting 14 days as the
maximum enrollment age in responding to the comments in the immediately
previous section of this preamble.
The Agency agrees with this comment to the extent that it
recommends a growth monitoring study of at least 15-weeks duration. As
the comment noted, the 15-week duration has been used extensively for
infant growth studies (Ref. 68), which provides a sound basis for
choosing this period for the growth monitoring studies required by this
interim final rule. Also, 15 weeks is a reasonable study duration
because this period maximizes the time between enrollment (2 weeks of
age) and the age at which many infants begin to consume a mixed diet
(17 weeks or 4 months). As explained previously in this document, the
consumption of a mixed diet by study subjects may complicate
interpretation of the study results regarding the nutritional
sufficiency of the test formula because, with a mixed diet, the formula
is no longer the sole source of nutrition for the infant. Accordingly,
FDA has revised the interim final rule to require a growth monitoring
study to be at least 15 weeks in duration.
(Comment 222) One comment recommended that, as an alternative, a
growth study be at least four months in duration, enrolling infants at
no more than one month of age. The comment noted that a 4-month study
period permits a slightly longer period of observation (as compared to
a 15-week study) and would provide greater ease of subject recruitment.
(Response) FDA disagrees with this comment and notes that this
alternative suggestion is what the Agency proposed in 1996 in proposed
Sec. 106.97(a)(1)(i)(A). FDA has concluded that the appropriate
duration for a growth monitoring study is 15 weeks and that study
subjects should be no more than 14 days old at the time of enrollment.
The Agency's reasons for these determinations are explained in its
response to the foregoing comments.
(Comment 223) One comment stated that growth studies are usually
conducted for 14 weeks (98 days), with subjects participating from
approximately age 14 days until age 112 days (i.e., from 2 to 16 weeks
of age). The comment also noted that in 1993, the European Commission
Scientific Committee on Food proposed a study period of at least 3
months to evaluate the nutritional adequacy of infant formula.
(Response) FDA disagrees with this comment to the extent that it
recommends a study of 14 weeks. Although the comment asserted that
growth studies are ``usually'' of 14 weeks duration, the comment
provided no data or other rationale to support the validity or
sufficiency of this length of a growth monitoring study. FDA has
determined that a 15 week study requirement is reasonable for the
reasons provided in previous comment responses.
(Comment 224) One comment asserted that selection of 16 weeks or 3
months, or 4 months as originally proposed by FDA, are based on
convenience and current well-baby visit schedules and not based on the
scientific assessments of sensitivity, validity, or the relationship of
growth over this period to health.
(Response) FDA disagrees with this comment. As explained in the
response to Comment 221 the 15-week study duration maximizes the time
during which study subjects are likely consuming the formula as the
sole source of nutrition. Once study subjects begin to consume a mixed
diet, the resulting data are more difficult to interpret because it is
not possible to distinguish between the nutritional effects of the
formula and the nutritional effects of the remainder of a subject's
diet, thereby hampering the accurate assessment of the nutritional
sufficiency of the formula.
(Comment 225) One comment recommended that growth studies of infant
formulas would ordinarily require testing through 8 to 12 months of age
in order to evaluate the formula throughout the period that it serves
as the only or main source of calories. Another comment stated that
because infant formula is given to babies from birth until 12 months of
age, 12 months is the appropriate duration of time for a study.
(Response) FDA disagrees with these comments. In order to perform
an accurate assessment of the nutritional adequacy of an infant
formula, there must be no competing or supplemental sources of
nutrition consumed by the study subjects. That is, if the study
subjects are consuming other foods, any results showing normal physical
growth may be attributable to the other foods and not to the infant
formula. For this reason, proposed Sec. 106.97(a)(1) stated that the
growth monitoring study must determine whether the formula supports
normal physical growth ``when the formula is fed as the sole source of
nutrition.'' As explained previously in this document, health care
professionals generally suggest that infants begin to consume a mixed
diet sometime after 4 months of age. Thus, it would be difficult if not
impossible to conduct a growth study with subjects 8 to 12 months of
age without including infants on a mixed diet and thereby, compromising
the study results. Also, physical growth rates slow after early
infancy, thereby resulting in a less sensitive measure to detect
differences in the ability of an infant formula to support normal
physical growth.
(Comment 226) Another comment stated that studies should extend for
years rather than months to detect the subtle effects of formula
feedings.
(Response) FDA has considered whether extending the duration of
growth monitoring studies to 12 months or longer has merit and has
concluded that it does not. The rate of physical growth in infants
slows after early infancy, thereby resulting in a less sensitive
measure to detect differences in the capability of a new formulation of
an infant formula to support normal physical growth. Also, consumption
of foods other than infant formula (typically started at about 4 to 6
months
[[Page 8014]]
of age) has the potential to confound the growth monitoring study
results from beyond the period when infant formula is consumed as the
sole source of nutrition.
Based on the foregoing, FDA is redesignating proposed Sec.
106.97(a)(1)(i)(A) as Sec. 106.96(b)(1) in the interim final rule and
revising the provision to require a growth monitoring study that ``[i]s
no less than 15 weeks in duration, enrolling infants no more than 2
weeks old at the time of entry into the study;''.
d. Review by institutional review board and protection of human
subjects. In the 1996 proposal, FDA recommended in proposed Sec.
106.97(a)(1)(ii)(C) that the study conducted under proposed Sec.
106.97(b) be reviewed by an IRB in accordance with 21 CFR part 56 and
that the manufacturer establish procedures to obtain informed consent
from the parent or legal representative of each study participant.
Thereafter, in the 2003 reopening (68 FR 22341 at 22343), FDA proposed
to delete the provisions relating to IRB review and informed consent
due to an independent FDA rulemaking (66 FR 20589, April 24, 2001), one
effect of which was to make an infant formula growth monitoring study
subject to the requirements of parts 50 and 56. Specifically, under
parts 50 and 56, data and information about a clinical study of an
infant formula, when submitted as part of an infant formula
notification under section 412(c) of the FD&C Act, constitute an
``application for research or marketing permit'' and thus, are subject
to the informed consent and IRB requirements related to such permits in
parts 50 and 56. Accordingly, as proposed in the 2003 reopening, FDA is
not including provisions relating to IRB approval and human subject
protection in the interim final rule because such provisions are
unnecessary as the requirements are codified in parts 50 and 56.
4. Collection and Evaluation of Anthropometric Data
In 1996, FDA proposed to require that a growth monitoring study
include the collection of anthropometric measures of physical growth,
including body weight, recumbent length, head circumference, and
average daily weight increment. Under the 1996 proposal, the
anthropometric measurements would have been required at the beginning
of the study, at 2 weeks, at 4 weeks, and at least monthly thereafter.
Subsequently, in the 2003 reopening, FDA requested comment on whether
certain Iowa data (which were discussed at the November 2002 meeting of
FDA FAC's Infant Formula Subcommittee) should serve as the comparison
for the anthropometric data collected during a growth monitoring study
(68 FR 22341 at 22342-22343).
In addition, in the 2006 reopening, in response to a recommendation
in the IOM report, FDA requested comment on whether the Agency should
require body composition measurement in a growth monitoring study
conducted under the interim final rule. At that time, FDA stated its
tentative conclusion that measures of body weight, recumbent length,
head circumference, and data to calculate average daily weight
increment would be adequate to assess the quality factor of normal
physical growth (71 FR 43392 at 43397).
In 1996, FDA also proposed that the anthropometric data be plotted
against 1977 reference curves (``growth charts'') from the National
Center for Health Statistics (NCHS). The 1977 NCHS growth charts were
substantially revised in 2000 and were referred to as the 2000 CDC
growth charts (Ref. 72).
In 2006, WHO released a new international growth standard for
children ages birth to 59 months that reflects normal physical growth
for all infants and children. For infants and children less than 24
months of age, the WHO standard includes charts based on measurements
of weight for age, length for age, weight for length, and head
circumference (Ref. 11). Thus, after 2006, two sets of growth charts,
the 2000 CDC growth charts and the 2006 WHO growth standards, were
available for assessing early childhood growth. On September 10, 2010,
CDC formally announced its recommendation that the WHO growth standards
be used to plot the growth of infants and children from birth to 24
months of age (published in November 2009).
The WHO growth standards are based on a high quality comprehensive,
longitudinal, world-wide study conducted in healthy women and their
breast-fed infants and included subjects from six countries, including
the United States, drawn from different ethnic and racial populations.
Anthropometric measurements of the infants were obtained at birth and
five additional times between birth and 8 weeks of age. CDC considered
the WHO study design and results, and conducted expert consultations
with National Institutes of Health and the AAP, and determined that the
longitudinal measurements of the WHO study provide the best available
information on which to base growth curves, rather than the
mathematical modeling used to develop the 2000 CDC growth charts. CDC
described these WHO growth standards as providing the standard for how
infants and children (birth to 24 months) should grow regardless of the
type of feeding.
The interim final rule incorporates the new CDC recommendation.
Specifically, Sec. 106.96(b)(4) of the interim final rule requires
that the anthropometric measurements obtained in a growth monitoring
study be plotted on the 2009 growth charts recommended by the CDC based
on the WHO Child Growth Standards (2009 CDC growth charts), as
incorporated by reference in Sec. 106.160 of the interim final rule.
This is a reasonable outcome for the interim final rule for two
reasons. First, it is appropriate for FDA to defer to CDC's
recommendation on this issue as CDC is the relevant authoritative
public health Agency. Second, the basis for the CDC's recommendation is
sound scientifically and is one with which FDA agrees. In particular,
the WHO Child Growth Standards, on which the 2009 CDC growth charts are
based, are derived from a longitudinal study of a number of diverse
populations with relatively frequent growth measurements. As such, the
2009 CDC growth charts describe growth of healthy children under
optimal conditions whereas the 2000 CDC charts describe how certain
children grew in a particular place and at a particular time (Ref. 11).
a. Measuring body composition.
(Comment 227) One comment recognized that there may be occasions in
which an assessment of body composition might be appropriate but did
not further elaborate what those occasions might be.
(Response) FDA notes that this comment did not explain when or why
body composition measurements are needed to assess normal physical
growth. Thus, FDA is not revising the rule in response to this comment.
(Comment 228) One comment disputed the IOM's recommendation to
measure body composition as part of the assessment of normal physical
growth. The comment asserted that body composition is not easily
measured in newborns and young infants and there are few references or
standards. The comment also claimed that there is potential for a great
deal of error with such measurements and that some methods of
measurement would require infants to be exposed to radiation, which
would be unacceptable. Two other comments stated that sufficient
reference data for infant body composition do not exist.
(Response) FDA agrees with these comments. The Agency has
considered
[[Page 8015]]
whether body composition measurements should be required as a means to
assess physical growth and has concluded that such measurements should
not be required because these measurements are not easily made in
newborns and young infants. In addition, as the comment noted,
references and standards are lacking, which means that even if the
measurements could be readily made, it would be difficult to assess
their significance. Also, as suggested in the comment, some risk is
associated with any radiation exposure (Ref. 71). Without an
established need for body composition data and a sound means to assess
their significance, FDA concludes, that, at this time, any risk from
the use of radiation in healthy newborns and young infants would not be
justified.
(Comment 229) One comment asserted that facilities and equipment
for body composition measurement are not standardized and are not
readily available, which would make it more difficult to conduct growth
monitoring studies, and including such a requirement would add to the
cost of such studies.
(Response) The comment did not include any data to support its
assertions about facilities and equipment availability to measure
infant body composition and FDA is not independently aware of such
availability information. The Agency has concluded, in view of the
challenge of making these measurements, the problems with measurement
accuracy, and the lack of suitable reference standards, not to require
body composition to be measured in growth monitoring studies conducted
under this interim final rule. Therefore, the interim final rule will
not require the growth monitoring study to include body composition
measurements.
b. Collection and maintenance of appropriate anthropometric data.
Several comments addressed the specific anthropometric measurements
identified in proposed Sec. 106.97(a)(1)(i)(B) to assess physical
growth, including a number of comments supporting the Agency's proposed
use of body weight, recumbent length, and head circumference for such
purpose.
(Comment 230) One comment requested that recumbent length
measurements be excluded from the study requirements because such
measurements in young infants may involve considerable error. The
comment recommended that recumbent length continue to be measured as
part of the standard growth protocol, allowing for calculation of BMI
and some body composition measures as needed, but that these data not
be routinely reported to the Agency.
(Response) FDA disagrees with this comment. As noted in the 1996
proposal (61 FR 36154 at 36183), ``[g]ains in weight and length of
young infants reflect the long-term, integrative physiological
processes that can only be achieved if the infant's nutritional needs
are met.'' Accordingly, recumbent length, along with head
circumference, provides a valuable context for interpreting weight
change data. Changes in length and head circumference data provide
especially valuable information for interpretation of the weight change
data in those situations in which weight change with a test formula is
significantly different than the weight change attained with the
control formula. Also, careful training of the persons who make the
recumbent length measurements will help to minimize errors. Therefore,
FDA is not removing the requirement to make recumbent length
measurements in response to this comment.
(Comment 231) Several comments recommended the exclusion of head
circumference measurements, claiming that head circumference is not
responsive to small changes in nutritional status citing the conclusion
of the 1988 CON/AAP consultation (Ref. 67).
(Response) FDA disagrees with this comment. As noted, recumbent
length and head circumference provide a valuable context for
interpreting weight change data. The conclusion of the CON/AAP
consultation (Ref. 67), cited as support by the comment, applies to a
situation in which no significant difference is observed in weight
change. Head circumference measurement may not be as responsive as body
weight as an indicator of nutritional status. However, because such
measurements can be routinely made, are not invasive, require no
specialized equipment, and are not expensive, the value of head
circumference measurements outweighs any risk or cost of collecting
these data.
(Comment 232) One comment asserted that the most sensitive method
of evaluating infant growth is a comparison of increments in recumbent
length and body weight over time (e.g., millimeters/day or grams/day)
rather than comparison of absolute size (e.g., length (centimeters) or
absolute weight (grams)) at a given age. The comment identified what it
characterized as suitable reference data (Refs. 68 and 69) for
evaluation of incremental changes in weight and length.
(Response) FDA agrees that body weight and rates of change in body
weight are useful measures of changes in body mass in the newborn and
the young infant, and that recumbent length and head circumference
measurements provide information for interpreting these weight change
data. In the 1996 proposal, the Agency proposed to require in Sec.
106.97(a)(1)(i)(B) that data on ``average daily weight increment'' be
collected and maintained as part of the growth monitoring study. At
that time, however, the Agency did not propose to require the
collection and maintenance of incremental recumbent length data. FDA
agrees with this comment that incremental gains for both body weight
and recumbent length provide sensitive comparisons of anthropometric
growth measurements in young infants. For this reason, the Agency
expects that these calculated values will be part of a manufacturer's
analysis of its growth monitoring study on a new formulation of an
infant formula. Accordingly, Sec. 106.96(b)(2) of the interim final
rule requires that a growth monitoring study include the collection and
maintenance of data on anthropometric measures of physical growth,
including body weight, recumbent length, head circumference, average
daily weight increment, and average daily recumbent length increment.
c. Schedule for and frequency of anthropometric measurements.
Section 106.97(a)(1)(i)(C) of the 1996 proposed rule would have
required that the anthropometric measurements in the growth monitoring
study be collected at the beginning of the study, at 2 weeks, at 4
weeks, at least monthly thereafter, and at the study's conclusion. The
Agency received a number of comments on this proposed requirement.
(Comment 233) One comment requested that proposed Sec.
106.97(a)(1)(i)(C) be deleted and recommended that the frequency of
body weight measurements be addressed in guidance and not in the
regulation.
(Response) FDA disagrees with this comment. It is important to
specify the frequency and the schedule for anthropometric measurements
in the growth monitoring study. This will ensure that the study data
will be of sufficient quality to evaluate whether the new formulation
of the infant formula supports normal physical growth. As noted
earlier, Agency guidance is not binding and thus, even if the frequency
of the measurements was specified in guidance, a manufacturer would be
free to establish a schedule and frequency of anthropometric
measurements that
[[Page 8016]]
deviated from the Agency's best thinking. As a result, the study data
may not provide an adequate basis for evaluating the formula's ability
to support normal physical growth.
(Comment 234) One comment stated that the proposed frequency of
measurement is unnecessarily burdensome to parents facilitating their
infants' participation in the growth studies because several of these
times do not coincide with a regularly scheduled well-baby visit. The
comment further asserted that clinical studies of new formulas are
often delayed because it is difficult to recruit sufficient numbers of
participants. The comment included a study design schematic that
illustrated the recommended frequency for anthropometric data
collection as follows:
Study Design Schematic
----------------------------------------------------------------------------------------------------------------
Scheme of data collection
-----------------------------------------------------------------------------------------------------------------
Enrollment 14 days of 28 days of 56 days of 84 days of 112 days of
visit \1\ age \2\ age \2\ age \2\ age \2\ age \2\
----------------------------------------------------------------------------------------------------------------
Enrollment/Randomization.... X ............ ............ ............ ............ ............
Demographic Data............ X ............ ............ ............ ............ ............
Weight, Length.............. X X X X X X
Interval History............ ............ X X X X X
Adverse Events.............. X X X X X X
----------------------------------------------------------------------------------------------------------------
\1\ Date of Birth is Day Zero of life (enrollment 0-14 days of age); enrollment may be on day 14 of age visit.
\2\ Visit window 3 days.
(Response) In the 1996 proposal, FDA addressed the timing and
interval between measurements (61 FR 36154 at 36184). FDA proposed that
more frequent anthropometric measurements, especially early in the
study, would enhance the study's ability to document physical growth
changes by measuring growth during the most rapid, and thus, the most
sensitive, phase of an infant's growth; this would increase the ability
to place individual infants accurately in the correct percentile to
track their growth patterns over time. In proposing the measurement
schedule in Sec. 106.97(a)(1)(i)(C), the Agency intended to have
sufficient serial measurements for comparison between study groups and
to derive reliable estimates of centile pattern growth and estimates of
growth rates based on measurements over the entire study period. This
proposed measurement schedule would accurately capture the curvilinear
nature of infant growth and would provide sufficient data to interpret
differences in growth and in growth rates, if differences exist.
Accordingly, FDA disagrees with the comment recommending fewer
measurements in the early portion of a growth monitoring study. The
approach recommended by this comment proposes only five measurements
for the period between 14 and 112 days of age, with only two
measurements proposed for the first 4 weeks of the study. Importantly,
no data were submitted with this comment to support the adequacy of
fewer measurements for evaluating the curvilinear nature of growth in
young infants. As noted previously in this document, the most rapid
phase of infant growth, and thus, the most sensitive period for
detecting perturbations in growth, is the earliest weeks of an infant's
life. Thus, it is critical that the anthropometric measurements be
concentrated in this time period. As noted in this document, the
interim final rule requires in Sec. 106.96(b)(3) that anthropometric
measurements be collected at the beginning of the study (maximum age of
2 weeks), 2 weeks into the study (maximum age of 4 weeks), and 4 weeks
into the study (maximum age of 6 weeks), which will result in
relatively more data from the earlier stages of an infant's life.
(Comment 235) One comment recommended that clinical studies of
infants be conducted from 8 to 112 days of age with collection of
anthropometric measurements at ages 8, 14, 28, and 42 days (2 days) and at ages 56, 84, and 112 days (4 days).
This alternative schedule was recommended because, the comment
asserted, it would match the measurement schedule of many reference
(historical) data.
(Response) The alternative suggested in this comment would result
in seven measurements over a roughly 15-week study period, with more
frequent measurements during the early phase of the study, starting at
8 days of age. However, as discussed previously in this document, the
Agency is establishing 14 days as the maximum age of enrollment to
provide flexibility to foster recruitment of infants. Therefore, FDA is
not persuaded by the information provided in the comment that the
interim final rule should require enrollment by 8 days of age.
FDA's concerns with the use of historical data as controls are
addressed previously in this document in the response to Comment 208.
FDA agrees that some degree of flexibility in the timing of the serial
measurements throughout the study is a reasonable design feature for
the growth monitoring study. Thus, the interim final rule requires
that, over the minimum 15 week study period needed to assess whether an
infant formula supports normal physical growth, anthropometric
measurements shall be made at the beginning and end of the study, with
three of the six total measurements made within the first 4 weeks of
the study and three measurements made at approximately 4-week intervals
over the remaining 11 weeks of the study. Therefore, proposed Sec.
106.97(a)(1)(i)(C) is renumbered as Sec. 106.96(b)(3) in the interim
final rule and is revised to require the growth monitoring study of
normal physical growth include ``anthropometric measurements made at
the beginning and end of the study, and at least four additional
measurements made at intermediate time points, with three of the six
total measurements made during the first 4 weeks of the study and three
measurements made at approximately four-week intervals over the
remaining 11 weeks of the study.''
To ensure the detection of biologically significant differences
between test and control groups, if they exist, it is important that
investigators make a diligent effort to take anthropometric
measurements on infants consuming the test formula at the same ages as
the measurements for the concurrent or historical control groups. FDA
recognizes that investigators may not always be able to collect
clinical data on all infants on the same day of age. FDA plans to
address this need for flexibility while maintaining the scientific
integrity of the study in future guidance.
d. Comparison of anthropometric data.
[[Page 8017]]
As noted previously in this document, in 1996, FDA proposed to
require that anthropometric data collected during a growth monitoring
study be plotted on the 1977 NCHS reference percentile body weight and
length curves and proposed to incorporate by reference the 1977 NCHS
growth charts. The Agency subsequently requested comment on whether
certain Iowa data should serve as the comparison for anthropometric
data collected during a growth monitoring study.
FDA received a number of comments on the collection and comparison
of anthropometric data in a growth monitoring study. The Agency
responds to those comments in this document.
(Comment 236) One comment stated that, in general, the use of
growth curves and historical databases are considered references, not
standards.
(Response) FDA agrees in part with this comment, which reflects the
information available at the time of the two comment period reopenings.
Until the WHO growth standards, upon which the 2009 CDC growth charts
are based, became available, growth charts (including the 2000 CDC
charts) were references that reflect how children in the United States
have grown, and were not a standard of how children should grow.
The Agency believes, however, that this comment misunderstood FDA's
use of the term ``standard'' in the 2003 reopening. In the 2003
reopening notice, the Agency requested comment on whether the Iowa
reference data ``should be the standard for clinical growth data rather
than the NCHS growth charts (68 FR 22341 at 22342-22343).'' In this
instance, FDA intended the term ``standard'' to refer to a set approach
of data evaluation and not to describe the growth charts.
(Comment 237) One comment suggested that new formulations of infant
formula be tested by comparison to a control group of the same
population receiving an appropriate control formula, rather than by
comparison with standard curves, in accordance with proposed Sec.
106.97(a)(1)(i)(B), because the curves are not considered accurate for
all ethnic groups.
(Response) FDA believes that this comment did not fully understand
the requirements of the proposed rule because the proposed rule would
have required, and this interim final rule requires, that the growth
monitoring study be an adequate and well-controlled study, which
includes concurrent controls. (The issue of concurrent versus
historical controls is addressed previously in this document in section
VIII.C.3.a. As noted in that discussion, a manufacturer that wishes to
use historical controls in a growth monitoring study may request an
exemption under Sec. 106.96(c)(2)(i) of the interim final rule to do
so.) FDA notes that the use of historic controls may be problematic
because the current study population would need to be matched to the
historic controls, which may not be possible. Thus, the anthropometric
data collected in a growth monitoring study will be required to be
compared to a concurrent control group as well as to the standard
reference data in the 2009 CDC growth charts.
FDA also notes that although the comment asserts that an
appropriate concurrent control group needs to be composed of the ``same
population'' as the infants consuming the test formula, the comment
neither elaborates on the ``same population'' concept nor provides data
or other information to support its assertion. Indeed, a clinical
investigation is ``well-controlled'' only if the control group is
appropriate to the purpose of the study. Thus, FDA expects that the
report of a growth monitoring study will address the appropriateness of
the selected control group. In addition, the interim final rule's
requirement to use the 2009 CDC growth charts will address the concern
expressed by this comment because, as discussed previously in this
document, the WHO growth charts are based on data from six countries
from different parts of the globe.
(Comment 238) One comment asserted that plotting anthropometric
data from a growth monitoring study on CDC ``growth'' charts
contributes little to the evaluation of the results.
(Response) FDA disagrees with this comment. Given the timing of the
submission of this comment, the commenter is likely referencing the
2000 CDC growth charts. In 1996, FDA proposed that the anthropometric
data collected during a growth monitoring study be compared to standard
measurements of infant physical growth as a means of assessing whether
the pattern of changes in weight and length of each individual infant
study participant (both on test and control formulas) was similar to
that observed for healthy infants of the same age, allowing for the
range of normal individual variation in body weight and length that the
2000 CDC growth chart percentiles would have provided. Importantly, FDA
does not intend that comparison with any growth chart be the sole
analysis of the anthropometric data collected during a growth
monitoring study. This comparison of the study data with growth charts
will complement the comparison of data from the two study groups and
will provide a context for interpreting the primary comparison of
growth data between test and control groups.
In addition, by evaluating whether, over time, each infant study
subject follows the generally expected growth rate for infants,
deviations in individual growth rate may be identified, thereby
alerting study investigators and FDA to a possible problem with formula
sufficiency. The Agency expects that such deviations would be promptly
scrutinized by study investigators to determine whether the deviations
are likely to be formula-related. Thus, individual subjects' growth
during the study may provide an early indication to investigators that
the new formulation of an infant formula is not nutritionally
sufficient. Also, monitoring individual infant rate of growth and
comparing such growth rate to the 2009 CDC growth charts, which
establish a standard for how infants should grow, may alert the study
investigator to an individual infant who may be in distress or
otherwise has potential issues and thereby, ensures the safety and
well-being of the study subjects. Accordingly, for two separate
reasons, it is important to compare each individual infant's growth to
the 2009 CDC growth charts to monitor individual infant growth
patterns.
(Comment 239) One comment challenged the use of individual growth
charts, asserting that such charts are not appropriate to establish
whether one group of infants differs from another group of infants in
terms of growth rates. The comment further asserted that the use of
curves to evaluate growth of infants could lead to inappropriate
conclusions concerning normal growth, and cited a 2002 paper by
Grummer-Strawn in support (Ref. 72).
(Response) FDA regards growth monitoring as the single most useful
tool in describing health and nutritional status at both the individual
and group level. Plotting the mean group data on a growth chart permits
a comparison of how groups of infants grow. In contrast, as described
previously in this document, plotting the growth of individual infants
on growth charts provides an early indication of a possible problem
with formula composition because it allows the investigator to observe
disturbances in the growth of individual subjects.
FDA agrees that growth charts based on reference data have
limitations, many of which have been addressed in the development of
the 2009 CDC growth charts. As discussed previously in this document,
the purpose of
[[Page 8018]]
plotting the anthropometric data of study subjects is to monitor
individual subjects' growth during the study. Under Sec. 106.96(b)(4)
of the interim final rule, the growth monitoring study must include a
concurrent control group, and the anthropometric data on the test and
control groups will be separately compared independent of the growth
chart activity to determine whether the new formula supports normal
physical growth. Comparing the anthropometric data to a growth chart is
intended to complement the use of concurrent controls and evaluation of
the data from such controls.
The 2002 paper by Grummer-Strawn does not contradict the interim
final rule's use of the 2009 CDC growth charts as a complement to the
use of a concurrent control group (Ref. 72). The Grummer-Strawn paper
explained why the use of the 2009 CDC growth charts is preferred to the
use of the 2000 CDC growth charts. Unlike the 2000 CDC growth charts,
the 2009 CDC growth charts are based on data from a longitudinal study
of healthy infants growing optimally.
(Comment 240) One comment asserted that the use of curves to
evaluate growth of infants could lead to inappropriate conclusions
concerning normal growth.
(Response) FDA disagrees with this comment and notes that the
comment did not explain how the complementary use of growth charts
could result in inappropriate conclusions about growth. As noted, there
is a two-fold purpose for plotting study subjects' individual growth
data on a growth chart. FDA is requiring the plotting of these data as
a check on the nutrition provided to both the test and control subjects
and also to monitor the growth of individual study participants as part
of the controls for human subject protection. The growth monitoring
study must include a concurrent control group for which anthropometric
data will be collected, analyzed, and used as a comparison to similar
data collected from the infants on test formula.
(Comment 241) One comment stated that because the NCHS growth
charts had been recently revised and published by the CDC in 2000, and
because new science is constantly accumulating, which may impact the
understanding of what constitutes ``expected'' physical growth, it
would be shortsighted to tie the assessment only to the currently
existing reference standards.
(Response) As discussed previously in this document, the CDC now
recommends the use of the 2009 CDC growth charts that are based on the
WHO Child Growth Standards for infants and children from birth to 24
months. To the extent that the CDC growth charts are revised in the
future, and new growth charts are developed, FDA would consider the
need to revise the growth charts required by this interim final rule at
that time.
(Comment 242) One comment stated that the Iowa reference data,
while excellent, may be less accessible than the NCHS growth charts,
and the growth charts do incorporate some mechanism for quantitative
assessment of growth patterns.
(Response) Data quality and not data accessibility is the relevant
issue here. Although the Iowa reference data have some value (Refs. 68
and 73), the value of these reference data has been superseded by the
2009 CDC growth charts (Ref. 11). The Iowa data lack the ethnic and
racial diversity that underlie the 2009 CDC growth charts. Also, the
2009 CDC growth charts establish a standard for the quantitative
assessment of infant growth patterns. Given these strengths of the data
provided in the WHO Child Growth Standards, Sec. 106.96(b)(4) of the
interim final rule requires that the anthropometric data be plotted on
the 2009 CDC growth charts that are based on the WHO Child Growth
Standards. A manufacturer who wishes to compare such data to other
reference data, such as the Iowa reference data, must request and meet
the requirements for an exemption under Sec. 106.96(c)(2)(i) of the
interim final rule.
(Comment 243) One comment stated that national data that reflect
the diversity of the U.S. population should be used instead of the Iowa
data, because Iowa has historically not represented diverse
populations.
(Response) As discussed previously in this document, the 2009 CDC
growth charts reflect appropriate racial and ethnic diversity and thus,
are appropriate for plotting the growth of infants in the U.S.
population.
(Comment 244) One comment recommended that for growth monitoring
studies conducted outside the United States, the comparisons of
anthropometric data should be plotted on growth charts that are
routinely used in the country in which the study is performed.
(Response) Although the 1996 proposed rule did not specifically
address the conduct of growth monitoring studies outside the United
States, the Agency does not disagree that such studies may potentially
be used as assurances for the quality factor of normal physical growth.
Importantly, however, any such study would have to meet the
requirements of the interim final rule, including the human subject
protections for pediatric studies in 21 CFR part 50, subpart D, and 21
CFR part 56 to ensure that the infant study subjects are not
inappropriately exposed to risk. When assessing the adequacy of a
growth monitoring study conducted in a foreign country, FDA would
consider whether the study satisfies good clinical practice, whether
the investigators have recognized competence to conduct the study,
whether the scientific evidence is valid, and whether the results are
applicable to the U.S. infant population (Ref. 74). FDA would also
consider whether the formula studied is the formula to be marketed in
the United States. If the studied formula is not the formula to be
marketed in the United States, the manufacturer would be required to
request and meet the requirements for an exemption under Sec.
106.96(c)(2)(i) of the interim final rule, and would be expected to
explain why the formulation studied would be considered an appropriate
proxy for the formula to be marketed in the United States.
In terms of the comment's specific concern, FDA notes that, as of
March 2012, more than 140 countries had adopted the WHO Child Growth
Standards. Thus, it is very likely that the WHO Child Growth Standards
would be used in the foreign country in which a growth monitoring study
is to be conducted, and such data would be consistent with the 2009 CDC
growth charts.
(Comment 245) One comment urged that that studies conducted to
evaluate infant growth test a sufficient number of infants to provide
precise estimates of mean growth in weight, length, and head
circumference (with confidence intervals around the mean that exclude
rates of growth that are outside the bounds of accepted standards.)
(Response) FDA notes that the comment did not identify ``accepted
standards'' or describe what would be considered ``outside the bounds''
of such standards.
Nonetheless, FDA agrees that a growth study must include a sample
size sufficient to permit detection of differences in growth, between
the control and test formula groups, if such differences exist.
Confidence intervals are used in statistics to describe a range of
values in an attempt to quantify the uncertainty of a particular
statistical estimate. A narrow confidence interval suggests a highly
precise estimate, and a wide confidence interval implies poor
precision. The desired confidence interval can be used to estimate
needed sample size as can a ``power'' calculation, and a wide
confidence
[[Page 8019]]
interval is often an indication of inadequate sample size. Absent an
adequate sample size, a study cannot sufficiently test the question
under study. Although FDA is not codifying statistical requirements for
a growth monitoring study, the Agency notes that such study must be
appropriately designed and conducted so as to produce data that can be
meaningfully interpreted on the question of whether the formula
supports normal physical growth.
(Comment 246) One comment noted that because sick infants may grow
at a slower rate and on lower percentiles due to their underlying
medical condition rather than any deficiency in the formula being
consumed, population reference standards are less useful for evaluating
growth of sick infants than that of healthy infants.
(Response) FDA is uncertain as to what the comment meant by ``sick
infants.'' Although the Agency would agree that, generally speaking,
due to an underlying medical condition, a sick infant will grow at a
slower rate and on lower percentiles, FDA would not expect a
manufacturer to plan purposefully to conduct a growth monitoring study
in a population of ``sick infants.''
It is possible that the comment had in mind a growth monitoring
study of a so-called ``exempt infant formula.'' Section 412(h)(1) of
the FD&C Act exempts certain infant formulas (those for infants with
inborn errors of metabolism, low birth weight, or other unusual medical
or dietary problems) from several statutory requirements, including the
requirement that a manufacturer provide assurances that a formula meets
the quality factor requirements established by the Secretary. Infants
for whom ``exempt infant formulas'' are developed could be considered
``sick.'' Importantly, however, as noted earlier in this preamble, this
interim final rule applies only to nonexempt infant formulas. Thus, the
manufacturer of an exempt infant formula is not required to comply with
the requirement to conduct a growth monitoring study. FDA's current
thinking on the application of the interim final rule to exempt infant
formula may be found in a draft FDA guidance document, a notice of
availability for which is published elsewhere in this issue of the
Federal Register. Accordingly, the comment about growth rates of ``sick
infants'' has no bearing on the interim final rule.
D. Exemptions From Quality Factor Requirements for Normal Physical
Growth
In the 1996 proposed rule, FDA set forth in proposed Sec.
106.97(a)(2) exemptions from the growth monitoring study requirements
of proposed Sec. 106.97(a)(1). Specifically, proposed Sec.
106.97(a)(2) provided exemptions from the need for a study to evaluate
physical growth in the following three situations:
The manufacturer has similar experience using an
ingredient, an ingredient mixture, or a processing method in the
production of an infant formula marketed in the United States and can
demonstrate that infant formula made with that ingredient, ingredient
mixture, or processing method meets quality factor requirements in
Sec. 106.96;
The manufacturer markets a formulation in more than one
form (e.g., liquid and powdered forms) and can demonstrate that the
quality factor requirements are met by the form of the formula that is
processed using the method that has the greatest potential for
adversely affecting nutrient content and bioavailability; and
The manufacturer can demonstrate that the requirements (of
Sec. 106.97(a)(1)) are not appropriate for the evaluation of a
specific infant formula, and that an alternative method or study design
for showing that the formula supports healthy growth in infants fed it
as their sole source of nutrition is available.
Several comments expressed confusion about the proposed exemptions.
In response to these comments, FDA has significantly revised the
proposed exemptions, which are set out in Sec. 106.96(c) of the
interim final rule. FDA's responses to the comments and the Agency's
explanation for the revisions of the proposed exemptions are set out in
this document.
(Comment 247) One comment recommended that a manufacturer be
responsible for demonstrating that a growth study is not needed rather
than exempting the manufacturer from conducting studies in a finite
number of circumstances.
(Response) FDA agrees that, in general, a manufacturer should be
responsible for demonstrating, in appropriate circumstances, that a
growth study is not needed and that some ``major changes'' may not
require a growth monitoring study to demonstrate that the formula
supports normal physical growth. Thus, in the interim final rule, Sec.
106.96(c)(1) contains a narrowly defined circumstance in which FDA will
grant a manufacturer an exemption from the growth monitoring study
requirement upon the manufacturer's request. The interim final rule's
three additional exemptions from the requirement to meet the specific
growth monitoring study requirements under Sec. 106.96(b) clearly
place the responsibility on the manufacturer to demonstrate to the
Agency's satisfaction that the conditions of the exemption have been
satisfied.
(Comment 248) Another comment stated that not every change in an
infant formula raises questions as to infant growth that cannot be
answered adequately by other scientific supportive data that may be
equally convincing and more appropriate.
(Response) FDA agrees with this comment to the extent that it
asserts that not every change in an infant formula will require the
manufacturer to conduct a growth monitoring study of a new formulation
of an infant formula. As noted in the response to the previous comment,
the interim final rule provides separate exemptions from the growth
monitoring study requirement in Sec. 106.96(c)(2) of the interim final
rule, including an exemption for the situation in which a manufacturer
establishes that an alternative method or study design that is based on
sound scientific principles can show that the formula supports normal
physical growth when fed as the sole source of nutrition (Sec.
106.96(c)(2)(i) of the interim final rule). Thus, FDA believes that the
interim final rule responds to this comment.
(Comment 249) One comment noted that the proposed rule contains a
broad definition of ``major change'' that would mandate the filing of a
premarket notification for numerous changes in processing or
formulation, and that, while the industry recognizes that a growth
study may be needed to assess some of these major changes (such as the
use of certain new ingredients with no prior history of use in infant
formula), there is no scientific basis to mandate a growth study for
other major changes (such as the manufacture of an infant formula on a
new processing line).
(Response) FDA disagrees with this comment to the extent that it
asserts that the proposed definition of ``major change'' is too broad.
The definition of ``major change'' in this interim final rule is
discussed previously in this document in section IV.C.2.
FDA agrees that a growth monitoring study may be needed to assess
some major changes (such as the use of certain new ingredients with no
prior history of use in infant formula). However, in the case of use of
a new processing line, some changes, such as
[[Page 8020]]
introduction of a new retort system with altered time and temperature
processing conditions, could potentially have an adverse effect on the
bioavailability of the formula, including the bioavailability of
nutrients in the formula. On the other hand, FDA also recognizes that
not all processing changes have the same potential to affect formula
bioavailability and bioavailability of nutrients. Thus, Sec.
106.96(c)(2)(ii) of the interim final rule provides an exemption from
the quality factor requirements for normal physical growth, Sec.
106.96(b) of the interim final rule, where the manufacturer provides
assurances, as required under Sec. 106.121 of the interim final rule,
that demonstrate that a ``major change'' to an existing formula does
not affect the bioavailability of the formula, including the
bioavailability of nutrients in such formula. In addition, the interim
final rule provides an exemption, upon the manufacturer's request, from
the requirements of Sec. 106.96(b) of the interim final rule, for a
change that is a ``major change,'' but is limited to altering the type
of packaging of an existing infant formula. For these reasons, FDA
declines to make revisions in response to this comment.
(Comment 250) One comment requested deletion of proposed Sec.
106.97(a)(2)(i) because, the comment asserted, providing that an
exemption ``may be available'' based on a requirement to
``demonstrate'' that a manufacturer or responsible party has experience
with an ingredient, ingredient mixture, or a processing method
constitutes premarket approval, not notification.
(Response) FDA disagrees with this comment to the extent that it
asserts that the structure of proposed Sec. 106.97(a)(2)(i)
constitutes premarket approval. The proposed exemption is part of FDA's
establishment of requirements for quality factors, an action expressly
required by section 412(b)(1) of the FD&C Act, and nothing in this
proposed exemption can or does alter the statutory process of premarket
notification established by section 412(c) of the FD&C Act. FDA is
deleting this specific exemption as unnecessary, however, because its
specific circumstances are covered by the broader exemption in Sec.
106.96(c)(2)(ii) of the interim final rule.
(Comment 251) One comment suggested that ``similar experience''
with an ingredient, an ingredient mixture, or a processing method
should be relevant regardless of whether it occurred in the United
States or elsewhere.
(Response) As noted, FDA is deleting the specific exemption in
proposed Sec. 106.97(a)(2)(i) because its circumstances will be
covered by the broader exemption in Sec. 106.96(c)(2)(ii) of the
interim final rule. As part of the showing required by Sec.
106.96(c)(2)(ii) of the interim final rule, a manufacturer may submit
data from marketing outside the United States. FDA expects that, in
such circumstances, the manufacturer will explain why such data are
both relevant to a change in an infant formula marketed in the United
States and why FDA should consider such data. Thus, under the interim
final rule, the information relating to a manufacturer's experience
outside the United States with an ingredient, ingredient mixture, or
processing method will not be categorically classified as irrelevant to
a change in a formula distributed in the United States.
(Comment 252) One comment requested deletion of Sec.
106.97(a)(2)(ii) from the final rule but did not state why. Another
comment agreed with the concept of choosing the most stringent case for
conducting quality factor testing, whenever possible, but also stated
that the choice of the representative formula should not be based
solely on greatest adverse nutrient effect and provided the following
example: If a product has two forms, one a liquid, ready-to-feed
formula for hospital use only, and the other a powder formula for
retail use, it may be more appropriate to study the form that is
intended for long term use (i.e., the powder) as opposed to the very
short term formula (i.e., the liquid), where processing actually may
have the greatest adverse nutrient effect.
(Response) FDA disagrees with this comment. All forms of infant
formula (ready-to-feed, concentrate, and powder) are marketed for
extended use and thus, all must be capable of supporting normal
physical growth of healthy term infants when used as the sole source of
nutrition. For this reason, FDA disputes the comment's suggestion that
powdered infant formula is the infant formula form intended for long-
term use and thus, is the form that should be used in a growth
monitoring study. The comment did not directly dispute FDA's view that
the infant formula form processed under the most severe conditions is
the form with the greatest likelihood of having adverse effects on its
nutrient content and, thus, on the formula's bioavailability to the
infant. In most cases, the most highly processed form of formula is the
liquid product that undergoes pasteurization plus a heat treatment
(typically, retorting to temperatures of 244[emsp14][deg]F) to ensure
commercial sterility. Such retorting is more severe than the heat
treatment applied during the production of powdered products, which
typically involves only pasteurization plus a relatively milder heat
treatment during spray drying (powder temperature reaching 110-175
[deg]F at the dryer outlet) (Ref. 75).
For this reason, FDA concludes that, in all likelihood, it would be
appropriate to test in a growth monitoring study the liquid form of an
infant formula processed under the most severe conditions, which
results would be applicable to the less highly processed powdered form
of the formula. For companies producing only powdered infant formula,
the appropriate formula to test would, of course, be the powdered form.
Given the disparities in processing and the effects of processing,
however, the results of a growth monitoring study of powdered product
generally would not be evidence that more highly processed liquid forms
of the formulation satisfy the quality factor of normal physical growth
in healthy term infants.
(Comment 253) One comment asserted that in applying the exemption
of proposed Sec. 106.97(a)(2)(ii), the manufacturer must be given
responsibility for determining the most representative form to test.
(Response) FDA notes that the exemption in proposed Sec.
106.97(a)(2)(ii) has been recodified at Sec. 106.96(c)(2)(iii) of the
interim final rule.
FDA disagrees in part with this comment to the extent that the
comment asserts that the manufacturer should be able to determine
unilaterally which form of a formulation to test in a growth monitoring
study. The provision in question is part of the assurances that a
formula satisfies the requirements for quality factors, which
requirements and assurances the statute authorizes FDA to establish.
Although the statutory scheme does not require the Agency to establish
exemptions from the assurances that such requirements are satisfied,
FDA has determined, in its discretion, to do so. Accordingly, it is
also within the Agency's discretion to establish the terms of such
exemptions, including the requirement that a manufacturer must satisfy
FDA that the conditions of an exemption exist.
Moreover, in this case, it is reasonable that a manufacturer
establish, to the Agency's satisfaction, that the form of the formula
tested in a growth monitoring study is the form processed using the
method with the greatest potential for adverse effects on the nutrient
content and bioavailability. This standard will provide the greatest
[[Page 8021]]
certainty that all forms of a formula will be nutritionally sufficient
regardless of the means of processing. FDA does agree, however, that
under this exemption, the manufacturer may initially choose which form
of a formulation to test for such purposes, but when submitting its
assurances to the Agency, the manufacturer must demonstrate that the
form tested meets the standard in Sec. 106.96(c)(2)(iii) of the
interim final rule.
(Comment 254) One comment argued that when studies have already
been carried out on a form of the product that meets neither criterion
(i.e., a formula with greatest potential for an adverse effect on
nutrients or a formula intended for long term use), but the new
formulation cannot reasonably be expected to differ significantly from
the formula in question in terms of nutrient levels or bioavailability,
those studies should also be able to provide the basis for exemption
from additional studies. The comment stated that to require duplicative
studies on different forms of a product that do not differ
significantly would be difficult to justify on an ethical basis.
(Response) As noted previously in this document, FDA has added an
exemption to the interim final rule allowing manufacturers to request
an exemption and provide assurances that demonstrate that an
alternative method or study design that is based on sound scientific
principles is available to show that the formula supports normal
physical growth in infants when the formula is fed as the sole source
of nutrition. This would permit a manufacturer to submit data relating
to a particular formulation and to demonstrate that, even if the
formulation tested is not the most heavily processed, sound science
principles support reliance on such data to demonstrate that all forms
of the formulation satisfy the quality factor of normal physical
growth. Thus, there is an option in the interim final rule for the
manufacturer to request an exemption from the need for a growth
monitoring study under the circumstances identified in the comment.
(Comment 255) One comment requested deletion of proposed Sec.
106.97(a)(2)(iii), but did not state why. Another comment noted FDA's
recognition of the flexibility necessary to accommodate evolution in
clinical study design and suggested that consideration should be given
to situations where formula is not intended as the sole source of
nutrition.
(Response) The request to allow infant formulas to be tested other
than as the sole source of nutrition was addressed previously in this
document in section VIII.C.4.c. Consistent with this discussion, the
Agency does not agree that ``sole source of nutrition'' should be
removed from the language in the exemption.
FDA acknowledged in proposed Sec. 106.97(a)(2)(iii) that it is
possible to assure the Agency that an alternative method or study
design may be appropriate for the evaluation of the ability of some
infant formulas to support normal physical growth. Therefore, FDA is
providing a mechanism whereby manufacturers may request an exemption
from the growth monitoring study requirement and use an alternate
method or study design to provide assurances of normal physical growth.
Because questions about the adequacy of a study design or method may be
varied and may raise unique questions about the ability of such method
or design to generate data to demonstrate normal physical growth, FDA
is requiring that the assurances, required under Sec. 106.121 of the
interim final rule for such an exemption, demonstrate that the
alternative method or study design be based on sound scientific
principles and show that the formula supports normal physical growth
when the formula is the sole source of nutrition (see section X for
further discussion on the assurances required by Sec. 106.121 of the
interim final rule). This exemption, as revised, is now Sec.
106.96(c)(2)(i) of the interim final rule.
(Comment 256) One comment suggested that proposed Sec.
106.97(a)(2) be revised to allow a manufacturer to request an exemption
from the individual testing requirements of proposed Sec. 106.97(a)(1)
if the manufacturer has determined that a change in formulation or
processing does not cause the formula to be adulterated under section
412(a) of the FD&C Act and provides to FDA the basis for this
determination. The comment argued that without the suggested change,
the proposed rule provides no exemptions for changes such as minor
changes in ingredient levels, replacing one nutrient form with another,
or insignificant changes in processing conditions. The comment argued
that such changes would require a submission under proposed Sec.
106.140, which includes assurances under proposed Sec. 106.121. The
comment asserted that it was not the Agency's intent or a correct
interpretation of section 412(d)(3) of the FD&C Act to require clinical
testing and protein efficiency ratio (PER) data for such minor changes.
(Response) FDA disagrees with this comment. The fact that the
proposed rule would have required a quality factors submission
complying with proposed Sec. 106.121 is clear evidence of FDA's
intent. This intent is consistent with the statute, which requires that
a manufacturer of a new infant formula provide assurance that the
formula meets quality factor requirements in a ``before first
processing'' (BFP) submission made under section 412(d)(3) of the FD&C
Act. In lieu of a growth monitoring study, the manufacturer may request
an exemption under Sec. 106.96(c)(2)(ii) of the interim final rule and
provide the scientific basis to explain why the changes in the formula
would not affect the bioavailability of the formula and its nutrients
and submit the results of the nutrient testing on finished product
required under Sec. 106.91(a) of the interim final rule.
The comment misunderstood the intent of the requirements for growth
monitoring studies. FDA does not intend to require a growth monitoring
study for all changes to a formula. A BFP notification under section
412(d)(3) of the FD&C Act must be submitted when the manufacturer
determines that a change in the formulation of the formula or a change
in the processing of the formula ``may affect whether the formula is
adulterated'' under section 412(a) of the FD&C Act, e.g., when there
are questions about whether a formula provides nutrients required by
section 412(i) of the FD&C Act, meets quality factor requirements, or
is in compliance with CGMP and quality control procedures. The 1986
Guidelines Concerning Notification and Testing of Infant Formulas
listed several examples of types of changes for BFPs, such as replacing
certain nutrient forms with another form or adjustments in the quantity
of a nutrient in a premix or individually added nutrient that results
in a specification change for that nutrient in the finished product, or
changes in time-temperature conditions of preheating during handling of
bulk product that cannot reasonably be expected to cause an adverse
impact on nutrient levels or nutrient availability.
E. Quality Factor: Protein Quality
In 1996, FDA proposed (Sec. 106.96(c)) protein of sufficient
biological quality as a second quality factor for infant formula and
stated that a formula must not only contain adequate amounts of protein
but also protein in a form that can be utilized by infants. At that
time, the Agency noted that protein quality depends on a number of
factors and complex interactions, including
[[Page 8022]]
differences in the digestibility of proteins from different sources and
on the processing method for the formula. FDA also observed that the
nutritive value of protein depends upon the presence of all essential
amino acids at levels and relative proportions that will support
healthy growth and stated that this quality factor would require an
evaluation of whether the formula contains the essential amino acids
and total nitrogen in the amount and proportion to permit normal tissue
and organ growth and development (61 FR 36154 at 36181). In proposed
Sec. 106.97(b)(1), FDA proposed to require that biological protein
quality be established using the Protein Efficiency Ratio (PER) rat
bioassay described in the Official Methods of AOAC International, which
the Agency proposed to incorporate by reference (61 FR at 36215). In
proposed Sec. 106.97(b)(2), the proposed rule identified two
situations in which the manufacturer could request an exemption from
the PER assay requirement.
FDA received no general comments on the Agency's proposal to
establish protein of sufficient biological quality as a quality factor
for infant formula. As noted previously in this document, FDA is
reorganizing and consolidating into Sec. 106.96 of the interim final
rule most of the content of proposed Sec. 106.96 and proposed Sec.
106.97 related to requirements for infant formula quality factors.
Thus, in the absence of comments, Sec. 106.96(e) of the interim final
rule establishes a second infant formula quality factor, biological
quality of protein sufficient to meet the protein requirements of
infants. Accordingly, Sec. 106.96(e) states the following: ``An infant
formula manufacturer shall meet the quality factor of sufficient
biological quality of protein.''
1. Methods for Determining Biological Quality of Protein in Infant
Formulas
(Comment 257) One comment objected that the proposal specified a
particular AOAC method for evaluating protein quality and stated that
the biological quality of the protein in infant formula could be
established with any AOAC approved method including the PER.
(Response) FDA disagrees with this comment. As noted, protein will
be of sufficient quality only if it contains sufficient amounts of all
amino acids essential for infants, is present in adequate amounts, and
is present in a form that infants can utilize. In the 1996 proposed
rule, the Agency explained that ``A protein source may contain the
necessary amino acids, but they may be in a form that the infant cannot
digest and absorb. Furthermore, processing methods may alter the
chemical nature of the protein source, possibly making the protein more
resistant to digestion by the infant'' (61 FR 36154 at 36187). FDA
proposed the PER method because, unlike chemical measures of protein
composition, PER provides an estimate of the bioavailability of the
protein. The Agency notes that the comment did not offer specific
objections to the PER method. Nor did the comment identify other
official AOAC methods that could successfully evaluate the presence and
bioavailability of protein in an infant formula. Accordingly, FDA is
not modifying this provision in response to this comment.
(Comment 258) Several comments questioned whether the PER is the
best method of determining the protein quality of an infant formula and
whether measurements of protein status in the infant would be more
appropriate.
(Response) FDA disagrees with these comments to the extent that
they challenge the use of the PER method. The PER method uses an animal
model and thus, will allow a manufacturer to assess an infant formula's
protein quality before the formula is fed to infants in a growth
monitoring study or otherwise. High quality proteins are easily
digestible and contain all of the essential amino acids in amounts that
humans require. As stated in the previous response, evaluating protein
quality requires both measuring the amount present and the amount that
is bioavailable. The PER permits a comparison of different protein
sources (i.e., is the test protein better or worse than the control
protein?). FDA is aware that the PER, although sensitive, is not
specific. The PER method has limitations (as discussed in this
document); however, FDA is not aware of any other available method to
assess protein bioavailability, and no comment, including this one,
identified any such method.
FDA notes that the Agency consulted with an expert panel
established by the Life Sciences Research Office (LSRO) of the
Federation of American Societies for Experimental Biology (FASEB). The
LSRO panel was asked about minimum and maximum levels of protein in
infant formula and considered methods that measured protein quality but
not protein bioavailability (Ref. 76). Although total protein
(measurement of nitrogen) as well as amino acid patterns can now be
measured and such measures may be appropriate for certain aspects of
protein quality, chemical measures of this type do not address the
protein's bioavailability. The ability to estimate protein
bioavailability is the advantage of a biological test system such as
the PER assay.
FDA is well aware of the limitations of the PER as these
limitations have been known for many years (Refs. 77 and 78). A
principal criticism of the PER is that it is highly correlated to
weight gain but does not characterize the protein, rather it reflects
the rate of weight gain of the rat consuming the test substance with
the weight gain of a control group. The Agency acknowledges that body
weight gain does not necessarily correspond to gain in muscle related
to protein intake nor does body weight gain detect changes in body
composition (Refs. 77 and 78). The PER assay has also been criticized
because, even under standardized conditions, laboratories may obtain
variable results in terms of the ratio percentage. However, PER is a
simple test with an AOAC standardized method that has improved the
assay (Ref. 79). Appropriate modifications of the PER are described in
this document.
For the foregoing reasons, FDA declines to delete the requirement
that infant formula protein be assayed using the PER method.
(Comment 259) One comment stated that when a manufacturer proposes
to alter the protein source or composition of an infant formula, the
manufacturer should be required to demonstrate that the serum amino
acid levels of infants consuming the altered formula are comparable to
those of breast-fed infants or infants fed other standard infant
formulas.
Another comment countered that universally requiring amino acid
determinations in infants consuming the altered infant formula would
add nothing to the assessment of new combinations of protein sources
and the potential for the use of additional invasive procedures to
collect these data would be considered unethical unless specifically
justified. The comment further stated that the need for such analyses
can only be determined on a case-by-case basis.
(Response) Determining serum free amino acid levels in infants
consuming the test formula would not be an adequate means of assessing
protein quality. Importantly, the comment did not provide evidence to
support this recommendation, and there are at least two reasons that
such tests would have limited value, if any. First, serum free amino
acids reflect circulating amino acids, which may be present in an
infant's blood either from the diet (i.e., the infant formula being
consumed) or from endogenous sources, such as the breakdown of the
infant's muscles. In
[[Page 8023]]
addition, determining serum levels of free amino acids would require
blood draws, an invasive procedure. Given the limited usefulness of
serum free amino acid analyses, requiring such analyses and thus, an
invasive procedure, is not reasonable. Accordingly, FDA declines to
revise the interim final rule to require formula manufacturers to
demonstrate routinely that serum amino acid levels of study infants are
comparable to those of breast-fed infants or of infants fed other
appropriate infant formulas.
(Comment 260) One comment disputed that PER measurements in young
rats would add anything to the data collected in human infants. The
comment asserted that anthropometric measures, nitrogen balance
studies, and biochemical markers required by FDA in the growth
monitoring study would provide an indication of the sufficiency of
protein quality and quantity and that these measures in human infants
would be sufficient to confirm that such quality and quantity are
adequate.
(Response) FDA disagrees with this comment. Contrary to what some
comments have suggested, FDA did not propose to require nitrogen
balance studies or biochemical markers as requirements for infant
formula quality factors. (A balance study is a study that measures each
individual study subject's intake and excretion of one or more
particular substances, such as required nutrients.)
Moreover, the PER analysis would contribute valuable information to
the assessment of an infant formula's nutritional adequacy, value not
provided by a growth monitoring study, for two reasons. First, as
noted, the PER analysis is conducted in an animal model and thus, will
permit determination of a formula's protein quality before infants are
exposed to the formula. This ensures that infants will not be fed a
formula with inadequate or biologically unavailable protein, which is
critical because when an infant formula is the sole source of
nutrition, any inadequacy in protein quality cannot be compensated for
by other dietary components, and such inadequacy may result in serious,
and in some cases, permanent, adverse effects on an infant's growth and
development (Ref. 80).
Second, as discussed previously in this document, a growth
monitoring study that includes anthropometric measurements assesses
whether the complete infant formula matrix supports normal physical
growth and contributes to an assessment of healthy growth. However, it
is imperative that protein quality be established prior to its use in
an infant formula, particularly where there is an accepted means (the
PER) to do so. It is critical that the composition of the protein,
e.g., type and amounts of essential amino acids, in a formula be
adequate to support the needs of a developing infant, and that the
formula containing the protein support normal physical growth.
Importantly, the failure of a formula to support normal physical growth
could be the result of a number of shortcomings in the formula. Thus,
the growth monitoring study will not provide information specific to
protein quality and bioavailability.
2. Method for Assessing Protein Efficiency Ratio (PER)
(Comment 261) One comment pointed out that the citation to the PER
method in proposed Sec. 106.97(b)(1) should be changed to Protein
Efficiency Ratio (PER) rat bioassay described in the ``Official Methods
of Analysis of AOAC INTERNATIONAL,'' 16th ed., AOAC[supreg] Official
Methods 960.48, Protein Efficiency Ratio Rat Bioassay and 982.30,
Protein Efficiency Ratio, Calculation Method.
(Response) In Sec. 106.96(f) of the interim final rule, FDA has
updated the references to AOAC International and to the AOAC methods,
and has used the current name and address for AOAC International in
Sec. 106.160, ``Incorporation by reference.''
(Comment 262) Another comment stated that proposed Sec.
106.97(b)(1) should be revised to recognize other AOAC methods as they
become available.
(Response) FDA will evaluate any AOAC method that becomes available
that might serve as a substitute for, or alternative to, the PER assay
and, if appropriate, will consider amending Sec. 106.96(f) to include
such method or methods.
Although FDA is not revising the requirement to use the PER assay
in response to comments, the Agency is making, in addition to several
minor editorial changes, three revisions to proposed Sec. 106.97(b)(1)
on its own initiative.
First, at the time of the 1996 proposal, certain language was
inadvertently omitted from proposed Sec. 106.97(b). In particular, the
phrase by ``an appropriate modification of'' should have been included
so that the sentence, as proposed, would read ``The manufacturer shall
establish the biological quality of the protein in its infant formula
by demonstrating that the protein source supports adequate growth using
an appropriate modification of the Protein Efficiency Ratio (PER) rat
bioassay described in the ''Official Methods of Analysis of the
Association of Official Analytical Chemists . . . .'' The basis for
this change is explained in this document.
The requirement to assess the quality of the protein component of
an infant formula was originally established in FDA's quality control
regulations for infant formula, 21 CFR 106.30(c)(2), which were issued
in 1982 (47 FR 17016 at 17026 (April 26, 1982)). Comments on the
proposed rule asserted that, without certain modifications, the
official AOAC assay for PER would not give valid test results for
infant formulas due to the type of fat and concentrations of lactose
and fat required in infant formula (47 FR 17016 at 17023). The Agency
agreed with this view and thus, Sec. 106.30(c)(2) of the final rule
provided that ``The biological quality of the protein shall be
determined by an appropriate modification of the AOAC bioassay method
of analysis.''
The purpose of the PER rat bioassay is to compare the quality of
protein in a finished infant formula product to a protein of known high
biological quality (casein) to demonstrate that the protein in a
proposed formula is bioavailable (supports comparable growth of the
rats), as a decrease in the protein's biological value would not be
detected by chemical analysis. As noted previously in this document,
the PER rat bioassay is currently the only method that accounts for
protein digestibility and absorption in a living animal system.
Digestibility and absorption are critical elements to ensuring, prior
to marketing, that an infant formula has sufficient protein quality.
The official AOAC method is based on weight gain in test animals
where one group of rats is fed a casein control diet and another group
is fed a diet containing the test product (infant formula) (Ref. 81),
and the animals' food intake and body weight are measured. The mean
protein efficiency ratio (PER) is calculated based on the protein
consumed by and weight gain of each animal group. Prior to study
initiation, the test product (finished infant formula) and the casein
control are subjected to a compositional assessment (proximate
analysis). The diets are then formulated to contain matching amounts of
protein, fat, minerals, fiber, and moisture. These diets are analyzed
for protein to confirm that they were formulated correctly, which
information is used to calculate the PER at completion of the trial.
Although the method has limitations with respect to assessment of
the quality of protein sources for infant formulas, the limitations are
greatly reduced by modification of the test and control diets. Three
dietary adjustments
[[Page 8024]]
commonly required for evaluation of the protein quality of infant
formulas are:
Adjustment of the fat content: In most cases, when the
infant formula is incorporated into the protein evaluation diet based
on the nitrogen content, the fat content will be above the limit (8
percent) specified by the AOAC Official Method. The fat content of the
reference control (casein) diet must be adjusted to match the fat
content of the infant formula test diet.
Carbohydrate composition adjustments: Lactose is the
carbohydrate component of most milk-based infant formulas. Rats do not
tolerate lactose well and often develop diarrhea, which may lead to an
underestimation of protein quality of the formula. The casein reference
control diet(s) must contain levels of lactose comparable to the amount
in the infant formula test diet to adjust for possible confounding of
the estimation of protein quality. If an infant formula contains a
carbohydrate source other than lactose (e.g., sucrose, corn syrup
solids), the source of carbohydrate in the formula should be used in
the control diet as well.
Removal of water from liquid infant formula: Infant
formula is incorporated into the protein evaluation diet based on its
nitrogen content. Because of the high water content of infant formulas
in liquid form, these products usually are below the lower limit of
total nitrogen (1.8 percent by weight) required for the PER bioassay.
Liquid infant formulas must be freeze-dried so that the test sample
contains more than 1.8 percent nitrogen before the infant formula test
diet is formulated.
Second, in order to ensure that determination of the biological
quality of the protein of a new formulation precedes the initiation of
the growth monitoring study required by Sec. 106.96(b) of the interim
final rule, the Agency is adding the following sentence in Sec.
106.96(f) of the interim final rule: ``The PER rat bioassay shall be
conducted on a formula and the results evaluated prior to the
initiation of a growth monitoring study of the formula that is required
under paragraph (b).'' This will prevent the exposure of growth
monitoring study subjects to a protein of undetermined biological
quality and any unnecessary attendant risk of such exposure.
Finally, proposed Sec. 106.97(b)(1) provided that ``[i]f the
manufacturer is unable to conduct a PER rat bioassay because of the
composition of the protein in the formula, then it shall demonstrate
that the amino acid composition of the protein meets the known amino
acid requirements of infants for whom the formula is intended.'' As an
example of a formula for which this proposed flexibility might be
necessary, the preamble cited the instance of an ``exempt infant
formula'' that contains an incomplete protein (61 FR 36154 at 36187).
As discussed previously in this document, this interim final rule only
applies to non-exempt infant formulas; the composition of the protein
of such non-exempt formulas would not preclude the use of the PER to
determine protein quality. Therefore, FDA is excluding as unnecessary
from Sec. 106.96(f) of the interim final rule the following
sentence:''If the manufacturer is unable to conduct a PER rat bioassay
because of the composition of the protein in the formula, then it shall
demonstrate that the amino acid composition of the protein meets the
known amino acid requirements of infants for whom the formula is
intended.''
F. Exemption From the Quality Factor of Protein Quality Sufficiency
As noted, the 1996 proposed rule identified two situations in which
the manufacturer could request an exemption from the PER assay
requirement in proposed Sec. 106.97(b)(2). Specifically, an exemption
from the PER requirement would have been available where the
manufacturer was already using the same protein source produced by the
same processing method in another infant formula marketed in the United
States, and the manufacturer could demonstrate that current formula met
the quality factor requirements of the proposed rule, and where the
protein source, including any processing method used to produce the
protein, would not have been a major change from its predecessor
formula and the manufacturer could demonstrate that the predecessor
formula met the quality factor requirements of the proposed rule.
As discussed previously in this document in section VIII.D. in this
interim final rule, FDA is revising the exemptions from conducting a
growth monitoring study under Sec. 106.96(b). Section 106.96(c)(1) of
the interim final rule provides that, in response to a manufacturer's
request, the Agency will exempt the manufacturer from the obligation to
conduct a growth monitoring study when the manufacturer requests an
exemption and provides assurances under Sec. 106.121 of the interim
final rule that the changes to the existing formula are limited to
changing the type of packaging for an existing infant formula.
An assay of protein quality would also not be required in the
foregoing circumstance because the change would not be expected to have
an effect on protein quality or on any of the other nutrients in the
formula that could affect the bioavailability of the protein.
Accordingly, Sec. 106.96(g)(1) of the interim final rule provides that
FDA will exempt a manufacturer from the requirement to conduct a PER
assay where the manufacturer requests an exemption and provides
assurances that the change to an existing infant formula is limited to
changing the type of packaging for an existing formula.
FDA also recognizes that not all changes to an infant formula have
the potential to affect the biological quality of the protein in the
formula. Accordingly, to provide flexibility in the interim final rule
for these types of circumstances, Sec. 106.96(g)(2) of the interim
final rule includes an additional exemption. FDA emphasizes that it is
the obligation of the manufacturer to establish that all the conditions
of the exemption are satisfied. Specifically, Sec. 106.96(g)(2) of the
interim final rule provides that a manufacturer may request an
exemption from the requirement to perform the PER assay if the
manufacturer demonstrates that a change made by the manufacturer to an
existing formula does not affect the quality or the bioavailability of
the protein.
G. Miscellaneous Comments on the Quality Factor for Sufficient
Biological Quality of Protein
(Comment 263) In response to the 2003 reopening notice, one comment
stated that protein quality for infant formula is based on estimates,
extrapolations, and safety margins that have caused some products to
provide protein intakes to formula-fed babies at twice the rate of
breastfed infants. The comment stated that ``Heat-treated proteins have
lower digestibility with high amounts contributing to metabolic and
excretory stress in the infant.''
(Response) This comment appears to raise issues related to the
quantity of protein in infant formulas rather than protein quality and
did not suggest changes to the proposed quality factor of protein
quality. The issue raised in this comment would be more appropriately
considered in any future revision of Sec. 107.100 and the maximum
protein levels for infant formulas, an issue that is outside the scope
of this interim final rule. Accordingly, no response to this comment is
required.
H. Application of Quality Factors to Currently Marketed and Previously
Marketed Formulas
As noted in section VIII.C.1, in 1996, FDA proposed ``normal
physical
[[Page 8025]]
growth'' as a quality factor (proposed Sec. 106.96(b)) and proposed
requirements for the assurances for such quality factor (proposed Sec.
106.97(a)). At the same time, FDA proposed ``sufficient biological
quality'' of the formula's protein component as a second quality factor
(proposed Sec. 106.96(c)) and proposed requirements for the assurances
for this quality factor (proposed Sec. 106.97(b)). As proposed, the
quality factors described in proposed Sec. 106.96 and the assurance
provisions of proposed Sec. 106.97 would have applied to all infant
formulas distributed in U.S. commerce and not simply ``new infant
formulas.'' Subsequently, in the 2003 reopening, the Agency expressly
requested comment on the appropriateness of the two quality factors
proposed in 1996 (68 FR 22341 at 22342-22343).
This interim final rule establishes two quality factors, the
quality factor of ``normal physical growth'' (Sec. 106.96(a) of the
interim final rule) and the quality factor of ``sufficient biological
quality of protein'' (Sec. 106.96(e)), and sets minimum requirements
for both quality factors (Sec. 106.96(b) and (f) of the interim final
rule, respectively). Under the interim final rule, for each quality
factor, the results of a single study, when conducted consistent with
the requirements of the interim final rule, are sufficient to establish
that the formula meets the quality factor. Thus, under the interim
final rule, a single study--a growth monitoring study conducted as
specified in Sec. 106.96(b) of the interim final rule--is sufficient
to demonstrate that an infant formula supports normal physical growth.
Similarly, a single study--a protein efficiency ratio (PER) study
conducted as specified in Sec. 106.96(f) of the interim final rule--is
sufficient to establish that a formula's protein component is of
sufficient biological quality.
Like the proposed rule, the quality factors set forth in the
provisions of Sec. 106.96(a) and (e) of the interim final rule apply
to all infant formulas distributed in interstate commerce. This means
that a ``not new'' infant formula (i.e., an infant formula that
previously was the subject of a new infant formula submission made
under section 412(c)(1) of the FD&C Act) must satisfy the two quality
factors established by this interim final rule. These ``not new''
infant formulas may be formulas that are not currently distributed as
well as formulas that are currently distributed in the United States.
Any formula, including a ``not new'' formula, that does not satisfy the
quality factor requirements established under section 412(b)(1) of the
FD&C Act is deemed adulterated under section 412(a)(2) of the FD&C Act.
As discussed in the introduction of this document, the 1986
amendments mandated that FDA establish by regulation requirements for
quality factors for infant formula. Section 412(b)(1) of the FD&C Act,
the quality factor requirements provision, is not self-executing and
thus, there have been no enforceable quality factor requirements
pending the issuance of this interim final rule. Prior to and since the
1986 amendments, a variety of infant formula products have been
distributed in the United States. Consistent with section 412(c) and
(d) of the FD&C Act, manufacturers of these products have been required
to notify FDA of their intent to market these infant formulas and to
make a new infant formula submission, and they have done so. In the
absence of implementing regulations, however, these notifications were
not required to provide assurances that the formula meets any quality
factor requirements.
Nevertheless, many notifications made after publication of the 1996
proposed rule have included information about the ability of the infant
formula that is the subject of the notification to support normal
physical growth and about the protein quality. Several submissions have
included growth information on the formula, some of which was derived
from growth studies that conform, more or less, to the provisions in
proposed Sec. 106.97(a). Some submissions have also included evidence
on the biological quality of the formula's protein component. Over this
same period, as manufacturers have brought to market new products
containing new ingredients, they have often stopped distributing
previous versions of the newer products. Thus, there is an existing
body of data and information, both published and unpublished, on many
currently marketed and previously marketed formulas that may be
relevant to whether such formulas support normal physical growth and
whether the protein component of each such formula is of sufficient
biological quality.
FDA evaluated the data and information available to the Agency that
is relevant to whether currently marketed infant formulas meet the two
quality factors established by the interim final rule. This information
includes material submitted to FDA and also published studies. The
Agency recognizes, however, that formula manufacturers may have
information on their products in addition to that available to FDA.
Importantly, none of the available evidence suggests that any currently
marketed infant formula fails to support normal physical growth or uses
a protein component that lacks sufficient biological quality. By the
same token, however, the available scientific record evaluated by FDA
did not include sufficient information to document that all currently
marketed infant formulas meet the quality factors of normal physical
growth and are composed of a protein of sufficient biological quality.
Although the data and information available to FDA may not be
sufficient to demonstrate that every currently marketed formula meets
the two quality factors, the Agency acknowledges that removal of infant
formula from the market, based on limitations in the data and
information that is available to FDA to date, would likely be very
disruptive. Therefore, the Agency has developed separate provisions and
an orderly process for these formulas to transition to the newly
established requirements. There are two reasons that an orderly process
that minimizes disruption in the marketplace is essential for a product
like infant formula.
First, as noted previously in this document, for many infants,
infant formula is the sole source or the primary source of nutrition in
the critical early months of growth and development, and formula often
continues to be an integral part of the diet of many infants through 12
months of age. Indeed, based on the CDC's study of breastfeeding rates
in the U.S., in 2010, one quarter of U.S. infants were formula-fed from
birth (approximately 1,027,000 infants) and by three months of age,
two-thirds of U.S. infants (approximately 2,700,000 infants) relied on
formula for some portion of their nutrition (http://www.cdc.gov/breastfeeding/data/reportcard.htm) (Ref. 82). Thus, it is essential
that an adequate supply of formula be maintained as infant formula
products transition to compliance with the requirements established by
the interim final rule.
Disruption in the infant formula supply in the United States could
be especially problematic for the USDA's Special Supplemental Nutrition
Program for Woman, Infants, and Children (WIC). More than half of the
infant formula fed to U.S. infants is purchased through the WIC
program. This program provides Federal grants to states for
supplemental foods, health care referrals, and nutrition education to
low-income pregnant, breastfeeding, and non-breastfeeding postpartum
women, and to infants and children up to age five who are at
nutritional risk. Under the current WIC program, each state contracts
with a single formula
[[Page 8026]]
manufacturer to provide formula to the WIC participants in the state.
Although it is possible for a state to change its contractual
arrangements, it is nevertheless important to avoid market disruptions
that could have an impact on the availability of formulas distributed
through the WIC program.
Second, maintaining sufficient availability of a variety of infant
formulas in the marketplace during this transition period is important.
Although all infant formula products must satisfy the nutrient
requirements of FDA's regulations in Sec. 107.100, these products
differ in their overall composition; such differences are not only in a
formula's protein source (cow milk protein or soy protein isolate) but
extend to other ingredients and components. The variations in formula
products may not be equally tolerated by every infant and, thus,
different infant formulas may not be interchangeable. For this reason,
pediatricians generally recommend that parents of a formula-fed infant
identify a single formula that their infant can tolerate and feed that
formula to their child. Thus, it is also important to maintain a
consistent supply of a variety of formula products.
As noted, there is a considerable body of evidence relevant to
whether currently marketed and previously marketed infant formulas are
likely to satisfy the quality factors established by the interim final
rule. These data and information consist of a variety of different
studies and sources of information. The studies may not, strictly
speaking, fulfill the detailed requirements of the interim final rule
in that, for example, there is not likely to be a single growth
monitoring study that satisfies all of the requirements of Sec.
106.96(b) of the interim final rule. Importantly, however, this
existing body of evidence, when viewed collectively, may show that a
particular infant formula supports normal physical growth. FDA further
recognizes that if these existing data and this existing information
were not considered in assessing currently marketed and previously
marketed formulas, it would likely be necessary for formula
manufacturers to conduct new growth monitoring studies on such
formulas, which would require infant study subjects to be exposed to
the risks, however small, of the study protocol. In contrast,
considering the existing clinical evidence to assess whether a
currently marketed or previously marketed formula supports normal
physical growth may avoid exposing infants to these additional risks.
Going forward, infant formula manufacturers will be aware of the
interim final rule's requirement for a growth monitoring study and the
design characteristics required for such a study. Thus, the Agency
fully expects that, in the future, the data and information used by a
manufacturer to demonstrate that a new infant formula supports normal
physical growth will conform to the specific requirements of Sec.
106.96(b) of the interim final rule unless the formula qualifies for an
exemption under Sec. 106.96(c) of the interim final rule.
To minimize market disruption and its potential public health
impact, and to limit the exposure of infants to the risks of additional
clinical studies while ensuring that a formula meets the quality
factors established in this interim final rule, the interim final rule
includes specific provisions that apply to certain currently marketed
and previously marketed formulas. The interim final rule designates
these formulas as ``eligible'' infant formulas.
The following discussion explains Sec. 106.96(i) of the interim
final rule and specifically addresses: (1) Which formulas are covered
by these provisions (2) the applicable standard for each quality factor
and its basis, (3) the voluntary petition process and the outcome of a
manufacturer's participation in the petition process, (4) records
maintenance requirements, (5) the consequences of engaging or not
engaging in the voluntary petition process, and (6) compliance dates.
The provisions of Sec. 106.96(i) of the interim final rule apply
to any infant formula that satisfies the definition of ``eligible
infant formula.'' An ``eligible infant formula'' is defined in Sec.
106.3 of the interim final rule as an infant formula that ``could have
been or was lawfully distributed in the United States on May 12, 2014.
Thus, any formula that has been the subject of a properly submitted
infant formula notification under section 412(c) of the FD&C Act at
least 1 day before the publication date of the interim final rule is
eligible to utilize the provisions in Sec. 106.96(i) of the interim
final rule.
All infant formulas, including eligible infant formulas, must
satisfy the two quality factors established by the interim final rule,
normal physical growth and sufficient biological quality of the protein
component of the formula. Section 106.96(i) of the interim final rule
establishes quality factor requirements for eligible infant formulas.
Although the requirements of Sec. 106.96(i) of the interim final rule
are somewhat more flexible than the interim final rule's quality factor
requirements for infant formulas that are not ``eligible'' infant
formulas, these requirements are substantial. In particular, each of
the three alternative means of demonstrating quality factor
satisfaction mandates that scientific evidence be used to demonstrate
that the formula meets the quality factors. Moreover, under Sec.
106.96(i)(4) of the interim final rule, the manufacturer of each
eligible infant formula is required to make and retain records to
substantiate the view that the formula meets the quality factors, and
such records must contain all relevant scientific data and information
relied upon by the manufacturer for such substantiation as well as a
narrative explanation of the manufacturer's conclusion.
It is reasonable to extend the provisions in Sec. 106.96(i) and
its more flexible standards to formulas that are lawfully marketed by
the 89th day after the publication date of this interim final rule
because these are the formulas currently fulfilling the needs of
formula-fed infants. Establishing a mechanism to facilitate their
continued availability and thus, to minimize disruptions in the
availability of this essential source of infant nutrition, is
imperative. It is also sound to extend these provisions only to those
formulas that may be lawfully marketed by the 89th day after the
publication of this interim final rule. With the publication of this
interim final rule, infant formula manufacturers are now fully aware of
the standards that its products must satisfy and thereby, are
positioned to develop the required data and information for any new
infant formula that is the subject of a submission under section 412(c)
of the FD&C Act, including information that satisfies Sec. 106.96(b)
and (f) of the interim final rule. By comparison, a manufacturer of an
eligible infant formula could not reasonably have been expected to
develop the data and information to fulfill the specific requirements
of Sec. 106.96(b) and (f) of the interim final rule.
Section 106.96(i)(1) of the interim final rule addresses the
quality factor of normal physical growth. Under this provision, an
``eligible infant formula'' that fulfills one or more of three criteria
meets the quality factor of normal physical growth. FDA recognizes that
there may be one or more eligible infant formulas for which no growth
monitoring studies may have been conducted. In such circumstances, FDA
recommends that the manufacturer conduct a growth monitoring study and
may choose to design and conduct the study in conformity with the
primary quality factor requirements of the interim final rule in Sec.
106.96(b). Thus, Sec. 106.96(i)(1)(i) of the interim final rule
[[Page 8027]]
provides that an eligible infant formula meets the quality factor of
normal physical growth if the scientific evidence on such formula
fulfills the requirements of Sec. 106.96(b) of the interim final rule.
Similarly, a manufacturer who previously chose to develop evidence of a
formula's ability to support normal physical growth may have, quite
reasonably, chosen to conduct a growth monitoring study, the design of
which conformed to the provisions proposed in 1996 as those proposed
provisions represented FDA's then-best judgment about the design and
conduct of a growth monitoring study. To provide for these
circumstances, the Agency has set forth in Sec. 106.96(i)(1)(ii) of
the interim final rule the requirements for a growth monitoring study
that were proposed in 1996, and Sec. 106.96(i)(1)(ii) of the interim
final rule states that an eligible infant formula meets the quality
factor of normal physical growth if the scientific evidence on such
formula meets the provisions of that paragraph. The growth charts that
the 1996 proposed rule stated should be used for plotting growth data
are incorporated by reference under Sec. 106.160 of the interim final
rule. Finally, there may be some eligible infant formulas for which
there is no single growth study satisfying Sec. 106.96(i)(1)(i) or
(i)(1)(ii) of the interim final rule but for which there is a body of
scientific evidence drawn from multiple sources that, taken as a whole,
demonstrates that the formula supports normal physical growth. Thus,
Sec. 106.96(i)(1)(iii) of the interim final rule provides that an
eligible infant formula meets the quality factor of normal physical
growth if the scientific evidence on such formula otherwise
demonstrates that the formula supports normal physical growth. This
third option will require FDA to exercise its scientific judgment about
the data and other information and whether that evidence demonstrates
that the formula supports normal physical growth.
Section 106.96(i)(2) of the interim final rule addresses the
quality factor of sufficient biological quality of a formula's protein
component. Under this provision, an ``eligible infant formula'' that
fulfills one or more of three criteria meets the quality factor of
sufficient biological quality of the protein component. FDA recognizes
that there may be eligible infant formulas for which a protein
efficiency ratio (PER) study was not conducted. The manufacturer may
choose to conduct a PER study as specified in Sec. 106.96(f) of the
interim final rule. Thus, Sec. 106.96(i)(2)(i) of the interim final
rule provides that an eligible infant formula satisfies the quality
factor of sufficient biological quality of the protein component if the
scientific evidence on such formula fulfills the requirements of Sec.
106.96(f) of the interim final rule. Similarly, a manufacturer who
previously chose to develop evidence of the sufficient biological
quality of a formula's protein component may have, quite reasonably,
chosen to conduct a PER study according to the proposed rule's
provisions. To provide for these circumstances, the Agency has set
forth in Sec. 106.96(i)(2)(ii) of the interim final rule the
requirements for establishing sufficient biological quality of a
formula's protein component that were proposed in 1996, and Sec.
106.96(i)(2)(ii) of the interim final rule states that an eligible
infant formula meets the quality factor of sufficient biological
quality of the protein component if the scientific evidence on such
formula meets the provisions of that paragraph. The official method of
analysis of AOAC to conduct a PER study that was proposed in the 1996
proposed rule is incorporated by reference in Sec. 106.160 of the
interim final rule. Finally, there are some eligible infant formulas
for which there may be a body of scientific evidence drawn from
multiple sources that, taken collectively, demonstrates that the
formula's protein component is of sufficient biological quality. Thus,
Sec. 106.96(i)(2)(iii) of the interim final rule provides that an
eligible infant formula satisfies the quality factor of sufficient
biological quality of the protein component if the scientific evidence
on such formula otherwise demonstrates that the protein component of
the formula has sufficient biological quality. Like Sec.
106.96(i)(1)(iii) of the interim final rule, this third option will
require FDA to exercise its scientific judgment about the data and
other information and whether that evidence demonstrates that the
protein component of the formula is of sufficient biological quality.
An infant formula, including a ``not new'' infant formula, that
does not comply with established quality factor requirements is deemed
adulterated under section 412(a)(2) of the FD&C Act. As an adulterated
food, this formula is subject to seizure, condemnation, and forfeiture
under section 304 of the FD&C Act. Similarly, those who ship the
formula in interstate commerce, cause its interstate shipment, or
commit another prohibited act related to an adulterated food may be
enjoined under sections 301 and 302 of the FD&C Act.
FDA recognizes that to facilitate marketing and distribution plans,
a manufacturer of an eligible infant formula may wish to understand the
Agency's assessment of the quality factor evidence for that formula. To
permit the manufacturer of an eligible infant formula to be aware of
FDA's view of the manufacturer's determination that their formula meets
the quality factor requirements of Sec. 106.96 of the interim final
rule prior to the compliance date for meeting the requirements under
106.96(i), Sec. 106.96(i)(3) of the interim final rule includes a
time-limited petition process that allows a manufacturer to submit a
citizen petition to FDA that contains scientific data and information
to demonstrate that an eligible formula supports normal physical
growth, that the formula's protein component is of sufficient
biological quality, or both. FDA emphasizes that although participation
in the petition process established by Sec. 106.96(i)(3) of the
interim final rule is voluntary, satisfying the two quality factor
requirements of the interim final rule is required of all infant
formulas distributed in interstate commerce. The Agency encourages any
manufacturer planning to file a petition under Sec. 106.96(i)(3) of
the interim final rule to contact FDA to discuss any questions.
The procedure in Sec. 106.96(i)(3) of the interim final rule uses
the FDA citizen petition process in 21 CFR 10.30, and allows such a
petition for an eligible formula to be submitted untilNovember 12,
2015. Although there is likely to be some existing scientific evidence
relating to quality factor status of many eligible formulas, some
manufacturers may need to design, conduct, and analyze the results of a
growth monitoring study before they can make a submission to FDA
through the voluntary petition process. Because the Agency recognizes
that one or more manufacturers of eligible infant formulas may need to
design, conduct, and analyze the results of a growth monitoring study
to develop evidence of the formula's ability to support normal physical
growth, the interim final rule establishes a separate compliance date
for certain quality factor provisions that apply to eligible infant
formulas. Specifically, Sec. Sec. 106.96(a), 106.96(e), 106.96(i)(5),
106.100(p)(2) and 106.100(q)(2) of the interim final rule are binding
as of November 12, 2015. This means that eligible infant formulas must
meet the quality factors, and keep records demonstrating that they meet
the quality factors, as of November 12, 2015. Postponing the compliance
date for these provisions for eligible infant formulas, combined with
the same nearly 2-year period to submit a
[[Page 8028]]
voluntary petition will provide manufacturers of eligible infant
formulas with sufficient time to develop the required data and
information to demonstrate that their products meet the quality
factors, and to submit such data and information to FDA through the
voluntary petition process.
FDA notes that under current Agency regulations and practice, a
response to a citizen petition is publicly available and is routinely
posted on the Agency's Web site. The Agency intends to follow this
practice for infant formula quality factor citizen petitions and FDA's
responses to such petitions by establishing a Web page dedicated to
such petitions and responses. This practice will allow the public,
including competitors, purchasers for retailer stores, and individual
consumers, to know whether the manufacturer of an eligible infant
formula product has availed itself of the opportunity to demonstrate
that the formula meets the quality factors of normal physical growth
and sufficient quality of the protein and to be informed of FDA's
response to such submission.
The petition process in Sec. 106.96(i)(3) of the interim final
rule is a voluntary process, one that will provide FDA with access to
important information relating to eligible infant formulas. For infant
formula manufacturers and other interested parties, this process has
the advantage of clarity and certainty in terms of whether FDA views a
formula to be in compliance with the relevant quality factor
requirements. Likewise, infant formula purchasers at all levels of the
supply chain will indirectly benefit from this process because they
will have access to scientific evidence and other information on the
quality factor status of eligible infant formulas as well as FDA's view
of that evidence.
Accordingly, under Sec. 106.96(i)(3) of the interim final rule,
the manufacturer of an eligible infant formula may, not later than
November 12, 2015, submit a citizen petition to FDA under 21 CFR 10.30
that such formula fulfills one or more of the criteria in Sec.
106.96(i)(1) of the interim final rule relating to the quality factor
of normal physical growth, one or more of the criteria in Sec.
106.96(i)(2) of the interim final rule relating to the quality factor
of sufficient biological quality of the protein component, or both.
Consistent with the citizen petition regulation, Sec. 10.30(a), a
petition filed under Sec. 106.96(i)(3) of the interim final rule must
contain all data and information relied upon by the manufacturer to
demonstrate that the formula fulfills one or more of the quality factor
requirements in Sec. 106.96(i)(1) or (i)(2) of the interim final rule.
Also, to help enhance the clarity and focus of these quality factor
petitions, Sec. 106.96(i)(4) of the interim final rule provides that
each such petition shall address only a single infant formula
formulation. Importantly, however, a single petition may address both
Sec. 106.96(i)(3)(i) and (i)(3)(ii) of the interim final rule for the
same formulation.
Additionally, as noted previously in this document, the
manufacturer of an infant formula, including an eligible infant
formula, is responsible for ensuring that the formula meets the two
quality factors established by the interim final rule. Regardless of
whether the formula is a new infant formula or a ``not new'' formula,
it is reasonable to expect the manufacturer to have scientific data and
information demonstrating that the quality factors are met because only
with such data and information can a manufacturer make an informed
decision to market and lawfully distribute a particular formula. Given
this responsibility and the means reasonably required to fulfill that
responsibility, an infant formula manufacturer must necessarily
establish and maintain records documenting that each eligible formula
meets the two quality factors. As noted, the provisions of the interim
final rule in Sec. 106.96(i) recognize this need for records of the
quality factor evidence for eligible infant formulas. Specifically,
Sec. 106.96(i)(5) of the interim final rule requires the manufacturer
of each eligible infant formula to make and retain records to
demonstrate that such formula supports normal physical growth in
infants when fed as the sole source of nutrition and to demonstrate
that the protein in such infant formula is of sufficient biological
quality. The records established under Sec. 106.96(i)(5) of the
interim final rule must contain all relevant scientific data and
information as well as a narrative explanation of why the data and
information demonstrate that the formula meets the two quality factors
established by the interim final rule. The requirement for a narrative
explanation is a logical extension of the responsibility for ensuring
that a formula meets the quality factors because without analyzing and
summarizing the relevant data and information, a manufacturer has
little or no basis to conclude that a particular formula supports
normal physical growth or that it contains protein of sufficient
biological quality. Additionally, this record requirement is
reasonable, because without records, FDA has no way of determining
whether a formula meets the quality factor requirements established
under section 412(b)(1) of the FD&C Act. As noted in sections III and
VIII.A, section 701(a) of the FD&C Act authorizes FDA to issue
regulations for the efficient enforcement of the FD&C Act in order to
effectuate an objective stated elsewhere in the FD&C Act. Thus, under
sections 701(a) and 412(b)(1) of the FD&C Act, FDA has the authority to
require a manufacturer of an eligible formula to maintain records
demonstrating that their formula meets the quality factor requirements
that apply to such formula. FDA emphasizes that this record-keeping
provision for quality factor data and information required by Sec.
106.96(i)(5) of the interim final rule applies to all eligible infant
formulas that a manufacturer distributes or intends to distribute in
interstate commerce and not simply to eligible formulas that are the
subject of a petition under Sec. 106.96(i)(3) of the interim final
rule.
Although there are several distinct advantages to a manufacturer of
an eligible infant formula that submits a petition to FDA under Sec.
106.96(i)(3) of the interim final rule, the Agency recognizes that some
manufacturers of eligible formulas may choose not to submit such a
petition. Where no petition is submitted for an eligible infant
formula, FDA intends to conduct an inspection of the formula's
manufacturer and to review and evaluate the records for the formula
that are required under Sec. 106.96(i)(5) of the interim final rule.
If the data and information or the narrative explanation in the records
made and retained under Sec. 106.96(i)(5) of the interim final rule do
not demonstrate that the formula supports normal physical growth and
that the protein in such infant formula is of sufficient biological
quality, FDA will consider the formula to be adulterated under section
412(a)(2) of the FD&C Act and will pursue the Agency's customary
regulatory process, which may include official communication with the
firm such as a Warning Letter followed by appropriate legal remedies.
FDA received several comments related to the issue of currently
marketed and previously marketed formulas. The Agency responds to these
comments in this document.
(Comment 264) One comment stated that it did not believe that it is
FDA's intent to require all infant formulas currently on the market in
the United States to undergo the study required by proposed Sec.
106.97(a) and if this is the Agency's intent, the comment strongly
objects to this requirement as unnecessarily burdensome and without
cause.
[[Page 8029]]
(Response) The commenter's statement of FDA's intent is not
correct. As discussed previously in this document, all currently
marketed formulas must be shown to meet the two quality factors
established by the interim final rule. The Agency's intent was clear in
that the 1996 proposed rule established quality factors for ``infant
formulas'' and did not describe any subset that would not be covered by
the requirements set forth in this interim final rule. Section
412(a)(2) of the FD&C Act states that infant formulas that do not meet
the quality factor requirements are deemed adulterated. Significantly,
this adulteration provision applies to all infant formulas (not just
``new infant formulas''). Thus, all infant formulas must meet the
quality factors established in this interim final rule. However, as
discussed in detail previously in this document, the interim final rule
includes in Sec. 106.96(i) specific quality factor requirements for a
formula that meets the definition of ``eligible infant formula.''
(Comment 265) One comment noted that not all infant formula
products currently marketed in the United States have undergone a
clinical study as described in proposed Sec. 106.97(a). The comment
asserted that there is no reason to believe these currently marketed
products do not support normal physical growth and suggested that
proposed Sec. 106.97(a)(2)(i) be revised to reduce unnecessary
clinical studies, particularly where currently marketed formulas that
have not been the subject of a growth monitoring study have undergone
small changes in formulation or processing. The comment stated that if
proposed Sec. 106.97(a)(2)(i) is not changed, it may pose an
``unresolvable'' dilemma in the case of future modifications of some
currently marketed infant formulas.
(Response) The comment did not provide data or other information to
explain the basis for its assertion that ``there is no reason to
believe these currently marketed products do not support ``normal
physical growth.'' FDA is a science-based Agency, and as such, must
rely on valid data and other sound scientific information to draw
conclusions about product safety, including the safety and nutritional
sufficiency of infant formula.
FDA disagrees that the expectation that all currently marketed
formulas be demonstrated with valid scientific evidence to satisfy the
quality factor of normal physical growth will result in an
``unresolvable'' dilemma. The interim final rule provides specific
provisions for manufacturers of eligible infant formulas to demonstrate
that their products meet the quality factors of normal physical growth
and sufficiency biological quality of the protein component, and Sec.
106.96(i) of the interim final rule clearly contemplates that
previously conducted growth studies, as well as other scientific data
and information, may be used to demonstrate satisfaction of these
quality factors. FDA believes that the opportunity to utilize existing
data is certain to reduce the likelihood of requiring unnecessary
growth monitoring studies.
Requirements to assure that quality factors have been met in the
case of small changes to formulations is discussed under Comment 256
regarding submissions made under section 412(d)(3) of the FD&C Act.
(Comment 266) Another comment stated that the Agency has no way of
being assured that an infant formula that may have been marketed at
some time in the past, but which is not currently on the market, would
meet quality factor requirements. Therefore, the comment asserts, if a
manufacturer wanted to reintroduce such a formula into the market, the
manufacturer would need to submit a new infant formula notification.
(Response) If a formula manufacturer wishes to reintroduce a
formula into the market place, the reintroduced formula would need to
meet the quality factors of normal physical growth and sufficient
biological quality of the protein component. The mechanism in Sec.
106.96(i) of the interim final rule contemplates this situation and
establishes quality factor requirements for eligible infant formulas,
which include certain previously marketed formulas. In addition, under
Sec. 106.96(i)(5) of the interim final rule, the manufacturer of an
eligible infant formula, including a previously marketed formula that
is reintroduced, is required to make and retain records that
demonstrate that such formula meets the two quality factors. FDA
disagrees, however, that a reintroduced formula must necessarily be the
subject of a new infant formula submission because the requirement to
make such a submission applies only to a formula that is a ``new infant
formula'' as defined by section 412(c) of the FD&C Act and Sec. 106.3
of the interim final rule. If a previously marketed formula is altered
such that the formula would be classified as a ``new infant formula,''
such formula would need to be the subject of a new infant formula
submission, and would not be eligible to meet the quality factors under
Sec. 106.96(i) of the interim final rule.
(Comment 267) One comment requested that FDA confirm that the
protein quality factor pertains only to new situations that arise after
the effective date of the quality factor requirements. The comment
argued that this is reasonable because the assurance of quality factors
of all currently marketed formulas has been provided by the good health
of infants that have been raised on those formulas over the years.
(Response) Under section 412(b)(1) of the FD&C Act, quality factor
requirements apply to all infant formulas; not only new infant
formulas. As such, currently marketed formulas must meet the quality
factors under this interim final rule, including the quality factor of
sufficient biological quality of protein. However, as is explained
previously in this document, currently marketed formulas that are
``eligible formulas'' under Sec. 106.96(i) of the interim final rule
have some flexibility in terms of how satisfaction of the two quality
factors may be demonstrated.
I. Records Demonstrating Compliance With the Quality Factor
Requirements for Infant Formulas That Are Not Eligible Infant Formulas
For consistency with other records requirements, FDA is adding a
provision in the interim final rule (Sec. 106.96(d)) that requires a
manufacturer of a new infant formula that is not an eligible infant
formula to make and retain certain records demonstrating that such
formula meets the quality factor of normal physical growth. Likewise,
FDA is adding a provision in the interim final rule (Sec. 106.96(h))
that requires a manufacturer of a new infant formula that is not an
eligible infant formula to make and retain certain records
demonstrating that the formula meets the quality factor of sufficient
biological quality of protein. As noted previously in this document in
section VIII.A, it is reasonable and necessary for the efficient
enforcement of the FD&C Act for FDA to require a manufacturer of infant
formula to make and retain records demonstrating that the formula
satisfies the quality factors requirements. These records may assist
FDA in determining whether an infant formula meets the quality factor
requirements.
As is discussed further in section IX.F, in order to comply with
this records requirement, a manufacturer of a new formula that is not
an eligible infant formula will be required to make and retain records
demonstrating compliance with the growth monitoring study requirements
under Sec. 106.96(b) of the interim final rule, or make and
[[Page 8030]]
retain records demonstrating satisfaction of an applicable exemption
under section Sec. 106.96(c) of the interim final rule.
In the proposed rule, proposed Sec. 106.97(a)(i)(B) would have
required a manufacturer to collect and maintain, in the growth study,
anthropometric measures of physical growth. This interim final rule
expands and clarifies this collection and maintenance requirement, to
require that a manufacturer make and retain records demonstrating
compliance with the growth monitoring study requirements under Sec.
106.96(b) of the interim final rule, or in the alternative, records
demonstrating satisfaction of an applicable exemption under section
Sec. 106.96(c) of the interim final rule.
Likewise, the interim final rule includes a provision (Sec.
106.96(h)) that requires a manufacturer of a new infant formula to make
and retain certain records demonstrating that the formula meets the
quality factor of sufficient biological quality of protein. With
respect to the quality factor of sufficient biological quality of
protein, the proposed rule would have required a manufacturer of an
infant formula to collect and maintain data establishing that the
biological quality of protein in the infant formulas is sufficient to
meet the protein requirements of infants proposed Sec. 106.97(b)(1) .
As is discussed in further detail in section IX.F, this interim final
rule clarifies that the requirement to make and retain records
demonstrating that the formula has sufficient biological quality of
protein includes, when applicable, records demonstrating satisfaction
of an applicable exemption under Sec. 106.96(g) of the interim final
rule. If the formula manufacturer is not seeking an exemption from the
requirements of Sec. 106.96(f) of the interim final rule, the formula
manufacturer would need to make and retain records demonstrating
compliance with the requirements under Sec. 106.96(f) of the interim
final rule.
J. Establishment of Other Quality Factors
1. General Comments
Several comments agreed with FDA's tentative conclusion in the 2003
reopening notice that the quality factors of normal physical growth and
protein biological quality are sufficient at this time for assessing
the bioavailability of nutrients in an infant formula and that the
physical growth and protein quality would be considered reasonable
benchmarks, presuming the infant formula contains all nutrients
required by section 412 of the FD&C Act. Other comments recommended
that the Agency identify additional quality factors and establish
requirements for such factors.
(Comment 268) One comment expressed concern about the Agency's
suggestion in the 1996 proposal (61 FR 36154 at 36181) that additional
quality factors may be identified on a case-by-case basis for specific
formula products, stating that this would create difficulties for
manufacturers without more explicit guidance as to what is required.
(Response) FDA is not including in the interim final rule
requirements for quality factors other than those for normal physical
growth and biological quality of the protein. The Agency notes that, in
the future, it may propose requirements for additional quality factors
for infant formula, or nutrients in such formula, in general or for
specific types of formula or for specific nutrients. However, any
additional quality factors requirements will be established in a future
rulemaking or FDA will make recommendations in a future guidance
established under FDA's GGPs (21 CFR 10.115). Both of these processes
would include prior notice and the opportunity for public
participation.
(Comment 269) One comment stated that, due to the increasing
complexity of infant formula ingredients, benchmarks such as growth and
protein quality do not evaluate the effect of new ingredients, such as
long-chain polyunsaturated fatty acids and probiotic microorganisms or
other complex ingredients. The comment suggested that instead, FDA
evaluate overall nutrient quality and availability, targeted vitamins,
minerals, and macronutrients.
(Response) The quality factors of normal physical growth and
sufficient biological protein quality are necessary to demonstrate that
the required nutritional components of infant formula are bioavailable,
in order to help ensure that the formula supports healthy growth.
Evaluation of normal physical growth by a well-controlled growth
monitoring study and evaluation of the biological quality of the
protein by PER rat bioassay are not intended to, and do not, evaluate
other purported effects of new ingredients (e.g., effects of long-chain
polyunsaturated fatty acids on visual development or effects of
probiotic microorganisms on gut flora). Thus, the suggestion of this
comment is beyond the scope of this interim final rule.
2. Quality Factors for Fat, Calcium, and Phosphorus
In the 1996 proposal (61 FR 36154 at 36182), FDA stated ``because
of the potential seriousness of the public health impact of not meeting
quality factors, FDA also believes that it is desirable to establish
additional quality factors, as soon as they are warranted by evolving
scientific knowledge, to ensure adequate nutrient bioavailability.''
The Agency notes that the CON/AAP Task Force (Ref. 67) recommended
metabolic balance studies to determine whether a formula meets quality
factors for fat, calcium, and phosphorus. FDA specifically requested
comment on whether the scientific evidence and usefulness of results
are sufficient to support establishing quality factor requirements for
nutrients other than protein, such as fat, calcium, and phosphorus, and
if so, what assurances should be established for such factors (61 FR
36154 at 36181). The Agency also requested comment on balance studies
or other methods that could be used to assess potential quality factor
requirements for these three nutrients. This opportunity was renewed
with the 2003 reopening of the comment period.
Several comments responded to FDA's request for comment on whether
quality factor requirements should be established for fat, calcium, and
phosphorus.
(Comment 270) One comment supported including quality factor
requirements for fat, calcium, and phosphorus in assessments of the
nutritional adequacy of formulas, and stated that manufacturers are
currently expected to include these measures in the clinical evaluation
of their formulas and the measurement of these quality factors should
not present difficulties to manufacturers or those involved in the
clinical study of infant formulas.
(Response) FDA disagrees with this comment to the extent that it
asserts that manufacturers currently measure the bioavailability of
fat, calcium, and phosphorus in their clinical evaluations of infant
formulas. To date, FDA has not recommended that manufacturers include
metabolic balance studies to evaluate the adequacy of fat, calcium, and
phosphorus in new infant formulas. In fact, in the 1996 proposal, FDA
tentatively concluded that the clinical and nutritional sciences had
not reached a level of development such that specific tests were
available to establish that infant formulas could be demonstrated to
satisfy quality factors for each of the essential nutrients listed in
Sec. 107.100, except for protein. In particular, the Agency expressed
[[Page 8031]]
concern about the absence of meaningful measures for the assessment of
the bioavailability of calcium and phosphorus. At the same time, FDA
noted that studies of infant excretion of fat indicate that the fats in
formula are highly digestible, thus mitigating questions about fat
bioavailability. The comment did not provide any information to
contradict the Agency's tentative conclusion that quality factor
requirements should not be established for nutrients other than
protein. Accordingly, FDA declines to establish quality factor
requirements for fat, calcium, and phosphorus in this interim final
rule.
(Comment 271) Some comments disagreed with FDA's statement in the
1996 proposal (61 FR 36154 at 36187) about the degree of technical
difficulty in performing fat balance studies, saying that metabolic
studies are difficult to perform well and are conducted at few research
centers (Ref. 67).
(Response) FDA agrees in part with this comment. In the 1996
proposed rule, FDA stated that the current method for measuring fat
excretion is noninvasive, by which FDA meant that these studies
consisted of collecting feces and urine which are naturally excreted
from the body of infants. However, as noted in the comment, the
accurate collection of such specimens is technically very difficult
and, in some or all cases, would require hospitalization to ensure
accurate sampling and measurement. The limitations on such studies are
a second separate reason not to require metabolic balance studies of
infant formula.
(Comment 272) With respect to fat balance studies, one comment
stated that the level of fat malabsorption that leads to clinical or
body composition effects is not well defined and may not be 15 percent
as stated in the 1996 proposal (61 FR 36154 at 36181). The comment
concluded that this factor adds to the limitations of fat balance
studies.
(Response) FDA agrees with this comment that the level of fat
malabsorption that leads to clinical or body composition effects is not
well defined and that this fact would be a further limitation to fat
balance studies. The mean amount of fat not absorbed is approximately
15%, but the degree of malabsorption depends on the type of fat at
issue. One source shows that the range of fat excreted (Ref. 83,
pp.164-165) is between 0.66 to 9.3 percent of intake when vegetable
oils are the fat source in a milk-based infant formula, and that
infants excrete a higher proportion of fat when homogenized cow milk is
consumed; the latter level is related to the type of fat in cow milk
(butterfat), which young infants cannot readily digest because they
lack the necessary bile salts and enzyme. Thus, this comment supports
the Agency's decision not to establish quality factor requirements for
fat.
(Comment 273) One comment opposed the establishment of quality
factor requirements for fat, calcium, and phosphorus because, the
comment asserted, the collection of formula intake and stool data by
untrained parents (which would be part of a metabolic balance study)
would result in extremely inaccurate data if studies were conducted on
term infants in the home.
(Response) FDA agrees that the use of untrained parents to collect
study data is one very practical limitation of a balance study and
thus, is an additional reason to not identify, and establish
requirements for, quality factors for fat, calcium, and phosphorus at
this time.
(Comment 274) Other comments noted that financial and, perhaps,
ethical difficulties may be associated with balance studies because
such studies may require hospitalization and restraint of infants. The
comment characterized hospitalization as ``invasive.''
(Response) FDA does not agree with the comment that hospitalization
is conventionally considered ``invasive.'' However, the Agency agrees
that to ensure maximum accuracy in the collection of infant input and
output information in a balance study, it could be necessary to confine
the infant study subjects to a hospital and, in some cases, to restrain
the subjects. FDA agrees that these two possibilities are significant
negatives of establishing a quality factor for fat and requiring a
balance study of a new formulation of an infant formula to demonstrate
that the quality factor is satisfied.
(Comment 275) Several comments suggested that fat, calcium, and
phosphorus balance studies should be performed on a voluntary basis
when the manufacturer believes they are necessary to assess specific
effects of a formula or ingredient.
(Response) FDA does not disagree with this comment. To the extent
that a formula manufacturer believes that fat, calcium, or phosphorus
studies would be meaningful for evaluating a particular infant formula,
FDA would generally not object to the conduct of such a study.
Importantly, however, prior to conducting any such study, the
manufacturer should be certain that data from such study are necessary
and will be meaningful so as to avoid subjecting the infants study
subjects to unnecessary testing.
(Comment 276) One comment stated that balance studies are more
useful for comparing formulas than for assessing adequacy of a
particular formula and suggested that the decision to include balance
studies should be made during development of a study protocol.
(Response) FDA agrees with this comment to the extent that it
asserts that a balance study must be designed to answer the research
question at issue. However, the comment did not explain how adequacy of
a particular formula could be determined without comparing the test
formula to a control formula that has already been evaluated for
nutritional adequacy.
Generally speaking, a balance study would be used to compare one
factor under investigation (e.g., the fat blend of a formula) while all
other factors are kept constant. Thus, in a study comparing the fat
blend of one formula to another, the study design would require that
the test and control formulas contain all the same nutrients except the
fat source, which would be different in the test and control formulas
(Refs. 83 and 84). As noted, however, FDA is affirming the Agency's
tentative 1996 decision that no metabolic balance studies will be
required of new formulations of infant formulas.
Several comments addressed specific aspects of balance study design
and methodology.
(Comment 277) One comment pointed out the desirability of using
comparable levels of minerals in both the test and control formulas
since mineral retention in balance studies tends to become more
positive with higher intakes.
(Response) FDA agrees that mineral retention in balance studies
tends to become more positive with higher intakes and that, when
conducting a balance study, it is desirable to use comparable levels of
minerals in test and control formulas to reduce the potential for
confounding, which could result in misinterpretation of study results.
As noted, however, FDA is affirming the Agency's tentative 1996
decision that no balance studies will be required of new formulations
of infant formulas.
(Comment 278) One comment asserted that serum alkaline phosphatase
determination would be of no value in calcium and phosphorus balance
studies as the time course of its response is slower than the brief
period of a balance study and there are age specific, gestational, and
nutrient effects that complicate its interpretation.
(Response) FDA agrees with this comment that alkaline phosphatase
[[Page 8032]]
analysis in balance studies would be of limited value for the reasons
given. As noted, however, FDA is affirming the Agency's tentative 1996
decision that no balance studies will be required of new formulations
of infant formulas. Therefore, this comment has no bearing on the
interim final rule.
(Comment 279) Another comment pointed out that preterm infants, who
have sometimes been used as subjects for balance studies, would not be
appropriate subjects for the studies of formulas for term infants.
(Response) FDA agrees with this comment. Preterm infants would not
be appropriate participants for balance studies evaluating the
bioavailability of infant formulas intended for term infants because
each group has specific nutrient needs that are not identical. In
particular, preterm infants are at great risk for malnutrition and
require relatively greater amounts of energy, protein, calcium,
phosphorus, vitamin D, and vitamin A levels compared to the needs of
healthy term infants. Thus, extrapolation of data from preterm infants
to healthy term infants could result in erroneous conclusions about
necessary nutrients for healthy term infants. For a study of a formula
intended for use in term infants, the study population must be composed
of such infants. Because the Agency has confirmed its 1996 tentative
decision not to require balance studies of infant formula, however, no
change in the interim final rule is required in response to this
comment.
(Comment 280) One comment indicated that sensitivity of balance
studies is greater with a crossover design (Ref. 67). Another comment
pointed out that crossover design would subject an infant to a longer
period of confinement and restraint and considered this unwarranted for
routine testing of all products.
(Response) FDA agrees that a crossover design could be used in a
balance study to increase the power of a study using a small study
population because each participant would serve as his or her own
control. Importantly, however, balance studies require that the infant
be confined to a hospital for 72 hours for each study period,
immobilized in a ``papoose-like'' devise that permits all urine and
feces to be continuously collected. Given these necessary conditions of
a balance study, this type of study should only be performed when
absolutely necessary because of its extremely restrictive nature (Ref.
85). Given the lack of sound methods for measuring essential nutrients
and the lack of predictive outcomes from many of these of studies, FDA
has determined that balance studies should not be required by this
interim final rule for any nutrient in infant formula.
Several comments addressed the use of methods other than balance
studies to evaluate bioavailability of total fat, calcium, and
phosphorus.
(Comment 281) One comment concurred with FDA's tentative conclusion
in the 1996 proposal that there is no current practical and generally
accepted alternative to balance studies for assessing bioavailability
of these nutrients (61 FR 36154 at 36188). However, the comment noted
that newer measures of assessing bone mineralization directly hold
considerable promise for evaluating these nutrients in infant formulas,
suggesting that these methods could be useful when they become more
standardized and more normative data become available for infants.
(Response) FDA agrees with this comment that, at the time of the
1996 proposal, new means of assessing bone mineralization directly,
such as dual-energy x-ray absorptiometry (DEXA) scans, appeared
promising. However, DEXA has not achieved sufficient reliability to be
considered a ``gold standard'' for body composition of infants and is
currently confined largely to use as a research tool. The Agency has
considered the data presented at the 2002 meeting of the FAC, as well
as recent studies (Refs. 86 and 87), and finds no basis to require DEXA
scans in growth monitoring studies. Accordingly, the Agency is not
persuaded at this time to add tests using these methods as a
requirement to demonstrate the bioavailability of an infant formula or
of calcium and phosphorus in infant formulas.
(Comment 282) One comment stated that, when alterations in fat
source or composition are proposed, the manufacturer should be required
to demonstrate that study subjects' serum fatty acid levels are
comparable to those of breast-fed infants or infants fed other standard
infant formulas.
(Response) FDA does not agree with this comment. The comment
provided no evidence or reasoning to support the recommendation that
the evaluation of serum fatty acid levels of infants consuming a new
infant formula formulation should be required to be measured and
determined to be equivalent to infants that are breast-fed or are
consuming a standard infant formula. Moreover, FDA is aware of no
scientific evidence that suggests that measurement of serum fatty acids
would be a means to assessing the ability of an infant formula to
ensure healthy growth. Although measuring serum fatty acids reflects,
to some extent, an infant's diet, serum fatty acids are also influenced
by other factors such as timing of the blood draw in relation to
formula consumption and hormonal responses. Finally, the fatty acids in
circulation do not predict growth. The levels of some fatty acids can
be used to determine whether there are adequate levels of essential
fatty acids (linoleic and linolenic) but these circulating levels are
not directly related to normal physical growth.
For the reasons discussed previously in this document, the Agency
is not establishing in this interim final rule requirements for quality
factors related to fat, calcium, or phosphorus.
3. Quality Factor for Iron
In the 1996 proposal (61 FR 36154 at 36182 and 36189), FDA
requested comment on whether a quality factor for iron should be
established and what data would be needed to establish that the iron in
an infant formula is sufficiently bioavailable and maintains the iron
status of infants that consume the formula. The Agency observed that
the data on iron bioavailability would need to demonstrate that an
infant formula provides enough iron to prevent iron deficiency and
anemia. The Agency expressed concern, however, that a growth monitoring
study of full-term infants aged zero to four to five months might not
be sensitive enough to detect significant differences in iron
bioavailability of a formula product because healthy, full-term infants
are usually born with adequate iron stores to maintain normal iron
status for the first three to four months of life--the time when the
growth monitoring study would be conducted. Without assurance that the
test results would be meaningful, the Agency tentatively decided not to
establish quality factor requirements for iron.
A number of comments supported the inclusion of a quality factor
for iron for infant formulas and supported establishing requirements
for such quality factor. Other comments objected to a general quality
factor for iron.
(Comment 283) One comment stated that manufacturers are currently
expected to include these measures in the clinical evaluation of their
formulas and thus, it is not anticipated that measurements of this
quality factor should present difficulties to manufacturers or those
involved in the clinical study of infant formulas.
(Response) FDA disagrees with this comment to the extent that it
asserts that manufacturers currently measure the bioavailability of
iron in their clinical
[[Page 8033]]
evaluations of infant formulas. To date, FDA has not recommended that
manufacturers include metabolic balance studies to evaluate the
adequacy of iron in new infant formulas. In fact, in the 1996 proposal,
FDA tentatively concluded that the clinical and nutritional sciences
had not reached a level of development such that specific tests were
available to establish that infant formulas could be demonstrated to
satisfy quality factors for each of the essential nutrients listed in
Sec. 107.100, except for protein (61 FR 36154 at 36182). This comment
did not provide any information to contradict the Agency's tentative
conclusion that quality factor requirements should not be established
for nutrients other than protein. Accordingly, FDA declines to
establish a quality factor for iron in this interim final rule.
(Comment 284) Another comment regarded the failure to include a
quality standard for iron as a problem, noting that iron deficiency
would not be detected by anthropometric (weight) measurements used to
evaluate the normal physical growth quality factor.
(Response) FDA disagrees in part with this comment. The Agency
agrees that iron insufficiency will not be readily detected in a growth
study evaluating normal physical growth. Importantly, however, as noted
in the preamble to the proposed rule, infants are born with iron stores
sufficient until age three to four months. For this reason, the growth
monitoring study required by Sec. 106.96(b) of the interim final rule
to assess normal physical growth will be neither sensitive enough nor
long enough to show iron deficiency. Thus, FDA is not adding a
requirement to measure iron to the requirements for the growth
monitoring study.
(Comment 285) Another comment strongly supported establishing a
quality factor for iron, concluding that implementation of the iron
status quality factor would go a long way toward providing the
scientific data to resolve the issue of what level of iron is correct
for infant formula.
(Response) FDA agrees that iron status is important to infants'
nutritional well-being. Although there are some available methods for
evaluating iron status, the most sensitive of these methods require
invasive procedures. Balance studies also offer a means to assess
bioavailability of iron but the balance method is less sensitive and,
as noted previously in this document, requires hospitalization and
prolonged restraint of the infants.
As noted in the 1996 proposed rule, term infants are generally born
with adequate iron stores to meet their needs for the first few months
of life. Even if suitably sensitive and noninvasive methods were
available to measure iron status in infants, it is questionable whether
such measurements made during early infancy would provide meaningful
information on the bioavailability of iron in infant formulas. For
these reasons, FDA does not agree that the Agency should establish a
quality factor for iron at this time.
The purpose of establishing a quality factor for a nutrient is to
require a determination of whether the nutrient is bioavailable in the
infant formula, i.e., that the nutrient is digested and absorbed by the
infant as the product is formulated for market. The question of what
level of a nutrient is ``correct'' for infant formula is better
addressed by studies with outcome measures designed to answer that
question specifically.
(Comment 286) One comment stated that a poorly available source of
iron would be a problem for an infant between the ages 4 and 12 months
fed only formula and noted that, while feeding only formula to healthy
infants from 4 to 12 months of age is not consistent with CON/AAP
recommendations, there are instances where a formula-only diet has been
fed for extended periods of time to infants 4 to 12 months of age.
(Response) FDA agrees that there may be rare cases in which formula
is the exclusive nourishment provided to infants after age 4 months and
that it could be problematic if that formula is deficient in iron.
Importantly, however, the comment included no evidence to establish the
concern that currently marketed formulas are poor sources of iron.
Infants are usually seen by their pediatricians every 1 to 2 months
during the first year of life, and, consistent with AAP
recommendations, most but not all infants are starting complementary
foods by 4 months of age (Refs. 70 and 88). Thus, these rare instances
of formula-only diets in older infants do not require the Agency to
establish a quality factor for iron, particularly given the factors
weighing against such establishment.
(Comment 287) One comment recommended that studies of iron status
in infants be performed only when the manufacturer believes that such
studies may help assess effects of a specific formula or ingredient.
(Response) FDA does not disagree with this comment. To the extent
that a formula manufacturer believes that an iron status study would be
meaningful for evaluating a particular infant formula with a specific
ingredient, FDA would not object to the conduct of such a study.
Importantly, however, before conducting any such study, the
manufacturer should be certain that data from such study are necessary
and will be meaningful so as to avoid subjecting the infant study
subjects to unnecessary testing.
(Comment 288) Several comments noted that the quality factor for
iron would be of little value in the first four months of life, when
the standard growth study would be conducted.
(Response) FDA agrees with this comment. As noted in the 1996
proposed rule, full-term infants are generally born with adequate iron
stores to meet their iron needs for the first few months of life, a
fact that restricts the ability to conduct an accurate assessment of
iron bioavailability during the period of the growth monitoring study.
The Agency did not receive data or other information challenging FDA's
statement about newborn iron stores nor did any comment dispute that
these stores would interfere with the ability to measure iron
bioavailability during the growth monitoring study.
(Comment 289) Other comments objected to establishment of a quality
factor for iron status because it would require an invasive procedure
of drawing blood. The comments further stated that when blood draws are
required in infants, physicians are more reluctant to conduct studies
on well babies and parents are much more likely to refuse enrollment or
drop out of the study.
(Response) FDA agrees that establishing a quality factor for iron
and a requirement to show that this quality factor is satisfied by an
infant formula would likely require blood draws of study subjects,
which would be an invasive procedure not otherwise required in the
growth monitoring study. However, as noted previously in this document,
FDA is not establishing a quality factor for iron because it is not
possible to perform an accurate assessment of iron's bioavailability in
the early months of infancy, the period during which formula is
consumed as the sole source of nutrition. FDA concludes that the risk,
however small, of the invasive procedure of a blood draw is not
justified given that any resulting iron bioavailability data would be
of very limited, if any, value.
(Comment 290) One comment noted that the creation of a quality
factor for iron is complicated by the presence in the U.S. market of
formulas with varying levels of iron fortification, some of which are
nutritionally adequate from the standpoint of iron and others which may
not be adequate, but still meet the
[[Page 8034]]
standards of the FD&C Act. The comment contended that it makes little
sense to develop a quality factor for a nutrient that is not required
by law in formulas for healthy infants in nutritionally adequate
amounts and that no quality factor recommendation would be appropriate
until and unless the FD&C Act is modified to establish a required level
of bioavailable iron.
(Response) FDA disagrees with this comment. Although the comment is
correct that Sec. 107.100 permits a wide range of iron content in
infant formula (0.15 to 3 mg/100 kcal), the comment appears to confuse
the range of permitted iron levels in infant formulas with the need for
the iron in formulas to be bioavailable. The iron in infant formula
must be bioavailable, regardless of the amount present. As noted, FDA
is not establishing a quality factor for iron in this interim final
rule, but not for the reason given in this comment.
(Comment 291) One comment recommended that FDA establish a quality
factor for iron and require animal assays to assess the iron's
bioavailability, rather than require additional assessment measures in
a standard growth study.
(Response) As explained previously in this document, FDA is not
establishing a quality factor for iron because of constraints on the
use of available methods for measuring the iron status of healthy term
human infants. The comment did not identify any animal assay that could
potentially be used to demonstrate that a particular infant formula
satisfies an established quality factor for iron. The Agency is aware
that nonhuman primate and rodent models have been used in studies of
iron status and infant neurocognitive and neurobehavioral development
(Ref. 89), and newborn piglets have also been used in studies of
nutrient absorption from infant formulas, but the comment provided no
animal data on iron bioavailability that could readily be applied to
infants. Without such information, FDA is not persuaded to establish a
quality factor for iron and to require an animal test to demonstrate
the bioavailability of iron in infant formula.
(Comment 292) Several comments that supported inclusion of a
quality factor for iron concluded that serum ferritin (i.e., a stage 1
measurement of iron status) would be the appropriate quality factor
measurement because if ferritin is sufficient in the infant, there is
no risk that stage 2 or 3 iron status will be reached. The comment
further suggested that a measurement of ferritin alone would make
studies more efficient, cost effective, and less invasive.
(Response) FDA agrees that serum ferritin is a very useful tool for
assessing iron nutritional status. However, as FDA noted in the
proposed rule (61 FR 36154 at 36182), healthy, full-term infants are
usually born with adequate iron stores to maintain normal iron status
for the first 3 to 4 months of life--the period of time that a growth
monitoring study will be conducted. Moreover, the serum ferritin
assessment requires an invasive procedure (blood draw). For these
reasons, FDA declines to establish the measurement of ferritin as a
quality factor requirement for new infant formulas.
For the foregoing reasons, FDA is not revising Sec. 106.96 in this
interim final rule to establish a quality factor for iron.
4. Standard Laboratory Measures
In the 1996 proposal, FDA requested, and received, comment on
whether the collection of standard laboratory measures, such as
complete blood count (white blood cell count and red blood cell count),
hemoglobin concentration or hematocrit percentage, and serum or plasma
concentrations of albumin, urea, nitrogen, electrolytes (sodium,
potassium, and chloride), alkaline phosphatase, and creatinine, would
be useful and necessary information for determining whether a formula
causes adverse consequences that may not be reflected in the quality
factor requirements for normal physical growth (61 FR 36154 at 36184).
(Comment 293) One comment pointed out that FDA did not propose to
make serum chemistries into quality factors and that there are
situations where the relevant clinical endpoints would be biochemical
indicators of nutritional status.
(Response) FDA notes that the comment did not submit any data or
other information identifying the particular situations that would
require serum chemistries to evaluate the nutritional adequacy of an
infant formula or why serum chemistry evaluations should be a standard
requirement for growth monitoring studies. The growth monitoring study,
which is often conducted on an outpatient basis, evaluates the adequacy
of the formula to support normal physical growth and an infant's
tolerance of the formula. Although the AAP report (Ref. 67) recommended
that some blood tests might be useful at the conclusion of the study
period, the decision lies with those responsible for designing and
conducting the study. FDA concludes, as discussed in the 1996 proposed
rule, that it is not appropriate to require invasive procedures, such
as blood draws, as part of this interim final rule. As discussed in
this document, the Agency encourages manufacturers to evaluate each new
formulation to determine whether the nature of the particular new
formulation suggests that serum blood chemistries should be required.
Accordingly, FDA is making no change in the interim final rule in
response to this comment.
(Comment 294) One comment stated that doing such blood work is not
a standard practice of investigators and that drawing blood would
violate the principles that the FDA cites for protecting the infant
from unnecessary testing. The comment further asserted that
establishing a requirement for drawing blood would cause many parents
to refuse to have their infants participate in a study. Thus, the
comment argued, collecting this information routinely would not be
useful and could be detrimental for the timely completion of clinical
studies.
(Response) FDA agrees with this comment. No comments submitted in
response to the Agency's request included data or other information to
demonstrate that standard blood chemistry measures are necessary to
evaluate whether an infant formula supports normal physical growth of
infants, and without question, collecting such data would require blood
draws, which is an invasive procedure. Accordingly, FDA is not
persuaded to require these standard laboratory measures as a part of
all growth studies.
FDA notes, however, that some or all of these measures may be
appropriate for the testing of certain formulas or for certain changes
in a particular formula. For example, if a formula is developed with an
unusual renal solute load, measures of albumin, urea, electrolytes, and
creatinine in serum may be appropriate. The Agency encourages
manufacturers to evaluate each new formulation to determine whether
testing a particular formulation requires some or all of these blood
chemistries.
For these reasons, FDA is making no change in the interim final
rule in response to these comments.
K. Miscellaneous Comments on Quality Factors
(Comment 295) One comment challenged the statement in the 1996
proposal (61 FR 36154 at 36179) that referred to selenium as a
``nonrequired nutrient.'' The comment asserted that selenium is an
essential nutrient for infants, i.e., a required nutrient for infants.
[[Page 8035]]
(Response) FDA is aware that selenium is an essential nutrient for
infants. In the preamble to the 1996 proposal (61 FR 36154 at 36155),
FDA stated ``For the purpose of this document, the nutrients that are
required to be in infant formula under Sec. 107.100 will be referred
to as ``required nutrients.'' Thus, the term ``nonrequired'' referred
to the status of selenium on the Congressionally-mandated list of
ingredients set out in section 412(i) of the FD&C Act and established
by regulation at 21 CFR 107.100. The list of minimum and maximum
specifications for nutrients in infant formulas was most recently
revised in 1986, 3 years before establishment of a recommended dietary
allowance for selenium for infants (Ref. 60).
Additionally, in the Federal Register of April 16, 2013 (78 FR
22442), FDA published a proposed rule to amend the regulations on
nutrient specifications and labeling for infant formula to add selenium
to the list of required nutrients and to establish minimum and maximum
levels of selenium in infant formula.
(Comment 296) One comment agreed with FDA's proposal (61 FR 36154
at 36178) to revoke the requirement in current Sec. 106.30(c)(2) for
determination of vitamin D by a rat bioassay method.
(Response) In this interim final rule, FDA is revoking the
requirements in current Sec. 106.30(c)(2) for the determination of
vitamin D by a rat bioassay method. As explained in the proposed rule,
this rat bioassay for vitamin D is no longer a reasonable requirement
because appropriate animals for conducting this test are difficult to
acquire (Ref. 90), and an alternate analytical method for the
determination of vitamin D in infant formulas has been approved by AOAC
(Ref. 91).
IX. Subpart F--Records and Reports
As noted in the introductory section of this preamble, in 1991, FDA
revised subpart C in part 106, and established records and reports
requirements for infant formula (56 FR 66566, December 24, 1991). These
regulations were authorized by section 412 of the FD&C Act, as amended
by the 1986 amendments, and replaced the original records regulations
established in 1982 (47 FR 17016, April 20, 1982).
Thereafter, in 1996, the Agency proposed additional revisions to
the infant formula records and reports regulations and proposed to
redesignate these requirements as subpart F in part 106. The proposed
requirements related to batch (production aggregate) records (proposed
Sec. 106.100(e)), records to document compliance with CGMP (proposed
Sec. 106.100(f)), infant formula distribution records (proposed Sec.
106.100(g)), and records of regularly scheduled audits (proposed Sec.
106.100(j)). As noted in the proposed rule, FDA is retaining 21 CFR
106.100(l) of the current infant formula regulations. Thus, all of the
records that are required to be maintained under this interim final
rule shall be made readily available for FDA inspection.
FDA received a number of comments on the proposed revisions to the
records and reports requirements. These comments are summarized in this
document along with the Agency's responses.
A. General Comments on Records (Proposed Sec. 106.100)
(Comment 297) One comment objected to the phrase that relevant
records shall ``include but are not limited to'' in proposed Sec.
106.100(e), (e)(1), (e)(3), (f), (f)(6), and (g). The comment asserted
that the required records should be limited to focus on and incorporate
the statutory reference to ``necessary'' documents, rather than the
broader language that was proposed.
(Response) FDA is removing the phrase ``but are not limited to''
language from the proposed sections identified in the comment, but not
for the reason stated in the comment. The language is unnecessary
because the words ``include,'' ``includes,'' and ``including'' have the
connotation that the itemized list that follows is not exclusive.
Importantly, however, the Agency did not intend to identify in the
proposed codified each and every record that may be required where
these terms appear. Section 412(b)(4)(A)(i) of the FD&C Act requires
the Secretary to establish requirements that provide for the retention
of all records ``necessary to demonstrate compliance with the good
manufacturing practices and quality control procedures. . . .''
Proposed Sec. 106.100(e), for example, would require a manufacturer to
prepare and maintain records that include ``complete information
relating to the production and control of the batch.'' Although
proposed Sec. 106.100(e) specifies certain records that must be
established and maintained under this section, this provision does not
list every record related to ``complete information relating to the
production and control of the batch.'' Thus, if a manufacturer includes
in its master manufacturing order certain documents that are related to
the production and control of a production aggregate of infant formula,
such information would be required to be maintained under this
regulation even if the documents are not expressly identified in
proposed Sec. 106.100(e)(1).
(Comment 298) One comment asserted that the proposed documentation
requirements are very burdensome and would necessitate additional
staffing to implement. However, the comment claimed that it was
difficult to quantify the additional cost without further clarification
and that it was not possible to comment further on the estimated annual
recordkeeping burden until the regulations are finalized.
(Response) This comment simply asserts that records requirements
are burdensome without any attempt to quantify recordkeeping costs or
to estimate the recordkeeping burden. Also, the comment included no
supporting data or information for FDA to consider and to which the
Agency could respond. Therefore, FDA is not revising the interim final
rule in response to this comment.
(Comment 299) Another comment observed that in the proposed rule,
FDA proposes large increases in recordkeeping, which will involve
recording results for each batch (production aggregate) of ingredients,
including the source of production, the batch (production aggregate)
number, the lot (production unit) number, and analysis records of raw
materials.
(Response) The records required by this interim final rule are
necessary to achieve the public health goals of the FD&C Act, including
the CGMP regulations, which are designed to prevent the adulteration of
infant formula caused by equipment or utensils, automatic equipment,
ingredients, containers, and closures, as well as to prevent
adulteration of formula during manufacturing, packaging, and labeling.
The comment does not challenge these goals or contradict the need for
these records. Accordingly, FDA is not revising the interim final rule
in response to this comment.
(Comment 300) One comment claimed that under the proposed rule,
production records such as pH, temperature, solids, fat, protein, and
lactose would also have to be retained for 2 years after the expiration
date of the product and that this will be very expensive and contribute
little to the overall quality of the product. The comment also
questioned the need to retain results for 2 years following a product's
withdrawal from marketing.
(Response) It is unclear which provision of the proposal is the
subject of this comment. The proposed rule did not contain, and the
interim final rule
[[Page 8036]]
does not contain, a 2-year record retention requirement.
The comment may be referring to current 21 CFR 106.100(n), which
requires retention of production records for 1 year after the
expiration of the shelf-life of a infant formula or 3 years from the
date of its manufacture, whichever is greater. FDA did not propose any
changes to this requirement, and is making no changes to this
requirement in this interim final rule. Although the comment asserted
that required records retention would be ``very expensive,'' the
comment did not offer any data or information to quantify any added
expense. Similarly, although the comment asserts that records retention
will contribute little to the overall quality of infant formula, the
comment provided no data, information, or explanation to support its
assertion about the alleged lack of effect on product quality.
Accordingly, FDA is making no revisions to the interim final rule in
response to this comment.
B. Production Aggregate Production and Control Records (Proposed Sec.
106.100(e))
As discussed in section IV.C, to improve the clarity of the interim
final rule and eliminate certain ambiguity and confusion, FDA is
establishing in this interim final rule new terminology to refer to the
basic volumes of formula produced by a manufacturer. The two new terms,
which are identified in Sec. 106.3 of the interim final rule, are
``production aggregate'' and ``production unit.'' In the discussion
that follows, FDA is adding the parenthetical ``(production
aggregate)'' or ``(production unit),'' as appropriate, after the word
``batch'' or ``lot'' when used in a comment summary and is substituting
the new term ``production aggregate'' or ``production unit'' for
``batch'' or ``lot,'' as appropriate, in responses to comments and
where ``batch'' or ``lot'' was used in the proposed rule.
(Comment 301) One comment acknowledged that complete documentation
of the manufacture and release of each batch (production aggregate) of
infant formula (which proposed Sec. 106.100(e) would require) is
essential, and such documentation must be readily available for review.
However, the comment argued that compilation of such documentation into
one record for each batch (production aggregate) would be redundant and
overly burdensome to manufacturers having established documentation
review systems designed to provide retrieval of all critical
information upon request. The comment requested that the Agency clarify
whether current practices could be continued under this regulation.
(Response) FDA is not able to respond directly to the request for
clarification concerning the continuation of current practices because
there are multiple infant formula manufacturers in the U.S. and the
practices of those manufacturers are both likely to be different and
are likely to have changed since the submission of the comment.
Importantly, however, the Agency agrees with the comment that
establishing and maintaining complete documentation of a production
aggregate of infant formula is essential because the manufacturer, FDA,
or both may need to access and consult the records rapidly in order to
identify and resolve a problem related to the production of a
particular production aggregate before the infant formula product is
released for distribution. In establishing Sec. 106.100(e) of the
interim final rule, FDA's goal is to ensure that the complete
production aggregate documentation is immediately available and
accessible to both FDA and the manufacturer. In the case of records
maintained as hard copies, immediate availability and accessibility is
accomplished by co-locating all required records relating to a
particular production aggregate (i.e., by establishing a single,
consolidated record in one physical location). For records that are
maintained electronically, immediate availability and accessibility is
accomplished by linking electronically all required records that
pertain to the same production aggregate in a way that will permit
their instantaneous retrieval.
The Agency disagrees that maintaining a single record for each
production aggregate would be overly burdensome to manufacturers who
have established documentation review systems that can retrieve all
critical information immediately upon the Agency's request. If such
documentation in written form is kept in a location other than the
production and control record for the particular production aggregate,
there is no way to review the entire production process during
manufacture without retrieving all of the critical information from
other records and storage locations. Similarly, if electronic records
are not properly linked, neither the producer nor FDA will have prompt
access to such records. Accordingly, FDA is clarifying the proposed
requirement in Sec. 106.100(e) of the interim final rule in response
to this comment, by amending Sec. 106.100(m) of the interim final rule
to explain that all records, no matter what their form, must be
maintained in a way that allows for immediate access.
1. Master Manufacturing Order Records
(Comment 302) One comment objected to the requirement in proposed
Sec. 106.100(e)(1)(ii) that where a manufacturing facility has more
than one set of equipment or more than one processing line, the master
manufacturing order identify the equipment and processing lines used in
making a particular batch (production aggregate). The comment suggested
that this provision be revised to require that, in such circumstances,
the master manufacturing order include the identity of only the major
equipment systems used in producing the batch (production aggregate).
The comment argued that it is reasonable to require the identity of
major equipment systems, such as processing systems and filling lines,
if more than one is available; however, it is not reasonable to expect
every piece of processing equipment, such as every transfer line, hook-
up station, jumper, and valve, to be identified in the production
records. The comment noted that infant formula manufacturing involves
multitudes of equipment pieces and lines, so the itemization of these
for every batch (production aggregate) would require significant
resources with no practical benefits.
(Response) FDA is not persuaded to revise Sec. 106.100(e)(1)(ii)
to limit the subject equipment to ``major equipment systems'' because
doing so may exclude equipment that, while not ``major,'' may, in the
event of a malfunction or contamination, be implicated nonetheless in
the adulteration of an infant formula. The purpose of this requirement
is in part to facilitate the identification of all production
aggregates of formula that may be affected by a particular instance of
equipment malfunction or that were produced on the same equipment as a
production aggregate that is discovered to be microbiologically
contaminated (61 FR 36154 at 36190). To achieve this purpose, a
manufacturer must identify such equipment and processing lines to
ensure, for example, that any equipment malfunctions that adulterate or
may lead to adulteration of the infant formula can be linked to any
implicated production aggregates of infant formula, which will
facilitate a material review and disposition decision and appropriate
corrective action. Similarly, it would be important to identify in the
production aggregate record any equipment components that could be a
source of adulteration but would not be readily
[[Page 8037]]
identified from the piece of equipment used.
Although FDA is not making the revision requested by this comment,
the Agency is adding a phrase to Sec. 106.100(e)(1)(ii) in the interim
final rule to clarify that records of the identity of the equipment and
processing lines only need to be kept for the equipment and processing
lines for which the manufacturer has identified points, steps, or
stages in the production process where control is necessary to prevent
adulteration. Thus, Sec. 106.100(e)(1)(ii) of the interim final rule
states: ``For a manufacturing facility that has more than one set of
equipment or more than one processing line, the identity of equipment
and processing lines for which the manufacturer has identified points,
steps, or stages in the production process where control is necessary
to prevent adulteration.''
(Comment 303) One comment requested that proposed Sec.
106.100(e)(1)(v) be revised to delete the requirement that the master
manufacturing order include copies of all labeling and substitute a
requirement that the master manufacturing order include copies of all
primary container labels used and the results of examinations during
finishing operations to provide assurance that containers and packages
have the correct label. The comment agreed with the requirement to
include a sample of the primary container label in each batch
(production aggregate) record, but asserted that including trays,
cartons, and shippers that are also considered labeling would
substantially increase the size of the batch (production aggregate)
record because the trays, cartons, and shippers are relatively bulky.
(Response) FDA agrees that it is adequate to include in the master
manufacturing order record only a copy of the labeling used on the
immediate container of the finished production aggregate of infant
formula. Such labels are usually distinctive in appearance and, unlike
trays, cartons, and shippers, generally are the labeling on which
consumers rely when purchasing and using a formula. FDA notes that, by
definition, the word ``label'' is written, printed, or graphic matter
affixed to the immediate container of a product. 21 U.S.C. 321(k).
Accordingly, FDA is modifying Sec. 106.100(e)(1)(v) in the interim
final rule to require that the master manufacturing order include a
copy of each label used on a finished production aggregate of infant
formula and the results of examinations conducted during the finishing
operations to provide assurance that all containers have the correct
label.
(Comment 304) One comment objected to the use of the phrase
``corrective actions'' in proposed Sec. 106.100(e)(2), (e)(3)(ii), and
(e)(4)(i) and requested that the phrase be replaced with ``specific
actions'' in each of these sections. The comment argued that, due to
timing, it is not always practical to include corrective actions in the
same batch (production aggregate) record as the documentation of
deviations. The comment explained that if the corrective action is
immediate, it would be reasonable to include documentation of the
corrective action in the batch (production aggregate) record. However,
the comment contended, it is impractical to include the corrective
action when the deviation requires investigation and research over an
extended period of time or involves the evaluation of multiple batches
(production aggregates) before the appropriate corrective action is
identified. In these cases, the comment maintained, it would be
impractical to place a copy of the corrective action taken into the
record of each affected batch (production aggregate) after the fact but
it would be sufficient to require documentation of the manufacturer's
response to each deviation in its respective batch (production
aggregate) record. The comment argued that this action would include
responses to the deviations, if immediately known, or a statement of
the need for further evaluation, or some other appropriate indication
of the status of the investigations or corrective action.
(Response) FDA is not persuaded by this comment because it ignores
the role of production records, including records of corrective
actions, in ensuring the safety of infant formula.
In the preamble to the 1996 proposal, FDA discussed why these
records must appear in the production aggregate production and control
record (61 FR 36154 at 36190-36191). These records have a critical role
helping the manufacturer to ensure that the infant formula is in
compliance with the CGMP requirements for infant formula and to ensure
that any deviation that has occurred during the production of the
infant formula will not adulterate or lead to adulteration of the
product. A manufacturer must not release a finished production
aggregate of infant formula until it determines that the production
aggregate meets all of its specifications, or until the documented
review of the failure to meet any of the manufacturer's specifications
finds that the failure does not result in, or could not lead to,
adulteration of the product (see Sec. 106.70(a) of the interim final
rule). A manufacturer would need to determine what, if any,
specifications are or may not be met and otherwise address a deviation
from the master manufacturing order before the production aggregate of
infant formula is released for distribution. Thus, any determination of
how to handle a deviation will occur during the time period when the
production and control record is being prepared. Once a manufacturer
has determined how to handle a deviation from specifications, any
corrective action shall be recorded and that record made part of the
production aggregate record at that time.
Furthermore, if a deviation is noted in the production and control
record for the production aggregate, documentation of any corrective
action taken must appear in the production aggregate record to make it
complete and to ensure that the deviation was appropriately
investigated and addressed. Therefore, documentation of any corrective
action(s) taken is appropriately part of the production and control
record for the production aggregate to provide a basis for the ultimate
decision to release (or not release) the production aggregate for
distribution. Because the record of a corrective action is part of the
history of a particular production aggregate, this documentation should
not be maintained in another record or location that is not linked
directly and closely to the production of the particular production
aggregate of infant formula. In addition, the comment provided no
rationale for why FDA should use the term ``specific actions'' instead
of ``corrective actions.'' For these reasons, FDA is not revising
proposed Sec. 106.100(e)(2), proposed Sec. 106.100(e)(3)(ii), and
proposed Sec. 106.100(e)(4)(i) in response to this comment, and these
provisions are included in this interim final rule as proposed.
2. Records of the Production and In-process Control System
(Comment 305) One comment suggested revising proposed Sec.
106.100(e)(3) by changing the term ``necessary'' to ``critical'' and
thus requiring that documentation be included where control is deemed
critical to prevent adulteration.
(Response) FDA is not persuaded by this comment. As discussed
previously in this document in section IV.C.8, FDA is not persuaded
that the word ``critical'' enhances the clarity of the phrase
``necessary to prevent adulteration.'' Therefore, FDA is not revising
proposed Sec. 106.100(e)(3) in response to this
[[Page 8038]]
comment, and this provision is included in this interim final rule as
proposed.
(Comment 306) One comment suggested that proposed Sec.
106.100(e)(4)(i) be revised to state ``any deviation from the
manufacturing order and any specific action taken to adjust or correct
a batch [production aggregate] in response to a deviation,'' and that,
as a result, proposed Sec. 106.100(e)(4)(iii) could be deleted as
redundant. (Proposed Sec. 106.100(e)(4)(iii) would require that the
batch (production aggregate) production and control record contain the
conclusions and followup, along with the identity, of the individual
qualified by training or experience who investigated a failure to meet
any standard or specification at any point, step, or stage in the
production process where control is necessary to prevent adulteration.)
(Response) FDA declines to make the suggested revisions to Sec.
106.100(e)(4) in the interim final rule. The comment did not provide a
reasoned basis for substituting the term ``specific action'' for
``corrective action'' or for inserting the phrase ``to adjust or
correct a batch in response to a deviation'' to describe the corrective
actions taken. Further, FDA disagrees that Sec. 106.100(e)(4)(iii)
would be redundant with proposed Sec. 106.100(e)(4)(i) even if the
latter provision were revised as suggested. The scope of proposed Sec.
106.100(e)(4)(i) and proposed Sec. 106.100(e)(4)(iii) are very
different. Proposed Sec. 106.100(e)(4)(i) covers only deviations from
the master manufacturing order. (A master manufacturing order provides
the plan for manufacture of the infant formula.) In contrast, proposed
Sec. 106.100(e)(4)(iii) relates to the investigation of a failure to
meet any specification in the production process where control is
deemed necessary to prevent adulteration, a provision that extends to
the entire production process, including a deviation from the master
manufacturing order and a deviation from any part of the manufacturing
process, such as a deviation from the provisions of proposed Sec. Sec.
106.10, 106.20, 106.30 106.35 or 106.40. Accordingly, FDA is not
revising Sec. 106.100(e)(4) as requested in this comment.
3. Records on Production Aggregate (Batch) Testing
(Comment 307) One comment objected to the stability testing record
requirements in proposed Sec. 106.100(e)(5), which would require that
the batch (production aggregate) production and control record include
records of the results of all testing performed on the batch
(production aggregate) of infant formula, including testing on the in-
process product, at the final product stage, and on finished product
throughout the shelf life of the product. The comment argued that the
requirement to include all stability test results in the individual
batch (production aggregate) records is an additional administrative
burden and can easily be avoided by requiring that shelf life testing
results be made available to the Agency upon request, either by outside
communication or through inspection. The comment stated that if a
requirement were made to store the data with the manufacturing work
order, an additional system would need to be developed to link the data
at an additional cost with no commensurate benefit to public health.
(Response) FDA is not persuaded that requiring all stability
testing results to be included in the production aggregate production
and control record would be an unwarranted administrative burden to
formula manufacturers. FDA notes that the comment's concern was limited
to the administrative burden of maintaining stability records in the
production and control record and did not explain why stability testing
records are different from all other testing records in terms of such
burden.
The principle underlying proposed Sec. 106.100(e)(5) is that all
testing records that relate to a specific production aggregate (batch)
must be co-located (or linked electronically) so that, should there be
an adulteration concern about a particular production aggregate, both
the manufacturer and FDA can have immediate access to all relevant
testing records for the formula in question. Also, maintaining
stability testing records in the production and control record will
help avoid duplication. This is because the final product testing that
would be required by proposed Sec. 106.91(a)(4) may also serve as the
initial (baseline) stability testing.
The Agency acknowledges that, with the exception of initial
stability testing, all stability testing is likely to occur after the
finished infant formula has been released for distribution, and the
production and control record for a production aggregate is likely to
be established at or near the time the formula is manufactured.
However, it is not unreasonable to require stability testing records to
be co-located (for hard copy records) or electronically linked (for
electronic records) with the production aggregate production and
control record and that any records created post-distribution may
simply be added to or linked with the production and control record. As
noted, the comment did not distinguish stability testing records from
other production records that this interim final rule requires to be
maintained in the production aggregate production and control record.
Absent such distinction, it is entirely reasonable that stability
testing records be maintained with other records relating to a
particular production aggregate.
Moreover, as discussed in section VI. Quality Control Procedures,
stability testing of finished infant formula is critical because it
evaluates whether all nutrients (both those required by Sec. 107.100
and those otherwise added by the manufacturer) are present in the
formula at the desired level throughout the formula's shelf life. A
formula that lacks one or more of these nutrients at the appropriate
level may be unable to support normal growth of the infants consuming
it as their sole source (or virtually sole source) of nutrition.
Similarly, the records of stability testing of a particular production
aggregate are an integral part of the history of the particular
production aggregate of formula and, like other production records that
supply the history of a production aggregate, these stability testing
records need to be immediately accessible to both the manufacturer and
FDA. For these reasons, FDA declines to revise Sec. 106.100(e)(5) in
response to this comment.
(Comment 308) Another comment suggested that because the results of
stability testing should be required as a part of the good
manufacturing practice records instead of as a part of the batch
(production aggregate) production and control records, the summary of
results from the stability testing program required by proposed Sec.
106.100(e)(5)(i)(B) should be incorporated into the good manufacturing
practice records.
(Response) FDA disagrees with this comment. As outlined in the
preceding response, records of stability testing are part of the
manufacturing history of the particular production aggregate and, as
such, are reasonably required to be maintained in the production
aggregate production and control record. The summary of such testing
required by Sec. 106.100(e)(5)(i)(B) of the interim final rule is
appropriately maintained as part of the same production and control
record. Thus, FDA is not making any revisions in response to this
comment.
(Comment 309) One comment suggested that FDA revise both proposed
Sec. 106.100(e)(5)(i)(A), which would require a summary table
identifying the stages of the manufacturing process at which the
manufacturer conducts the nutrient analysis required under proposed
[[Page 8039]]
Sec. 106.91(a) for each required nutrient, and proposed Sec.
106.100(e)(5)(i)(B), which would require a summary table of the
stability testing program that would be required under proposed Sec.
106.91(b), including the nutrients tested and the testing frequency for
nutrients throughout the shelf life of the product. The comment
suggested that ``table'' should be changed to ``document'' because
``document'' implies a reference best suited to the manufacturer's
system, as opposed to a specific type of a reference, such as table.
(Response) FDA agrees with this comment. It is reasonable to
provide formula manufacturers with flexibility to create a summary
document so long as the chosen format accurately and succinctly conveys
the data identified as appropriate in proposed Sec. 106.91(a) and
proposed Sec. 106.91(b). The summary document may, but is not required
to, be in the form of a table, if the manufacturer determines that such
format is a convenient and accurate summary document. Thus, in response
to this comment FDA is modifying both Sec. 106.100(e)(5)(i)(A) and
(e)(5)(i)(B) by changing the word ``table'' to ``document.''
C. Records of CGMP (Proposed Sec. 106.100(f))
FDA did not receive any comments requesting modification of
proposed Sec. 106.100(f)(1) and proposed Sec. 106.100(f)(3). Thus,
these provisions are included in this interim final rule as proposed.
FDA received a comment on proposed Sec. 106.100(f)(2), which suggested
that the words ``standards'' be omitted from that provision. As
discussed previously in this document, the Agency agrees generally with
this comment and has revised several provisions in this interim final
rule, including proposed Sec. 106.100(f)(2), by deleting ``standard
or.''
1. Records on Equipment and Utensils
(Comment 310) One comment objected to the inclusion of the ``lot
number'' in proposed Sec. 106.100(f)(4), which would require that
records be maintained, in accordance with proposed Sec. 106.30(f), on
equipment cleaning, sanitizing, and maintenance that show, among other
things, the lot number of each batch (production aggregate) of infant
formula processed between equipment startup and shutdown for cleaning,
sanitizing, and maintenance. Proposed Sec. 106.100(f)(4) also would
require the person performing and checking the cleaning, sanitizing,
and maintenance to date and sign or initial the record indicating that
the work was performed. The comment contended that the requirement to
document all lot numbers of batches (production aggregates) produced
between all equipment cleaning, sanitizing, and maintenance is an
overwhelming administrative requirement that is unnecessary on a daily
basis. The comment asserted that the records should have sufficient
detail and reference points (e.g., time, location) to allow
reconstruction of this type of information if needed, but to require it
routinely serves no purpose.
(Response) FDA disagrees. Accurate recordkeeping on equipment
cleaning, sanitizing, and maintenance showing the date and time of such
activities will provide a means by which the manufacturer can ensure
that equipment is being cleaned and maintained regularly and that the
frequency of such cleaning is appropriate in light of the actual use of
the equipment. Moreover, records that identify the production unit
number or production aggregate number (see Sec. 106.3 of the interim
final rule) of each production unit or production aggregate of infant
formula processed between equipment startup and shutdown for cleaning,
sanitizing, and maintenance are essential in situations of equipment
contamination because such records will permit a manufacturer to
determine which production units or production aggregates of infant
formula are or may be adulterated. Thus, the requirements of Sec.
106.100(f)(4) are both reasonable and critical to the production of
safe infant formulas.
FDA is not persuaded that Sec. 106.100(f)(4) should be modified
because other records could be used to reconstruct this information, if
needed. The most reliable and accurate way to develop this type of
information is to create an appropriate record in real time for this
specific purpose. Maintaining this type of information would be
particularly important when equipment maintenance, planned or
unplanned, might have an impact on infant formula production aggregates
produced between the previous maintenance and the time the equipment
was repaired. In such a case, it may be necessary for a firm to
investigate and identify which production aggregates were manufactured
between those time periods. These records will complement the
production aggregate production and control records and will facilitate
a manufacturer's trace back to all potentially affected production
units or production aggregates when there is an instance of an
equipment failure that might result in an adulterated product (e.g.,
microbiological contamination). Therefore, FDA is not revising proposed
Sec. 106.100(f)(4) in response to this comment, and this provision is
included in this interim final rule, with minor editorial changes, as
proposed.
2. Records on Automatic Equipment
(Comment 311) One comment suggested, consistent with the comment's
recommendation that proposed Sec. 106.35 be deleted, the deletion of
proposed Sec. 106.100(f)(5), which relates to records on automatic
(mechanical or electronic) equipment required in accordance with
proposed Sec. 106.35(c).
(Response) As discussed previously in this document in section V.G,
FDA does not agree that proposed Sec. 106.35 should be eliminated. As
noted in that discussion, the Agency has clarified the application of
validation to the manufacture of infant formula. Because the comment
provides no independent basis for deleting proposed Sec.
106.100(f)(5), FDA declines to eliminate the recordkeeping requirements
of proposed Sec. 106.100(f)(5) in response to this comment.
(Comment 312) One comment suggested that proposed Sec.
106.100(f)(5)(i), which requires a list of all systems used with a
description of computer files and the inherent limitations of each
system, be revised to require a list of all systems used with a
description of computer files and the defined capabilities of each
system. The comment asserted that the range in capability of a system
is a better description than the inherent limitations of a system and
would include at least the same information.
(Response) FDA disagrees that providing the defined capabilities of
each system would provide a better description of the system rather
than a description of the system's inherent limitations. The purpose of
proposed Sec. 106.100(f)(5)(i) is to require that the records for
automatic equipment include a sufficiently detailed description of the
system to enable the manufacturer to operate and troubleshoot the
system. The Agency disagrees that a description of the defined
capabilities of a system would include the same information as a
description of the inherent limitations of a system. A description of
the defined capabilities of a system identifies what the system is
designed to do while a description of the system's inherent limitations
identifies what the system is incapable of doing. Upon further
consideration, FDA has determined that in order for a manufacturer to
operate and troubleshoot a system, it is essential that a
manufacturer's records include a description of both the defined
capabilities and inherent limitations of
[[Page 8040]]
the system. Accordingly, FDA is revising Sec. 106.100(f)(5)(i) to
require ``A list of all systems used with a description of the computer
files and the defined capabilities and inherent limitations of each
system.''
(Comment 313) One comment on proposed Sec. 106.100(f)(5)(vii)
asserted that hard copy recording should be reduced to a minimum and
attempts made to ensure that all key process results are obtained
electronically because the latest instruments automatically record to a
computer with data processing, graphing, and alarm signals produced
instantaneously. The comment claimed that back-up methods can eliminate
fears of data loss so there is now no need for burdensome recording
better suited to the last century.
(Response) FDA agrees that technology has changed since publication
of the proposal and has made modifications to the interim final rule to
permit the use of back-up systems that may become available in the
future as well as those systems currently in use. Specifically, FDA is
revising Sec. 106.100(f)(5)(vii) to delete the reference to specific
older storage systems (e.g., diskettes) and to substitute the term
``electronic records.'' This will provide a manufacturer with the
option to use newly developed technologies, if the manufacturer chooses
to do so. Thus, Sec. 106.100(f)(5)(vii) of the interim final rule
requires ``A backup file of data entered into a computer or related
system. The backup file shall consist of a hard copy or alternative
system, such as duplicate electronic records, tapes, or microfilm,
designed to ensure that backup data are exact and complete, and that
they are secure from alteration, inadvertent erasures, or loss.''
D. Records on Infant Formula for Export Only (Proposed Sec.
106.100(g))
(Comment 314) One comment requested clarification of proposed Sec.
106.100(g), which requires that the manufacturer maintain all records
pertaining to distribution of an infant formula, including records
showing that products produced for export only are exported. The
comment stated that it is reasonable to expect a manufacturer to
maintain distribution records regarding shipment of infant formula
under the manufacturer's control. However, the comment contended that
once the infant formula is in the hands of the retailer, customer,
consumer, or exporter, the manufacturer can no longer be responsible
for obtaining or keeping these records and should not retain that
responsibility after the infant formula has left its control. The
comment also stated that sometimes manufacturers ship infant formula to
a customer who, in turn, intends it only for export. Because the
manufacturer is not responsible for the actual export, the manufacturer
would have no records regarding distribution of such infant formula
after it is turned over to the exporter.
(Response) FDA agrees that an infant formula manufacturer must
maintain distribution records regarding shipment of infant formula
under the manufacturer's control, including records of shipments to a
manufacturer's consignees. Such distribution records are routinely
maintained by manufacturers. Thus, if a consignee is a foreign
purchaser, the manufacturer would have records of shipment to such
consignee. A sale of infant formula for export only directly to a
foreign purchaser would be consistent with the requirement in section
801(e)(1)(D) of the FD&C Act (21 U.S.C. 381(e)(1)(D)) that a product
not be ``sold or offered for sale in domestic commerce,'' provided that
the product is, in fact, exported. In contrast, if a manufacturer sells
an infant formula to a distributor in the U.S., the manufacturer would
not be in compliance with section 801(e)(1)(D) of the FD&C Act because
this transaction would involve the sale (or the offer for sale) of the
infant formula in domestic commerce. FDA recognizes that, in some
cases, however, a manufacturer may transfer an infant formula to a
domestic third-party (e.g., contractor or other agent of the
manufacturer) who, on behalf of the manufacturer, exports the product
to a foreign consignee. This latter transaction would not be considered
a ``sale'' of the infant formula in domestic commerce for the purposes
of section 801(e)(1)(D) of the FD&C Act because there is no transfer of
ownership to the third-party acting on behalf of the manufacturer. In
such situation, FDA expects that the manufacturer would have access to
the records of export of such third-party. Therefore, where the
manufacturer ships its product to a foreign consignee, either directly
or through a third-party who ships such product to a foreign consignee,
the manufacturer would have the necessary access to distribution
records (e.g., bill of lading) showing that the infant formula produced
for export only is actually exported. The distribution records are
required under section 412(g) of the FD&C Act and are required by
current Sec. 106.100(l) to be available for inspection. FDA notes that
these and other records may also be required under 21 CFR 1.101(b)(4)
for foods, in general, that are for export only.
For the foregoing reasons, FDA is only making minor editorial
changes to Sec. 106.100(g).
In the proposed rule, FDA expressed concerns about infant formulas
produced for export only that are diverted and sold in the United
States (61 FR 36154 at 36194). Proposed Sec. 106.100(g) was intended,
in part, to be a means to verify that the infant formula was not in
fact sold or offered for sale in domestic commerce. Id. A manufacturer
of an infant formula for export only has a responsibility under section
801(e)(1)(D) of the FD&C Act and section 412(b)(2) of the FD&C Act to
ensure that it or any third-party acting on its behalf exports the
infant formula for export only and does not divert it for sale in
domestic commerce. As noted previously in this document, under section
801(e) of the FD&C Act, an infant formula for export only is deemed not
to be adulterated or misbranded if the formula satisfies the criteria
in section 801(e) of the FD&C Act, including that it is not sold or
offered for sale in domestic commerce. In order to move such a product
lawfully in interstate commerce, the manufacturer must take the
necessary steps to ensure that the product complies with section 801(e)
of the FD&C Act. See United States v. Parfait Powder Puff Co., 163 F.2d
1008, 1010 (7th Cir. 1947) (explaining that ``one who owes a certain
duty to the public and entrusts its performance to another, whether it
be an independent contractor or agent, becomes responsible criminally
for the failure of the person to whom he has delegated the obligation
to comply with the law, if the nonperformance of such duty is a
crime''). Further, a manufacturer of infant formula for export only,
which formula is otherwise adulterated or misbranded under U.S. law,
has an obligation under section 412 of the FD&C Act to establish
adequate controls under CGMP respecting the distribution of such
product to ensure that adulterated product is not sold or offered for
sale in domestic commerce.
Section 412(d) of the FD&C Act requires a formula manufacturer to
make certain submissions that provide assurances that the firm's
formula is not adulterated. FDA is not requiring, under the
requirements in Sec. 106.120 of the interim final rule for new infant
formula submissions, that a manufacturer of infant formula for export
only submit the same information that would be required for a formula
intended or offered for sale in domestic commerce. Instead, to meet the
requirements in
[[Page 8041]]
sections 412(d)(1)(C) and (D) of the FD&C Act and Sec. 106.120 of the
interim final rule, such a manufacturer may provide assurances that
include, among other commitments, that the infant formula will not be
sold or offered for sale in domestic commerce, consistent with section
801(e) of the FD&C Act. In addition, to ensure that a manufacturer
takes the necessary precautions to prevent an infant formula it
distributes for export only from being diverted for sale in domestic
commerce, FDA is requiring in this interim final rule, as part of the
submission requirements in Sec. 106.120(c) of the interim final rule,
that a manufacturer of infant formula for export only certify that it
has adequate controls in place to ensure its formula for export only is
actually exported (see discussion in section X.C.3 for Sec. 106.120(c)
of the interim final rule). In making this certification, the
manufacturer is assuring that the product will not be sold or offered
for sale in domestic commerce and thereby meets the requirements of the
FD&C Act under sections 412(d)(1)(C) and (D) that, if not met, would
result in the formula being deemed adulterated under sections 412(a)(2)
and (3) of the FD&C Act.
E. Means of Recordkeeping (Sec. 106.100(m))
(Comment 315) One comment recommended that the final regulation
reflect the acceptability of electronic recordkeeping.
(Response) FDA agrees that it may be appropriate to use electronic
recordkeeping to meet the requirements of Sec. 106.100, provided that
the records are maintained in accordance with part 11 (21 CFR part 11).
Part 11 applies to any electronic records that are maintained to comply
with the requirements of this interim final rule. The Agency advises
that the use of electronic records is voluntary and thus, a paper
record system may be used to comply with these recordkeeping
requirements. In response to this comment, FDA is revising Sec.
106.100(m) to state that records required under part 106 may be
retained as original records, as true copies of the original records in
a form such as photocopies, microfilm, microfiche, or other accurate
reproductions of the original records, or as electronic records. In
addition, FDA is modifying Sec. 106.100(m) to require all electronic
records maintain under part 106 to comply with part 11.
The requirements for electronic records extend to electronic
signatures. FDA has issued final guidance for industry on this topic.
The guidance entitled ``Part 11, Electronic Records; Electronic
Signatures Scope and Application'' sets out the Agency's enforcement
policies with respect to certain aspects of part 11. The guidance is
available at http://www.fda.gov/RegulatoryInformation/Guidances/ucm125067.htm. This guidance applies to any electronic record,
including electronic signatures, established or maintained to meet a
requirement in this interim final rule.
F. Records of Quality Factors (Sec. 106.100(p) and (q))
For consistency with other records requirements, FDA is adding two
new provisions to Sec. 106.100 of the interim final rule to clarify
the requirements for making and retaining records that demonstrate that
an infant formula meets the quality factor requirements. All of the
records requirements for part 106 are located in subpart F. Therefore,
for comprehensiveness and clarity, FDA is adding language to Sec.
106.100 in the interim final rule to include the recordkeeping
requirements for quality factors.
As is discussed in section VIII.I, the interim final rule contains
the requirement that an infant formula manufacturer make and retain
records demonstrating that such formula meets the quality factors
requirements. Section VIII.I also explains that, although both
``eligible'' and non-eligible formulas will be required to meet the
quality factors of normal physical growth and sufficient biological
quality of protein, ``eligible infant formulas'' will be able to use
separate established criteria to demonstrate compliance with those
quality factors. As such, these new provisions in subpart F describe
the separate quality factor records requirements for eligible formulas
and non-eligible formulas. For a formula that is not an eligible
formula, the manufacturer of the formula must make and retain records
that demonstrate compliance with the requirements in Sec. 106.96(b)
and (f) of the interim final rule, or, as applicable, an exemption to
either provision. An eligible formula manufacturer must make and retain
records that demonstrate compliance with the requirements in Sec.
106.96(i)(1) and (i)(2) of the interim final rule.
G. Adulteration as a Consequence of the Failure To Keep Records (Sec.
106.100(r))
For clarity, FDA is also adding a paragraph to Sec. 106.100 in the
interim final rule that discusses when an infant formula will be
considered adulterated for the failure to make or retain a record.
As noted, the records requirements in part 106 are located in
subpart F. However, despite the fact that these records provisions are
located in subpart F, many of these records are considered to be a
current good manufacturing practice, quality control procedure, or
quality factor requirement. For example, Sec. 106.100(e)(3) of the
interim final rule requires records documenting the monitoring at any
point, step, or stage in the manufacturer's production process where
control is deemed necessary to prevent adulteration. Such monitoring is
a part of good manufacturing practices. Thus, although the substance of
the recordkeeping requirement to make and retain records of this
practice is located in subpart F, Sec. 106.100(e)(3) of the interim
final rule is also a part of current good manufacturing practices.
Because some of the requirements in subpart F are a part of the
current good manufacturing practices, quality control procedures, and
quality factor requirements, the failure to follow some of the
requirements in subpart F will necessarily adulterate the infant
formula. The failure to follow any CGMP or quality control requirement
will adulterate the formula under section 412(a)(3) of the FD&C Act.
Likewise, the failure to follow any quality factor requirement will
adulterate the formula under section 412(a)(2) of the FD&C Act.
X. Subpart G--Registration, Submission, and Notification Requirements
In the 1996 proposed rule, FDA proposed a new subpart G to
establish requirements for registration by an infant formula
manufacturer (implementing section 412(c)(1)(A) of the FD&C Act),
submission of information relating to a new infant formula
(implementing section 412(d) of the FD&C Act), and notification
relating to any adulterated or misbranded infant formula that has left
the control of a manufacturer (implementing section 412(e) of the FD&C
Act.) The 2003 reopening requested comments on all aspects of the 1996
proposal, including proposed Subpart G.
FDA received comments on a number of the provisions in proposed
subpart G. The Agency's responses are set out in this document.
A. General Comments
Several comments stated that the premarket notification
requirements of section 412(c) and (d) of the FD&C Act do not
constitute a premarket approval process for infant formula and cited
legislative history in support of their assertion.
[[Page 8042]]
(Comment 316) One comment stated that FDA's role in the premarket
notification process was perceived by Congress as comprising the task
of confirming that the required [nutrient] specifications are met for
each new or significantly modified formula.
(Response) FDA disagrees with the comment to the extent that it
suggests that FDA's role in the premarket notification process is
limited to confirming that the FD&C Act's nutrient specifications are
met. In fact, through the premarket notification process in section 412
of the FD&C Act, Congress assigned FDA a comprehensive role in
evaluating new infant formulas. As noted in the 1996 proposal, the FD&C
Act requires that the manufacturer of a new infant formula submit a
variety of information on the new infant formula, including information
on its quantitative composition, on any reformulation, on any changes
in processing, assurances that quality factor requirements have been
met, assurances that the nutrient requirements have been met, and
assurances that the manufacturing adhere to CGMP and quality control
procedures. All of this information is reviewed by the Agency to ensure
that the infant formula will be a safe product that adheres to all
applicable laws and regulations.
(Comment 317) Another comment asserted that, over the years, the
practices and procedures FDA has followed in reviewing notifications
under section 412 of the FD&C Act have consistently taken on more and
more of the trappings of premarket approval systems quite different
from the limited, precise review function contemplated in the statutory
scheme.
(Response) As explained in the previous response, FDA disagrees
that the Agency's review role under section 412 of the FD&C Act is a
narrow one. In addition, the comment did not provide any underlying
details to explain its assertion that FDA's review procedures have
``taken on the trappings of premarket approval systems.''
Accordingly, the Agency is making no changes to the rule in
response to Comments 316 and 317.
(Comment 318) One comment requested that the Agency establish and
make public a well-defined, transparent, and practical process for the
receipt, review, and disposition of various infant formula submissions
from industry. The comment suggested that the process include review
time lines, the definition of the review process, the identification of
reviewers, and a response and dialogue process, and asserted that such
process definition is necessary for industry planning and
implementation of infant formula advancements in a mutually cooperative
manner.
(Response) FDA disagrees in part with this comment. The interim
final rule provides a well-defined, transparent, and practical process
for the receipt and review of the infant formula submissions required
by section 412 of the FD&C Act. The interim final rule clearly
identifies the information that must be provided to FDA in the various
submissions, the form in which it is to be submitted, and where the
information is to be submitted. Under the FD&C Act, a manufacturer must
make a submission to FDA at least 90 days before marketing a new infant
formula.
FDA does not agree that certain matters should be made available to
the public, as suggested by the comment. In particular, review time
lines, a description of the review process, and the identification of
Agency reviewers are all internal administrative management items and
are not relevant to a manufacturer's obligations or responsibilities
under the FD&C Act. Indeed, the comment itself did not explain why
formula manufacturers need such information. Accordingly, the interim
final rule does not commit FDA to disclosing these types of details.
B. New Infant Formula Registration (Proposed Sec. 106.110)
In 1996, FDA proposed to establish requirements to implement
section 412(c)(1)(A) of the FD&C Act. Specifically, FDA proposed in
Sec. 106.110 that, before a new infant formula may be introduced or
delivered for introduction into interstate commerce, the manufacturer
of such formula must register with FDA and provide the name of such
formula, the name of the manufacturer, the manufacturer's place of
business, and all establishments at which the manufacturer intends to
manufacture such formula.
The Agency responds in this document to the comments received on
proposed Sec. 106.110.
(Comment 319) One comment suggested that FDA revise proposed Sec.
106.110 on new infant formula registration to require that
manufacturers of infant formula for export register with FDA. The
comment suggested revising Sec. 106.110 to include the requirement
that infant formula products for export only comply with section 801(e)
of the FD&C Act and deleting the requirement in Sec. 106.120(c), a
revision that would, the comment asserted, reduce the time and expense
for preparing and reviewing submissions for infant formula intended for
export.
(Response) FDA agrees that the interim final rule should require a
manufacturer of an infant formula product intended for export only to
register with FDA. Section 412(c)(1)(A) of the FD&C Act requires that
no person shall introduce or deliver for introduction into interstate
commerce any new infant formula unless such person has registered with
the Secretary (and by delegation, FDA). The act of exporting infant
formula necessarily requires the introduction or delivery for
introduction into interstate commerce of the formula. Infant formula
manufactured for export only may nonetheless be a ``new infant
formula'' as defined in Sec. 106.3 of the interim final rule.
Therefore, FDA is revising Sec. 106.110(a) in the interim final rule
to clarify that a manufacturer who produces formula for export only is
required to register with FDA. The Agency is also revising Sec.
106.110(a) to update the contact information for FDA's Center for Food
Safety and Applied Nutrition. Thus, Sec. 106.110(a) of the interim
final rule states ``Before a new infant formula may be introduced or
delivered for introduction into interstate commerce, including a new
infant formula for export only, the manufacturer of the formula shall
register with the Food and Drug Administration, Center for Food Safety
and Applied Nutrition, Office of Nutrition, Labeling, and Dietary
Supplements, Infant Formula and Medical Foods Staff (HSF-850), 5100
Paint Branch Pkwy., College Park, MD 20740-3835.''
The Agency disagrees that proposed Sec. 106.110 should be revised
to require that infant formula products intended for export comply with
section 801(e) of the FD&C Act and that proposed Sec. 106.120(c) be
deleted for the reasons the comment provided. A manufacturer of an
infant formula for export only must still provide a submission under
sections 412(c)(1)(B) and (d)(1) of the FD&C Act. Section 412(c)(1)(B)
of the FD&C Act requires that no person shall introduce or deliver for
introduction into interstate commerce any new infant formula unless
such person has at least 90 days before marketing such new infant
formula made the submission required under the FD&C Act. The failure to
provide notice under section 412(c) of the FD&C Act, including the
submission in section 412(d)(1) of the FD&C Act, is a prohibited act
under section 301(s) of the FD&C Act (21 U.S.C. 331(s)). However, as is
explained in response to Comment 328, FDA is revising Sec. 106.120(c)
in the interim final
[[Page 8043]]
rule to clarify the assurances that must be provided for infant formula
for export only.
(Comment 320) One comment suggested that proposed Sec.
106.110(b)(4), which would require that the new infant formula
registration include all establishments at which the manufacturer
intends to manufacture such new infant formula, be revised to require
the name and addresses of all establishments at which the manufacturer
intends to manufacture such new infant formula.
(Response) FDA agrees with this comment. The name and address of
the establishments is a necessary component of the registration and
will allow the Agency to identify and locate each establishment; only
if FDA can locate an establishment can the Agency inspect such firms
and otherwise carry out its regulatory responsibilities. Therefore,
Sec. 106.110(b)(4) of the interim final rule requires that the new
infant formula registration include the name and street address of each
establishment at which the manufacturer intends to manufacture a new
infant formula.
C. New Infant Formula Notifications (Proposed Sec. 106.120)
In 1996, FDA proposed to establish requirements to implement
section 412(c)(1)(B) and 412(d)(1) of the FD&C Act. Specifically, FDA
proposed in Sec. 106.120 that at least 90 days before the interstate
distribution of a new infant formula, a manufacturer submit certain
information to FDA pertaining to the new infant formula.
FDA received a number of comments on proposed Sec. 106.120 and
responds in this document to those comments.
1. Form of Submission (Proposed Sec. 106.120(a))
The proposed rule, Sec. 106.120(a), would have required that an
original and two copies of a new infant formula submission be provided
to FDA. As discussed previously in this document, in response to a
comment, Sec. 106.100(m) of the interim final rule permits a
manufacturer to maintain records as original paper records, as true
copies of the originals (e.g., microfilm), or as electronic records.
Such electronic records are required to conform to 21 CFR Part 11.
Consistent with this revision, FDA is, on its own initiative, revising
Sec. 106.120(a) in the interim final rule to permit new infant formula
submissions to be submitted electronically and, in such case, to
require only a single copy of such electronic submission. Thus, Sec.
106.120(a) of the interim final rule states, ``At least 90 days before
a new infant formula is introduced or delivered for introduction into
interstate commerce, a manufacturer shall submit notice of its intent
to do so to the Food and Drug Administration at the address given in
Sec. 106.110(a). An original and two paper copies of the notice of its
intent to do so shall be submitted, unless the notice is submitted in
conformance with part 11 of this chapter, in which case, a single copy
shall be sufficient.''
2. Contents of a New Infant Formula Submission (Proposed Sec.
106.120(b))
Proposed Sec. 106.120(b) would have established the required
contents of a new infant formula submission. FDA received comments on a
number of the provisions of proposed Sec. 106.120(b), and responds in
this section.
a. Quantitative formulation (Proposed Sec. 106.120(b)(3)).
(Comment 321) One comment questioned the requirement in proposed
Sec. 106.120(b)(3) that the quantitative formulation of the new infant
formula be submitted in units per volume for liquid formulas. The
comment asserted that formulations are routinely listed and have
traditionally been submitted to the Agency in units per weight of
liquid. The comment also requested clarification of the volume units to
use in the quantitative formulation and whether the information should
be provided on an ``as sold'' or ``as fed'' basis in the submission.
(Response) The Agency has examined previously received infant
formula submissions and determined that the formulations of liquid
formulas have been provided to the Agency in either units per weight
(e.g., milligrams/kilogram) or in units per volume (e.g., milligrams/
liter). Accordingly, the interim final rule, at Sec. 106.120(b)(3),
permits a manufacturer to provide the quantitative formulation of a new
infant formula either in units per weight or units per volume, and on
an ``as sold'' or ``as fed'' basis, provided that the manufacturer
specifies whether the quantitative formulation is on an ``as sold'' or
``as fed'' basis. For a powdered infant formula, the submission must
also specify the weight of powder to be reconstituted in a specific
volume of water (e.g., grams (g) of powder per fluid (fl) ounce (oz) of
water).
(Comment 322) One comment requested clarification on whether FDA
requires a table of nutrients as well as a table of ingredients as part
of the quantitative formulation.
(Response) The interim final rule does not require a manufacturer
to submit a table reflecting the amount of various nutrients in an
infant formula formulation as part of the requirement to provide the
quantitative formulation. FDA is taking this opportunity to clarify
that the ``quantitative formulation'' required by section 412(d)(1)(A)
and (d)(3) of the FD&C Act is a list of all ingredients (including
individual ingredients and premixes of two or more ingredients) in a
product and the amount by weight of each ingredient in a set volume or
weight of the formula. For example, several ingredients in an infant
formula formulation may contain calcium. Thus, the quantitative
formulation would identify each individual ingredient (e.g., calcium
phosphate, calcium carbonate, calcium hydroxide) and the amount (by
weight or volume) of each ingredient. For mineral salts, the state of
hydration must be provided because the amount of water contained in the
salt affects the amount of mineral (e.g. calcium) provided. For
vitamins, the source of the vitamin (e.g., vitamin A palmitate or
vitamin A acetate) must be provided because the proportion of vitamin
differs with each source.
If a nutrient is added to the formulation as a part of a premix,
the form of the nutrient and the amount the nutrient must be provided
(listed) as part of the premix information.
Not all sources of nutrients may be readily apparent in
quantitative formulations, as some nutrients may be endogenous to
certain ingredients (e.g., calcium and phosphorous in condensed skim
milk). In such a case, the identity and amount of the ingredient (e.g.,
the condensed skim milk) is required to be listed in the quantitative
formulation--the amounts of endogenous nutrients (e.g., the calcium and
phosphorus contained in the condensed skim milk) would also need to be
provided, and their listing is analogous to the listing requirement for
premixes.
Although not required by the interim final rule, including a
separate table of nutrients per 100 kcal in the submission will help to
expedite FDA's review of the new infant formula submission.
FDA notes that under Sec. 106.130 of the interim final rule, a
manufacturer is required to provide in the verification submission for
a new infant formula the level of all nutrients contained in the
formula product that reflect the analysis of the product at the
finished product stage.
b. Description of a change in processing (Proposed Sec.
106.120(b)(4)).
(Comment 323) One comment objected to the requirement of proposed
Sec. 106.120(b)(4) that the description of any change in processing of
the infant formula identify the specific change and include side-by-
side, detailed schematic
[[Page 8044]]
diagrams comparing the new processing to the previous processing
(including processing times and temperatures). The comment asserted
that, to date, a narrative description of the change has been
acceptable and that preparing side-by-side, detailed schematic diagrams
of current and new systems would require substantial amounts of
additional administrative support, and no deficiencies in the narrative
description have been identified.
(Response) FDA disagrees with this comment. The Agency regards the
two elements in proposed Sec. 106.120(b)(4) (narrative description of
change and side-by-side diagrams) as complementary parts that will
ensure that the Agency receives a complete picture of the proposed
processing change(s). A narrative can provide a succinct means of
describing the specific parameters of the change; however, it is not
always apparent where the change fits into the overall processing
operation, and detailed side-by-side diagrams of the current and new
processing systems provide an efficient way to present the entire
picture of the infant formula production and draw attention to the
specific change or changes. These diagrams assist the Agency in
understanding the manufacturer's processing methods, the
interrelationship of various parts of the manufacturing process, and
the sequence of production events for an infant formula. At least some
infant formula manufacturers understand the value of these comparative
diagrams because they are routinely included in their infant formula
submissions to complement the narrative description of a processing
change. Because manufacturers must update their schematic processing
diagrams as part of their CGMP procedures, it seems unlikely that
requiring comparative diagrams in new infant formula submissions will
be an undue burden. For these reasons, FDA is not persuaded to revise
proposed Sec. 106.120(b)(4) in response to these comments. Section
106.120(b)(4) is included in this interim final rule as proposed, with
the exception of minor editorial changes.
c. Assurance for quality factors (Proposed Sec. 106.120(b)(5)).
In 1996, FDA proposed to implement section 412(d)(1)(C) of the FD&C
Act through proposed Sec. 106.120(b)(5). Proposed Sec. 106.120(b)(5)
would have required a new infant formula submission to include
assurances that the infant formula would not be marketed unless the
formula met the quality factor requirements of section 412(b)(1) of the
FD&C Act and the nutrient content requirements of section 412(i) of the
FD&C Act. Proposed Sec. 106.120(b)(5)(i) provided that the assurances
relating to quality factor requirements would be satisfied by a
submission complying with proposed Sec. 106.121, and proposed Sec.
106.120(b)(5)(ii) provided that assurances relating to nutrient content
would be satisfied by a statement that the formula would not be
marketed unless it met the nutrient requirements of Sec. 107.100, as
demonstrated by required quality control testing.
FDA received no comments on proposed Sec. 106.120(b)(5) that are
not addressed elsewhere in the interim final rule.
d. Assurance for processing infant formulas (Proposed Sec.
106.120(b)(6)).
The 1996 proposal (proposed Sec. 106.120(b)(6)) would have
required that the new infant formula submission include assurance that
the processing of the infant formula complies with section 412(b)(2) of
the FD&C Act. Proposed Sec. 106.120(b)(6)(ii) would have required that
the submission include the basis on which each ingredient meets the
requirements of Sec. 106.40(a) and that any claim that an ingredient
is GRAS be supported by citation to the Agency's regulations or by an
explanation of the basis for the general recognition of safety of the
ingredient in infant formula. The proposed rule would have required
that such explanation include a list of published studies and a copy of
those publications that provide the basis for the general recognition
of safety for the use of the ingredient in infant formula.
FDA received several comments on proposed Sec. 106.120(b)(6)(ii)
and responds to those comments directly below.
(Comment 324) One comment requested that FDA delete proposed Sec.
106.120(b)(6)(ii), challenging FDA's legal interpretation that this
information could be required as a part of the new infant formula
submission. The comment asserted that in promulgating the Infant
Formula Act, Congress intended that the law be used to ensure that the
manufacturer produce formulas that meet the Infant Formula Act nutrient
composition requirements and that are not contaminated with substances
or organisms that might adulterate the product.
(Response) FDA disagrees with this comment. The authority for the
requirement in proposed Sec. 106.120(b)(6)(ii) is derived from section
412(d)(1)(D) of the FD&C Act. The submission requirement under section
412(d)(1)(D) of the FD&C Act requires infant formula manufacturers to
provide assurances that the formula complies with section 412(b)(2) of
the FD&C Act. The FD&C Act is silent as to the specific assurances that
must be made to demonstrate that the formula is processed in accordance
with section 412(b)(2) of the FD&C Act. Because the FD&C Act is silent,
the Agency may issue a regulation to fill any gaps in the statutory
requirement to provide assurances that an infant formula is processed
in accordance with section 412(b)(2) of the FD&C Act so long as the
regulation is not ``arbitrary, capricious, or manifestly contrary to
statute.'' See Chevron, 467 U.S. at 844.
Section 412(b)(2) of the FD&C Act requires FDA to issue regulations
to establish good manufacturing practices and quality control
procedures that the Secretary (and by delegation, FDA) determines are
necessary to assure that the formula provides nutrients in accordance
with section 412(i) of the FD&C Act and is manufactured in a manner
designed to prevent adulteration of the formula.
Compliance with proposed Sec. 106.120(b)(6)(ii) will provide
assurance that an infant formula is manufactured in a manner designed
to prevent adulteration. As noted previously in this document, under
the CGMP requirement in Sec. 106.40(a) of the interim final rule, the
only substances that may be used in infant formula are those that are
GRAS for such use, are used in accordance with a food additive
regulation, or are authorized by a prior sanction. The failure to use a
lawful ingredient in the manufacture of an infant formula would
adulterate such formula. To provide adequate assurance that this CGMP
requirement has been met, FDA is including a requirement that a new
infant formula submission include the basis on which each ingredient
satisfies the requirements of Sec. 106.40(a) of the interim final
rule.
Infant formula manufacturers may add ingredients to infant formula
that are not ``nutrients'' as defined in this interim final rule. In
fact, many infant formulas on the market today contain ingredients that
are not required by section 412(i) of the FD&C Act, such as DHA, ARA,
and microorganisms referred to as ``probiotics.'' In circumstances in
which the manufacturer has determined that an ingredient is GRAS for
use in infant formula, there is no requirement under the FD&C Act that
FDA review such ingredient prior to its use in infant formula and
before the formula is marketed for use by infants. For certain
ingredients (e.g., oligosaccharides, oils containing long chain
polyunsaturated fatty acids, or intentionally added microorganisms),
identification of the
[[Page 8045]]
ingredient and the supplier is necessary in order for FDA to determine
whether the manufacturer is using the ingredient that has gone through
the food additive petition or GRAS notification process.
FDA considers the provision in proposed Sec. 106.120(b)(6)(ii) to
be important in ensuring public health protection to this particularly
vulnerable population. The submission of the information required under
Sec. 106.120(b)(6)(ii) of the interim final rule will provide FDA with
the information it needs to ensure that a manufacturer has considered
the basis for why each ingredient used in its infant formula is lawful
prior to using an ingredient in the manufacture of infant formula. By
identifying the basis on which each ingredient is believed to lawful,
assurances are provided under section 412(d)(1)(D) of the FD&C Act that
the use of each ingredient is safe and suitable under the applicable
food safety provisions of the FD&C Act, as required by Sec. 106.40(a)
of the interim final rule. Therefore, FDA is not removing Sec.
106.120(b)(6)(ii) in response to this comment, and Sec.
106.120(b)(6)(ii) is included in this interim final rule as proposed.
(Comment 325) One comment objected to this provision arguing that
Congress did not intend to give FDA premarket approval authority over
infant formula or, in this case, over food ingredients employed in
formula. The comment further asserted that 21 CFR 170.30 does not
mandate that the information the manufacturer is relying upon be
submitted to the Agency or be formally acknowledged or listed as GRAS.
(Response) As is explained previously in this document, Congress
gave FDA the authority to establish regulations to assure that formula
is manufactured in a manner designed to prevent its adulteration, and
also gave FDA the authority to require that manufacturers provide
assurance that the formula is manufactured in such a manner. To the
extent that the comment asserts that proposed Sec. 106.120(b)(6)(ii)
establishes premarket approval authority for infant formula or its
ingredients, FDA disagrees. Proposed Sec. 106.120(b)(6)(ii) would
simply require that the manufacturer provide the basis for why each
ingredient it uses in its infant formula is safe under the FD&C Act.
The review of ingredient safety under section 409 of the FD&C Act is
separate and distinct from the responsibility for a manufacturer, as
part of CGMP, to ensure that the formula satisfies the requirements
designed to prevent the use of an unlawful ingredient in infant
formula. Therefore, FDA is making no changes to Sec. 106.120(b)(6)(ii)
in the interim final rule in response to this comment.
(Comment 326) One comment stated that in many or most cases,
manufacturers will, in the interest of reducing regulatory
uncertainties, find it in their own self-interest to submit such
information required under proposed Sec. 106.120(b)(6)(ii); however,
such submissions should remain voluntary. Therefore, the comment
concluded, the manufacturer should be able to market the infant formula
without submitting this information, because it is the manufacturer's
responsibility to ensure the safety and suitability of its individual
infant formula products.
(Response) As discussed previously in this document, FDA disagrees
that proposed Sec. 106.120(b)(6)(ii) should be removed from the
interim final rule, and thus, does not believe that the provisions in
proposed Sec. 106.120(b)(6)(ii) should be voluntary. Additionally, FDA
notes that ensuring that the ingredients used to produce an infant
formula are lawful under the separate applicable statutory and
regulatory requirements of the FD&C Act is still the responsibility of
the infant formula manufacturer. Nothing in this interim final rule
relieves a manufacturer of its obligations to evaluate the safety of
the ingredients in its infant formula products and to comply with other
substantive provisions of the FD&C Act relating to the safety of
ingredients in infant formula.
(Comment 327) Several comments requested that proposed Sec.
106.120(b)(6)(ii) be revised to apply only to ``newly added''
ingredients and not to ingredients already found in infant formula. The
comments asserted that absent this change, information in infant
formula submissions would be redundant and that this information is
unnecessary for ingredients previously used and submitted by a
manufacturer.
(Response) FDA disagrees with this comment. Only substances that
are GRAS for use in infant formula, used in accordance with a food
additive regulation, or authorized by a prior sanction may be used in
infant formula. FDA notes that it may be appropriate in certain
situations for a formula manufacturer to reference a previous
submission in order to provide the basis that an ingredient in the
formula satisfies Sec. 106.40(a) of the interim final rule.
3. Products for Export Only (Proposed Sec. 106.120(c))
Proposed Sec. 106.120(c) would have required that for products
intended for export only, a new infant formula submission include, in
lieu of the information required under proposed Sec. 106.120(b), a
statement that the infant formula complies with section 801(e) of the
FD&C Act (i.e., that the formula meets the specifications of the
foreign purchaser, does not conflict with the laws of the country to
which it is intended for export, is labeled on the outside of the
shipping package to indicate that it is intended for export only, and
will not be sold or offered for sale in domestic commerce).
(Comment 328) One comment objected to proposed Sec. 106.120(c)
asserting that is it redundant with section 801(e) of the FD&C Act.
(Response) FDA disagrees that proposed Sec. 106.120(c) is
redundant with section 801(e) of the FD&C Act. Proposed Sec.
106.120(c) would permit a manufacturer of new infant formula for export
only to submit, in lieu of the information required under Sec.
106.120(b), a statement that the infant formula meets the
specifications of the foreign purchaser, does not conflict with the
laws of the country to which it is intended for export, is labeled on
the outside of the shipping package to indicate that it is intended for
export only, and will not be sold or offered for sale in domestic
commerce. A manufacturer of a new infant formula, including a new
infant formula for export only, is required by section 412(c)(1)(B) of
the FD&C Act to make a submission to FDA 90 days prior to going to
market. The failure to provide the notice required by section 412(c) of
the FD&C Act (which includes a submission to FDA required by section
412(d) of the FD&C Act) is a prohibited act under section 301(s) of the
FD&C Act (21 U.S.C. 321(s)). Section 412(d)(1) of the FD&C Act requires
all persons who introduce a new infant formula, or deliver such formula
for introduction into interstate commerce, to make a submission. Such
persons include those who manufacture a new infant formula for export
only; although such formula is exported, the formula is still
introduced or delivered for introduction into ``interstate commerce,''
as such term is defined in section 201(b) of the FD&C Act (21 U.S.C.
321(b)). There is no exception for an infant formula for export only in
either section 412 or section 801 of the FD&C Act to the submission
requirements of section 412 of the FD&C Act. Thus, a manufacturer that
produces an infant formula for export only is required to make a
submission under section 412(c) of the FD&C Act. Consequently, FDA is
not removing from the interim final rule the
[[Page 8046]]
submission requirement for these formulas.
However, FDA is revising Sec. 106.120(c) in the interim final rule
to clarify the assurances that must be provided under section 412(d) of
the FD&C Act for a new infant formula for export only.
Proposed Sec. 106.120(c) would allow a manufacturer of a new
infant formula for export only to make a submission to FDA that
includes a statement that the formula meets the specifications of the
foreign purchaser, does not conflict with the laws of the foreign
country to which it is intended for export, is labeled on the outside
of the package that it is intended for export only, and that it will
not be sold in domestic commerce.
A product intended for export shall not be deemed to be adulterated
or misbranded under the provisions of the FD&C Act if such product
satisfies the criteria in section 801(e) of the FD&C Act. Thus, an
infant formula for export only would not need to show that its formula
meets those requirements of section 412 of the FD&C Act that, if not
met, would cause the product to be adulterated, provided that the
manufacturer shows that the formula meets the requirements in section
801(e) of the FD&C Act. This fact means that the submission of a
manufacturer of a new infant formula intended for export could differ
from the submission of a manufacturer of a new infant formula that is
to be sold in domestic commerce, specifically with respect to the
requirements of section 412(d)(1)(C) of the FD&C Act (quality factor
and nutrient requirements) and section 412(d)(1)(D) of the FD&C Act
(CGMP and quality control requirements), both of which establish
conditions under which a formula would be adulterated under section
412(a) of the FD&C Act. In lieu of providing assurances that the
processing of the formula complies with applicable quality factor,
nutrient, and CGMP requirements under section 412(d)(1)(C) and
(d)(1)(D) of the FD&C Act, a manufacturer of an infant formula for
export only would notify FDA in its submission that its formula
satisfies the criteria in section 801(e) of the FD&C Act.
Importantly, however, the submission requirements in sections
412(d)(1)(A) and (d)(1)(B) of the FD&C Act do not relate to
adulteration: Section 412(d)(1)(A) of the FD&C Act requires a
submission that includes the quantitative formulation of the formula
and section 412(d)(1)(B) of the FD&C Act requires a description of any
reformulation or change in the processing of the formula. The proposed
rule would not have required a manufacturer of a new infant formula for
export only to submit the quantitative formulation of the new infant
formula or a description of any reformulation or change in the
processing of the formula.
Because proposed Sec. 106.120(c) would allow a manufacturer of a
new infant formula for export only to make an alternate submission to
fulfill all of the submission requirements, including the requirements
not specifically related to adulteration of the infant formula, FDA is
revising Sec. 106.120(c) to permit a manufacturer of a new infant
formula for export only to make an alternative submission to satisfy
only those requirements of section 412(d)(1) of the FD&C Act that are
related to adulteration. Thus, under the interim final rule, a
manufacturer of a new infant formula for export only is required, as it
would be for an infant formula for domestic commerce, to submit the
quantitative formulation of the formula and a description of any
reformulation or change in the processing of such formula. By providing
such information, the manufacturer of a new infant formula for export
only will be complying with the submission requirement in section
412(d)(1) of the FD&C Act in a way that is consistent with the
requirements in section 801(e) of the FD&C Act. Additionally, as
explained previously in this document, FDA is revising proposed Sec.
106.120(c) to require that, as a condition of making the alternate
submission under Sec. 106.120(c), a manufacturer of a new infant
formula for export only certify that the manufacturer has adequate
controls in place to ensure that such formula is actually exported.
(Comment 329) Several comments claimed that manufacturers of infant
formulas for export only should not be required to make the submission
under proposed Sec. 106.120(c) 90 days before marketing, asserting
that there may be situations in which 90 days advance notice could
cause hardship to a manufacturer. One comment proposed that a
manufacturer could notify FDA of its intent to export infant formula
prior to commercial distribution, arguing that this process should not
cause FDA hardship because the relative simplicity of the export
notification and the brevity of the review typically required.
(Response) As explained in response to the previous comment, every
manufacturer of a new infant formula, including a new infant formula
for export only, is required by section 412(c)(1)(B) of the FD&C Act to
make a submission to FDA 90 days prior to going to market. Thus, FDA is
making no changes to Sec. 106.120(c) in response to this comment.
(Comment 330) One comment suggested that proposed Sec. 106.120(c)
should be revised to state ``For products for export only and in
compliance with Section 801(e) of the FD&C Act, the information under
paragraph (b) of this section is not required and need not be
submitted.'' The comment asserted that FDA's proposed requirements
under proposed Sec. 106.120(c) are adequately covered under the FDA
Export Reform Enhancement Act and its implementing regulations (21 CFR
part 1).
(Response) FDA disagrees with this comment. The requirements in
this interim final rule are separate and distinct from those issued
under other authorities related to requirements in 21 CFR part 1.
Section 106.120(c) of the interim final rule specifies what must be
included in a submission required under section 412(d)(1) of the FD&C
Act for a new infant formula intended for export only. As explained
previously in this document, this submission is required for all new
infant formulas, including a new infant formula for export only. The
requirements in 21 CFR Part 1, Subpart E, do not implement section 412
of the FD&C Act. Therefore, FDA is not making the changes requested in
this comment.
4. Administrative Procedures for Handling Notifications (Proposed Sec.
106.120(d), (e), and (f))
Proposed Sec. 106.120 includes several subparts that address the
administrative aspects of new infant formula submissions. Specifically,
proposed Sec. 106.120(d) would have provided that a submission would
not constitute notice under section 412 of the FD&C Act unless the
submission complied fully with proposed Sec. 106.120(b) and was
readily understandable, and that FDA would notify the submitter of the
inadequacy of a submission. Proposed Sec. 106.120(e) would have
provided that FDA would acknowledge receipt of an adequate submission
and the date of receipt (``the filing date''), and restated the
prohibition against marketing the new infant formula until 90 days
after the filing date. Finally, proposed Sec. 106.120(f) would have
stipulated that if a manufacturer supplemented a new infant formula
submission, FDA would determine whether it was a substantive amendment,
and if so, the Agency would assign a new filing date and notify the
submitter of the new date.
(Comment 331) One comment suggested that proposed Sec. 106.120(d)
be revised to require FDA to notify the submitter within 10 working
days if the submission is not complete because it
[[Page 8047]]
does not meet the requirements of sections 412(c) and (d) of the FD&C
Act. The comment asserted that manufacturers filing a new infant
formula submission need certainty for planning purposes, that an Agency
notice of inadequacy received well into the 90-day review period can be
seriously disruptive, and that a submission should receive immediate
review for completeness.
(Response) FDA agrees that a new infant formula submission should
be checked immediately for completeness to ensure that it contains all
elements required under proposed Sec. 106.120(b). A submission lacking
any element required under proposed Sec. 106.120(b) will not be filed,
and the Agency will notify the submitter in a timely manner that the
submission is not complete. FDA would anticipate that this completeness
determination could generally be made within 10 business days. However,
given the constraints and conflicting demands on Agency resources at
various times, the Agency declines to add this time restriction to
Sec. 106.120(d).
(Comment 332) One comment suggested that FDA delete the last
sentence of proposed Sec. 106.120(e), which would have stipulated that
a manufacturer not market a new infant formula until 90 days after the
filing date, because this language is not found in the FD&C Act and is
unnecessarily restrictive. The comment noted that the 1996 proposal
stated (61 FR 36154 at 36198) that the purpose of the 90 day notice is
to provide the Agency sufficient time to examine the submission and
decide whether there is any basis for concern about the marketing of
the formula, and, the comment contended, a manufacturer should not be
prohibited from marketing a formula if, prior to the 90th day, the
Agency has made its determination that there is no concern.
(Response) FDA disagrees with this comment. Section 412(c)(1)(B) of
the FD&C Act states that no ``person shall introduce or deliver for
introduction into interstate commerce any new infant formula unless . .
. such person has at least 90 days before marketing such new infant
formula, made the submission to the Secretary required by subsection
(c)(1).'' \8\ The clear import of this provision is that a new infant
formula shall not be marketed until the passage of the 90 day period.
The statute does not require FDA to communicate with the submitter, and
the Agency, in its discretion, has chosen not to impose such an
obligation on itself because the requirement is unnecessary and would
be burdensome. In these circumstances, a manufacturer will know that
marketing of its new infant formula is lawful only with the passing of
the 90th day. FDA notes that, if the Agency's review of a new infant
formula submission uncovers deficiencies such that the new infant
formula in question would not be in compliance with the FD&C Act, the
Agency intends to notify the manufacturer of such deficiencies prior to
the 90th day. Accordingly, FDA declines to revise proposed Sec.
106.120(e) in response to this comment.
---------------------------------------------------------------------------
\8\ FDA has previously stated the view that this reference to
subsection (c)(1) is a drafting error and is understood to refer to
subsection (d)(1)). (61 FR 36154 at 36195, footnote 6).
---------------------------------------------------------------------------
(Comment 333) One comment suggested that proposed Sec. 106.120(e)
be revised to state that if a new infant formula submission is complete
and includes all information required by Sec. 106.120(b), FDA will
acknowledge its receipt and notify the submitter of the date of the
receipt. The comment expresses concern that the Agency might wish to
delay the starting date of the 90 day period when the notification is
complete but questions or disagreement remain with respect to the
content. The comment contended that the marketing of an infant formula
should not be deferred while the Agency takes issue with minor elements
of the notification and that when FDA receives a notification that
supplies information in accordance with Sec. 106.120, the 90-day clock
must begin to run.
(Response) FDA stated in the response to Comment 331 that, in the
Agency's view, there is a distinction between verifying a submission's
completeness versus determining that the information satisfies the
requirements of the law and the relevant regulations by providing the
necessary assurances and demonstrating that the new infant formula will
not be adulterated under the FD&C Act. The latter determination
requires complete and careful examination of the submitted material by
Agency personnel with the necessary expertise, such as manufacturing
specialists, statisticians, microbiologists, nutritionists, food
technologists, and medical officers. In contrast, once the Agency
determines that a new infant formula submission is complete in that it
purports to address all the requirements of Sec. 106.120(b) of the
interim final rule, FDA intends to provide the submitter with a prompt
acknowledgement letter, and the 90 day period will begin as of the date
that the Agency receives a complete submission.
In response to the foregoing comments, FDA is revising proposed
Sec. 106.120(e) to clarify the distinction between an FDA notification
that a submission is complete and a notification that the submission
does not provide the assurances required by section 412(d)(1) of the
FD&C Act and the regulations implementing those assurances.
(Comment 334) One comment suggested that, in proposed Sec.
106.120(f), instead of referring to the ``manufacturer'' providing
additional information in support of a new infant formula submission
and FDA notifying the manufacturer of the new filing date, it would be
more appropriate to refer to the ``submitter'' providing additional
information and FDA notifying the ``submitter'' of the new filing date.
(Response) FDA disagrees with the suggestion of this comment and,
for the reasons discussed below, is retaining the term ``manufacturer''
in Sec. 106.120(f) of the interim final rule. For purposes of
uniformity, the Agency is also revising Sec. Sec. 106.120(d),
106.130(c), and 106.140(c) by replacing the term ``submitter'' with
``manufacturer.''
The manufacturer of an infant formula is ultimately responsible for
ensuring that that its formula products are lawful. In the case of a
new infant formula, FDA must be provided with all the information
required in a new infant formula submission at least 90 days before the
new formula is distributed in commerce. Thus, the formula manufacturer
must ensure that such information is provided in a timely fashion to
FDA. Also, section 412(c) of the FD&C Act refers to ``person'' and
requires such person to notify FDA of all establishments at which such
person intends to manufacture the new infant formula. Thus, ``person,''
as used in section 412(c) of the FD&C Act, refers to the manufacturer
of the infant formula.
FDA recognizes that a manufacturer may contract with other entities
to execute certain aspects of formula production. However, the
manufacturer will be held responsible for the information submitted to
FDA, whether submitted by the manufacturer or another person who
submits it on behalf of the manufacturer, and FDA will notify the
manufacturer, under Sec. 106.120(f) of the interim final rule, whether
the Agency considers additional information submitted by any person on
behalf of the manufacturer in support of the submission to constitute a
substantive amendment resulting in a new filing date.
For these reasons, FDA is retaining the term ``manufacturer'' in
Sec. 106.120(f) of the interim final rule, and, for consistency
reasons, is amending Sec. Sec. 106.120(d), 106.130(c), and
[[Page 8048]]
106.140(c) in the interim final rule by replacing the term
``submitter'' with the term ``manufacturer.''
(Comment 335) One comment requested that FDA revise proposed Sec.
106.120(f) by adding a time period (5 working days) within which FDA
would acknowledge receipt of additional information provided to support
a new infant formula submission that is a substantive amendment to the
submission, asserting that FDA must be bound by some reasonable time
requirements so that manufacturers can plan appropriately.
(Response) FDA agrees that the Agency should promptly notify a
manufacturer of receipt of a supplement to a new infant formula
submission, but the Agency declines to add a 5-day time limit to
proposed Sec. 106.120(f) within which to acknowledge such receipt. FDA
would anticipate that this acknowledgement could generally be made
within 5 business days. However, given the constraints and conflicting
demands on Agency resources at various times, the Agency declines to
add this time restriction or any other specific time restriction to
Sec. 106.120(f) in the interim final rule. There is no assurance that
FDA can meet this 5-day time limit given constraints that may be placed
on Agency resources at various times.
5. Submissions for Exempt Infant Formulas (Proposed Sec. 106.120(g))
On its own initiative, FDA is adding Sec. 106.120(g) to the
interim final rule to clarify that the submission requirements for
exempt infant formulas are codified in 21 CFR 107.50. Section
106.120(g) of the interim final rule states: ``Submissions relating to
exempt infant formulas are subject to the provisions of Sec. 107.50 of
this chapter.'' The regulations in 21 CFR 107.50 pertaining to exempt
infant formula were finalized in 1985 (50 FR 48183) prior to the 1986
amendments. As explained in the 1996 proposal, the Agency will address
in a separate rulemaking the effect of the 1986 amendments on the
exempt infant formula regulations and exempt infant formulas (61 FR
36154 at 36201-36202). Until FDA publishes such rulemaking, exempt
infant formula submissions are subject to Sec. 107.50.
D. Quality Factor Submissions for Infant Formulas (Proposed Sec.
106.121)
To provide assurance that an infant formula meets the quality
factor requirements set forth in subpart E, the proposed rule described
in detail the requirements for a quality factor submission in proposed
Sec. 106.121. The Agency received comments on these proposed
requirements, and responds below. Although much of the substance of
proposed Sec. 106.121 has been retained in the interim final rule, FDA
notes that the numbering of the section has been revised.
1. General Comments
(Comment 336) One comment suggested that proposed Sec. 106.121 be
revised to clarify that the quality factor submission requirements of
proposed Sec. 106.121 only apply to ``new infant formulas'' as defined
by these regulations.
(Response) FDA agrees with this comment. Under section 412(d)(1) of
the FD&C Act, any infant formula subject to section 412(c) must make a
submission to FDA. Each ``new infant formula'' is subject to section
412(c) of the FD&C Act. As such, FDA is making revisions to Sec.
106.121 in the interim final rule to clarify that the submission
requirements only apply to a ``new infant formula.'' The Agency notes,
however, that all infant formulas, whether new or ``not new,'' are
required to satisfy the applicable quality factor requirements of Sec.
106.96 of the interim final rule.
(Comment 337) One comment recommended that Sec. 106.121(a) be
retained as proposed and that the remaining paragraphs in Sec. 106.121
applying to the quality factor of normal physical growth (proposed
Sec. 106.121(b), (c), (d), and (f)) be deleted for the reasons
identified in the comments objecting to establishment of ``normal
growth'' as a quality factor. The comment's support for retention of
proposed Sec. 106.121(a), as well as its support for deletion of Sec.
106.121(d), was contingent on FDA's acceptance of the comment's
suggested changes to proposed Sec. 106.120(b)(6)(i), (ii), and (iii).
Another comment on proposed Sec. 106.121 identified various changes to
infant formula and suggested a decision-tree approach to determining
the documentation that would be required for each such change to
support nutritional adequacy. The comment concluded that FDA should
provide information about presentation of clinical growth study data in
an Agency guidance and not the final rule.
(Response) FDA disagrees with the comment that all information on
the presentation of growth monitoring study data should be incorporated
into an FDA guidance and not codified in Sec. 106.121. The data and
information required in a quality factor submission to assure normal
physical growth (proposed Sec. 106.121(b), (c), (d), and (f)) provide
the basic factual information that is needed for the Agency's review of
the growth monitoring study. Because these items are necessary to an
adequate review of the study, they should not, and cannot, be described
as optional elements of a submission. Therefore, FDA declines to delete
proposed Sec. 106.121(b), (c), (d), and (f), and these requirements
are, with minor editorial changes, incorporated into the interim final
rule recodified as Sec. 106.121(a)(2), (a)(3), (a)(4), and (h)
respectively. Proposed Sec. 106.121(a) is recodified as Sec.
106.121(a)(1) in the interim final rule, with minor editorial changes.
Additional comments were submitted for proposed Sec. 106.121(b),
(c), and (f) and are addressed below.
2. Submission of Growth Data (Proposed Sec. 106.121(b))
Proposed Sec. 106.121(b) would have required that a quality factor
submission include certain data from the growth monitoring study. FDA
received several comments that addressed the types of data that should
be submitted to comply with proposed Sec. 106.121(b).
(Comment 338) One comment objected to submitting data for
individual subjects or a subgroup of individuals from a formula feeding
group. This comment expressed concern that, because few infants will be
at the lower or upper end of a particular growth parameter in a normal
distribution, the characteristics of these individuals could
erroneously be considered representative of a significant subgroup of
the sample. The comment requested that FDA clarify that group
statistics will provide the primary basis for the manufacturer's
finding that normal physical growth has been attained and that the
growth data for individual study infants will be considered as
supportive data and only to demonstrate that there was no significant
subgroup of the study group that experienced adverse effects.
(Response) FDA declines to implement the suggestion of this
comment. Although the Agency intends to rely primarily on the group
data of a growth monitoring study to demonstrate the safety, including
the nutritional adequacy, of an infant formula, it has been the
Agency's experience that the review of summary data may raise issues
the resolution of which requires the consideration of individual or
subgroup data. For example, by examining detailed data, FDA has been
able to determine that there were no subgroups of the test population
for whom the formula had adverse effects. Thus, providing individual
subject data will facilitate FDA's review of the submission because the
Agency will be able to review individual data promptly and resolve
particular questions without
[[Page 8049]]
an intervening request to the manufacturer for additional data and
information. This efficiency is especially important given the limited
time (90 days) provided by the statute for the Agency's review of a new
infant formula submission. Accordingly, FDA is not persuaded to revise
the requirement of proposed Sec. 106.121(b), and this provision is
codified with minor editorial changes in the interim final rule as
Sec. 106.121(a)(2).
(Comment 339) One comment suggested that growth data be presented
as plotted growth curves of the group means and that the Agency not
require individual case report forms and data. The comment pointed out
that including data on individual infants would add to the length of
the submission and to the length of the FDA's review without providing
a meaningful benefit to the public.
(Response) FDA disagrees with this comment. As noted previously in
this document, the prompt availability of individual study results will
support the efficiency of FDA's review of the growth study and the
prompt resolution of issues identified by the Agency's review of the
group study results. Growth curves reflecting group means only may be
submitted but their submission is not an acceptable alternative for
submission of individual data. Importantly, FDA notes that in terms of
the form of individual study results, original records are not required
but may be submitted. In addition to the requirement to submit data
plotted on the 2009 CDC growth charts, manufacturers may submit such
information in any easily understandable format, which includes
spreadsheets, data tables, copies of investigators' original clinical
study records, or case report forms with original data (for example,
individual anthropometric data sheets). A submission form that contains
the individual subject data in an accessible format will satisfy FDA's
need for comprehensive information.
(Comment 340) One comment requested that the preamble acknowledge
that the ``records'' contemplated by proposed Sec. 106.121(b) need not
be the investigator's original records, but could be records that
contain the necessary information drawn from the investigator's
original records.
(Response) As noted in the response to the preceding comment, to
comply with Sec. 106.121(a)(2) of the interim final rule, a
manufacturer may submit the required information in any easily
interpretable format. Original records are not required to, but may, be
submitted to comply with Sec. 106.121(a)(2) of the interim final rule.
(Comment 341) One comment on proposed Sec. 106.121(b) disagreed
with the requirement to submit the records that contain the information
required by proposed Sec. 106.97(a)(1)(ii).
(Response) As discussed previously in this document in section
VIII.C, FDA is not finalizing the Agency's proposed recommendations for
a clinical study protocol in the interim final rule. However, not
issuing proposed Sec. 106.97(a)(1)(ii) in the interim final rule does
not change FDA's need to review the data and information that were
covered by proposed Sec. 106.121(b) to provide assurance that a new
infant formula meets the quality factor requirement of normal physical
growth. Thus, Sec. 106.96(b) of the interim final rule identifies the
data and other information that must be collected during a growth
monitoring study. FDA's reasons for retaining these substantive
requirements are discussed previously in this document in section
VIII.C. Accordingly, the Agency is not revising proposed Sec.
106.121(b) in response to this comment; the provision is recodified as
Sec. 106.121(a)(2) in the interim final rule with minor editorial
changes.
3. Statistical Power Calculations (Proposed Sec. 106.121(c)(2))
Proposed Sec. 106.121(c)(2) would have required the quality factor
submission to include the calculation of the statistical power of a
study at its completion. FDA received several comments on this proposed
requirement.
(Comment 342) One comment noted that a calculation of a study's
statistical power is needed before a study is initiated and it is
reasonable to expect from a study report that there was an a priori
calculation of the study's power, the number of subjects to be
recruited, and the number of subjects who actually completed the study.
The comment asserted that a calculation of a study's power at its
completion, as would have been required by proposed Sec.
106.121(c)(2), is unnecessary and of unproven value and could be a
confounding and burdensome calculation. Accordingly, the comment
recommended that FDA not require inclusion of such a calculation in a
quality factor submission.
(Response) FDA agrees with this comment to the extent that it
asserts that the statistical power of a study should be calculated
prior to study initiation to determine the number of subjects needed to
answer the clinical question. It is both reasonable and reflects a
sound scientific approach for a manufacturer to perform a prospective
power calculation and include that calculation in a quality factor
submission relating to the growth monitoring study. A prospective power
calculation may be used to determine whether the study, as designed,
will have sufficient statistical power to answer the question of
whether a formula has the ability to satisfy the quality factor of
normal physical growth. Thus, the interim final rule requires a
manufacturer to calculate the statistical power of a growth monitoring
study prior to its initiation and to submit that calculation to FDA in
a new infant formula submission.
The proposed rule would have required the calculation of the
statistical power of the growth monitoring study at its completion and
the inclusion of the calculation in the quality factor submission. A
prospective calculation of study power and sample size is based on
predicted variance and expected dropout rates whereas a power
calculation conducted at the end of a study uses actual values for the
study size and drop-out rates. As explained in the 1996 proposal (61 FR
36154 at 36199), a study may not achieve the power predicted by the
prospective power calculation if dropout rates or measurement errors
are greater than anticipated. Thus, an end-of-study calculation can
help determine whether the failure to detect a difference between
formulas occurred because the clinical study lacked the statistical
power to detect differences if such differences existed. Failure to
detect real differences could result in an erroneous conclusion that a
formula supports normal physical growth, when in fact, it does not.
Although post hoc analyses are generally discouraged, a planned, post-
study statistical power calculation is, in FDA's view, necessary to
ensure that the study, as actually conducted, achieved the statistical
power projected by the prospective statistical power analysis.
FDA disagrees that a post-study power calculation is confounding
and burdensome. The data needed for these calculations are required to
be collected during the growth monitoring study, and the calculations
are straightforward and performed using standard statistical software
packages. For these reasons, the Agency is not deleting proposed Sec.
106.121(c)(2) in response to this comment.
Based on the foregoing comments, the interim final rule requires
that the quality factor portion of a new infant formula submission
include both a prospective and a retrospective power calculation. Thus,
proposed
[[Page 8050]]
Sec. 106.121(c)(2) is included in this interim final rule as Sec.
106.121(a)(3)(ii) and states ``Calculations of the statistical power of
the study before study initiation and at study completion.''
4. Protein Quality (Proposed Sec. 106.121(e))
Proposed Sec. 106.121(e) would have required that the quality
factor submission include the results of the PER study, consistent with
proposed Sec. 106.97(b). FDA received comments on this proposed
requirement.
(Comment 343) One comment suggested that proposed Sec. 106.121(e)
be deleted and that the results of the PER be submitted to the Agency
after the first production, and before the introduction into interstate
commerce, of the new infant formula, as part of the verification
submission required by proposed Sec. 106.130. The comment further
suggested that proposed Sec. 106.130(b) be revised to require that the
verification submission include an assurance that the bioassay for
protein biological quality has commenced, and that the PER results will
be provided to FDA within 10 working days of their receipt by the
manufacturers or responsible party as a supplement to the verification
submission.
The comment also asserted that if the use of new production
equipment triggers the 90-day premarket notification requirement, a
requirement to submit the PER testing in the 90-day premarket
submission would accelerate the need to start testing by 5 months (2
months to conduct the PER test plus three months to be able to give the
notification 90 days before marketing). This would delay the start-up
with the new equipment by 5 months or require the manufacturer to
convince FDA that the research production system was ``close enough''
to the full scale system so that the product of the former would be
viewed as representative of the latter.
(Response) FDA is not persuaded by this comment to require the
submission of PER bioassay results as part of the verification
submission under Sec. 106.130. Nor is the Agency persuaded to require
that the verification submission only require an assurance that the
bioassay for protein biological quality was commenced, and that the
results will be forwarded to FDA within 10 working days of their
receipt by the manufacturer.
Requiring the results of the PER bioassay to be submitted in a new
infant formula submission is consistent with both the relevant law and
sound science. As discussed previously in this document in section
VIII.E, FDA has established biological quality of the protein as a
quality factor for infant formula and has identified the PER bioassay
(appropriately modified) as the requirement that must be met to provide
assurance that this quality factor is satisfied. Section 412(d)(1) of
the FD&C Act requires that a new infant formula submission contain
assurances that the formula will not be marketed unless it satisfies
the quality factors established under section 412(b)(1) of the FD&C
Act. Indeed, in the 1996 proposal (61 FR 36154 at 36196), FDA
tentatively concluded that it would be appropriate to require the
assurance that the quality factors will be met by the submission of
data under proposed Sec. 106.120(b)(5)(i) and not as part of the
verification submission so that the Agency has all the information
relevant to the nutritional adequacy of the formula for a period of
time sufficient to conduct a meaningful review. Further, as discussed
previously in this document, it is appropriate that the biological
quality of a formula's protein component be established by the
manufacturer prior to initiation of a growth monitoring study to avoid
exposing infants to a test formula for which the protein quality has
not been confirmed. For these reasons, FDA concludes that it is
appropriate to require that the results of the PER assay be submitted
to the Agency as a part of the new infant formula submission made under
Sec. 106.120 of the interim final rule.
5. Certification Statement (Proposed Sec. 106.121(f))
Proposed Sec. 106.121(f) would have required that a new infant
formula submission include a statement that certifies that the
manufacturer has collected and considered all information on the
ability of an infant formula to satisfy the quality factor requirements
and that the manufacturer is unaware of other information or data that
would show that the formula did not satisfy the quality factors
requirements. FDA received one comment on this provision.
(Comment 344) One comment suggested a change to proposed Sec.
106.121(f). The comment requested that FDA change ``certifying'' to
``of assurance'' to reflect the language of section 412(d)(1)(C) and
(d)(1)(D) of the FD&C Act, which language refers to ``assurances'' and
not ``certifications.''
(Response) FDA is not persuaded by this comment. The requirement
that a manufacturer include this certification in a quality factor
submission is a means of assuring FDA that the manufacturer has
considered the totality of available information and is not aware of
any information or data that would show that the formula does not meet
quality factor requirements. Therefore, FDA declines to revise proposed
Sec. 106.121(f) in response to this comment. Accordingly, proposed
Sec. 106.121(f) is recodified as Sec. 106.121(i) and is included in
this interim final rule as proposed.
6. Satisfaction of an Exemption From Certain Quality Factor
Requirements
As discussed in section VIII.D, FDA is including exemptions from
the quality factor requirements in Sec. 106.96(b) and (f) as part of
this interim final rule (see Sec. 106.96(c) and (g) of the interim
final rule). A manufacturer may rely on an exemption, as applicable, in
a new infant formula submission to provide assurances that the formula
meets a quality factor requirement. Therefore, FDA is adding conforming
changes to Sec. 106.121 of the interim final rule to clarify the
requirements pertaining to each of these exemptions. To the extent a
manufacturer relies on an exemption in a new infant formula submission,
the applicable requirement in Sec. 106.121 of the interim final rule
would provide the Agency with the data and information in such
submission that the manufacturer relies on to demonstrate that the
formula satisfies such exemption from the quality factor requirements.
E. Verification Submissions (Proposed Sec. 106.130)
In 1996, FDA proposed to implement section 412(d)(2) of the FD&C
Act by requiring that, after the first production, but before the
introduction into interstate commerce, of a new infant formula, a
manufacturer verify in a written submission to FDA that the formula
complies with the FD&C Act and is not adulterated. The proposal would
have required that the verification submission summarize test results
and records demonstrating that the formula satisfies the requirements
of section 412(b)(1), (b)(2)(A), (b)(2)(B)(i), (b)(2)(B)(iii),
(b)(3)(A), (b)(3)(C), and (i) of the FD&C Act.
FDA received several comments on the proposed verification
requirement.
1. Scope of Verification Submission Requirement
(Comment 345) One comment requested that FDA clarify that infant
formulas for export only are not required to submit a verification
submission under proposed Sec. 106.130.
(Response) FDA agrees that clarification about how a manufacturer
of a new infant formula for export only can comply with Sec. 106.130
is needed.
[[Page 8051]]
The verification that must be submitted to FDA under section 412(d)(2)
of the FD&C Act relates to whether the formula is adulterated under
section 412(a) of the FD&C Act. As discussed previously in this
document, a manufacturer of a new infant formula for export only may
choose to comply with Sec. 106.120(c) of the interim final rule
instead of Sec. 106.120(b) of the interim final rule. If a
manufacturer complies with Sec. 106.120(c) of the interim final rule,
there would not be a need for the manufacturer of a product that is for
export only to submit a verification concerning compliance with
requirements that relate to the adulteration provisions. FDA would
consider the submission under Sec. 106.120(c) of the interim final
rule to satisfy the verification submission requirement in Sec.
106.130 of the interim final rule for such formula. Therefore, FDA has
revised Sec. 106.130(a) in the interim final rule as follows: ``A
manufacturer shall, after the first production and before the
introduction into interstate commerce of a new infant formula (except
for a new infant formula that is for export only for which a submission
is received in compliance with Sec. 106.120(c)), verify in a written
submission to FDA at the address given in Sec. 106.110(a) that the
infant formula complies with the requirements of the Federal Food,
Drug, and Cosmetic Act and is not adulterated.''
2. Identification Number (Proposed Sec. 106.130(b)(1))
(Comment 346) One comment suggested that proposed Sec.
106.130(b)(1), which would have required that the verification
submission include the identification number assigned by the Agency to
the new infant formula submission, should be qualified to state that
the verification submission must include this identification number, if
available. The comment asserted that oftentimes, the identification
number might not have been assigned or be available.
(Response) FDA does not agree with this comment. Including the FDA-
assigned identification number in the verification submission is a
simple and reasonable means to permit FDA to link a verification
submission with the corresponding new infant formula submission. As
part of its standard procedures, FDA assigns an identification number
to each new infant formula submission received and includes this number
in a letter to the manufacturer acknowledging the new infant formula
submission. An infant formula manufacturer that does not receive, in a
timely way, an Agency acknowledgement letter in response to an infant
formula submission should contact FDA during the 90-day review period.
Accordingly, FDA is not revising proposed Sec. 106.130(b)(1), and this
provision is included in this interim final rule as proposed.
3. Verified Formula Matches Notified Formula (Proposed Sec.
106.130(b)(2))
(Comment 347) One comment requested that proposed Sec.
106.130(b)(2), which would have required that the verification
submission include a statement that the infant formula to be introduced
into interstate commerce is the same as the infant formula that was the
subject of the new infant formula submission and for which the
manufacturer provided assurances in accordance with the requirements of
Sec. 106.120, should be modified to allow that if the infant formula
is not the same, the verification submission must include an
explanation of how the infant formula is different and why this
difference does not affect the quality factor requirements. In support
of this change, the comment stated that occasionally, a minor change
may be made to an infant formula between the time a 90-day submission
is made and the first production occurs and that, although these
changes are not expected to have an adverse impact on nutrient levels
or nutrient availability, the two formulations would not be ``the
same.'' Thus, the comment asserted that the verification submission
should provide a mechanism to record and explain these situations.
(Response) FDA disagrees with this comment. Section 412(d)(2) of
the FD&C Act requires that an infant formula manufacturer submit a
written verification to FDA after the first production of an infant
formula (the ``first-produced'' formula) subject to section 412(c) of
the FD&C Act and before such formula is introduced into interstate
commerce. Therefore, the FD&C Act requires that the infant formula
addressed by the verification submission be the same formula that is
the subject of the new infant formula submission (the ``notified
formula'') previously submitted under section 412(c) of the FD&C Act.
In the proposed rule (61 FR 36154 at 36200), FDA tentatively concluded
that if a manufacturer can make the statement that would have been
required by proposed Sec. 106.130(b)(2), it means that the quality
factor assurances that the manufacturer provided in the new infant
formula submission continue to be relevant and applicable to the
product and thus, no additional information would need to be included
in the verification submission to demonstrate compliance with sections
412(b)(1) and 412(b)(2)(A) of the FD&C Act. FDA concludes that the
statement in proposed Sec. 106.130(b)(2) is necessary and is in lieu
of additional test results or records demonstrating compliance of the
``first-produced'' formula with these sections of the FD&C Act. If the
``first-produced'' formula differs from the ``notified formula'' in
ways that would constitute a major change or if the ``first-produced''
formula has otherwise been changed such that previous submission on
quality factor requirements and ingredient safety is no longer
relevant, the manufacturer could not truthfully make the statement in
proposed Sec. 106.130(b)(2). Thus, a manufacturer must evaluate
whether it can make the statement in Sec. 106.130(b)(2) in light of
any changes to the formula.
For these reasons, FDA is not revising proposed Sec. 106.130(b)(2)
in response to this comment, and this provision is included in this
interim final rule as proposed.
4. Certification Statement (Proposed Sec. 106.130(b)(4))
(Comment 348) One comment suggested that proposed Sec.
106.130(b)(4) be revised to delete the proposed requirement that a
verification submission contain a certification that the manufacturer
has established current good manufacturing practices, including quality
control procedures and in-process controls such as testing, designed to
prevent adulteration of this formula in accordance with subparts B and
C of part 106, and instead, to require that the verification submission
contain assurance that the manufacturer has done so. The comment states
that the suggested use of ``assurance'' was based on the provisions of
the Infant Formula Act relating to verification that refer specifically
to ``assurance'' as opposed to certification.
(Response) FDA is not persuaded by this comment. First, although
FDA agrees that the word ``assurance'' is used in section 412 of the
FD&C Act, the comment does not describe the difference, material or
otherwise, between a suggested requirement that a manufacturer provide
``assurance'' and the proposed requirement that a manufacturer provide
a ``certification'' as to compliance with CGMP requirements. Absent
such a distinction, FDA sees no reason to change the language proposed.
The certification is the means by which a manufacturer provides the
assurance required under section 412(d) of the FD&C Act.
Second, the proposed certification requirement is reasonable. FDA
is
[[Page 8052]]
responsible for reviewing the manufacturer's submission to ensure the
infant formula complies with the FD&C Act, and the Agency must be
satisfied that a manufacturer has, in accordance with subparts B and C
of part 106, established current good manufacturing practices,
including quality control procedures, in-process controls, and testing
required by CGMP that is designed to prevent adulteration of the
formula. Section 412(d)(2) of the FD&C Act requires that after the
first production of a new infant formula and before its introduction
into interstate commerce, the formula manufacturer submit written
verification summarizing test results and records demonstrating that
the formula complies with the requirements of section 412(b)(1),
(b)(2)(A), (b)(2)(B)(i), (b)(2)(B)(iii), (b)(3)(A), (b)(3)(C), and (i)
of the FD&C Act. As the Agency tentatively concluded in the proposed
rule, and concludes in this interim final rule, additional test results
or records demonstrating compliance with section 412(b)(2)(B)(i),
(b)(3)(A), and (b)(3)(C) of the FD&C Act are unnecessary because such
testing is subsumed under Sec. 106.130(b)(3) of the interim final rule
in the summary of test results for the level of each nutrient required
by Sec. 107.100. Section 106.130(b)(3) of the interim final rule
includes the test results for the level of nutrients required by 412(i)
of the FD&C Act. Further, the Agency concludes that it would be
unnecessary to require submission of the records demonstrating
compliance with section 412(b)(1) of the FD&C Act because the records
demonstrating compliance with quality factors would have been submitted
as part of the submission under section 412(c) and (d)(1)(C) of the
FD&C Act. The certification requirement in proposed Sec. 106.130(b)(4)
is a means to satisfy the statutory provision that a manufacturer
summarize test results and records to demonstrate compliance with
sections 412(b)(2)(A) and (b)(2)(B)(iii) of the FD&C Act. Such records
would be available for inspection by FDA. This requirement will be a
strong incentive to a manufacturer to confirm that the test results and
records that demonstrate compliance with section 412(b)(2)(A) and
(b)(2)(B)(iii) of the FD&C Act are complete based on the manufacturer's
established procedures. For these reasons, FDA is not revising proposed
Sec. 106.130(b)(4) in response to this comment, and the provision is
included in this interim final rule as proposed.
5. Administrative Procedures for Handling Verification Submissions
(Proposed Sec. 106.130(c))
(Comment 349) One comment suggested modifying proposed Sec.
106.130(c), which states that a submission will not constitute written
verification under section 412(d)(2) of the FD&C Act when any data
prescribed by proposed Sec. 106.130(b) are lacking or are not set
forth so as to be readily understood and that, in such circumstances,
the Agency will notify the submitter that the verification is not
adequate. The comment suggested that this proposed provision be revised
to state that the Agency will notify the submitter within 5 working
days that the notice is not complete and asserted that without such
rapid notice, a manufacturer will not be able to market its product
with assurance that FDA found the submission acceptable. The comment
also recommended that the FDA develop a form for verifications that
will help in FDA's review of the sufficiency of these submissions.
(Response) FDA disagrees with this comment. Although the Agency
fully intends to notify a manufacturer of the inadequacy of a
verification submission as promptly as possible, it is not reasonable
for FDA to commit to a specific time frame for such notice where it is
not compelled by statute and where, in some cases, competing priorities
or diminished resources may affect the Agency's ability to respond.
Similarly, it is not necessary for the Agency to develop a form for
verification notifications because proposed Sec. 106.130 specifies the
information required in such a notification, and the Agency's review
will focus on those requirements. Development and clearance of such a
form would require Agency resources, and the comment did not
specifically identify the efficiencies or other benefits from the use
of the suggested form that would be expected to offset these
development and clearance costs. Accordingly, FDA is not revising
proposed Sec. 106.130(c) in response to this comment, and, with minor
editorial changes, the provision is included in this interim final rule
as proposed.
F. Submission Concerning a Change in Infant Formula That May Adulterate
the Product (Proposed Sec. 106.140)
In 1996, the Agency proposed submission requirements to implement
section 412(d)(3) of the FD&C Act by issuing proposed Sec. 106.140.
Proposed Sec. 106.140 would have required that when a manufacturer
makes a change in the formulation or processing of an infant formula
that may affect whether the formula is adulterated under section 412(a)
of the FD&C Act, the manufacturer shall, before the first processing of
such formula, make a submission to FDA at the address given in proposed
Sec. 106.110(a).
The Agency received several comments on proposed Sec. 106.140, and
responds below.
(Comment 350) One comment expressed concern that infant formula
manufacturers may be reluctant to make minor changes in packaging
materials because they may think that these changes would require
additional stability testing of their formulas and additional
notifications to FDA under proposed Sec. 106.140. The comment
requested that FDA clarify that an infant formula manufacturer does not
need to conduct special stability testing or make a filing with FDA, in
accordance with proposed Sec. 106.140, when a packaging change is made
that clearly will not affect potential migration of packaging
components to the formula or the integrity of the packaging.
(Response) FDA is not persuaded to make changes to the codified
based on this comment. Section 412(d)(3) of the FD&C Act provides that
a manufacturer is to make the determination as to whether a change in
the processing may affect whether the formula is adulterated. FDA
considers that a change in packaging constitutes a change in processing
for purposes of section 412(d)(3) of the FD&C Act. Therefore, if a
manufacturer determines that a packaging change may affect whether a
formula may be adulterated, a notification to FDA, in accordance with
Sec. 106.140 of the interim final rule, is required.
Stability testing is governed by Sec. 106.91(b)(2) of the interim
final rule. Under that provision, a manufacturer is responsible for
ensuring that an infant formula satisfies the nutrient requirements of
the FD&C Act throughout the shelf life of the product. When a
manufacturer makes a packaging change for a specific formula, the
manufacturer must determine whether that change requires the
manufacturer to conduct additional stability testing to ensure that the
infant formula will contain the required nutrients throughout the shelf
life of the product. Moreover, the definition of ``major change''
includes a situation where there is a fundamental change in the type of
packaging used and such a change would make the formula a ``new''
infant formula for which a submission would be required under section
412(c) of the FD&C Act.
[[Page 8053]]
Accordingly, FDA is not revising proposed Sec. 106.140 in response
to this comment, and the provision is included in this interim final
rule as proposed.
1. ``Before First Processing'' (BFP) Submissions (Proposed Sec.
106.140(a))
(Comment 351) One comment suggested that proposed Sec. 106.140(a)
be revised to state that when a manufacturer makes a change in the
formulation or processing of a formula that the manufacturer or
responsible party determines may affect whether the formula is
adulterated under section 412(a) of the FD&C Act, the manufacturer
shall, before the first processing of such formula, make a submission
to the FDA. The comment asserted that this revision would clarify what
constitutes a ``minor change'' versus a ``major change.''
(Response) Elsewhere in this preamble, FDA has declined to define
``minor change'' and reaffirms that decision now in response to this
comment. FDA notes that this comment suggests changes to proposed Sec.
106.140 that the comment believes would clarify what constitutes a
``major'' or ``minor'' change. However, the definition of ``major
change'' is addressed in section 412(c) of the FD&C Act and is defined
in Sec. 106.3 of the interim final rule. The comment does not explain
the utility or necessity of defining ``minor change,'' and such a
definition is not necessary. Also, unlike ``major change,'' for which
there are regulatory consequences (for example, filing a submission
under Sec. 106.120), there are no regulatory consequence identified in
the law or by the comment for a change that would be a ``minor
change.'' For this reason, FDA declines to define ``minor change'' in
response to this comment.
(Comment 352) Another comment stated that under current practice,
infant formula manufacturers currently evaluate all changes to
formulation or processing of their infant formulas and if the
manufacturer determines the change may affect the nutrient content of
the formulation, the manufacturer notifies FDA. The comment asserted
that this requirement will increase the number of these submissions and
require additional personnel if a manufacturer is required to notify
FDA when any of the changes listed as examples of ``notifiable
changes'' in the preamble to the proposed rule occurs.
(Response) Proposed Sec. 106.140 was designed to implement section
412(d)(3) of the FD&C Act, which requires that a manufacturer make a
submission to FDA before the first processing of a formula when the
manufacturer determines that a change in formulation or in the
processing of an infant formula may affect whether a formula is
adulterated under section 412(a) of the FD&C Act; the submission is
required by section 412(d)(3) of the FD&C Act to conform to the
requirements in section 412(d)(1) of the FD&C Act. A change that
constitutes a ``major change'' within the meaning of Sec. 106.3 of the
interim final rule is not the type of change that requires notification
under Sec. 106.140 because a ``major change'' makes a formula a ``new
infant formula'' and under section 412(c)(1) of the FD&C Act, the
manufacturer of a ``new infant formula'' must notify FDA of the change
in accordance with section 412(c)(1) of the FD&C Act and Sec. 106.120
of the interim final rule. The comment cited examples of changes that
FDA identified in the preamble to the proposed rule that could affect
whether a formula is adulterated and stated that increased submissions
and a need for additional personnel would be required, but the comment
did not explain why such examples are inconsistent with section
412(d)(3) of the FD&C Act. The examples FDA provided are of the type
that the Agency considers appropriate for submission under section
412(d)(3) of the FD&C Act and proposed Sec. 106.140(a).
Based on the foregoing, FDA is not revising proposed Sec.
106.140(a) in response to these comments, and proposed Sec. 106.140(a)
is included in this interim final rule, with minor editorial changes,
as proposed.
No comments were received requesting modification of proposed Sec.
106.140(b)(1). Thus, proposed Sec. 106.140(b)(1) is included in this
interim final rule as proposed.
2. Steps To Ensure That Formula Will Not Be Adulterated (Proposed Sec.
106.140(b)(2))
(Comment 353) One comment suggested that proposed Sec.
106.140(b)(2), which requires that the submission explain why the
change in formulation or processing may affect whether the formula is
adulterated, also would require that the submission explain the steps
that will be taken to ensure that the formula will not be introduced
into interstate commerce unless it is not adulterated. The comment
asserted that this suggested requirement will enable FDA to receive a
more complete explanation of the change.
(Response) FDA agrees with this comment. The Agency believes that
requiring a manufacturer to consider how it will resolve a question of
whether the formula is actually adulterated and to provide that
explanation to FDA will help to ensure that no adulterated formula will
enter distribution. Accordingly, FDA is revising Sec. 106.140(b)(2) in
response to this comment to require that the submission explain the
steps that will be taken to ensure that, before the formula is
introduced into interstate commerce, the formula will not be
adulterated.
3. Administrative Procedures (Proposed Sec. 106.140(c))
(Comment 354) One comment suggested that proposed Sec. 106.140(c),
which provides that the Agency will notify the submitter if a notice is
not adequate because it does not meet the requirements of section
412(d)(3) of the FD&C Act, be revised to state that FDA will promptly
acknowledge receipt and notify the submitter if the notice is not
adequate because it does not meet the requirements of section 412(d)(3)
of the FD&C Act. The comment asserted that FDA should be required to
notify manufacturers within 1 week, or some other reasonable period of
time, if a submission is not adequate and that otherwise, a
manufacturer will not be able to market its product with assurance that
FDA found the submission to be adequate.
(Response) FDA disagrees with this comment. The Agency's current
practice is to acknowledge the receipt of a new infant formula
submission. However, FDA declines to revise the interim final rule to
require such acknowledgment because future changes in Agency resources
and program priorities may make the current practice of acknowledgement
not feasible. Also, a manufacturer may make independent arrangements to
confirm FDA's receipt of its submission, such as by sending the
submission via U.S. mail with return receipt service.
Similarly, although the Agency intends to notify a manufacturer of
the inadequacy of a submission made under Sec. 106.140 of the interim
final rule as promptly as possible, it is not reasonable for FDA to
commit to a specific time frame for such notice where such timing is
not compelled by statute and where, in some cases, competing priorities
or diminished resources may affect the Agency's ability to respond.
Thus, FDA is not persuaded to revise proposed Sec. 106.140(c) in
response to this comment, and this provision is included in this
interim final rule, with minor editorial changes, as proposed.
4. Infant Formulas Intended for Export Only
(Comment 355) One comment requested clarification as to whether
[[Page 8054]]
infant formulas intended only for export must make the submission
concerning a change in infant formula that may adulterate the product.
The comment suggested that Sec. 106.140 include a paragraph (d) that
would state that the requirements of Sec. 106.140 do not apply to any
infant formula product legally exported under section 801(e) of the
FD&C Act.
(Response) The Agency is not revising Sec. 106.140 in response to
this comment. Notification under Sec. 106.140 is only necessary when
the manufacturer makes a change to the formula that affects whether the
formula may be adulterated under section 412(a) of the FD&C Act. As
explained previously in this document, an infant formula intended for
export is not deemed to be adulterated under the FD&C Act, including
under section 412(a) of the FD&C Act, if it is in compliance with
section 801(e) of the FD&C Act. FDA would not consider an infant
formula intended for export that is in compliance with Sec. 106.120(c)
of the interim final rule and section 801(e) of the FD&C Act to be
adulterated under section 412(a) of the FD&C Act. Therefore, an infant
formula for export only that is in compliance with Sec. 106.120(c) of
the interim final rule and section 801(e) of the FD&C Act would not be
required to make any notification under Sec. 106.140 of the interim
final rule.
However, the Agency advises that if a manufacturer makes a change
to its infant formula for export only that constitutes a ``major
change'' within the meaning of Sec. 106.3 of the interim final rule,
the manufacturer would be required to make a 90-day new infant formula
submission under Sec. 106.120 of the interim final rule. As stated in
earlier in this preamble, a new infant formula that is for export only
shall comply with Sec. Sec. 106.110 and 106.120 of the interim final
rule. Importantly, a manufacturer of a new infant formula for export
only may make an alternative submission under Sec. 106.120(c) of the
interim final rule for the submission requirements that relate to
whether the new infant formula is adulterated under section 412(a) of
the FD&C Act. However, if a manufacturer of a new infant formula for
export only elects to make a new infant formula submission under Sec.
106.120(b) of the interim final rule, the manufacturer would be
required to submit a verification submission under Sec. 106.130 of the
interim final rule and the submission concerning a change in infant
formula that may adulterate the product, if the formula was changed
under Sec. 106.140 of the interim final rule. When a manufacturer
makes a new infant formula submission under Sec. 106.120(b) of the
interim final rule, the Agency reviews the application using the
requirements in the FD&C Act and FDA's implementing regulations to
determine whether the formula meets these requirements and thus, is
eligible to be marketed in the United States. If a manufacturer elects
to have its formula reviewed as a formula to be marketed in the United
States, it must make all of the relevant submissions required by the
FD&C Act for such formulas.
G. Notification of an Adulterated or Misbranded Infant Formula
(Proposed Sec. 106.150)
In the 1996 proposal, FDA proposed to recodify Sec. 106.120(b) in
subpart G and to designate the recodified provision as Sec. 106.150.
The proposed recodification included several minor editorial changes to
the text of current Sec. 106.120(b).
The Agency received several comments on this proposed
recodification, and responds below.
(Comment 356) One comment suggested a modification of proposed
Sec. 106.150(a)(2), which would have required that a manufacturer
promptly notify FDA if an infant formula that the manufacturer has
processed and that has left the manufacturer's control may be
adulterated or misbranded. The comment suggested adding the following:
``In the case of 'adulteration' based on a failure to follow CGMP, the
failure must be of such a nature as to reasonably call into question
the suitability of the formula. Notification shall not be required for
minor or technical misbranding.'' In support of this suggestion, the
comment asserted that a violation of the infant formula CGMP, no matter
how minor or inconsequential, will constitute a ``technical
adulteration or misbranding'' of the product, that formula
manufacturers are of the only members of the food industry compelled to
notify FDA when a distributed product is or may be ``adulterated'' or
``misbranded,'' and thus, it is critical to weigh each proposed
regulation for the consequences of a finding of ``adulteration'' or
``misbranding'' to ensure that such regulations are appropriate. The
comment concluded that only adulteration of public health significance
and only significant or actionable misbranding should trigger
notification.
(Response) FDA disagrees that with this comment. Proposed Sec.
106.150, and its predecessor, current Sec. 106.120(b), implement
section 412(e)(1)(B) of the FD&C Act. This statutory provision requires
a formula manufacturer to notify the Secretary (and by delegation, FDA)
when the manufacturer has knowledge which reasonably supports the
conclusion that an infant formula which has been processed by the
manufacturer and which has left an establishment subject to the control
of the manufacturer may not provide the nutrients required by section
412(i) of the FD&C Act or ``may be otherwise adulterated or
misbranded.'' Section 412(e)(1) of the FD&C Act provides that the
Secretary (and by delegation, FDA), and not the manufacturer, shall
determine whether the released infant formula presents a risk to human
health. Thus, it is incumbent upon the FDA to evaluate the public
health risk that may be associated with an adulterated or misbranded
infant formula, and the modification requested in this comment would be
inconsistent with the governing statutory provision.
In addition, FDA disagrees that Sec. 106.150(a) should be modified
so that notification of adulteration based on a failure to follow CGMP
need only be made if the failure to follow CGMP reasonably calls into
question the suitability of the formula. A failure to follow CGMP
indicates that a manufacturer's process is not under appropriate
control, and thus, a manufacturer should promptly and fully address
such failure following discovery. Only if FDA is aware of the finding
of a breach of infant formula CGMP can the Agency appropriately monitor
the manufacturer and ensure that further problems do not develop.
Moreover, as noted elsewhere in this preamble, safety considerations
are of unique importance with infant formula because such formula is
intended to be the sole source of nutrition for infants during the
early period of significant development and growth. Therefore, it is
incumbent upon the Agency to evaluate the public health risks that may
be associated with an adulterated or misbranded infant formula.
FDA recognizes that some infant formula CGMP failures may not have
public health consequences. However, the Agency must be made aware of
all formulas that have left the control of the manufacturer that may be
adulterated or misbranded so that FDA can discharge its obligation
under section 412(e)(1) of the FD&C Act. Accordingly, FDA declines to
modify proposed Sec. 106.150 in response to this comment.
The Agency is, however, modifying Sec. 106.150(b) to update the
contact information for submission of a notification of an adulterated
or misbranded infant formula. Thus, Sec. 106.150(b) of the interim
final rule
[[Page 8055]]
requires, in part, that the manufacturer ``shall promptly send written
confirmation of the notification to the Food and Drug Administration,
Center for Food Safety and Applied Nutrition, Office of Compliance,
Division of Enforcement (HFS-605), Recall Coordinator, 5100 Paint
Branch Parkway, College Park, MD 20740, and to the appropriate FDA
district office.''
H. Incorporation by Reference
Certain material is incorporated by reference in the interim final
rule with the approval of the Director of the Federal Register. For
purposes of clarity and ease of reference, FDA has gathered in a single
place in the interim final rule (Sec. 106.160) a list of the material
that is incorporated by reference and information about how these
materials may be obtained from their source.
XI. Conforming Amendments to Part 107
In 1996, FDA proposed revisions to the regulations in part 107 to
reflect the changes made by the 1986 amendments and the regulations
that FDA was proposing to adopt in part 106. The Agency also proposed
certain editorial changes. FDA received no comments on the proposed
revisions to part 107.
As explained elsewhere in this preamble, the interim final rule
revises certain proposed provisions in part 106, which revisions were
made in response to comments or for other reasons. Also, due to the
passage of time, additional technical changes to part 107 are necessary
to update Agency addresses and telephone numbers. Accordingly, as
included in this interim final rule, part 107 reflects the revisions
proposed in 1996 modified by additional technical changes and changes
required for consistency with the provisions of part 106.
XII. Environmental Impact
The Agency has determined under 21 CFR 25.30(j) and 25.32(n) that
this action is of a type that does not individually or cumulatively
have a significant effect on the human environment. Therefore, neither
an environmental assessment nor an environmental impact statement is
required.
XIII. Federalism
FDA has analyzed this interim final rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the rule does not contain policies that have substantial direct effects
on the States, on the relationship between the National Government and
the States, or on the distribution of power and responsibilities among
the various levels of government. Accordingly, the Agency concludes
that the rule does not contain policies that have federalism
implications as defined in the Executive order and, consequently, a
federalism summary impact statement is not required.
XIV. Regulatory Impact Analysis for Interim Final Rule
FDA has examined the impacts of this interim final rule under
Executive Order 12866, Executive Order 13563, the Regulatory
Flexibility Act (5 U.S.C. 601-612), and the Unfunded Mandates Reform
Act of 1995 (Pub. L. 104-4). Executive Orders 12866 and 13563 direct
Agencies to assess all costs and benefits of available regulatory
alternatives and, when regulation is necessary, to select regulatory
approaches that maximize net benefits (including potential economic,
environmental, public health and safety, and other advantages;
distributive impacts; and equity). We have developed a detailed
Regulatory Impact Analysis (RIA) that presents the benefits and costs
of this interim final rule (Ref. 92) which is available at http://www.regulations.gov (enter Docket No. FDA-1995-N-0036). The full
economic impact analyses of FDA regulations are no longer (as of April
2012) published in the Federal Register but are submitted to the docket
and are available at http://www.regulations.gov. We believe that the
interim final rule is not a significant regulatory action as defined by
Executive Order 12866.
The Regulatory Flexibility Act requires Agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. According to our analysis, we believe that the
interim final rule will not have a significant economic impact on a
substantial number of small entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that Agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $141 million, using the most current (2012) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
interim final rule to result in any 1-year expenditure that would meet
or exceed this amount.
The analyses that we have performed to examine the impacts of this
interim final rule under Executive Order 12866, Executive Order 13563,
the Regulatory Flexibility Act, and the Unfunded Mandates Reform Act of
1995 are included in the RIA (Ref. 92).
We included a Summary of the Economic Analysis of the Proposed Rule
in the RIA (Ref. 92. We received comments on our analysis of the
impacts presented in those sections, and the RIA (Ref. 92) contains our
responses to those comments.
XV. Paperwork Reduction Act of 1995
This interim final rule contains information collection
requirements that are subject to review by the Office of Management and
Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-
3520) (the PRA). A description of these provisions with estimates of
the annual reporting, recordkeeping, and third-party disclosure burden
are included in the RIA in section IV, entitled ``Paperwork Reduction
Act of 1995'' (Ref. 92). An agency may not conduct or sponsor, and a
person is not required to respond to, a collection of information
unless it displays a currently valid OMB control number.
In the July 9, 1996, proposed rule, FDA included an analysis of the
information collection provisions of the proposal under the PRA and
requested comments on four questions relevant to that analysis (61 FR
at 36205-36206). Subsequently, in 2003, the Agency reopened the comment
period to update comments and to receive any new information on all
issues, including on the PRA analysis (68 FR 22341). In response to
these requests, FDA received no comments specifically referring to the
Agency's 1996 PRA analysis or otherwise referring to the PRA. FDA did
receive comments on the substantive provisions of the proposed rule,
including comments on the proposed recordkeeping and other provisions
of the proposal that would result in information collections. FDA has
summarized and responded to these comments in the RIA (Ref. 92).
As noted, the 1996 proposal included a PRA analysis. FDA is re-
estimating the burden of this interim final rule using current burden
analysis methodology. The Agency invites comments on new issues
relating to the following topics: (1) Whether the proposed collection
of information is necessary for the proper performance of FDA's
functions, including whether the information will have practical
utility; (2) the accuracy of
[[Page 8056]]
FDA's estimate of the burden of the proposed collection of information,
including the validity of the methodology and assumptions used; (3)
ways to enhance the quality, utility, and clarity of the information to
be collected; and (4) ways to minimize the burden of the collection of
information on respondents, including through the use of automated
collection techniques, when appropriate, and other forms of information
technology.
In compliance with the PRA, FDA has submitted the information
collection provisions of this interim final rule to OMB for review.
Prior to the effective date of this interim final rule, FDA will
publish a notice in the Federal Register announcing OMB's decision to
approve, modify, or disapprove the information collection provisions in
this interim final rule. An Agency may not conduct or sponsor, and a
person is not required to respond to, a collection of information
unless it displays a currently valid OMB control number.
XVI. Comments
The requirements in this interim final rule will be in effect on
July 10, 2014. FDA invites the public to comment on this interim final
rule. Comments submitted in response to this interim final rule should
be limited to those that present new issues or new information.
Comments previously submitted to the Division of Dockets Management
have been considered and addressed in this interim final rule and
should not be resubmitted.
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) either electronic or written comments regarding this
interim final rule. It is only necessary to send one set of comments.
Identify comments with the docket number found in brackets in the
heading of this document. Received comments may be seen in the Division
of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.
XVII. References
The following references have been placed on display in the
Division of Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville,
MD 20852, and may be seen by interested persons between 9 a.m. and 4
p.m., Monday through Friday. We have verified all the Web site
addresses in the References section, but we are not responsible for any
subsequent changes to the Web sites after this document publishes in
the Federal Register.
1. Iverson, C., N. Mullane, B. McCardell, et al. ``Cronobacter gen.
nov., a new genus to accommodate the biogroups of Enterobacter
sakazakii, and proposal of Cronobacter sakazakii gen. nov., comb.
nov., Cronobacter malonaticus sp. nov., Cronobacter turicensis sp.
nov., Cronobacter muytjensii sp. nov., Cronobacter dublinensis sp.
nov., Cronobacter genomospecies 1, and of three subspecies,
Cronobacter dublinensis subsp. dublinensis subsp. nov., Cronobacter
dublinensis subsp. lausannensis subsp. nov. and Cronobacter
dublinensis subsp. lactaridi subsp. nov.'' International Journal of
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List of Subjects
21 CFR Part 106
Food grades and standards, Infants and children, Incorporation by
reference, Nutrition, Reporting and recordkeeping requirements.
21 CFR Part 107
Food labeling, Infants and children, Nutrition, Reporting and
recordkeeping, Signs and symbols.
[[Page 8059]]
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts
106 and 107 are amended as follows:
0
1. Revise part 106 to read as follows:
PART 106--INFANT FORMULA REQUIREMENTS PERTAINING TO CURRENT GOOD
MANUFACTURING PRACTICE, QUALITY CONTROL PROCEDURES, QUALITY
FACTORS, RECORDS AND REPORTS, AND NOTIFICATIONS
Subpart A--General Provisions
Sec.
106.1 Status and applicability of the regulations in part 106.
106.3 Definitions.
Subpart B--Current Good Manufacturing Practice
106.5 Current good manufacturing practice.
106.6 Production and in-process control system.
106.10 Controls to prevent adulteration by workers.
106.20 Controls to prevent adulteration caused by facilities.
106.30 Controls to prevent adulteration caused by equipment or
utensils.
106.35 Controls to prevent adulteration due to automatic (mechanical
or electronic) equipment.
106.40 Controls to prevent adulteration caused by ingredients,
containers, and closures.
106.50 Controls to prevent adulteration during manufacturing.
106.55 Controls to prevent adulteration from microorganisms.
106.60 Controls to prevent adulteration during packaging and
labeling of infant formula.
106.70 Controls on the release of finished infant formula.
106.80 Traceability.
106.90 Audits of current good manufacturing practice.
Subpart C--Quality Control Procedures
106.91 General quality control.
106.92 Audits of quality control procedures.
Subpart D--Conduct of Audits
106.94 Audit plans and procedures.
Subpart E--Quality Factors for Infant Formulas
106.96 Requirements for quality factors for infant formulas.
Subpart F--Records and Reports
106.100 Records.
Subpart G--Registration, Submission, and Notification Requirements
106.110 New infant formula registration.
106.120 New infant formula submission.
106.121 Quality factor assurances for infant formulas.
106.130 Verification submission.
106.140 Submission concerning a change in infant formula that may
adulterate the product.
106.150 Notification of an adulterated or misbranded infant formula.
106.160 Incorporation by reference.
Authority: 21 U.S.C. 321, 342, 350a, 371.
Subpart A--General Provisions
Sec. 106.1 Status and applicability of the regulations in part 106.
(a) The criteria set forth in subparts B, C, and D of this part
prescribe the steps that manufacturers shall take under section
412(b)(2) and (b)(3) of the Federal Food, Drug, and Cosmetic Act (21
U.S.C. 350a(b)(2) and (b)(3)) in processing infant formula. If the
processing of the formula does not comply with any regulation in
subparts B, C, or D of this part, the formula will be deemed to be
adulterated under section 412(a)(3) of the Federal Food, Drug, and
Cosmetic Act.
(b) The criteria set forth in subpart E of this part prescribe the
requirements for quality factors that infant formula shall meet under
section 412(b)(1) of the Federal Food, Drug, and Cosmetic Act. If the
formula fails to comply with any regulation in subpart E of this part,
it will be deemed to be adulterated under section 412(a)(2) of the
Federal Food, Drug, and Cosmetic Act.
(c) The criteria set forth in subpart F of this part prescribe
records requirements for quality factors under section 412(b)(1) of the
Federal Food, Drug, and Cosmetic Act and for good manufacturing
practices and quality control procedures, including distribution and
audit records, under section 412(b)(2). If an infant formula
manufacturer fails to comply with the quality factor record
requirements in subpart F of this part with respect to an infant
formula, the formula will be deemed to be adulterated under section
412(a)(2) of the Federal Food, Drug, and Cosmetic Act. If an infant
formula manufacturer fails to comply with the good manufacturing
practices or quality control procedures record requirements in subpart
F of this part with respect to an infant formula, the infant formula
will be deemed to be adulterated under section 412(a)(3) of the Federal
Food, Drug, and Cosmetic Act. The criteria set forth in subpart F of
this part also implement record retention requirements under section
412(b)(4) of the Federal Food, Drug, and Cosmetic Act. Failure to
comply with any regulation in subpart F of this part is a violation of
section 301(e) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
331(e)).
(d) The criteria set forth in subpart G of this part describe, in
part, certain good manufacturing practices, quality control procedures,
and quality factor records requirements under section 412(b)(1) and
(b)(2) of the Federal Food, Drug and Cosmetic Act. If an infant formula
manufacturer fails to comply with such records requirements with
respect to an infant formula, the infant formula will be deemed to be
adulterated under section 412(a)(2) or (a)(3) of the Federal Food,
Drug, and Cosmetic Act, as applicable. The criteria set forth in
subpart G of this part also describe the circumstances in which an
infant formula manufacturer is required to register with, submit to, or
notify the Food and Drug Administration, and the content of a
registration, submission, or notification, under section 412(c), (d),
and (e) of the Federal Food, Drug, and Cosmetic Act. Failure to comply
with any regulation in subpart G of this part is a violation of section
301(s) of the Federal Food, Drug, and Cosmetic Act.
Sec. 106.3 Definitions.
The definitions in this section and the definitions contained in
section 201 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321)
shall apply to infant formula requirements in 21 CFR parts 106 and 107
of this chapter.
Eligible infant formula means an infant formula that could have
been or was lawfully distributed in the United States on May 12, 2014.
Final product stage means the point in the manufacturing process,
before distribution of an infant formula, at which the infant formula
is homogeneous and is not subject to further degradation due to
processing.
Indicator nutrient means a nutrient whose concentration is measured
during the manufacture of an infant formula to confirm complete
addition and uniform distribution of a premix or other substance of
which the indicator nutrient is a part.
Infant means a person not more than 12 months of age.
Infant formula means a food which purports to be or is represented
for special dietary use solely as a food for infants by reason of its
simulation of human milk or its suitability as a complete or partial
substitute for human milk.
In-process production aggregate means a combination of ingredients
at any point in the manufacturing process before packaging.
Major change in an infant formula means 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 of nutrients, or any
[[Page 8060]]
change that causes an infant formula to differ fundamentally in
processing or in composition from any previous formulation produced by
the manufacturer. Examples of infant formulas deemed to differ
fundamentally in processing or in composition include:
(1) Any infant formula produced by a manufacturer who is entering
the U.S. market;
(2) Any infant formula powder processed and distributed by a
manufacturer who previously only produced liquids (or vice versa);
(3) Any infant formula having a significant revision, addition, or
substitution of a macronutrient (i.e., protein, fat, or carbohydrate),
with which the manufacturer has not had previous experience;
(4) Any infant formula manufactured on a new processing line or in
a new plant;
(5) Any infant formula manufactured containing a new constituent
not listed in section 412(i) of the Federal Food, Drug, and Cosmetic
Act (21 U.S.C. 350a(i)), such as taurine or L-carnitine;
(6) Any infant formula processed by a manufacturer on new equipment
that utilizes a new technology or principle (e.g., from terminal
sterilization to aseptic processing); or
(7) An infant formula for which there has been a fundamental change
in the type of packaging used (e.g., changing from metal cans to
plastic pouches).
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
distribution. The term ``manufacturer'' does not include a person who
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.
Microorganisms means yeasts, molds, bacteria, and viruses and
includes, but is not limited to, species having public health
significance.
New infant formula means:
(1) An infant formula manufactured by a person that has not
previously manufactured an infant formula, 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, or which has not previously been the
subject of a submission under section 412(c) of the Federal Food, Drug,
and Cosmetic Act for the U.S. market.
Nutrient means any vitamin, mineral, or other substance or
ingredient that is required in accordance with the ``Nutrients'' table
set out in section 412(i)(1) of the Federal Food, Drug, and Cosmetic
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 Institute of Medicine through its development of a Dietary
Reference Intake, or that has been identified as essential for infants
by the Food and Drug Administration through a Federal Register
publication.
Nutrient premix means a combination of ingredients containing two
or more nutrients received from a supplier or prepared by an infant
formula manufacturer.
Production aggregate means 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.
Production unit means 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 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.
Quality factors means those factors necessary to demonstrate the
bioavailability and safety of the infant formula, as prepared for
market and when fed as the sole source of nutrition, including the
bioavailability of individual nutrients in the formula, to ensure the
healthy growth of infants.
Representative sample means a sample that consists of a number of
units that are drawn based on rational criteria, such as random
sampling, and intended to ensure that the sample accurately portrays
the material being sampled.
Shall is used to state mandatory requirements.
Subpart B--Current Good Manufacturing Practice
Sec. 106.5 Current good manufacturing practice.
(a) The regulations set forth in this subpart define the minimum
current good manufacturing practices that are to be used in, and the
facilities or controls that are to be used for, the manufacture,
processing, packing, or holding of an infant formula. Compliance with
these provisions is necessary to ensure that such infant formula
provides the nutrients required under Sec. 107.100 of this chapter and
is manufactured in a manner designed to prevent its adulteration. A
liquid infant formula that is a thermally processed low-acid food
packaged in a hermetically sealed container is also subject to the
regulations in part 113 of this chapter, and an infant formula that is
an acidified food, as defined in Sec. 114.3(b) of this chapter, is
also subject to the regulations in part 114 of this chapter.
(b) The failure to comply with any regulation in this subpart in
the manufacture, processing, packing, or holding of an infant formula
shall render such infant formula adulterated under section 412(a)(3) of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 350a(a)(3)); the
failure to comply with any regulation in part 113 of this chapter in
the manufacture, processing, packing, or holding of a liquid infant
formula shall render such infant formula adulterated under section
412(a)(3); and the failure to comply with any regulation in part 114 of
this chapter in the manufacture, processing, packing, or holding of an
infant formula that is an acidified food shall render such infant
formula adulterated under section 412(a)(3).
Sec. 106.6 Production and in-process control system.
(a) A manufacturer shall conform to the requirements of this
subpart by implementing a system of production and in-process controls.
This production and in-process control system shall cover all stages of
processing, from the receipt and acceptance of the raw materials,
ingredients, and components through the storage and distribution of the
finished product and shall be designed to ensure that all the
requirements of this subpart are met.
(b) The production and in-process control system shall be set out
in a written plan or set of procedures that is designed to ensure that
an infant formula is manufactured in a manner that will prevent
adulteration of the infant formula.
(c) At any point, step, or stage in the production process where
control is necessary to prevent adulteration, a manufacturer shall:
(1) Establish specifications to be met;
(2) Monitor the production and in-process control point, step, or
stage;
[[Page 8061]]
(3) Establish a corrective action plan for use when a specification
established in accordance with paragraph (c)(1) of this section is not
met;
(4) Review the results of the monitoring required by paragraph
(c)(2) of this section, and review and evaluate the public health
significance of any deviation from specifications that have been
established in accordance with paragraph (c)(1) of this section. For
any specification established in accordance with paragraph (c)(1) of
this section that a manufacturer fails to meet, an individual qualified
by education, training, or experience shall conduct a documented review
and shall make a material disposition decision to reject the affected
article, to reprocess or otherwise recondition the affected article, or
to approve and release the article for use or distribution; and
(5) Establish recordkeeping procedures, in accordance with Sec.
106.100(e)(3), that ensure that compliance with the requirements of
this section is documented.
(d) Any article that fails to meet a specification established in
accordance with paragraph (c)(1) of this section shall be controlled
under a quarantine system designed to prevent its use pending the
completion of a documented review and material disposition decision.
Sec. 106.10 Controls to prevent adulteration by workers.
(a) A manufacturer shall employ sufficient personnel, qualified by
education, training, or experience, to perform all operations,
including all required recordkeeping, in the manufacture, processing,
packing, and holding of each infant formula and to supervise such
operations to ensure that the operations are correctly and fully
performed.
(b) Personnel working directly with infant formula, infant formula
raw materials, infant formula packaging, or infant formula equipment or
utensil contact surfaces shall practice good personal hygiene to
protect the infant formula against contamination. Good personal hygiene
includes:
(1) Wearing clean outer garments and, as necessary, protective
apparel such as head, face, hand, and arm coverings; and
(2) Washing hands thoroughly in a hand washing facility with soap
and running water at a suitable temperature before starting work, after
each absence from the work station, and at any other time when the
hands may become soiled or contaminated.
(c) Any person who reports that he or she has, or appears by
medical examination or supervisory observation to have, an illness,
open lesion (including boils, sores, or infected wounds), or any other
source of microbial contamination that creates a reasonable possibility
that the safety of an infant formula may be adversely affected, shall
be excluded from direct contact with ingredients, containers, closures,
in-process materials, equipment, utensils, and infant formula product
until the condition is corrected or determined by competent medical
personnel not to jeopardize the safety of the infant formula.
Sec. 106.20 Controls to prevent adulteration caused by facilities.
(a) Buildings used in the manufacture, processing, packing, or
holding of infant formula shall be maintained in a clean and sanitary
condition and shall have space for the separation of incompatible
operations, such as the handling of raw materials, the manufacture of
the product, and packaging and labeling operations.
(b) Separate areas or another system of separation, such as a
computerized inventory control, a written card system, or an automated
system of segregation, shall be used for holding raw materials, in-
process materials, and final infant formula product at the following
times:
(1) Pending release for use in infant formula production or pending
release of the final product;
(2) After rejection for use in, or as, infant formula; and
(3) After release for use in infant formula production or after
release of the final product.
(c) Lighting shall allow easy identification of raw materials,
packaging, labeling, in-process materials, and finished products that
have been released for use in infant formula production and shall
permit the easy reading of instruments and controls necessary in
processing, packaging, and laboratory analysis. Any lighting fixtures
directly over or adjacent to exposed raw materials, in-process
materials, or bulk (unpackaged) finished product shall be protected to
prevent glass from contaminating the product in the event of breakage.
(d) A manufacturer shall provide adequate ventilation or control
equipment to minimize odors and vapors (including steam and noxious
fumes) in areas where they may contaminate the infant formula; and
shall minimize the potential for contamination of raw materials, in-
process materials, final product infant formula, packing materials, and
infant formula-contact surfaces, through the use of appropriate
measures, which may include the use of air filtration.
(e) All rodenticides, insecticides, fungicides, fumigating agents,
and cleaning and sanitizing agents shall be stored and used in a manner
that protects against contamination of infant formula.
(f) Potable water used in the manufacture of infant formula shall
meet the standards prescribed in the Environmental Protection Agency's
(EPA's) Primary Drinking Water regulations in 40 CFR part 141, except
that the water used in infant formula manufacturing shall not be
fluoridated or shall be defluoridated to a level as low as possible
prior to use.
(1) The water shall be supplied under continuous positive pressure
in a plumbing system that is free of defects that could contaminate an
infant formula.
(2) A manufacturer shall test representative samples of the potable
water drawn at a point in the system at which the water is in the same
condition that it will be when it is used in infant formula
manufacturing.
(3) A manufacturer shall conduct the tests required by paragraph
(f)(2) of this section with sufficient frequency to ensure that the
water meets the EPA's Primary Drinking Water Regulations but shall not
conduct these tests less frequently than annually for chemical
contaminants, every 4 years for radiological contaminants, and weekly
for bacteriological contaminants.
(4) A manufacturer shall make and retain records, in accordance
with Sec. 106.100(f)(1), of the frequency and results of testing of
the water used in the production of infant formula.
(g) There shall be no backflow from, or cross-connection between,
piping systems that discharge waste water or sewage and piping systems
that carry water for infant formula manufacturing.
(h) Only culinary steam shall be used at all direct infant formula
product contact points. Culinary steam shall be in compliance with the
3-A Sanitary Standards, No. 60903, which is incorporated by reference
at Sec. 106.160. Boiler water additives in the steam shall be used in
accordance with Sec. 173.310 of this chapter.
(i) Each infant formula manufacturing site shall provide its
employees with readily accessible toilet facilities and hand washing
facilities that include hot and cold water, soap or detergent, single-
service towels or air dryers in toilet facilities. These facilities
shall be maintained in good repair and in a sanitary condition at all
times. These facilities shall provide for proper disposal of the
sewage. Doors to the
[[Page 8062]]
toilet facility shall not open into areas where infant formula
ingredients, containers, or closures are stored, or where infant
formula is processed or stored.
Sec. 106.30 Controls to prevent adulteration caused by equipment or
utensils.
(a) A manufacturer shall ensure that equipment and utensils used in
the manufacture, processing, packing, or holding of an infant formula
are of appropriate design and are installed to facilitate their
intended function and their cleaning and maintenance.
(b) A manufacturer shall ensure that equipment and utensils used in
the manufacture, processing, packing, or holding of an infant formula
are constructed so that surfaces that contact ingredients, in-process
materials, or infant formula are made of nontoxic materials and are not
reactive or absorptive. A manufacturer shall ensure that such equipment
and utensils are designed to be easily cleanable and to withstand the
environment of their intended use and that all surfaces that contact
ingredients, in-process materials, or infant formula are cleaned and
sanitized, as necessary, and are maintained to protect infant formula
from being contaminated by any source. All sanitizing agents used on
such equipment and utensils that are regulated as pesticide chemicals
under 21 U.S.C. 346a(a) shall comply with the Environmental Protection
Agency's regulations established under such section, and all other such
sanitizers shall comply with all applicable Food and Drug
Administration laws and regulations.
(c) A manufacturer shall ensure that any substance, such as a
lubricant or a coolant, that is required for operation of infant
formula manufacturing equipment and which would render the infant
formula adulterated if such substance were to come in contact with the
formula, does not come in contact with formula ingredients, containers,
closures, in-process materials, or with infant formula product during
the manufacture of an infant formula.
(d) A manufacturer shall ensure that each instrument used for
measuring, regulating, or controlling mixing time and speed,
temperature, pressure, moisture, water activity, or other parameter at
any point, step, or stage where control is necessary to prevent
adulteration of an infant formula during processing is accurate, easily
read, properly maintained, and present in sufficient number for its
intended use.
(1) The instruments and controls shall be calibrated against a
known reference standard at the time of or before first use and
thereafter at routine intervals, as specified in writing by the
manufacturer of the instrument or control, or as otherwise deemed
necessary to ensure the accuracy of the instrument or control. The
known reference standard shall be certified for accuracy at the
intervals specified in writing by the manufacturer of the instrument or
control, or at routine intervals otherwise deemed necessary to ensure
the accuracy of the instrument or control. A manufacturer shall make
and retain records of the calibration activities in accordance with
Sec. 106.100(f)(2).
(2) Instruments and controls that cannot be adjusted to agree with
the reference standard shall be repaired or replaced.
(3) If calibration of an instrument shows a failure to meet a
specification for a point where control is deemed necessary to prevent
adulteration of infant formula product, a written evaluation of all
affected product, and of any actions that need to be taken with respect
to that product, shall be made, in accordance with Sec. 106.100(f)(2).
(e) The following provisions apply to thermal processing and cold
storage of infant formulas:
(1) Equipment and procedures for thermal processing of infant
formula packaged in hermetically sealed containers shall conform to the
requirements in 21 CFR parts 108 and 113.
(2)(i) Except as provided in paragraph (e)(2)(ii) of this section,
a manufacturer shall maintain all areas of cold storage at a
temperature of 40 [deg]F (4.4 [deg]C) or below.
(ii) A manufacturer may maintain a cold storage area for an in-
process infant formula or for a final infant formula at a temperature
not to exceed 45 [deg]F (7.2 [deg]C) for a defined period of time
provided that the manufacturer has scientific data and other
information to demonstrate that:
(A) Compliance with paragraph (e)(2)(i) of this section would have
an adverse effect on the quality of the in-process or the final infant
formula through, e.g., destabilization or loss of homogeneity; and
(B) The time and temperature conditions of such storage are
sufficient to ensure that there is no significant growth of
microorganisms of public health significance during the period of
storage of the in-process or final infant formula product.
(3)(i) Cold storage compartments and thermal processing equipment
shall be equipped with easily readable, accurate temperature-indicating
devices.
(ii) A manufacturer shall ensure that the temperature of each cold
storage compartment is maintained by:
(A) Monitoring the temperature of the cold storage compartment on a
temperature-indicating device and recording this temperature in a
record with such frequency as is necessary to ensure that temperature
control is maintained;
(B) Equipping the cold storage compartment with one or more
temperature-recording devices that will reflect, on a continuing basis,
the true temperature, within the compartment;
(C) Equipping the cold storage compartment with a high temperature
alarm that has been validated to function properly and recording the
temperature in a record with such frequency as is necessary to ensure
that temperature control is maintained; or
(D) Equipping the cold storage compartment with a maximum-
indicating thermometer that has been validated to function properly and
recording this temperature in a record with such frequency as is
necessary to ensure that temperature control is maintained.
(iii) A manufacturer shall, in accordance with Sec. 106.100(f)(3),
make and retain records of the temperatures recorded in compliance with
Sec. 106.30(e)(3)(ii).
(4) When a manufacturer uses a temperature-recording device for a
cold storage compartment, such device shall not read lower than the
reference temperature-indicating device.
(5) A manufacturer shall monitor the temperature in thermal
processing equipment at points where temperature control is necessary
to prevent adulteration. Such monitoring shall be at such frequency as
is required by regulation or is necessary to ensure that temperature
control is maintained.
(f) A manufacturer shall ensure that equipment and utensils used in
the manufacture of infant formula are cleaned, sanitized, and
maintained at regular intervals to prevent adulteration of the infant
formula.
(1) An individual qualified by education, training, or experience
to conduct such a review shall review all cleaning, sanitizing, and
maintenance to ensure that it has been satisfactorily completed.
(2) A manufacturer shall make and retain records on equipment
cleaning, sanitizing, and maintenance, in accordance with Sec.
106.100(f)(4).
(g) A manufacturer shall ensure that compressed air or other gases
that are mechanically introduced into infant formula, that are used to
clean any equipment, or that come into contact
[[Page 8063]]
with any other surface that contacts ingredients, in-process materials,
or infant formula product are treated in such a way that their use will
not contaminate the infant formula with unlawful or other chemical,
physical, or microbiological contaminants. When compressed gases are
used at product filling machines to replace air removed from the
headspace of containers, a manufacturer shall install, as close as
practical to the end of the gas line that feeds gas into the space, a
filter capable of retaining particles 0.5 micrometer or smaller.
Sec. 106.35 Controls to prevent adulteration due to automatic
(mechanical or electronic) equipment.
(a) For the purposes of this section:
(1) ``Hardware'' means all automatic equipment, including
mechanical and electronic equipment (such as computers), that is used
in production or quality control of infant formula.
(2) ``Software'' means any programs, procedures, rules, and
associated documentation used in the operation of a system.
(3) ``System'' means a collection of components (including software
and hardware) organized to accomplish a specific function or set of
functions in a specified environment.
(4) ``Validation'' means establishing documented evidence that
provides a high degree of assurance that a system will consistently
produce a product meeting its predetermined specifications and quality
characteristics.
(b) All systems shall be designed, installed, tested, and
maintained in a manner that will ensure that they are capable of
performing their intended function and of producing or analyzing infant
formula in accordance with this subpart and subpart C of this part.
(1) A manufacturer shall ensure that hardware that is capable of
being calibrated is routinely calibrated according to written
procedures, and that all hardware is routinely inspected and checked
according to written procedures.
(2) A manufacturer shall check and document the accuracy of input
into, and output generated by, any system used in the production or
quality control of an infant formula to ensure that the infant formula
is not adulterated. The degree and frequency of input/output
verification shall be based on the complexity and reliability of the
system and the level of risk associated with the safe operation of the
system.
(3) A manufacturer shall ensure that each system is validated prior
to the release for distribution of any infant formula manufactured
using the system.
(4) A manufacturer shall ensure that any system that is modified is
revalidated following the modification and prior to the release for
distribution of any infant formula manufactured using the modified
system. All modifications to software shall be made by a designated
individual and shall be checked by the infant formula manufacturer to
ensure that infant formula that is produced or analyzed using the
modified software complies with this subpart and with subpart C of this
part.
(c) A manufacturer shall make and retain records, in accordance
with Sec. 106.100(f)(5), concerning mechanical or electronic
equipment.
Sec. 106.40 Controls to prevent adulteration caused by ingredients,
containers, and closures.
(a) The only substances that may be used in an infant formula are
substances that are safe and suitable for use in infant formula under
the applicable food safety provisions of the Federal Food, Drug, and
Cosmetic Act; that is, a substance is used in accordance with the
Agency's food additive regulations, is generally recognized as safe
(GRAS) for such use, or is authorized by a prior sanction.
(b) Infant formula containers and closures shall not be reactive or
absorptive so as to affect the safety of the infant formula. The
following substances may be used as packaging material that comes in
contact with an infant formula:
(1) A food additive that is the subject of a regulation issued
under section 409(c) of the Federal Food, Drug, and Cosmetic Act (21
U.S.C. 348(c)) and is used consistent with the conditions of use of
that regulation;
(2) A food contact substance that is the subject of an effective
notification under section 409(h) of the Federal Food, Drug, and
Cosmetic Act and is used consistent with the conditions of use in that
notification;
(3) A substance that is exempt from regulation as a food additive
under Sec. 170.39 of this chapter and its use conforms to the use
identified in the exemption letter;
(4) A substance that is generally recognized as safe for use in or
on infant formula or for use in infant formula packaging;
(5) A substance the use of which is authorized by a prior sanction
from the Food and Drug Administration or from the U.S. Department of
Agriculture; and
(6) A substance that is not a food additive within the meaning of
section 201(s) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
321(s)) because the substance is not reasonably expected to become a
component of food or otherwise affect the characteristics of food.
(c) Ingredients, containers, and closures used in the manufacture
of infant formula shall be identified with a lot number to be used in
recording their disposition.
(d) A manufacturer shall develop written specifications for
ingredients, containers, and closures used in manufacturing infant
formula and shall develop and follow written procedures to determine
whether all ingredients, containers, and closures meet these
specifications. When any specification is not met, an individual
qualified by education, training, or experience shall conduct a
documented review, shall determine whether a failure to meet such a
specification could result in an adulterated infant formula, and shall
make and document a material disposition decision to reject the
ingredient, container, or closure or the affected infant formula; to
reprocess or otherwise recondition the ingredient, container, or
closure or the affected infant formula; or to approve and release the
ingredient, container, or closure or the affected infant formula for
use.
(e) Ingredients, containers, and closures shall be stored in
separate areas or separated by a system of segregation, such as a
computerized inventory control, a written card system, or an automated
system of segregation, clearly designated for materials pending release
for use; materials released for use; or materials rejected for use in
infant formula production.
(1) Any lot of an ingredient, a container, or a closure that does
not meet the manufacturer's specifications shall be quarantined under a
system designed to prevent its use in the manufacture of infant formula
until an individual qualified by education, training, or experience has
conducted a documented review, has determined whether such failure
could result in an adulterated infant formula, and has made and
documented a material disposition decision to reject the ingredient,
container, closure, or the affected infant formula; to reprocess or
otherwise recondition the ingredient, container, closure, or the
affected infant formula; or to approve and release the ingredient,
container, closure, or the affected infant formula for use.
(2) Any ingredient, container, or closure that has been reprocessed
or otherwise reconditioned shall be the subject of a documented review
and
[[Page 8064]]
material disposition decision by an individual qualified by education,
training, or experience to determine whether it may be released for
use.
(3) A manufacturer shall not reprocess or otherwise recondition an
ingredient, container, or closure rejected because it is contaminated
with microorganisms of public health significance or other
contaminants, such as heavy metals.
(f) If an ingredient, container, or closure that complies with a
manufacturer's specifications, or that has been released for use
following a material review and disposition decision, is subsequently
exposed to air, heat, or other conditions that may adversely affect it,
or if a manufacturer reasonably believes that an ingredient, container,
or closure that complies with a manufacturer's specifications, or that
has been released for use following a material review and disposition
decision, has been exposed to air, heat, or other conditions that may
adversely affect it, the ingredient, container, or closure shall be
quarantined under a system designed to prevent its use in the
manufacture of infant formula until an individual qualified by
education, training, or experience has conducted a documented review
and has made and documented a material disposition decision to reject
the ingredient, container, or closure; to reprocess or otherwise
recondition the ingredient, container, or closure; or to approve and
release the ingredient, container, or closure for use.
(1) Any ingredient, container, or closure that is reprocessed or
otherwise reconditioned shall be retested or reexamined and be the
subject of a documented review and material disposition decision by an
individual qualified by education, training, or experience to determine
whether the ingredient, container, or closure should be rejected,
further reprocessed or otherwise further reconditioned, or approved and
released for use.
(2) Any rejected ingredient, container, or closure shall be clearly
identified as having been rejected for use in infant formula
manufacturing or processing operations and shall be controlled under a
quarantine system designed to prevent its use in infant formula
manufacturing or processing operations.
(3) Any ingredient, container, or closure that has not been
manufactured, packaged, labeled, or held under conditions to prevent
adulteration under section 402(a)(1) through (a)(4) of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 342(a)(1) through (a)(4)) shall
not be approved and released for use.
(g) A manufacturer shall make and retain records, in accordance
with Sec. 106.100(f)(6), on the ingredients, containers, and closures
used in the manufacture of infant formula.
Sec. 106.50 Controls to prevent adulteration during manufacturing.
(a) A manufacturer shall prepare and follow a written master
manufacturing order that establishes controls and procedures for the
production of an infant formula.
(1) The manufacturer shall make and retain records, in accordance
with Sec. 106.100(e), that include complete information relating to
the production and control of the production aggregate. An individual
qualified by education, training, or experience shall conduct an
investigation of any deviations from the master manufacturing order and
document any corrective action taken.
(2) Changes made to the master manufacturing order shall be
drafted, reviewed, and approved by a responsible official and include
an evaluation of the effect of the change on the nutrient content and
the suitability of the formula for infants.
(b) A manufacturer shall establish controls to ensure that each raw
or in-process ingredient required by the master manufacturing order is
examined by one person and checked by a second person or system. This
checking shall ensure that the correct ingredient is added during the
manufacturing process, that the ingredient has been released for use in
infant formula, and that the correct weight or measure of the
ingredient is added to the production unit.
(c) A manufacturer shall establish a system of identification for
the contents of all compounding and storage containers, processing
lines, and major equipment used during the manufacture of a production
aggregate of an infant formula. The system shall permit the
identification of the processing stage and the unique identification
number for the particular production unit or production aggregate of
infant formula.
(d) A manufacturer shall establish controls to ensure that the
nutrient levels required by Sec. 107.100 of this chapter are
maintained in the formula, and that the formula is not contaminated
with microorganisms or other contaminants. Such controls shall include:
(1) The mixing time; the speed, temperature, and flow rate of
product; and other critical parameters necessary to ensure the addition
of required ingredients to, and the homogeneity of, the formula;
(2) The spray-drying process for powdered infant formula, including
the filtering of the intake air before heating, to prevent microbial
and other contamination;
(3) The removal of air from the finished product to ensure that
nutrient deterioration does not occur;
(4) Ensuring that each container of finished product is properly
sealed. Such controls shall involve use of established procedures,
specifications, and intervals of examination that are designed by
qualified individuals and are sufficient to:
(i) Detect visible closure or seal defects, and
(ii) Determine closure strength through destructive testing. A
manufacturer of a liquid infant formula that is a thermally processed
low-acid food packaged in a hermetically sealed container shall perform
such closure integrity testing in accordance with Sec. 113.60(a) of
this chapter.
(e) A manufacturer shall establish controls that ensure that the
equipment used at points where control is deemed necessary to prevent
adulteration is monitored, so that personnel will be alerted to
malfunctions.
(f) A manufacturer shall establish controls for in-process material
as follows:
(1) For any specification established in accordance with Sec.
106.6(c)(1) that a manufacturer fails to meet for in-process material,
an individual qualified by education, training, or experience shall
conduct a documented review and shall make a material disposition
decision to reject the affected in-process material, to reprocess or
otherwise recondition the affected in-process material, or to approve
and release the affected in-process material for use or distribution;
(2) Pending a documented review and material disposition decision,
any in-process material that fails to meet any specification
established in accordance with Sec. 106.6(c)(1) shall be clearly
identified as such and shall be controlled under a quarantine system
designed to prevent its use in manufacturing or processing operations
until completion of the documented review and material disposition
decision;
(3) Any in-process material that has been reprocessed or otherwise
reconditioned shall be the subject of a documented review and material
disposition decision by an individual qualified by education, training,
or experience to determine whether it may be released for use; and
(4) Any rejected in-process material shall be clearly identified as
having been rejected for use in infant formula
[[Page 8065]]
and shall be controlled under a quarantine system designed to prevent
its use in infant formula manufacturing or processing operations.
Sec. 106.55 Controls to prevent adulteration from microorganisms.
(a) A manufacturer of infant formula shall establish a system of
process controls covering all stages of processing that is designed to
ensure that infant formula does not become adulterated due to the
presence of microorganisms in the formula or in the processing
environment.
(b) A manufacturer of liquid infant formula shall comply, as
appropriate, with the procedures specified in part 113 of this chapter
for thermally processed low-acid foods packaged in hermetically sealed
containers and part 114 of this chapter for acidified foods.
(c) A manufacturer of powdered infant formula shall test
representative samples of each production aggregate of powdered infant
formula at the final product stage, before distribution, to ensure that
each production aggregate meets the microbiological quality standards
in the table in paragraph (e) of this section.
(d) A manufacturer shall make and retain records, in accordance
with Sec. 106.100(e)(5)(ii) and (f)(7), on the testing of infant
formulas for microorganisms.
(e) A powdered infant formula that contains any microorganism that
exceeds the M value listed for that microorganism in the table in
paragraph (e) of this section shall be deemed adulterated under
sections 402(a)(1), 402(a)(4), and 412(a)(3) of the Federal Food, Drug,
and Cosmetic Act (21 U.S.C. 350a(a)(3)). The Food and Drug
Administration will determine compliance with the M values listed below
using the latest edition of the Bacteriological Analytical Manual (BAM)
(http://www.fda.gov/Food/FoodScienceResearch/LaboratoryMethods/BacteriologicalAnalyticalManualBAM/default.htm) (accessed April 8,
2013).
----------------------------------------------------------------------------------------------------------------
Microorganism n \1\ Sample size M value
----------------------------------------------------------------------------------------------------------------
Cronobacter spp............................... 30 10 g (grams).................... \2\ 0.
Salmonella spp................................ 60 25 g............................ \2\ 0.
----------------------------------------------------------------------------------------------------------------
\1\ Number of samples.
\2\ None detected.
Sec. 106.60 Controls to prevent adulteration during packaging and
labeling of infant formula.
(a) A manufacturer shall examine packaged and labeled infant
formula during finishing operations to ensure that all containers and
packages in the production aggregate have the correct label, the
correct use-by date, and the correct code established under Sec.
106.80.
(b) Labels shall be designed, printed, and applied so that the
labels remain legible and attached during the conditions of processing,
storage, handling, distribution, and use.
(c) Packaging used to hold multiple containers of an infant formula
product shall be labeled as follows:
(1) Where all containers are the same infant formula product and
all bear the same code established under Sec. 106.80, the packaging
label shall include the product name, the name of the manufacturer,
distributor, or shipper, and the code established under Sec. 106.80.
(2) Where the containers are not the same infant formula product or
do not all bear the same code established under Sec. 106.80, the
packaging label shall:
(i) Include the product name of each product, the name of the
manufacturer, distributor, or shipper of each product, the code
established under Sec. 106.80 for each product, and a ``use by'' date
that is no later than the ``use by'' date of the container exhibiting
the closest ``use by'' date applied to satisfy the requirement of Sec.
107.20(c) of this chapter; or
(ii) Include a unique identification number assigned by the
packager, provided that the distributor of the package maintains a
record linked to such unique number that identifies the product name of
each product, the name of the manufacturer, distributor, or shipper of
each product, the code established under Sec. 106.80 for each product,
and the ``use by'' date for each product applied to satisfy the
requirement of Sec. 107.20(c) of this chapter.
Sec. 106.70 Controls on the release of finished infant formula.
(a) A manufacturer shall control under a quarantine system designed
to prevent use or distribution of each production aggregate of infant
formula until it determines that the production aggregate meets all of
the manufacturer's specifications, including those adopted to meet the
standards of Sec. 106.55 on microbiological contamination and of Sec.
106.91(a) on quality control procedures, or until the documented review
of the failure to meet any of the manufacturer's specifications finds
that the failure does not result in, or could not lead to, adulteration
of the product.
(b) Any production aggregate of infant formula that fails to meet
any of the manufacturer's specifications shall be quarantined under a
system designed to prevent its use in the manufacture of infant formula
or its distribution until an individual qualified by education,
training, or experience has conducted a documented review and has made
and documented a material disposition decision to reject the infant
formula; to reprocess or otherwise recondition the infant formula; or
to approve and release the infant formula. Any production aggregate of
infant formula that is reprocessed or otherwise reconditioned shall be
the subject of a documented review and material disposition decision by
an individual qualified by education, training, or experience to
determine whether it may be released for use or distribution.
(c) Any rejected infant formula shall be clearly identified as
having been rejected for use and shall be controlled under a quarantine
system designed to prevent its release or distribution.
(d) A production aggregate of infant formula, including a
reprocessed or reconditioned production aggregate, that does not meet
the nutrient requirements of section 412(i) of the Federal Food, Drug,
and Cosmetic Act (21 U.S.C. 350a(i)) or that has not been manufactured,
packaged, labeled, and held under conditions to prevent adulteration
under sections 402(a)(1) through (a)(4) of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 342(a)(1) through (a)(4)) shall not be approved
and released for distribution.
Sec. 106.80 Traceability.
Each production aggregate of infant formula shall be coded with a
sequential number that identifies the product and the establishment
where the product was packed and that permits tracing of all stages of
manufacture of that production aggregate, including the year, the days
of the year, and the period during those days that the product was
packed, and the receipt and handling of raw materials used.
[[Page 8066]]
Sec. 106.90 Audits of current good manufacturing practice.
(a) A manufacturer of an infant formula, or an agent of such
manufacturer, shall conduct regularly scheduled audits to determine
whether the manufacturer has complied with the current good
manufacturing practice regulations in this subpart. Such audits shall
be conducted at a frequency that is required to ensure compliance with
such regulations.
(b) The audits required by paragraph (a) of this section shall be
performed by an individual or a team of individuals who, as a result of
education, training, or experience, is knowledgeable in all aspects of
infant formula production and of the Agency's regulations concerning
current good manufacturing practice that such individual or team is
responsible for auditing. This individual or team of individuals shall
have no direct responsibility for the matters that such individual or
team is auditing and shall have no direct interest in the outcome of
the audit.
Subpart C--Quality Control Procedures
Sec. 106.91 General quality control.
(a) During manufacture, a manufacturer shall test each production
aggregate for nutrients as follows:
(1) Each nutrient premix used in the manufacture of an infant
formula shall be tested for each nutrient (required under Sec. 107.100
of this chapter or otherwise added by the manufacturer) that the
manufacturer is relying on the premix to provide, to ensure that the
premix is in compliance with the manufacturer's specifications;
(2) During the manufacturing process, after the addition of the
premix, or at the final product stage but before distribution, each
production aggregate of infant formula shall be tested for at least one
indicator nutrient for each of the nutrient premixes used in the infant
formula to confirm that the nutrients supplied by each of the premixes
are present, in the proper concentration, in the production aggregate
of infant formula.
(3) At the final product stage, before distribution of an infant
formula, each production aggregate shall be tested for vitamins A, C,
E, and thiamin.
(4) During the manufacturing process or at the final product stage,
before distribution, each production aggregate shall be tested for all
nutrients required to be included in such formula under Sec. 107.100
of this chapter for which testing is not conducted for compliance with
paragraphs (a)(1) or (a)(3) of this section and for any nutrient added
by the manufacturer for which testing is not conducted for compliance
with paragraph (a)(1) of this section.
(b) A manufacturer shall test each production aggregate of finished
product for nutrients as follows:
(1) For an infant formula that is a new infant formula, Sec.
106.3, the manufacturer shall collect, from each manufacturing site and
at the final product stage, a representative sample of the first
production aggregate of packaged, finished formula in each physical
form (powder, ready-to-feed, or concentrate) and evaluate the levels of
all nutrients required under Sec. 107.100 of this chapter and all
other nutrients added by the manufacturer. The manufacturer shall
repeat such testing every 3 months thereafter throughout the shelf-life
of the product.
(2) The manufacturer shall collect, from each manufacturing site
and at the final product stage, a representative sample of each
subsequent production aggregate of packaged, finished formula in each
physical form (powder, ready-to-feed, or concentrate) and evaluate the
levels of all nutrients required under Sec. 107.100 and all other
nutrients added by the manufacturer. The manufacturer shall repeat such
testing at the midpoint and at the end of the shelf-life of the
product.
(3) If the results of the testing required by paragraph (b)(1) of
this section do not substantiate the shelf life of the infant formula,
the manufacturer shall either repeat the testing required by such
paragraph on a subsequently produced production aggregate to
substantiate the shelf life of the infant formula or revise the shelf
life label statement for such product so that such statement is
substantiated by the stability testing results.
(4) If results of the testing required by paragraph (b)(2) of this
section show that any required nutrient is not present in the
production aggregate of infant formula at the level required by Sec.
107.100 of this chapter or that any nutrient added by the manufacturer
is not present at the level declared on the label of the production
aggregate of infant formula, the manufacturer shall:
(i) Investigate the cause of such variance in the level of any
required or added nutrient;
(ii) Evaluate the significance, if any, of the results for other
production aggregates of the same formula that have been released for
distribution;
(iii) Address, as appropriate, all production aggregates of formula
released for distribution that are implicated by the testing results;
and
(iv) Determine whether it is necessary to repeat the testing
required by paragraph (b)(1) of this section.
(5) The testing required by paragraphs (b)(1) and (b)(2) of this
section is not required to evaluate the level of minerals present in
the infant formula.
(c) All quality control testing shall be conducted using
appropriate, scientifically valid test methods.
(d) A manufacturer shall make and retain quality control records in
accordance with Sec. 106.100(e)(5)(i).
Sec. 106.92 Audits of quality control procedures.
(a) A manufacturer of an infant formula, or an agent of such a
manufacturer, shall conduct regularly scheduled audits to determine
whether the manufacturer has complied with the requirements for quality
control procedures that are necessary to ensure that an infant formula
provides nutrients in accordance with section 412(b) and (i) of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 350a(b) and (i)) and is
manufactured in a manner designed to prevent adulteration of the infant
formula under section 412(a)(1) and (a)(3) of the Federal Food, Drug,
and Cosmetic Act. Such audits shall be conducted at a frequency that is
required to ensure compliance with the requirements for quality control
procedures.
(b) The audits required by paragraph (a) of this section shall be
performed by an individual or a team of individuals who, as a result of
education, training, or experience, is knowledgeable in all aspects of
infant formula production and of the regulations concerning quality
control procedures that such individual or team is responsible for
auditing. This individual or team of individuals shall have no direct
responsibility for the matters that such individual or team is auditing
and shall have no direct interest in the outcome of the audit.
Subpart D--Conduct of Audits
Sec. 106.94 Audit plans and procedures.
(a) A manufacturer shall develop and follow a written audit plan
that is available at the manufacturing facility for Food and Drug
Administration inspection.
(b) The audit plan shall include audit procedures that set out the
methods the manufacturer uses to determine whether the facility is
operating in accordance with current good manufacturing practice, with
the quality control procedures that are necessary to ensure that an
infant formula provides nutrients in accordance with sections
[[Page 8067]]
412(b) and (i) of the Federal Food, Drug, and Cosmetic Act, and in a
manner designed to prevent adulteration of the infant formula.
(c) The audit procedures shall include:
(1) An evaluation of the production and in-process control system
established under Sec. 106.6(b) by:
(i) Observing the production of infant formula and comparing the
observed process to the written production and in-process control plan
required under Sec. 106.6(b);
(ii) Reviewing records of the monitoring of points, steps, or
stages where control is deemed necessary to prevent adulteration; and
(iii) Reviewing records of how deviations from any specification at
points, steps, or stages where control is deemed necessary to prevent
adulteration were handled; and
(2) A review of a representative sample of all records maintained
in accordance with Sec. 106.100(e) and (f).
Subpart E--Quality Factors for Infant Formulas
Sec. 106.96 Requirements for quality factors for infant formulas.
The regulations set forth in this subpart define the minimum
requirements for quality factors for infant formulas:
(a) An infant formula shall meet the quality factor of normal
physical growth.
(b) A manufacturer of an infant formula that is not an eligible
infant formula shall demonstrate that a formula supports normal
physical growth in infants when fed as a sole source of nutrition by
conducting, in accordance with good clinical practice, an adequate and
well-controlled growth monitoring study of the infant formula that:
(1) Is no less than 15 weeks in duration, enrolling infants no more
than 2 weeks old at time of entry into the study;
(2) Includes the collection and maintenance of data on formula
intake and anthropometric measures of physical growth, including body
weight, recumbent length, head circumference, average daily weight
increment, and average daily recumbent length increment;
(3) Includes anthropometric measurements made at the beginning and
end of the study, and at least four additional measurements made at
intermediate time points with three of the six total measurements made
within the first 4 weeks of the study and three measurements made at
approximately 4-week intervals over the remaining 11 weeks of the
study;
(4) Compares the anthropometric data for the test group to a
concurrent control group or groups at each time point and compares the
anthropometric data for each infant (body weight for age, body length
for age, head circumference for age, and weight for length) in the test
group and the control group to the 2009 CDC growth charts, which are
incorporated by reference at Sec. 106.160; and
(5) Compares the data on formula intake of the test group with a
concurrent control group or groups and a scientifically appropriate
reference.
(c) The Food and Drug Administration will exempt a manufacturer
from the requirements of paragraph (b) of this section, if:
(1) The manufacturer requests an exemption and provides assurances,
as required under Sec. 106.121, that the changes made by the
manufacturer to an existing infant formula are limited to changing the
type of packaging of an existing infant formula (e.g., changing from
metal cans to plastic pouches); or
(2) The manufacturer requests an exemption and provides assurances,
as required under Sec. 106.121, which demonstrate that:
(i) An alternative method or study design that is based on sound
scientific principles is available to show that the formula supports
normal physical growth in infants when the formula is fed as the sole
source of nutrition;
(ii) The change made by the manufacturer to an existing formula
does not affect the bioavailability of the formula, including the
bioavailability of nutrients in such formula; or
(iii) The manufacturer markets a formulation in more than one form
(e.g., liquid and powdered forms) and the quality factor requirements
are met by the form of the formula that is processed using the method
that has the greatest potential for adversely affecting nutrient
content and bioavailability.
(d) A manufacturer of a new infant formula that is not an eligible
infant formula shall, in accordance with Sec. 106.100(p)(1), make and
retain records demonstrating that the formula meets the quality factor
of normal physical growth.
(e) An infant formula shall meet the quality factor of sufficient
biological quality of protein.
(f) A manufacturer of an infant formula that is not an eligible
infant formula shall demonstrate that a formula meets the quality
factor of sufficient biological quality of protein by establishing the
biological quality of the protein in the infant formula when fed as the
sole source of nutrition using an appropriate modification of the
Protein Efficiency Ratio (PER) rat bioassay described in the ``Official
Methods of Analysis of AOAC International,'' 18th ed., sections 45.3.04
and 45.3.05, ``AOAC Official Method 960.48 Protein Efficiency Ratio Rat
Bioassay,'' which is incorporated by reference at Sec. 106.160. The
PER rat bioassay shall be conducted on a formula and the results
evaluated prior to the initiation of a growth monitoring study of the
formula that is required under paragraph (b) of this section.
(g) The Food and Drug Administration will exempt a manufacturer
from the requirements of paragraph (f) of this section, if:
(1) The manufacturer requests an exemption and provides assurances
as required under Sec. 106.121 that the changes made by the
manufacturer to an existing infant formula are limited to changing the
type of packaging of an existing infant formula (e.g., changing from
metal cans to plastic pouches); or
(2) The manufacturer requests an exemption and provides assurances,
as required under Sec. 106.121, that demonstrate that the change made
by the manufacturer to an existing formula does not affect the
bioavailability of the protein.
(h) A manufacturer of a new infant formula that is not an eligible
infant formula shall, in accordance with Sec. 106.100(q), make and
retain records demonstrating that the formula meets the quality factor
of sufficient biological quality of protein.
(i) The following provisions for requirements for quality factors
apply only to an ``eligible infant formula'' as defined in Sec. 106.3:
(1) An eligible infant formula that fulfills one or more of the
following criteria meets the quality factor of normal physical growth:
(i) The scientific evidence on such infant formula meets the
requirements of paragraph (b) of this section that apply to infant
formula that is not an eligible infant formula;
(ii) The scientific evidence on such infant formula meets the
following provisions:
(A) The evidence is an adequate and well-controlled growth study,
conducted in accordance with good clinical practice, to determine
whether an infant formula supports normal physical growth in infants
when the formula is fed as the sole source of nutrition;
(B) The growth study is no less than 4 months in duration,
enrolling infants no more than 1 month old at time of entry into the
study;
[[Page 8068]]
(C) The growth study collects from the study subjects data on
anthropometric measures of physical growth, including body weight,
recumbent length, head circumference, and average daily weight
increment, and plots the data on the following charts from ``Physical
Growth: National Center for Health Statistics Percentiles'' for body
weight, body length, and head circumference, which are incorporated by
reference at Sec. 106.160:
(1) Figure 1. Length by age percentiles for girls aged birth-36
months (p. 609);
(2) Figure 2. Length by age percentiles for boys aged birth-36
months (p. 610);
(3) Figure 3. Weight by age percentiles for girls aged birth-36
months (p. 611);
(4) Figure 4. Weight by age percentiles for boys aged birth-36
months (p. 612);
(5) Figure 5. Head circumference by age percentiles for girls aged
birth-36 months (p. 613);
(6) Figure 6. Weight by length percentiles for girls aged birth-36
months (p. 613);
(7) Figure 7. Head circumference by age percentiles for boys aged
birth-36 months (p. 614); and
(8) Figure 8. Weight by length percentiles for boys aged birth-36
months (p. 614); and
(D) The growth study collects anthropometric measurements at the
beginning of the growth study, at 2 weeks, at 4 weeks, at least monthly
thereafter, and at the conclusion of the study; or
(iii) The scientific evidence on such infant formula otherwise
demonstrates that such formula supports normal physical growth.
(2) An eligible infant formula that fulfills one or more of the
following criteria meets the quality factor of sufficient biological
quality of the protein:
(i) The scientific evidence on such infant formula meets the
requirements of paragraph (f) of this section that apply to infant
formula that is not an eligible infant formula;
(ii) The scientific evidence on such infant formula is a study that
establishes the biological quality of the protein in an infant formula
by demonstrating that the protein source supports adequate growth using
the Protein Efficiency Ratio (PER) rat bioassay described in sections
45.3.04 and 45.3.05 of the ``Official Methods of Analysis of the
Association of Official Analytical Chemists,'' 16th ed., which are
incorporated by reference at Sec. 106.160; or
(iii) The scientific evidence on such infant formula otherwise
demonstrates that the protein in such infant formula is of sufficient
biological quality.
(3) The manufacturer of an eligible infant formula may, not later
than November 12, 2015, submit a petition to the Food and Drug
Administration under Sec. 10.30 of this chapter that:
(i) Demonstrates that such formula fulfills one or more of the
criteria in paragraph (i)(1) of this section; or
(ii) Demonstrates that such formula fulfills one or more of the
criteria in paragraph (i)(2) of this section.
(4) A petition filed under paragraph (i)(3) of this section shall
address only one infant formula formulation and shall contain all data
and information relied upon by the manufacturer to demonstrate that
such formulation fulfills one or more of the criteria in paragraph
(i)(1) or in paragraph (i)(2) of this section. A manufacturer may
combine petitions submitted under paragraphs (i)(3)(i) and (i)(3)(ii)
of this section that relate to the same formulation.
(5) The manufacturer of each eligible infant formula shall make and
retain, in accordance with Sec. 106.100(p)(2), records to demonstrate
that such formula supports normal physical growth in infants when fed
as the sole source of nutrition and shall make and retain, in
accordance with Sec. 106.100(q)(2), records to demonstrate that that
the protein in such infant formula is of sufficient biological quality.
The records required by this paragraph shall include all relevant
scientific data and information and a narrative explanation of why the
data and information demonstrate that the formula supports normal
physical growth and a narrative explanation of why the data and
information demonstrate that the protein in such infant formula is of
sufficient biological quality.
Subpart F--Records and Reports
Sec. 106.100 Records.
(a) Every manufacturer of infant formula shall maintain the records
specified in this regulation in order to permit the Food and Drug
Administration to determine whether each manufacturer is in compliance
with section 412 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
350a)).
(b) The manufacturer shall maintain all records that pertain to
food-packaging materials subject to Sec. 174.5 of this chapter and
that bear on whether such materials would cause an infant formula to be
adulterated within the meaning of section 402(a)(2)(C) of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 342(a)(2)(C)).
(c) The manufacturer shall maintain all records that pertain to
nutrient premix testing that it generates or receives. Such records
shall include, but are not limited to:
(1) Any results of testing conducted to ensure that each nutrient
premix is in compliance with the premix certificate and guarantee and
specifications that have been provided to the manufacturer by the
premix supplier, including tests conducted when nutrients exceed their
expiration date or shelf life (retest date).
(2) All certificates and guarantees given by premix suppliers
concerning the nutrients required by section 412(i) of the Federal
Food, Drug, and Cosmetic Act and Sec. 107.100 of this chapter.
(d) The premix supplier shall maintain the results of all testing
conducted to provide all certificates and guarantees concerning
nutrient premixes for infant formulas. Such records shall include but
are not limited to:
(1) The results of tests conducted to determine the purity of each
nutrient required by section 412(i) of the Federal Food, Drug, and
Cosmetic Act or Sec. 107.100 of this chapter and any other nutrient
listed in the certificate and guarantee;
(2) The weight of each nutrient added;
(3) The results of any quantitative tests conducted to determine
the amount of each nutrient certified or guaranteed; and
(4) The results of any quantitative tests conducted to identify the
nutrient levels present when nutrient premixes exceed their expiration
date or shelf life (retest date).
(e) For each production aggregate of infant formula, a manufacturer
shall prepare and maintain records that include complete information
relating to the production and control of the production aggregate.
These records shall include:
(1) The master manufacturing order. The master manufacturing order
shall include:
(i) The significant steps in the production of the production
aggregate and the date on which each significant step occurred;
(ii) For a manufacturing facility that has more than one set of
equipment or more than one processing line, the identity of equipment
and processing lines for which the manufacturer has identified points,
steps, or stages in the production process where control is necessary
to prevent adulteration;
(iii) The identity of each lot of ingredients, containers, and
closures used in producing the production aggregate of formula;
(iv) The amount of each ingredient to be added to the production
aggregate of
[[Page 8069]]
infant formula and a check (verification) that the correct amount was
added; and
(v) A copy of each infant formula label used on a finished
production aggregate of infant formula and the results of examinations
conducted during the finishing operations to provide assurance that the
containers and packages have the correct label.
(2) Any deviations from the master manufacturing order and any
corrective actions taken because of the deviations.
(3) Documentation, in accordance with Sec. 106.6(c), of the
monitoring at any point, step, or stage in the manufacturer 's
production process where control is deemed necessary to prevent
adulteration. These records shall include:
(i) A list of the specifications established at each point, step,
or stage in the production process where control is deemed necessary to
prevent adulteration, in accordance with Sec. 106.6(c)(1), including
documentation of the scientific basis for each specification;
(ii) The actual values obtained during the monitoring operation,
any deviations from established specifications, and any corrective
actions taken; and
(iii) Identification of the person monitoring each point, step, or
stage in the production process where control is deemed necessary to
prevent adulteration.
(4) The conclusions and followup, along with the identity of the
individual qualified by education, training, or experience who
investigated:
(i) Any deviation from the master manufacturing order and any
corrective actions taken;
(ii) A finding that a production aggregate or any of its
ingredients failed to meet the infant formula manufacturer's
specifications; and
(iii) A failure to meet any specification at any point, step, or
stage in the production process where control is deemed necessary to
prevent adulteration.
(5) The results of all testing performed on the production
aggregate of infant formula, including testing on the in-process
production aggregate, at the final product stage, and on finished
product throughout the shelf life of the product. The results recorded
shall include:
(i) The results of all quality control testing conducted in
accordance with Sec. 106.91(a) and (b) to verify that each nutrient
required by Sec. 107.100 of this chapter is present in each production
aggregate of infant formula at the level required by Sec. 107.100 of
this chapter, and that all other nutrients added by the manufacturer
are present at the appropriate level. The record of the results of the
quality control testing shall include:
(A) A summary document identifying the stages of the manufacturing
process at which the nutrient analysis for each required nutrient is
conducted as required under Sec. 106.91(a); and
(B) A summary document on the stability testing program conducted
under Sec. 106.91(b), including the nutrients tested and the frequency
of nutrient testing throughout the shelf life of the product.
(ii) For powdered infant formula, the results of any testing
conducted in accordance with Sec. 106.55(c) to verify compliance with
the microbiological quality standards in Sec. 106.55(e).
(f) A manufacturer shall make and retain all records described in
subparts B and C of this part, including:
(1) Records, in accordance with Sec. 106.20(f)(4), of the
frequency and results of testing of the water used in the production of
infant formula;
(2) Records, in accordance with Sec. 106.30(d), of accuracy checks
of instruments and controls. A certification of accuracy of any known
reference standard used and a history of recertification shall be
maintained. At a minimum, such records shall specify the instrument or
control being checked, the date of the accuracy check, the standard
used, the calibration method used, the results found, any actions taken
if the instrument is found to be out of calibration, and the initials
or name of the individual performing the test. If calibration of an
instrument shows that a specification at a point, step, or stage in the
production process where control is deemed necessary to prevent
adulteration has not been met, a written evaluation of all affected
product, and any actions that need to be taken with respect to that
product, shall be made.
(3) Records, in accordance with Sec. 106.30(e)(3)(iii).
(4) Records, in accordance with Sec. 106.30(f), on equipment
cleaning, sanitizing, and maintenance that show the date and time of
such cleaning, sanitizing, and maintenance and the lot number of each
production aggregate of infant formula processed between equipment
startup and shutdown for cleaning, sanitizing, and maintenance. The
person performing and checking the cleaning, sanitizing, and
maintenance shall date and sign or initial the record indicating that
the work was performed.
(5) Records, in accordance with Sec. 106.35(c), on all mechanical
and electronic equipment used in the production or quality control of
infant formula. These records shall include:
(i) A list of all systems used with a description of the computer
files and the defined capabilities and inherent limitations of each
system;
(ii) A copy of all software used;
(iii) Records that document installation, calibration, testing or
validation, and maintenance of the systems used;
(iv) A list of all persons authorized to create or modify software;
(v) Records that document modifications to software, including the
identity of the person who modified the software;
(vi) Records that document retesting or revalidation of modified
systems; and
(vii) A backup file of data entered into a computer or related
system. The backup file shall consist of a hard copy or alternative
system, such as duplicate electronic records, tapes, or microfilm,
designed to ensure that backup data are exact and complete, and that
they are secure from alteration, inadvertent erasures, or loss.
(6) Records, in accordance with Sec. 106.40(g), on ingredients,
containers, and closures used in the manufacture of infant formula.
These records shall include:
(i) The identity and quantity of each lot of ingredients,
containers, and closures;
(ii) The name of the supplier;
(iii) The supplier's lot numbers;
(iv) The name and location of the manufacturer of the ingredient,
container, or closure, if different from the supplier;
(v) The date of receipt;
(vi) The receiving code as specified; and
(vii) The results of any test or examination (including retesting
and reexamination) performed on the ingredients, containers, or
closures and the conclusions derived there from and the disposition of
all ingredients, containers, or closures.
(7) A full description of the methodology used to test powdered
infant formula to verify compliance with the microbiological quality
standards of Sec. 106.55(c) and the methodology used to do quality
control testing, in accordance with Sec. 106.91(a).
(g) A manufacturer shall maintain all records pertaining to
distribution of the infant formula, including records that show that
formula produced for export only is exported. Such records shall
include all information and data necessary to effect and monitor
recalls of the manufacturer's infant formula products in accordance
with subpart E of part 107 of this chapter.
[[Page 8070]]
(h) The manufacturer shall maintain all records pertaining to the
microbiological quality and purity of raw materials and finished
powdered infant formula.
(i) [Reserved]
(j) The manufacturer shall make and retain records pertaining to
regularly scheduled audits, including the audit plans and procedures,
the findings of the audit, and a listing of any changes made in
response to these findings. The manufacturer shall make readily
available for authorized inspection the audit plans and procedures and
a statement of assurance that the regularly scheduled audits are being
conducted. The findings of the audit and any changes made in response
to these findings shall be maintained for the time period required
under paragraph (n) of this section, but need not be made available to
the Food and Drug Administration.
(k) The manufacturer shall maintain procedures describing how all
written and oral complaints regarding infant formula will be handled.
The manufacturer shall follow these procedures and shall include in
them provisions for the review of any complaint involving an infant
formula and for determining the need for an investigation of the
possible existence of a hazard to health.
(1) For purposes of this section, every manufacturer shall
interpret a ``complaint'' as any communication that contains any
allegation, written or oral, expressing dissatisfaction with a product
for any reason, including concerns about the possible existence of a
hazard to health and about appearance, taste, odor, and quality.
Correspondence about prices, package size or shape, or other matters
that could not possibly reveal the existence of a hazard to health
shall not, for compliance purposes, be considered a complaint and
therefore need not be made available to a Food and Drug Administration
investigator.
(2) When a complaint shows that a hazard to health possibly exists,
the manufacturer shall conduct an investigation into the validity of
the complaint. Where such an investigation is conducted, the
manufacturer shall include in its file on the complaint the
determination as to whether a hazard to health exists and the basis for
that determination. No investigation is necessary when the manufacturer
determines that there is no possibility of a hazard to health. When no
investigation is necessary, the manufacturer shall include in the
record the reason that an investigation was found to be unnecessary and
the name of the responsible person making that determination.
(3) When there is a reasonable possibility of a causal relationship
between the consumption of an infant formula and an infant's death, the
manufacturer shall, within 15 days of receiving such information,
conduct an investigation and notify the Agency as required in Sec.
106.150.
(4) The manufacturer shall maintain in designated files all records
pertaining to the complaints it receives. The manufacturer shall
separate the files into two classes:
(i) Those complaints that allege that the infant became ill from
consuming the product or required treatment by a physician or health
care provider and
(ii) Those complaints that may involve a possible existence of a
hazard to health but do not refer to an infant becoming ill or the need
for treatment by physician or a health care provider.
(5) The manufacturer shall include in a complaint file the
following information concerning the complaint:
(i) The name of the infant formula;
(ii) The batch number;
(iii) The name of complainant;
(iv) A copy of the complaint or a memo of the telephone
conversation or meeting and all correspondence with the complainant;
(v) By reference or copy, all the associated manufacturing records
and complaint investigation records needed to evaluate the complaint.
When copies of such records are not maintained in the complaint file,
they must be available within 24 hours when requested by a Food and
Drug Administration official.
(vi) All actions taken to followup on the complaint; and
(vii) All findings and evaluations of the complaint.
(6) The manufacturer should maintain the files regarding infant
formula complaints at the establishment where the infant formula was
manufactured, processed, or packed. When the manufacturer wishes to
maintain all consumer complaints for the entire firm at one location
other than at the facility where an infant formula was manufactured,
processed, or packed, the manufacturer may do so as long as all records
required by this section are available within 24 hours of request for
inspection at that facility. However, all records of consumer
complaints, including summaries, any reports, and any files, maintained
at the manufacturing facility or at any other facility shall be made
available to investigators for review and copying upon request.
(l) The manufacturer shall make readily available for authorized
inspection all records required under this part or copies of such
records. Records shall be available at any reasonable time at the
establishment where the activities described in such records occurred.
(Infant formula complaint files may be maintained at one facility, as
provided in paragraph (k)(6) of this section, if all required records
are readily available at that facility.) These records or copies
thereof shall be subject to photocopying or other means of reproduction
as part of such inspection. Records that can be immediately retrieved
from another location by electronic means shall be considered as
meeting the requirements of this paragraph.
(m) A manufacturer shall maintain all records required under part
106 in a manner that ensures that both the manufacturer and the Food
and Drug Administration can be provided with immediate access to such
records. The manufacturer may maintain the records required under part
106 as original records, as true copies such as photocopies, microfilm,
microfiche, or other accurate reproductions of the original records, or
as electronic records. Where reduction techniques, such as
microfilming, are used, suitable reader and photocopying equipment
shall be readily available. All electronic records maintained under
part 106 shall comply with part 11 of this chapter.
(n) Production control, product testing, testing results,
complaints, and distribution records necessary to verify compliance
with parts 106, 107, 109, 110, and 113 of this chapter, or with other
appropriate regulations, shall be retained for 1 year after the
expiration of the shelf life of the infant formula or 3 years from the
date of manufacture, whichever is greater.
(o) The manufacturer shall maintain quality control records that
contain sufficient information to permit a public health evaluation of
any batch of infant formula.
(p) A manufacturer shall make and retain records that demonstrate
that the formula meets the quality factor of normal physical growth.
(1) For an infant formula that is not an eligible infant formula,
in accordance with Sec. 106.96(d), these records shall include:
(i) Records demonstrating compliance with the requirements in Sec.
106.96(b), including records made in compliance with Sec. 106.121; or
(ii) Records demonstrating satisfaction of an applicable exemption
under Sec. 106.96(c), including records made in compliance with Sec.
106.121.
[[Page 8071]]
(2) For an eligible infant formula, in accordance with Sec.
106.96(i)(5), these records shall include records demonstrating that
the formula fulfills one or more of the criteria listed in Sec.
106.96(i)(1).
(q) A manufacturer shall make and retain records that demonstrate
that a formula meets the quality factor of sufficient biological
quality of protein.
(1) For an infant formula that is not an eligible infant formula,
in accordance with Sec. 106.96(h), these records shall include:
(i) Records demonstrating compliance with the requirements in Sec.
106.96(f), including records made in compliance with Sec. 106.121; or
(ii) Records demonstrating satisfaction of an applicable exemption
under Sec. 106.96(g), including records made in compliance with Sec.
106.121.
(2) For an eligible infant formula, in accordance with Sec.
106.96(i)(5), these records shall include records demonstrating that
the formula fulfills one or more of the criteria listed in Sec.
106.96(i)(2).
(r) The failure to comply with the records requirements in this
section applicable to the quality factors shall render the formula
adulterated under section 412(a)(2) of the Federal Food, Drug, and
Cosmetic Act. The failure to comply with the records requirements in
this section applicable to the good manufacturing practices and quality
control procedures, including distribution and audit records
requirements, with respect to an infant formula shall render the
formula adulterated under section 412(a)(3) of the Federal Food, Drug,
and Cosmetic Act. A failure to retain or make available records
applicable to the quality factor requirements, quality control
procedures, or current good manufacturing practices requirements in
compliance with paragraph (l), (m), or (n) of this section with respect
to a formula shall render the formula adulterated under section
412(a)(2) or (a)(3) of the Federal Food, Drug, and Cosmetic Act, as
applicable.
Subpart G--Registration, Submission, and Notification Requirements
Sec. 106.110 New infant formula registration.
(a) Before a new infant formula may be introduced or delivered for
introduction into interstate commerce, including a new infant formula
for export only, the manufacturer of the formula shall register with
the Food and Drug Administration, Center for Food Safety and Applied
Nutrition, Office of Nutrition, Labeling, and Dietary Supplements,
Infant Formula and Medical Foods Staff (HFS-850), 5100 Paint Branch
Pkwy., College Park, MD 20740-3835.
(b) The new infant formula registration shall include:
(1) The name of the new infant formula;
(2) The name of the manufacturer;
(3) The street address of the place of business of the
manufacturer; and
(4) The name and street address of each establishment at which the
manufacturer intends to manufacture such new infant formula.
Sec. 106.120 New infant formula submission.
(a) At least 90 days before a new infant formula is introduced or
delivered for introduction into interstate commerce, a manufacturer
shall submit notice of its intent to do so to the Food and Drug
Administration at the address given in Sec. 106.110(a). An original
and two paper copies of such notice of intent shall be submitted,
unless the notice is submitted in conformance with part 11 of this
chapter, in which case a single copy shall be sufficient.
(b) The new infant formula submission shall include:
(1) The name and description of the physical form (e.g., powder,
ready-to feed, or concentrate) of the infant formula;
(2) An explanation of why the formula is a new infant formula;
(3) The quantitative formulation of each form of the infant formula
that is the subject of the notice in units per volume or units per
weight for liquid formulas, specified either as sold or as fed, and
units per dry weight for powdered formulas, and the weight of powder to
be reconstituted with a specified volume of water, and, when
applicable, a description of any reformulation of the infant formula,
including a listing of each new or changed ingredient and a discussion
of the effect of such changes on the nutrient levels in the
formulation;
(4) A description, when applicable, of any change in processing of
the infant formula. Such description shall identify the specific change
in processing, including side-by-side, detailed schematic diagrams
comparing the new processing to the previous processing and processing
times and temperatures;
(5) Assurance that the infant formula will not be marketed unless
the formula meets the requirements for quality factors of section
412(b)(1) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
350a(b)(1)) and the nutrient content requirements of section 412(i) of
the Federal Food, Drug, and Cosmetic Act.
(i) Assurance that the formula meets the requirements for quality
factors, which are set forth in Sec. 106.96, shall be provided by a
submission that complies with Sec. 106.121;
(ii) Assurance that the formula complies with the nutrient content
requirements, which are set forth in Sec. 107.100 of this chapter,
shall be provided by a statement that the formula will not be marketed
unless it meets the nutrient requirements of Sec. 107.100 of this
chapter, as demonstrated by testing required under subpart C of this
part; and
(6) Assurance that the processing of the infant formula complies
with section 412(b)(2) of the Federal Food, Drug, and Cosmetic Act.
Such assurance shall include:
(i) A statement that the formula will be produced in accordance
with subparts B and C of this part; and
(ii) The basis on which each ingredient meets the requirements of
Sec. 106.40(a), e.g. that it is an approved food additive, that it is
authorized by a prior sanction, or that it is generally recognized as
safe (GRAS) for its intended use. Any claim that an ingredient is GRAS
shall be supported by a citation to the Agency's regulations or by an
explanation, including a list of published studies and a copy of those
publications, for why, based on the published studies, there is general
recognition of the safety of the use of the ingredient in infant
formula.
(c) For a new infant formula for export only, a manufacturer may
submit, in lieu of the information required under paragraphs (b)(5) and
(b)(6) of this section, a statement certifying that the infant formula
meets the specifications of the foreign purchaser, the infant formula
does not conflict with the laws of the country to which it is intended
for export, the infant formula is labeled on the outside of the
shipping package to indicate that it is intended for export only, and
the infant formula will not be sold or offered for sale in domestic
commerce. Such manufacturer shall also submit a statement certifying
that it has adequate controls in place to ensure that such formula is
actually exported.
(d) The submission will not constitute notice under section 412 of
the Federal Food, Drug, and Cosmetic Act unless it complies fully with
paragraph (b) of this section, as applicable, and the information that
it contains is set forth in a manner that is readily understandable.
The Agency will notify the manufacturer if the notice is not complete
because it does not meet the requirements in section 412(c) and (d) of
the Federal Food, Drug, and Cosmetic Act.
(e) If a new infant formula submission contains all the information
required by
[[Page 8072]]
paragraph (b) of this section, as applicable, the Food and Drug
Administration will acknowledge its receipt and notify the manufacturer
of the date of receipt. The date that the Agency receives a new infant
formula submission that is complete is the filing date for such
submission. The manufacturer shall not market the new infant formula
before the date that is 90 days after the filing date. If the
information in the submission does not provide the assurances required
under section 412(d)(1) of the Federal Food, Drug, and Cosmetic Act and
the regulations of this chapter, the Food and Drug Administration will
so notify the manufacturer before the expiration of the 90th day.
(f) If the manufacturer provides additional information in support
of a new infant formula submission, the Agency will determine whether
the additional information is a substantive amendment to the new infant
formula submission. If the Agency determines that the new submission is
a substantive amendment, the Food and Drug Administration will assign
the new infant formula submission a new filing date. The Food and Drug
Administration will acknowledge receipt of the additional information
and, when applicable, notify the manufacturer of the new filing date,
which is the date of receipt by the Food and Drug Administration of the
information that constitutes the substantive amendment to the new
infant formula submission.
(g) Submissions relating to exempt infant formulas are subject to
the provisions of Sec. 107.50 of this chapter.
Sec. 106.121 Quality factor assurances for infant formulas.
To provide assurance that an infant formula meets the requirements
for quality factors set forth in Sec. 106.96, the manufacturer shall
submit the following data and information:
(a) Unless the manufacturer of a new infant formula can claim an
exemption under Sec. 106.96(c)(1) or (c)(2), the following assurances
shall be provided to ensure that the requirements of Sec. 106.96(a)
and (b) have been met:
(1) An explanation, in narrative form, setting forth how
requirements for quality factors in Sec. 106.96(b) have been met;
(2) Records that contain the information required by Sec.
106.96(b) to be collected during the study for each infant enrolled in
the study. The records shall be identified by subject number, age,
feeding group, gender, and study day of collection.
(3) Data, which shall include:
(i) Statistical evaluation for all measurements, including group
means, group standard deviations, and measures of statistical
significance for all measurements for each feeding group at the
beginning of the study and at every point where measurements were made
throughout the study, and
(ii) Calculations of the statistical power of the study before
study initiation and at study completion.
(4) A report on attrition and on all occurrences of adverse events
during the study, which shall include:
(i) Identification of the infant by subject number and feeding
group and a complete description of the adverse event, including
comparisons of the frequency and nature of occurrence in each feeding
group and information on the health of the infant during the course of
the study, including the occurrence and duration of any illness;
(ii) A clinical assessment by a health care provider of the
infant's health during each suspected adverse event; and
(iii) A list of all subjects who did not complete the study,
including the subject number and the reason that each subject did not
complete the study.
(b) If the manufacturer is requesting an exemption from the growth
monitoring study requirements under Sec. 106.96(c)(1), the
manufacturer shall include a detailed description of the change made by
the manufacturer to an existing infant formula and an explanation of
why the change made by the manufacturer to an existing infant formula
satisfies the criteria of Sec. 106.96(c)(1).
(c) If the manufacturer is requesting an exemption under Sec.
106.96(c)(2)(i), the manufacturer shall include a detailed description
of the alternative method or alternative study design, an explanation
of why the method or study design is based on sound scientific
principles, and data that demonstrate that the formula supports normal
physical growth in infants when the formula is fed as the sole source
of nutrition.
(d) If the manufacturer is requesting an exemption under Sec.
106.96(c)(2)(ii), the manufacturer shall include a detailed description
of the change and an explanation of why the change made by the
manufacturer to an existing infant formula does not the affect the
bioavailability of the formula, including the bioavailability of the
nutrients in such formula.
(e) If the manufacturer is requesting an exemption under Sec.
106.96(c)(2)(iii), the manufacturer shall include a detailed
description of the two formulations and an explanation of why the
quality factor requirement of normal physical growth is met by the form
of the formula that is processed using the method that has the greatest
potential for adversely affecting nutrient content and bioavailability.
(f) Unless the manufacturer of a new infant formula is requesting
an exemption under Sec. 106.96(g), the results of the Protein
Efficiency Ratio bioassay shall be provided in accordance with Sec.
106.96(f).
(g) If the manufacturer is requesting an exemption under Sec.
106.96(g)(1), the manufacturer shall include a detailed description of
the change made by the manufacturer to an existing infant formula and
an explanation of why the change made by the manufacturer to an
existing infant formula satisfies the criteria listed in Sec.
106.96(g)(1).
(h) If the manufacturer is requesting an exemption under Sec.
106.96(g)(2), the manufacturer shall include a detailed description of
the change and an explanation of why the change made by the
manufacturer to an existing infant formula does not affect the
bioavailability of the protein.
(i) A statement certifying that the manufacturer has collected and
considered all information and data concerning the ability of the
infant formula to meet the requirements for quality factors and that
the manufacturer is not aware of any information or data that would
show that the formula does not meet the requirements for quality
factors.
Sec. 106.130 Verification submission.
(a) A manufacturer shall, after the first production and before the
introduction into interstate commerce of a new infant formula (except
for a new infant formula that is for export only for which a submission
is received in compliance with Sec. 106.120(c)), verify in a written
submission to the Food and Drug Administration at the address given in
Sec. 106.110(a) that the infant formula complies with the requirements
of the Federal Food, Drug, and Cosmetic Act and is not adulterated.
(b) The verification submission shall include the following
information:
(1) The name of the new infant formula; the filing date for the new
infant formula submission, in accordance with Sec. 106.120, for the
subject formula; and the identification number assigned by the Agency
to the new infant formula submission:
(2) A statement that the infant formula to be introduced into
interstate commerce is the same as the infant formula that was the
subject of the new infant formula notification and for which the
manufacturer provided
[[Page 8073]]
assurances in accordance with the requirements of Sec. 106.120;
(3) A summary of test results of the level of each nutrient
required by Sec. 107.100 of this chapter and any nutrient added by the
manufacturer in the formula, presented in units per 100 kilocalories at
the final product stage.
(4) A certification that the manufacturer has established current
good manufacturing practices, including quality control procedures and
in-process controls, and testing required by current good manufacturing
practice, designed to prevent adulteration of this formula in
accordance with subparts B and C of this part.
(c) The submission shall not constitute written verification under
section 412(d)(2) of the Federal Food, Drug, and Cosmetic Act (21
U.S.C. 350a(d)(2)) when any data prescribed in paragraph (b) of this
section are lacking or are not set forth so as to be readily
understood. In such circumstances, the Agency will notify the
manufacturer that the notice is not adequate.
Sec. 106.140 Submission concerning a change in infant formula that
may adulterate the product.
(a) When a manufacturer makes a change in the formulation or
processing of the formula that may affect whether the formula is
adulterated under section 412(a) of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 350a(a)), the manufacturer shall, before the
first processing of such formula, make a submission to the Food and
Drug Administration at the address given in Sec. 106.110(a). An
original and two copies shall be submitted.
(b) The submission shall include:
(1) The name and physical form of the infant formula (i.e., powder,
ready-to-feed, or concentrate);
(2)(i) An explanation of why the change in formulation or
processing may affect whether the formula is adulterated; and
(ii) What steps will be taken to ensure that, before the formula is
introduced into interstate commerce, the formula will not be
adulterated; and
(3) A statement that the submission complies with Sec.
106.120(b)(3), (b)(4), (b)(5), and (b)(6). When appropriate, a
statement to the effect that the information required by Sec.
106.120(b)(3), (b)(4), (b)(5), or (b)(6) has been provided to the
Agency previously and has not been affected by the changes that are the
subject of the current submission, together with the identification
number assigned by the Agency to the relevant infant formula
submission, may be provided in lieu of such statement.
(c) The submission shall not constitute notice under section 412 of
the Federal Food, Drug, and Cosmetic Act unless it complies fully with
paragraph (b) of this section, and the information that it contains is
set forth in a manner that is readily understandable. The Agency will
notify the manufacturer if the notice is not adequate because it does
not meet the requirements of section 412(d)(3) of the Federal Food,
Drug, and Cosmetic Act.
Sec. 106.150 Notification of an adulterated or misbranded infant
formula.
(a) A manufacturer shall promptly notify the Food and Drug
Administration in accordance with paragraph (b) of this section when
the manufacturer has knowledge (that is, actual knowledge that the
manufacturer had, or the knowledge which a reasonable person would have
had under like circumstances or which would have been obtained upon the
exercise of due care) that reasonably supports the conclusion that an
infant formula that has been processed by the manufacturer and that has
left an establishment subject to the control of the manufacturer:
(1) May not provide the nutrients required by section 412(i) of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C 350d(i)) or by
regulations issued under section 412(i)(2); or
(2) May be otherwise adulterated or misbranded.
(b) The notification made according to paragraph (a) of this
section shall be made by telephone, to the Director of the appropriate
Food and Drug Administration district office. After normal business
hours (8 a.m. to 4:30 p.m.), the Food and Drug Administration's
emergency number, 1-866-300-4374 shall be used. The manufacturer shall
promptly send written confirmation of the notification to the Food and
Drug Administration, Center for Food Safety and Applied Nutrition,
Office of Compliance, Division of Enforcement (HFS-605), Recall
Coordinator, 5100 Paint Branch Pkwy., College Park, MD 20740, and to
the appropriate Food and Drug Administration district office.
Sec. 106.160 Incorporation by reference.
(a) Certain material is incorporated by reference into this part
with the approval of the Director of the Federal Register under 5
U.S.C. 552(a) and 1 CFR part 51. To enforce any edition other than that
specified in this section, the Food and Drug Administration must
publish notice of change in the Federal Register and the material must
be available to the public. All approved material is available for
inspection at the Food and Drug Administration library at 10903 New
Hampshire Ave., Building 2, Third Floor, Silver Spring, MD 20993, 301-
796-2039, and is available from the sources listed below. This material
is also available for inspection at the National Archives and Records
Administration (NARA). For information on the availability of this
material at NARA, call 202-741-6030 or go to: http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html.
(b) 3-A Sanitary Standards, Inc., 6888 Elm St., Suite 2D, McLean,
VA 22101-3829, 703-790-0295, and may be ordered online at http://www.3-a.org/:
(1) 3-A Sanitary Standards, No. 609-03: A Method of Producing
Culinary Steam, adopted November 21, 2004, into Sec. 106.20(h).
(2) [Reserved]
(c) American Society for Nutrition, 9650 Rockville Pike, Bethesda,
MD 20814-3998, 301-634-7279, http://www.nutrition.org:
(1) Physical growth: National Center for Health Statistics
percentiles, Hamill, P.V.V., T.A. Drizd, C.L. Johnson, R.B. Reed, A.F.
Roche, and W.M. Moore, American Journal of Clinical Nutrition, vol. 32,
pp. 607-614, dated March 1979, into Sec. 106.96(i)(1)(ii)(c).
(2) [Reserved]
(d) AOAC International, 481 North Frederick Ave., suite 500,
Gaithersburg, MD 20877-2417, 301-924-7078:
(1) Official Methods of Analysis of AOAC International, 16th ed.,
dated 1995, into Sec. 106.96(i)(2)(ii):
(i) Section 45.3.04, AOAC Official Method 960.48 Protein Efficiency
Ratio Rat Bioassay, and
(ii) Section 45.3.05, AOAC Official Method 982.30 Protein
Efficiency Ratio Calculation Method.
(2) Official Methods of Analysis of AOAC International, 18th ed.,
dated 2005, into Sec. 106.96(f):
(i) Section 45.3.04, AOAC Official Method 960.48 Protein Efficiency
Ratio Rat Bioassay, and
(ii) Section 45.3.05, AOAC Official Method 982.30 Protein
Efficiency Ratio Calculation Method.
(e) Centers for Disease Control and Prevention, 1600 Clifton Rd.,
Atlanta, GA 30333, 1-800-232-4636, http://www.cdc.gov/growthcharts/who_charts.htm.
(1) Birth to 24 months: Boys Head circumference-for-age and Weight-
for-length percentiles, dated November 1, 2009, into Sec.
106.96(b)(4).
(2) Birth to 24 months: Boys Length-for-age and Weight-for-age
percentiles, dated November 1, 2009, into Sec. 106.96(b)(4).
[[Page 8074]]
(3) Birth to 24 months: Girls Head circumference-for-age and
Weight-for-length percentiles, dated November 1, 2009, into Sec.
106.96(b)(4).
(4) Birth to 24 months: Girls Length-for-age and Weight-for-age
percentiles, dated November 1, 2009, into Sec. 106.96(b)(4).
PART 107--INFANT FORMULA
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2. The authority citation for 21 CFR part 107 continues to read as
follows:
Authority: 21 U.S.C. 321, 343, 350a, 371.
0
3. Add Sec. 107.1 to subpart A to read as follows:
Sec. 107.1 Status and applicability of the regulations in part 107.
(a) The criteria in subpart B of this part describe the labeling
requirements applicable to infant formula under section 403 of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C 343). Failure to comply
with any regulation in subpart B of this part will render an infant
formula misbranded under section 403 of the Federal Food, Drug, and
Cosmetic Act.
(b) The criteria in subpart C of this part describe the terms and
conditions for the exemption of an infant formula from the requirements
of section 412(a), (b), and (c) of the Federal Food, Drug, and Cosmetic
Act (21 U.S.C. 350a(a), (b), and (c)). Failure to comply with any
regulations in subpart C of this part will result in withdrawal of the
exemption given under section 412(h)(1) of the Federal Food, Drug, and
Cosmetic Act.
(c) Subpart D of this part contains the nutrient requirements for
infant formula under section 412(i) of the Federal Food, Drug, and
Cosmetic Act. Failure to comply with any regulation in subpart D of
this part will render an infant formula adulterated under section
412(a)(1) of the Federal Food, Drug, and Cosmetic Act.
(d) An exempt infant formula is subject to the provisions of Sec.
107.50 and other applicable Food and Drug Administration food
regulations.
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4. Amend Sec. 107.3 by revising the definition of ``Manufacturer'' to
read as follows:
Sec. 107.3 Definitions.
* * * * *
Manufacturer. 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. The
term ``manufacturer'' does not include a person who 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.
* * * * *
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5. Amend Sec. 107.10 by revising paragraph (a) introductory text,
paragraph (a)(2) introductory text, and paragraph (b)(5) to read as
follows:
Sec. 107.10 Nutrient information.
(a) The labeling of infant formulas, as defined in section 201(z)
of the Federal Food, Drug, and Cosmetic Act, shall bear in the order
given, in the units specified, and in tabular format, the following
information regarding the product as prepared in accordance with label
directions for infant consumption:
* * * * *
(2) A statement of the amount, supplied by 100 kilocalories, of
each of the following nutrients and of any other nutrient added by the
manufacturer:
* * * * *
(b) * * *
(5) Any additional vitamin may be declared at the bottom of the
vitamin list and any additional minerals may be declared between iodine
and sodium, provided that any additionally declared nutrient:
(i) Has been identified as essential by the Food and Nutrition
Board of the Institute of Medicine through its development of a Dietary
Reference Intake, or has been identified as essential by the Food and
Drug Administration through a Federal Register publication; and
(ii) Is provided at a level considered in these publications as
having biological significance, when these levels are known.
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6. Amend Sec. 107.50 by revising paragraph (e) to read as follows:
Sec. 107.50 Terms and conditions.
* * * * *
(e) Notification requirements. (1) Information required by
paragraphs (b) and (c) of this section shall be submitted to the Food
and Drug Administration, Center for Food Safety and Applied Nutrition,
Office of Nutrition, Labeling, and Dietary Supplements, Infant Formula
and Medical Foods Staff (HFS-850), Food and Drug Administration, 5100
Paint Branch Pkwy., College Park, MD 20740.
(2) The manufacturer shall promptly notify the Food and Drug
Administration when the manufacturer has knowledge (as defined in
section 412(c)(2) of the Federal Food, Drug, and Cosmetic Act) that
reasonably supports the conclusion that an exempt infant formula that
has been processed by the manufacturer and that has left an
establishment subject to the control of the manufacturer may not
provide the nutrients required by paragraph (b) or (c) of this section,
or when there is an exempt infant formula that may be otherwise
adulterated or misbranded and if so adulterated or misbranded presents
a risk of human health. This notification shall be made, by telephone,
to the Director of the appropriate Food and Drug Administration
district office specified in part 5, subpart M of this chapter. After
normal business hours (8 a.m. to 4:30 p.m.), contact the Food and Drug
Administration Emergency Call Center at 866-300-4374. The manufacturer
shall send a followup written confirmation to the Center for Food
Safety and Applied Nutrition (HFS-605), Food and Drug Administration,
5100 Paint Branch Pkwy., College Park, MD 20740, and to the appropriate
FDA district office specified in part 5, subpart M of this chapter.
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7. Revise Sec. 107.240 to read as follows:
Sec. 107.240 Notification requirements.
(a) Telephone report. When a determination is made that an infant
formula is to be recalled, the recalling firm shall telephone within 24
hours the appropriate Food and Drug Administration district office
listed in Sec. 5.115 of this chapter and shall provide relevant
information about the infant formula that is to be recalled.
(b) Initial written report. Within 14 days after the recall has
begun, the recalling firm shall provide a written report to the
appropriate FDA district office. The report shall contain relevant
information, including the following cumulative information concerning
the infant formula that is being recalled:
(1) Number of consignees notified of the recall and date and method
of notification, including recalls required by Sec. 107.200,
information about the notice provided for retail display, and the
request for its display.
(2) Number of consignees responding to the recall communication and
quantity of recalled infant formula on hand at each consignee at the
time the communication was received.
(3) Quantity of recalled infant formula returned or corrected by
each consignee contacted and the quantity of recalled infant formula
accounted for.
(4) Number and results of effectiveness checks that were made.
(5) Estimated timeframes for completion of the recall.
(c) Status reports. The recalling firm shall submit to the
appropriate FDA district office a written status report on the recall
at least every 14 days until the recall is terminated. The status
report shall describe the steps taken by the
[[Page 8075]]
recalling firm to carry out the recall since the last report and the
results of these steps.
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8. Amend Sec. 107.250 by revising the introductory text to read as
follows:
Sec. 107.250 Termination of an infant formula recall.
The recalling firm may submit a recommendation for termination of
the recall to the appropriate FDA district office for transmittal to
the Recall Coordinator, Division of Enforcement (HFS-605), Office of
Compliance, Center for Food Safety and Applied Nutrition, 5100 Paint
Branch Pkwy., College Park, MD 20740, or by email to
[email protected], for action. Any such recommendation shall
contain information supporting a conclusion that the recall strategy
has been effective. The Agency will respond within 15 days of receipt
by the Division of Enforcement of the request for termination. The
recalling firm shall continue to implement the recall strategy until it
receives final written notification from the Agency that the recall has
been terminated. The Agency will send such notification, unless the
Agency has information from FDA's own audits or from other sources
demonstrating that the recall has not been effective. The Agency may
conclude that a recall has not been effective if:
* * * * *
Dated: January 28, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-02148 Filed 2-6-14; 8:45 am]
BILLING CODE 4160-01-P