[Federal Register Volume 61, Number 132 (Tuesday, July 9, 1996)]
[Proposed Rules]
[Pages 36154-36219]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-17058]
[[Page 36153]]
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Part III
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
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21 CFR Parts 106 and 107
Current Good Manufacturing Practice, Quality Control Procedures,
Quality Factors, Notification Requirements, and Records and Reports,
for the Production of Infant Formula; Proposed Rule
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 /
Proposed Rules
[[Page 36154]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 106 and 107
[Docket No. 95N-0309]
RIN 0910-AA04
Current Good Manufacturing Practice, Quality Control Procedures,
Quality Factors, Notification Requirements, and Records and Reports,
for the Production of Infant Formula
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to revise
its infant formula regulations to establish requirements for quality
factors and current good manufacturing practice (CGMP); to amend its
quality control procedure, notification, and records and report
requirements for infant formulas; to require that infant formulas
contain, and be tested for, required nutrients and for any nutrient
added by the manufacturer throughout their shelf life, and that they be
produced under strict microbiological controls; and to require that
manufacturers implement the CGMP and quality control procedure
requirements by establishing a production and in-process control system
of their own design. This action is being taken to improve the
protection of infants that use infant formula products.
DATES: Comments by October 7, 1996, except that comments regarding
information collection should be submitted by August 8, 1996. The
agency proposes that any final rule that may issue based on this
proposal become effective 120 days after its date of publication.
ADDRESSES: Submit written comments, data, or information to the Dockets
Management Branch (HFA-305), Food and Drug Administration, rm. 1-23,
12420 Parklawn Dr., Rockville, MD 20857. Comments regarding information
collection to the Office of Information and Regulatory Affairs, OMB,
New Executive Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC
20503, ATTN: Desk Officer for FDA.
FOR FURTHER INFORMATION CONTACT: Carolyn W. Miles, Center for Food
Safety and Applied Nutrition (HFS-456), Food and Drug Administration,
200 C St. SW., Washington, DC 20204, 202-401-9858.
SUPPLEMENTARY INFORMATION:
I. Background
A. The Infant Formula Act of 1980
In 1978, a major manufacturer of infant formula reformulated two of
its soy products by discontinuing the addition of salt. This
reformulation resulted in infant formula products that contained an
inadequate amount of chloride, an essential nutrient for growth and
development in infants. By mid-1979, a substantial number of infants
had been diagnosed with hypochloremic metabolic alkalosis, a syndrome
associated with chloride deficiency. Development of this syndrome in
these infants was found to be associated with prolonged exclusive use
of chloride-deficient soy formulas.
After reviewing the matter, Congress determined that, to improve
protection of infants using infant formula products, greater regulatory
control over the formulation and production of infant formula was
needed, including modifications of industry's and FDA's recall
procedures. Accordingly, Congress passed, and the President signed into
law on September 26, 1980, the Infant Formula Act of 1980 (the 1980
act) (Pub. L. 96-359). This law amended the act to include section 412
(21 U.S.C. 350a).
In 1982, FDA adopted infant formula recall procedures, establishing
subpart D of part 107 of its regulations (21 CFR part 107) (47 FR
18832, April 30, 1982), and infant formula quality control procedures
(21 CFR part 106 (47 FR 17016, April 20, 1982)). In 1985, FDA further
implemented the 1980 act by establishing subparts B, C, and D in 21 CFR
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).
B. The 1986 Amendments to the Infant Formula Act
In 1986, Congress, as part of the Drug Enforcement, Education, and
Control Act of 1986 (the 1986 amendments) (Pub. L. 99-570) completely
revamped section 412 of the act to address concerns that had been
expressed by Congress and consumers about the 1980 act and FDA's
implementation of that statute. These concerns included whether the
quality control testing, CGMP, recordkeeping, and recall requirements
that FDA had adopted would prevent children ``from ever again being
threatened by defective baby formula'' (Ref. 1). The 1986 amendments:
(1) State that an infant formula is deemed to be adulterated unless it
provides certain required nutrients, meets the quality factor
requirements established by the Secretary of Health and Human Services
(the Secretary) (and, by delegation, FDA), and is manufactured in
accordance with CGMP and quality control procedures established by the
Secretary; (2) require that the Secretary issue regulations
establishing requirements for quality factors and CGMP, including
quality control procedures; (3) require that infant formula
manufacturers regularly audit their operations to ensure that those
operations comply with CGMP and quality control procedure regulations;
(4) expand the circumstances in which manufacturers must make a
submission to the agency to include when a manufacturer makes major
changes in an infant formula, and when a manufacturer makes changes
that may affect whether the formula is adulterated; (5) specify the
nutrient quality control testing that must be done on each batch of
infant formula; (6) modify the infant formula recall requirements; and
(7) give the Secretary authority to establish requirements for
retention of records, including records necessary to demonstrate
compliance with CGMP and quality control procedures.
In 1989, the agency responded to the provisions of the 1986
amendments on recalls (sections 412(f) and (g) of the act) by
establishing subpart E in part 107 (54 FR 4006, January 27, 1989). In
1991, the agency adopted infant formula record and record retention
requirements that implemented the 1986 amendments by revising
Sec. 106.100 (56 FR 66566, December 24, 1991).
Although the agency has adopted regulations that respond to a
number of the provisions of the 1986 amendments, it has not issued
regulations on infant formula CGMP and quality factors or revised the
notification procedures and quality control procedures to reflect the
1986 amendments. Since the passage of the 1986 amendments, agency
representatives have visited infant formula plants to observe the
manufacturing practice and quality control procedures that they employ,
and the agency has solicited and received recommendations on CGMP from
the Infant Formula Council. In addition, FDA has contracted with the
Committee on Nutrition of the American Academy of Pediatrics (CON/AAP)
to obtain expert advice on clinical testing of infant formulas with
respect to the quality factor requirements. Moreover, both industry and
the agency have
[[Page 36155]]
increased experience with the quantity and quality of information that
should be submitted to meet the notification requirements of section
412(c) and (d) of the act.
This proposal addresses CGMP, quality control procedures, quality
factors, and notification procedures and incorporates information
resulting from the interactions between FDA and industry and between
FDA and AAP. This proposal updates the language in part 107 to reflect
the 1986 amendments and the November 1992 reorganization of the Center
for Food Safety and Applied Nutrition (CFSAN).
C. FDA's Regulations on Nutrient Requirements
Section 412(i) of the act includes a table that lists nutrients
that every infant formula must contain. This section also establishes a
minimum level for each of the listed nutrients and a maximum level for
eight of the listed nutrients. In addition, section 412(i)(2) of the
act grants the Secretary (and by delegation FDA) the authority to
revise the list of nutrients in section 412(i), and the minimum and
maximum levels of those nutrients, by regulation. In the Federal
Register of October 30, 1995, FDA established the nutrient requirements
for infant formulas in Sec. 107.100 (50 FR 45106). 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,'' and
the levels of these required nutrients established in Sec. 107.100 will
be referred to as ``required levels.''
II. The Need for Regulation
Relative to per unit of body weight, nutrient requirements are
generally greater in infancy than at any other time during life. During
the first year, the rate of growth is at its maximum, with birth weight
typically doubling by 4 months of age and tripling by 1 year (Refs. 2
and 3). Moreover, the metabolic rate in infants is greater, and the
turnover of nutrients is more rapid, than in adults (Ref. 4). Thus,
infants must ingest adequate nutrients to support a rapid rate of
growth and of developmental changes and to supply maintenance needs.
Without adequate nutrition, infants would be unable to achieve their
genetic potential for growth and development.
These nutritional needs must be met in early infancy by food in
liquid form. Sucking and involuntary swallow reflexes are the
mechanisms by which very young infants ingest food until teeth and
motor coordination develop. Consequently, for infants who are not fed
breast milk, infant formula often serves as the sole source, or the
major source, of nutrition during this time of rapid growth and
development.
Therefore, the importance of proper infant formula manufacture,
composition, and nutrient levels cannot be overstated. Senator
Metzenbaum explained why infant formula needs more regulation than
other foods when he stated ``there is simply no margin for error in the
production of baby formula. An infant relies on the formula to sustain
life and provide the proper nourishment at a time of rapid physical and
mental development'' (Ref. 1). The requirements contained in this
proposal are designed to ensure that the formula fed to American
infants fulfills its important function.
The CGMP and quality control procedures that FDA is proposing are
designed to prevent the production of an adulterated infant formula.
Defining CGMP will help to ensure that all of the required nutrients
are included at appropriate levels in the formula, and that the formula
is not contaminated with microorganisms or other materials that may be
harmful to the infant.
Quality control procedures are designed to ensure that an infant
formula contains the nutrients that are necessary to support growth and
development, at the appropriate levels, not only when it enters into
commerce but throughout its shelf life. FDA is proposing that each
batch of infant formula be tested for all required nutrients and any
nutrient added by the manufacturer, and that finished batches be
periodically sampled and tested for nutrients throughout the shelf life
of the product.
Quality factors are designed to ensure that the required nutrients
and any nutrient added by the manufacturer actually reach the infant in
a useable form. Quality factors ``pertain to the bioavailability of a
nutrient and the maintenance of level or potency of nutrients during
the expected shelf life of the product'' (Ref. 5). The 1986 amendments
directed that the Secretary, by regulation, ``establish requirements
for quality factors for infant formulas to the extent possible
consistent with current scientific knowledge, including quality factor
requirements for the nutrients required by (section 412(i) of the
act).''
In 1986, FDA advised Congress that the technology and science with
respect to quality factors was still evolving, and that it was only
possible to establish a quality factor for one nutrient. The agency
said that it had already done so. However, in the 1986 Congressional
Record (Ref. 1), Senator Metzenbaum stated that ``the legislation
contemplates that the Secretary will move to promptly develop and issue
appropriate quality factor standards for different nutrients as the
state of the science progresses.'' Since that time, as stated above,
FDA has contracted with CON/AAP to obtain expert advice on quality
factors; i.e., on the clinical testing of infant formula with respect
to its nutritional safety and suitability for term infants.
In 1988, CON/AAP submitted a report (Ref. 6) under the contract
that identified and discussed the types of clinical studies that might
be considered for evaluation of the nutritional suitability of a
formula for normal term infants. FDA has reviewed this report and the
available scientific literature and has identified quality factors for
protein and for complete infant formulas. The agency is proposing to
adopt these quality factors as part of these regulations.
FDA has received numerous inquiries from industry for specific
guidance on what information must be submitted to meet the requirements
of sections 412(c) and (d) of the act, which state when a manufacturer
must register with, submit to, or notify the agency about a new or
changed infant formula, and what must be in the registration,
submission, or notification. The agency is responding to these requests
in this proposal. The agency is providing this information not only in
response to these inquiries but also to facilitate more consistent
registrations, submissions, and notifications. The lack of consistency
in the format and content of registrations, submissions, and
notifications has caused inefficiencies and delays in the agency's
review. Accordingly, the agency is proposing to establish a consistent
format and content for infant formula registrations, submissions, and
notifications.
Within the past year, FDA has investigated a number of instances in
which infant formula manufactured in the United States has been
diverted from normal distribution channels and relabeled, sometimes
with counterfeit labels for the same brand of infant formula but in
other instances with counterfeit labels for different formulations.
Infant formula bearing counterfeit labels is a potentially serious
public health problem. It could cause infant formula that is past the
use by date to enter the marketplace if the counterfeit label bears an
incorrect use by date. The more serious consequence of this practice,
however, is that it could cause infants that are intolerant to certain
infant formula ingredients to be fed an incorrect formula, with serious
consequences to the health of the infant,
[[Page 36156]]
if an infant formula has been relabeled with an incorrect label (e.g.,
a milk-based infant formula relabeled to indicate that it is a soy-
based infant formula). Therefore, as part of this proposed regulation,
the agency is requesting comments on new or modified procedures or
controls that could be instituted during the labeling, packaging, or
distribution of infant formula and that would be effective in
preventing or reducing the potential for the diversion of infant
formula from normal distribution channels and its relabeling with
counterfeit labels.
III. Scope of this Document
To implement the 1986 amendments, the agency is proposing to amend
its regulations by adding new subparts B, D, and E to part 106 and by
redesignating existing subparts B, C, and D as subparts C, F, and G.
Table 1 sets out the current and proposed subpart designations.
Table 1
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Subparts Current regulation Proposed regulation
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A................. General Provisions........................... General Provisions.
B................. Quality Control Procedures for Assuring Current Good Manufacturing Practice.
Nutrient Content of Infant Formulas.
C................. Records and Reports.......................... Quality Control Procedures.
D................. Notification Requirements.................... Conduct of Audits.
E................. None......................................... Quality Factors for Infant Formulas.
F................. None......................................... Records and Reports.
G................. None......................................... Registration, Submission, and Notification
Requirements.
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The proposed regulation adds a new Sec. 107.1 and will amend
Sec. 107.10(a)(2) by requiring that ``any nutrient added by the
manufacturer'' be listed on the label. The proposed regulation amends
Secs. 107.240 and 107.250 by changing the reference to the Division of
Regulatory Guidance to the Division of Enforcement to reflect the
November 1992 reorganization of CFSAN.
IV. The Proposed Regulations
A. General Provisions
To reflect the expanded scope of the proposed regulations, FDA is
revising the heading of part 106 to read, ``Infant Formula-Requirements
Pertaining to Current Good Manufacturing Practice, Quality Control
Procedures, Quality Factors, Records and Reports, and Notifications.''
1. Status and Applicability of the Regulations in Part 106
Proposed Sec. 106.1 sets out the authority for each of the proposed
subparts and the consequences under the act of failure to comply with
any of the regulations in the proposed subparts. FDA is including
proposed Sec. 106.1 because it is important for manufacturers to be
aware of the legal consequences of failure to comply with these
regulations, which are being issued to implement specific sections of
the act.
2. Definitions
The agency is proposing to amend Sec. 106.3 by adding several
definitions that are needed to explain activities that specifically
concern the infant formula industry. It is important whenever possible
to maintain consistent terminology throughout the agency's regulations.
Therefore, as described in detail below, FDA has relied, where
possible, on existing definitions in 21 CFR parts 105, 110, and 210 in
arriving at these proposed definitions. Other definitions were derived
from specific provisions in the act.
Proposed Sec. 106.3(a), (g), (h), and (p) incorporate into part 106
the definitions for ``batch,'' ``lot,'' ``lot number, control number,
or batch number,'' and ``representative sample'' derived from 21 CFR
210.3(b)(2), (b)(10), (b)(11), and (b)(21), respectively. In addition
to promoting consistency in the agency's regulations, FDA has
tentatively determined that use of these definitions in part 106 is
appropriate because they permit the agency to refer to the product in
terms that reflect the fact that it is produced in bulk rather than on
a unit-by-unit basis.
Proposed Sec. 106.3(k), (q), and (r) incorporate into part 106 the
definitions for ``microorganisms,'' ``shall,'' and ``should'' from 21
CFR 110.3(i), (p), and (q), respectively. In addition to promoting
consistency, these definitions reflect the generally recognized
scientific or legal meaning of these terms.
Proposed Sec. 106.3(c), (f), (j), and (n) incorporate into part 106
the definitions for ``indicator nutrient,'' ``in-process batch,''
``manufacturer,'' and ``nutrient premix'' from current Sec. 106.3. The
definition of ``manufacturer'' in proposed Sec. 106.3(j) warrants
particular note. In the past there has been some confusion about who is
and who is not a manufacturer of infant formula. This definition makes
clear that a manufacturer is not only a person who combines raw
ingredients together to produce an infant formula but also is a person
who reconstitutes or otherwise changes the physical or chemical
characteristics of an infant formula or who packages or labels the
product in a container for distribution. For example, the agency is
aware of a firm that reconstitutes powdered infant formulas and puts
the reconstituted formula in bottles to sell to hospitals. This
definition makes clear that this firm is a ``manufacturer.''
Proposed Sec. 106.3(d) incorporates into part 106 the definition
for ``infant'' from 21 CFR 105.3(e).
In addition to the definitions derived from FDA's existing
regulations, the agency is proposing to amend Sec. 106.3 by adding
definitions that are derived from the definitions provided by Congress
in the act.
Proposed Sec. 106.3(e) and (l) incorporate into part 106 the
definitions for ``infant formula'' and ``new infant formula'' from
sections 201(aa) (21 U.S.C. 321(aa)) and 412(c)(2), respectively.
Proposed Sec. 106.3(e) defines ``infant formula'' as a food that
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. The
phrase ``solely as a food for infants'' is somewhat ambiguous. Where
there is an ambiguity in a statutory provision, it is appropriate to
look to the legislative history to determine the appropriate
interpretation. In the legislative history of the Infant Formula Act,
whenever the words ``sole'' or ``solely'' are used, they appear in the
context of describing infant formula as the ``sole'' or primary source
of nutrition for infants or babies. For example, in explaining how the
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1980 act would change existing laws, then-Congressman Gore stated:
``First it would require that any infant formula marketed in the United
States as the sole source of nutrition for normal babies include
minimum amounts of all essential nutrients.'' (Ref. 7.) Congressman
Mottl stated that the 1980 act ``is concerned with human lives at their
most vulnerable stage. We are talking about food that may be the sole
source of nourishment for infants.'' (Ref. 7.) This language and other
similar language in the legislative history evidence that Congress
intended the act to apply to any food that purports to be or that is
represented as an infant formula, regardless of whether other possible
uses of the product are suggested in its labeling. If the law only
applied to foods that are represented only for use as infant formula,
then manufacturers could easily evade the requirements of the act for
infant formula by representing their products for a second purpose.
Such an interpretation would be inconsistent with the remedial purposes
of the infant formula provisions of the act.
Proposed Sec. 106.3(b) incorporates into part 106 the definition
for ``final-product-stage'' derived from section 412(b)(3)(E) of the
act. FDA has modified the definition, however, by adding the phrase
``due to processing'' at the end of the definition to clarify that the
final-product-stage is when the infant formula ``is homogeneous and is
not subject to further degradation due to processing'' and to
distinguish the point in time after which the formula is subject to
further degradation during the shelf life of the product.
Proposed Sec. 106.3(i) incorporates into part 106 a definition of
``major change'' that is derived from section 412(c)(2)(B) of the act,
which states that ``* * * the term `major change' has the meaning given
to such term in section 106.30(c)(2) of title 21, Code of Federal
Regulations (as in effect on August 1, 1986), and guidelines issued
thereunder'' (Ref. 8). Proposed Sec. 106.3(i) defines ``major change''
as it is defined in current Sec. 106.30(c)(2). It also provides a
number of examples of infant formulas deemed to differ fundamentally in
processing or in composition. These examples are derived from the
guidelines that were issued by the agency and were incorporated into
the definition of ``major change'' in section 412(c) of the act by the
1986 amendments.
Proposed Sec. 106.3(m) revises the definition for ``nutrient'' in
current Sec. 106.3(d) to reflect changes to the act made by the 1986
amendments. As stated above, the 1986 amendments moved the nutrient
table from section 412(g) to section 412(i)(1) and moved the provision
on promulgation of standards for nutrients from section 412(a)(2)(A) to
section 412(i)(2). The proposed regulation references the new section
numbers. Proposed Sec. 106.3(m) also includes the statement that
nutrients are substances determined to be essential by the Food and
Nutrition Board of the National Research Council or by FDA. The agency
is including this statement in the proposed definition to provide
consistency with Sec. 107.10(b)(5) on labeling nutrient information.
This paragraph allows such information to include any vitamin or
mineral in the formula, provided that the nutrient has been identified
as essential by the National Academy of Sciences through its
development of a recommended dietary allowance or an estimated safe and
adequate daily dietary intake range, or the nutrient has been
identified as essential by FDA through a Federal Register publication.
Proposed Sec. 106.3(o) defines ``quality factors.'' The definition
that FDA is proposing derives from the language of the act and its
legislative history. Section 412(b)(1) of the act states that the
Secretary shall ``establish requirements for quality factors for infant
formulas * * *, including quality factor requirements for the nutrients
required by subsection (i).'' House Report 96-936 (Ref. 5) states that
quality factors ``pertain to the bioavailability of a nutrient and the
maintenance of level or potency of nutrients during the expected shelf
life of the product.'' The language of the act and the House report
show that Congress intended that infant formulas marketed in the United
States should not only be safe, and contain all of the nutrients
required to support infant growth and health, but should provide those
nutrients in a bioavailable form that will mean that, throughout its
shelf life, the formula will support optimal infant growth and health.
Thus, quality factors encompass something different than the
analyzable nutrient content of the finished infant formula. Quality
factor requirements not only ensure that the nutrient potency and
biological effectiveness of a formula, as formulated, are adequate to
support healthy growth, but also that subsequent processing, ingredient
interactions, and time do not reduce the biological effectiveness of a
formula. Quality factor requirements also ensure that unsafe nutrient
``super potencies'' or by-products are not created from ingredient
breakdowns or interactions caused by processing or time.
B. CGMP
1. Introduction
The agency is proposing to adopt a new subpart B to implement the
CGMP requirements in section 412(b)(2) of the act. Proposed Sec. 106.5
is introductory. It reflects FDA's tentative view that the CGMP
requirements set out in subpart B are the minimum necessary to ensure
that the infant formula that is produced contains all the requisite
nutrients and is not otherwise adulterated.
To develop the proposed CGMP regulations, as stated above, agency
representatives visited infant formula plants to observe the
manufacturing practice that they employ, and the agency has solicited
and received recommendations on CGMP from the infant formula industry
through the Infant Formula Council (Ref. 9). The agency also is relying
on its knowledge of industry manufacturing practices gained through
inspections of infant formula manufacturing establishments, review of
infant formula submissions received from industry since 1986, and
monitoring of infant formula recalls.
The proposed CGMP regulations also are based in part on FDA's
existing regulations concerning CGMP for foods (21 CFR part 110) and
for drugs (21 CFR part 211). Because infant formulas are foods, they
should, at a minimum, be manufactured in a manner that is consistent
with CGMP for all foods under section 402(a)(4) of the act (21 U.S.C.
342(a)(4)). Moreover, infant formulas are often the sole source of
nutrition for infants during a period of rapid growth and development
and, hence, are used during a period of nutritional vulnerability.
Thus, if the formula is to promote optimal infant health and growth,
each batch of infant formula must provide the nutrients prescribed
under section 412(i) of the act at the levels specified in that
section, much like each batch of drugs must meet compositional
requirements for active ingredients if they are to have their intended
effect. Therefore, FDA has tentatively concluded that some of the
manufacturing practices required of drug manufacturers are relevant to
infant formula manufacturers.
2. Production and In-Process Control System
Section 412(b)(2)(B)(iii) of the act states that CGMP and quality
control procedures shall include requirements for ``in-process controls
including, where necessary, testing required by CGMP designed to
prevent adulteration of each batch of infant formula.'' In the past,
manufacturers of infant formula have referred to production and in-
[[Page 36158]]
process control systems intended to ensure that required nutrients are
included in the formula and to prevent adulteration by such terms as
``quality control plans,'' ``standard operating procedures,'' or
``master manufacturing procedures.'' Infant formula manufacturers also
have investigated adopting a system, known as the ISO.9000 series,
developed by the International Organization for Standardization (ISO).
The agency is proposing to establish a framework in which decisions
about the production of infant formula are left to the manufacturer but
that charges the manufacturer with incorporating into its production
process measures that are designed to ensure the safety and nutritional
quality of the formula.
For example, proposed Sec. 106.10(a) requires that there be
sufficient personnel, qualified by training and 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 they are correctly and
fully performed. This provision is a performance standard for
determining how many employees are necessary, i.e., that there be
enough to achieve, maintain, and document CGMP. FDA is not proposing to
provide the specific number of employees required, the specific type of
training that they must have, the specific task they are to perform, or
the specific method by which records are to be kept.
In another example, proposed Sec. 106.35(b)(4) requires that infant
formula manufacturers ensure that automatic (mechanical or electronic)
systems are validated before their first use to manufacture commercial
product. However, in this provision, the agency is not stipulating any
standards or specifications for the validation process because the
extent of the validation that is necessary is related to the level of
risk that each component of the system presents. These decisions about
the validation necessary are left to the infant formula manufacturer to
make.
As a third example, proposed Sec. 106.91(b) requires that the
manufacturer conduct nutrient stability testing at the beginning,
midpoint, and end of the shelf life of the infant formula and with
sufficient frequency to ensure that the formula complies with
Sec. 107.100 throughout its shelf life. Because manufacturers have
experience with the nutrient stability of the infant formula matrices
that they produce and are in a position to determine how frequently
testing is necessary, the agency is proposing only to require testing
``with sufficient frequency,'' instead of specifying what frequency is
required.
Proposed Sec. 106.6(a) requires that infant formula manufacturers
comply with the requirements of subpart B of part 106 by implementing a
system of production and in-process controls that covers all stages of
processing, from receipt and acceptance of raw materials, ingredients,
and components through storage and distribution of finished product,
and that is designed to ensure that all requirements of subpart B of
part 106 are met.
Infant formula manufacturing requires a degree of sophistication
(e.g., in research and development, production equipment and
procedures, and analytical equipment and methodology) that a vast
majority of companies in the food processing industry do not have. A
manufacturer must maintain constant control because a seemingly
innocuous change in formulation or in a preparation method, or exposure
to an unanticipated environmental condition, could create a health
hazard. Moreover, infant formula manufacturers must be concerned not
only that something is present in the formula that may adulterate that
formula, such as a contaminant or a level of a required nutrient that
exceeds the maximum level allowed by Sec. 107.100, but also that
something is absent from the formula, such as the lack or
unavailability of a required nutrient. For example, the lack of a
nutrient or the unavailability of an added nutrient has been
responsible for a number of documented problems that have occurred in
infant formulas (Ref. 1). Thus, FDA has tentatively concluded that the
use of a production and in-process control system covering all stages
of processing is necessary to ensure that the infant formula is
manufactured in a manner that will prevent adulteration of the infant
formula.
Proposed Sec. 106.6(b) requires that the production and in-process
control system be set out in a written plan, or set of procedures, that
is designed to ensure that the infant formula is manufactured in a
manner that will prevent adulteration of the formula. FDA has
tentatively concluded that requiring that the production and in-process
control system be set out in a written plan or a set of procedures is
necessary to provide consistency in production of different batches of
infant formula and to facilitate the preparation of each batch of
infant formula. Consistency is provided because the plan means that
there is a single set of procedures established that are to be followed
in producing the formula. The plan also facilitates preparation of the
formula because, given the sophistication of the infant formula
manufacturing process, a written plan to which ready and easy reference
can be had is essential. The importance of a written plan is well-
recognized by industry. The use of a written plan or set of procedures
for production of a batch of infant formula is already a wide-spread
practice.
The agency has sought to develop a basic list of items that a firm
would need to consider in developing its plan or procedures, but the
agency is reluctant to offer such a list at this stage of the
rulemaking, before it has received comments on the proposed good
manufacturing practice regulations. The agency requests comments on
whether such a basic list, over and above the provisions of Subpart B
itself, is possible or desirable, and if it is, what such a list should
include.
The agency would conceive of such a list, at a minimum, as
consisting of a number of items. It would need to direct the
manufacturer to establish the safeguards that it will rely upon to
protect against the foreseeable sources of adulteration in the
production of infant formula. It would also need to direct the
manufacturer to establish procedures for ensuring that the
manufacturing process functions properly. Several of the procedures
that would have to be established to do so are defined in the proposed
regulations, including: (1) Procedures, in accordance with proposed
Sec. 106.35(b)(2), to calibrate, inspect, and check hardware; (2)
specifications, in accordance with proposed Sec. 106.40(d), for the
acceptance or rejection of ingredients, containers, and closures used
in infant formula manufacture; (3) the master manufacturing orders in
accordance with proposed Sec. 106.50(a)(1); and (4) testing procedures,
under proposed Sec. 106.55(b), to ensure that powdered infant formula
complies with the microbiological quality standards. Other items that
would also seem to be appropriately included on such a list would be
procedures for controlling the release of product, for ensuring its
traceability, and for conducting GMP audits. However, FDA requests
comments on whether these items provide an adequate checklist for the
development of the type of written plan that is necessary under these
proposed regulations.
For now, FDA is leaving the specific content of the procedures that
are in the written plan to the manufacturer's discretion. FDA requests
comment on whether the agency should develop guidance on the content of
any of the
[[Page 36159]]
procedures that are part of the written plan.
Proposed Sec. 106.6(c) specifies requirements for a manufacturer's
handling of any point, step, or stage in its production process where
control of the process is necessary to prevent adulteration of the
formula. These in-process control points, steps, or stages may include
retorting or other heating steps, cooling steps, points where specific
sanitation procedures are needed, product formulation control steps,
points where cross contamination may occur, and steps where employee
and environmental hygiene are necessary to prevent adulteration of the
product.
Proposed Sec. 106.6(c)(1) requires that infant formula
manufacturers establish standards or specifications to be met at such
points, steps, or stages. These standards or specifications establish
the boundaries of safety at the point, step, or stage. Such standards
or specifications may include, for example, upper and lower limits for
parameters such as temperature, time, pH, visual appearance, and
moisture level as well as chemical, nutrient, and microbiological
specifications for raw materials. These standards or specifications can
be set based on published or unpublished studies, on regulatory levels
established by FDA, or on consultation with experts in infant formula
production. As discussed in more detail below, FDA is proposing (see
proposed Sec. 106.100(e)(3)(i)) that manufacturers make and retain a
list of the standards and specifications that they establish under
proposed Sec. 106.6(c)(1) including documentation of the scientific
basis for each standard or specification. Maintaining such a list will
mean that these standards and specifications are readily available for
comparison to the actual values obtained in monitoring (i.e., making a
planned sequence of observations or measurements) the production and
in-process control system.
Proposed Sec. 106.6(c)(2) requires that infant formula
manufacturers monitor the points, steps, or stages in their production
process where control is necessary to prevent adulteration of the
infant formula. Regular monitoring of these points is necessary to
ensure that the product meets the standards and specifications set
under proposed Sec. 106.6(c)(1) and to ensure that any trend toward
loss of control is quickly identified. Quick identification will mean
that adjustments can be made to prevent a deviation from occurring, or,
in the event that a deviation does occur, that effective corrective
actions can be taken to remove adulterated product from the system.
For many standards or specifications, continuous monitoring is
possible. For example, temperature and time for a scheduled thermal
process can be recorded continuously on temperature- recording charts.
When it is not possible to monitor a particular point, step, or stage
on a continuous basis, monitoring intervals need to be reliable enough
to permit the manufacturer to determine whether the production control
point is under control.
Monitoring involves not only making observations at an appropriate
frequency but also ensuring that the instruments and equipment, such as
thermometers, temperature-recording devices, and computer software,
that the manufacturer relies on to make its observations are accurate
and reliable (see proposed Sec. 106.30(d)).
Proposed Sec. 106.6(c)(3) requires that infant formula
manufacturers establish corrective action plans for use when a standard
or specification established in accordance with proposed
Sec. 106.6(c)(1) is not met. FDA has tentatively concluded that this
requirement is necessary because a manufacturer will often need to take
corrective action quickly, and the best way to ensure that a corrective
action is appropriate is to determine the action in advance. The
corrective action plans should provide, for example, for the
disposition of any infant formula or of any partially manufactured
infant formula that was produced when a deviation was occurring.
Proposed Sec. 106.6(c)(4) requires that infant formula
manufacturers review the results of the monitoring required under
proposed Sec. 106.6(c)(2). This review will reveal whether the
monitoring is actually being done and being done correctly, and whether
standards and specifications are being met.
Proposed Sec. 106.6(c)(4) further requires that infant formula
manufacturers review, and evaluate the public health significance of,
any deviations from standards or specifications established in
accordance with proposed Sec. 106.6(c)(1). This proposed requirement is
necessary to ensure that products that may have been affected by a
deviation do not enter commerce if they are likely to be unsafe. It
also will ensure that the disruption of a manufacturer's business is
minimized when a deviation does occur. For example, if review of
monitoring records reveals that an ingredient premix does not contain
the required nutrients at the required levels, the manufacturer can
take steps to dispose of the premix before it is used in the
manufacture of an infant formula. If the monitoring records are not
reviewed, a product made with a deficient premix may be placed on the
market, and a costly and embarrassing recall may be required.
Proposed Sec. 106.6(c)(4) also requires that this review be
conducted by an individual qualified by training and experience to
conduct such reviews. This proposed requirement is necessary to ensure
that the review is conducted by a person who understands the production
and in-process control system, understands the significance of a
processing deviation, and knows how to respond to a deviation. Such
understanding and knowledge will ensure that the review is
appropriately conducted, and that the response to any deviation is
measured and appropriate.
Proposed Sec. 106.6(c)(5) requires that infant formula
manufacturers establish recordkeeping procedures, in accordance with
proposed Sec. 106.100(e)(3), that ensure that compliance with the
requirements of proposed Sec. 106.6(c) is documented. As discussed
below in the description of the proposed revisions to subpart F of part
106, FDA has authority to require that these records be made and
retained under section 412(b)(4)(A)(i) of the act. FDA is proposing to
provide a complete description of all recordkeeping requirements in
subpart F. When applicable, FDA is including cross-references to these
recordkeeping requirements in the regulations in subparts B, C, and D.
These records will allow manufacturers to discern trends or to pinpoint
the onset of a problem if a standard or specification is not being met
at a point where control is deemed necessary to prevent adulteration,
or if a batch of infant formula is associated with an adverse event.
3. Controls to Prevent Adulteration by Workers
Proposed Sec. 106.10(a) requires that there be sufficient
personnel, qualified by training and 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 they are correctly and fully
performed. Proposed Sec. 106.10(a) is consistent with existing
regulations concerning CGMP for foods (Sec. 110.10(c)) and drugs
(Sec. 211.25). In this provision, FDA is proposing a general standard
for determining how many employees are necessary, i.e., that there be
enough to achieve, maintain, and document CGMP. However, FDA is leaving
the determination of the actual number of employees necessary to the
manufacturer's discretion.
[[Page 36160]]
Proposed Sec. 106.10(a) also requires that such personnel be
qualified by training and experience. Training is necessary to ensure
that employees know how to correctly and fully perform the operations
in question and to ensure that employees are competent to produce a
safe and clean infant formula. The extent and frequency of training is
left to the manufacturer's discretion.
Proposed Sec. 106.10(b) requires that personnel working directly
with infant formula, infant formula raw materials, infant formula
packaging, or infant formula equipment or utensil contact surfaces
practice good personal hygiene to protect the product against
contamination. Proposed Sec. 106.10(b) is consistent with existing
regulations concerning CGMP for foods (Sec. 110.10(b)) and drugs
(Sec. 211.28(a) and (b)). FDA has tentatively concluded that it is
necessary that these employees practice good hygiene so that they will
not transmit disease to others in the workforce, and so that they will
not transmit filth or pathogenic microorganisms to the infant formula.
In addition, proposed Sec. 106.10(b) enumerates the basic elements
of good personal hygiene. Proposed Sec. 106.10(b)(1) lists clean outer
garments and protective apparel as one element. To be ``clean,''
clothing must be free of filth or microorganisms that may contaminate
the infant formula. Protective apparel, such as head, face, hand, and
arm coverings, will help to ensure that the infant formula is protected
from contaminants such as hair.
Proposed Sec. 106.10(b)(2) states that good personal hygiene
includes workers washing their 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 hands may become soiled or contaminated. Filth and
pathogenic microorganisms can be brought into the processing
environment on the employee's hands from outside areas, restrooms,
contaminated raw materials, waste or waste receptacles, and other
insanitary objects (Refs. 10, 11, and 12). FDA has tentatively
concluded that requiring workers to practice good personal hygiene by
washing their hands at the times specified will help to prevent the
introduction of this type of contamination into infant formula.
Proposed Sec. 106.10(c) requires that 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 the formula may be
adversely affected, 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. Proposed Sec. 106.10(c) is consistent with existing
regulations concerning CGMP for foods (Sec. 110.10(a)) and drugs
(Sec. 211.28(d)). Employees can transmit the organisms responsible for
diseases, such as salmonellosis, shigellosis, and hepatitis, to the
infant formula. Additionally, open sores, boils, or infected wounds
present the potential for contamination of the infant formula with such
pathogenic microorganisms as Staphylococcus aureus (Refs. 14 and 15).
Thus, proposed Sec. 106.10(c) will exclude employees who carry
potential microbial contamination that may adversely affect the safety
of the formula from direct contact with the infant formula and from
direct contact with materials and surfaces that come in contact with
the infant formula and thus will minimize the potential for employees
to transmit microorganisms to the infant formula that may cause the
infant formula to pose a health hazard to the infant.
4. Controls to Prevent Adulteration Caused by Facilities
Proposed Sec. 106.20(a) requires that buildings used in the
manufacture, processing, packing, or holding of infant formula be
maintained in a clean and sanitary condition. This proposed requirement
is necessary to prevent contamination of the infant formula. It is
consistent with FDA's existing regulations concerning CGMP for foods
(Secs. 110.20(b) and 110.35(a)) and drugs (Sec. 211.42). Trash, litter,
and waste must be disposed of to avoid creating conditions that attract
and harbor potentially pathogenic microorganisms and attract and harbor
pests, such as rodents or insects. Such pests can carry a variety of
human disease agents, including microorganisms that are potentially
pathogenic in infants, and introduce them into the manufacturing
environment (Refs. 10 and 12). They are also sources of feces and hair
that can contaminate infant formula.
Proposed Sec. 106.20(a) also requires that buildings used in the
manufacture of infant formula 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. If
raw materials are not separated from the site of product manufacture,
there is a significant possibility that they will be used in infant
formula manufacture before they have been tested and found acceptable
for use in infant formula. Therefore, FDA has tentatively concluded
that the separation of incompatible operations is necessary to ensure
that infant formula is manufactured in a manner designed to prevent
adulteration. The proposed requirement that incompatible operations be
separated is consistent with FDA's existing regulations concerning CGMP
for foods (Sec. 110.20(b)(2)) and drugs (Sec. 211.42(c)) and is
consistent with the recommendations made to FDA by the Infant Formula
Council (Ref. 9).
Proposed Sec. 106.20(b) requires separate holding areas to protect
against mixups that could lead to contamination of infant formula.
Failure to separate raw materials or in-process materials that have not
been released, or that have been rejected but not disposed of, from
those that have been released creates the potential for the use of
ingredients that do not meet the applicable specifications and thereby
can lead to the production of finished infant formula that is
adulterated. Similar types of problems can develop if final product
that has not been released, or that has been rejected but not disposed
of, is not separated from final product that has been released.
Proposed Sec. 106.20(b) is consistent with FDA's existing regulations
concerning CGMP for drugs (Sec. 211.42(c)).
Proposed Sec. 106.20(c) defines a standard for adequate lighting
and allows the manufacturer to exercise discretion in determining the
precise level of lighting that is sufficient to meet that standard.
Adequate lighting is important. Inadequate lighting may make it
difficult to read a label or an instrument, and as a result incorrect
ingredients may be used in infant formula production, or instruments
may be read incorrectly, which increases the risk of producing an
adulterated infant formula.
Proposed Sec. 106.20(c) also requires that any lighting fixtures
directly over or adjacent to exposed raw materials, in- process
materials, or bulk (unpackaged) finished product be protected to
prevent glass from contaminating the product in the event of breakage.
Glass in an infant formula may be a safety hazard and would render the
formula adulterated (Ref. 14). Proposed Sec. 106.20(c) is consistent
with FDA's existing regulations concerning CGMP's for food
(Sec. 110.20(b)(5)) and drugs (Sec. 211.44).
FDA is proposing a requirement in Sec. 106.20(d) for air filtration
systems to improve air quality in production areas
[[Page 36161]]
and thus reduce the potential for contamination by air-borne sources
(Ref. 15). This proposed requirement is consistent with FDA's existing
regulations concerning CGMP for drugs (Sec. 211.46(c)).
Proposed new requirements in Sec. 106.20(e) protect against the
contamination of infant formula by pest control agents and cleaning
agents. The agency recognizes that these agents are needed in infant
formula facilities. However, because many of them are toxic, they must
be handled and stored in a manner that prevents contamination of the
infant formula. Proposed Sec. 106.20(e) is consistent with FDA's
existing regulations concerning CGMP for food (Sec. 110.35(b)(2)) and
drugs (Sec. 211.56(c)).
Proposed Sec. 106.20(f)(1) states that potable water used in the
manufacturer of infant formula must meet the Environmental Protection
Agency's (EPA's) Primary Drinking Water Regulations (40 CFR part 141)
(with the one exception that the fluoride level be as low as possible,
as discussed below). This proposed regulation is consistent with FDA's
existing regulations concerning CGMP for drugs (Sec. 211.48(a)).
The Safe Drinking Water Act gives EPA the responsibility for
establishing standards for public drinking water. Therefore, FDA is
proposing to use EPA's standards for water used in the production of
infant formulas. Application of these standards will ensure that the
water used in infant formula is safe. The agency is proposing to
require that water from both municipal sources and the firm's own wells
meet these standards.
The safety and sanitary quality of water from public water systems
is generally ensured through public water treatment, chlorination, or
monitoring and control by local health authorities. Private sources of
water, however, particularly surface waters or water from shallow
wells, may be subject to microbiological, chemical, or radiological
contamination attributable to the source itself or to surface
contamination at the well head or intake. Private sources are also
frequently untreated or minimally treated. Thus, under the proposed
regulation, when a manufacturer uses a private source of water, it will
need to take steps to ensure that the water is safe and sanitary. These
steps may include ensuring that the well design has been approved by
the local health authority, ensuring that the well meets coliform test
standards, performing periodic inspections of the sanitary condition of
the well head and source intake, and performing and monitoring
appropriate water treatment procedures, including filtration,
sedimentation, and chlorination. The type and frequency of controls
exercised by the manufacturer will be based upon the type of source
water and its historic safety and sanitary quality.
Proposed Sec. 106.20(f)(1) makes one exception to the use of EPA
standards for drinking water. On April 2, 1986, EPA issued a maximum
contaminant level (MCL) for fluoride in drinking water of 4 milligrams
per liter (mg/L) (51 FR 11396) and reaffirmed this level on December
29, 1993 (58 FR 68826). The National Academy of Sciences (NAS)
recommends 0.1 to 0.5 mg/day as the safe and adequate intake for
infants from 0 to 6 months of age. Mottling of teeth in children has
been observed at 2 to 8 milligrams/kilogram (mg/kg) concentration of
fluoride in diet and drinking water (Ref. 16). Thus, if 4 mg of
fluoride/L of water was allowed in the water used in infant formula
manufacture, infants consuming ready-to-feed infant formula could
receive enough fluoride to adversely affect their teeth. Currently, no
infant formulas are manufactured with fluoridated water (Ref. 17), so
that the pediatrician or other health care provider is able to decide
whether a fluoride supplement is appropriate for formula-fed infants,
principally by considering whether the formula was diluted with
fluoridated water (Ref. 18).
NAS has established a safe and adequate daily dietary intake of
fluoride for infants (Ref. 19). The agency is considering proposing to
revise the infant formula nutrient requirements in Sec. 107.100 to
include fluoride and other nutrients that NAS has determined are
essential for infants. FDA will consider fluoride levels for infant
formulas at that time. FDA has tentatively concluded that, until it has
revised the levels of required nutrients, manufacturers should continue
their practice of not using fluoridated water in the manufacture of
infant formula.
Proposed Sec. 106.20(f)(1) also requires that the water be supplied
under continuous positive pressure in a plumbing system that is free of
defects that could contaminate an infant formula. FDA has tentatively
concluded that this requirement is necessary to ensure that all potable
water coming into the plant is not adversely affected by the in-plant
plumbing. Contaminated water can serve as a vehicle for contamination
of infant formula, both when used as an ingredient in the infant
formula and when allowed to enter the product indirectly, as can occur,
for example, when water is used to cool the product after retorting.
Thus, FDA tentatively concludes that it is appropriate to include this
positive requirement in this regulation.
Proposed Sec. 106.20(f)(2), which sets forth requirements for
testing representative samples of potable water used in infant formula
manufacturing, is necessary to provide assurance that the water used in
infant formula manufacturing meets EPA's standards. Proposed
Sec. 106.20(f)(3) requires that manufacturers conduct these tests with
appropriate frequency. The regulation allows manufacturers some
discretion in determining the testing frequency necessary to ensure
that EPA standards are met, but it requires a minimum frequency of
testing for certain contaminants (i.e., chemical contaminants,
radiological contaminants, and bacteriological contaminants). FDA is
basing these proposed minimum frequencies on those adopted by EPA for
primary drinking water. This frequency of testing is consistent with
FDA's own regulations concerning processing and bottling of bottled
drinking water (Sec. 129.35(a)(3)).
Proposed Sec. 106.20(f)(4) requires that manufacturers make and
retain records of the frequency and the results of the testing that
they do on the water used in the production of infant formula. These
records will document that the manufacturer is complying with the
potable water testing requirements of Sec. 106.20(f)(2) and (f)(3), and
that the water complies with EPA standards. They will identify any
trend toward loss of compliance with these standards, so that the
manufacturer can take corrective actions before the water becomes
inappropriate for use in infant formula. As discussed below in the
description of the proposed revisions to subpart F, FDA has authority
to require the creation and retention of these records under section
412(b)(4)(A)(i) of the act.
In proposed Sec. 106.20(g), FDA sets out requirements regarding
piping systems to prevent a source of contamination (i.e., waste water)
from coming in contact with the infant formula. Cross connections could
allow back siphonage into a potable system from a nonpotable system
under negative pressure conditions and thus could result in the
chemical or microbiological contamination of the potable water system
(Ref. 20). Proposed Sec. 106.20(g) is consistent with FDA's regulations
concerning CGMP for food (Sec. 110.37(b)(5)) and drugs
(Sec. 211.48(b)).
Proposed Sec. 106.20(h) requires that steam that comes in direct
contact with infant formula be safe and free of rust
[[Page 36162]]
and other particulate matter that could contaminate the formula. Steam
comes in direct contact with infant formula when the steam is injected
into the head space of a can of infant formula to create a vacuum.
Thus, this proposed requirement is necessary to ensure that the steam
does not adulterate the infant formula.
Proposed Sec. 106.20(h) also requires that boiler water additives
in the steam meet safety standards set forth in FDA regulations at 21
CFR 173.310 which lists boiler water additives that may be safely used
in the preparation of steam that will contact food and the conditions
for the safe use of those boiler water additives. This proposed
requirement is necessary because boiler water additives dissolve in
water and can be carried over as a residue in the steam. A proposed
requirement that boiler water additives in the steam comply with
Sec. 173.310 will ensure that any residue is safe to come in contact
with the infant formula.
Proposed Sec. 106.20(i) requires that each infant formula
manufacturing site provide its employees with readily accessible toilet
and hand washing facilities. This proposed requirement is consistent
with good sanitary practice common to all food-processing facilities
and is consistent with FDA's CGMP regulations for foods (Sec. 110.37(d)
and (e)) and drugs (Sec. 211.52). The requirement is also a necessary
adjunct to the requirement in proposed Sec. 106.10(b)(2) that employees
wash their hands before starting work, after each absence from the work
station, and at any other time when the hands may become soiled or
contaminated. Hand-washing facilities are not likely to be used in an
appropriate manner by employees if the facilities are not conveniently
located.
Proposed Sec. 106.20(i) also requires that these facilities be
equipped with hot and cold water, ordinary soap or detergent, and
single-service towels to ensure that microbiological contamination does
not occur through the repeated use of the same towel by several
individuals.
In addition, proposed Sec. 106.20(i) requires that toilet
facilities be maintained in good repair and in a sanitary condition at
all times, and that these facilities provide for proper disposal of
sewage, so that the processing environment is protected against
pathogenic microorganisms shed in fecal material. Restroom floors and
the grounds around the processing facility can become contaminated with
pathogens if fecal material is not removed by an adequate sewage
system. Foot traffic over the affected areas can introduce pathogens
into the processing room and cause product contamination. Insanitary
toilet facilities can also increase the potential for contamination of
employees' hands and, ultimately, of the product itself (Refs. 10 and
11). Proposed Sec. 106.20(i) further protects against potential
microbiological contamination by setting forth requirements for the
positioning of toilet facility doors.
5. Controls to Prevent Adulteration Caused by Equipment or Utensils
Equipment used in infant formula manufacture, packaging, or holding
that is of an inappropriate design or an inadequate size, or that is
installed improperly, can result in a variety of problems. For example,
a mixer for the blending of powdered ingredients will not properly
perform its function if the blade is too small relative to the size of
the mixer, or if the mixer blade or auger is not properly positioned in
the inside of the mixer. Such a mixer may produce infant formula that
is not uniform in composition throughout a batch and that is,
consequently, adulterated because the required nutrients are not
provided at the required levels throughout the batch.
Installing equipment in a manner that will facilitate its cleaning
and maintenance is also important in preventing adulteration. Equipment
that is not properly cleaned can be the source of contaminants that
adulterate the infant formula. Equipment that is not properly
maintained can result in a variety of problems. For example, improper
maintenance of equipment such as a mixer may result in inadequate
compositional uniformity in a batch of formula. Improper maintenance of
equipment used to measure a parameter such as temperature may result in
the processing of the infant formula at a temperature that can
adversely affect the product. In either case, the product would be
adulterated. Design and installation of equipment also needs to be
checked when the equipment is modified or repaired to ensure that the
equipment is still designed and installed to function as intended as
part of the manufacturing process. Thus, proposed Sec. 106.30(a)
requires that equipment be appropriately designed and installed. This
proposed requirement is consistent with FDA's CGMP regulations for
foods (Sec. 110.40(a)) and drugs (Sec. 211.63).
If a food-contact surface is constructed of toxic material, the
product may be directly contaminated with that material (Ref. 11).
Therefore, FDA is proposing to require in Sec. 106.30(b) that equipment
and utensils be made of materials that are not reactive or absorptive,
so that the equipment and utensil materials do not contaminate the
infant formula and cause it to be adulterated. Proposed Sec. 106.30(b)
also requires that such equipment and utensils be designed to be easily
cleanable because they can be vehicles for microbial contamination of
both raw and finished products. Utensils, equipment, and other food-
contact surfaces that are made of corrosive material, or that contain
breaks, pits, cuts, or grooves, are difficult to clean because the
pores and crevices shield the microorganisms from the action of
cleaning and sanitizing agents (Ref. 21). In addition proposed
Sec. 106.30(b) requires that equipment and utensils be designed to
withstand the environment in which they are used. This requirement will
ensure that equipment and utensils are constructed of materials that
will not corrode or undergo other types of chemical or physical
degeneration resulting from their use in infant formula production.
Degeneration of the equipment and utensils may introduce contaminants
into the formula and thereby lead to adulteration. Surfaces that are
not adequately cleaned and sanitized can be a source of filth, an
attractant for vermin, and a reservoir for microorganisms.
Proposed Sec. 106.30(b) requires regular, effective cleaning and
sanitizing of all food-contact surfaces to minimize the probability of
contamination of the infant formula (Ref. 21) and prescribes
requirements for effective sanitizing agents. An effective sanitizing
agent is one that has a good bactericidal effect on the types of
microorganisms normally present in the plant environment and that is
safe, stable, and convenient for use (Ref. 22). Sanitizing agents are
indirect food additives and must be used in accordance with 21 CFR
178.1010, which prescribes their conditions of safe use. Examples of
sanitizing agents that comply with Sec. 178.1010 include hypochlorites,
iodophors, and quaternary ammonium compounds. However, sanitizers can
achieve their intended effect only if they are applied to a surface
that has been thoroughly cleaned, and if they are applied at a proper
concentration (Ref. 22).
Thus, it is important that effective cleaning compounds be used. An
effective cleaning compound is one that will lower the surface tension
of water so that spills can be lifted and flushed away (Ref. 23).
Ordinary soap has a limited ability to solubilize fats, oils, and
proteins, and inorganic alkaline
[[Page 36163]]
detergents can dissolve food solids such as fats and proteins, but
mineral deposits will frequently require the use of acid cleaners (Ref.
23).
In order to ensure that infant formula is not contaminated with
unsafe substances that are a part of the manufacturing process, FDA is
proposing requirements in Sec. 106.30(c) regarding substances necessary
for the operation of equipment, such as lubricants or coolants.
Proposed Sec. 106.30(d)(1) sets forth requirements for maintaining
the accuracy of instruments, since an instrument that is not easily
read, or that is not properly calibrated, may not provide accurate
measurements. If an instrument is not properly maintained, it may not
be reliable over time, and the readings obtained from it may lead to
adulteration of the infant formula during processing. This proposed
regulation also requires that such instruments be sufficient in number
for their intended use. For example, if the temperature of a large
piece of equipment needs to be monitored, several temperature-
indicating devices may be needed to accurately monitor the temperature
in all parts of the equipment. Also, instruments and controls must be
tested for accuracy (i.e., calibrated) against a known reference
standard before first use and at routine intervals thereafter, as
specified in writing by the manufacturer of the instrument or control,
or as otherwise deemed necessary to ensure the accuracy of the
instrument. FDA has tentatively concluded that this requirement is
necessary because equipment used to manufacture infant formula must
operate properly to ensure production of a safe, uniform product with a
consistent nutrient content throughout a lot or a batch.
The accuracy of an instrument is the degree to which it produces a
correct result. The instruments used to measure parameters such as
temperature or pressure at points where control is deemed necessary to
prevent adulteration must reflect the true measurement so that, for
example, a manufacturer can have confidence that when a thermometer
indicates that the temperature is 240 deg.F, the temperature really is
240 deg.F. FDA's experience is that calibration of the instrument
using a reference standard is the most reliable method to ensure
accuracy. FDA is proposing to require that this test for accuracy be
done before first use to provide assurance that the instruments and
controls will perform as intended and at routine intervals afterward to
ensure that the instruments and controls continue to perform as
intended.
Reliability is the instrument's accuracy over time. The reliability
of the instrument will determine the length of time that it can be used
before it begins to lose accuracy. The manufacturer of the instrument
is in the best position to establish how frequently recalibration is
needed because that manufacturer is responsible for putting together
the technology by which the instrument operates. However, if the infant
formula manufacturer's experience with the instrument demonstrates that
the instrument needs to be calibrated more frequently than the
instrument manufacturer suggests, FDA has tentatively concluded that
the infant formula manufacturer must act on its own experience with the
instrument and calibrate it as often as necessary to ensure the
accuracy of the instrument.
Proposed Sec. 106.30(d)(1) further requires that the known
reference standard be certified for accuracy at routine intervals
specified in writing by the manufacturer of the instrument, or as
otherwise deemed necessary. Known reference standard devices are
accompanied by certificates of accuracy, but these certificates do not
preclude the possibility that these instruments will go out of
calibration. Just as a calibration routine needs to be established for
the process instrumentation, a recertification of the known reference
standard needs to be established in accordance with the equipment
manufacturer's recommendations. For example, the length of time that a
certified thermometer can be considered reliable will depend on the
materials used in its manufacture, the degree of control exercised in
its manufacture, and its use, as would be the case for the indicating
thermometer used in the production line. The accuracy of a calibrated
thermometer is only going to be as good as the accuracy of the known
reference standard that is used during its calibration.
Proposed Sec. 106.30(d)(1) also requires that manufacturers make
and retain records of accuracy checks in accordance with the provisions
of proposed Sec. 106.100(f)(2). As discussed below in the description
of the proposed revisions to subpart F of part 106, FDA has authority
to require these records under section 412(b)(4)(A)(i) of the act.
These records will enable the manufacturer to establish the historical
performance of the instrument to determine whether the calibration
schedule is sufficient to ensure the accuracy of the instrument and
will provide information on when and how the instruments were
calibrated to assist the manufacturer in identifying the cause of a
problem that may arise with a batch of infant formula.
Proposed Sec. 106.30(d)(2) requires that instruments and controls
that cannot be adjusted to agree with the reference standard be
repaired or replaced. FDA is proposing this requirement because an
instrument or control cannot be trusted for use in infant formula
production if it cannot be adjusted to agree with the reference
standard. Adjustments made to reach agreement with a known accurate or
reference standard must also be done in accordance with any adjustment
range limitations specified by the vender of the instrument.
Proposed Sec. 106.30(d)(3) provides that if calibration of an
instrument (testing for accuracy against a known reference standard)
shows that a specification or standard has not been met at a point
where control is deemed necessary to prevent adulteration, a written
evaluation must be made of all affected product and of any actions that
need to be taken. FDA has tentatively concluded that this written
evaluation is necessary because if an instrument has been giving
inaccurate readings, all infant formula produced subject to such
inaccuracies must be identified and evaluated for the possibility that
the inaccuracies resulted in the production of adulterated formula. If
the manufacturer determines that adulterated formula has been produced,
the firm must decide what actions, if any, need to be taken to prevent
such formula from reaching infants.
FDA is also requiring that this written evaluation needs to be
maintained in the firm's records. FDA tentatively concludes that this
record is necessary to demonstrate that the firm has complied with
CGMP. As discussed below in the description of the proposed revisions
to subpart F of part 106, FDA has authority to require that these
records be retained under section 412(b)(4)(A)(i) of the act.
Proposed Sec. 106.30(e)(1) requires that the temperature in cold
storage compartments used to store raw materials, in-process materials,
or final product, as well as the temperature of 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. The frequency of the
monitoring is left to the manufacturer to determine. Growth of
microorganisms can occur and cause spoilage if materials that should be
kept in cold storage compartments are not maintained at the proper
temperature. Infant formula may also be adulterated if thermal
processing equipment is not
[[Page 36164]]
operated at the proper temperature, and the final liquid infant formula
product is not commercially sterile. Therefore, FDA tentatively
concludes that their requirement is appropriate.
In addition, FDA is proposing that a temperature of 40 deg.F (4.4
deg.C) is appropriate in cold storage compartments to minimize the
growth of pathogens (Ref. 24) and the deterioration of liquid
ingredients, nutrients, and the formulated product before canning
(proposed Sec. 106.30(e)(2)).
Proposed Sec. 106.30(e)(3)(i) requires that cold storage
compartments and thermal processing equipment be equipped with easily
readable, accurate temperature-indicating devices. These devices are
necessary to ensure that the manufacturer can monitor the temperatures
where materials are stored or where product is processed. Proposed
Sec. 106.30(e)(3)(ii) requires that thermal processing equipment be
equipped with temperature-recording devices that reflect the true
temperature on a continuing basis, so that the manufacturer will be
able to determine whether the product was thermally processed at a
minimum temperature for an appropriate period of time. Two factors,
temperature and time, are relevant in ensuring that thermal processing
is conducted in a manner that will produce commercially sterile infant
formula after retorting. Thus, recording the temperature that is
maintained during the time period used will show whether the thermal
process is conducted properly.
Proposed Sec. 106.30(e)(3)(ii) also requires that cold storage
compartments be equipped with either a temperature-recording device
that will reflect the true temperature within the compartment on a
continuing basis, or a high-temperature alarm or a maximum-indicating
thermometer that has been verified to function properly. These
temperature records will show whether the materials were stored at an
appropriate temperature to minimize the growth of pathogens and the
deterioration of ingredients and formulated product. If the
manufacturer does not wish to equip cold storage compartments with such
temperature- recording devices, FDA is proposing to require that it
maintain a temperature log in which the temperature in the compartment
is noted with such frequency as is necessary to achieve control. The
agency is leaving it to the manufacturer's discretion to determine what
frequency of temperature notation is necessary to achieve control.
The agency has tentatively concluded that it is not necessary for
the manufacturer to record the temperature of the cold storage
compartment on a continuous basis as long as the manufacturer can
determine that the temperature of the cold storage compartment has gone
above 40 deg.F. A high-temperature alarm set to go off when the cold
storage compartment goes above 40 deg.F will allow the manufacturer to
make this determination. Likewise, a maximum-indicating thermometer
will remain at the highest temperature that it ever reaches. If the
maximum indicating thermometer indicates a temperature above 40 deg.F,
the infant formula manufacturer must assume that the temperature has
been above 40 deg.F since the last check of the thermometer. Thus, FDA
has tentatively concluded that either a high-temperature alarm or a
maximum-indicating thermometer are acceptable alternatives for
determining whether the cold storage compartment has gone above 40
deg.F.
In some cases, the actual location of the sensors may be an
important factor in ensuring the accurate representation of
temperature. For example, one sensor located at the end of a large
piece of thermal processing equipment may not accurately represent the
temperature in the whole piece of equipment. In addition, these
temperature devices must often be read under less than ideal plant
conditions, so they should be installed in a location that facilitates
easy reading. Temperature-recording devices can be easily jarred and
rendered inaccurate. They can be recalibrated against a reference
temperature-indicating device (e.g., a thermometer) quite easily,
however. Manufacturers should do so at least at the beginning and end
of each production day in order to determine whether the instrument was
accurate throughout the day's production. For thermal processing
equipment used to produce commercially sterile liquid infant formula,
the mandatory and recommended procedures of 21 CFR part 113 apply.
FDA is also proposing that manufacturers make and retain records,
in accordance with the provisions of proposed Sec. 106.100(f)(3), of
the temperatures indicated or recorded by these devices (see
Sec. 106.30(e)(3)). As discussed below in the description of the
proposed revisions to subpart F of part 106, FDA has authority to
require these records under section 412(b)(4)(A)(i) of the act. They
are needed to show that the thermal processing equipment or cold
storage compartments are being maintained at the correct temperatures
to prevent adulteration of the product. They also will enable the
manufacturer to identify trends in temperature fluctuations that can
signal the need to perform nonscheduled maintenance.
Proposed Sec. 106.30(e)(4) requires that for thermal processing,
the temperature-recording device not read higher than the calibrated
temperature-indicating device because it is important to ensure that
the infant formula is processed at a minimum temperature for a
continual period of time. A temperature-recording device reading higher
than the reference temperature-indicating device for thermal processing
equipment would show that the product had been processed at a
temperature higher than the true processing temperature. Because
thermal processing is used to destroy microorganisms, a temperature-
recording device reading higher than the true processing temperature
may mean that the product has not been processed at a temperature that
is high enough to destroy all microorganisms.
For cold storage compartments, the temperature-recording device
must not read lower than the temperature-indicating device because when
raw materials, in-process materials, or finished product must be stored
at a cold temperature, it is important to ensure that the infant
formula was not exposed to a temperature above the maximum temperature.
A temperature-recording device reading lower than the reference
temperature-indicating device for cold storage equipment would show the
materials in the compartment as having been held at a lower temperature
than the true temperature. Because cold storage is used to prevent
microbiological growth, a temperature-recording device reading lower
than the reference temperature-indicating device would mean that the
material was actually being stored at a higher temperature than the
recorded temperature, and that, as a result, microbial growth may have
occurred.
Proposed Sec. 106.30(f) requires that all equipment and utensils
used in the manufacture of infant formula be cleaned, sanitized, and
maintained at regular intervals to prevent adulteration of the infant
formula. Any equipment or utensil that is not cleaned and maintained
properly can be a source of contamination. FDA is therefore proposing
to require that cleaning, sanitizing, and maintaining be done at
regular intervals. The details of sanitation procedures e.g., equipment
cleaning, can differ from plant to plant depending upon the type of
operation and other conditions. In one plant, it may be necessary to
disassemble all or part of the equipment to clean it. In other plants,
breaking down the
[[Page 36165]]
equipment may not be necessary. Likewise, different cleaning compounds
may be needed from one plant to another to solve specialized problems
such as buildups of mineral deposits. Each manufacturer should study
its own plant and develop a procedure that is tailored to that plant's
needs and circumstances.
FDA considers that cleaning, sanitizing, and maintaining equipment
and utensils is so important for ensuring that adulterated infant
formula is not produced that it is proposing to require that the
cleaning, sanitizing, and maintenance be checked for satisfactory
completion by an individual qualified to conduct such a review. Such an
individual will understand the importance of ensuring that cleaning,
sanitizing, and maintenance is properly done, so that equipment and
utensils do not contribute to the adulteration of the infant formula.
Also, the agency has tentatively concluded that this requirement will
ensure that there is accountability for proper performance of this
function.
In addition, proposed Sec. 106.30(f) requires that manufacturers
make and retain records on equipment cleaning, sanitizing, and
maintenance in accordance with proposed Sec. 106.100(f)(4). As
discussed below in the description of the proposed revisions to subpart
F, FDA has authority to require these records under section
412(b)(4)(A)(i) of the act. These records will document when the
cleaning, sanitizing, and maintenance of equipment occurs and will
allow the manufacturer to trace all formula that may be affected if
cleaning, sanitizing, or maintenance is not properly performed.
In order to ensure that compressed air or other gases will not
contaminate the infant formula with unlawful indirect food additives or
other chemical, physical, or microbiological contaminants, FDA is
proposing to require in Sec. 106.30(g) that they be appropriately
treated. Air or other gases that are not properly treated and filtered,
or air that is not of the proper purity, can introduce contaminants
into the infant formula that may render it adulterated. Also,
compressed gases can be contaminated with oil from the compressor or
with filth or microbiological contaminants from the compression,
storage, or distribution equipment. Filtration at the air intake and
after compression, storage, and distribution is an effective means of
reducing the risk that such contaminants will enter the gases and,
thereby, the food. Therefore, FDA is also proposing in Sec. 106.30(g)
to require the use of a filter when compressed gases are used at
product filling machines to replace air removed from the headspace of
containers. The filter will prevent contaminants from entering the
infant formula during that operation (Ref. 25).
6. Controls to Prevent Adulteration Due to Automatic (Mechanical or
Electronic) Equipment
Manufacturers of infant formula are increasingly relying on
automatic equipment (including mechanical and electronic equipment) in
production and quality control. In some cases, manufacturers are
replacing manually initiated processing procedures with automated
process control systems to ensure proper formulation (addition of
ingredients and premixes), mixing, or processing of an infant formula
or to test a batch of infant formula. Such automated process control
systems frequently consist of a computer or system of computers that
controls many or all stages of production, in-process sampling, and
testing. In other cases, manufacturers are relying on programmable
equipment (such as an autoanalyzer) to perform a critical function,
such as testing a batch of infant formula to ensure that the batch
meets the nutrient requirements of the act. In all cases, it is
important that such systems and equipment function as expected to
ensure that the infant formula contains the required nutrients at the
required levels and is manufactured according to the CGMP and quality
control procedures prescribed under section 412(b)(2) of the act and
therefore is not adulterated under section 412(a)(1) or (a)(3) of the
act.
FDA is proposing to define ``hardware,'' ``software,'' ``system,''
and ``validation'' in Sec. 106.35 because the use of these terms will
simplify the language of the proposed regulations and will clarify
which sections of the proposed regulations apply to hardware only, to
software only, or to systems consisting of both hardware and software.
The definition of ``hardware'' in proposed Sec. 106.35(a)(1) is
based on common usage of the term and makes clear that the regulations
in proposed Sec. 106.35 apply to all automatic equipment, whether the
equipment is mechanical or electronic in nature. Proposed
Sec. 106.35(a)(1) also makes clear that electronic equipment includes,
but is not limited to, computers. This definition of ``hardware''
distinguishes those elements of equipment that have a physical form
from the elements considered to be intellectual property that may be
encoded on a physical element such as a diskette, tape, or
microprocessing chip.
Software may be developed by an infant formula manufacturer, by a
manufacturer of equipment purchased by the infant formula manufacturer,
or by a third party vendor (such as the vendor of a computer operating
system). The definition of ``software'' in proposed Sec. 106.35(a)(2)
derives from the ISO International Guideline ISO-9000-3 1 (Ref.
26) and the Institute for Electrical and Electronics Engineers, Inc.
(IEEE) Standard 610-12-1990 2 (Ref. 27) and is consistent with the
definition of software in FDA's ``Glossary of Computerized Systems and
Software Development Terminology (Ref. 28). FDA is proposing to
incorporate this definition into the agency's infant formula
regulations because the definition is derived from internationally
accepted definitions, includes documentation, applies to the operation
of all types of hardware (rather than the narrowly defined ``data
processing system'' or ``computer system'' included in the definitions
from the ISO and IEEE, respectively), and is consistent with current
FDA terminology. Software documentation consists of the instructions on
how to use the software. FDA has tentatively concluded that such
instructions need to be included in the definition of ``software'' to
ensure the proper operation of the software.
---------------------------------------------------------------------------
\1\ ISO is a world-wide federation of national standards bodies
that set quality assurance guidelines for products that will enter
international commerce. The ISO defines software as an
``intellectual creation comprising the programs, procedures, rules
and any associated documentation pertaining to the operation of a
data processing system'' (Ref. 26).
\2\ IEEE is a trade organization comprised of several societies.
IEEE standards are developed within the technical committees of the
IEEE societies and represent a consensus opinion of experts from
within IEEE as well as experts who are not members of IEEE. IEEE
defines software as ``computer programs, procedures, and possibly
associated documentation and data pertaining to the operation of a
computer system'' (Ref. 27).
---------------------------------------------------------------------------
The definition of ``system'' in proposed Sec. 106.35(a)(3) derives
from the IEEE Standard 610.12-1990 (Ref. 27). FDA is proposing to
incorporate this definition because many of the requirements in
proposed Sec. 106.35 cannot be related to software or hardware alone
but rather to systems in which software is used in conjunction with
hardware. For example, testing software under simulated conditions of
use may be beneficial during the early and middle stages of software
development, but validation of the software must be performed in
conjunction with the relevant hardware in the operational environment
it is
[[Page 36166]]
intended to be used in. Therefore in proposed Sec. 106.35(b)(4), FDA is
proposing that all systems be validated ``before their first use to
manufacture commercial product.''
Proposed Sec. 106.35(a)(4) defines ``validation'' as 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. It is important that a
process control system comply with specified requirements each time it
operates. 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''
(Ref. 26)); 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'' (Ref. 27)); 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. 28). FDA is proposing to incorporate these definitions into its
regulations because they are applicable to the types of systems used in
infant formula manufacture, are derived from internationally accepted
definitions, are consistent with existing FDA terminology, make clear
that the process of evaluation includes the complete system (i.e., the
hardware used in conjunction with the software), and include the
concept of consistency.
Proposed Sec. 106.35(b)(1) sets forth requirements for designing,
installing, testing, and maintaining all systems so that they function
as intended. Some systems may work properly only within a narrow range
of environmental conditions, such as temperature and humidity, and some
might be particularly sensitive to electromagnetic interference. The
actual conditions of use of a system should be considered as early as
possible in its design and development. Systems need to be installed in
a manner that takes into account the inherent limitations of the
system, tested under conditions that reflect actual conditions of use,
and properly maintained to ensure that they continue to function as
expected during their lifetime.
Proposed Sec. 106.35(b)(2) requires that the manufacturer ensure
that all hardware is routinely calibrated, inspected, and checked
according to written procedures. FDA has tentatively concluded that
this provision is necessary to ensure that any infant formula
manufactured under the control of automatic equipment meets the
requirements of the act and is manufactured in a manner designed to
prevent adulteration. For example, a batch of infant formula may lack
the required levels of nutrients if equipment used for the automatic
dispensing of a nutrient premix is out of calibration or has a clogged
delivery line. The routine calibration, inspection, and checking of
hardware will ensure that it continues to perform as intended, and that
its operation will not result in a process that deviates from
established specifications. The establishment of written procedures for
the calibration, inspection, and checking of hardware will ensure that
these procedures are performed consistently and in an appropriate way.
The incorporation of software into the operation of automatic
equipment has not only increased the complexity of such equipment but
also has resulted in a process that may operate differently for each
execution because a software-based control system can be configured at
will by the operator or by the system itself. Therefore, proposed
Sec. 106.35(b)(3), (b)(4), and (b)(5) require that manufacturers
exercise appropriate controls over systems and, in particular, over the
software used in the systems.
Proposed Sec. 106.35(b)(3) prescribes procedures for ensuring that
systems are checked for input and output errors resulting from faulty
data entry, faulty programming, or equipment malfunction. Such errors
can result in serious production or quality control errors leading to a
contaminated or adulterated infant formula. For example, a faulty
position sensor on a downstream valve that improperly indicates that it
is closed may result in a post-sterilization contamination. An
improperly installed (or empty) ink cartridge in a color printer or
multi-pen recorder may cause portions of a record to not be printed.
FDA has tentatively concluded that the regulation is necessary to
ensure that the infant formula produced or analyzed using the system is
not adulterated. However, proposed Sec. 106.35(b)(3) also provides that
the degree and frequency of input/output checks are to be based on the
complexity and reliability of the system and the level of risk
associated with the safe operation of the system.
Proposed Sec. 106.35(b)(4) requires that manufacturers ensure that
all systems are validated before their first use to manufacture
commercial product. FDA has tentatively concluded that it is necessary
that software programs that are used in a process control system to
monitor and control established points deemed necessary to prevent
adulteration (such as the speed of a pump, temperature of a heat
exchanger, addition of vital nutrients, and air overpressure in an
aseptic storage tank) be validated to ensure that use of the process
control system will produce compliance with the specifications or
standards at each control point. For example, if a continuous flow
process is designed to heat an in-process batch of infant formula in a
plate-to-plate heat exchanger to a specification of 271 deg.F, as
indicated by the temperature at the end of the hold tube, and the
system is mistakenly programmed to divert the product to the raw
(unsterilized) surge tank only if the temperature drops below 261
deg.F, an in-process batch of infant formula heated to 261 deg.F would
not be diverted to the raw surge tank but rather would be handled by
the computer as if it were adequately processed. Such an underprocessed
batch of infant formula would likely pose a foodborne biological
hazard. Thus, FDA has tentatively concluded that the validation
required under proposed Sec. 106.35(b)(4) is necessary to ensure that
infant formula that is produced or analyzed using the system is not
adulterated.
The validation of software ordinarily includes the following
elements: Requirements development, design, coding, debugging, testing
(with the hardware), and maintenance (Refs. 29, 30, and 31). Software
validation also includes a review for correctness of the software
documentation to ensure that the instructions prompt the input of the
proper commands or data by the user. However, depending on the nature
of the software and the hardware that it controls, some or all of these
aspects of the validation process may be done by the infant formula
manufacturer, by the manufacturer of equipment that is purchased by the
infant formula manufacturer, or by a third party vendor.
Proposed Sec. 106.35(b)(4) leaves the identity of the person that
does the validation to the discretion of the infant formula
manufacturer but makes clear that the infant formula manufacturer is
responsible for ensuring that the system is validated. The proposal
does not stipulate any standards or specifications for the validation
process because the extent of the validation necessary is
[[Page 36167]]
related to the level of risk that each component of the system
presents.
More emphasis should be placed on validating portions of the system
that represent major risk than on those that confer moderate or minor
risk. A major risk is associated with systems that control or monitor a
point where such control or monitoring is deemed necessary to prevent
adulteration of the infant formula; for example, systems that control
or monitor nutrient addition or processing temperature present a major
risk. A moderate risk is associated with systems that influence, but
that do not control or monitor, a point where control or monitoring is
deemed necessary to prevent adulteration of the infant formula. For
example, the speed of computer processing presents a moderate risk if
software that is designed to be used on a high-speed computer is used
on a slower computer. A minor risk is associated with systems that do
not involve a point where control or monitoring is deemed necessary to
prevent adulteration. For example, systems that control pallet stacking
or product conveying present a low risk.
Proposed Sec. 106.35(b)(5) requires that any system that is
modified be revalidated after any modification and before use of the
modified system to manufacture commercial product. FDA has tentatively
concluded that revalidation is necessary to ensure that no errors are
introduced into the system during the modification and to ensure that a
modification in one aspect of a process control system does not,
unknowingly but adversely, affect other aspects of the process control
system, particularly those operations that follow the modified aspect
of the system.
Under Sec. 106.35(b)(5), FDA is also proposing that a specific
individual (or group of individuals) is designated to modify software
to prevent the indiscriminate modification of software and to ensure
that all modifications are made consistently. The designated individual
may be employed by the infant formula manufacturer, the manufacturer of
equipment purchased by the infant formula manufacturer, or by a third
party. The regulation states, however, that the infant formula
manufacturer is responsible for ensuring that modified software is
retested or revalidated regardless of who does the modification.
Proposed Sec. 106.35(c)requires that infant formula manufacturers
make and retain records concerning automatic (mechanical or electronic)
equipment. FDA is proposing this requirement under the authority of
section 412(b)(4)(A)(i) of the act, which requires the retention of all
records necessary to demonstrate compliance with the CGMP and quality
control procedures prescribed under section 412(b)(2) of the act,
including the results of all testing required under section
412(b)(2)(B) of the act. These records will allow manufacturers to
readily determine whether this crucial equipment is being appropriately
operated and maintained. They will allow manufacturers to troubleshoot
and to operate these systems with a minimum of downtime when problems
occur because the records will include a copy of all software used and
a backup file of data entered into the computer or related system which
can be used to reload the system. The records will also provide
information that the manufacturer can use in trying to determine why a
problem with the system is occurring or why the system is not producing
an infant formula that complies with the manufacturer's specifications
for the product.
7. Controls to Prevent Adulteration Caused by Ingredients, Containers,
and Closures
Proposed Sec. 106.40(a) specifies that the only substances that may
be used in infant formulas are food ingredients that are generally
recognized as safe (GRAS) for use in infant formula, that are used in
accordance with the agency's food additive regulations, or that are
authorized by a prior sanction issued by FDA. Under section
412(b)(2)(A) of the act, FDA is to establish CGMP's that it determines
are necessary to ensure that the infant formula is manufactured in a
way that is designed to prevent adulteration of the formula. Unless the
safety of the ingredients of an infant formula has been established,
the formula is adulterated under section 402(a)(1) and (a)(2)(C) of the
act. Thus, the agency has tentatively concluded that CGMP requires that
the manufacturer ensure that the ingredients that it uses in its
formula are safe and suitable.
Proposed Sec. 106.40(b) requires that infant formula containers and
closures not be reactive or absorptive so as to affect the safety of
the infant formula, and that all packaging material that comes in
contact with an infant formula be composed of authorized substances and
be used in accordance with any prescribed limitations. Various
regulations that authorize the use of a material in contact with the
food product also set conditions and limitations on that use. Thus, the
agency proposes to require that the manufacturer not only use only
materials specified in proposed Sec. 106.40(b), but also that the
materials be used as specified in the regulations authorizing their
use. This provision will ensure that the food contact surface of
containers and closures will not adulterate the infant formula.
In order for the manufacturer to maintain a complete record of how
each ingredient, container, or closure was used and to determine which
lots of infant formula are adulterated if a problem is ultimately
identified with a particular lot of ingredients, containers, or
closures, FDA is proposing, in Sec. 106.40(c), that they be identified
with batch or lot numbers. This batch or lot number can be used to
identify ingredients, containers, or closures that have been released
for use in infant formula or rejected for use in infant formula
manufacture. It also can be used to track the ingredients, containers,
or closures that were used in the manufacture of each batch of infant
formula.
Proposed Sec. 106.40(d) requires that infant formula manufacturers
develop written specifications that stipulate the standards for
acceptance or rejection of ingredients, containers, and closures.
Stipulating the standards for acceptance or rejection of ingredients
used to supply nutrients is important to ensure that all the required
nutrients are present in the formula at the required levels. For
example, the level of endogenous nutrients that a manufacturer expects
will be supplied by an ingredient should be stipulated as a standard
for acceptance or rejection of that ingredient. Endogenous nutrients
are nutrients provided as a part of other nutrients, such as minerals
provided as a part of the protein source. Sodium, for example, is
frequently provided as part of the protein ingredient ``caseinate.''
To ensure that the mineral is provided in the infant formula at at
least the minimal level, and not above the maximum level, required by
Sec. 107.100, the infant formula manufacturer must know what amount of
a mineral is provided to the formula by all ingredients that are
sources of the mineral. Thus, a standard for the level of the
endogenous nutrient that is to be provided by an ingredient is an
appropriate specification for the manufacturer to develop. If the level
of the mineral is too high in the ingredient, it may cause the formula
to exceed the maximum established in Sec. 107.100. Similarly, if the
level is too low, the formula may not meet the required minimal level.
Developing standards for acceptance or rejection of ingredients
used in infant formula manufacture is also important to ensure that
contaminants in the
[[Page 36168]]
ingredients that may lead to adulteration of the product are not
present in the formula. Examples of contaminants that may lead to
adulteration of an infant formula include certain heavy metals, such as
lead. Infant formula manufacturers are currently setting standards for
the lead in the ingredients that they use in infant formula to ensure
that the lead level in infant formulas is at or below the
quantification limit of the method used for lead determination (Ref.
32).
Stipulating the standards for acceptance or rejection of containers
or closures used in infant formula manufacture is important to ensure
that the integrity of the container and of the closure is maintained to
prevent leakage of the formula and to prevent an infant formula from
becoming adulterated, which can occur if the container or closure is
not impenetrable to air (which can cause nutrient degradation), or if
the container or closure allows outside contaminants to get into the
infant formula.
Proposed Sec. 106.40(d) also requires that manufacturers establish
written specifications that stipulate the procedures for determining
whether the ingredients, containers, and closures meet the standards.
Examples of procedures manufacturers may use to determine whether they
meet the standards are acceptance of a supplier's guarantee or
certification and testing conducted by the infant formula manufacturer.
In some cases, manufacturers must conduct their own testing to ensure
that the standards for acceptance or rejection of the ingredient are
met. For example, section 412(b)(3)(B) of the act requires that
manufacturers test each nutrient premix for each relied-upon nutrient
to ensure that the premix complies with its specifications or
certifications by a premix supplier, but the act does not require
testing of individual nutrient ingredients when such nutrients are not
supplied as a nutrient premix. However, a manufacturer may find through
experience that the best way to ensure that the final product will meet
all specifications is to test certain nutrient ingredients for
identity, purity, and potency before using them in the infant formula.
In addition, manufacturers should have controls in place to ensure
that any ingredients, containers, or closures that do not meet any of
their specifications are not used in production of a batch of infant
formula. However, if these controls fail, and any such ingredients,
containers, or closures are used in a batch of formula, FDA is
proposing under Sec. 106.40(d) that an individual qualified by training
or experience conduct an investigation to ensure that the failure does
not lead to release into the marketplace of an adulterated product.
Proposed Sec. 106.40(e) requires that ingredients, containers, and
closures be stored in areas clearly designated for materials pending
release for use, materials released for use, or materials rejected for
use in infant formula production in order to prevent mixups in using
materials that are inappropriate for infant formula manufacturing. FDA
is further proposing to require that any lot of ingredients,
containers, or closures that does not meet the manufacturer's
specifications be rejected and controlled under a quarantine system
designed to prevent its use in the manufacture of infant formula.
Failure to protect against the use of these materials would
significantly increase the likelihood that an adulterated product will
be produced.
Some ingredients used in infant formula are vulnerable to
degradation when they are exposed to heat or air. Moreover, containers
or closures may be exposed to air containing dust and dirt and become
contaminated. Thus, the ingredients, containers, and closures may need
to be reexamined after they are exposed to air, heat, or other
conditions that may adversely affect them to ensure that they still
meet the manufacturer's specifications. Thus, FDA is proposing, in
Sec. 106.40(f), to require retesting or reexamination after approved
materials have been exposed to conditions that may adversely affect
them.
Proposed Sec. 106.40(g) requires that manufacturers make and retain
records on ingredients, containers, and closures used in the
manufacture of infant formula so that if adulteration of formula
occurs, the manufacturer will be able to determine the source of the
material, so that its use can be halted. In addition, the records will
show the basis on which each ingredient, container, and closure was
released for use in infant formula production, if questions about such
release later arise. FDA has authority to require these records, under
section 412(b)(4)(A)(i) of the act.
8. Controls to Prevent Adulteration During Manufacturing
The infant formula manufacturing process involves a number of
complicated processes that may cause adulterated formula to be produced
if the processes are not properly conducted or monitored. Therefore,
FDA is proposing, under section Sec. 106.50, to require that
manufacturers establish controls to minimize the risk that
manufacturing process errors will produce an adulterated or unsafe
formula. The proposed requirements reflect many of the practices
currently used by infant formula manufacturers and manufacturers of
other commodities that require strict production controls to prevent
product adulteration (e.g., Ref. 9 and 21 CFR 211.100 through 211.115).
Proposed Sec. 106.50(a)(1) carries forward and amends the
requirement in current Sec. 106.25(a) that a master manufacturing order
be prepared and followed. A master manufacturing order is necessary to
ensure that the manufacturer will produce each batch of a particular
infant formula the same way. If the master manufacturing order is not
followed, all necessary ingredients may not be added to the formula in
the appropriate concentrations and in the appropriate manner.
FDA is also proposing that manufacturers make and retain records
that include complete information relating to the production and
control of the batch at the time each manufacturing operation is
performed (see proposed Sec. 106.50(a)(2)). This proposed requirement
will ensure that the complete history of each batch of infant formula
is available for review in the event that a problem arises with a
particular batch.
Proposed Sec. 106.50(a)(2) also requires that an individual
qualified by training or experience conduct an investigation of any
deviations from the master manufacturing order and any corrective
actions taken. This investigation is necessary to ensure that any
deviations from the master manufacturing order do not lead to an
adulterated product.
If any changes are made to the master manufacturing order, proposed
Sec. 106.50(a)(3) requires that they 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. This process is necessary to prevent unintended adverse
effects that could result from changes to the master manufacturing
order made by persons not qualified to assess their impact. The
production of infant formula is a sophisticated process, and all
organizational units that are involved in critical formulation and
production steps, such as production, engineering, research, and
regulatory affairs, should review and approve changes to the master
manufacturing order. FDA has tentatively concluded, however, that all
changes to the master manufacturing order need to be
[[Page 36169]]
reviewed by at least one responsible official, and that this official
will need to evaluate how the change will affect the nutrient content
and the suitability of the product for infants, to ensure that the
infant formula is not adulterated.
A significant change in the master manufacturing order without
proper approval may result in the production of an infant formula that
lacks a required nutrient or that is not manufactured in an appropriate
way. For example, homogenization of an infant formula is done to ensure
a uniform dispersion throughout the formula of the lipid ingredients as
well as the fat-soluble nutrients. If the master manufacturing order
were changed, and the homogenization process done before the fat source
was added, the fat-soluble nutrients would not be uniformly dispersed
in the formula, and the formula would be adulterated. The system of
review and approval required by proposed Sec. 106.50(a)(3) will
minimize the possibility that a significant change could result in an
adulterated product.
In order to ensure that the appropriate ingredients are added
during the manufacturing process, and that the formula contains all of
the nutrients required by Sec. 107.100 and therefore is not
adulterated, FDA is proposing in Sec. 106.50(b) that each raw or in-
process ingredient required by the master manufacturing order be
examined by one person and checked by a second person or system. This
requirement will ensure that there will be a check to prevent mixups in
the use of ingredients and to prevent the use of unapproved
ingredients. Confirmation that the master manufacturing order is being
followed, and that ingredients are being properly added, is
particularly important because these matters are fundamental to
ensuring that the formula is manufactured correctly, and that it
contains the nutrients required by Sec. 107.100 but not unapproved
ingredients that might adulterate the formula.
In proposed Sec. 106.50(c), FDA is requiring the identification of
all compounding and storage containers, processing lines, and major
equipment used during the production of a batch of infant formula.
Identification of these items 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 mixups 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. The
presence of the lot or batch number will help to identify the product
if a problem does occur.
Proposed Sec. 106.50(d) requires that manufacturers establish
controls to ensure that required nutrient levels are maintained in the
formula, and that the formula is not contaminated with microorganisms
or other contaminants and thereby adulterated. In addition, the agency
is proposing to require establishment of controls for mixing time,
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. These parameters are determined by
the manufacturer according to its experience and knowledge of what will
result in a homogeneous, safe, and uniform product. It is essential
that controls be established for each of these parameters, or the
likelihood that there will be inconsistencies in production from batch
to batch will be greatly increased. For example, if processing
temperatures are not specified, the formula could be processed at high
temperatures that can destroy vitamins or other essential nutrients,
resulting in a product that is adulterated because it does not meet the
nutrient requirements specified in section 412(i) of the act.
Similarly, without established procedures for mixing time and speed,
the product may be produced using processing parameters that will not
result in formula that is uniformly mixed and thus does not contain all
nutrients at the required levels.
FDA is proposing to require that manufacturers establish controls
for the spray-drying process for powdered infant formula to prevent
microbial and other contamination (Sec. 106.50(d)(2)). Although spray
drying involves a heat treatment, the temperature is not sufficient to
sterilize the formula. Consequently, powdered infant formulas are
vulnerable to microbial contamination during the spray-drying process.
Even if the equipment and the formula are free of microbial and other
forms of contamination initially, the spray-drying process may permit
contamination of the product as a result of dust or other air-borne
gross particulates in the intake air. Thus, FDA has tentatively
concluded that it is important that the manufacturer establish controls
for the spray-drying process that will ensure that the powdered formula
does not become contaminated with microorganisms or other contaminants.
The controls that manufacturers should consider include: (1) Using
equipment constructed to ensure that static accumulation of particulate
matter is controlled; (2) using and maintaining equipment constructed
to protect the product from dust and environmental contamination; (3)
controlling condensation, moisture, and temperature conditions
throughout the plant to prevent Salmonella and Listeria growth in
static materials; (4) controlling condenser cooling water to prevent
potential Salmonella and other bacterial contamination; (5) controlling
sampling and cleanout ports on the evaporator for buildup of static
material and avenues for airborne contaminants; and (6) controlling
product flow through the plant to prevent unnecessary product movement
between areas that may increase the likelihood of cross-contamination.
As stated above, contaminants may enter the product in the air
introduced into the spray-drying equipment during the spray- drying
process. Air can contain free microorganisms or particulate material
that is contaminated with microorganisms. Controls to prevent microbial
contamination of the formula by airborne sources must address not only
the presence of microorganisms themselves but also the sources of dust,
moisture, and other airborne contaminants that may be sources of
microbial contamination. Therefore, proposed Sec. 106.50(d)(2) requires
that manufacturers filter the intake air before heating to remove dust
or other air-borne gross particulates that can result in the production
of adulterated formula.
FDA is proposing to require that manufacturers control the removal
of air from finished product containers (proposed Sec. 106.50(d)(3))
and ensure that containers of finished products are properly sealed
(proposed Sec. 106.50(d)(4)), that visible closure and seal defects are
detected (proposed Sec. 106.50(d)(4)(i)), and that destructive tests
are performed to determine closure strength (proposed
Sec. 106.50(d)(4)(ii)). These requirements are necessary to prevent
oxidation and deterioration of nutrients in the formula caused by air
or contaminants during the product's shelf life. FDA is also proposing
that equipment that is used to prevent adulteration be monitored,
either by personnel or monitoring equipment, to alert the manufacturer
to malfunctions (see Sec. 106.50(e)). As a result of such monitoring,
the manufacturer will be
[[Page 36170]]
able to minimize the amount of product produced subject to a
malfunction that may develop and to take prompt corrective actions.
In order to prevent rejected in-process materials from being
inadvertently commingled with acceptable materials, FDA is proposing
that manufacturers establish controls that ensure that the rejected
materials are clearly identified and quarantined, and that reprocessed
materials will not produce adulterated formula (see Sec. 106.50(f)).
9. Controls to Prevent Adulteration from Microorganisms
An infant formula that is contaminated with microorganisms may,
depending on the characteristics of the microorganisms, raise a safety
concern that would cause the infant formula to be adulterated under
section 402(a)(1) of the act. For example, all serotypes of the genus
Salmonella can cause illness (often gastrointestinal) in infants and
adults (Refs. 33 and 34) and the infectious dose is low (Ref. 35).
Moreover, microorganisms that are generally harmless in older children
and adults can cause serious bacterial infections in infants because
the immune systems of infants are still developing (Ref. 36). For
example, newborns and infants are susceptible to infection with
Listeria monocytogenes that may cause severe illness or death (Ref. 37)
and, as in the case of Salmonella, the infectious dose is believed to
be low (Ref. 38).
Likewise, Staphylococcus aureus is harmful to infants because some
strains of this microorganism produce an enterotoxin that causes acute
gastrointestinal illness (nausea, vomiting, cramps) soon after the food
is ingested (Ref. 39). Bacillus cereus can produce diarrhea and
vomiting in adult humans (Ref. 40) when food contaminated with at least
10\5\ B. cereus cells is consumed. The infectious dose of B. cereus for
infants is not known; however, as already noted, infants are more
susceptible to bacterial infections than are healthy adults and older
children because the immune systems of infants are not fully developed.
FDA has long held that health concerns may arise due to the
presence of any detectable Salmonella, 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 infant
formula. Such health concerns would cause the agency to consider an
infant formula that is so contaminated to be adulterated under section
402(a)(1) of the act (see 54 FR 3783, Jan. 26, 1989, and 56 FR 66566,
Dec. 24, 1991).
Moreover, the presence of 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 sections 402(a)(4) and 412 of
the act. For example, the presence of Escherichia coli in a sample of
infant formula is an indicator of fecal contamination, implying that
the infant formula has been contaminated by manufacturing practices
conducted under insanitary conditions and therefore is adulterated
under sections 402(a)(4) and 412 of the act. In addition, consistent
with the standard adopted by the International Commission on
Microbiological Specifications for Foods (ICMSF) of the Food and
Agricultural Organization of the United Nations and the World Health
Organization (WHO) and based on the results from FDA and Canadian
Surveys (Refs. 41, 42, and 43), an aerobic plate count (APC) (i.e., the
number of microorganisms that will grow under certain specified
conditions) that is greater than 10,000 CFU's per g of a powdered
infant formula evidences that the formula has been prepared, packed, or
held under insanitary conditions.
Illnesses from the use of microbiologically contaminated infant
formulas have occurred (Ref. 33). Moreover, as recently as May 1993,
infant formula contaminated with Salmonella bacteria was the subject of
a recall (Ref. 44). Thus, contamination of infant formula with
microorganisms of public health significance is more than a theoretical
possibility. Therefore, FDA has tentatively concluded that
manufacturers need to have in place controls to ensure that formulas
are not microbiologically contaminated at levels of public health
significance, and that, if they are, those formulas do not enter
interstate commerce. Proposed Sec. 106.55 requires manufacturers to
establish such controls.
Proposed Sec. 106.55(a) requires that manufacturers of liquid
infant formula comply with the procedures specified in part 113. These
products are thermally-processed low-acid foods that are packaged in
hermetically sealed containers that are heated to achieve commercial
sterility. Therefore, they are appropriately subject to the
requirements of part 113.
Proposed Sec. 106.55(b) requires that manufacturers of powdered
infant formula test representative samples of every batch of the
formula at the final product stage, before distribution, to ensure that
the infant formula meets the microbiological quality standards
specified in proposed Sec. 106.55(c). This proposed requirement is
necessary because although powdered infant formulas are heat treated
during processing, they are not thermally processed to achieve
commercial sterility. Proposed Sec. 106.55(b) requires testing at the
final product stage because microbiological contamination can be
inadvertently introduced by ingredients at any time during production
or through improper processing or holding procedures (Ref. 45).
Proposed Sec. 106.55(c) establishes that any powdered infant
formula that contains any microorganism at levels that exceed the
microbiological quality standards for that microorganism as listed in
this section will be deemed to be adulterated under sections 402 and
412 of the act. Proposed Sec. 106.55(c) defines microbiological quality
standards as the maximum allowable number of microorganisms present in
1 g of dry formula, expressed as CFU/g or ``most probable number''
(MPN)/g, and herein designated the ``M value'' for the specific
microorganism.
The microorganisms for which FDA is proposing M values are those
that are of known public health significance or that are indicators
that the formula have been prepared, packed, or held under insanitary
conditions. The microorganisms and each proposed M value listed in
proposed Sec. 106.55(c) are adapted from guidelines previously
published and discussed in the proposed and final rules on infant
formula record and record retention requirements (see 54 FR 3783, Jan.
26, 1989, and 56 FR 66566, Dec. 24, 1991, respectively). The agency
notes, however, that microorganisms that must be tested for in infant
formula and the proposed M values for each microorganism listed in this
proposed rule represent minimum requirements for the microbiological
quality of an infant formula based on standards and methods currently
available.
a. Aerobic plate count (APC). Proposed Sec. 106.55(c) establishes
an APC M value of 10,000 CFU/g as the maximum level that is consistent
with sanitary conditions in the facility in which a powdered infant
formula is produced. An APC M value greater than the proposed standard
indicates that the formula was produced under insanitary conditions
whereby it may have been rendered injurious to health and thus is
adulterated under sections 402(a)(4) and 412 of the act.
The APC is the number of microorganisms that will grow on the APC
nutrient medium, incubated at 35 deg.C for 24 hours in air (Ref. 46).
``Microorganisms'' (as defined in
[[Page 36171]]
proposed Sec. 106.3(k)) include yeasts, molds, bacteria, and viruses.
The APC medium supports the growth of most microorganisms, including
yeasts, molds, and all bacteria required to be tested for under
proposed Sec. 106.55(c); however, the APC medium does not support the
growth of viruses. The APC count is expressed in CFU's because multiple
microorganisms may adhere together or attach to the same location on an
agar plate, and microbiologists cannot determine whether one or several
individual microorganisms initiated the colony that they detect growing
on the plate.
This M value for the APC proposed in Sec. 106.55(c) is consistent
with the standard adopted by the ICMSF and the WHO and the results from
FDA and Canadian Surveys (Refs. 41, 42, and 43). The ICMSF based its
standards on the degree of health hazard the microorganisms present and
conditions of use of the product (Ref. 41).
FDA has tentatively arrived at this APC M value because the
microbial quality of products consumed by infants is of primary concern
(Ref. 43). When infant formulas are produced under good commercial
processing, the available evidence shows that the APC will be below
this M value (Refs. 42 and 43). The agency is notaware of adverse
events occurring in infants who consumed products with an APC below
this M value.
b. Coliforms, fecal coliforms, and E. coli. E. colli are bacteria,
including some strains that are pathogenic for infants, that thrive in
the human intestinal tract. The presence of E. coli in a sample of
powdered infant formula is an indicator that the infant formula has
been contaminated by manufacturing practices conducted under insanitary
conditions and therefore is adulterated under sections 402(a)(4) and
412 of the act.
E. coli bacteria are a subset of a more diverse group of bacteria
known collectively as fecal coliforms, which also thrive in the human
intestinal tract and therefore are also indicators of fecal
contamination. Fecal coliforms are destroyed by pasteurization, and the
presence of these microorganisms in a pasteurized product evidences
that there has been post-process contamination of the formula (Ref.
47). Fecal coliforms in turn are a subset of a still further diverse
group of bacteria known as coliforms, which include bacteria that may
or may not be indicators of fecal contamination. However, contamination
with coliforms is a reliable indicator of post-process contamination of
the formula, even if the source of the contamination is not fecal.
In previously issued guidelines, the agency recommended that
powdered infant formulas be tested for the presence of E. coli (54 FR
3783); however, one comment on this recommendation suggested that, to
allow greater flexibility and reduce the cost for manufacturers, the
manufacturer should be given the option of testing for coliforms, fecal
coliforms, or E. coli. Specific tests for contamination with E. coli
provide the most definitive evidence of fecal contamination, but tests
for specific bacteria are more cumbersome than general tests for a
group of bacteria such as fecal coliforms. Similarly, general tests for
fecal coliforms are more cumbersome than universal tests for an even
more diverse group of bacteria such as coliforms.
The agency is proposing in Sec. 106.55(c) that manufacturers screen
their samples of powdered infant formula for evidence of contamination
with E. coli using sequential tests for detecting and enumerating
coliforms and fecal coliforms. Under the proposal, manufacturers
ordinarily would only perform the simplest test (i.e., the test for
coliforms) using a test sample of the infant formula. The results of
the coliform test determine whether the manufacturer needs to followup
with a more specific test for fecal coliforms using as the test sample
cultured bacteria prepared during the coliform test. As discussed
below, the agency is not proposing that manufacturers followup a
positive result in the fecal coliform test with a more specific test
for E. coli but rather is proposing that a violative sample in the
fecal coliforms test will represent conclusive evidence that the infant
formula is adulterated.
The general test for coliforms is an example of an MPN test. MPN
counts are estimates of the number of organisms present in a sample.
Methods resulting in an MPN require inoculation of multiple tubes of
liquid culture medium with multiple dilutions of the sample. The method
specified in FDA's Bacteriological Analytical Manual (BAM) (Ref. 46)
requires inoculation of 3 replicate tubes of culture medium with each
of 3 sample dilutions, for a total of 9 tubes. The tubes contain
culture medium selective for the microorganism of interest. After
appropriate incubation (time, temperature, and atmosphere), each tube
is scored as positive or negative for the presence of the organism.
Examples of a positive result include the presence of growth, a
biochemical color change, and the production of gas.
A mathematical formula is used to calculate the MPN of
microorganisms present based on the number of positive tubes in each of
the three separate dilutions. Since the calculation in question
involves a repetitious process, the mathematical formula used to
calculate the MPN has been employed to create easy-to-use tables that
are available in the BAM and in other books of statistical tables. Most
tables present both a value for the MPN and confidence limits for that
value. The calculated table values for the MPN, using BAM methods, are
dependent on the level of the dilution in which a positive result is
found. The following table values are based on an inoculation series of
0.1, 0.01 g, and 0.001 g (or mL) of the infant formula. When no tubes
in any dilution produce a positive result, the calculated MPN value is
zero.3 When a single tube in the greatest dilution (least
concentrated) produces a positive result, the calculated MPN value is
equal to 3.01.4 When a single tube in the middle dilution produces
a positive result, the calculated MPN value is equal to 3.05.5 In
all other situations in which there is a positive result in at least
one tube (including a single positive tube in the lowest dilution
(greatest concentration)), the calculated MPN value is greater than
3.05.
---------------------------------------------------------------------------
\3\ The calculated MPN value of zero when no tubes in any
dilution produce a positive result is a recent change that appears
in the MPN tables of the 8th ed. of the BAM. In previous editions of
the BAM, the calculated MPN value when no tubes in any dilution
produce a positive result was ``less than 3.''
\4\ The calculated MPN value of 3.01 when a single tube in the
greatest dilution produces a positive result is a recent change that
appears in the MPN tables of the 8th ed. of the BAM. In previous
editions of the BAM, the calculated MPN value when a single tube in
the greatest dilution produces a positive result was 3.
\5\ The calculated MPN value of 3.05 when a single tube in the
middle dilution produces a positive result is a recent change that
appears in the MPN tables of the 8th ed. of the BAM. In previous
editions of the BAM, the calculated MPN value when a single tube in
the middle dilution produces a positive result was 3.
---------------------------------------------------------------------------
If no tubes in any dilution produce a positive result in a test for
bacterial contamination of a powdered infant formula (i.e., if the MPN
is zero), such contamination is unlikely. If a single tube in any
dilution produces a positive result in a test for bacterial
contamination of the product, such contamination is a possibility.
However, there are two situations in which a single positive tube is
generally considered to reflect a false positive test result: (1) When
no tube in the lowest dilution (greatest concentration) produces a
positive result, but a single tube in the middle dilution produces a
[[Page 36172]]
positive result (i.e., the calculated MPN value is equal to 3.01); or
(2) when no tube in the lowest dilution produces a positive result, but
a single tube in the greatest dilution (least concentration) produces a
positive result (i.e., the calculated MPN value is equal to 3.05). FDA
considers that if a sample of a powdered infant formula produces
positive test results that reflect one of these two situations,
bacterial contamination also is unlikely.
However, in all other situations (e.g., if a single tube in the
lowest dilution (greatest concentration) produces a positive result, or
if two or more tubes in any dilution produce a positive result),
bacterial contamination of a powdered infant formula is likely.
Therefore, when the calculated MPN value in a test for bacterial
contamination is greater than 3.05, that is if a sample of powdered
infant formula produces positive test results in which a single tube in
the lowest dilution produces a positive result or in which two or more
tubes in any dilution produce a positive result, the powdered infant
formula likely is contaminated with bacteria.
FDA is proposing to use the calculated MPN values in the BAM as a
means of setting a numerical specification because these tables are
generally available, represent standard practice in the industry, and
provide a simple way to classify samples as violative or nonviolative.
Based on the above discussion of calculated MPN values, FDA is
proposing in Sec. 106.55(c) that powdered infant formula be classified
as nonviolative for coliforms in all situations in which the calculated
MPN value is less than or equal to 3.05 and classified as presumptively
violative for coliforms in all situations in which the calculated MPN
value is greater than 3.05. In other words, FDA is proposing that an
MPN value of 3.05 represents the maximum allowable number of coliforms
present in 1 g of dry infant formula. This proposal is consistent with
current FDA infant formula microbiological guidelines. The agency
requests comment on the specification of 3.05 MPN/g as the maximum
allowable number of coliforms in dry infant formula.
FDA has stated that infant formula with a calculated MPN value of
greater than 3.05 in the coliform test is presumptively violative
because, under proposed Sec. 106.55(c), the manufacturer may either
consider the sample violative without further testing or may conduct an
additional test, the fecal coliform test. Although an MPN value of
greater than 3.05 MPN/g is a valid quality indicator of microbial
contamination, coliform contamination may not be fecal in origin, and
it may not reflect the presence of infant pathogenic microorganisms.
Therefore, FDA has tentatively concluded that an infant formula for
which an MPN value of greater than 3.05 MPN/g is found in the coliform
test need not be considered violative if a negative result is found in
a more specific test for fecal coliforms.
If the coliform test using powdered infant formula samples results
in an M value greater than 3.05 MPN/g, the manufacturer may use the
cultured bacteria from one or more of the tubes producing the positive
result as a sample inoculum for the fecal coliform test. A sample
inoculum producing an MPN value in the fecal coliform test of less than
or equal to 3.05 would indicate that the coliform contamination is not
fecal in origin, because under incubation conditions that are specific
for fecal coliforms, the bacteria were not detected. The testing would
effectively screen out coliforms that are not of concern, which is not
possible with the more general test. Therefore, FDA has tentatively
concluded that an MPN value less than or equal to 3.05 in the fecal
coliform test be classified as nonviolative. FDA also has tentatively
concluded that an MPN value greater than 3.05 in the fecal coliform
test is a valid quality indicator demonstrating that the formula
contains fecal coliforms such as E. coli and, therefore, is adulterated
under sections 402(a)(4) and 412 of the act. The agency is proposing
that powdered infant formula that results in an MPN value greater than
3.05 in the fecal coliform test be classified as violative.
If the E. coli test was performed, the sample inoculum would be the
cultured bacteria from positive tubes in the fecal coliforms test.
However, the agency is not proposing to require specific testing for
the presence of E. coli, or to set a specification for an M value for
E. coli, because the specification of less than or equal to 3.05 MPN/g
in the fecal coliforms test is sufficient to ensure that nonviolative
samples do not contain E. coli since E. coli is a type of fecal
coliform. Moreover, FDA has tentatively concluded that an MPN value
greater than 3.05 in the fecal coliform test is a sufficient quality
indicator of fecal contamination that the agency need not propose, as
an option, that a manufacturer may conduct an additional specific test
for the presence of E. coli. The agency requests comments on the
proposed requirements for sequential testing for coliforms and fecal
coliforms, with no testing for E. coli.
c. Salmonella. Tests for the presence of Salmonella involve the
enrichment in a broth of the entire analytical unit followed by plating
onto culture plates rather than the culture of a series of dilutions
that is performed in tests for coliforms. A positive result in a test
for Salmonella is based on the detectable presence of the microorganism
on the culture plate rather than on the mathematical calculations that
result in a MPN.
Proposed Sec. 106.55(c) requires that powdered infant formula be
tested for Salmonella and provides that the formula is adulterated if
any Salmonella is found. All serotypes of this genus of bacteria can
cause illness (often gastrointestinal) in infants and adults (Refs. 33
and 34). The presence of any Salmonella in infant formula could render
it injurious to an infant who consumes it because the infectious dose
of these bacteria is low (Ref. 35). Therefore, FDA has tentatively
concluded that the risk from Salmonella is of such significance that an
M value of zero (i.e., none detectable) for Salmonella in infant
formula is necessary to protect the health of infants.
d. Listeria monocytogenes. Tests for the presence of L.
monocytogenes are similar to those for Salmonella and a positive result
is based on the detectable presence of the microorganism on the culture
plate rather than on the mathematical calculations that result in a
MPN.
Proposed Sec. 106.55(c) requires that powdered infant formula be
tested for L. monocytogenes and provides that the formula is
adulterated if any L. monocytogenes is found. Individuals with immune
systems that make them susceptible to infections, such as newborns and
infants with incompletely developed immune systems, are susceptible to
infection with L. monocytogenes which may cause severe illness or death
(Ref. 37). The infectious dose of this bacterium is believed to be low
(Ref. 38). Because the specific dose of this bacterium that may cause
illness is not known but is believed to be low, FDA has tentatively
concluded that the risk from L. moncytogenes is of such significance
that an M value of zero (i.e., none detectable) for L. monocytogenes in
powdered infant formula is necessary to protect the health of infants.
The agency requests comment on this proposed specification for L.
monocytogenes.
e. Staphylococcus aureus. S. aureus is harmful to infants because
some strains of this microorganism produce an enterotoxin that causes
acute gastrointestinal illness (nausea,
[[Page 36173]]
vomiting, cramps) soon after the food is ingested (Ref. 39). Tests for
S. aureus involve liquid culture of series of dilutions as was
discussed previously in reference to coliform and fecal coliform
testing and results are calculated as MPN based on tables in the BAM.
Proposed Sec. 106.55(c) requires that powdered infant formula be tested
for S. aureus and establishes an M value of 3.05 for this
microorganism. FDA has tentatively concluded that the risk from S.
aureus is of such significance that an M value of 3.05 is necessary to
protect the health of infants.
f. Bacillus cereus. Tests for B. cereus involve liquid culture of a
series of dilutions as was discussed previously in reference to
coliform and fecal coliform testing and results are calculated as MPN
based on tables in the BAM. Proposed Sec. 106.55(c) requires that
powdered infant formula be tested for B. cereus when the APC exceeds
100 CFU/g and establishes an M value for B. cereus of 100 MPN/g or 100
CFU/g. This proposed M value for B. cereus is lower than the M value of
1,000 MPN/g or 1,000 CFU/g in the current recommended infant formula
microbiological guidelines (54 FR 3783). B. cereus can produce diarrhea
and vomiting in adult humans (Ref. 40) when food contaminated with at
least 105 B. cereus cells is consumed. The infectious dose of B.
cereus for infants is not known; however, because the immune systems of
infants are not fully developed, infants are more susceptible to
bacterial infections than are healthy adults and older children. In the
absence of data on the dose of B. cereus capable of causing disease in
infants, the agency is concerned that a safety standard of 1,000 MPN/g
or 1,000 CFU/g poses a potential risk to infants who consume rehydrated
formula because B. cereus in rehydrated powdered infant formula is
capable of rapid growth and can reach 4.9 x 106 cells/g within 24
hours at 26 deg.C (Ref. 48), a level sufficient to cause disease.
Therefore, FDA has tentatively concluded that the risk from B. cereus
is of such significance that an M valve that is lower than the current
standard of 1,000 MPN/g or 1,000 CFU/g is necessary to protect the
health of infants.
Powdered infant formulas and similar products (e.g., powdered milk)
produced under CGMP contain less than 100 MPN/g or 100 CFU/g of B.
cereus (Refs. 43 and 48). Additionally, an FDA survey of different
production lots of milk-, soy-, and protein hydrolysate-based powdered
infant formulas (Ref. 49) showed that the maximum APC was 103 CFU/g,
and that the proportion of B. cereus in the samples ranged from 1.2 to
63.9 percent of the APC. Therefore, FDA has tentatively concluded that
an M value of 100 MPN/g or 100 CFU/g for B. cereus will adequately
protect the health of infants. Moreover, because this M value is higher
than the B. cereus levels typically found in infant formula currently
being produced (Refs. 43, 48, and 49), the proposed M value of 100 MPN/
g or 100 CFU/g will not be overly burdensome.
g. Methods. Proposed Sec. 106.55(c) states that the agency intends
to determine compliance with the proposed M values using the methods in
the BAM. These methods provide reproducible, consistent, and accurate
results at different laboratories. The agency proposes to incorporate
the BAM by reference in Sec. 106.55(c) in accordance with 5 U.S.C.
552(a) and 1 CFR part 51. While manufacturers may use other equivalent
methods, a manufacturer who uses methods that do not provide results
that are consistent with the results obtained by methods approved by
FDA will bear the risk that the firm's product is not in compliance
with the law.
The agency intends to test for Salmonella using the method
described in Chapter 5, BAM, including the sample preparation
procedures described in section C, paragraph 1 and the sampling plan
described in Chapter 1, BAM; for L. monocytogenes using the method
described in Chapter 10, BAM and the sampling plan described in Chapter
1, BAM; for coliforms, fecal coliforms, and E. coli using the MPN
method described in Chapter 4, BAM; for S. aureus using the MPN method
described in Chapter 12, BAM; for B. cereus using the MPN or plate
count method described in Chapter 14, BAM. The agency intends to
determine the APC using the method described in Chapter 3, BAM. All
chapter references are to the 8th ed. BAM. FDA intends to update the
reference to reflect the most recent edition of the BAM at the time the
final rule based on this proposed rule is issued.
h. Records. Proposed Sec. 106.55(d) requires that manufacturers
make and retain records, in accordance with proposed Sec. 106.100
(e)(5)(ii) and (f)(7) on the testing of infant formula for
microorganisms. As discussed in the description of the revisions to
proposed subpart F of part 106, FDA has the authority to require such
records under section 412(b)(4)(A)(i) of the act. These records will
document whether the batch of powdered infant formula meets the
microbiological quality standards of proposed Sec. 106.55(c) and is
therefore not adulterated. Records that describe the full methodology
for testing powdered infant formula for microbiological quality will
provide consistency in the testing of the microbiological quality of
the formula, even if different laboratory personnel conduct the tests.
The accuracy and reproducibility of microbiological quality testing
depend on the procedure used to conduct the test. In addition, the
records will provide the manufacturer with data to evaluate any
complaints received associated with a particular batch of infant
formula by showing whether microbiological contamination could have
contributed to the adverse event.
10. Controls to Prevent Adulteration During Packaging and Labeling of
Infant Formula
Because consumers rely on correct labels to select a formula to
meet their childrens' individual needs and to have proper instructions
for the use of the formula, FDA is proposing Sec. 106.60(a) which
requires manufacturers examine packaged and labeled infant formula to
ensure that containers and packages bear the correct labels, use-by
dates, and traceability codes. The proposal also requires that labels
be designed, printed, and applied so that they remain attached and
legible during processing, handling, storage, and use (proposed
Sec. 106.60(b)), and that all formula held in a single package be the
same product bearing the same traceability code, and that the package
carry the product name, name of the manufacturer, and the code
(proposed Sec. 106.60(c)).
These proposed requirements will ensure that infants who have
allergies will not be placed at risk by consuming formula containing
ingredients to which they are allergic, and that consumers will be
aware of the date when the product may no longer be appropriate for
use. In addition, the traceability codes will show the origin of the
product if there were a recall, and the packaging requirements will
make it more difficult for counterfeit formula, or formula with
counterfeit labels, to be shipped in interstate commerce. There have
been cases of counterfeit shipments in which a single package held more
than one product, or held a single product which bore more than one
code. The proposed regulations are not only intended to reduce the
incidence of counterfeit activities, but to ensure that firms that
receive the formula are aware that only one product should be in the
packaging, and that all containers should be identified with the code
shown on the package. This requirement will not impose an additional
burden on industry because manufacturers routinely package a
[[Page 36174]]
single infant formula product bearing the same code.
11. Controls on the Release of Finished Infant Formula
Proposed Sec. 106.70(a) requires that the manufacturer determine
that each batch of formula meets all of the manufacturer's
specifications before releasing the batch for distribution.
Specifically, each batch must meet the requirements of Sec. 106.55 on
microbiological contamination to ensure that the infant formula does
not contain microorganisms at levels that may be injurious to the
health of infants and render the formula adulterated and must meet the
requirements of Sec. 106.91(a) on quality control procedures to ensure
that the infant formula provides the required nutrients at the required
levels, and that it provides any nutrient added by the manufacturer.
Proposed Sec. 106.70(a) is designed to ensure that any infant formula
that fails to meet the manufacturer's specifications, or that is
adulterated for any reason, will not be introduced into interstate
commerce.
Proposed Sec. 106.70(b) requires that each batch of infant formula
that fails to meet the manufacturer's specifications be rejected.
Although proposed Sec. 106.70(b) recognizes that the formula may be
reprocessed, it requires that the reprocessed product be shown to meet
the requirements of Sec. 106.70(a) before the product is released. FDA
has tentatively concluded that this proposed requirement is necessary
to ensure that any defect that caused a batch of infant formula to be
rejected is corrected before the formula is released into commerce.
Proposed Sec. 106.70(c) requires that an individual qualified by
training or experience conduct an investigation of a finding that a
batch of infant formula fails to meet any manufacturer's
specifications. This investigation is necessary to determine why such a
failure occurred and to assist the manufacturer in developing controls
to ensure that such a failure does not reoccur. FDA has proposed to
require that the individual who conducts the investigation be qualified
to ensure that the investigation is properly conducted.
12. Traceability
Section 412(g)(1) of the act requires that each manufacturer make
and retain such distribution records as may be necessary to effect and
monitor recalls of the formula, and section 412(b)(4)(A)(vi) requires
that each manufacturer retain all complaints concerning infant formulas
that may reveal the possible existence of a hazard to health.
Therefore, infant formulas must be traceable to permit identification
of the product that is the subject of a complaint and to make it
possible to determine whether that batch of infant formula presents a
possible hazard to health. Traceability of an infant formula is also
necessary so that the recall requirements of the act can be met.
The agency's view, based on its experience, is that coding is the
most effective method for ensuring traceability. It provides a uniform
system that is able to identify large numbers of batches of infant
formula with a distinctive code that is easily understood and that can
be used by manufacturers, retailers, and consumers. A code also allows
a large amount of information to be presented on the container of
infant formula in a very small space. Therefore, the agency is
proposing, under sections 412 (b)(4)(A)(vi) and (g)(1) and 701(a) of
the act that batches of infant formula be identified with a distinctive
code that will allow the traceability of an infant formula.
Current Sec. 106.90 requires that manufacturers ensure traceability
by coding all infant formulas in conformity with the coding
requirements in Sec. 113.60(c) for thermally processed low- acid foods
packaged in hermetically sealed containers. Section 113.60(c) requires
that the code identify the establishment where the product is packed,
the product contained therein, the year packed, the day packed, and the
period during which packed, and that the packing period code be changed
with sufficient frequency to permit ready identification of lots during
their sale and distribution. FDA is proposing to carry the requirement
that manufacturers code their product in accordance with Sec. 113.60(c)
forward in proposed Sec. 106.80(a).
FDA has tentatively determined that it is appropriate to code
liquid infant formulas in this manner because they are thermally
processed low-acid foods, and a batch is produced in a relatively short
period of time, usually a day. It also may be appropriate for coding
some powdered infant formulas in this manner if they are processed in a
short enough time to make the day packed and the period during which
packed meaningful information.
Proposed Sec. 106.80(b) allows for alternative coding of batches of
powdered infant formula. Powdered infant formula is usually
manufactured in stages over a longer period of time than liquid infant
formula. Some powdered infant formulas are dry mixed in a number of
stages over an extended period of time. In other cases, powdered infant
formula is mixed in liquid form at one manufacturing facility and
shipped to a second site for spray drying and packaging. Powdered
infant formula manufacturing is often not completed in a short enough
period of time for coding based on the date packed or the period of
time in which it was packed to be meaningful information. Therefore,
under the alternate method that FDA is proposing, a sequential code
would be assigned so that all the essential information needed to track
any problems with the infant formula could be determined.
13. Audits of CGMP
Proposed Sec. 106.90 requires that manufacturers (or their agents)
conduct regularly scheduled audits to determine whether they are
complying with CGMP. This provision derives from section
412(b)(2)(B)(iv) of the act, which requires that the CGMP include ``the
conduct by the manufacturer of an infant formula or an agent of such
manufacturer of regularly scheduled audits to determine that such
manufacturer has complied with the regulations prescribed under''
section 412(b)(2)(A) of the act. Section 412(b)(2)(A) requires that the
Secretary (and by delegation FDA) establish CGMP's by regulation.
FDA is proposing to require that regularly scheduled audits be part
of CGMP because such audits are the best way to ensure overall
compliance with CGMP and to identify recurring problems that may
dictate an alteration in the master manufacturing order. For example,
regularly scheduled audits of all deviations from the manufacturer's
specifications or procedures will accentuate deviations that occur
repeatedly and will enable the manufacturer to identify specifications
or procedures that should be reassessed.
Section 412(b)(2)(B)(iv) of the act also specifies that such audits
are to ``be conducted by appropriately trained individuals who do not
have any direct responsibility for the manufacture or production of
infant formula.'' FDA is therefore proposing that an individual be
knowledgeable in all aspects of infant formula production perform the
audit. Without such broad knowledge, the individual conducting the
audit will not be able to adequately evaluate the manufacturer's
production and in-process control procedures. In addition, because the
purpose of the audit is to determine whether the manufacturer is
complying with the CGMP regulations issued under section 412(b)(2)(A)
of the act, the agency has tentatively concluded that the person
conducting the audit needs to be knowledgeable in
[[Page 36175]]
these regulations. Without such knowledge, the person would be unable
to make the determinations that are the very purpose of the audit.
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. Therefore, FDA
has tentatively concluded that the audit must be conducted by someone
who has no direct interest in the outcome of the audit.
C. Quality Control Procedures
1. Introduction
FDA is proposing to redesignate and revise subpart B of part 106 as
subpart C of part 106. Under this proposal, several sections of the
current regulations will be revoked, and several sections will be
redesignated without change. The latter sections are being recodified,
however, to fit the organization of the proposed regulations. Table II
describes the current and proposed regulations as follows:
Table II
------------------------------------------------------------------------
Current regulation Proposed regulation
------------------------------------------------------------------------
INGREDIENT CONTROL
------------------------------------------------------------------------
Sec. 106.20(a), Sec. 106.20(b)(1), Sec. Changed by Secs.
106.20(b)(2). 106.91(a)(1) and 106.40(d).
------------------------------------------------------------------------
IN-PROCESS CONTROL
------------------------------------------------------------------------
Sec. 106.25(a)........................... Sec. 106.50(a)(1).
Sec. 106.25(b)(1)........................ Omitted.
Sec. 106.25(b)(2)........................ Sec. 106.91(a)(4).
Sec. 106.25(b)(3)........................ Sec. 106.91(a)(2).
Sec. 106.25(b)(4)........................ Sec. 106.91(a)(4) with
modification.
Sec. 106.25(b)(5)........................ Sec. 106.91(a)(3) with
modification.
------------------------------------------------------------------------
FINISHED PRODUCT EVALUATION
------------------------------------------------------------------------
Sec. 106.30(a)........................... Sec. 106.91(a).
Sec. 106.30(b)(1)(i)..................... Sec. 106.91(a)(3).
Sec. 106.30(b)(1)(ii).................... Sec. 106.91(a) with
modification.
Sec. 106.30(b)(2), Sec. 106.30(b)(3).... Sec. 106.91(b) with
modification.
Sec. 106.30(c)(1)........................ Omitted.
Sec. 106.30(c)(2)........................ Sec. 106.3(i)
Secs. 106.91(b)(1) and
106.97(b)(1) with
elimination of the
osmolality and vitamin D
assay.
Sec. 106.30(d)........................... Omitted.
------------------------------------------------------------------------
FDA is proposing quality control procedures under the authority
granted by section 412(b)(2), (b)(3), and (b)(4) of the act, which
direct the Secretary (and by delegation, FDA) to establish by
regulation the quality control procedures that he or she determines are
necessary to ensure that an infant formula provides the required
nutrients at the required levels. In the Congressional Record of
September 27, 1986, Senator Metzenbaum stated: ``The most important
provision of this amendment is the simple requirement that each batch
of formula must be tested for each essential nutrient that must be
contained in the formula'' (Ref. 1). The quality control procedures in
proposed subpart C of part 106 are the minimum practices that
manufacturers must implement to ensure that the infant formula that
they produce contains the required nutrients at the required levels
throughout the shelf life of the product. Under section 412(a)(3) of
the act, an infant formula is deemed to be adulterated if the
processing of the formula does not comply with quality control
procedures prescribed by the Secretary.
2. Nutrient Testing
Proposed Sec. 106.91(a) describes the testing that FDA has
tentatively concluded each manufacturer must conduct on each batch of
infant formula to ensure that it provides the required nutrients at the
required levels and provides any nutrient added by the manufacturer.
FDA is proposing these requirements under the authority of two sections
of the act. Section 412(b)(2)(B)(i) of the act provides that the
quality control procedures shall include requirements for testing, in
accordance with section 412(b)(3), of each batch of infant formula for
each required nutrient, before distribution of such batch. Section
412(b)(3)(D) of the act states that if the Secretary adds a required
nutrient, the Secretary must require that the manufacturer of the
infant formula test each batch of such formula for that nutrient in
accordance with section 412(b)(3)(A), (b)(3)(B), and (b)(3)(C) of the
act.
Current Sec. 106.20(a) and (b)(2), which FDA is proposing to
replace with Sec. 106.91(a)(1), do not require that manufacturers
analyze nutrient premixes if the premixes come with a supplier's
guarantee or certification. Proposed Sec. 106.91(a)(1), however,
requires that each nutrient premix used in the manufacture of an infant
formula be tested by the formula manufacturer for each nutrient that
the manufacturer is relying on the premix to provide to ensure that the
premix complies with the manufacturer's specification. This change is
required by section 412(b)(3)(B) of the act. Section 412(b)(3)(B) was
included in the 1986 amendments because infant formula manufacturers
were increasingly relying on the use of formula premixes, and Congress
felt that relying on a premix supplier's written assurance that its
premix product was properly tested was inadequate (Ref. 1). In 1985,
the Department of Justice sought an injunction against a premix
supplier because, ``as a result of inadequate quality control, numerous
* * * vitamin and mineral mixes--used in infant formula--have been
misbranded and adulterated'' (Ref. 3). The premix supplier entered into
a consent decree of permanent injunction that enjoined it from shipping
any of its vitamin/mineral premixes for use in infant formulas until it
completed a number of specific acts that were designed to improve its
quality control (Ref. 50).
FDA is proposing to redesignate current Sec. 106.25(b)(3) as
Sec. 106.91(a)(2), which requires that after the addition of the
premix, or at the final-product stage but before distribution, each
batch of infant formula be tested to confirm that the nutrients
contained in any nutrient premix used in such infant formula are
present in each batch of infant formula in the proper concentration.
This requirement implements section 412(b)(3)(C)(ii) of the act, which
requires that infant formula be tested to ensure that any nutrient
premixes used by the manufacturer are actually included in the batch of
infant formula in the proper amount. Without this check, inadvertent
failure to include the premix could go undetected, and infant formula
that is deficient in the nutrients that were to be provided by the
premix would be introduced into the market.
Current Sec. 106.30(b)(1)(i) requires that the manufacturer analyze
representative samples of each batch of finished infant formula for
specific nutrients to assess process degradation. FDA is carrying
forward a modified version of this requirement in proposed
Sec. 106.91(a)(3), which requires that each batch of infant formula be
tested for vitamins A, C, and
[[Page 36176]]
E and thiamin at the final-product stage, before distribution. This
regulation is proposed under section 412(b)(3)(A) of the act, which
states: ``At the final product stage, each batch of infant formula
shall be tested for vitamin A, vitamin B1, vitamin C, and vitamin E * *
*.'' In the Congressional Record, Senator Metzenbaum stated that
testing for these vitamins is required at the final-product stage
because they are vulnerable to degradation (Ref. 1). Testing at the
final-product stage will ensure that these nutrients are present in the
infant formula at the end of all the processing steps that may destroy
them.
Proposed Sec. 106.91(a)(4) requires that, before distribution, each
batch of infant formula be tested for all nutrients required to be
included, and any others that have been included, but for which testing
to comply with Sec. 106.91(a)(1) or (a)(3) was not conducted. This
proposed provision takes a markedly different tack than current
Sec. 106.30(b)(1)(ii), which states that no analyses are needed for
linoleic acid, vitamin D, vitamin K, choline, inositol, and biotin
before release of a batch of infant formula for commercial or
charitable distribution. This change in approach is necessary because
section 412(b)(3)(C) of the act, which was added by the 1986
amendments, states that each batch of formula must be tested for each
nutrient required by the law to be present in an infant formula. Also,
manufacturers are adding nutrients not required by Sec. 107.100, such
as selenium, to infant formulas. These nutrients meet the definition
for ``nutrient'' in proposed Sec. 106.3(m) because they have been
identified as essential for infants by NAS through its development of a
Recommended Dietary Allowance or an Estimated Safe and Adequate Daily
Dietary Intake range. The agency has not objected to the addition of
nutrients not required by Sec. 107.100 to infant formulas. However, it
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
and be uniform throughout the batch 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 and in a particular batch 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 throughout
the batch of infant formula.
3. Stability Testing
Current Sec. 106.30(c) requires that the manufacturer, using
representative samples collected from finished product batches, conduct
stability analysis for selected nutrients with sufficient frequency to
substantiate the maintenance of nutrient content throughout the shelf
life of the product. The 1986 amendments added subsection
412(b)(2)(B)(ii) to the act, which requires ``regularly scheduled
testing, by the manufacturer of an infant formula or an agent of such
manufacturer, of samples of infant formula during the shelf life of
such formula to ensure that such formulas are in compliance with''
section 412 of the act. To implement this section of the act, the
agency is redesignating and revising current Sec. 106.30(b)(3) as
proposed Sec. 106.91(b), which requires quarterly collection of samples
of infant formula for stability testing to provide a check on nutrient
stability. This periodic check will alert the manufacturer if nutrient
stability has changed in some unpredicted way so that the formula no
longer complies with section 412 of the act. Quarterly testing of
infant formulas for nutrient stability is currently conducted by the
industry (Refs. 51 and 52), and the agency is not aware of any problems
that have resulted from this frequency of testing. The agency requests
comment on whether this proposed frequency of sample collection for
stability testing is appropriate.
The agency has tentatively concluded that this periodic sample
collection to check on nutrient stability must be performed on a batch
of each physical form (powder, ready-to-feed, or concentrate) of each
infant formula, at each different manufacturing facility, because
different forms of the product may contain different ingredients, and
different forms of infant formula are subjected to different processing
procedures. Therefore, ensuring the nutrient stability of one form of
the product, such as the powder, will not answer questions about the
nutrient stability of other forms of the product. Thus, the agency has
tentatively concluded that each form of the infant formula must be
sampled on a periodic basis for nutrient stability. Also, the agency
has tentatively concluded that the sampling of one batch of each
physical form of each infant formula must be conducted at each
manufacturing facility. This proposed requirement is necessary because
manufacturers may produce the same infant formula at more than one
facility, and the manufacturing conditions at one facility may not be
the same as the conditions at another facility. The differences in
conditions cannot be allowed to affect the quality of the formula.
Proposed Sec. 106.91(b) further requires testing at the beginning,
midpoint, and end of the shelf life of the infant formula. Testing at
the beginning of the shelf life shows that the formula is in compliance
with the nutrient requirements of the act when it is released for
distribution. Testing at the midpoint of the shelf life will alert the
manufacturer if any nutrient is deteriorating at a rate different from
that predicted, so that the nutrient may not be in the formula at a
level to comply with the act throughout the formula's shelf life.
Testing at the end of shelf life will ensure that the formula contained
all the nutrients needed to comply with the act throughout its shelf
life and will provide continued justification for the predicted shelf
life.
Additional testing may be necessary to ensure that a formula
complies with section 412 of the act throughout its shelf life. Such
testing is likely to focus on a particular nutrient and its stability
within the matrix of the formulation. This additional testing will
ensure that, if there is a significant deterioration in the level of
the nutrient in the formula, the manufacturer will be aware of this
fact and will be able to take steps promptly to have the product
removed from the market, before a significant number of infants are
exposed to a deficient product.
The agency is not proposing to specify what frequency is required
because manufacturers have experience with the nutrient stability of
the infant formula matrices that they produce and are thus in a
position to determine how frequently testing is necessary. For example,
the manufacturer is in a position to know whether the nutrient levels
of a milk-based infant formula need to be tested on a different basis
than that of a soy-based product, or whether the nutrient levels of an
infant formula that contains hydrolyzed protein needs to be tested more
frequently than that of an infant formula that contains non-hydrolyzed
protein. Manufacturers will be able to comply with section
412(b)(2)(B)(ii) of the act by testing different nutrients at different
frequencies. For example, unstable nutrients, such as vitamins, may
require testing on a more frequent basis than more stable nutrients,
such as minerals. Proposed Sec. 106.91(b) allows the manufacturers the
discretion to determine the necessary frequency of testing to ensure
that their infant formula complies with the nutrient
[[Page 36177]]
requirements of the act, as long as the minimum testing (i.e., at the
beginning, middle, and end of the shelf life) required by proposed
Sec. 106.91(b) is accomplished.
Proposed Sec. 106.91(b)(1) provides for an addition to the
stability testing required under Sec. 106.91(b). FDA is proposing that
the first batch of each form of a new infant formula be subjected to
such testing to ensure that the product complies with the nutrient
requirements of section 412 of the act throughout its shelf life.
Proposed Sec. 106.91(b)(2) requires the sampling of the first batch
of an infant formula in which there has been a change in formulation or
in processing that could affect whether the formula is adulterated
under section 412(a) of the act and requires testing of these samples
for each nutrient that has been, or may have been, affected by the
change. The change in formulation or processing referred to here would
not be a ``major change'' because a ``major change'' would mean that
the formula is a ``new infant formula.'' Examples of the types of
changes that are subject to proposed Sec. 106.91(b)(2) are: (1)
Reducing a ``required nutrient'' in a minor way or increasing a
``required nutrient'' that is subject to maximum limits in Sec. 107.100
in a minor way; (2) replacing one nutrient form with another form, such
as replacing vitamin A acetate with vitamin A palmitate or replacing
calcium carbonate with tricalcium phosphate; (3) changing a time-
temperature condition of preheating, handling, mixing, or sterilizing
an in-process product; or (4) changing the oxygen content of a packaged
product that might have a minimal effect on the level of nutrients.
Requiring sample collection for stability testing when a manufacturer
makes changes such as these in the manufacture of the product will
ensure that the manufacturer can verify the predicted shelf life of the
changed formula.
Proposed Sec. 106.91(b)(2) requires that the manufacturer ensure
that the infant formula meets all the nutrient requirements of section
412 of the act. This provision is proposed under the authority of
section 412(b)(2)(A) of the act, which provides for the establishment
of CGMP's for infant formulas, including quality control procedures
that are necessary to assure that the infant formula provides nutrients
in accordance with section 412 (b) and (i) of the act, as well as
section 412(b)(2)(B)(ii). If the formulation or processing of the
infant formula has been changed, the manufacturer must consider what
nutrients may have been affected by the change and test for each of
these nutrients in the final-product stage of the first batch of the
changed formula. For example, if the manufacturer makes a change in the
amount of a protein source used in the infant formula, the firm must
test the formula for protein content and for any nutrients provided
endogenously to the formula by the protein, such as minerals like
calcium and phosphorus. The manufacturer is aware of how much of each
mineral it is relying on the protein source to provide to the formula.
When the amount of the protein source used in the formula is changed,
the manufacturer must test for the level of all nutrients it relies on
the protein source to provide to the formula to ensure that all
nutrients in the formula meet the requirement of Sec. 107.100.
4. Quality Control Records
Proposed Sec. 106.91(c) requires that manufacturers make and retain
records of the results of all testing performed on the batch of infant
formula in accordance with proposed Sec. 106.100(e)(5)(i) and a full
description of the methodology used in accordance with proposed
Sec. 106.100(f)(7). As discussed in the description of the proposed
revisions to subpart F of part 106, FDA has authority to require these
records under section 412(b)(4)(A)(i) of the act. Providing a record of
the results of quality control testing will verify that each nutrient
required by Sec. 107.100 is present in each batch of infant formula at
the required level, and that any nutrients added by the manufacturer
are present at the appropriate level. These records will show the
levels of nutrients in the formula and will provide data needed to
evaluate a batch of infant formula if problems, such as adverse events
in infants, occur later with that particular batch. Records that
describe the full methodology used to conduct the quality control
testing will provide consistency in the procedure that the manufacturer
is using to test for the nutrients in each batch of infant formula,
even when different laboratory personnel are conducting the testing.
The accuracy and reproducibility of quality control testing depend on
the procedure used to conduct the test.
5. Audits of Quality Control Procedures
Proposed Sec. 106.92 requires that the manufacturer of an infant
formula, or an agent of such a manufacturer, conduct regularly
scheduled quality control audits to ensure that an infant formula
provides required nutrients and has been manufactured in a manner
designed to prevent adulteration. Proposed Sec. 106.92 derives from
section 412(b)(2)(B)(iv) of the act, which requires that the quality
control procedures prescribed by the Secretary include ``the conduct by
the manufacturer of an infant formula or an agent of such manufacturer
of regularly scheduled audits to determine that such manufacturer has
complied with the regulations prescribed under'' section 412(b)(2)(A)
of the act (stating that the Secretary (and FDA by delegation)
establish by regulation ``quality control procedures that the Secretary
determines are necessary to assure that an infant formula provides
nutrients in accordance with'' section 412 (b) and (i) and ``is
manufactured in a manner designed to prevent adulteration of the
formula''. FDA is proposing to require that regularly scheduled audits
be part of quality control procedures because such audits will document
compliance with the quality control procedures and will identify
recurring problems that may dictate an alteration in the master
manufacturing order. For example, regularly scheduled audits of the
results of tests of nutrient levels in infant formulas and of any
deviations from the manufacturer's specifications or procedures for
acceptable nutrient levels will reveal deviations that occur on a
repeated basis and will enable the manufacturer to identify
specifications or procedures that should be reassessed.
Proposed Sec. 106.92 further requires that the audits be performed
by an individual who, as a result of education, training, and
experience, is knowledgeable in all aspects of infant formula
production and of the agency's regulations concerning quality control
procedures, but who has no direct responsibilities for the matters
being audited. The legal authority for this provision, the importance
of the responsible individual's knowledge in all aspects of infant
formula production and the agency's regulations, and the need for the
audit to be performed by an individual who has no direct responsibility
for the matters being audited were discussed previously under the
proposed CGMP regulations in Sec. 106.90.
By proposing different regulations (proposed Secs. 106.90 and
106.92) that require audits of CGMP and of quality control procedures,
the agency is not suggesting that it will require that separate audits
be conducted. These regulations are being proposed separately to make
clear that the regularly scheduled audits required by section
412(b)(2)(B)(iv) of the act are an aspect both of CGMP and of quality
control procedures. The agency would have no objection to a combined
audit
[[Page 36178]]
of CGMP and of quality control procedures.
6. Revocation of the Requirement for Determination of Vitamin D by the
Rat Bioassay Method
FDA is proposing to revoke the requirement in current
Sec. 106.30(c)(2) for the determination of vitamin D by a rat bioassay
method. This rat bioassay for vitamin D is no longer a viable assay
because appropriate animals for conducting this test are difficult to
acquire (Ref. 53), and an alternate analytical method for the
determination of vitamin D in infant formulas has been approved by the
Association of Official Analytical Chemists (Ref. 54).
D. Conduct of Audits
Section 412(b)(2)(B)(iv) of the act provides that CGMP and quality
control procedures include regularly scheduled audits to determine
whether the manufacturer is complying with CGMP, including following
the quality control procedures that are necessary to ensure that an
infant formula provides the required nutrients at the required levels,
and whether it is operating in a manner designed to prevent
adulteration of the formula. FDA is proposing to require in
Sec. 106.94(a) that manufacturers develop and follow a written audit
plan that is available at the manufacturing facility for FDA
inspection. A written audit plan is necessary to provide consistency in
how audits are conducted and to ensure that the auditor can determine
whether the facility is operating in compliance with the applicable
procedures.
Proposed Sec. 106.94(b) requires that the audit plan include the
procedures that the manufacturer uses to determine whether the facility
is operating in accordance with CGMP, with the applicable quality
control procedures, and in a manner designed to prevent adulteration of
the infant formula it produces. This proposed requirement derives from
current Sec. 106.100(j), which defines audit procedures as the methods
used to review the manufacturing and quality control procedures and is
intended to direct the manufacturer's attention to the fundamental
goals of the manufacturing process in formulating its audit plan.
Proposed Sec. 106.94(c) sets out the minimum requirements for the
audit procedures that are to be employed by manufacturers. Under
proposed Sec. 106.94(c)(1) these procedures are to include a review of
how the production and in-process control system established under
Sec. 106.6(b) is operating. In particular, proposed
Sec. 106.94(c)(1)(i) specifies that the evaluation of the production
and in-process control system include observation of the production of
infant formula and a comparison of the observed process to the written
production and in-process control plan required under proposed
Sec. 106.6(b). FDA has tentatively concluded that such observations
will show whether the production and in-process control system is being
followed appropriately, and, if not, they will identify any deviations
from the production and in-process control system, so that the
manufacturer can take corrective actions to ensure that infant formula
is produced in compliance with the production and in-process control
system.
Proposed Sec. 106.94(c)(1)(ii) requires that the evaluation of the
production and in-process control system include a review of records of
the monitoring of points, steps, or stages where control is deemed
necessary to prevent adulteration. As discussed below, proposed
Sec. 106.100(e)(3) requires that the batch production and control
records document the monitoring of all points where control is deemed
necessary to prevent adulteration in the manufacturing of the batch.
FDA has tentatively concluded that proposed Sec. 106.94(c)(1)(ii) is
necessary because the auditor can observe the production of only a
limited number of batches of infant formula. A review of the production
and in-process control records of all batches produced in a given
period of time will ensure that the production and in-process control
system is working appropriately on a continuous basis, will identify
any point that monitoring reveals is out of control on a recurring
basis, and will identify where the production and in-process control
system needs improvement.
Proposed Sec. 106.94(c)(1)(iii) requires that the evaluation of the
production and in-process control system include a review of records of
how deviations from any standard or specification at points, steps, or
stages where control is deemed necessary to prevent adulteration were
handled. As discussed below, proposed Sec. 106.100(e)(4)(iii) requires
that the batch records include the conclusions and followup of an
investigation of the failure to meet any specification or standard at
any point where control is deemed necessary to prevent adulteration. A
review of these records as a part of the audit will identify failures
that occur on a repeated basis and will show how these failures are
handled by the manufacturer. The auditor will be able to evaluate
whether the conclusions and followup of these investigations are
appropriate for each failure to meet the specification or standard.
Proposed Sec. 106.94(c)(2) requires that the audit procedures
include a review of a representative sample of all records maintained
in accordance with proposed Sec. 106.100 (e) and (f). As discussed
below, proposed Sec. 106.100(e) sets out the requirements for the batch
production and control records, and proposed Sec. 106.100(f) sets out
the requirements for records related to observance of CGMP. A review of
a representative sample of these records will show the auditor whether
there has been compliance with the appropriate regulations in producing
the batches of product so that the formula is not adulterated. Section
412(b)(2)(B)(iv) of the act states that the audit is conducted to
determine whether the manufacturer has complied with the regulations
establishing CGMP for infant formulas, including quality control
procedures. FDA has tentatively concluded that review of a
representative sample of the records maintained in accordance with
Sec. 106.100 (e) and (f) is necessary to determine whether the
manufacturer is complying with these regulations.
E. Quality Factors for Infant Formulas
1. What Are Quality Factors?
The agency is proposing to create a new subpart E to implement the
quality factor requirements of sections 412 (a)(2) and (b)(1) of the
act. Section 412(a)(2) of the act states that an infant formula is
adulterated unless it meets the quality factor requirements that are
established under section 412(b)(1). Section 412(b)(1) of the act
states that the Secretary shall by regulation establish requirements
for quality factors, including quality factor requirements for required
nutrients for infant formulas to the extent possible consistent with
current scientific knowledge. Therefore, it is incumbent on
manufacturers to establish that the infant formula that they produce
meets the minimum quality factor requirements that FDA adopts.
What Congress meant by ``quality factors'' is discussed in the
report of the House Committee on Interstate and Foreign Commerce that
accompanied the 1980 act. The report states that quality factors
``pertain to the bioavailability of a nutrient and the maintenance of
levels or potency of nutrients during the expected shelf life of the
product'' (Ref. 5). FDA, in proposed Sec. 106.3(o), has defined
``quality factors'' in a manner that encompasses several basic
concepts, including the concepts of
[[Page 36179]]
``bioavailability'' and of ``healthy growth.''
The concept of ``healthy growth'' was discussed in the report of
the House Committee on Interstate and Foreign Commerce that accompanied
the 1980 act. The report states that infant formulas are often the sole
source of nutrition for infants, and that ``the growth of infants
during the first few months of life often determines the pattern of
development and quality of health in adult life'' (Ref. 5). 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.
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.
``Bioavailability'' of a nutrient for an infant means that the
nutrient is physiologically available in sufficient quantities to
perform its metabolic functions (Ref. 55). In a formula product,
bioavailability of individual nutrients is affected by the net effect
of the formulation and processing of the product on the chemical form
of the nutrient. These processes are influenced by such factors as the
chemical form of the nutrient in the ingredient source, the chemical
form of the nutrient after processing, and the net effect of various
inhibitors and enhancers in a food or meal on the chemical form of the
nutrient and its ability to be absorbed and utilized by the infant. In
the infant, the bioavailability of a nutrient is determined by the net
effect of the amount of nutrient that is converted during digestion to
an absorbable form, the proportion of the nutrient that is absorbed
into the bloodstream, the proportion of the absorbed nutrient that is
converted to its biologically useful form, and the proportion that is
lost through excretory processes (Ref. 55). Bioavailability varies
among nutrients within a given food product and, for a given nutrient,
among foods. The factors affecting nutrient bioavailability are complex
and can be difficult to predict based on analyzed nutrient values
alone.
Bioavailability issues are particularly critical for infants during
the first few months of life, where a single food (infant formula)
serves as the sole source of all nutrients at a period when rapid
physical growth and development and maturation of various organ systems
makes the infant particularly vulnerable to harm by nutritional
insults. Unlike the mixed diet of persons beyond infancy where poor
bioavailability in one food can be compensated for by other foods in
the diet, a problem with bioavailability in an infant formula affects
the total amount of nutrient available to that infant for several
months after birth. Furthermore, requirements for nutrients are higher
per kilogram body weight during early infancy than at any other time
during the life cycle. Because numerous critical developmental
milestones (e.g., neurocognitive or immune functions) must be achieved
by young infants, a nutrient insufficiency during infancy can quickly
develop into serious, and in some cases, permanent adverse effects on a
range of developmental processes, including physical growth and organ
maturation. Thus, a problem with bioavailability is far more critical
for a food such as infant formula than it is for foods that are used as
part of a mixed diet by the general population.
Furthermore, the rapidly changing and increasingly complex
physical, chemical, and biologically significant characteristics of
ingredients used in new and reformulated infant formulas make it
important to continually ensure that quality factor requirements are
met. Changes in formulation of infant formulas are made by
manufacturers for a variety of reasons, including enhancing the
functional characteristics of the formula (e.g., to prevent separation
of ingredients or to prevent clumping that will plug nipples on
bottles), to enhance digestibility of the formula (e.g., different
sources or blends of fats), or to improve the nutritional quality
(e.g., a different source of protein or of a vitamin or mineral, or
adding a nonrequired nutrient such as selenium). For example, in some
formulas, novel sources of vegetable oils (e.g., fractions of plant
oils that are particularly rich in certain types of fatty acids) have
partially or fully replaced cow's milk fat as the fat source (Refs. 56
and 57). Whey proteins or highly processed proteins (e.g., hydrolyzed
proteins) are now frequently used as partial or complete replacements
for more traditional cow's milk protein sources. In other cases,
nutrient/nutrient interactions (e.g., high iron inhibiting absorption
of zinc) or nutrient/ingredient interactions (e.g., phytates from soy
protein isolates inhibiting absorption of zinc, or the replacing of the
milk sugar (lactose) that enhances absorption of calcium with a sugar
source that does not have this ability) can adversely affect nutrient
availability.
New processing methods may also have unintended consequences when
used with established ingredients or formulations. For example, a new
processing method that subjects the formula to conditions that are less
denaturing to cow's milk proteins than traditional heat treatments
could produce a formula that is less digestible and that causes
reactivity of the gastrointestinal wall, such as has been seen with
whole cow's milk (Ref. 58).
In summary, consideration of quality factors goes beyond analytical
measures of the presence or absence of a nutrient in the formula
product and is needed to provide assurance that adverse effects on the
nutritional value of the formula for the infant do not unintentionally
or unknowingly occur as a result of the formulation or the processing
of an infant formula. Chemical analysis of the formula product to
define its nutrient composition often overestimates the amount of
nutrient that is bioavailable for physiological use by the infant. The
quality factors, therefore, provide a means of evaluating whether a
nutrient has become less bioavailable than would be expected, so that
it is not sufficiently effective to meet its normal nutritive
functions, or whether its bioavailability has been enhanced to a level
that raises safety concerns.
Quality factor requirements are distinctly different from quality
control procedures. While ``quality control procedures are intended to
insure that the safety and nutritional potency of a formula is built
into the manufacturing process'' (Ref. 5), 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 (Ref.
5). Changes in ingredient sources and processing can affect the
chemical forms of nutrients in the formula product. Such changes can
affect the digestion and absorption of food nutrients such that: (1)
Absorption is incomplete, (2) absorbed nutrients are not in a form that
allows use by metabolic pathways, or (3) the nutrient may interact with
other dietary substances to cause excessive excretion. Thus, the amount
of nutrients (i.e., the analyzable amounts) in formulas must generally
be higher than the physiological requirements of infants (i.e., the
amounts of nutrients needed by the body to meet metabolic and growth
needs of infants). Although these inefficiencies are generally taken
into account when recommending nutrient levels for infant formulas,
there
[[Page 36180]]
is always the potential for affecting nutrient bioavailabilities in
unexpected ways.
In summary, a demonstration that both the quantitative and quality
factor requirements for essential nutrients in an infant formula are
met is necessary to ensure that the infant formula is likely to meet
all of the known physiological 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.
2. Identification of Quality Factors
In testimony before the passage of the 1986 amendments, the agency
informed the Senate that the state of knowledge and science with
respect to quality factors was still evolving, and that, therefore,
there was a basis for only one quality factor for a nutrient. (Although
the testimony to the Senate does not specify the identity of the
nutrient for which there was a basis for a quality factor, the quality
factor was the protein efficiency ratio used for assessing protein
quality (Ref. 1).) Senator Metzenbaum stressed that the amendments
contemplated that additional quality factors would emerge, and that the
Secretary should implement requirements for such factors as quickly as
scientific advances would allow.
The agency subsequently took a major step toward establishing
quality factors through a contract in 1986 with the CON/AAP. The AAP
earlier had published recommendations regarding the quantities of
nutrients needed in infant formulas (Ref. 59). These recommendations
were relied upon during the development of the nutrient specifications
of the act (Ref. 60). In its report to FDA, ``Clinical Testing of
Infant Formulas with Respect to Nutritional Suitability for Term
Infants'' (Ref. 6), the CON/AAP identified those conditions in which
changes in formula composition warranted clinical testing. The CON/AAP
stated that ``clinical testing is primarily useful for determining (1)
acceptability of the formula, (2) ability of the formula to support
normal growth, and (3) availability of selected nutrients.'' The CON/
AAP also discussed the limitations of the available measurements,
providing an assessment of the limits of scientific knowledge.
The agency has considered the CON/AAP report carefully and has also
considered new scientific information published since the release of
that report to determine what quality factors are appropriate for
nutrients in infant formula. Based on its consideration, FDA is
proposing to adopt Sec. 106.96. This section, if adopted, will require
that all infant formula be of sufficient quality that it meets the
nutritional requirements of infants for healthy growth when fed as the
sole source of nutrition, as indicated by a general quality factor for
physical growth, assessed using anthropometric measures of infants
consuming the formula, and by a nutrient-specific quality factor for
protein biological quality, assessed by an animal bioassay using the
formula.
The agency is not proposing to require that manufacturers measure,
individually, the absorption, metabolism, metabolic transformation, or
utilization of any of the other essential nutrients. These measures are
often technically difficult or unavailable, difficult to interpret, or
invasive, thus causing unnecessary testing of infants without potential
for providing meaningful results. Rather, the agency has tentatively
concluded that current scientific knowledge and ethical and practical
considerations are supportive only of requiring two quality factor
measures: (1) Physical growth of infants consuming the formula as an
integrative indicator of the net effect of the overall nutritional
quality of the formula, and (2) a rat bioassay of protein quality in
the formula product to ensure that the infant's needs for individual
amino acids will be met.
The agency has tentatively determined that these are minimum
requirements. The agency recognizes that, on a case-by-case basis as
warranted by the formulation and intended use of a particular infant
formula, demonstration of additional quality factors may be necessary.
For example, a formula intended for use by premature infants who are at
a particularly vulnerable developmental stage relative to nutritional
needs to support neurocognitive development may need to be subject to
testing that includes measurement of this endpoint to ensure that the
formula supports healthy growth. In addition, a formula in which a
novel fatty acid has been added to enhance the formula's ability to
meet nutritional needs for supporting visual development may need to be
evaluated to determine whether it has adverse nutritional effects on
other aspects of healthy growth (e.g., on development of immune
function).
3. The Regulation
Proposed Sec. 106.96(a) sets forth quality factor requirements that
reflect the minimum measures needed to evaluate the nutritional quality
of an infant formula product, taking into account current scientific
knowledge and the usefulness of the outcome measures for evaluating
quality factors, while minimizing unnecessary testing of infants
serving as subjects in clinical trials. Infant formula is defined in
the act as a complete or partial substitute for human milk (section
201(aa) of the act). Obviously, the greatest need for a nutritionally
complete formula that meets all quality factors is when the formula is
used as a complete substitute for human milk. When no other form of
nutriture is available to the infant, the formula must provide all of
the nutrients needed for the healthy growth of the infant. There is no
room for error or miscalculation. The absence or an inadequate level of
an essential nutrient will be evidenced by growth failure and other
signs or symptoms resulting from nutritional insufficiencies. FDA has
tentatively concluded, therefore, that an evaluation of the ability of
a formula to support healthy growth must be made under its most
demanding conditions of use, i.e., when it is used as the sole source
of nutrition, because other foods may mask or compensate for
deficiencies in the formula that would occur if the formula were used
as a complete substitute for human milk, which would produce results
that cannot be meaningfully interpreted.
Proposed Sec. 106.96(b) identifies ``normal physical growth'' as a
quality factor. This quality factor reflects the CON/AAP recommendation
that the determination of physical growth rate is the most valuable
component of the clinical evaluation of an infant formula (Ref. 6).
Physical measures of growth such as weight gain are the most widely
accepted and used markers of a young infant's overall ability to digest
and utilize those nutrients provided by the formula. The very rapid
rate of growth in early infancy means that abnormalities in growth rate
can be detected in a few months, providing an easily measured and
sensitive, although nonspecific, indication of nutritional
insufficiencies (Ref. 4). Physical measures of growth rate are easily
done, are familiar to both parents and health professionals, and are a
normal part of routine office visits. They are noninvasive and pose
little or no risk to infants and provide meaningful results for
evaluating the ability of an infant formula to support physical growth
in very young infants. Thus, the agency has tentatively concluded that
the ability of the formula, when fed as a sole source of nutrition, to
meet the nutritional requirements of young infants for normal physical
growth is a
[[Page 36181]]
necessary indicator of the overall nutritional quality of the formula.
Proposed Sec. 106.96(c) requires that the protein in infant
formulas be of sufficient biological quality to meet the protein
nutritional requirements of infants. Protein, while generally discussed
as a single nutrient, depends for its nutritive value on the inclusion
of all essential amino acids at levels and relative proportions needed
to support healthy growth. The protein requirement is really the sum of
different requirements for 10 essential amino acids that occur at
different levels and proportions in various food protein sources.
Protein quality is also affected by differences in digestibility of
different protein sources, by factors that modify digestion, and by
chemical reactions that affect the ability of enzymes in the infant's
gastrointestinal tract to digest and absorb the amino acids in the
protein source. Once absorbed, the relative proportions of the amino
acids can affect their uptake by body tissues because of competition
for receptors and transport systems. Thus, protein quality depends on a
number of complex interactions and conditions that can be difficult to
predict.
Chemical analysis of foods generally only measures the amount of
total protein present and does not identify specific amino acids or
their ability to meet the physiological needs of infants for the
essential amino acids. Chemical analysis alone, therefore, is not
capable of predicting whether adequate amounts of all essential amino
acids are present, or whether the amino acids present are able to
support healthy growth in infants. Yet ensuring that the protein in an
infant formula's is of high biological value is critical to an infant's
health. For example, during the first year of life, the protein content
of an infant's body increases from 11 to 15 percent at the same time
that the infant's body weight increases by 7 kg. The average increase
in body protein is about 3.5 g/day for the first 4 months of life and
about 3.1 g/day for the next 8 months. These protein requirements must
be met by a formula that not only contains adequate protein but also
contains protein of high biological quality in a form that can be
utilized by the infant. Because biological quality varies among protein
sources and may be adversely affected by processing methods and other
constituents present in the formula, the agency has tentatively
concluded that the biological quality of the protein in an infant
formula is a necessary quality factor. This quality factor will require
an evaluation of whether the formula contains the essential amino acids
and total nitrogen in the amounts and proportions necessary to permit
normal tissue and organ growth and development. As discussed later in
this document, the agency is proposing in Sec. 106.97(b) that the
biological quality of the test protein be measured by the Protein
Efficiency Ratio (PER) rat bioassay and be comparable to the biological
quality of the milk protein casein.
Proposed Sec. 106.96 does not include quality factor requirements
for all nutrients required by infants because methods to determine
whether these requirements are met are not available or are not
practical for most nutrients (e.g., results cannot be meaningfully
interpreted, or methods are invasive, thus causing unnecessary testing
of infants). Nonetheless, FDA has tentatively concluded that, as the
science evolves, establishing quality factor requirements for other
nutrients needed by infants would provide assurance, beyond that
provided by the general quality factor of physical growth in proposed
Sec. 106.96(b) and the specific protein quality factor in
Sec. 106.96(c), that a formula will meet the overall nutritional needs
of infants. As the science evolves, FDA anticipates being able to
progress beyond generalized, nonspecific indicators of overall
nutritional intakes (e.g., measures of physical growth), to more
specific and sensitive measures of biochemical and functional
nutritional status. FDA also has tentatively concluded that, on a case-
by-case basis, additional quality factors may be needed for a specific
formula product if formulation or processing concerns raise sufficient
quality factor questions such that additional measures are necessary to
adequately ensure that the nutritional quality of the formula supports
healthy growth. FDA asks for comment on criteria as to when such
measures are required.
4. Request for Comment on Need for Establishing Requirements for Other
Quality Factors
Proposed Sec. 106.96(b) and (c) set forth minimum requirements for
quality factors (physical growth and protein quality) that all infant
formulas should meet. FDA has tentatively concluded that these quality
factors are consistent with current state-of- the-art science and
provide significant information on the nutritional quality of the
infant formula without requiring unnecessary or meaningless testing of
infant enrollees in studies.
As discussed above, the 1986 amendments contemplated that when
scientific research identified criteria that could be used to establish
quality factors for specific nutrients in infant formula, the agency
would establish quality factor requirements for those nutrients.
Proposed Sec. 106.96 will establish two quality factors (physical
growth and protein quality) because the agency has tentatively
concluded that there is sufficient scientific evidence of the
importance of these quality factors, and because adequate methods exist
to meaningfully and ethically measure these factors.
However, the CON/AAP report discussed other nutrients necessary for
healthy growth of infants and for which the report recommended
establishing quality factor requirements (Ref. 6). The agency has
studied the evidence supporting the establishment of quality factor
requirements for these other nutrients, and the methods available for
determining whether an infant formula meets quality factor requirements
for these nutrients. FDA has tentatively concluded that establishing
quality factor requirements for the three additional nutrients
recommended by CON/AAP (i.e., (a) fat, as measured by fat balance; (b)
calcium and phosphorus, as measured by calcium and phosphorus balance;
and (c) iron as measured by iron bioavailability) is not warranted at
this time. FDA, however, solicits additional information that it will
consider before reaching a final decision on whether the scientific
evidence and usefulness of results are sufficient to support
establishing these additional quality factor requirements. Therefore,
the agency requests comments and information on: (1) The scientific
evidence on the importance of the amount, type, and sources of fat,
calcium and phosphorus, and iron in infant formula, and (2) the
appropriate methods and interpretative criteria to determine whether an
infant formula meets the nutritional requirements for fat, calcium and
phosphorus, and iron of infants consuming the formula as the sole
source of nutrition. The basis upon which the agency is considering
establishing quality factor requirements for these nutrients is
discussed below.
a. Fat. The agency requests comment on a quality factor for fat
balance that would require that all infant formulas be formulated and
manufactured to provide fat in a manner that allows the fat to be
absorbed and retained by infants at a level that the energy and other
nutritional requirements of the infant are not adversely affected (Ref.
6). Normal, healthy, full-term infants fed various mixtures of the fats
traditionally used in infant formulas in the United States rarely
excrete more than 15 percent of their fat intake (Ref. 6). This level
of fat excretion is an indication
[[Page 36182]]
that the fat is highly digestible. The use of a fat with lower
digestibility would adversely affect energy balance, could reduce the
absorption of fat-soluble vitamins and other nutrients, and could have
a negative impact on healthy growth of the infants.
b. Iron. The agency solicits comment on a quality factor that would
require that all infant formula be formulated and manufactured such
that the iron used is bioavailable and meets the iron requirements of
the growing infant. The maintenance of adequate iron status in the
infant is important because iron is required to transport oxygen in the
red blood cells to body tissues (as a component of hemoglobin), to
supply oxygen to muscle tissue (as a component of myoglobin), and to
support normal mental development. Full-term infants are generally born
with adequate iron stores to meet their iron needs for the first few
months of life, but the iron needs of premature infants and older
infants must be met by the diet.
Iron bioavailability from infant formulas is low compared to the
iron bioavailability from human milk (Refs. 61 and 62).
Nutrient sources and other ingredients, such as protein sources,
can affect the chemical form of iron, thus interfering with its
potential for absorption (Ref. 63). Furthermore, factors that enhance
iron bioavailability from human breast milk are poorly understood and
currently are not present in commercial formulas. Consequently, infant
formulas are fortified with up to 10 times the amount of iron found in
human milk. If, however, the bioavailability of the iron in the infant
formula is substantially improved by a change in the formulation or
processing of the formula, then reductions in the amounts of iron added
to the infant formula may be necessary to prevent the infant from
absorbing excessive amounts of iron which could be unsafe because high
dietary intakes of iron can adversely interfere with the
bioavailabilities of other nutrients (59 FR 51030, October 6, 1994).
If, however, the iron was bound to another ingredient such that it
interfered with absorption, the infant's physiological needs for iron
might not be met. Infant formula iron levels and iron bioavailability,
thus, represent a delicate balance between effectiveness and safety
that cannot be adequately predicted by chemical analysis of the iron
content of the formula, but can best be assessed by measurement of
clinical indicators of iron status.
Early changes in iron nutritional status are not likely to be
detected by the general quality factor of physical growth. Therefore, a
quality factor requirement for an infant formula to meet the iron
requirements of infants, and to contain sufficient bioavailable iron
for this purpose, may be needed. The agency, however, is concerned that
clinical studies, as described in proposed Sec. 106.97(a), in which
selection criteria include requirements that enrollees be healthy,
full-term infants aged 0 to 4 and 5 months, may not be sensitive enough
to detect significant differences in iron bioavailability of a formula
product. 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 clinical trial would be conducted.
Without assurance that the test results are meaningful, the agency has
tentatively decided not to require a specific quality factor for iron
bioavailability.
c. Calcium and phosphorus. The agency also requests comment on a
quality factor that would require that all infant formulas be
formulated and manufactured such that the calcium and phosphorus are
bioavailable and meet the calcium and phosphorus needs of infants.
Calcium and phosphorus are essential for healthy bone mineralization
and growth in infants. Calcium bioavailability is of particular concern
because inadequate intakes of calcium impair bone mineralization and
can cause rickets in severe cases (Refs. 64 and 65).
Interactions with other ingredients and manufacturing processes can
reduce calcium and phosphorus bioavailability. High concentrations of
calcium and phosphorus can interact to form insoluble complexes that
may be unavailable (Ref. 66). Calcium can interact with free fatty
acids and form soaps that are not absorbed (Ref. 66). Lactose-free
formulas have been found to have lower calcium absorption than formulas
containing this sugar (Refs. 67 and 68).
Some phosphorus compounds, such as the phytates found in plant
protein sources, may not be readily digested and absorbed by infants
(Ref. 69). Inadequate dietary phosphorus can cause a loss of calcium
from the body as a result of bone resorption (i.e., loss of bone mass)
(Ref. 70). Formulation or processing changes that affect other formula
ingredients that influence calcium and phosphorus absorption require
careful consideration of their potential effects on calcium and
phosphorus bioavailability and the calcium and phosphorus status of the
infant.
A dietary insufficiency of calcium and phosphorus of a magnitude
that decreases bone formation may not be detected by physical measures
of growth (Ref. 71). Therefore, a quality factor requirement for an
infant formula to ensure that it meets the calcium and phosphorous
requirements of infants, and to ensure that it contains sufficient
bioavailable calcium and phosphorus for this purpose, may be needed.
FDA is concerned, however, that meaningful measures for assessing the
bioavailability of calcium and phosphorus may not be available.
d. Summary. FDA has tentatively concluded that the clinical and
nutritional sciences have not reached a state where specific tests are
available that would permit manufacturers to establish that they meet
quality factors for each of the essential nutrients listed in
Sec. 107.100, except for protein. Therefore, except for the quality
factor requirements for physical growth and protein quality discussed
above and set forth in proposed Sec. 106.96 (b) and (c), the agency has
tentatively concluded that it is not useful to propose quality factor
requirements for specific nutrients at this time.
Thus, to meet the nutritional needs of infants consuming formula,
manufacturers must use forms or sources of essential nutrients that are
bioavailable. The agency is concerned that manufacturers could
unintentionally or unknowingly use forms of nutrients that have a
relatively low bioavailability or ingredients or processing methods
that will produce interactions that adversely affect the
bioavailability of nutrients, thereby adulterating the formula because
it no longer meets the nutritional needs of the infant. However, at
this time, FDA is not aware of a means to systematically identify those
circumstances that could adversely affect all nutrient
bioavailabilities. FDA does not believe that it is ethical to
unnecessarily subject infants to testing protocols when meaningful
results cannot be assured. However, 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.
FDA, therefore, requests comment on the: (a) Need for routine
testing of quality factors, in addition to measures of physical growth
and protein quality; (b) criteria to be used in determining that such a
need can be meaningfully implemented, and (c) if a need is established,
the type of qualitative and quantitative measurements that could be
used by manufacturers to demonstrate
[[Page 36183]]
that an infant formula meets with those quality factors. If FDA
receives information demonstrating the need for additional quality
factors, it will consider including them in any final rule that results
from this proceeding.
5. Assurances for Quality Factors
a. Quality factor--physical growth of infants. Proposed
Sec. 106.97(a)(1) requires that the manufacturer conduct an adequate
and well-controlled clinical study to determine whether the formula
supports normal physical growth in infants when it is fed as the sole
source of nutrition. The CON/AAP Task Force on Clinical Testing of
Infant Formulas (Ref. 6) concluded that the capability to support
physical growth is the most widely accepted and used measurement
available of the nutritional adequacy of an infant formula. Gains 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.
A randomized, controlled study represents the most sensitive type
of study to measure the nutritional adequacy of infant formula. The use
of concurrent treatment and control groups is in agreement with the
CON/AAP Task Force recommendations (Ref. 6) and with the agency's
recommendations for human bioavailability studies of drugs (21 CFR
320.25). Although comparisons to historical controls (e.g., population
reference standards) have been used by some investigators to evaluate
growth of infants consuming a particular formula product, this type of
study lends itself to misleading results because population reference
standards are generally for the total population of infants (regardless
of birth weight, health status, socioeconomic status, or other factors
that can affect growth unrelated to nutritional components). In a study
to evaluate the nutritional adequacy of a formula, on the other hand,
selection criteria are usually used to limit enrollment to healthy,
full-term infants. Thus, differences or similarities in growth between
study infants and population reference standards cannot be meaningfully
interpreted. Therefore, the agency is proposing to require that
adequate and well-controlled clinical studies be conducted to collect
the data needed to determine whether a formula satisfies the quality
factor requirements for physical growth. To assist manufacturers in
understanding the general principles for adequate and well-controlled
clinical studies, FDA has prepared the ``Guideline for the Format and
Content of the Clinical and Statistical Sections of New Drug
Applications,'' U.S. Department of Health and Human Services, July,
1988 (Ref. 72).
FDA has tentatively concluded that it is necessary to enroll
infants into a clinical study shortly after birth, and that the studies
be at least 4 months in duration (see proposed
Sec. 106.97(a)(1)(i)(A)), to ensure that the study focuses on the
period during which infant formula generally serves as the sole source
of nutrition, and, thus, the infant is most vulnerable to a problem
with a formula since the infant is not consuming other foods that could
mask or compensate for a deficiency in the formula. Also, the
sensitivity of growth studies for identifying nutritional problems with
an infant formula is highest during early infancy. Young infants, those
less than 4 to 5 months, allocate a substantially higher percentage of
the intakes of energy, protein, and other nutrients for growth than do
older infants. After this early period of rapid growth, the rate of
physical growth slows, and the allocation of nutrient intakes for
growth is lower. Thus, early infancy is the period of greatest
nutritional risk and is the age associated with the most sensitive
growth phase.
Because of the rapid rate of growth in infants less than 4 months
of age, adverse nutritional impacts that affect growth rate can be
detected within a few months (Ref. 4). Growth studies in older infants,
where growth rates are of smaller magnitude and where solid foods are
also consumed, are not sensitive enough to provide a meaningful
evaluation of the ability of the formula to support healthy growth.
The CON/AAP Task Force (Ref. 6) also recommended that clinical
studies be conducted for a period of 3 to 4 months, and that growth be
examined at least during the first 8 weeks of life, because nutrient
requirements per kg body weight are greatest during this period. It
also pointed out that such a study will cover a period when the infant
is not consuming solid foods, and the infant formula is fed as a sole
source of nutrition.
Therefore, FDA has tentatively concluded that a clinical trial that
lasts at least 4 months will be long enough to detect adverse effects
of nutritional inadequacies on growth rate. FDA also has tentatively
concluded that a clinical trial must be conducted with infants less
than 1 month of age at the time of their entry into the study (see
proposed Sec. 106.97(a)(1)(i)(A)) to ensure that the formula is tested
during the period of time when growth rate and nutrient requirements
are proportionately greatest, and when the infant formula serves as the
sole source of nutrition. These requirements are intended to ensure
that the study assesses the nutritional adequacy of the formula for
supporting normal physical growth in the young infant.
Under proposed Sec. 106.97(a)(1)(i)(B), the manufacturer will be
required to collect and maintain individual and group summary data on
anthropometric measures of physical growth and plot the data on
National Center for Health Statistics (NCHS) reference percentile body
weight and body length curves, which are standard measurements of
infant physical growth (Refs. 73, 74, and 75) and provide the most
widely accepted assessment of infant growth (Ref. 6).
Plotting each infant's anthropometric data on NCHS reference
percentile body weight and body length curves, and providing individual
data on increments of weight gain, provide a means to make a
quantitative assessment of the growth pattern over the 4 months
duration of the study for individual infants. There is normally wide
variation in body weights and lengths among healthy infants, with some
being smaller than average and others average or above average. Single
point measures of weight or length are difficult to interpret relative
to a given infant because one does not know whether, for example, a
smaller than average weight is attributable to inadequate nutrition or
to a healthy and thriving infant whose body size is smaller than
average.
Over time, young infants tend to individualize their track within a
given percentile on population reference growth standards. An infant at
the 25th percentile level for weight shortly after birth tends to stay
at or near the 25th percentile for weight throughout the first few
months of life. When multiple longitudinal measures of weight (or
length) of an infant are plotted on a weight-for-age reference chart, a
reviewer can make a quick assessment as to whether an infant's pattern
of weight or length gain is similar to that expected for healthy
infants of the same age, taking into account the range of normal
individual variation in body weights and lengths and that infant's
percentile track. Similar comparisons can be made with a given infant's
weight or length incremental gain data relative to population reference
standards. These data allow for identification of infants with
unusually slow or rapid growth, an observation that is masked by
grouped data.
Thus, plots of changes in individual infant's weight and length in
conjunction with comparisons of increments per unit time of weight or
length gains against population
[[Page 36184]]
reference standards allow researchers and reviewers to identify those
infants whose growth is not following expected longitudinal patterns
and, therefore, for whom a more thorough review of their medical and
dietary histories is necessary to assess the possibility that the
infant formula is responsible for reduced growth rates in a subgroup of
infants. This careful review of individual infant growth patterns in
addition to group summary data is particularly important because
studies, while adequate to evaluate differences in group means between
test and control formulas, often lack the statistical power to detect
subgroups of infants whose growth patterns deviate from normal. These
data will also provide useful information on possible trends towards
failure to thrive or obesity, or on catchup growth in infants who
experienced transient adverse effects relative to expected growth
rates.
FDA has tentatively concluded that a comparison of a manufacturer's
data to well-established population reference standards can provide the
basis for an evaluation of the growth patterns of individual infants to
identify, and to provide the basis for an investigation of, possible
causes of unusually slow or fast rates of gain. Thus, the agency is
proposing that the NCHS growth charts for individuals and for grouped
data be incorporated by reference into the regulation (proposed
Sec. 106.97(a)(1)(i)(B)).
Proposed Sec. 106.97(a)(1)(i)(C) requires that the manufacturer
collect the anthropometric measurements at the beginning of the
clinical study, at 2 weeks and at 4 weeks of the study, at least
monthly thereafter, and at the conclusion of the study. These
measurements will permit the calculation of incremental gains in the
different measurements. Incremental gains, such as weight gain per unit
of time, are generally considered the most sensitive indicator of the
ability of a formula to support the physical growth of individual
infants over time (Ref. 4). Also, because growth rate and nutritional
requirements are curvilinear rather than linear during early infancy,
multiple measurements help in assessing whether the formula meets the
nutritional needs throughout the period of the clinical study and aids
in more accurately placing infants in their ``correct'' reference
percentile tract, particularly since age of enrollment varies somewhat
among infants (although, if adopted, this regulation should serve to
minimize that variation). Additionally, measures of an infant's body
weight, the most critical anthropometric measure, are subject to a
number of measurement errors unrelated to the nutritional value of the
formula (e.g., timing of weighing of infant relative to feeding or
defecation or urination).
For these reasons, multiple measures over a relatively long period
(e.g., 4 months) provide a more accurate picture of the pattern of
growth of infants than do one or two point measures. The agency has
tentatively concluded that the requirement of four measurements taken 1
month apart will provide a sufficient number of measurements to permit
evaluation of whether the formula meets the nutritional needs for
physical growth of the infant throughout the study period. However, the
agency requests comment, supported by data, on which measurements are
needed to provide evidence that the formula meets the nutritional needs
for physical growth of infants.
FDA has tentatively concluded that more frequent measurements are
needed during the early stages of the study because variations in
measured body weight that are a result of factors unrelated to the
nutritional quality of the formula can be particularly serious in early
infancy. For example, during the first week of life, there is a normal
loss of body weight by the infant because of fluid loss that may reach
6 to 10 percent of body weight (Ref. 76). This weight loss will reduce
the apparent growth of the infant as measured by body weight. This
reduction may affect the ability to evaluate and interpret the weight
gain data collected early in the study. FDA has tentatively concluded
that requiring more frequent anthropometric measurements, especially
for weight, early in the study, increases the ability to accurately
place individual infants in the correct percentile track for monitoring
their growth patterns in relation to the population reference curves
and for monitoring physical growth during the most sensitive part of
their growth phase.
To minimize the burdens of this regulation, FDA has not proposed to
require that blood samples obtained from infants during the time period
of their enrollment in the clinical study, or at completion of the
study, be analyzed for biochemical and clinical indicators of
nutritional and growth status. However, the CON/AAP Task Force (Ref. 6)
recommended that some blood tests be conducted at the conclusion of
required clinical studies to provide a more comprehensive evaluation of
the nutritional adequacy of a formula. Thus, the agency requests
comments on whether it would be useful for the manufacturer to collect
and maintain data on standard laboratory measures, including 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. These
measurements are standard practice when infants are seen clinically and
can be made with very small quantities of blood. The maintenance of
these indicators within normal limits at the end of the study provides
additional assurance over and above measures of physical growth that
the infant's general state of well-being is healthy and ``normal,''
particularly because changes in biochemical measures may occur before
detectable differences in physical growth are identified or may not be
detected by measures of physical growth. General anthropometric
measurements of physical growth provide indirect, although very
important, evidence that the formula is able to help the infant
maintain overall good health, but they are not as specific, and may not
be as sensitive, as are biochemical indicators of health.
FDA also requests comment on whether requiring some, or all, of the
biochemical and clinical tests described above would provide useful and
necessary information for determining whether a formula causes adverse
consequences that may not be reflected in the quality factor
requirements for measurements of physical growth in proposed
Sec. 106.97(a)(1)(i).
The identification of deviations from expected values for these
biochemical and clinical measurements, throughout the duration of the
clinical study, could serve as an early warning of unexpected risk to
infants enrolled in the study and, therefore, result in early actions
to prevent undue risk to infant enrollees in the study. Conversely,
collection of blood samples throughout the study could discourage
parents from continuing their infants in the study, thus causing a high
attrition rate and producing final study results that are difficult to
interpret.
Proposed Sec. 106.97(a)(1)(ii) sets forth guidelines for the design
of clinical study protocols. A comprehensive clinical study protocol
will ensure that individual investigators understand and follow
generally accepted scientific principles for the design and conduct of
clinical trials, thus enhancing the likelihood of interpretable results
while maintaining minimal or no risk to infants enrolled in the
studies. In the conduct of all studies, manufacturers should use the
general principles,
[[Page 36185]]
described in Sec. 314.126 (21 CFR 314.126) for adequate and well-
controlled clinical studies to ensure that the design and conduct of
the study are adequate to permit scientific review and interpretation
of the study's results. Studies that cannot produce meaningful results
because of poor or inadequate study design and conduct mean that
infants will be subjected to unnecessary testing. Such a situation
places infant enrollees at undue risk and is clearly unethical.
In this section, FDA is not establishing mandatory elements for
inclusion in a protocol, nor requiring that manufacturers provide the
agency with the protocol used for a study intended to provide data to
show that an infant formula meets the quality factor requirements.
However, as discussed above, a protocol is an essential part of the
design and execution of a well- controlled scientific study.
Furthermore, a protocol often provides invaluable information that
assists in the analysis and interpretation of the study data.
Consequently, the agency strongly encourages manufacturers to develop
and use protocols that incorporate the specific elements in proposed
Sec. 106.97(a)(1)(ii) in all research studies using infants because
these elements will ensure that the study is designed and conducted in
a manner that will produce results that will permit meaningful
evaluation of the usefulness of the infant formula.
The steps outlined in proposed Sec. 106.97(a)(1)(ii)(A) represent
standard practice in the design and conduct of clinical studies (Ref.
72). Proposed Sec. 106.97(a)(1)(ii)(B) states that the clinical study
protocol should describe the necessary qualifications and experience of
the investigators. It is essential that clinical studies be conducted
by personnel with sufficient experience and training to ensure that
their work will yield interpretable and meaningful results. If a study
is conducted by an investigator who is not qualified, it increases the
likelihood that the study will have to be redone, and that more infants
will be exposed to risk. Therefore, it is important that in the
protocol, the manufacturer define the requisite qualifications to
conduct the study it is designing.
Proposed Sec. 106.97(a)(1)(ii)(C) states that the protocol should
be reviewed and approved by an Institutional Review Board (IRB) in
accordance with part 56 (21 CFR part 56), and that the manufacturer
should establish procedures to obtain written informed consent from the
parents or legal representatives of the infants enrolled in the study
in accordance with part 50 (21 CFR part 50). These steps are necessary
to protect the rights and safety of subjects involved in the studies.
Proposed Sec. 106.97(a)(1)(ii)(D) states that the clinical study
protocol should explain how the study population represents the
population for which the new infant formula is intended. FDA has
tentatively concluded that such an explanation is necessary so that if
questions about the relevance of the study population arise, the answer
is readily available and free of any taint that it is a post hoc
rationalization. For example, FDA has recently had questions about a
study that involved hospitalized infants that were offered to support
use of the product on post-discharge infants. If there had been the
type of explanation available that FDA is proposing in this guideline,
it would have greatly minimized the questions about this product.
Proposed Sec. 106.97(a)(1)(ii)(D) also states that the clinical
study protocol should explain how the study addresses the intended
conditions of use of the formula. FDA has tentatively concluded that,
by having manufacturers consider this question before the study is
conducted, this guideline will prevent clinical studies that are
conducted under conditions of use that do not accurately reflect the
proposed conditions of use. For example, a clinical study protocol for
testing a formula designed to be used by premature infants throughout
infancy should explain how the study design will provide information to
support the claim that the formula supports healthy growth under these
conditions.
Proposed Sec. 106.97(a)(1)(ii)(E) states that the clinical study
protocol should describe the sample size calculations and the power
calculations and the basis for selecting the sample size and study
design. This information is necessary to establish the likelihood that
the study will not fail to detect a real difference, should there be a
difference for the measurements of interest, between the infant formula
being tested and the control. For example, a study might not find a
difference in incremental rate of weight gain between infants consuming
two formulas because too few infants were enrolled in the study to
provide sufficient statistical power to detect this difference.
Inadequate statistical power could mask the nutritional inferiority of
a product and could result in the marketing of a formula that does not
meet the quality factor requirements and, therefore, is not safe for
its intended use. Therefore, FDA has tentatively concluded that this
guideline is needed to ensure that manufacturers design their growth
studies to be capable of detecting biologically meaningful differences
for the endpoints of interest between the two formulas. Identification
of differences would raise safety concerns or serious questions of
nutritional quality of the test formula product.
Proposed Sec. 106.97(a)(1)(ii)(F) states that the clinical study
protocol should include a plan to identify and evaluate any adverse
events. This proposed guideline is necessary to document that
appropriate attention is given to the systematic evaluation and
recording of any adverse events that may occur during the course of the
study. Inadequate planning for and conduct of the monitoring of adverse
events may result in an erroneous conclusion that the formula is safe
and suitable, when in fact the formula is not safe and suitable for
infants under intended conditions of use.
Proposed Sec. 106.97(a)(1)(ii)(G) states that the clinical study
protocol should describe the quality control procedures that the
investigator will use to ensure the validity and reliability of the
measurements collected. This proposed guideline represents standard
practice in the design and conduct of clinical studies and is necessary
to allow a meaningful interpretation of study results. Data obtained
with unreliable measures, or with indicators that do not accurately or
meaningfully measure identified endpoints, may produce misleading study
results that are uninterpretable and that suggest that a formula is
safe and suitable, when more valid or reliable measures would not have
supported this conclusion. The institution of adequate quality control
procedures before beginning a study provides a mechanism for
manufacturers to ensure that the data collected are reliable, and that
the study provides interpretable results.
Proposed Sec. 106.97(a)(1)(ii)(H) states that the clinical study
protocol should describe and compare the composition of the control and
test formulas. These descriptions of the control and the test formulas
are necessary to establish that the formula used as the control
provides an adequate comparison for evaluating the quality factors of
the test formula. If the control formula is not comparable to (i.e.,
bioequivalent to) formulas in current use, differences between the test
and control formulas have no meaning. They cannot be generalized to
projected conditions of use. For example, comparable or enhanced
physical growth in infants consuming a test formula as compared to
infants consuming a control formula when the control formula does not
meet
[[Page 36186]]
requirements in Sec. 107.100 for nutrients, or is not bioequivalent
relative to quality factors to currently marketed formulas in the
United States, cannot be interpreted as supporting healthy growth
because it is not possible to determine whether the apparent ``equal''
or ``enhanced'' physical growth is attributable to the fact that the
formula is nutritionally adequate, or whether the formula looks
adequate because it is being compared to a nutritionally inadequate
formula. The nature of the differences between control and test
formulas will also affect sample size and measurement (endpoint)
considerations.
FDA's experience in reviewing clinical data submitted with 90-day
notifications has been that the absence of information on control
formulas is not uncommon. Thus, FDA has tentatively concluded that a
guideline on the information that needs to be considered in selecting a
control formula is necessary to ensure that study results are
meaningful and interpretable.
If the test formula used in a study is not identical to the formula
that is intended to be marketed in the United States, proposed
Sec. 106.97(a)(1)(ii)(I) states that the clinical protocol should
describe the basis upon which the manufacturer has decided that the
test formula is appropriate for use in the study. This proposed
guideline is necessary to ensure that the manufacturer considers such
factors as the bioequivalence of the studied (test) formula relative to
the formula that is to be marketed in this country and can document why
its choice of test formulas is appropriate. Without this documentation,
it would not be possible to determine whether the marketed formula
meets the quality factor requirement in proposed Sec. 106.96(b).
FDA has had experience under the 1986 amendments in which
manufacturers have submitted data on test formulas that were
significantly different (e.g., in calorie levels) from the formula that
they intended to market as evidence of the safety and suitability of
the latter formula. In these instances, the agency has had considerable
difficulty in interpreting study results. Therefore, if the guidance in
proposed Sec. 106.97(a)(1)(ii)(I) is followed, this significant study
design issue will be critically reviewed by manufacturers before they
initiate their studies, and, as a result, they will be more likely to
design and conduct a study that will produce data that can be
meaningfully interpreted as evidence that an infant formula is safe,
and that it supports healthy growth.
As provided in proposed Sec. 106.97(a)(2), however, FDA recognizes,
that while changes in ingredients or in the processes used in the
manufacture of infant formulas can have a significant adverse impact on
the levels or availability of nutrients that affect healthy growth of
infants, other changes may not be likely to do so. In the latter
circumstances, it may be possible to demonstrate that the quality
factor requirements are met by means of measures or data that do not
involve the use of clinical trials. If such assurances can be provided
without clinical trials, then infants will not be subjected to
unnecessary testing. Therefore, FDA sets out in proposed
Sec. 106.97(a)(2), the circumstances in which a manufacturer can
request an exemption from the clinical study requirement.
Proposed Sec. 106.97(a)(2)(i) provides for an exemption if the
manufacturer can cite experience that shows that the ingredient,
ingredient mixture, or processing method has been used to make an
infant formula that meets the quality factor requirements in proposed
Sec. 106.96(a). For example, if the manufacturer has previously
submitted information to FDA in response to the quality factor
requirements of the act that showed that an infant formula that
contains the ingredient or ingredient mixture, or that was produced by
the processing method, in question supported adequate physical growth,
this information could form the basis on which the new infant formula
could qualify for an exemption from this quality factor requirement.
Under this provision, FDA will evaluate the experience cited in support
of an exemption on a case-by-case basis. FDA requests comment on this
proposed provision.
Proposed Sec. 106.97(a)(2)(ii) provides for an exemption if a
manufacturer that markets a formulation in more than one form (such as
liquid and powdered forms) can demonstrate that the quality factor
requirements are met by the form of the formula that is processed using
the method that has the greater potential for adversely affecting the
formula's nutrient content and bioavailability. For example, the
temperatures used to retort liquid formulas during processing can cause
a loss of protein quality compared to powdered forms processed at lower
temperatures (Refs. 77 and 78). Thus, if the liquid formula is tested
and shown to meet the quality factors requirements, it will provide
reasonable assurance that the powdered form of the formula, that is,
the less processed form is of appropriate nutritional quality. Thus,
FDA tentatively concludes that it would be unnecessary to test the less
processed form.
Proposed Sec. 106.97(a)(2)(iii) provides for an exemption if the
manufacturer can demonstrate that the requirements of proposed
Sec. 106.97(a)(1) are not appropriate for the formula, and an
alternative method or study design for showing that the formula
supports healthy growth in infants fed the formula as a sole source of
nutrition is available. As stated above, double- blind, well-
controlled, clinical studies are generally the most powerful and
sensitive method for demonstrating that an infant formula will support
physical growth. Nonetheless, the agency anticipates that there will be
circumstances in which a clinical study of a new infant formula would
not be appropriate. For example, double-blind clinical studies would
not be appropriate in situations such as those involving some exempt
infant formulas in which they would cause withholding of conventional
treatment and, therefore, would be unethical. Other situations that may
not be amenable to double-blind clinical trials are those in which it
would be difficult to enroll an adequate number of infants (e.g., for
exempt infant formulas where the formula is intended for a rare
disease). Alternative study designs may also be appropriate in
situations in which a manufacturer has access to extensive reference
data, such as a database on many similarly conducted clinical studies
using infants from the same potential study population, provided that
the manufacturer can demonstrate that the reference data apply to the
new infant formula, its intended use, and its study population. FDA has
tentatively concluded that such an exemption will permit flexibility in
the design of suitable experimental protocols but still provide
reasonable and documentable assurance that the study design can
demonstrate the safety and suitability of the infant formula.
b. Specific quality factors. Proposed Sec. 106.97(b) establishes
requirements for demonstrating that a formula meets the protein quality
factor requirement in proposed Sec. 106.96(c) and requires that the
manufacturer collect and maintain data that establish that the
biological quality of protein in an infant formula is sufficient to
meet the protein requirements of infants by demonstrating that the
protein source supports adequate growth using the PER rat bioassay,
which the agency proposes to incorporate by reference. The PER provides
an estimate of the bioavailability and relative proportion of the
essential amino acids in the protein-containing ingredient.
[[Page 36187]]
A chemical analysis of the protein can identify the amino acids
contained in a protein source but does not measure their
bioavailability. 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. FDA has tentatively concluded that the rat
bioassay is necessary to establish that the amino acids in a protein
source are present, and that adequate amounts and proportions of all
essential amino acids are capable of being digested by an infant. Such
a showing is particularly important when a manufacturer is using a
novel protein source (e.g., a hydrolyzed protein), a new protein
mixture, a new processing method that could affect the chemical form or
bonding of amino acids, or a formulation that provides an amount of
protein near the minimum required level (<2.0 g/100 kilocalorie (kcal))
specified in Sec. 107.100.
Proposed Sec. 106.97(b)(1) also provides that if the manufacturer
is unable to conduct a PER rat bioassay, it must demonstrate that the
amino acid composition of the protein meets the known amino acid
requirements of infants for whom the formula is intended. For example,
FDA is aware that a PER would not provide useful data for an exempt
infant formula intended for use in infants that cannot metabolize a
specific amino acid and from which that amino acid has been
purposefully omitted or is limited to a level inadequate to support
healthy growth. The lack of that amino acid is necessary for the
dietary management of the intended infant population but would result
in an incomplete protein and would reduce the growth rate of the rat,
invalidating the conditions upon which the PER rat bioassay is based.
FDA is not aware of alternative methods for ensuring bioavailability of
such a protein source. In these circumstances, proposed
Sec. 106.97(b)(1) will provide an alternate means of evaluating whether
the protein at least contains adequate amounts of essential amino acids
to meet the known amino acid requirements of the infant, even though
the bioavailability of these amino acids cannot be assured using
available methods.
Proposed Sec. 106.97(b)(2) establishes the circumstances in which a
manufacturer may request an exemption from the requirements of proposed
Sec. 106.97(b)(1). Proposed Sec. 106.97(b)(2)(i) provides that if the
protein source (including the processing method used to produce it) is
already used in another of the infant formulas marketed by its
manufacturer in the United States, the manufacturer may request an
exemption if it can demonstrate that such other infant formula meets
the quality factor requirements prescribed in Sec. 106.96(b)(1). The
purpose of the PER or amino acid analyses is to estimate the quality of
the protein in the proposed formula. Once a manufacturer has
established standard sources and processing of protein in a formula,
and has demonstrated that the technology is effective, in its hands, in
producing a formula that meets the quality factor requirement for
protein, other formulation changes would not be expected to markedly
affect protein quality. Thus, the quality of the processed protein
would be retained in other formulas. However, under proposed
106.97(b)(2)(i), it will be incumbent on the manufacturer to
demonstrate that the quality of the protein is not affected.
Proposed Sec. 106.97(b)(2)(ii) provides for an exemption if the
protein source, or the processing method used to produce the protein
source, in the infant formula does not constitute a major change from
the infant formula that it replaces, and the manufacturer can
demonstrate that the infant formula that it replaces meets the quality
factor requirements prescribed in Sec. 106.96(b). FDA is proposing to
allow this exemption because it is unlikely that the methods for
assessing protein quality prescribed are sensitive enough to measure
any change in protein quality that is not a major change.
Because FDA has, as a matter of policy, been requesting that infant
formula manufacturers submit data from a PER or amino acid analysis as
part of their submission 90 days prior to marketing infant formula,
many infant formulas that are on the market have been shown to meet the
proposed quality factor requirement for protein. Therefore, if the
proposed exemption criteria in Sec. 106.97(b)(2) are adopted, those
formulas that contain protein sources, or proteins which were produced
using processing methods, that were the subject of a submission to FDA
in response to the quality factor requirements of the act may qualify
for an exemption.
6. Request for Comment on Establishing Assurances for Other Quality
Factors
As discussed above, FDA has solicited comment on whether to
establish quality factor requirements for fat, iron, and calcium and
phosphorus. If such quality factors are adopted, appropriate methods
will be needed to provide assurance that an infant formula meets these
nutrient-specific quality factors. Therefore, FDA discusses below
measurements of fat balance and of calcium and phosphorus balance, as
well as measurements that reflect iron bioavailability. The agency
requests comments and information on these or other methods for these
three quality factors:
a. Apparent fat absorption. Apparent digestibility and apparent
absorption measure the amount of fat that was able to be digested and
absorbed by the infant. Apparent digestibility is expressed as a
percentage of intake, while apparent absorption is expressed in units
of fat (e.g., g) absorbed per day. If a quality factor for fat were
established, manufacturers would be required to collect and maintain
data establishing that the apparent digestibility or apparent
absorption by the infant of the fat in an infant formula is adequate to
meet the infant's energy requirements. These data would be necessary
because fat represents the major dietary source of energy for the
infant and must be readily digested and absorbed if the formula is to
support healthy growth.
The CON/AAP Task Force (Ref. 6) recommended that studies that are
conducted to determine whether a formula meets the quality factor for
fat should use a cross-over experimental design. This type of study
requires that the manufacturer compare apparent fat absorption of
infants fed the test formula at one time and a currently marketed
formula at another time. An experiment using this design would enable a
manufacturer to make measurements of apparent fat absorption using a
small number of infants, since the variance in fat excretion of infants
fed most fat sources currently available is less than 5 percent.
Furthermore, the method is noninvasive, is easily implemented, and does
not require costly or sophisticated equipment to conduct. Other
experimental designs could be used but would require larger numbers of
infants and would be more expensive. Thus, FDA asks for comments on
whether there should be a specific requirement that manufacturers
measure apparent fat absorption using cross-over studies.
The CON/AAP Task Force (Ref. 6) recommended that studies that are
conducted to determine the apparent absorption of fat be conducted such
that measurements are made using infants fed each formula for at least
72 hours. The Task Force report suggested that measurements of apparent
fat absorption for this length of time would accurately reflect the
apparent
[[Page 36188]]
absorption of the fat in the formula being tested. FDA is considering
requiring that a study of at least 72 hours for each formula tested be
conducted and requests comment on what duration would be appropriate.
FDA also is considering whether to require that the manufacturer
document the method that it used to analyze for fat and explain the
reason for choosing that method. The agency believes that this
information is important because the method used to analyze the
excreted fat must be appropriate for the specific type of fat in the
formula.
FDA also is considering whether circumstances exist that would
justify establishing an exemption from the requirements to measure fat
balance. FDA has tentatively concluded that the reasons and
justification for such an exemption are essentially those set forth
above in the discussion of proposed Sec. 106.97(b)(2). FDA requests
comment on whether, if the agency adopts a quality factor for fat, it
should provide for exemptions from testing, to show that the formula
meets that quality factor, such as those set forth in proposed
Sec. 106.97(b)(2), and to allow manufacturers to assure the agency that
their products meet that quality factor requirement without subjecting
infants to unnecessary testing.
b. Calcium and phosphorus balance. If FDA were to establish a
quality factor for calcium and phosphorus, manufacturers would be
required to collect and maintain data from clinical studies conducted
in infants to show that the calcium and phosphorus contained in the
infant formula are sufficient to meet the infant's requirements. There
are currently no satisfactory clinical laboratory measurements that are
practical for directly assessing calcium and phosphorus nutritional
status in infants (Ref. 79). Furthermore, there are no accurate
indirect measurements that could be made on the infant formula itself
that would be useful in predicting how effective the amount and the
sources of calcium and phosphorus in the formula would be in meeting
the needs of infants consuming that formula. Therefore, FDA is
considering requiring that manufacturers implement the recommendations
of the CON/AAP Task Force and make a measurement that provides a
reasonable estimate of the amount of calcium and phosphorus that is
capable of being absorbed and retained for use by infants (i.e.,
calcium and phosphorus balance) from the formula.
FDA asks for comment concerning the appropriateness and usefulness
of a measurement of calcium and phosphorus balance as one that reflects
both the bioavailability of the calcium and phosphorus in the formula
and how well the diet meets the metabolic requirements for these two
minerals. As discussed above with regard to the conduct of trials to
measure apparent fat absorption, FDA requests comment on whether it is
necessary to require that a cross-over study design be used for
clinical studies to measure calcium and phosphorus balance.
FDA also requests comment on what would be an appropriate duration
for studies to measure calcium and phosphorus balance. The CON/AAP task
force suggested that calcium and phosphorus balance studies be
conducted for a 72-hour balance period after an 11-day adaptation
period. FDA requests comment on whether these time periods are
appropriate, both to minimize the effects of previous dietary intake on
the availability of calcium from the formula being tested (Ref. 6) and
to ensure that the results of the balance study are reliable and
interpretable, and on whether they provide a meaningful basis on which
to determine that a formula meets the quality factor requirement for
calcium and phosphorus.
FDA is considering requiring that the formula used as the control
in any clinical studies to measure calcium and phosphorus balance
contain approximately the same calcium and phosphorus levels as the
test formula because the absolute amounts of these nutrients absorbed
and retained by infants may be different between formulas with
different calcium and phosphorus levels. FDA is asking for comment on
requirements for appropriate control formulas for calcium and
phosphorus balance studies.
Amounts of calcium and phosphorus in urine and feces, along with
calculated amounts absorbed and retained expressed in milligrams per
kilogram and as percentages of intake, provide evidence of the rates of
absorption and retention of these nutrients but do not specifically
measure the ability of the formula to provide adequate calcium and
phosphorus for proper bone mineralization, the most important need for
these minerals in the infant. FDA is considering requiring that serum
alkaline phosphatase be measured in situations in which calcium and
phosphorus balance studies are required in order to assess the adequacy
of formula minerals to support normal bone mineralization. Alkaline
phosphatase is an enzyme involved in bone remodeling and in maintaining
serum calcium concentration (Ref. 64). Increased serum alkaline
phosphatase activity may be a marker of reduced bone mineralization
(Ref. 80) and therefore may be useful in determining whether a formula
meets a quality factor requirement for calcium and phosphorus.
Because of the limits of metabolic balance studies, including short
duration, dependence on previous diet, and expense, the agency is
considering the appropriateness of alternative methods for the
assessment of bone mineral accretion. The agency is aware that
sophisticated instruments, such as single-photon absorptiometry and
dual-energy x-ray absorptiometry, have been tested for measuring bone
mineral content in infants (Refs. 81 through 84), and that some
authorities recommend them for determining bone mineralization in
infants (Ref. 85). These types of measurements have the potential to
provide an accurate measure of bone mineral accretion over the duration
of use of the formula, while at the same time reducing many sources of
variation inherent in balance studies. The agency is concerned,
however, that these methods have not been adequately validated in
infants, and that reference standards for mineralization in infants
have not been established to support a requirement for manufacturers to
measure bone mineralization in order to provide assurance that a
formula satisfies a quality factor requirement for calcium and
phosphorus. The agency asks for comment on the usefulness of these
methods of analysis of bone mineral accretion in infants, and on
whether they should be used in lieu of calcium and phosphorus balance
studies as measurements of whether an infant formula meets the quality
factor requirements for calcium and phosphorus assuming that the agency
adopts such a quality factor. The agency also asks for comment on the
criteria that it should use, on a case-by-case basis, in deciding
whether to require these types of measures when there is particular
reason to be concerned that calcium and phosphorus bioavailability may
be problematic.
FDA also is considering whether circumstances exist that would
justify establishing an exemption from a requirement to measure calcium
and phosphorus balance. FDA has tentatively concluded that the reasons
and justification for such an exemption are essentially those set forth
above in the discussion of proposed Sec. 106.97(b)(2), and requests
comment on whether, if it adopts a quality factor for calcium and
phosphorus, it should provide for exemptions from testing to show that
the formula meets the quality
[[Page 36189]]
factor similar to those in proposed Sec. 106.97(b)(2) and allow
manufacturers to assure the agency that their products meet that
requirement without requiring redundant testing.
c. Iron status. If FDA were to adopt a quality factor for iron,
manufacturers would be required to collect and maintain data that
establish that the iron in an infant formula is bioavailable and
maintains the iron status of infants that consume the formula. These
data would be necessary to demonstrate that an infant formula provides
enough iron to prevent iron deficiency and anemia.
Alterations in a number of biochemical measurements are useful
signs associated with inadequate iron intake or the development of iron
deficiency. Early signs of inadequate iron intake, which reflect the
depletion of iron storage sites, are reductions in serum ferritin
concentration and transferrin saturation (Ref. 86). If the dietary
intake of iron remains inadequate, impaired erythropoiesis (i.e., the
process whereby the body produces new red blood cells) may be reflected
in alterations in erythrocyte maturation and increases in erythrocyte
size, erythrocyte protoporphyrin concentration, or serum transferrin
receptor levels. If the period of inadequate iron intake continues,
erythropoiesis is further impaired, and hemoglobin concentration,
hematocrit, and mean corpuscular volume decrease.
Iron deficiency without anemia should be considered to be a risk
factor for iron-deficiency anemia, which may be associated with long-
lasting, adverse effects in infants (Ref. 86). Therefore, FDA is
considering requiring one measurement of iron status that is sensitive
to each of the three stages of inadequate iron intake (stage 1,
decreased stores, normal erythropoiesis; stage 2, decreased stores and
early stage impaired erythropoiesis; and stage 3, decreased stores and
late stage impaired erythropoiesis). For example, FDA is considering
requiring that manufacturers measure: (1) Serum ferritin concentration,
because such a measurement is sensitive to decreased iron stores and
normal erythropoiesis; (2) transferrin saturation or erythrocyte
protoporphyrin concentration, because such measures are sensitive to
decreased iron stores and early stage impaired erythropoiesis; and (3)
hematocrit percentage, hemoglobin concentration, or mean corpuscular
volume, because such measurements are sensitive to decreased iron
stores and late stage impaired erythropoiesis. This approach would be
consistent with the recommendations of the CON/AAP Task Force (Ref. 6).
It would also provide reasonable assurance that low iron availability
in an infant formula would be detected, and that an infant formula that
does not provide sufficient iron to meet the infant's requirement, and
thereby does not meet the quality factor requirement for iron, will not
be marketed.
FDA also is considering whether circumstances exist that would
justify establishing an exemption from the requirements to determine
iron status. FDA has tentatively concluded that the reasons and
justification for such an exemption are essentially those set forth
above in the discussion of proposed Sec. 106.97(b)(2). FDA requests
comment on whether, if it adopts a quality factor for iron, it should
provide for exemptions from testing similar to those set forth in
proposed Sec. 106.97(b)(2) to show that the formula meets that factor
and allow manufacturers to assure the agency that their products meet
that quality factor requirement without requiring redundant testing.
F. Records and Reports
1. Introduction
Under subpart C of part 106, FDA is proposing to revise the
requirements on the records that must be made and retained. FDA is
proposing requirements on batch records; records on CGMP and quality
control procedures; maintenance of distribution records on formulas for
export only; audits; and notifications to FDA. These proposed changes
to current Sec. 106.100 are outlined in Table III below:
Table III
------------------------------------------------------------------------
Current Regulation Proposed Regulation
------------------------------------------------------------------------
Sec. 106.100(a).......................... No Change.
Sec. 106.100(b).......................... No Change.
Sec. 106.100(c).......................... No Change.
Sec. 106.100(d).......................... No Change.
Sec. 106.100(e), (f), and (h)............ Current Sec. 106.100(e),
(f), and (h) will be
incorporated into proposed
Sec. 106.100(e).
New Sec. 106.100(f) will
codify the records required
for the CGMP regulations
found in proposed subpart
B.
Sec. 106.100(g).......................... Current Sec. 106.100(g)
with modification.
Sec. 106.100(h).......................... Current Sec. 106.100(h) is
incorporated into Sec.
106.100(e). Sec.
106.100(h) Reserved.
Sec. 106.100(i).......................... No Change.
Sec. 106.100(j).......................... Current Sec. 106.100(j)
with modification.
Sec. 106.100(k).......................... Current Sec. 106.100(k)
with modification.
Sec. 106.100(l).......................... No Change.
Sec. 106.100(m).......................... No Change.
Sec. 106.100(n).......................... No Change.
Sec. 106.100(o).......................... No Change.
------------------------------------------------------------------------
2. Batch Production and Control Records
Proposed Sec. 106.100(e) requires that manufacturers make and
retain records (hereafter referred to as ``batch records'') that
include complete information relating to the production and control of
each batch of infant formula. Section 412(b)(4)(A)(i) of the act
requires the establishment, by regulation, of requirements for the
retention of all records, including records containing the results of
all testing required under section 412(b)(2)(B) of the act, necessary
to demonstrate compliance with the CGMP requirements and quality
control procedures prescribed under section 412(b)(2). In proposed
Sec. 106.100(e) FDA is proposing to require that manufacturers prepare
and maintain records that include complete information relating to the
production and control of the batch to ensure that the complete history
of each batch of infant formula is available for review in the event
that a problem arises with a particular batch.
Proposed Sec. 106.100(e)(1) requires that the batch records include
the appropriate master manufacturing order. As discussed above,
proposed Sec. 106.50(a) requires that manufacturers produce each infant
formula in accordance with a master manufacturing order that has been
approved by a responsible official of the company. The master
manufacturing order thus provides fundamental information about the
batch. Having all the information concerning the production of a batch
of infant formula, including the master manufacturing order, in one
place as a part of a batch record will ensure that there is a document
available that makes readily apparent whether a batch was properly
produced. It will also ensure that all the information needed to
evaluate the cause of any problem that may develop with a batch of
infant formula is readily available. Thus, FDA has tentatively
concluded that the master manufacturing order is an essential part of
the batch record.
Proposed Sec. 106.100(e)(1)(i) requires that the master
manufacturing order include the significant steps in the production of
the batch of infant formula and the date on which each
[[Page 36190]]
significant step occurred. Thus, the master manufacturing order will
include a list of the significant steps for the production of each
infant formula and a space to write in the date the step was performed.
Thus, it will provide both a check that the step was performed and a
record of when it was performed. FDA has tentatively concluded that
this information is necessary because all production activities for a
specific batch of infant formula may not be accomplished in one day but
may occur over a number of days, and people who begin work the second
day will know what work has been completed, and what has not been.
Moreover, each date is needed so that a batch of formula can be traced
if, at a later date, a problem that may adversely affect an infant
formula is identified at a specific production stage. Having the date
available will allow the manufacturer to identify all batches that may
have been affected by the problem.
Proposed Sec. 106.100(e)(1)(ii) requires that, if the manufacturer
has more than one line or set of equipment in the plant in which the
formula is made, the master manufacturing order include the identity of
equipment and processing lines used in producing the batch of infant
formula. This information will allow the manufacturer to ensure that
the equipment on which the formula was produced met the requirements of
Sec. 106.30. This information also will facilitate the identification
of all batches of formula that may be affected by equipment
malfunctions or that were produced on the same equipment as a batch
that is discovered to be microbiologically contaminated.
Proposed Sec. 106.100(e)(1)(iii) requires that the master
manufacturing order include the identity of each batch or lot of
ingredients, containers, and closures used in producing the batch of
infant formula. All materials used in infant formula will have to meet
the specifications of proposed Sec. 106.40(d) and be identified by a
batch or lot number as specified in proposed Sec. 106.40(c). FDA has
tentatively concluded that it is necessary to propose that the identity
of each batch or lot of ingredients, containers, and closures used in
producing the batch of infant formula be recorded in the master
manufacturing order to enable the manufacturer to ensure that all of
those materials met the requirements of Sec. 106.40, particularly the
standards for acceptance or rejection of the materials. Recording this
information also will allow the manufacturer to evaluate the
contribution of specific ingredients, containers, and closures to any
problem with a batch of infant formula that may develop.
FDA is not proposing to require that the batch records contain the
results of any tests conducted on ingredients, containers, and closures
in accordance with proposed Sec. 106.40(d) because the same lot of raw
materials may be used in multiple batches. The identification of the
batch or lot of all ingredients, containers, and closures in the master
manufacturing order should be sufficient to allow the manufacturer to
locate and review relevant test results if problems arise with a
particular batch of infant formula.
Proposed Sec. 106.100(e)(1)(iv) requires that the master
manufacturing order include the amount of each ingredient to be added
to the batch of infant formula and a check (verification) that the
correct amount was added. As discussed above, proposed Sec. 106.50(b)
requires that the manufacturer establish controls to ensure that raw
and in-process ingredients required by the master manufacturing order
are examined by one person and checked by a second person or system to
ensure that the correct weight or measure of the ingredient is added to
the batch. The agency has tentatively concluded that recording in the
master manufacturing order the amount of each ingredient added to the
batch of formula, and a check (verification) that the correct amount
was added, are appropriate controls to ensure that the correct weight
or measure of the ingredient is added to the batch. This proposed
requirement is necessary to ensure that there is compliance with
proposed Sec. 106.50(b), to provide a record that the batch of infant
formula includes all of the ingredients in the amounts specified in the
master manufacturing order, and to provide assurance that the product
contains all of the required nutrients.
Proposed Sec. 106.100(e)(1)(v) requires that the master
manufacturing order include copies of all labeling used and the results
of the examinations conducted during the finishing operations to ensure
that containers and packages in the batch are correctly labeled. (The
importance of ensuring that containers are correctly labeled was
discussed in conjunction with proposed Sec. 106.60(b).) The inclusion
in the batch records of copies of the labeling used on each batch of
infant formula will provide a record of such labeling and will document
that the finishing operation examinations, required by proposed
Sec. 106.60(b), are conducted.
Proposed Sec. 106.100(e)(2) requires that the batch record include
any deviations from the master manufacturing order and any corrective
actions taken. While the manufacturer's goal should be to produce the
infant formula in accordance with the master manufacturing order, on
occasion deviations may occur. On these occasions, the deviations, and
any corrective actions taken because of the deviations, should become a
part of the batch record. For example, if a batch of liquid infant
formula was thermally processed at a different temperature than the
temperature specified in the master manufacturing order, the batch
record would state the actual processing temperature. The record would
also state any corrective actions taken because of this processing
temperature, such as a change in processing time. A record of
deviations from the master manufacturing order and of the corrective
actions taken by the manufacturer will allow the manufacturer to
quickly determine whether all deviations have been appropriately
addressed, and if they have not been, whether the actions needed to
correct the deviations have been identified. It will also provide
relevant information if a problem arises with that batch of infant
formula.
Proposed Sec. 106.100(e)(3) requires that the batch records include
documentation of the monitoring at any production and in-process
control point, step, or stage where control is deemed necessary to
prevent adulteration. As discussed above, proposed Sec. 106.6(c)(2)
requires this monitoring. FDA is proposing that the documentation that
the monitoring required by proposed Sec. 106.6(c)(2) is occurring be
included in the batch records to ensure that a measurement or
observation made at one particular point in time can be related to a
particular batch. The linkage of the record to the batch is especially
important when a standard or specification is not met. It will enable
the manufacturer to determine what batches may have been affected by a
deviation and to take appropriate action, such as withholding a batch
from distribution.
Proposed Sec. 106.100(e)(3)(i) requires that the batch records
include a list of the standards or specifications established at each
point, step, or stage in the production process where control is deemed
necessary to prevent adulteration, and that it include documentation of
the scientific basis for each standard or specification. As discussed
above, proposed Sec. 106.6(c)(1) requires the establishment of such
standards or specifications. The agency has tentatively concluded that
a list of these standards or specifications must be a part of the batch
record so that the manufacturer will have them readily
[[Page 36191]]
available to compare to the actual values obtained during the
monitoring operation of the production and in-process control system.
Also, the documentation of the scientific basis for each standard or
specification will verify that each was established by trained and
experienced sources. Such documentation will summarize the work
performed to establish the standard or specification and will establish
the source used. If changes to the standard or specification become
necessary, this documentation of the scientific basis for each standard
or specification will assist the manufacturer in making such changes.
Proposed Sec. 106.100(e)(3)(ii) requires that the batch records
include the actual values obtained during the monitoring (such as the
actual temperatures and actual times that the measurements were taken),
any deviations from the established standards or specifications, and
any corrective actions taken. For example, notations that refrigeration
temperatures are satisfactory or unsatisfactory, without a record of
the actual temperatures, are subject to varying interpretation and thus
will not ensure that preventive controls are working. It is important
that the actual values be recorded. In addition, actual values are
necessary to discern trends or to pinpoint the onset of a problem. The
record of any corrective actions taken will show what the manufacturer
did when a standard or specification was violated, and how the
manufacturer is ensuring that the infant formula is not adulterated.
Entry of information on the records at the time of the monitoring
ensures that the record does not rely on the memory of the observer and
thus is as accurate and valid as possible.
Proposed Sec. 106.100(e)(3)(iii) requires that the batch records
identify the person monitoring each point where control is deemed
necessary to prevent adulteration. FDA has tentatively concluded that
it is important that the responsible individuals be identified in the
batch record so that the manufacturer can check that a qualified person
is actually monitoring the point, step, or stage where control is
deemed necessary to prevent adulteration, and so that such individual
can be contacted if a problem with a batch of infant formula is
identified at a later date. These individuals are in the best position
to know of any other information that may not have seemed pertinent at
the time but, in retrospect, could be important in identifying the
cause of the problem and initiating actions to prevent it from
recurring.
Proposed Sec. 106.100(e)(4) requires that the batch records include
the conclusions and followup, along with the identity, of the qualified
individual who investigated any deviations, or failures to meet
specifications, that occurred during the production of the batch. Under
these proposed regulations, individuals qualified by training or
experience must conduct an investigation of any deviation from the
master manufacturing order and of the corrective actions taken
(Sec. 106.50(a)(2)); conduct an investigation of a finding that a batch
or any of its ingredients failed to meet any manufacturer's
specifications (Secs. 106.40(d) and 106.70(c)); and conduct an
investigation of a failure to meet any specification or standard at any
point where control is deemed necessary to prevent adulteration
(Sec. 106.6(c)(4)).
FDA has tentatively concluded that the record of the conclusions
and followup of these investigations is necessary to enable the
manufacturer to ensure that it has complied with proposed
Secs. 106.6(c)(4), 106.40(d), 106.50(a)(2), and 106.70(c). Such records
will provide information on how the production of the batch of infant
formula deviated from established standards or specifications and on
the cause of any problem with the formula, if infants are reported to
have been adversely affected by the product at a later date.
Identification of the qualified individual who conducted the
investigations will ensure that there is responsibility and
accountability for the investigation and will allow the responsible
individuals to be contacted, if necessary. These individuals will be in
the best position to provide information if additional details about
the record are needed.
Proposed Sec. 106.100(e)(5) requires that the batch records include
the results of all testing performed on the batch of infant formula,
including testing on the in-process batch, at the final-product stage,
and on finished product throughout the shelf life of the product.
Section 412(b)(2)(B) of the act requires that manufacturers conduct
such testing. FDA has tentatively concluded that the assembly of such
records in one place will enable the manufacturer to ensure that the
batch of infant formula complies with proposed Secs. 106.55 and 106.91
and will facilitate the review of the test results in the event that a
problem arises with the batch.
Proposed Sec. 106.100(e)(5)(i) states that the batch records are to
include the results of any quality control testing conducted, in
accordance with proposed Sec. 106.91(a) and (b), to verify that each
nutrient required by Sec. 107.100 is present at the required level, and
that any nutrient added by the manufacturer is present at the
appropriate level. Including the results of this testing in the batch
records will provide data needed to evaluate compliance of the batch of
infant formula with proposed Sec. 106.91, and provide data needed to
evaluate a batch of infant formula if problems, such as adverse events
in infants, occur later with that particular batch. These records will
show the levels of nutrients in the formula and will provide
information to help the manufacturer determine whether any problems
associated with the formula are attributable to the nutrient levels in
the product.
Proposed Sec. 106.100(e)(5)(i)(A) requires that manufacturers
maintain a summary table in the batch record that identifies the stages
of the manufacturing process at which the nutrient analysis is
conducted for each nutrient, in accordance with proposed
Sec. 106.91(a). As discussed above, proposed Sec. 106.91(a) provides
flexibility in the stage at which many of the nutrients are tested. A
summary table will facilitate the manufacturer's compliance with
quality control procedures because it will allow a manufacturer to
quickly verify that it has tested for all the nutrients required by
Sec. 107.100 during the production of the infant formula.
Proposed Sec. 106.100(e)(5)(i)(B) requires that the quality control
records in the batch record include a summary table on the stability
testing program, conducted in accordance with proposed Sec. 106.91(b),
including the nutrients tested and the frequency of testing of
nutrients throughout the shelf life of the product. As discussed above,
proposed Sec. 106.91(b) requires that manufacturers test infant formula
at the beginning, midpoint, and end of the shelf life, and with
sufficient frequency to ensure that the manufacturer is aware if there
is a significant deterioration in the required level of a nutrient.
Therefore, proposed Sec. 106.91(b) provides flexibility in the testing
frequency, depending on the shelf life and the characteristics of the
product. A summary table will facilitate the manufacturer's compliance
with quality control procedures because it will allow a manufacturer to
quickly determine whether it has tested for all the nutrients required
by Sec. 107.100 with sufficient frequency to verify that the ``use by''
date on the formula is appropriate.
Proposed Sec. 106.100(e)(5)(ii) requires that the batch records for
powdered infant formula include the results of any testing conducted in
accordance with proposed Sec. 106.55(b) to document that the tests were
done and to verify compliance with the microbiological
[[Page 36192]]
quality standards in proposed Sec. 106.55(c). As discussed above,
proposed Sec. 106.55(b) requires that manufacturers test representative
samples of each batch of powdered infant formula to ensure that the
batch meets the microbiological quality standards in proposed
Sec. 106.55(c) and therefore is not adulterated. This record will also
provide the manufacturer with data to evaluate adverse events that
infants may have experienced after consuming this batch of infant
formula by showing whether microbiological contamination could have
contributed to the adverse event.
3. CGMP Records
Proposed Sec. 106.100(f) identifies the records that manufacturers
must make and retain pertaining to CGMP described in proposed subpart B
of part 106. Section 412(b)(4)(A)(i) of the act requires the
establishment by regulation of requirements for the retention of all
records necessary to demonstrate compliance with the CGMP, including
testing designed to prevent the adulteration of infant formula. FDA has
already discussed proposed regulations (proposed Sec. 106.100(e))
respecting the retention of records relating to each batch of infant
formula. FDA also is proposing regulations respecting the retention of
records relating to the overall operation of the plant and the
maintenance of equipment, because these records are necessary to
demonstrate that the infant formula was manufactured in a manner
designed to prevent adulteration. Maintenance of these records will
help manufacturers identify trends in the processing of the infant
formula, in particular trends that show when the process is breaking
down in a way that will lead to the production of adulterated product.
These records also will provide information to assist the manufacturer
in tracking the cause of adverse events to a formula, if such events
are reported.
Proposed Sec. 106.100(f)(1) requires that manufacturers make and
retain records of the frequency and results of the testing of water
used in the production of infant formula. These records will show if
problems are starting to develop with the water supply so that
manufacturers can take corrective actions before the water is
inappropriate for use in infant formula.
Proposed Sec. 106.100(f)(2) requires that manufacturers make and
retain records, in accordance with Sec. 106.30(d), of accuracy checks
on instruments and controls. Under this proposal, these records must
include a certification of the accuracy of any known reference standard
used and a history of its recertification. As discussed previously, the
accuracy of the reference standard must be ensured before it can be
used to ensure that the production instruments are properly calibrated.
These records also will provide information to assist the manufacturer
in tracing the source of a problem, if one arises, with a batch of
infant formula. For example, if infants have adverse events to a batch
of infant formula, records containing a certification of accuracy of
the reference standards used and a history of their recertification
would assist the manufacturer in determining whether the problem was
created because a production instrument was calibrated with an
inaccurate reference instrument.
FDA is proposing to require that, at a minimum, the records 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. These records will enable the manufacturer to determine, based on
the performance of the instrument, whether the calibration schedule is
sufficient to ensure the accuracy of the instrument. These records also
will provide information on when and how the instruments were
calibrated to assist the manufacturer in identifying the cause of a
problem, if one arises, with a batch of infant formula.
Including the date of the accuracy check in the record will permit
a determination of the accuracy of the instrument or control over time;
including the standard used will allow the manufacturer to verify that
the standard was properly calibrated; and including the calibration
method used will ensure that the instrument is being calibrated free
from the variability that can occur when different laboratory personnel
perform the same calibration. The results of the accuracy check in the
record will show whether the instrument or control is accurate, or
whether a correction was necessary. Documenting the actions taken if
the instrument is found to be out of calibration will enable the
manufacturer to ensure that a correction was made. Requiring that the
individual performing the test note his or her initials or name in the
record will document who was last responsible for ensuring the accuracy
of the instrument or control and will allow the manufacturer to discuss
questions that may arise about the record with the person in the best
position to know additional, but unrecorded, details about the record.
If calibration of an instrument shows that a specification or
standard, 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 of any actions that
need to be taken with respect to that product, needs to be made. For
example, if the manufacturer is monitoring temperature to ensure that a
specification or standard of 250 deg.F is maintained as a minimum
temperature, and calibration of the temperature indicating instruments
against a reference standard reveals that it was reading a true
temperature of 248 deg.F, an evaluation of the health hazard
significance of this temperature deviation must be made. This proposed
requirement is necessary because, if an instrument is found to have
been giving inaccurate readings, all infant formula produced subject to
such inaccuracies must be identified and evaluated for the possibility
that the inaccuracies caused the formula to be adulterated. In
identifying the affected product to ensure that the health of
potentially affected infants is fully protected, in the absence of
evidence to the contrary, such evaluation would cover all product
manufactured since the last time the instrument was calibrated and
found to be accurate.
Proposed Sec. 106.100(f)(3) requires that manufacturers make and
retain records, in accordance with proposed Sec. 106.30(e)(3)(ii), of
the temperatures monitored for cold storage compartments and thermal
processing equipment. These records are needed to show that the thermal
processing equipment or cold storage compartments are being maintained
at the correct temperatures to prevent adulteration of the product. The
records of these temperatures will enable the manufacturer to identify
trends in temperature fluctuations that can signal the need to perform
nonscheduled maintenance.
FDA is proposing in Sec. 106.100(f)(4) that equipment cleaning,
sanitizing, and maintenance records, showing the date and time of
maintenance, as well as the lot number of each batch of infant formula
processed between equipment startup and shutdown for cleaning,
sanitizing, and maintenance, be made and maintained. These records will
allow the manufacturer to ensure that equipment and utensils are being
cleaned and maintained regularly and to check that the frequency of
such cleaning, sanitizing, and maintenance is appropriate in light of
the actual, as
[[Page 36193]]
opposed to planned, use of the equipment. For example, a manufacturer
may need to increase the frequency of cleaning, sanitizing, and
maintenance if actual rate of production consistently exceeds the
predicted rate of production. These records also will allow the
manufacturer to trace all formula that may be affected if evidence
becomes available that a particular cleaning, sanitizing, or
maintenance was improperly performed.
Proposed Sec. 106.100(f)(4) also requires that the person
performing and checking the cleaning, sanitizing, or maintenance date
and sign or initial the record indicating that the work was performed.
Identification of the person performing and checking the cleaning,
sanitizing, or maintenance will allow the manufacturer to ensure that a
qualified person is doing these tasks and to discuss questions that may
arise about the record with the person in the best position to know
additional, but unrecorded, details about the record.
Proposed Sec. 106.100(f)(5) requires that manufacturers make and
retain records, in accordance with Sec. 106.35(c), on all automatic
(mechanical or electronic) equipment used in the production or quality
control of infant formula. Proposed Sec. 106.100(f)(5)(i) requires that
the automatic equipment records include a list of all systems used,
with a description of computer files and of the inherent limitations of
each system. The manufacturer cannot effectively operate the system,
and correct problems that arise, if it does not understand the system.
It is not always possible for the individuals who developed and best
understand the system to be present when the system is operating.
Therefore, these records will enable the manufacturer to operate and
troubleshoot the systems even when the individuals who best know the
system are not available.
Proposed Sec. 106.100(f)(5)(ii) requires that the automatic
equipment records include a copy of all software used. Having a copy of
all software used will minimize the manufacturer's down time if
problems occur, and parts of the software are lost from the system. For
example, if a computer virus is found in the software used to run the
processing lines, having a copy of the software to reload into the
hardware will minimize the time lost. Likewise, if there is a problem
with the software used to perform quality control testing, having
copies of this software will ensure that the testing can continue with
a minimum amount of time lost.
Proposed Sec. 106.100(f)(5)(iii) further requires that the
automatic equipment records document installation, calibration, testing
or validation, and maintenance of the systems used. These requirements
are necessary for compliance with section 412(b)(4)(A)(i) of the act.
As discussed more fully above with respect to proposed Sec. 106.35
(b)(1), (b)(2), and (b)(4) CGMP requires that all systems be installed,
calibrated, and maintained in a manner necessary to ensure that they
are capable of performing their intended function and of producing or
analyzing infant formula as intended, and that all systems be validated
before their first use to manufacture commercial product. In addition
to documenting that the manufacturer is complying with CGMP, records
documenting installation, calibration, testing or validation, and
maintenance of systems are necessary to provide information if the
manufacturer later tries to determine why a problem with the system is
occurring or tries to determine why the system is not producing an
infant formula that complies with the manufacturer's specifications for
the product.
Proposed Sec. 106.100(f)(5)(iv) requires that the automatic
equipment records include a list of all persons authorized to create or
modify software. This record will help to minimize delays when the name
of a person with those skills is needed quickly.
Proposed Sec. 106.100(f)(5)(v) requires that the automatic
equipment records document modifications to software, including the
identity of the person who modified it. This documentation will ensure
that the manufacturer is aware of any changes made to the software, and
that it has a record of how the changed system works, so that it can
continue to operate the system even in the absence of the responsible
individual who made the modification to the system. A record of the
identity of the person who modified the software will show who was
responsible for modifying the software if problems arise with the
operation of the system and will identify the person in the best
position to know additional, but unrecorded, details about the software
modification to help in troubleshooting the software problems.
Proposed Sec. 106.100(f)(5)(vi) requires that the automatic
equipment records include documentation of retesting or revalidation of
modified systems. This proposed requirement is necessary for compliance
with section 412(b)(4)(A)(i) of the act. As discussed more fully above
in the section on proposed Sec. 106.35(b)(5), CGMP requires that all
modifications to software be made by a designated individual, and that
all systems be revalidated after any modification to ensure that infant
formula produced or analyzed using the modified software complies with
subparts B and C. FDA has tentatively concluded that records on
retesting or revalidation of the modified systems, just like records on
the initial testing or validation of the system
(Sec. 106.100(f)(5)(iii)), are necessary to document that the work has
been done properly and to provide information if the manufacturer later
tries to determine why a problem with the system is occurring or tries
to determine why the system isnot producing an infant formula that
complies with the manufacturer's specifications for the product.
Proposed Sec. 106.100(f)(5)(vii) requires that the manufacturer
make and retain a backup file of data entered into a computer or
related system. It also requires that this backup file consist of a
hard copy or alternative system, such as duplicate diskettes, tapes, or
microfilm, designed to ensure that backup data are exact and complete,
and that they are secure from alteration, inadvertent erasures, or
loss. This proposed requirement is necessary to ensure compliance with
CGMP because computer files can be easily altered or erased. Backup
files of data will allow the manufacturer to readily reload the files
of data if problems occur in the operation of the computer or related
system, so that the manufacturer's down time is minimized, and so that
the data entered into the system will be an exact copy of the data
previously used in the system.
Proposed Sec. 106.100(f)(6) requires that manufacturers make and
retain records on ingredients, containers, and closures, including the
identity and quantity of each lot, the name of the supplier, the
supplier's lot number, the name and location of the manufacturer (if
different from the supplier), the date of receipt, and the receiving
code as specified (proposed Sec. 106.100(f)(6) (i) through (vi)). These
records will enable the manufacturer to document that it is complying
with proposed Sec. 106.40(g). Moreover, this information is needed to
enable the manufacturer to track the source of each ingredient,
container, or closure used in infant formula if a problem arises. If an
ingredient, container, or closure is found to cause adulteration of the
formula, it is important to be able to determine the source of the
material, so that use of such materials can be halted and prevented in
the future.
Proposed Sec. 106.100(f)(6)(vii) requires that the records on
ingredients, containers, and closures include the results and
conclusions of any test or examination, including retesting and
[[Page 36194]]
reexamination, performed on them and their disposition. These records
will document that appropriate testing is being conducted to ensure
that the ingredients will not adulterate the infant formula, and that
the containers and closures will protect the infant formula against
adulteration. Further, these records will show the basis on which each
ingredient, container, and closure was released for use in infant
formula production if questions about such release later arise.
Individual lots of ingredients, containers, and closures are likely to
be used in a number of different batches of infant formula; therefore,
the agency is proposing that the records on ingredients, containers,
and closures be a part of the records pertaining to CGMP. Retaining
such records in the CGMP records, rather than in each batch record,
will eliminate the duplication of records and simplify the
recordkeeping. The disposition of the ingredients, containers, and
closures will show which materials were destroyed because they did not
meet the manufacturers specifications (and not used in manufacture in
compliance with Sec. 106.40(d)), and which batches of infant formula
were made using each lot of ingredients, containers, or closures. Thus,
the manufacturer will know which lots of ingredients, containers, or
closures were used in making infant formula and will be able to confirm
that those lots complied with proposed Sec. 106.40(d). Moreover, if a
batch of formula is shown to be adulterated, these records will help
the manufacturer to identify the source of the adulteration.
Proposed Sec. 106.100(f)(7) requires that manufacturers make and
retain records that include a full description of the methodology used
to test powdered infant formulas to verify compliance with proposed
Sec. 106.55(c) and the methodology used to conduct quality control
testing in accordance with Sec. 106.91 (a) and (b). The agency has not
specified in these regulations the methodologies that must be used to
conduct microbiological and quality control testing. Thus, FDA has
tentatively concluded that a manufacturer needs to maintain a record
that fully describes the methodology that it has decided to use to test
powdered infant formula for microorganisms and for quality control
testing. Such a record is necessary if there is to be consistency in
the procedure that the manufacturer follows in testing each batch of
infant formula, particularly in light of the fact that the laboratory
personnel conducting the testing are likely to vary. The accuracy and
reproducibility of microbiological and quality control testing depend
on the procedure used to conduct the test.
FDA is proposing that the full description of the methodology be
retained as part of the CGMP records, rather than in the batch record
provided for in proposed Sec. 106.100(e)(5), because these methods will
be used to test multiple batches of infant formula. Retaining such
records in the CGMP records, rather than in each batch record, will
mean that the manufacturer has to maintain only one document, rather
than having to reproduce it each time that it runs a batch of formula.
Thus, the proposed approach will eliminate duplication of records and
simplify recordkeeping.
4. Records on Distribution of Infant Formulas
Proposed Sec. 106.100(g) adds to current Sec. 106.100(g) a
requirement that records pertaining to distribution of the infant
formula show that products intended for export only are in fact
exported. It has recently come to the attention of the agency that
infant formulas produced for export have been diverted and sold in the
United States. All persons introducing any new infant formula into
interstate commerce, which includes persons exporting an infant formula
to a foreign country, are required by section 412(c) of the act to
register and make a submission to the agency 90 days before marketing
the formula. (See discussion of proposed Secs. 106.110 and 106.120.)
As discussed in the section of this preamble on proposed
Sec. 106.120(c), the agency has tentatively concluded that it will not
require manufacturers who produce infant formula for export only to
submit the same information that would be required for products
intended or offered for sale in the United States. In lieu of the
information required by Sec. 106.120(b), FDA is proposing to allow
manufacturers of products for export only to give assurances that the
infant formula will not be sold or offered for sale in domestic
commerce. This provision is based, in part, on section 801(e) of the
act, which states that a food will not be deemed to be adulterated or
misbranded under the act if, among other things, it is not sold or
offered for sale in domestic commerce. Thus, the agency has tentatively
concluded that the additional recordkeeping requirement on distribution
of infant formulas for export only in proposed Sec. 106.100(g) is
necessary so that verification that the infant formula was not in fact
sold or offered for sale in domestic commerce will be readily available
in the manufacturer's records.
5. Audit Records
Proposed Sec. 106.100(j) carries forward the requirement in current
Sec. 106.100(j) that the manufacturer make and retain records, which
include the audit plans and procedures, that pertain to regularly
scheduled audits. As discussed above, the written audit plan, which
includes audit procedures, is required under proposed Sec. 106.94(a)
and (b). The proposed section further requires that records of audits
include the findings of the audit and a listing of any changes made in
response to these findings. This requirement is proposed under the
authority of section 412(b)(4)(A)(v) of the act, which requires that
manufacturers retain all records of the results of regularly scheduled
audits conducted under the requirements prescribed by the Secretary
(and by delegation, FDA) under the authority of section
412(b)(2)(B)(iv).
Proposed Sec. 106.100(j) also requires that the manufacturer make
readily available for authorized inspection the audit plans and
procedures and a statement of assurance that the regularly scheduled
audits are being conducted. This provision implements section
412(b)(4)(B)(ii) of the act, which requires that the manufacturer
provide written assurance that the regularly scheduled audits are being
conducted by the manufacturer. However, proposed Sec. 106.100(j) also
provides that the findings of the audit and any changes made in
response to these findings need not be made available to FDA. This
provision is brought forward from current Sec. 106.100(j) and reflects
section 412(b)(4)(B)(ii) of the act, which states that a ``manufacturer
need only provide written assurances to the Secretary that the
regularly scheduled audits required by'' section 412(b)(2)(B)(iv) of
the act ``are being conducted by the manufacturer, and need not make
available to the Secretary the actual written reports of such audits.''
6. Modification of Current Sec. 106.100(k)(3)
The agency also is revising current Sec. 106.100(k)(3) to reflect
the numbering changes in the regulations on notifying the agency of a
causal relationship between the consumption of an infant formula and an
infant's death. The agency is moving the requirements of current
Sec. 106.120(b) to Sec. 106.150 to reflect the changes it is proposing
in subpart G. Thus, the reference to Sec. 106.120 in Sec. 106.100
(k)(3) will be changed to read ``Sec. 106.150,'' if the
[[Page 36195]]
agency adopts the relevant proposed changes.
G. Registration, Submission, and Notification Requirements
1. Introduction
The act provides for three types of notices that manufacturers of
infant formula must provide to FDA and sets forth the general
information that must be included in each type of notice. First,
manufacturers of a new infant formula must register with FDA, in
accordance with section 412(c)(1)(A) of the act, providing the name and
address of the firm and all establishments that will manufacture the
new infant formula. Second, manufacturers must submit to FDA, in
accordance with section 412(d) of the act, certain information
concerning a new infant formula or an infant formula in which there is
a change in formulation or processing that may affect whether the
formula is adulterated under section 412(a) of the act. Third,
manufacturers must notify FDA, in accordance with section 412(e) of the
act, of any adulterated or misbranded infant formula that has left
their control.
The agency has not specified the information that must be included
in an infant formula registration, submission, or notification. While
firms have been able to function under these requirements since the
1986 amendments were enacted with respect to the notice that
manufacturers must provide to the agency under section 412(c) and (d)
of the act, inquiries from industry suggest that manufacturers are
uncertain about the information that they must provide. Some
manufacturers have needed to make multiple submissions for a new infant
formula because of deficiencies in the initial submission. For example,
some submissions have contained information concerning more than one
formula without clearly identifying which information applied to which
formula. Some submissions have not contained the information required
by section 412(d)(1) of the act. Therefore, FDA recognizes that it will
be useful both to manufacturers and to the agency to issue regulations
to ensure that registrations and submissions required by the act follow
a consistent format and contain the necessary information for the
agency to determine whether there is a basis to object to the marketing
of a new infant formula. Such regulations will facilitate the
manufacturer's preparation of the notice and also will facilitate the
agency's review of the notice once FDA receives it.
These proposed regulations also will make clear when a
registration, notification, or submission to the agency is needed. For
example, as stated above, it has recently come to the attention of the
agency that some firms that manufacture infant formula intended only
for export are not aware of their registration and submission
responsibilities. Section 412(c)(1) of the act requires that a person
introducing a new infant formula into interstate commerce (which
includes export to a foreign country) must register the infant formula
and make the proper submission 90 days before marketing it. These
proposed regulations make clear that registration and submission
requirements apply to infant formulas intended only for export as well
as to infant formula intended for the domestic market.
Finally, for completeness, FDA has decided that it would be useful
to both manufacturers and the agency, to carry forward current
Sec. 106.240, concerning notification of a violative infant formula, as
Sec. 106.150. Doing so will consolidate in one place in the agency's
regulations all requirements concerning notice to the agency to meet
the requirements of section 412(c), (d), and (e) of the act.
2. New Infant Formula Registration
Proposed Sec. 106.110(a) requires that a manufacturer of a new
infant formula register with FDA before introducing the formula, or
delivering it for introduction, into interstate commerce. Because
``interstate commerce'' is defined in section 201(b) of the act as
``(1) commerce between any State or Territory and any place outside
thereof, and (2) commerce within the District of Columbia or within any
other Territory not organized with a legislative body,'' under this
provision, a manufacturer is required to register with FDA before
introducing a new infant formula into the United States market or
before beginning exporting the formula. Proposed Sec. 106.110(a) sets
out how to comply with section 412(c)(1)(A) of the act. Failure to
provide the notice required by section 412(c)(1)(A) of the act is a
prohibited act under section 301(s).
Under section 412(c)(1)(A) of the act, proposed Sec. 106.110(b)
sets out the information required in a new infant formula registration.
While manufacturers may register at any time before introducing a new
formula into interstate commerce, FDA urges that they do so at the same
time that they submit notice of their intent to market a new infant
formula in accordance with section 412(c)(1)(B) and (d)(1) of the act.
Receiving registration and the 90 day submission at the same time will
facilitate the agency's review.
3. New Infant Formula Submission
Section 412(c)(1)(B) of the act requires that manufacturers of a
new infant formula submit to FDA a notice of their intent to market the
new formula that complies with section 412(d)(1) of the act. The notice
must be submitted at least 90 days before the infant formula is
introduced or delivered for introduction into interstate commerce
6. Proposed Sec. 106.120 implements this requirement.
---------------------------------------------------------------------------
\6\ While section 412(c)(1) and (c)(1)(B) of the act state ``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'' section 412(c)(1) of the act, FDA has
recognized since 1986 that this citation is in error (see
``Requirements for Infant Formulas'' published by FDA's Industry
Programs Branch, CFSAN), and that the correct citation is section
412(d)(1). This correction agrees with the language of section
412(d)(1) of the act, which states what a submission about any
infant formula subject to section 412(c) of the act should include.
It is also consistent with the rules of statutory construction. See
Colonial Life & Accident Insurance Co. v. American Family Life
Assurance Co., 846 F. Supp. 454, 463 n. 14(D.S.C. 1994) (where the
legislature has made a mistake in reference, and its intent is
manifest, the statute may be read as corrected in order to give
effect to the legislative intent).
---------------------------------------------------------------------------
Proposed Sec. 106.120(a) sets out the requirement that a
manufacturer submit a notice of its intent to market a new infant
formula and provides the address to which such notices are to be
submitted.
Proposed Sec. 106.120(b) sets forth the information that
manufacturers must include in their new infant formula submission. This
proposed regulation implements and specifies the information called for
in section 412(d)(1) of the act.
a. General information required in a 90-day submission. Because the
registration of a new infant formula (proposed Sec. 106.110) need not
accompany the new infant formula submission (proposed Sec. 106.120),
and because a third submission on a newinfant formula that verifies
that the new infant formula, as produced, contains all required
nutrients (see proposed Sec. 106.130) will be submitted separately, FDA
has tentatively concluded that the name of the infant formula is needed
to ensure that all information on a particular infant formula is filed
together and is available to determine whether the agency should object
to the marketing of the formula. Information on the form of the product
is necessary for an accurate evaluation of the product because
different
[[Page 36196]]
requirements may apply to different forms of a formula. For example,
powdered infant formula must meet the microbiological quality
requirements in proposed Sec. 106.55, whereas liquid forms of a formula
do not. Therefore, FDA is proposing to require this information in
Sec. 106.120(b)(1), under the authority of sections 412(d)(1) and
701(a) of the act, even though it is not explicitly required in section
412(d)(1).
Proposed Sec. 106.120(b)(2) requires that the submission include an
explanation of why the formula is a new infant formula to facilitate a
determination by the agency as to the type of evaluation the new infant
formula requires. For example, if the formula is a new infant formula
because a new manufacturing plant will be used to produce it, but the
formulation of the product is not changed, FDA will evaluate the
processing and arrange to inspect the new facility but may conclude
that testing to provide assurance that quality factor requirements have
been met is not necessary. Thus, FDA is proposing to require the
submission of this information, even though, like the information
required under proposed Sec. 106.120(b)(1), submission of this
information is not specifically provided for in the act. The agency
tentatively concludes that this information is necessary for the
efficient enforcement of sections 412(c)(1)(B) and (d)(1) of the act.
b. Formulation and processing information required in a 90-day
submission. Pursuant to section 412(d)(1)(A) of the act, proposed
Sec. 106.120(b)(3) requires that the submission include the
quantitative formulation of the infant formula. The agency is proposing
that, if the notice concerns more than one form of the formula, the
submission include quantitative information on each form of the formula
that is the subject of the notice. FDA is proposing to require that
manufacturers submit the formulation in units per volume (for liquid
formulas) or units per dry weight (for powdered formulas) because
formulations expressed in these units will facilitate agency
understanding of the formula. Manufacturers already will have the
formulation available in these units as a part of the master
manufacturing order, and submitting the formulations in these units
should not require additional calculations by the manufacturer.
Proposed Sec. 106.120(b)(3) also requires, under section
412(d)(1)(B) of the act, that the submission include 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. For example, if the
protein source in an infant formula is replaced with a protein source
that contains a different amount of protein (e.g., from casein to a
mixture of casein and whey), it is important to ensure that the amount
of the new protein source used will provide the amount of protein
required by Sec. 107.100. As another example, if an ingredient such as
sodium selenite is added to the formula for the first time, it is
important to ensure that the level of the ingredient provides selenium
(in the form of selenite) at a level that is consistent with the
infant's needs and yet within the safe range of selenium intake.
Proposed Sec. 106.120(b)(4) requires that the submission include a
description, when applicable, of any change in processing of the infant
formula, and that such description identify the specific change in
processing, including side-by-side, detailed schematic diagrams
comparing the new processing to the previous processing (including
processing times and temperatures). This proposed requirement
implements section 412(d)(1)(B) of the act, which states that the
submission must include a description of any change in the processing
of an infant formula. FDA is proposing that the description of the
change in processing include detailed schematic diagrams comparing the
new processing to the previous processing because schematic diagrams
are efficient tools for identifying the nature and significance of
changes in processing.
c. Assurance that the infant formula will not be marketed unless it
meets quality factor and nutrient requirements of the act. Pursuant to
section 412(d)(1)(C) of the act, proposed Sec. 106.120(b)(5) requires
that the submission include an assurance that the infant formula will
not be marketed unless it meets the quality factor requirements of
section 412(b)(1) of the act and the nutrient content requirements of
section 412(i) of the act.
Proposed Sec. 106.120(b)(5)(i) requires that the assurance that the
formula meets the quality factor requirements, which are set forth in
subpart E of part 106, be provided by a submission that complies with
Sec. 106.121. Section 412(d)(1)(C) of the act requires that, 90 days
before marketing a new infant formula, a manufacturer submit assurances
that the infant formula will not be marketed unless it meets the
quality factor requirements established by regulations under section
412(b)(1). Section 412(d)(2) of the act requires that, after the first
production of a new infant formula and before introduction into
interstate commerce of such formula, the manufacturer submit a written
verification that summarizes test results and records demonstrating
that such formula complies with the quality factor requirements.
However, FDA has tentatively concluded that to implement sections 412
(d)(1) and (d)(2) of the act in a way that ensures that the statutory
goals are achieved--that is, to ensure that the agency has all the
relevant information for a sufficient period of time to conduct a
meaningful review of the nutritional adequacy of the formula while
enabling the infant formula manufacturer to market its product as
expeditiously as possible--it is appropriate to require that the
assurances that the quality factors will be met be provided by means of
data that would otherwise be required as part of the verification
submission. FDA notes that such a requirement would only codify current
practice. Since passage of the 1986 amendments, infant formula
manufacturers have been providing data demonstrating that a new infant
formula meets the quality factor requirements as a part of the
submission made 90 days before marketing.
Proposed Sec. 106.120(b)(5)(ii) requires that the assurance that
the formula complies with the nutrient content requirements, which are
set forth in Sec. 107.100, be provided by a statement assuring that the
formula will not be marketed unless it meets the nutrient requirements
of Sec. 107.100, as demonstrated by testing required under subpart C of
part 106.
The agency acknowledges that there is an apparent inconsistency in
how it interprets the word ``assurance'' in section 412(d)(1)(C) of the
act as it relates to assurance that the infant formula meets the
quality factor requirements and assurance that the infant formula meets
nutrient content requirements. FDA has tentatively concluded, however,
that assurance that the formula will meet the quality factor
requirements is a threshold question that must be answered
affirmatively before the effort in setting up the line for first
production of the infant formula would be justified. Therefore, the
agency is proposing to require that the assurance that the infant
formula will meet the quality factor requirements be provided by data
submitted 90 days before marketing the formula.
On the other hand, the agency is proposing that the assurance that
the formula will not be marketed unless it meets the nutrient
requirements of Sec. 107.100 can be provided by a statement to that
effect (as opposed to data) submitted 90 days before marketing of the
formula because the
[[Page 36197]]
data and records demonstrating that the formula complies with the
nutrient requirements of Sec. 107.100 will not be available until the
production line is set up, and the first production of the infant
formula has occurred. FDA will receive verification that the formula
meets the nutrient requirements as a part of the submission required by
section 412(d)(2) of the act (see proposed Sec. 106.130(b)(3), below).
Therefore, FDA has tentatively concluded that it is adequate to receive
a commitment from the manufacturer, 90 days before marketing, that the
infant formula will not be marketed unless it meets the nutrient
requirements of Sec. 107.100.
d. Assurance that the processing of the infant formula complies
with the CGMP and quality control procedures of the act. Under section
412(d)(1)(D) of the act, proposed Sec. 106.120(b)(6) requires that the
submission include assurance that the processing of the infant formula
complies with section 412(b)(2) of the act (CGMP, including quality
control procedures).
Proposed Sec. 106.120(b)(6)(i) requires that the assurance that the
processing of the infant formula complies with section 412(b)(2) of the
act include a statement that the formula will be produced in accordance
with subparts B and C of part 106. This proposed requirement is a
necessary element of the assurance required by section 412(d)(1)(D) of
the act because the requirements for CGMP are set forth in subpart B
and the requirements for quality control procedures are set forth in
subpart C. In the Congressional Record (Ref. 1), Senator Metzenbaum
stated that the amendments to the Infant Formula Act set up
requirements ``which will prevent our Nation's Children from ever again
being threatened by defective baby formula. The most important
provision of this amendment is the simple requirement that each batch
of formula must be tested for each essential nutrient that must be
contained in the formula'' (Ref. 1).
Proposed Sec. 106.120(b)(6)(ii) requires that the assurance that
the processing of the infant formula complies with section 412(b)(2) of
the act include the basis on which the manufacturer has concluded that
each ingredient meets the requirement of proposed Sec. 106.40(a), i.e.,
that the ingredient is an approved food additive, is authorized by a
prior sanction issued by the agency, or is GRAS for its intended use.
The statute provides that the manufacturer submit, 90 days before
marketing a new infant formula, assurance that the processing of the
formula complies with the CGMP regulations, and that the formula is
manufactured in a way that is designed to prevent its adulteration. FDA
has tentatively concluded that, to implement the act in a way that will
ensure that the statutory goals are achieved, that is, to ensure that
the agency has all the relevant information for a sufficient period of
time to conduct a meaningful review of the formula while enabling the
manufacturer to market its product as expeditiously as possible, it is
appropriate to require that the assurance that none of the ingredients
will adulterate the formula be provided by an explanation of how each
ingredient meets proposed Sec. 106.40(a). FDA has tentatively concluded
that this approach is appropriate because, like the evidence that the
formula meets the quality factors, evidence that all the ingredients in
the infant formula are safe goes to a threshold question that must be
answered affirmatively before the effort in setting up the production
line for the first production of the infant formula would be justified.
Moreover, an infant formula manufacturer would want to have information
demonstrating that each of the ingredients in the formula is safe
before marketing the formula, because without such information, a
responsible manufacturer would not include the ingredient in its
product.
FDA will review the new infant formula submission to ensure that a
safe product will be produced (sections 201(s), 402(a)(1) and (a)(2),
and 409 of the act). If the agency is not presented with basis on which
it can be satisfied that the use of an ingredient in an infant formula
will be safe, FDA will not be able to acquiesce in the marketing of the
formula. The legislative history of the 1986 amendments supports that
Congress anticipated that FDA would provide this type of review. In the
Congressional Record of September 27, 1986, Senator Metzenbaum stated:
I continue to be concerned, however, that our food and drug laws
do not differentiate between foods and infant formulas. But they are
fundamentally different. An infant formula is designed as the sole
source of nutrition for a baby. An infant formula is used daily. A
baby must thrive from its content for the first and most formative
months of his or her life. I expect the Secretary to look closely at
whether or not our standards in this area for foods are adequate
standards for infant formula. I have no reason at this time to
suspect that there is a problem here. But I continue to urge the
Secretary to give thorough consideration to the important
distinctions between infant formula and other foods, as well as food
additives which may be used with infant formulas. (Ref. 1)
One way for a manufacturer to satisfy the agency that proposed
Sec. 106.40(a) is met would be for the manufacturer to use only
ingredients that are: (1) Listed as GRAS for such use in 21 CFR part
182 or affirmed as GRAS for such use in 21 CFR part 184 or otherwise
GRAS for such use under the regulations included in those parts; (2)
approved for such use by a food additive regulation; or (3) authorized
by a prior sanction issued by FDA.
Alternatively, the requirements of proposed Sec. 106.40(a) can be
met by a showing that the substance is GRAS within the meaning of
Sec. 170.30 (21 CFR 170.30), which states that ``general recognition of
safety may be based only on the view of experts qualified by scientific
training and experience to evaluate the safety of substances directly
or indirectly added to foods'' (Sec. 170.30(a)). To clarify this point,
Sec. 170.30(a) states that ``[g]eneral recognition of safety requires
common knowledge about the substance throughout the scientific
community knowledgeable about the safety of substances directly or
indirectly added to food.'' The qualified experts can base their views
on either: (1) Scientific procedures, or (2) in the case of a substance
used in food prior to January 1, 1958, through experience based on
common use in food (section 201(s) of the act).
Under Sec. 170.30(b), general recognition of safety based upon
scientific procedures requires the same quantity and quality of
scientific evidence as is required to obtain approval of the ingredient
as a food additive, and it must ordinarily be based on published
studies, which may be corroborated by unpublished studies and other
data and information. If the manufacturer of an infant formula wishes
to use an ingredient because there is general recognition of safety
based upon scientific procedures, FDA is proposing to require in
Sec. 106.120(b)(6)(ii) that the manufacturer include as a part of its
new infant formula 90-day submission the rationale for why the
ingredient is GRAS and the evidence that demonstrates that there is
common knowledge about the safety of the substance throughout the
scientific community knowledgeable about the safety of such substance.
FDA is proposing that this evidence include a bibliography of published
studies, copies of those scientific publications about the substance,
and an explanation as to why, based on the published studies, the use
of the substance in infant formula is GRAS.
Under Sec. 170.30(c)(1), if a substance is GRAS based on common use
in food prior to January 1, 1958, this determination must be based
solely on
[[Page 36198]]
food use of the substance before January 1, 1958, and must ordinarily
be based upon generally available data and information. Thus, GRAS
based on common use in food prior to January 1, 1958, may be determined
without the quantity or quality of scientific procedures required for
approval of a food additive regulation. If the manufacturer of an
infant formula wishes to use an ingredient based solely on food use of
the substance prior to January 1, 1958, it should provide as a part of
the new infant formula 90-day submission the evidence supporting that
the ingredient was in common use in infant formula prior to January 1,
1958, and an explanation of why that use provides the basis for general
recognition of the safety of the substance.
FDA has recognized that it is impractical to list all substances
that are GRAS for their intended use based on their common use in food
prior to 1958 (see 21 CFR 182.1(a)). The agency regards such common
food ingredients as salt, pepper, vinegar, and baking powder as safe
for their intended use. Also, current Sec. 170.30(d) provides that a
``food ingredient of natural biological origin that has been widely
consumed for its nutrient properties in the United States prior to
January 1, 1958, without known detrimental effects, which is subject
only to conventional processing as practiced prior to January 1, 1958,
and for which no known safety hazard exists, will ordinarily be
regarded as GRAS * * *.'' Some ingredients are used in infant formulas
even though they are not listed or affirmed as GRAS by the agency for
their intended use. Vitamin K, for example, is required to be a part of
an infant formula under section 412(i) of the act and, in the form of
phylloquinone, is considered to be safe and suitable for infant
formulas when used in accordance with prescribed levels in
Sec. 107.100, although no source of vitamin K, such as phytonadione or
phylloquinone, has been listed or affirmed as GRAS by the agency.
Likewise, sodium selenite has been added to infant formulas to provide
the amount of selenium that has been determined to be essential for
infants by NAS (Ref. 19). Published experimental and clinical data
provide a basis upon which experts qualified by scientific training and
experience could evaluate the safety of sodium selenite as a source of
selenium for use in infant formula and could conclude that it is safe.
The agency anticipates that other ingredients may be shown to be GRAS
because they are generally accepted sources of substances that are
established as essential for infants by an authoritative body such as
NAS. However, manufacturers should not take this acknowledgment to mean
that they are free to declare that the use of any ingredient they want
to use is GRAS. Any ingredient that cannot meet the standard of
Sec. 170.30 for a GRAS determination will be viewed by the agency as a
food additive, and any infant formula that contains a food additive
that the agency has not approved for use in infant formula is subject
to being acted against by the agency.
If the safety of an ingredient is not expressly recognized in an
FDA regulation, the burden will rest on the manufacturer of the infant
formula to include in its new infant formula submission an explanation
of why the substance is GRAS under Sec. 170.30, along with the
published and other information that provides the basis for that
explanation, in accordance with proposed Sec. 106.120(b)(6)(ii). If the
agency adopts this approach, a failure of the agency to object to a
manufacturer's determination that an ingredient is GRAS in a new infant
formula submission will not constitute a GRAS affirmation by the
agency. However, if FDA knows of no reason to question the safety of an
ingredient to be used in infant formula, the agency will not object to
the manufacturer's relying on its own determination that use of the
substance is GRAS.
e. Submission 90 days before marketing a new infant formula
intended only for export. When a new infant formula is intended only
for export, proposed Sec. 106.120(c) provides that manufacturers may
submit, in lieu of the information required under proposed
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 to be exported, 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. This proposed requirement recognizes that under section
801(e) of the act, in certain limited circumstances, manufacturers may
lawfully export products that are adulterated or misbranded. The
information required under proposed Sec. 106.120(c) will demonstrate
that those limited circumstances exist. FDA has tentatively concluded
that proposed Sec. 106.120(c) will provide manufacturers with the
flexibility allowed under section 801(e) of the act while meeting the
requirements of sections 412(c) and (d) of the act.
f. Submission 90 days before marketing--administrative procedures.
Proposed Sec. 106.120(d) states that the submission will not constitute
notice under section 412 of the act unless it complies fully with
Sec. 106.120(b), and the information that it contains is set forth in a
manner that is readily understandable, so that FDA can complete its
review in a timely manner and advise the manufacturer if it has any
concerns about the marketing of the formula before the 90 days is up.
Proposed Sec. 106.120(d) makes clear that the agency will notify the
submitter if the notice is not adequate because it does not meet the
requirements of sections 412(c) and (d) of the act.
Proposed Sec. 106.120(e) provides that if a new infant formula
submission contains all the information required by proposed
Sec. 106.120(b), FDA will acknowledge its receipt and notify the
manufacturer of the date of receipt, which will be the filing date for
the submission (and the manufacturer will be able to plan those actions
necessary to begin marketing the new formula in reliance on that date).
Further, pursuant to section 412(c)(1)(B) of the act, proposed
Sec. 106.120(e) also requires that the manufacturer not market the new
infant formula until 90 days after the filing date. Congress provided
for 90-day notice so that the agency would have sufficient time to
examine all of the material submitted and decide whether there is any
basis for concern about the marketing of the formula.
Proposed Sec. 106.120(f) makes clear that if the manufacturer
provides additional information in support of a new infant formula
submission, FDA will determine whether it represents a substantive
amendment to the submission, and that, if it does, FDA will assign the
new infant formula submission a new filing date. FDA is proposing to
adopt Sec. 106.120(f) to clarify how it will treat amendments to infant
formula notifications. In the 9 years since the passage of the 1986
amendments, the treatment of additional submissions has been the source
of some confusion. FDA has tentatively concluded that it is necessary
to give a new filing date to a new infant formula submission when a
substantive amendment is made to it so that the agency has time to
examine all of the material submitted and to determine whether there is
any basis for concern about the marketing of the formula.
4. Quality Factor Submission
Proposed Sec. 106.121 sets forth the requirements for specific
information that a manufacturer must submit to
[[Page 36199]]
FDA, in accordance with proposed Sec. 106.120(b)(5), to provide
assurance that the infant formula meets the quality factor requirements
set forth in subpart E of part 106. FDA has tentatively concluded that
agency access to study records and data are necessary so that it can
ensure that study results are meaningfully interpretable, and that the
manufacturer's conclusion that the infant formula meets the quality
factor requirements withstands scientific scrutiny and evaluation.
Failure to adequately document study results and interpretation raises
questions as to the validity of conclusions and could mean that infants
have been unnecessarily subjected to testing procedures.
Proposed Sec. 106.121(a) requires that the manufacturer submit an
explanation, in narrative form, setting forth its conclusions on how
all quality factor requirements of subpart E of part 106 have been met.
This narrative will facilitate the agency's review by summarizing the
results, and their interpretation, that provide the basis on which the
manufacturer has concluded that the quality factor requirements have
been met, or that the subject infant formula is eligible for the
exemptions described in proposed Sec. 106.97(a)(2) and (b)(2).
Proposed Sec. 106.121(b) requires that the manufacturer submit
records that contain the information collected during the study for
each infant enrolled in the study. The measurements and information
collected for each infant enrolled in the study are necessary to an
evaluation of whether the infant formula supported healthy growth.
Proper identification of the records is necessary for proper use and
analysis of the records.
Proposed Sec. 106.121(c)(1) requires that the manufacturer submit a
statistical evaluation of the data from the clinical study, 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. This evaluation forms the basis for the
manufacturer's conclusion as to whether the formula meets the quality
factor requirements. Without knowledge of the statistical basis upon
which the manufacturer drew its conclusions, FDA would not have
sufficient information to evaluate the conclusions reported by the
manufacturer.
Proposed Sec. 106.121(c)(2) requires that the manufacturer submit a
calculation of the statistical power of the study at its completion.
Proposed Sec. 106.97(a)(1)(ii)(E) recommends that the power calculation
used to design the study be included in the study protocol. FDA is
aware that circumstances (e.g., attrition, difficulty in recruiting
sufficient numbers of infants, unexpectedly high measurement error in a
particular variable) may unintentionally result in sample sizes and
feeding group assignments that lack adequate statistical power for
detecting differences between treatment and control groups, regardless
of the apparent adequacy in planning for the study protocol. Reviewers
must be aware of changes in the statistical power of a study so that
they do not inadvertently misinterpret the absence of differences that
occur between different formulas as meaning there are no differences.
Failure to detect differences, if they are real, could result in
erroneously concluding that a formula is safe and suitable for its
intended use when, in fact, it is not. The agency is proposing to
require that the manufacturer submit this calculation to FDA so that
the agency can meaningfully review and interpret the data and study
results contained in the submission.
Proposed Sec. 106.121(d) requires that the manufacturer submit
reports on attrition and on all occurrences of adverse events during
the study.
FDA has tentatively found that information on the occurrence of
adverse events is a critical element of the data that must be evaluated
to determine whether a formula meets quality factor requirements and is
safe and suitable for infants. Adverse events associated with the use
of an infant formula, although unexpected, can be a sign or symptom of
a nutritional inadequacy or of a safety problem with the infant
formula, and failure to use these results could result in inadvertent
release of an unsafe product. Conversely, adverse events can be
unrelated to a formula product (e.g., flu), but their occurrence can
affect the way in which results are interpreted and used. For example,
illnesses can influence the interpretation of growth data and of the
laboratory measurements collected to evaluate the infant formula.
For these reasons, FDA has tentatively concluded that complete
reports, including the results of followup investigations, on the
occurrence of all adverse events during the study, regardless of
whether the adverse events are attributable to the use of the new
infant formula or to some other illnesses, are necessary to properly
evaluate the conclusions drawn from a clinical study (proposed
Sec. 106.121(d)(1)). FDA has tentatively concluded that a complete
report on the occurrence of an adverse event must include
identification of the infant by subject number to permit evaluation of
infant growth measurements; identification of the feeding group to show
whether there is a pattern of adverse events in one feeding group
versus another; and a complete description of the adverse event,
including comparisons of the frequency of occurrence in each feeding
group and information on the health of the infants during the course of
the study, including the occurrence and duration of any illness, that
occurred during the trial, so that it is possible to evaluate the
significance of the illness.
As discussed above, it is very important to be able to evaluate
whether the adverse event is a result of a nutritional quality factor
problem with the formula product. The results and evaluation of the
infant's clinical status are essential to make this evaluation, and the
health of the infant is also relevant to interpreting study endpoints,
for example, growth data. Therefore, knowledge of the infant's health
status is an essential piece of information in evaluating the
circumstances surrounding an observed adverse event associated with use
of a formula product. Thus, FDA has tentatively concluded that
evaluations by a health care professional are necessary to provide the
agency with relevant information on the circumstances surrounding the
adverse event (see Sec. 106.121(d)(2)) to assist the agency in
evaluating the nutritional adequacy and safety of the formula product
for supporting healthy growth in infants. In some cases, this clinical
assessment may be carried out by the infant's health care provider,
rather than the investigators conducting this clinical study, because
some parents will contact the infant's health care provider if the
infant experiences any adverse event during the course of the study.
The agency expects that the study investigators will take sufficient
measures to obtain all available information to enhance the likelihood
of being able to meaningfully interpret the likely relationship of the
adverse event to the formula product and its impact on study
conclusions.
Attrition of infants from a study can result not only from adverse
events and illnesses but also from a variety of reasons having no
bearing on whether the new infant formula meets the quality factor
requirements. For example, an infant enrolled in the study may be
withdrawn from the study because the parents moved from the area. The
effect of attrition on study results, however, must be evaluated in
order to be able to meaningfully
[[Page 36200]]
interpret those results. To properly evaluate the impact of attrition
on study results, FDA must have information that permits it to evaluate
the likely cause of the attrition and its relationship to product use
and study measurements. Therefore, the agency is proposing to require
the submission of this information on attrition under
Sec. 106.121(d)(3).
Proposed Sec. 106.121(e) requires that the manufacturer submit the
results of the Protein Efficiency Ratio. This proposed submission
requirement is necessary to provide assurance that the manufacturer has
complied with proposed Sec. 106.97(b) and to provide assurance that the
infant formula meets the specific quality factor for protein quality.
Under proposed Sec. 106.121(f), the manufacturer is required to
submit a statement certifying that it has collected and considered all
information and data on the ability of the infant formula to meet the
quality factor requirements, and that it is not aware of anything that
would show that the formula does not meet the quality factors. This
proposed requirement is necessary to provide assurance that the
manufacturer has complied with the regulations and considered all
information and data of which it is aware, and that it has not made a
selective submission of information that gives a false impression of
the degree or extent to which a formula meets the quality factor
requirements.
5. Verification Submissions
Proposed Sec. 106.130(a) requires that manufacturers, after the
first production, but before the introduction into interstate commerce,
of a new infant formula, verify in a written submission that the infant
formula complies with the requirements of the act and is not
adulterated. This proposed requirement implements section 412(d)(2) of
the act, which requires the submission of a written verification that
summarizes test results and records demonstrating that a formula meets
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 act. The failure
to provide the notice required by section 412(d) of the act is a
prohibited act under section 301(s) of the act.
Proposed Sec. 106.130(b)(1) requires that the verification
submission include the name of the new infant formula, the filing date
for the new infant formula submission required under proposed
Sec. 106.120, and the identification number assigned by FDA to the new
infant formula submission, so that FDA is able to match the
verification submission with the appropriate new infant formula
submission.
Proposed Sec. 106.130(b)(2) requires that the verification
submission include a statement that the infant formula to be introduced
into interstate commerce is the same as that which was the subject of
the new infant formula submission and for which the manufacturer
provided assurances in accordance with the requirements of proposed
Sec. 106.120. FDA has tentatively concluded that if this statement can
be made by the manufacturer, it means that the assurances that the
manufacturer provided in the new infant formula submission with respect
to the quality factor requirements and the safety of the ingredients
remain relevant and applicable to the product. Thus, no additional
information need be included in the verification to demonstrate
compliance, in accordance with section 412(d)(2) of the act, with
section 412(b)(1) or with this aspect of section 412(b)(2)(A).
Proposed Sec. 106.130(b)(3) requires a summary of test results that
show the levels of each nutrient required by Sec. 107.100 in the
formula and of any nutrient added by the manufacturer. This proposed
requirement is necessary to demonstrate compliance with section 412(i)
of the act. Section 412(i) of the act sets forth those nutrients that
an infant formula must contain in order not to be adulterated, and the
submission of a summary of test results as required by section
412(d)(2), and implemented by Sec. 106.130(b)(3), is necessary to show
that an infant formula, after the first production, contains all of the
required nutrients at the required levels.
FDA has tentatively concluded that it is not necessary to require
that the verification submission summarize test results or records
demonstrating compliance with sections 412(b)(2)(A) and (b)(2)(B)(iii)
of the act because the underlying records will be available for
inspection by FDA. FDA has tentatively concluded that to require the
manufacturer to create a report based on these records would be to
require an unnecessary expenditure of effort. However, the agency is
proposing to require (under Sec. 106.130(b)(4)) that the manufacturer
certify as a part of its verification submission that it has
established procedures that comply with sections 412(b)(2)(A) and
(b)(2)(B)(iii) of the act.
FDA has tentatively concluded that requiring additional test
results or records demonstrating compliance with section
412(b)(2)(B)(i), (b)(3)(A), and (b)(3)(C) of the act would be
unnecessary because such showings would be subsumed in the testing to
show whether the formula meets the requirements of Sec. 107.100 (under
Sec. 106.130(b)(3)).
Proposed Sec. 106.130(c) makes clear the consequences of failing to
comply with Sec. 106.130 and that in such circumstances, the agency
will notify the submitter that the notice is not adequate, and that the
manufacturer has not met the requirements of section 412(d)(2) of the
act.
6. Submissions Concerning a Change in Infant Formula That May
Adulterate the Product
Proposed Sec. 106.140(a) provides that, 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 act, it
shall make a submission to FDA before the first processing of such
formula. This proposed requirement implements section 412(d)(3) of the
act, which requires that manufacturers make the submission to FDA
required by section 412(d)(1) of the act before first processing when
they determine that a change in formulation or in the processing of an
infant formula may affect whether the formula is adulterated under
section 412(a) of the act. Examples of changes that may affect whether
a formula is adulterated under section 412(a) of the act include, but
are not limited to:
(1) A change in the level of an ingredient that does not constitute
a major change but that may affect whether the formula meets the
requirements of section 412(i) of the act (for example, decreasing the
amount of an ingredient such as sodium chloride could affect whether
the formula provides two nutrients required by Sec. 107.100);
(2) A change in an ingredient in an infant formula that does not
constitute a major change but that may affect whether the formula meets
the quality factor requirements of subpart E of part 106 (for example,
a change in the level of an emulsifier could result in a change in the
bioavailability of fat because the emulsifier may interfere with fat
digestion); or
(3) A change in the processing of the infant formula that does not
constitute a major change but that may affect whether the CGMP
requirements or the quality control procedures of subparts B and C of
part 106 are met (for example, a change in the processing of the infant
formula may affect whether a specification or a standard for a
particular point in the manufacturing process where control is deemed
[[Page 36201]]
necessary to prevent adulteration is met; a change in a processing
temperature or holding time may allow microorganisms to develop in
violation of Sec. 106.55; or a change in a processing temperature may
affect the level of a labile (temperature sensitive) nutrient in the
formula).
Proposed Sec. 106.140(b)(1) requires that the submission include
information on the name and physical form of the product, so that the
change in the formula can be evaluated with other information that the
agency has received on the formula, and so that an accurate evaluation
of the product can be made because different requirements may apply to
different forms of a formula.
Proposed Sec. 106.140(b)(2) requires an explanation of why the
change in formulation or processing may affect whether the formula is
adulterated, so that the agency can determine what type of evaluation
the submission requires. For example, if a change in formulation may
affect nutrient levels, the agency needs to evaluate the nutrient
content of the formula to be assured that this formulation change will
not lead to production of a formula that will not provide a required
nutrient at the required amount. Likewise, if a change in processing
may affect whether the formula is adulterated, the agency will need to
evaluate the formula's processing to be assured that the processing of
the formula will still comply with the CGMP regulations in subpart B of
part 106.
Proposed Sec. 106.140(b)(3) requires that the submission comply
with Sec. 106.120(b)(3), (b)(4), (b)(5), and (b)(6). This proposed
requirement implements section 412(d)(3) of the act, which provides
that manufacturers make the submission required by section 412(d)(1).
FDA has tentatively concluded that requiring that the submission comply
with these aspects of Sec. 106.120(b) will promote consistency in the
form and substance of the information that industry must submit, and
FDA must review. If the information required on processing by
Sec. 106.120(b)(4) has already been provided in compliance with
Sec. 106.140(b)(2) as a part of the explanation of why the change in
processing may affect whether the formula is adulterated, the same
information does not need to be repeated in the submission. To avoid
redundant submissions, proposed Sec. 106.140(b)(3) further provides
that if the information required by Sec. 106.120(b)(3), (b)(4), (b)(5),
or (b)(6) has been provided to the agency previously, and that
information is not affected by the change that is the subject of the
submission, a statement to that effect, together with the
identification number assigned by the agency to the relevant infant
formula submission, can be provided in lieu of a new submission.
Proposed Sec. 106.140(b)(3) requires inclusion of the
identification number assigned by the agency to the infant formula
submission so that the agency can have ready access to the relevant
information that was previously submitted. For example, if the
manufacturer makes a submission as a result of a change in processing,
but the formulation will remain the same, the manufacturer need not
provide the information required by Sec. 106.120(b)(3). Likewise, if
the manufacturer makes a submission as a result of a change in
formulation, but the processing of the formula remains the same, the
manufacturer need not submit the information required by
Sec. 106.120(b)(4).
A determination of whether the assurances required by
Sec. 106.120(b)(5) and (b)(6) need to be given is based on the
manufacturer's reason for providing the submission. For example, if the
submission is provided because a change in formulation or processing
may affect whether the formula is adulterated because it does not meet
the quality factors set forth in subpart E of part 106, the assurance
required by Sec. 106.120(b)(5)(i) would have to be provided. Likewise,
if the submission is provided because a change in formulation or
processing may affect whether the formula is adulterated because it
does not meet the nutrient requirements of Sec. 107.100, the assurance
required by Sec. 106.120(b)(5)(ii) would have to be provided. Further,
if the submission is provided because a change in processing may affect
whether the formula is adulterated because the processing of such
formula may no longer be in compliance with CGMP or with appropriate
quality control, as set forth in subparts B and C of part 106, or
whether the formula is manufactured in a manner designed to prevent
adulteration, the assurance required by Sec. 106.120(b)(6) would have
to be provided.
In proposed Sec. 106.140(c), the agency sets forth requirements
necessary to ensure that the data and other information provided in the
submission are in a form that will allow FDA to complete its review in
a timely manner and to advise the manufacturer if the agency has any
concerns about the marketing of the formula. Proposed Sec. 106.140(c)
also makes clear that the agency will notify the submitter if the
notice is not adequate because it does not meet the requirements of
section 412(d)(3) of the act.
7. Notification of an Adulterated or Misbranded Infant Formula
If FDA adopts the other regulations that it has proposed, it will
redesignate current Secs. 107.240(a) and (b) as Sec. 106.150 so that
all notification requirements on infant formulas can be found in one
place in the agency's regulations. In Sec. 106.150(b), FDA has revised
the address to reflect the reorganization of CFSAN.
H. Conforming and Editorial Changes to Part 107--Infant Formula
The agency is making conforming and editorial changes to part 107
to reflect the changes made by the 1986 amendments and the regulations
that FDA is proposing to adopt in part 106. The references in part 107
to the Division of Regulatory Guidance are being changed to the
Division of Enforcement to reflect the reorganization of CFSAN in
November 1992.
1. Changes in Subpart A
The agency is proposing to add a new Sec. 107.1 which will parallel
proposed Sec. 106.1. Proposed Sec. 107.1 describes the authority for
each of the proposed subparts and the consequences under the act of
failure to comply with any of the regulations in the proposed subparts.
2. Changes in Subpart B of Part 107--Labeling
The agency is proposing to amend Sec. 107.10 to require a statement
of the amount, supplied by 100 kcal, of each of any nutrient added by
the manufacturer as well as of the listed nutrients. As discussed
previously in the quality control section of this document, infant
formula manufacturers are adding ingredients to infant formula to
provide nutrients, such as selenium, that are not required by
Sec. 107.100 to be in infant formulas. The proposed change to
Sec. 107.10 requires that the amount of the added nutrients supplied by
100 kcal of the formula be declared on the label of the infant formula.
This proposed requirement is necessary to inform the consumer on a
consistent basis of the level of all nutrients included in an infant
formula.
3. Subpart C of Part 107--Exempt Infant Formulas
At this time the agency is not proposing to revise the regulations
in Sec. 107.50 pertaining to infant formulas that are subject to
section 412(h) of the act. These regulations were finalized in 1985 (50
FR 48183), before passage of the 1986 amendments. In the near future,
the agency intends to reevaluate
[[Page 36202]]
the exempt infant formula regulations and the effect of the 1986
amendments on exempt infant formulas and to issue a proposed rule to
reflect the results of this reevaluation. The agency also plans to
evaluate the effect of the Nutrition Labeling and Education Act of 1990
(Pub. L. 101-535) (the 1990 amendments) on the regulations for exempt
infant formulas. Exempt infant formulas are specifically exempted from
requirements for health claims and nutrient content claims by section
403(r)(5)(A) of the act. The basis for being an exempt infant formula,
according to section 412(h)(1) of the act, is how the product is
represented and labeled for use. This category of infant formula
recognizes that infants who suffer from special medical disorders, such
as maldigestion and malabsorption, inborn errors of metabolism such as
phenylketonuria or maple syrup urine disease, or severe kidney disease,
require formulas tailored specifically to their medical needs.
Therefore, it is important that any claims made for these products be
truthful, not misleading, and adequately substantiated because these
infants make up a vulnerable population and must receive the
appropriate nutrients for their medical condition. Because these
formulas are exempt from the regulations governing claims that were
developed under the 1990 amendments, the agency plans to evaluate how
claims for these products need to be substantiated to ensure that
infants with special nutritional needs are receiving appropriate infant
formulas.
4. Subpart E--Infant Formula Recalls
Current Sec. 107.240(a) sets out the requirements for notification
of a violative infant formula, and current Sec. 107.240(b) sets out the
method of notification. As stated above, the agency is moving the
provisions of current Sec. 107.240(a) and (b) to Sec. 106.150, so that
all of the agency's notification requirements are in one place. The
agency is renumbering current Sec. 107.240(c)(1), (c)(2), and (c)(3) as
Sec. 107.240(a), (b), and (c).
Section 107.250 gives directions on the termination of an infant
formula recall. The agency is changing the reference to the Division of
Regulatory Guidance to the Division of Enforcement in Sec. 107.250 to
reflect the 1992 reorganization of CFSAN.
V. Environmental Impact
The agency has carefully considered the potential environmental
effects of this action. FDA has concluded that the action will not have
a significant impact on the human environment, and that an
environmental impact statement is not required. The agency's finding of
no significant impact and the evidence supporting that finding,
contained in an environmental assessment, may be seen in the Dockets
Management Branch (address above) between 9 a.m. and 4 p.m., Monday
through Friday.
VI. Analysis of Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).
Executive Order 12866 directs 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). According to Executive
Order 12866, a regulatory action is ``economically significant'' if it
meets any one of a number of specified conditions, including having an
annual effect on the economy of $100 million or adversely affecting in
a material way a sector of the economy, competition, or jobs. A
regulation is considered ``significant'' under Executive Order 12866 if
it raises novel legal or policy issues.
The Regulatory Flexibility Act requires Federal agencies to
minimize the economic impact of their regulations on small businesses.
FDA finds that this proposed rule is neither an economically
significant nor a significant regulatory action as defined by Executive
Order 12866. In compliance with the Regulatory Flexibility Act, the
agency certifies that this proposed rule, if issued, will not have a
significant impact on a substantial number of small businesses.
Therefore, under the Regulatory Flexibility Act, no further analysis is
required. The agency examined three options in determining the economic
impact of this proposed regulations. A summary of the options follow:
A. Options
FDA has three primary options: (1) Adopt regulations with more
stringent requirements than the proposed regulations; (2) adopt the
proposed regulations; or (3) adopt regulations with less stringent
requirements than the proposed regulations.
1. Option 1--Adopt Regulations More Stringent Than the Proposed
Regulations
FDA believes infant formula manufacturers already comply with most
of the requirements of this proposed rule. One option would be to add
provisions to this proposed rule that would require activity beyond
that which is currently engaged in by infant formula manufacturers or
that is likely to be engaged in by manufacturers entering the infant
formula industry. Potential requirements of this type include specific
production and in- process control systems, specific equipment or types
of personnel, and additional testing and recordkeeping.
Under this option, incumbent manufacturers would face higher
production costs and would pass most of the costs on to consumers of
infant formula. In addition, the startup and operating costs would
increase, and thus discourage entry into the infant formula industry.
The ability of new firms to enter an industry is an important element
in promoting price competition and innovation. These additional
requirements would reduce price competition in the infant formula
industry.
The price of infant formula is probably linked to certain risky
infant feeding practices. With very high infant formula prices, some
consumers may increase risks to infants by improperly diluting formula
with water or other substances; using inappropriate substitutes for
formula or breast milk; or prematurely switching from formula to cow's
milk. For example, preliminary results of an FDA study on infant
formula feeding practices showed that approximately 20 percent of
infants (younger than 2 months) had their formula diluted by cereal,
which is cheaper than infant formula.
2. Option 2--Adopt the Proposed Regulations
There are two types of costs associated with this option: precluded
future cost cutting behavior and direct compliance costs.
a. Future cost cutting behavior. This type of cost may arise
because the proposed rule precludes cost cutting behavior by either
incumbent firms or firms entering the infant formula industry. Infant
formula manufacturers currently undertake a considerable amount of
activity, such as infant growth studies, that is designed to ensure the
safety of infant formula but is not explicitly required by either
current law or regulation. In the absence of this regulation, which
mandates this activity, either incumbent or future manufacturers may
choose not to undertake this activity in the future. However, because
of reputation effects and liability laws, these costs are likely to be
low.
[[Page 36203]]
b. Direct compliance costs. (i). CGMP. FDA believes that infant
formula manufacturers already comply with most of the proposed CGMP's.
These CGMP's include those dealing with: (1) Production and in-process
control systems, including the evaluation of any deviation from these
procedures or from established standards or specifications; (2)
controls designed to prevent adulteration of infant formula by workers,
by facilities, and during packaging and labeling; (3) controls to
prevent adulteration during manufacturing, including recording and
justifying deviations from the master manufacturing order and
evaluating deviations from processing times; (4) controls on the
release and storage of finished infant formula; (5) all requirements
relating to batch production and control records, and to coding; and
(6) all requirements dealing with general quality control procedures,
including the testing of one batch of each physical form of infant
formula at least once every 3 months.
If all manufacturers already comply with these proposed CGMP's,
then no compliance costs will result from them. FDA requests comments
on whether all infant formula manufacturers are already in compliance
with the proposed CGMP's listed above.
FDA believes that all infant formula manufacturers already comply
with the proposed CGMP's dealing with controls to prevent adulteration
caused by ingredients, containers, and closures. The provision that FDA
may object to the use of a particular substance in an infant formula
during its prenotification review of ingredients used in a formula
because it believes that the substance is not safe and suitable for
that use does not represent a change in the way FDA reviews infant
formula ingredients. This provision recognizes the fact that
manufacturers may make independent GRAS determinations about
ingredients. When a manufacturer makes such a determination, that
manufacturer is not necessarily required to have the relevant
ingredient affirmed as GRAS by FDA. However, FDA is reserving the right
to review infant formula ingredient lists and documentation concerning
whether particular ingredients are safe and suitable for use in infant
formula. Theoretically, this provision could lead to a reduction in the
number of ingredients that are independently determined to be GRAS and
a corresponding increase in the number of ingredients for which food
additive petitions are required. Petitions for direct food additives
can take between 1 to 6 years to complete and cost approximately $1
million per year. However, because manufacturers of infant formula
generally obtain FDA concurrence on the safety and suitability of
ingredients used in infant formula before making these determinations,
FDA believes no additional compliance costs will be generated by this
provision.
FDA also believes that infant formula manufacturers already comply
with many of the other proposed CGMP's. Provisions of CGMP's that some
infant formula manufacturers may not currently be in compliance include
the following:
(1) Controls to prevent adulteration caused by equipment or
utensils. Some manufacturers may not repair or replace instruments and
controls when those instruments and controls cannot be adjusted to
within essential agreement with the reference standard. In addition,
most manufacturers probably do not perform a written evaluation of all
affected product, or of actions taken when calibration results indicate
that a specification or standard for a point where control is deemed
necessary to prevent adulteration has not been met. FDA cannot estimate
the repair or replacement costs of instruments and controls at this
time. Written evaluations will take a supervising technician an
estimated 2 hours to complete, which will generate some small
compliance costs.
(2) Controls to prevent adulteration because of automatic,
mechanical, and electronic equipment. Most manufacturers will probably
have to perform additional analysis of software modifications. FDA
preliminarily estimates this analysis will add approximately 1 month to
the time required to analyze programming and software modifications.
One or two software modifications are probably made each year at each
of the fifteen plants that produce infant formula. Assuming that a
single computer scientist works on the additional activity required,
compliance costs are estimated to be about $100,000 per year.
ii. Audits, Quality factors, registration and notification
requirements, and infant formula recalls. FDA believes that infant
formula manufacturers already comply with the following provisions: (1)
Regularly scheduled audits to determine compliance with CGMP's and
Quality Control Procedures (QCP's), (2) growth and development studies
to be submitted under certain conditions and new notification
requirements (FDA already requests and receives these quality factor
growth and development studies and notification material based on FDA's
interpretation of the language of the 1986 amendments), and (3) all
provisions involving registration and notification requirements.
If infant formula manufacturers are already complying with these
provisions, then no compliance costs will be generated by these
provisions.
FDA requests information on whether all infant formula
manufacturers already comply with all provisions listed above,
particularly those provisions dealing with quality factors.
iii. Records. Under the current proposal, the records produced and
maintained by infant formula manufacturers to establish compliance with
FDA regulations will have to be expanded to include all new CGMP's and
QCP's. FDA believes most of the specified records are already being
kept by all firms; however, some records may not be. A plausible
assumption is that current annual industry expenditures on
recordkeeping may increase by about 10 percent, or $450,000 per year
based on information received from industry on current recordkeeping
costs. FDA requests information on the cost of increased recordkeeping.
iv. Administrative costs. Interpreting and implementing changes in
CGMP and QCP regulations generate administrative costs even when all
activity required in those CGMP's and QCP's is already being done. FDA
does not have information on the administrative costs involved in
interpreting and implementing changes in CGMP and QCP regulations;
however, it is plausible to suppose that 20 percent of the total
compliance costs other than administrative costs may be used to reflect
administrative costs.
Administrative costs under this assumption would be approximately
$100,000 and would accrue in the first year only. FDA requests
information on administrative costs.
3. Option 3--Adopt Regulations Less Stringent Than the Proposed
Regulations
Another option is to limit the activity required by this proposed
rule to activity already engaged in by all incumbent infant formula
manufacturers. In this case, there would be no compliance costs based
on current behavior. However, in the absence of this proposed rule,
incumbent or new manufacturers might choose not to undertake all
activity specified in this proposed rule. Therefore, the only costs
associated with this option are the costs associated with precluded
potential future behavior on the part of incumbent or new
manufacturers.
[[Page 36204]]
B. Benefits
1. Option 1--Adopt Regulations More Stringent Than the Proposed
Regulations
More stringent regulations for infant formula would cause infant
formula manufacturers to undertake further activity to ensure the
safety of infant formula. If there were identifiable risks from infant
formula that were not addressed by this proposal, then this additional
activity might decrease those health risks. However, FDA is not aware
of identifiable health risks from infant formula that are not addressed
by this proposal.
2. Option 2--Adopt the Proposed Regulations
The proposed regulation has two primary benefits: A potential
direct reduction in the health risks posed by infant formula, and a
potential reduction in the cost of entering the infant formula
industry. The latter effect could lead to an increase in the
competitiveness of the infant formula industry, resulting in lower
infant formula prices and a reduction in the incidence of risky infant
feeding practices linked to high infant formula prices.
One example of a current activity that can be linked to a direct
reduction in health risks but that is not explicitly required by
current law or regulation is the performance of growth studies for new
infant formulas. FDA currently requests and receives these studies to
demonstrate that the infant formula meets the quality factor
requirements of section 412(b)(1) of the act. However, because section
412(b)(1) of the act does not list specific quality factors that infant
formulas must meet, a quality factor for healthy growth currently is
not expressly stipulated. In the absence of this proposed rule,
manufacturers could decline to perform these growth studies in the
future with a potential consequence that products that do not support
normal growth would be marketed. Low growth rates would not be detected
by existing regulatory and legal requirements that measure only the
levels of required nutrients because the required nutrients may be
present but not be bioavailable, and there is no mechanism for testing
bioavailability other than the proposed studies.
An example of a formula associated with low growth rates that would
not have been detected in the absence of growth studies was an
experimental formula that contained a source of fatty acids not
previously used in infant formula. Because only a small amount of the
new fat source was added to a commercial formula, it is reasonable to
assume that all required nutrients were present within legal
specifications. Consequently, it would likely have met all current
regulations. Nonetheless, this formula was found to result in low
infant growth rates (Ref. 87). In this case, the manufacturer undertook
the necessary growth studies and detected the problem on its own.
However, manufacturers might not undertake these studies on their own
in the future. In addition, even if manufacturers continue to undertake
these studies in the absence of this regulation, they may not do these
studies correctly.
In general, low rates of infant growth are associated with higher
than normal levels of infant morbidity. If a problem of this type were
to occur, a large number of infants could potentially be affected.
Other types of current activity can also be linked to a direct
reduction in health risks and also are not explicitly required by
current law or regulation. In the absence of this regulation, incumbent
or new manufacturers may not undertake this activity in the future.
However, as explained earlier, because of reputation effects and legal
liability, such a refusal seems unlikely.
An example of a health risk from infant formula is the 1978
incident, discussed elsewhere in this document, in which a required
nutrient was missing from an infant formula. Recurrence of this
particular problem is unlikely because section 412(d)(1)(A) of the act
already explicitly requires the submission of the quantitative
formulation of an infant formula as part of the mandatory FDA
notification of a new infant formula. Recurrence of this problem is
also made unlikely because section 412(b)(2) of the act already
explicitly requires the testing of infant formula for all required
nutrients. However, the risk of a formula being sold without a required
nutrient is minimized to the extent possible by specifically clarifying
this part of the infant formula law in the regulation.
Another example of a health risk associated with infant formula is
an incident in which infant formula was found to contain Salmonella. It
appears that the manufacturer was testing for Salmonella in a manner
consistent with the testing requirements of this proposed rule, and
therefore it is not clear that this particular incident would have been
avoided if the proposed rule had been in effect. This proposed rule
will reduce the risk of microbiological contamination, however, because
it requires manufactures to institute a production and in-process
control system. The production and in-process control system
establishes standards or specifications to be met throughout the
production of their product. Other provisions of the proposed
regulation that will also help to prevent microbiological contamination
of infant formulas are controls to prevent adulteration by workers
(proposed Sec. 106.10), controls on the required temperature of cold
storage compartments used for storing ingredients and uncanned infant
formula (proposed Sec. 106.30(e)(2)), controls on the monitoring of the
temperature of both cold storage and thermal processing equipment
(proposed Sec. 106.30(e)), controls on the spray-drying process for
powdered infant formula including the filtering of the intake air
before heating to prevent microbial growth (proposed
Sec. 106.50(d)(2)), and controls to ensure that each container of
finished product is properly sealed (proposed Sec. 106.50(d)(4)).
The incident in which infant formula was found to contain
Salmonella resulted in two reported cases of salmonellosis in infants.
The average value of preventing a single case of salmonellosis is
estimated to be about $2,000 (Ref. 88). If an incident like this is
avoided in the future because of this proposed rule, the value of the
adverse health effects avoided would be a benefit of this proposed
rule.
This incident also resulted in two recalls. FDA estimates a
combined cost, including costs that accrued to both the manufacturer
and FDA of approximately $0.7 million per recall. If an incident like
this is avoided in the future because of this proposed rule, the recall
costs that would otherwise have been associated with this incident
would also be a benefit of this proposed rule.
Another benefit of the proposed regulations is a potential
reduction in the administrative and time costs of entering the infant
formula industry. Currently, infant formula manufacturers must analyze
and interpret the relevant laws to determine the legal requirements
involved in the manufacture of infant formula. Incumbent firms have
tended to accept FDA's interpretations of these laws and have received
information on this interpretation incrementally over time, chiefly
through direct contact with FDA on various issues.
It is reasonable to expect that potential entrants into the infant
formula industry would also prefer to rely on FDA's interpretations of
the relevant laws. However, considerable time and administrative costs
are involved in obtaining this information because there is no
established
[[Page 36205]]
mechanism by which manufacturers can obtain this information other than
direct communication with FDA on various particular issues. By
providing an explicit specification of the activities that are required
by the relevant laws, the proposed regulations, if adopted, will reduce
the time and administrative costs involved in entering this industry.
In order to determine the net effect of the proposed rule on the
cost of entering the infant formula industry, the reduction in time and
administrative costs must be weighed against the additional compliance
costs imposed by this proposed rule on new firms. These countervailing
compliance costs are probably low because new firms will probably
undertake voluntarily the same activity that is currently undertaken
voluntarily by incumbent manufacturers. Therefore, the net effect of
this proposed rule is likely to be the reduction in the cost of
entering the infant formula industry. Publication of the proposed and
final regulations will provide a means of expedited entry for new firms
into the infant formula market.
A reduction in the cost of entering the infant formula industry
will promote both price competition and innovation in this industry.
Increased price competition may lead to health benefits because, as
stated above, high infant formula prices may encourage some consumers
to: (1) Improperly dilute infant formula to reduce the cost per
serving; (2) prematurely switch from infant formula to cow's milk; or
(3) use inappropriate substitutes for breast milk and infant formula.
A final benefit of this proposed rule is the cost savings generated
by the elimination of the current FDA requirement that a vitamin D rat
bioassay be performed for all major changes in infant formula. In 1992,
there were approximately 50 major changes. The cost of a rat bioassay
for vitamin D for infant formula at a private lab is about $1,070 (Ref.
89). Infant formula manufacturers should therefore save approximately
$54,000 in testing costs per year.
3. Option 3--Adopt Regulations Less Stringent than the Proposed
Regulations
Except for the value of the risk reductions resulting from
requirements that go beyond activity currently undertaken by infant
formula manufacturers the benefits of this option are identical to
those of Option 2.
C. Conclusions
In accordance with Executive Order 12286, FDA has analyzed the
economic effects of this proposed rule and has determined that this
rule, if issued, will not be a significant rule as defined by that
order. In accordance with the Regulatory Flexibility Act, FDA certifies
that the proposed rule will not have a significant impact on a
substantial number of small businesses.
The primary compliance costs of Option 2 include both direct costs
of new requirements and precluded production cost reductions which may
occur without this regulation. FDA has estimated direct costs to
incumbent manufacturers to be approximately $0.7 million in the first
year and $0.6 million each additional year. An additional cost to
incumbent manufacturers is the cost of repairing or replacing
instruments and controls when those instruments and controls cannot be
adjusted to agreement with the reference standard. FDA has insufficient
information to estimate this cost. FDA does not expect compliance with
the proposed regulations to cause any significant increase in the price
of infant formula products. However, the agency requests comments about
any potential effects of the proposed regulations on the price of
infant formula products.
The primary benefit of Option 2 is the reduction in the risk that
defective infant formula will be produced, go undetected, and reach the
market. FDA has insufficient information to estimate this potential
benefit. In addition, this proposed rule is also expected to reduce the
time and administrative costs of entering the infant formula industry.
This benefit may increase price competition in the infant formula
industry and reduce the health risks associated with high infant
formula prices. FDA also has insufficient information to estimate these
benefits.
Except for the costs and benefits associated with activity required
by this proposed rule that some incumbent manufacturers do not
currently undertake, the costs and benefits of Option 3 are identical
to those of Option 2. FDA has insufficient information to estimate
either the costs or benefits of this option.
Option 1 is expected to have higher costs and lower benefits than
either Option 2 or Option 3.
VII. Paperwork Reduction Act of 1995
This proposed rule contains information collection provisions that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The
title, description, and respondent description for the proposed
collection of information are shown below, along with an estimate of
the annual recordkeeping and periodic reporting burden. Included in the
estimate is the time for reviewing instructions, searching existing
data sources, gathering and maintaining the necessary information, and
completing and submitting the registrations, notifications, and other
submissions that would be required under the proposed regulations.
FDA solicits public comment in order to: (1) Evaluate whether the
proposed collection of information is necessary for the proper
performance of the functions of the agency, including whether the
information will have practical utility; (2) evaluate the accuracy of
the agency's estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (3) enhance the quality, utility, and clarity of the information
to be collected; and (4) minimize the burden of the collection of
information on those who are to respond, including through the use of
automated collection techniques, where appropriate or other forms of
information technology.
Title: Current Good Manufacturing Practice, Quality Control
Procedures, Quality Factors, Notification Requirements, and Records and
Reports, for the Production of Infant Formula.
Description: FDA is proposing regulations on recordkeeping
requirements that include: (1) Records pertaining to batch production
and control; (2) records pertaining to current good manufacturing
practice and quality control; (3) records pertaining to distribution of
the infant formula; and (4) records pertaining to regularly scheduled
audits. FDA is also proposing regulations on reporting requirements
pertaining to: (1) Registration of a new infant formula; (2) submission
requirements for a new infant formula; (3) submission requirements to
provide assurance that an infant formula meets the quality factor
requirements; (4) submission requirements when there is a change in the
formulation or processing of the formula that may affect whether the
formula is adulterated; and (5) submission requirements to provide
assurance that the infant formula complies with the requirements of the
Federal Food, Drug, and Cosmetic Act and is not adulterated.
Description of Respondents: Infant Formula Manufacturers.
[[Page 36206]]
Estimated Annual Recordkeeping Burden
----------------------------------------------------------------------------------------------------------------
Annual Total
21 CFR No. of frequency of annual Hours per Total hours
recordkeepers recordkeeping records recordkeeping
----------------------------------------------------------------------------------------------------------------
106.6.................................... 5 1 5 200 1,000
106.20(f)(4) and 106.100(f)(1)........... 5 52 260 3 780
106.30(d) and 106.100(f)(2).............. 5 25 125 4 500
106.30(e)(3)(ii) and 106.100(f)(3)....... 5 365 1,825 2 3,650
106.30(f) and 106.100(f)(4).............. 5 365 1,825 3 5,475
106.35(c) and 106.100(f)(5).............. 5 2 10 500 5,000
106.40(d)................................ 5 20 100 30 3,000
106.40(g) and 106.100(f)(6).............. 5 122 610 4 2,440
106.50................................... 5 1 5 200 1,000
106.55(d) 106.100(e)(5)(ii), and
106.100(f)(7)........................... 5 182 910 3 2,730
106.60(c)................................ 5 1 5 40 200
106.91(c), 106.100(e)(5)(i), and
106.100(f)(7)........................... 5 365 1,825 4 7,300
106.94................................... 5 1 5 88 440
106.97................................... 5 0.6 3 225 675
106.100(e)............................... 5 365 1,825 9 16,425
------------
Total................................ ............. ............. ........... ............. 50,615
----------------------------------------------------------------------------------------------------------------
Estimated Annual Reporting Burden
----------------------------------------------------------------------------------------------------------------
Annual
No of frequency Total Hours per
21 CFR respondents per annual response Total hours
response responses
----------------------------------------------------------------------------------------------------------------
106.110........................................ 3 NA 20 1 20
106.120........................................ 3 NA 20 49 980
106.121........................................ 3 NA 10 50 500
106.130........................................ 3 NA 20 2 40
106.140........................................ 3 NA 25 5-10 125-250
------------
Total...................................... ........... ........... ........... ........... 1,790
============
Total Recordkeeping and Reporting Burden... 52,405
----------------------------------------------------------------------------------------------------------------
FDA tentatively concludes that there are no capital costs or
operating and maintenance costs associated with the reporting and
recordkeeping provisions of this proposed rule. However, the agency
welcomes comments on any such anticipated costs.
As required by section 3507(d) of the Paperwork Reduction Act of
1995, FDA has submitted a copy of this proposed rule to OMB for its
review of the information collection requirements. Other organizations
and individuals interested in submitting comments regarding this burden
estimate or any aspect of these information collection requirements,
including suggestions for reducing the burden, should direct them to
the Office of Information and Regulatory Affairs, OMB, New Executive
Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, ATTN:
Desk Officer for FDA. Written comments on the information collection
should be submitted by August 8, 1996.
VIII. Requests for Comments
Interested persons may, on or before October 7, 1996, submit to the
Dockets Management Branch (address above) written comments regarding
this proposal. Two copies of any comments are to be submitted, except
that individuals may submit one copy. Comments are to be identified
with the docket number found in brackets in the heading of this
document. Received comments may be seen in the office above between 9
a.m. and 4 p.m., Monday through Friday.
IX. References
The following references have been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
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43. Collins-Thompson, D. L., K. F. Weiss, G. W. Riedel, and S.
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44. FDA Enforcement Report, July 14, 1993.
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Salmonellosis and Similar Foodborne Infections,'' Food Control,
2(1), pp. 26-34, 1991.
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of Bacillus cereus in Ready-to-Serve Foods,'' Journal of Food
Protection, 54(5):372-374, 1991.
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Vitamin D Rat Bioassay, May 12, 1994.
54. Tanner, J. T., S. A. Barnett, and M. K. Mountford, ``Analysis of
Milk-based Infant Formula,'' Phase IV. Iodine, Linoleic Acid, and
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Assessment of Nutrient Bioavailability,'' in Nutrient Availability:
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Johnson, and G. R. Fenwick, Royal Society of Chemistry, 1989.
56. Jensen, R. G., M. M. Hagerty, and K.E. McMahon, ``Lipids of
Human Milk and Infant Formulas: A Review,'' American Journal of
Clinical Nutrition, 31:990-1016, 1978.
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[[Page 36208]]
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59. American Academy of Pediatrics, ``Commentary on Breast-Feeding
and Infant Formulas, with Proposed Standards for Formulas,''
Pediatrics, 57:278-285, 1976.
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26, 1980.
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in Infants: High Bioavailability of Breast Milk Iron as Indicated by
the Extrinsic Tag Method of Iron Absorption and by the Concentration
of Serum Ferritin,'' Journal of Pediatrics, 91:36-39, 1977.
62. Hallberg, L., L. Rossander-Hulten, M. Brune, A. Gleerup,
``Bioavailability in Man of Iron in Human Milk and Cow's Milk in
Relation to Their Calcium Contents,'' Pediatric Research, 31:524-
527, 1992.
63. Derman, D. P., D. Ballot, T. H. Bothwell, B. J. MacFarlane, R.
D. Baynes, A. P. MacPhail, M. Gillooly, J. E. Bothwell, and W. R.
Bezwoda, ``Factors Influencing the Absorption of Iron From Soya-Bean
Protein Products,'' British Journal of Nutrition, 57:345-353. 1987.
64. Koo, W. W. K., and R. G. Tsang, ``Calcium, Magnesium,
Phosphorus, and Vitamin D,'' In Nutrition Needs of the Preterm
Infant, edited by Tsang, R. C., et al., Academic Press, 1993
65. Steichen, J. J., T. L. Gratton, and R. C. Tsang, ``Osteopenia of
Prematurity: The Cause and Possible Treatment,'' Journal of
Pediatrics, 96:528-34, 1980.
66. Koletzko, B., R. Tangerman, R. Von Kries, et al. ``Intestinal
Milk-Bolus Obstruction in Formula-Fed Premature Infants Given High
Doses of Calcium,'' Journal of Pediatric Gastroenterology and
Nutrition 7:548-553, 1988.
67. Ziegler, E. E., and S. J. Fomon, ``Lactose Enhances Mineral
Absorption in Infancy,'' Journal of Pediatric Gastroenterology and
Nutrition, 2:288-294, 1983.
68. Moya, M., E. Cortes, M. I. Ballester et al., ``Short-term
Polycose Substitution for Lactose Reduces Calcium Absorption in
Healthy Term Babies,'' Journal of Pediatric Gastroenterology and
Nutrition, 14:57-61, 1992.
69. Shenai, J. P., B. M. Jhaveri, J. W. Reynolds et al.,
``Nutritional Balance Studies in Very Low Birth Weight Infants: Role
of Soy Formula,'' Pediatrics, 67:631-637, 1981.
70. Lindroth, M., U. Westgren, and S. Laurin, ``Rickets in Very Low
Birth Weight Infants; Influence of Supplementation with Vitamin D,
Phosphorus, and Calcium,'' Acta Pediatrica Scandinavica, 75:927-931,
1986.
71. Chan, G. M., and L. J. Mileur, ``Posthospitalization Growth and
Bone Mineral Status of Normal Preterm Infants,'' American Journal of
Diseases in Childhood, 139:896-8, 1985.
72. Food and Drug Administration, Public Health Service, U.S.
Department of Health and Human Services, Guidelines for the Format
and Content of the Clinical and Statistical Sections of New Drug
Applications July, 1988.
73. American Academy of Pediatrics. Pediatric Nutrition Handbook, 3d
ed., 1993.
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Length From 1 to 12 Mo of Age: Reference Data for 1-Mo Increments,''
American Journal of Clinical Nutrition, 49:599-607, 1989.
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Saunders Co., Philadelphia, 1992.
77. Sarwar, G., R. W. Peace, and H. G. Botting, ``Differences in
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of Clinical Nutrition, 49:806-13, 1989.
78. Rudloff, S., and B. Lonnerdal, ``Solubility and Digestibility of
Milk Proteins in Infant Formulas Exposed to Different Heat
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79. Fomom, S. J., and S. E. Nelson, Chapter 11, Calcium, Phosphorus,
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80. Ryan, S. A., J. Truscott, M. Simpson, and J. James, ``Phosphate,
Alkaline Phosphatase and Bone Mineralization in Preterm Neonates,''
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82. Steichen, J. J., P. A. Steichen Asch, and R. C. Tsang, ``Bone
Mineral Content Measurement in Small Infants by Single-photon
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89. Memorandum of telephone conversation between Hazleton Labs and
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List of Subjects
21 CFR Part 106
Food grades and standards, Infants and children, Nutrition,
Reporting and recordkeeping requirements, Incorporation by reference.
21 CFR Part 107
Food labeling, Infants and children, Nutrition, Reporting and
recordkeeping requirements, Signs and symbols.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to Commissioner of Food and Drugs, it is proposed
that 21 CFR parts 106 and 107 be amended as follows:
PART 106--INFANT FORMULA--REQUIREMENTS PERTAINING TO CURRENT GOOD
MANUFACTURING PRACTICE, QUALITY CONTROL PROCEDURES, QUALITY
FACTORS, RECORDS AND REPORTS, AND NOTIFICATIONS
1. The authority citation for 21 CFR part 106 continues to read as
follows:
Authority: Secs. 201, 412, 701 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 321, 350a, 371).
2. The heading for part 106 is revised to read as set forth above.
3. Section 106.1 is revised to read as follows:
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 must take under section
412(b)(2) and (b)(3) of the Federal Food, Drug, and Cosmetic Act (the
act) 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 act.
(b) The criteria set forth in subpart E of this part prescribe the
quality factor requirements that infant formula must
[[Page 36209]]
meet under section 412(b)(1) of the 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 act.
(c) The criteria set forth in subpart F of this part implement the
record retention requirements established in section 412(b)(4) of the
act. Failure to comply with any regulation in subpart F of this part is
a violation of section 301(e) of the act.
(d) The criteria set forth in subpart G of this part describe the
circumstances in which infant formula manufacturers are required to
register with, submit to, or notify the Food and Drug Administration,
and the content of those registrations, submissions, or notifications,
under section 412(c), (d), and (e) of the act. Failure to comply with
any regulation in subpart G of this part is a violation of section
301(s) of the act.
4. Section 106.3 is revised to read as follows:
Sec. 106.3 Definitions.
The definitions in this section and the definitions contained in
section 201 of the Federal, Food, Drug, and Cosmetic Act (the act)
shall apply to infant formula requirements in 21 CFR part 106 and part
107 of this chapter.
(a) Batch means 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.
(b) 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.
(c) 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.
(d) Infant means a person not more than 12 months of age.
(e) 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.
(f) In-process batch means a combination of ingredients at any
point in the manufacturing process before packaging.
(g) Lot means 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.
(h) Lot number, control number, or batch 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 batch
or lot of infant formula or other material can be determined.
(i) 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 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 introduced for
commercial or charitable distribution 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 act, 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., a change from
terminal sterilization to aseptic processing); and
(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).
(j) 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.
(k) Microorganisms means yeasts, molds, bacteria, and viruses and
includes, but is not limited to, species having public health
significance.
(l) New infant formula means:
(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.
(m) Nutrient means 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 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 Council 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.
(n) Nutrient premix means a combination of ingredients containing
two or more nutrients received from a supplier or prepared by an infant
formula manufacturer.
(o) Quality factors mean 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.
(p) 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.
(q) Shall is used to state mandatory requirements.
(r) Should is used to state recommended or advisory procedures or
to identify recommended equipment.
5. Part 106 is amended by redesignating subparts B, C, and D as
subparts C, F, and G, respectively, and adding new subparts B, D, and
E; and by revising newly redesignated subparts C and G to read as
follows:
* * * * *
[[Page 36210]]
Subpart B--Current Good Manufacturing Practice
Sec.
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 Quality factors in infant formulas.
106.97 Assurances for quality factors.
* * * * *
Subpart G--Registration, Submission, and Notification Requirements
106.110 New infant formula registration.
106.120 New infant formula submission.
106.121 Quality factor submission.
106.130 Verification submission.
106.140 Submission concerning a change in infant formula that may
adulterated the product.
106.150 Notification of an adulterated or misbranded infant
formula.
* * * * *
Subpart B--Current Good Manufacturing Practice
Sec. 106.5 Current good manufacturing practice.
(a) The regulations set forth in this subpart and, for liquid
infant formulas, in part 113 of this chapter 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.
(b) The failure to comply with any regulation set forth in this
subpart or, for liquid infant formulas, in part 113 of this chapter 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 (the act).
Sec. 106.6 Production and in-process control system.
(a) Manufacturers 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, the manufacturer shall:
(1) Establish standards or specifications to be met;
(2) Monitor the production and in-process control point, step, or
stage;
(3) Establish corrective action plans for use when a standard or
specification established in accordance with paragraph (b)(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 deviations from standards or specifications that
have been established in accordance with paragraph (c)(1) of this
section. This review shall be conducted by an individual qualified by
training and experience to conduct such reviews; 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.
Sec. 106.10 Controls to prevent adulteration by workers.
(a) There shall be sufficient personnel, qualified by training and
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
they 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, but is not limited to:
(1) Wearing clean outer garments and, as necessary, protective
apparel such as head, face, hands, 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 shall be designated for holding raw materials,
in-processing materials, and final product infant formula:
(1) Pending release for use in infant formula production or pending
release of the final product,
(2) After rejection for use in infant formula and before
disposition, 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,
[[Page 36211]]
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) Air filtration systems, including prefilters and particulate
matter air filters, shall be used on air supplies to production areas
where ingredients or infant formula are directly exposed to the
atmosphere.
(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)(1) 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 set forth in 40 CFR
part 141, except that the fluoride level of the water used in infant
formula manufacturing shall be as low as possible. 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) Manufacturers 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) Manufacturers 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) Manufacturers 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) When steam comes in direct contact with infant formula, it
shall be safe and free of rust and other particulate matter that may
contaminate the formula. 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, and
single-service towels and that are maintained in good repair and in a
sanitary condition at all times, and that these facilities provide for
proper disposal of the sewage. Doors to the toilet facility shall not
open into areas where infant formula ingredients, containers, or
closures are stored, or where infant formula is processed or stored.
Sec. 106.30 Controls to prevent adulteration caused by equipment or
utensils.
(a) Equipment used in the manufacture, processing, packing or
holding of an infant formula shall be of appropriate design and shall
be installed to facilitate its intended function and its cleaning and
maintenance.
(b) Equipment and utensils used in the manufacture, processing,
packing, or holding of an infant formula shall be constructed so that
surfaces that contact ingredients, in-process materials, or infant
formula are made of nontoxic materials and are not reactive or
absorptive. Such equipment and utensils shall be designed to be easily
cleanable and to withstand the environment of their intended use. All
surfaces that contact ingredients, in-process materials, or infant
formula shall be cleaned, sanitized, and maintained to protect infant
formula from being contaminated by any source. Sanitizing agents used
on food-contact surfaces must comply with Sec. 178.1010 of this
chapter.
(c) Manufacturers shall ensure that substances, such as lubricants
or coolants, that are required for operation of infant formula
manufacturing equipment, but that would render the infant formula
adulterated if they contaminated the formula, do not come in contact
with formula ingredients, containers, closures, or in-process materials
or with infant formula itself.
(d)(1) Manufacturers shall ensure that instruments used for
measuring, regulating, or controlling mixing time and speed,
temperature, pressure, moisture, water activity, or other parameters at
points where control is deemed necessary to prevent adulteration in the
processing of an infant formula are accurate, easily read, properly
maintained, and present in sufficient number for their intended use.
The instruments and controls shall be tested for accuracy (calibrated)
against a known reference standard 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. The known reference standard shall be
certified for accuracy at routine intervals specified in writing by the
manufacturer of the instrument, or as otherwise deemed necessary to
ensure the accuracy of the instrument. Manufacturers shall make and
retain records of the accuracy checks 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 (testing for accuracy against a
known reference standard) shows that a specification or standard for a
point where control is deemed necessary to prevent adulteration has not
been met, 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)(1) The temperature in cold storage compartments that are used
to store raw materials, in-process materials, or final product, and in
thermal processing equipment used at points where temperature control
is necessary to prevent adulteration, shall be monitored with such
frequency as is necessary to ensure that temperature control is
maintained.
(2) Cold storage compartments shall be maintained at a temperature
of 40 deg.F (4.4 deg.C) or below.
(3)(i) Cold storage compartments and thermal processing equipment
shall be equipped with easily readable, accurate temperature-indicating
devices.
(ii) Thermal processing equipment shall be equipped with
temperature-recording devices that will reflect the true temperature on
a continuing basis. Cold storage compartments shall 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. If the manufacturer uses either of the latter options, it
shall maintain a temperature log in which it notes temperature with
such frequency as is necessary to achieve control. Manufacturers shall
make and retain records, in accordance with Sec. 106.100(f)(3), of the
temperatures indicated or recorded by these devices.
[[Page 36212]]
(4) When a temperature-recording device is used, such device shall
not read higher than the calibrated temperature-indicating device for
thermal processing equipment or lower than the reference temperature-
indicating device for cold storage compartments.
(f) Equipment and utensils used in the manufacture of infant
formula shall be cleaned, sanitized, and maintained at regular
intervals to prevent adulteration of the infant formula. An individual
qualified by training or experience to conduct such a review shall
check all cleaning, sanitizing, and maintenance to ensure that it has
been satisfactorily completed. Manufacturers shall make and retain
records on equipment cleaning, sanitizing, and maintenance, in
accordance with Sec. 106.100(f)(4).
(g) Compressed air or other gases that are mechanically introduced
into infant formula, that are used to clean any equipment, or that come
into contact with any other surface that contacts ingredients, in-
process materials, or infant formula shall be treated in such a way
that their use will not contaminate the infant formula with unlawful
indirect food additives 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, the
manufacturer shall install a 0.5 micrometer or smaller filter as close
to the end of the gas line that feeds gas into the space, as practical.
Sec. 106.35 Controls to prevent adulteration due to automatic
(mechanical or electronic) equipment.
(a)(1) For the purposes of this section, ``hardware'' means all
automatic equipment, including mechanical and electronic equipment
(including computers), that is used in production or quality control of
a infant formula.
(2) For the purposes of this section, ``software'' means any
programs, procedures, rules, and associated documentation used in the
operation of a system.
(3) For the purposes of this section, ``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) For the purposes of this section, ``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)(1) 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.
(2) The infant formula manufacturer shall ensure that hardware is
routinely calibrated, inspected, and checked according to written
procedures.
(3) The infant formula 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. 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.
(4) The infant formula manufacturer shall ensure that all systems
are validated before their first use to manufacture commercial product.
(5) The infant formula manufacturer shall ensure that any system
that is modified is revalidated after the modification and before use
of the modified system to manufacture commercial product. 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) The infant formula manufacturer shall make and retain records,
in accordance with Sec. 106.100(f)(5), concerning automatic (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 infant formulas are
food ingredients whose use in infant formula is safe and suitable under
the applicable food safety provisions of the Federal Food, Drug, and
Cosmetic Act; that is, the substance is generally recognized as safe
(GRAS) for such use, is used in accordance with the agency's food
additive regulations, 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, and all
packaging material that comes in contact with infant formula shall be
composed of substances that are GRAS for use in or on food, GRAS for
their intended use in food packaging, authorized by a prior sanction
issued by the agency, or authorized for use as an indirect food
additive. Any packaging material that comes in contact with infant
formula shall be used in accordance with any prescribed limitations.
(c) Ingredients, containers, and closures used in the manufacture
of infant formula shall be identified with a batch or lot number to be
used in recording their disposition.
(d) Infant formula manufacturers shall develop written
specifications for their acceptance or rejection of ingredients,
containers, and closures used in infant formula manufacture. These
specifications shall stipulate the standards for acceptance or
rejection of such ingredients, containers, and closures as well as the
procedures for determining whether the ingredients, containers, and
closures meet that standard. An individual qualified by training or
experience shall conduct an investigation of a finding that any
ingredients, containers, or closures used in a batch of infant formula
failed to meet any of the manufacturer's specifications.
(e) Ingredients, containers and closures shall be stored in areas
clearly designated for:
(1) Materials pending release for use,
(2) Materials released for use, or
(3) Materials rejected for use in infant formula production. Any
lot of ingredients, containers, or closures that does not meet the
manufacturer's specifications shall be rejected and controlled under a
quarantine system designed to prevent its use in the manufacture of
infant formula.
(f) If an ingredient, a container, or a closure that has been
tested and examined is exposed to air, heat, or other conditions that
may adversely affect it, the ingredient, container, or closure shall be
retested or reexamined to ensure that it still meets the manufacturer's
specifications.
(g) Manufacturers 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)(1) Manufacturers shall prepare and follow a written master
manufacturing order that establishes controls and procedures for the
production of an infant formula.
(2) 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 batch. An individual qualified by
training or experience shall conduct an investigation of any
[[Page 36213]]
deviations from the master manufacturing order and any corrective
actions taken.
(3) 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) The 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 will 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 batch.
(c) The manufacturer shall 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 of an infant
formula.
(d) The 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 but
not be limited to:
(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.
Manufacturers of liquid infant formulas, which are thermally processed
low-acid foods packaged in hermetically sealed containers, shall
perform such closure integrity testing in accordance with
Sec. 113.60(a) of this chapter.
(e) The 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) The manufacturer shall establish controls that ensure that
rejected in-process materials:
(1) Are clearly identified as having been rejected for use in an
infant formula;
(2) Are controlled under a quarantine system designed to prevent
their use in manufacturing or processing operations for which they are
unsuitable;
(3) Meet the appropriate specifications, if reprocessed, before
being released for use in infant formula.
Sec. 106.55 Controls to prevent adulteration from microorganisms.
(a) Manufacturers of liquid infant formula shall comply with the
procedures specified in part 113 of this chapter for liquid infant
formula.
(b) Manufacturers of powdered infant formula shall test
representative samples of every batch of the formula at the final
product stage, before distribution, to ensure that the infant formula
meets the microbiological quality standards listed in paragraph (c) of
this section.
(c) Any powdered infant formula that contains any microorganism
that exceeds the M value listed for that microorganism in Table 1 of
this section will be deemed to be adulterated under sections 402 and
412 of the Federal Food, Drug, and Cosmetic Act (the act). FDA will
determine compliance with the M values listed below using the
Bacteriological Analytical Manual (BAM), 8th ed. (1995), published by
the AOAC International Association of Official Analytical Chemists,
which is incorporated by reference in accordance with 5 U.S.C. 552(a)
and 1 CFR part 51. Copies are available from the Association of
Official Analytical Chemists, 481 North Frederick Ave., suite 500,
Gaithersburg, MD 20877, or may be examined at the Center for Food
Safety and Applied Nutrition's Library, 200 C St. SW., rm. 3321,
Washington, DC, or may be examined at the Office of the Federal
Register, 800 North Capitol St. NW., suite 700, Washington, DC.
------------------------------------------------------------------------
Microorganism M value \1\
------------------------------------------------------------------------
Aerobic Plate Count (APC)................. 10,000 CFU/gram (g). \2\
Coliforms \3\............................. 3.05 MPN/g. 4,5
Fecal coliforms \6\....................... 3.05 MPN/g.
Salmonella................................ 0. \7\
Listeria monocytogenes.................... 0. \7\
Staphylococcus aureus..................... 3.05 MPN/g.
Bacillus cereus \8\....................... 100 MPN/g or CFU/g.
------------------------------------------------------------------------
\1\ The M value is the maximum allowable number of microorganisms
present in 1 g of dry infant formula.
\2\ CFU/g, colony forming units per g.
\3\ M values for coliforms greater than 3.05 are not violative if
testing for fecal coliforms results in an M value equal to or less
than 3.05.
\4\ MPN/g, most probable number per g.
\5\ The MPN value of 3.05 in this table is derived from the tables of
calculated MPN values that appear in the 8th ed. of the BAM when using
an inoculation series of 0.1, 0.01, and 0.001g (or ml) of the infant
formula sample.
\6\ No testing for fecal coliforms is required when the M value for
coliforms is less than or equal to 3.05.
\7\ None detected.
\8\B. cereus testing must be performed only if the APC exceeds 100 CFU/
g.
(d) Manufacturers 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.
Sec. 106.60 Controls to prevent adulteration during packaging and
labeling of infant formula.
(a) Manufacturers shall examine packaged and labeled infant formula
during finishing operations to ensure that containers and packages in
the lot 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) All infant formula held in a single package shall be the same
product bearing the same code, established under Sec. 106.80. Packaging
used to hold multiple containers of infant formula shall be labeled
with the product name, the name of the manufacturer or shipper, and the
code.
Sec. 106.70 Controls on the release of finished infant formula.
(a) The manufacturer shall hold, or maintain under its control,
each batch of infant formula until it determines that the batch meets
all of its specifications, including those adopted to meet the
requirements of Sec. 106.55 on microbiological contamination and
Sec. 106.91(a) on quality control procedures, and releases the batch
for distribution.
(b) Each batch of infant formula that fails to meet the
manufacturer's specifications shall be rejected. Although the batch may
be reprocessed, any batch of infant formula that is reprocessed shall
be shown to meet the
[[Page 36214]]
requirements of Sec. 106.70(a) before it is released.
(c) An individual qualified by training or experience shall conduct
an investigation of a finding that a batch of infant formula fails to
meet any manufacturer's specifications.
Sec. 106.80 Traceability.
(a) Manufacturers shall ensure traceability by coding infant
formulas in conformity with the coding requirements prescribed in
Sec. 113.60(c) of this chapter for thermally processed low-acid foods
packaged in hermetically-sealed containers, except as provided in
paragraph (b) of this section.
(b) Batches of powdered infant formula that are manufactured in
stages over more than 1 day, in lieu of being coded in accordance with
Sec. 113.60(c) of this chapter, may 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
batch, 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.
Sec. 106.90 Audits of current good manufacturing practice.
Manufacturers of an infant formula, or an agent of such
manufacturers, shall conduct regularly scheduled audits to determine
whether the manufacturer has complied with the current good
manufacturing practice regulations in this subpart. These audits shall
be performed by an individual who, as a result of education, training,
and experience, is knowledgeable in all aspects of infant formula
production and of the agency's regulations concerning current good
manufacturing practice but who has no direct responsibility for the
matters being audited.
Subpart C--Quality Control Procedures
Sec. 106.91 General quality control.
(a) Nutrient testing to ensure that each batch of infant formula
provides nutrients in accordance with Sec. 107.100. Manufacturers shall
test each batch as follows:
(1) Each nutrient premix used in the manufacture of an infant
formula shall be tested for each nutrient 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
batch 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 batch of infant formula.
(3) At the final-product-stage, before distribution of an infant
formula, each batch shall be tested for vitamins A, C, E, and thiamin.
(4) During the manufacturing process or at the final-product-stage,
before distribution, each batch shall be tested for all nutrients
required to be included in such formula under Sec. 107.100 of this
chapter and for any nutrient added by the manufacturer for which
testing is not conducted for compliance with paragraphs (a)(1) or
(a)(3) of this section.
(b) Stability testing. Every 3 months, manufacturers shall collect
representative samples from the final-product-stage of one batch of
each physical form (powder, ready-to-feed, or concentrate) of each
infant formula, at each manufacturing facility. The manufacturer shall
test these samples for each nutrient required under Sec. 107.100 of
this chapter and for any nutrient added by the manufacturer. The
frequency of such testing shall be at the beginning, midpoint, and end
of the shelf life of the infant formula and, depending on the nutrient
and its stability within the matrix of the formulation, with additional
frequency as is necessary to ensure that such formula complies with
section 412 of the Federal Food, Drug, and Cosmetic Act (the act)
throughout the shelf life of the infant formula; except that:
(1) If the infant formula is a new infant formula, manufacturers
shall collect a representative sample from the final-product-stage of
each physical form (powder, ready-to-feed, or concentrate) of the first
batch of the new infant formula and test these samples according to the
requirements of this section; and
(2) If an infant formula 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 act,
the manufacturer shall collect a representative sample from the final-
product-stage of each physical form (powder, ready-to-feed, or
concentrate) of the first batch of the infant formula and shall test
these samples according to the frequency required by this section for
each nutrient that has been or may have been affected by the change.
(c) Quality control records. Manufacturers shall make and retain
quality control records in accordance with Sec. 106.100(e)(5)(i) and
(f)(7).
Sec. 106.92 Audits of quality control procedures.
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 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 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. These audits
shall be performed by an individual who, as a result of education,
training, and experience, is knowledgeable in all aspects of infant
formula production and of the agency's regulations concerning quality
control procedures but who has no direct responsibility for the matters
being audited.
Subpart D--Conduct of Audits
Sec. 106.94 Audit plans and procedures.
(a) Manufacturers shall develop and follow a written audit plan
that is available at the manufacturing facility for FDA 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 assure that an
infant formula provides nutrients in accordance with section 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, but not be limited to:
(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 standard or
specification at points, steps, or stages where control is deemed
necessary to prevent adulteration were handled; and
[[Page 36215]]
(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 Quality factors in infant formulas.
(a) All infant formulas shall, when fed to infants as a sole source
of nutrition, be of sufficient quality to meet the nutritional
requirements for healthy growth. The regulations set forth in this
subpart define the minimum quality factors for infant formulas.
(b) All infant formulas shall be capable of supporting normal
physical growth of infants.
(c) All infant formulas shall be formulated and manufactured such
that the protein is of sufficient biological quality to meet the
protein requirements of infants.
Sec. 106.97 Assurances for quality factors.
(a) General quality factor of normal physical growth. (1) The
manufacturer shall conduct an adequate and well-controlled clinical
study, 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.
(i) The manufacturer shall:
(A) 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.
(B) Collect and maintain data in the study on anthropometric
measures of physical growth, including body weight, recumbent length,
head circumference, and average daily weight increment, and plot the
data on National Center for Health Statistics (NCHS) reference
percentile body weight and body length curves. The NCHS growth charts
are incorporated by reference in accordance with 5 U.S.C. 552(a) and 1
CFR part 51. Copies are available from the Office of Constituent
Operations (HFS-565), Center for Food Safety and Applied Nutrition,
Food and Drug Administration, 200 C St. SW., Washington, DC 20204, may
be examined at the Office of Special Nutritionals (HFS-456), Center for
Food Safety and Applied Nutrition, Food and Drug Administration, 200 C
St. SW., Washington, DC 20204, or the Office of the Federal Register,
800 North Capitol St. NW., suite 700, Washington, DC.
(C) Collect anthropometric measurements at the beginning of the
clinical study, at 2 weeks, at 4 weeks, at least monthly thereafter,
and at the conclusion of the study.
(ii) The clinical study protocol should:
(A) Describe the scientific basis and objectives of the study, the
planned control and treatment feeding regimens, the entrance criteria
used to enroll infants in the study, the method of randomization used
for the assignment of infants to feeding groups, the collection of
specific measurements and other data, the methods used to limit sources
of bias, and the planned methods of statistical analysis;
(B) Describe the necessary qualifications and experience of
investigators;
(C) Be reviewed and approved by an Institutional Review Board (IRB)
in accordance with part 56 of this chapter. The manufacturer shall
establish procedures to obtain written informed consent from parents or
legal representatives of the infants enrolled in the study in
accordance with part 50 of this chapter;
(D) Explain how the study population represents the population for
which the new infant formula is intended and how the study addresses
the intended conditions of use of the formula.
(E) Describe the sample size calculations and the power
calculations and the basis for selecting the sample size and study
design;
(F) Describe the plan to identify and evaluate any adverse effects;
(G) Describe the quality control procedures used to ensure the
validity and reliability of the measurements collected.
(H) Describe and compare the composition of the test and control
formulas.
(I) Describe the basis upon which the test formula is appropriate
for use in evaluating the formula that the manufacturer intends to
market, if the test formula used in a study is not identical to the
formula that is intended to be marketed in the United States.
(2) The manufacturer may request an exemption from the requirements
of paragraph (a)(1) of this section if:
(i) 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 the quality factor requirements in Sec. 106.96;
(ii) 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;
(iii) The manufacturer can demonstrate that the requirements of
paragraph (a)(1) of this section are not appropriate for 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.
(b) Specific quality factor for protein quality of infant formula.
(1) The manufacturer shall collect and maintain data that establish
that the biological quality of protein in an infant formula is
sufficient to meet the protein requirements of infants. The
manufacturer shall establish the biological quality of the protein in
its infant formula by demonstrating that the protein source supports
adequate growth using the Protein Efficiency Ratio (PER) rat bioassay
described in the ``Official Methods of Analysis of the Association of
Official Analytical Chemists,'' 16th ed., sections 43.3.04 and 43.3.05,
``AOAC Official Method 960.48 Protein Efficiency Ratio Rat Bioassay''
which is incorporated by reference in accordance with 5 U.S.C. 552(a)
and 1 CFR part 51. Copies are available from the Association of
Official Analytical Chemists, 481 North Frederick Ave., suite 500,
Gaithersburg, MD 20857, or the Office of Special Nutritionals (HFS-
456), Center for Food Safety and Applied Nutrition, Food and Drug
Administration, 200 C St. SW., Washington, DC 20204, or may be examined
at the Office of the Federal Register, 800 North Capitol St. NW.,
Washington, DC. 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.
(2) The manufacturer may request an exemption from the requirements
of paragraph (b)(1) of this section if:
(i) The protein source, including any processing method used to
produce the protein source, is already used in another infant formula
marketed in the United States, manufactured by the same manufacturer,
and the manufacturer can demonstrate that such infant formula meets the
quality factor requirements prescribed in Sec. 106.96;
(ii) The protein source, including any processing methods used to
produce the protein source, is not a major change from the infant
formula it replaces, and the manufacturer can demonstrate that the
infant formula it replaces meets the
[[Page 36216]]
quality factor requirements prescribed in Sec. 106.96.
6. In newly redesignated subpart F, Sec. 106.100 is amended by
revising paragraphs (e), (f), (g), (j), and (k)(3), and by removing and
reserving paragraph (h) to read as follows:
Sec. 106.100 Records.
* * * * *
(e) Batch production and control records. For each batch of infant
formula, manufacturers shall prepare and maintain records that include
complete information relating to the production and control of the
batch. These records shall include but are not limited to:
(1) The master manufacturing order. The master manufacturing order
shall include but is not limited to:
(i) The significant steps in the production of the batch and the
date on which each significant step occurred;
(ii) The identity of equipment and processing lines used in
producing the batch, if the plant in which the formula is made includes
more than one set of equipment or more than one processing line;
(iii) The identity of each batch or lot of ingredients, containers,
and closures used in producing the batch of formula;
(iv) The amount of each ingredient to be added to the batch of
infant formula and a check (verification) that the correct amount was
added; and
(v) Copies of all labeling used and the results of examinations
conducted during the finishing operations to provide assurance that
containers and packages in the lot 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 their production process
where control is deemed necessary to prevent adulteration. These
records shall include, but not be limited to:
(i) A list of the standards or specifications established at each
point, step, or stage in their production process where control is
deemed necessary to prevent adulteration including documentation of the
scientific basis for each standard or specification;
(ii) The actual values obtained during the monitoring operation,
any deviations from established standards or specifications, and any
corrective actions taken;
(iii) Identification of the person monitoring each point, step, or
stage in their production process where control is deemed necessary to
prevent adulteration.
(4) The conclusions and followup, along with the identity, of the
individual qualified by training or experience who investigated:
(i) Any deviation from the master manufacturing order and any
corrective actions taken;
(ii) A finding that a batch or any of its ingredients failed to
meet the infant formula manufacturer's specifications; and
(iii) A failure to meet any specification or standard 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 batch of infant
formula, including testing on the in-process batch, at the final-
product stage, and on finished product throughout the shelf life of the
product. The results recorded shall include but are not limited to:
(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 batch of
infant formula at the level required by Sec. 107.100, and that any
nutrient added by the manufacturer is present at the appropriate level
with:
(A) A summary table identifying the stages of the manufacturing
process at which the nutrient analysis for each required nutrient under
Sec. 106.91(a) is conducted, and
(B) A summary table on the stability testing program, including the
nutrients tested and the frequency of testing of nutrients throughout
the shelf life of the product under Sec. 106.91(b); and
(ii) For powdered infant formula, the results of any testing
conducted in accordance with Sec. 106.55(b) to verify compliance with
the microbiological quality standards in Sec. 106.55(c).
(f) Manufacturers shall make and retain all records pertaining to
current good manufacturing practice as described in subpart B of this
part, including but not limited to:
(1) Records, in accordance with Sec. 106.20(f)(3), 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 (testing for accuracy against a known reference standard)
shows that a specification or standard 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)(ii), of the
temperatures monitored for cold storage compartments and thermal
processing equipment.
(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
batch 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 automatic
(mechanical or electronic) equipment used in the production or quality
control of infant formula. These records shall include but not be
limited to:
(i) A list of all systems used with a description of computer files
and the 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 diskettes, 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, but are not limited to:
[[Page 36217]]
(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, and 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, and
closures and the conclusions derived therefrom 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) and (b).
(g) The manufacturer shall maintain all records pertaining to
distribution of the infant formula, including records that show that
products produced for export only are exported. Such records shall
include, but not be limited to, 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.
(h) [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 Sec. 106.100(n), but need not be made available to FDA.
(k) * * *
(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.
* * * * *
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, the manufacturer of such formula
shall register with the Food and Drug Administration, Center for Food
Safety and Applied Nutrition, Office of Special Nutritionals, Division
of Programs and Policy Enforcement (HFS-455), Infant Formula
Coordinator, 200 C St. SW., Washington, DC 20204. An original and two
copies of this registration shall be submitted.
(b) The new infant formula registration shall include:
(1) The name of the new infant formula,
(2) The name of the manufacturer,
(3) The place of business of the manufacturer, and
(4) All establishments 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 copies of the notice of its intent to do so shall be submitted.
(b) The new infant formula submission shall include:
(1) The name and 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 (for liquid
formulas) or units per dry weight (for powdered formulas). When
applicable, the submission shall include 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 (including
processing times and temperatures);
(5) Assurance that the infant formula will not be marketed unless
the formula meets the quality factor requirements of section 412(b)(1)
of the Federal Food, Drug, and Cosmetic Act (the act) and the nutrient
content requirements of section 412(i) of the act.
(i) Assurance that the formula meets the quality factor
requirements, which are set forth in subpart E of this part, 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 assuring 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;
(6) Assurance that the processing of the infant formula complies
with section 412(b)(2) of the act. Such assurance shall include but not
be limited to:
(i) A statement that the formula will be produced in accordance
with subparts B and C of this part;
(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 issued by the agency, or that it is 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 products for export only, a manufacturer may submit, in
lieu of the information required under paragraph (b) of this section, 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.
(d) The submission will not constitute notice under section 412 of
the 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 submitter if the
notice is not adequate because it does not meet the requirements of
section 412(c) and (d) of the act.
(e) If a new infant formula submission is adequate, FDA will
acknowledge its receipt and notify the manufacturer of the date of
receipt. The date that the agency receives the new infant formula
[[Page 36218]]
submission is the filing date for the submission. The manufacturer
shall not market the new infant formula before the date that is 90 days
after the filing date.
(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, FDA will assign the new infant formula
submission a new filing date. FDA 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 FDA of the
information that constitutes the substantive amendment to the new
infant formula submission.
Sec. 106.121 Quality factor submission.
To provide assurance that an infant formula meets the quality
factor requirements set forth in subpart E of this part, the
manufacturer shall submit the following data and information:
(a) An explanation, in narrative form, setting forth how all
quality factor requirements of subpart E of this part have been met.
(b) Records that contain the information required by proposed
Sec. 106.97 (a)(1)(i) and (a)(1)(ii) 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.
(c)(1) 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.
(2) Calculation of the statistical power of the study at its
completion.
(d) A report on attrition and on all occurrences of adverse events
during the study, which shall include:
(1) 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;
(2) A clinical assessment, by a health care provider, of the
infant's health during each suspected adverse event;
(3) A complete listing of all infants who did not complete the
study, including the infant's subject number and the reason that each
infant left the study.
(e) The results of the Protein Efficiency Ratio, in accordance with
Sec. 106.97(b).
(f) A statement certifying that the manufacturer has collected and
considered all information and data concerning the ability of the
infant formula to meet the quality factor requirements, and that the
manufacturer is not aware of any information or data that would show
that the formula does not meet the quality factors requirements.
Sec. 106.130 Verification submission.
(a) Manufacturers shall, after the first production and before the
introduction into interstate commerce of the new infant formula, 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 (the act) and is not adulterated. An
original and two copies of this verification shall be submitted.
(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 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, including 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 will not constitute written verification under
section 412(d)(2) of the act 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 submitter
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 (the act), it 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) An explanation of why the change in formulation or processing
may affect whether the formula is adulterated; and
(3) A submission that 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 is the subject of this submission,
together with the identification number assigned by the agency to the
relevant infant formula submission, may be provided in lieu of such
submission.
(c) The submission will not constitute notice under section 412 of
the 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 submitter if the
notice is not adequate because it does not meet the requirements of
section 412(d)(3) of the act.
Sec. 106.150 Notification of an adulterated or misbranded infant
formula.
(a) A manufacturer shall promptly notify FDA in accordance with
paragraph (b) of this section, when the manufacturer has knowledge
(that is, the 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
act or by regulations issued under section 412(i)(2); or
[[Page 36219]]
(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.), FDA's emergency number, 202-857-8400,
shall be used. The manufacturer shall send written confirmation of the
notification to the Food and Drug Administration, Center for Food
Safety and Applied Nutrition, Office of Special Nutritionals, Division
of Programs and Policy Enforcement (HFS-455), Infant Formula
Coordinator, 200 C St. SW., Washington, DC 20204, and to the
appropriate Food and Drug Administration district office specified in
Sec. 5.115 of this chapter.
PART 107--INFANT FORMULA
7. The authority citation for 21 CFR part 107 continues to read as
follows:
Authority: Secs. 201, 403, 412, 701 of the Federal Food, Drug,
and Cosmetic Act (21 U.S.C. 321, 343, 350a, 371).
8. Section 107.1 is added to subpart A to read as follows:
Sec. 107.1 Status and applicability of the regulations in part 107.
(a) The criteria set forth in subpart B of this part describes the
labeling requirements applicable to infant formula under section 403 of
the Federal Food, Drug, and Cosmetic Act (the act). Failure to comply
with any regulation in subpart B of this part will render an infant
formula misbranded under that section of the act.
(b) The criteria set forth in subpart C of this part describes the
terms and conditions for the exemption of an infant formula from the
requirements of section 412(a), (b), and (c) of the act. Failure to
comply with any regulations in subpart C of this part will result in
the withdrawal of the exemption given under section 412(h)(1) of the
act.
(c) Subpart D of this part sets forth the nutrient requirements for
infant formula under section 412(i) of the 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 act.
9. Section 107.10 is amended by revising the introductory text of
paragraph (a)(2) to read as follows:
Sec. 107.10 Nutrient information.
(a) * * *
(2) A statement of the amount, supplied by 100 kilocalories, of
each of the following nutrients and of any nutrient added by the
manufacturer:
* * * * *
10. Section 107.240 is revised 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 Food and Drug Administration 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 the time it 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 Food and Drug Administration 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
recalling firm to carry out the recall since the last report and the
results of these steps.
11. Section 107.250 is amended 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 Food and Drug Administration district
office listed in Sec. 5.115 of this chapter for transmittal to the
Division of Enforcement (HFS-605), Office of Field Programs, Center for
Food Safety and Applied Nutrition, 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 (HFS-605), Office of Field
Programs, Center for Food Safety and Applied Nutrition, 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 it has information, from FDA's own audits or from
other sources demonstrating the recall has not been effective. The
agency may conclude that a recall has not been effective if:
* * * * *
Dated: April 19, 1996.
David A. Kessler,
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 96-17058 Filed 7-8-96; 8:45 am]
BILLING CODE 4160-01-P