[Federal Register: July 9, 1996 (Volume 61, Number 132)]
[Proposed Rules]
[Page 36153-36219]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr09jy96-41]
[[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
[[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 <SUP>1 (Ref.
26) and the Institute for Electrical and Electronics Engineers, Inc.
(IEEE) Standard 610-12-1990 <SUP>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
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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
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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 val