96-17058. Current Good Manufacturing Practice, Quality Control Procedures, Quality Factors, Notification Requirements, and Records and Reports, for the Production of Infant Formula  

  • [Federal Register Volume 61, Number 132 (Tuesday, July 9, 1996)]
    [Proposed Rules]
    [Pages 36154-36219]
    From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
    [FR Doc No: 96-17058]
    
    
          
    
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    Part III
    
    
    
    
    
    Department of Health and Human Services
    
    
    
    
    
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    Food and Drug Administration
    
    
    
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    21 CFR Parts 106 and 107
    
    
    
    Current Good Manufacturing Practice, Quality Control Procedures, 
    Quality Factors, Notification Requirements, and Records and Reports, 
    for the Production of Infant Formula; Proposed Rule
    
    Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / 
    Proposed Rules
    
    [[Page 36154]]
    
    
    
    DEPARTMENT OF HEALTH AND HUMAN SERVICES
    
    Food and Drug Administration
    
    21 CFR Parts 106 and 107
    
    [Docket No. 95N-0309]
    RIN 0910-AA04
    
    
    Current Good Manufacturing Practice, Quality Control Procedures, 
    Quality Factors, Notification Requirements, and Records and Reports, 
    for the Production of Infant Formula
    
    AGENCY: Food and Drug Administration, HHS.
    
    ACTION: Proposed rule.
    
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    SUMMARY: The Food and Drug Administration (FDA) is proposing to revise 
    its infant formula regulations to establish requirements for quality 
    factors and current good manufacturing practice (CGMP); to amend its 
    quality control procedure, notification, and records and report 
    requirements for infant formulas; to require that infant formulas 
    contain, and be tested for, required nutrients and for any nutrient 
    added by the manufacturer throughout their shelf life, and that they be 
    produced under strict microbiological controls; and to require that 
    manufacturers implement the CGMP and quality control procedure 
    requirements by establishing a production and in-process control system 
    of their own design. This action is being taken to improve the 
    protection of infants that use infant formula products.
    
    DATES: Comments by October 7, 1996, except that comments regarding 
    information collection should be submitted by August 8, 1996. The 
    agency proposes that any final rule that may issue based on this 
    proposal become effective 120 days after its date of publication.
    
    ADDRESSES: Submit written comments, data, or information to the Dockets 
    Management Branch (HFA-305), Food and Drug Administration, rm. 1-23, 
    12420 Parklawn Dr., Rockville, MD 20857. Comments regarding information 
    collection to the Office of Information and Regulatory Affairs, OMB, 
    New Executive Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC 
    20503, ATTN: Desk Officer for FDA.
    
    FOR FURTHER INFORMATION CONTACT: Carolyn W. Miles, Center for Food 
    Safety and Applied Nutrition (HFS-456), Food and Drug Administration, 
    200 C St. SW., Washington, DC 20204, 202-401-9858.
    
    SUPPLEMENTARY INFORMATION:
    
    I. Background
    
    A. The Infant Formula Act of 1980
    
        In 1978, a major manufacturer of infant formula reformulated two of 
    its soy products by discontinuing the addition of salt. This 
    reformulation resulted in infant formula products that contained an 
    inadequate amount of chloride, an essential nutrient for growth and 
    development in infants. By mid-1979, a substantial number of infants 
    had been diagnosed with hypochloremic metabolic alkalosis, a syndrome 
    associated with chloride deficiency. Development of this syndrome in 
    these infants was found to be associated with prolonged exclusive use 
    of chloride-deficient soy formulas.
        After reviewing the matter, Congress determined that, to improve 
    protection of infants using infant formula products, greater regulatory 
    control over the formulation and production of infant formula was 
    needed, including modifications of industry's and FDA's recall 
    procedures. Accordingly, Congress passed, and the President signed into 
    law on September 26, 1980, the Infant Formula Act of 1980 (the 1980 
    act) (Pub. L. 96-359). This law amended the act to include section 412 
    (21 U.S.C. 350a).
        In 1982, FDA adopted infant formula recall procedures, establishing 
    subpart D of part 107 of its regulations (21 CFR part 107) (47 FR 
    18832, April 30, 1982), and infant formula quality control procedures 
    (21 CFR part 106 (47 FR 17016, April 20, 1982)). In 1985, FDA further 
    implemented the 1980 act by establishing subparts B, C, and D in 21 CFR 
    part 107 regarding the labeling of infant formula, exempt infant 
    formulas, and nutrient requirements for infant formula, respectively 
    (50 FR 1833, January 14, 1985; 50 FR 48183, November 22, 1985; and 50 
    FR 45106, October 30, 1985).
    
    B. The 1986 Amendments to the Infant Formula Act
    
        In 1986, Congress, as part of the Drug Enforcement, Education, and 
    Control Act of 1986 (the 1986 amendments) (Pub. L. 99-570) completely 
    revamped section 412 of the act to address concerns that had been 
    expressed by Congress and consumers about the 1980 act and FDA's 
    implementation of that statute. These concerns included whether the 
    quality control testing, CGMP, recordkeeping, and recall requirements 
    that FDA had adopted would prevent children ``from ever again being 
    threatened by defective baby formula'' (Ref. 1). The 1986 amendments: 
    (1) State that an infant formula is deemed to be adulterated unless it 
    provides certain required nutrients, meets the quality factor 
    requirements established by the Secretary of Health and Human Services 
    (the Secretary) (and, by delegation, FDA), and is manufactured in 
    accordance with CGMP and quality control procedures established by the 
    Secretary; (2) require that the Secretary issue regulations 
    establishing requirements for quality factors and CGMP, including 
    quality control procedures; (3) require that infant formula 
    manufacturers regularly audit their operations to ensure that those 
    operations comply with CGMP and quality control procedure regulations; 
    (4) expand the circumstances in which manufacturers must make a 
    submission to the agency to include when a manufacturer makes major 
    changes in an infant formula, and when a manufacturer makes changes 
    that may affect whether the formula is adulterated; (5) specify the 
    nutrient quality control testing that must be done on each batch of 
    infant formula; (6) modify the infant formula recall requirements; and 
    (7) give the Secretary authority to establish requirements for 
    retention of records, including records necessary to demonstrate 
    compliance with CGMP and quality control procedures.
        In 1989, the agency responded to the provisions of the 1986 
    amendments on recalls (sections 412(f) and (g) of the act) by 
    establishing subpart E in part 107 (54 FR 4006, January 27, 1989). In 
    1991, the agency adopted infant formula record and record retention 
    requirements that implemented the 1986 amendments by revising 
    Sec. 106.100 (56 FR 66566, December 24, 1991).
        Although the agency has adopted regulations that respond to a 
    number of the provisions of the 1986 amendments, it has not issued 
    regulations on infant formula CGMP and quality factors or revised the 
    notification procedures and quality control procedures to reflect the 
    1986 amendments. Since the passage of the 1986 amendments, agency 
    representatives have visited infant formula plants to observe the 
    manufacturing practice and quality control procedures that they employ, 
    and the agency has solicited and received recommendations on CGMP from 
    the Infant Formula Council. In addition, FDA has contracted with the 
    Committee on Nutrition of the American Academy of Pediatrics (CON/AAP) 
    to obtain expert advice on clinical testing of infant formulas with 
    respect to the quality factor requirements. Moreover, both industry and 
    the agency have
    
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    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,
    
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    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             
    ----------------------------------------------------------------------------------------------------------------
    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.                               
    ----------------------------------------------------------------------------------------------------------------
    
        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-
    
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    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
    
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    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.
    
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        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
    
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    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
    
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    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
    
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    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
    
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    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
    
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    equipment may not be necessary. Likewise, different cleaning compounds 
    may be needed from one plant to another to solve specialized problems 
    such as buildups of mineral deposits. Each manufacturer should study 
    its own plant and develop a procedure that is tailored to that plant's 
    needs and circumstances.
        FDA considers that cleaning, sanitizing, and maintaining equipment 
    and utensils is so important for ensuring that adulterated infant 
    formula is not produced that it is proposing to require that the 
    cleaning, sanitizing, and maintenance be checked for satisfactory 
    completion by an individual qualified to conduct such a review. Such an 
    individual will understand the importance of ensuring that cleaning, 
    sanitizing, and maintenance is properly done, so that equipment and 
    utensils do not contribute to the adulteration of the infant formula. 
    Also, the agency has tentatively concluded that this requirement will 
    ensure that there is accountability for proper performance of this 
    function.
        In addition, proposed Sec. 106.30(f) requires that manufacturers 
    make and retain records on equipment cleaning, sanitizing, and 
    maintenance in accordance with proposed Sec. 106.100(f)(4). As 
    discussed below in the description of the proposed revisions to subpart 
    F, FDA has authority to require these records under section 
    412(b)(4)(A)(i) of the act. These records will document when the 
    cleaning, sanitizing, and maintenance of equipment occurs and will 
    allow the manufacturer to trace all formula that may be affected if 
    cleaning, sanitizing, or maintenance is not properly performed.
        In order to ensure that compressed air or other gases will not 
    contaminate the infant formula with unlawful indirect food additives or 
    other chemical, physical, or microbiological contaminants, FDA is 
    proposing to require in Sec. 106.30(g) that they be appropriately 
    treated. Air or other gases that are not properly treated and filtered, 
    or air that is not of the proper purity, can introduce contaminants 
    into the infant formula that may render it adulterated. Also, 
    compressed gases can be contaminated with oil from the compressor or 
    with filth or microbiological contaminants from the compression, 
    storage, or distribution equipment. Filtration at the air intake and 
    after compression, storage, and distribution is an effective means of 
    reducing the risk that such contaminants will enter the gases and, 
    thereby, the food. Therefore, FDA is also proposing in Sec. 106.30(g) 
    to require the use of a filter when compressed gases are used at 
    product filling machines to replace air removed from the headspace of 
    containers. The filter will prevent contaminants from entering the 
    infant formula during that operation (Ref. 25).
    6. Controls to Prevent Adulteration Due to Automatic (Mechanical or 
    Electronic) Equipment
        Manufacturers of infant formula are increasingly relying on 
    automatic equipment (including mechanical and electronic equipment) in 
    production and quality control. In some cases, manufacturers are 
    replacing manually initiated processing procedures with automated 
    process control systems to ensure proper formulation (addition of 
    ingredients and premixes), mixing, or processing of an infant formula 
    or to test a batch of infant formula. Such automated process control 
    systems frequently consist of a computer or system of computers that 
    controls many or all stages of production, in-process sampling, and 
    testing. In other cases, manufacturers are relying on programmable 
    equipment (such as an autoanalyzer) to perform a critical function, 
    such as testing a batch of infant formula to ensure that the batch 
    meets the nutrient requirements of the act. In all cases, it is 
    important that such systems and equipment function as expected to 
    ensure that the infant formula contains the required nutrients at the 
    required levels and is manufactured according to the CGMP and quality 
    control procedures prescribed under section 412(b)(2) of the act and 
    therefore is not adulterated under section 412(a)(1) or (a)(3) of the 
    act.
        FDA is proposing to define ``hardware,'' ``software,'' ``system,'' 
    and ``validation'' in Sec. 106.35 because the use of these terms will 
    simplify the language of the proposed regulations and will clarify 
    which sections of the proposed regulations apply to hardware only, to 
    software only, or to systems consisting of both hardware and software.
        The definition of ``hardware'' in proposed Sec. 106.35(a)(1) is 
    based on common usage of the term and makes clear that the regulations 
    in proposed Sec. 106.35 apply to all automatic equipment, whether the 
    equipment is mechanical or electronic in nature. Proposed 
    Sec. 106.35(a)(1) also makes clear that electronic equipment includes, 
    but is not limited to, computers. This definition of ``hardware'' 
    distinguishes those elements of equipment that have a physical form 
    from the elements considered to be intellectual property that may be 
    encoded on a physical element such as a diskette, tape, or 
    microprocessing chip.
        Software may be developed by an infant formula manufacturer, by a 
    manufacturer of equipment purchased by the infant formula manufacturer, 
    or by a third party vendor (such as the vendor of a computer operating 
    system). The definition of ``software'' in proposed Sec. 106.35(a)(2) 
    derives from the ISO International Guideline ISO-9000-3 1 (Ref. 
    26) and the Institute for Electrical and Electronics Engineers, Inc. 
    (IEEE) Standard 610-12-1990 2 (Ref. 27) and is consistent with the 
    definition of software in FDA's ``Glossary of Computerized Systems and 
    Software Development Terminology (Ref. 28). FDA is proposing to 
    incorporate this definition into the agency's infant formula 
    regulations because the definition is derived from internationally 
    accepted definitions, includes documentation, applies to the operation 
    of all types of hardware (rather than the narrowly defined ``data 
    processing system'' or ``computer system'' included in the definitions 
    from the ISO and IEEE, respectively), and is consistent with current 
    FDA terminology. Software documentation consists of the instructions on 
    how to use the software. FDA has tentatively concluded that such 
    instructions need to be included in the definition of ``software'' to 
    ensure the proper operation of the software.
    ---------------------------------------------------------------------------
    
        \1\ ISO is a world-wide federation of national standards bodies 
    that set quality assurance guidelines for products that will enter 
    international commerce. The ISO defines software as an 
    ``intellectual creation comprising the programs, procedures, rules 
    and any associated documentation pertaining to the operation of a 
    data processing system'' (Ref. 26).
        \2\ IEEE is a trade organization comprised of several societies. 
    IEEE standards are developed within the technical committees of the 
    IEEE societies and represent a consensus opinion of experts from 
    within IEEE as well as experts who are not members of IEEE. IEEE 
    defines software as ``computer programs, procedures, and possibly 
    associated documentation and data pertaining to the operation of a 
    computer system'' (Ref. 27).
    ---------------------------------------------------------------------------
    
        The definition of ``system'' in proposed Sec. 106.35(a)(3) derives 
    from the IEEE Standard 610.12-1990 (Ref. 27). FDA is proposing to 
    incorporate this definition because many of the requirements in 
    proposed Sec. 106.35 cannot be related to software or hardware alone 
    but rather to systems in which software is used in conjunction with 
    hardware. For example, testing software under simulated conditions of 
    use may be beneficial during the early and middle stages of software 
    development, but validation of the software must be performed in 
    conjunction with the relevant hardware in the operational environment 
    it is
    
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    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
    
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    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
    
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    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 values for each microorganism listed in this 
    proposed rule represent minimum requirements for the microbiological 
    quality of an infant formula based on standards and methods currently 
    available.
        a. Aerobic plate count (APC). Proposed Sec. 106.55(c) establishes 
    an APC M value of 10,000 CFU/g as the maximum level that is consistent 
    with sanitary conditions in the facility in which a powdered infant 
    formula is produced. An APC M value greater than the proposed standard 
    indicates that the formula was produced under insanitary conditions 
    whereby it may have been rendered injurious to health and thus is 
    adulterated under sections 402(a)(4) and 412 of the act.
        The APC is the number of microorganisms that will grow on the APC 
    nutrient medium, incubated at 35  deg.C for 24 hours in air (Ref. 46). 
    ``Microorganisms'' (as defined in
    
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    proposed Sec. 106.3(k)) include yeasts, molds, bacteria, and viruses. 
    The APC medium supports the growth of most microorganisms, including 
    yeasts, molds, and all bacteria required to be tested for under 
    proposed Sec. 106.55(c); however, the APC medium does not support the 
    growth of viruses. The APC count is expressed in CFU's because multiple 
    microorganisms may adhere together or attach to the same location on an 
    agar plate, and microbiologists cannot determine whether one or several 
    individual microorganisms initiated the colony that they detect growing 
    on the plate.
        This M value for the APC proposed in Sec. 106.55(c) is consistent 
    with the standard adopted by the ICMSF and the WHO and the results from 
    FDA and Canadian Surveys (Refs. 41, 42, and 43). The ICMSF based its 
    standards on the degree of health hazard the microorganisms present and 
    conditions of use of the product (Ref. 41).
        FDA has tentatively arrived at this APC M value because the 
    microbial quality of products consumed by infants is of primary concern 
    (Ref. 43). When infant formulas are produced under good commercial 
    processing, the available evidence shows that the APC will be below 
    this M value (Refs. 42 and 43). The agency is notaware of adverse 
    events occurring in infants who consumed products with an APC below 
    this M value.
        b. Coliforms, fecal coliforms, and E. coli. E. colli are bacteria, 
    including some strains that are pathogenic for infants, that thrive in 
    the human intestinal tract. The presence of E. coli in a sample of 
    powdered infant formula is an indicator that the infant formula has 
    been contaminated by manufacturing practices conducted under insanitary 
    conditions and therefore is adulterated under sections 402(a)(4) and 
    412 of the act.
        E. coli bacteria are a subset of a more diverse group of bacteria 
    known collectively as fecal coliforms, which also thrive in the human 
    intestinal tract and therefore are also indicators of fecal 
    contamination. Fecal coliforms are destroyed by pasteurization, and the 
    presence of these microorganisms in a pasteurized product evidences 
    that there has been post-process contamination of the formula (Ref. 
    47). Fecal coliforms in turn are a subset of a still further diverse 
    group of bacteria known as coliforms, which include bacteria that may 
    or may not be indicators of fecal contamination. However, contamination 
    with coliforms is a reliable indicator of post-process contamination of 
    the formula, even if the source of the contamination is not fecal.
        In previously issued guidelines, the agency recommended that 
    powdered infant formulas be tested for the presence of E. coli (54 FR 
    3783); however, one comment on this recommendation suggested that, to 
    allow greater flexibility and reduce the cost for manufacturers, the 
    manufacturer should be given the option of testing for coliforms, fecal 
    coliforms, or E. coli. Specific tests for contamination with E. coli 
    provide the most definitive evidence of fecal contamination, but tests 
    for specific bacteria are more cumbersome than general tests for a 
    group of bacteria such as fecal coliforms. Similarly, general tests for 
    fecal coliforms are more cumbersome than universal tests for an even 
    more diverse group of bacteria such as coliforms.
        The agency is proposing in Sec. 106.55(c) that manufacturers screen 
    their samples of powdered infant formula for evidence of contamination 
    with E. coli using sequential tests for detecting and enumerating 
    coliforms and fecal coliforms. Under the proposal, manufacturers 
    ordinarily would only perform the simplest test (i.e., the test for 
    coliforms) using a test sample of the infant formula. The results of 
    the coliform test determine whether the manufacturer needs to followup 
    with a more specific test for fecal coliforms using as the test sample 
    cultured bacteria prepared during the coliform test. As discussed 
    below, the agency is not proposing that manufacturers followup a 
    positive result in the fecal coliform test with a more specific test 
    for E. coli but rather is proposing that a violative sample in the 
    fecal coliforms test will represent conclusive evidence that the infant 
    formula is adulterated.
        The general test for coliforms is an example of an MPN test. MPN 
    counts are estimates of the number of organisms present in a sample. 
    Methods resulting in an MPN require inoculation of multiple tubes of 
    liquid culture medium with multiple dilutions of the sample. The method 
    specified in FDA's Bacteriological Analytical Manual (BAM) (Ref. 46) 
    requires inoculation of 3 replicate tubes of culture medium with each 
    of 3 sample dilutions, for a total of 9 tubes. The tubes contain 
    culture medium selective for the microorganism of interest. After 
    appropriate incubation (time, temperature, and atmosphere), each tube 
    is scored as positive or negative for the presence of the organism. 
    Examples of a positive result include the presence of growth, a 
    biochemical color change, and the production of gas.
        A mathematical formula is used to calculate the MPN of 
    microorganisms present based on the number of positive tubes in each of 
    the three separate dilutions. Since the calculation in question 
    involves a repetitious process, the mathematical formula used to 
    calculate the MPN has been employed to create easy-to-use tables that 
    are available in the BAM and in other books of statistical tables. Most 
    tables present both a value for the MPN and confidence limits for that 
    value. The calculated table values for the MPN, using BAM methods, are 
    dependent on the level of the dilution in which a positive result is 
    found. The following table values are based on an inoculation series of 
    0.1, 0.01 g, and 0.001 g (or mL) of the infant formula. When no tubes 
    in any dilution produce a positive result, the calculated MPN value is 
    zero.3 When a single tube in the greatest dilution (least 
    concentrated) produces a positive result, the calculated MPN value is 
    equal to 3.01.4 When a single tube in the middle dilution produces 
    a positive result, the calculated MPN value is equal to 3.05.5 In 
    all other situations in which there is a positive result in at least 
    one tube (including a single positive tube in the lowest dilution 
    (greatest concentration)), the calculated MPN value is greater than 
    3.05.
    ---------------------------------------------------------------------------
    
        \3\ The calculated MPN value of zero when no tubes in any 
    dilution produce a positive result is a recent change that appears 
    in the MPN tables of the 8th ed. of the BAM. In previous editions of 
    the BAM, the calculated MPN value when no tubes in any dilution 
    produce a positive result was ``less than 3.''
        \4\ The calculated MPN value of 3.01 when a single tube in the 
    greatest dilution produces a positive result is a recent change that 
    appears in the MPN tables of the 8th ed. of the BAM. In previous 
    editions of the BAM, the calculated MPN value when a single tube in 
    the greatest dilution produces a positive result was 3.
        \5\ The calculated MPN value of 3.05 when a single tube in the 
    middle dilution produces a positive result is a recent change that 
    appears in the MPN tables of the 8th ed. of the BAM. In previous 
    editions of the BAM, the calculated MPN value when a single tube in 
    the middle dilution produces a positive result was 3.
    ---------------------------------------------------------------------------
    
        If no tubes in any dilution produce a positive result in a test for 
    bacterial contamination of a powdered infant formula (i.e., if the MPN 
    is zero), such contamination is unlikely. If a single tube in any 
    dilution produces a positive result in a test for bacterial 
    contamination of the product, such contamination is a possibility. 
    However, there are two situations in which a single positive tube is 
    generally considered to reflect a false positive test result: (1) When 
    no tube in the lowest dilution (greatest concentration) produces a 
    positive result, but a single tube in the middle dilution produces a
    
    [[Page 36172]]
    
    positive result (i.e., the calculated MPN value is equal to 3.01); or 
    (2) when no tube in the lowest dilution produces a positive result, but 
    a single tube in the greatest dilution (least concentration) produces a 
    positive result (i.e., the calculated MPN value is equal to 3.05). FDA 
    considers that if a sample of a powdered infant formula produces 
    positive test results that reflect one of these two situations, 
    bacterial contamination also is unlikely.
        However, in all other situations (e.g., if a single tube in the 
    lowest dilution (greatest concentration) produces a positive result, or 
    if two or more tubes in any dilution produce a positive result), 
    bacterial contamination of a powdered infant formula is likely. 
    Therefore, when the calculated MPN value in a test for bacterial 
    contamination is greater than 3.05, that is if a sample of powdered 
    infant formula produces positive test results in which a single tube in 
    the lowest dilution produces a positive result or in which two or more 
    tubes in any dilution produce a positive result, the powdered infant 
    formula likely is contaminated with bacteria.
        FDA is proposing to use the calculated MPN values in the BAM as a 
    means of setting a numerical specification because these tables are 
    generally available, represent standard practice in the industry, and 
    provide a simple way to classify samples as violative or nonviolative. 
    Based on the above discussion of calculated MPN values, FDA is 
    proposing in Sec. 106.55(c) that powdered infant formula be classified 
    as nonviolative for coliforms in all situations in which the calculated 
    MPN value is less than or equal to 3.05 and classified as presumptively 
    violative for coliforms in all situations in which the calculated MPN 
    value is greater than 3.05. In other words, FDA is proposing that an 
    MPN value of 3.05 represents the maximum allowable number of coliforms 
    present in 1 g of dry infant formula. This proposal is consistent with 
    current FDA infant formula microbiological guidelines. The agency 
    requests comment on the specification of 3.05 MPN/g as the maximum 
    allowable number of coliforms in dry infant formula.
        FDA has stated that infant formula with a calculated MPN value of 
    greater than 3.05 in the coliform test is presumptively violative 
    because, under proposed Sec. 106.55(c), the manufacturer may either 
    consider the sample violative without further testing or may conduct an 
    additional test, the fecal coliform test. Although an MPN value of 
    greater than 3.05 MPN/g is a valid quality indicator of microbial 
    contamination, coliform contamination may not be fecal in origin, and 
    it may not reflect the presence of infant pathogenic microorganisms. 
    Therefore, FDA has tentatively concluded that an infant formula for 
    which an MPN value of greater than 3.05 MPN/g is found in the coliform 
    test need not be considered violative if a negative result is found in 
    a more specific test for fecal coliforms.
        If the coliform test using powdered infant formula samples results 
    in an M value greater than 3.05 MPN/g, the manufacturer may use the 
    cultured bacteria from one or more of the tubes producing the positive 
    result as a sample inoculum for the fecal coliform test. A sample 
    inoculum producing an MPN value in the fecal coliform test of less than 
    or equal to 3.05 would indicate that the coliform contamination is not 
    fecal in origin, because under incubation conditions that are specific 
    for fecal coliforms, the bacteria were not detected. The testing would 
    effectively screen out coliforms that are not of concern, which is not 
    possible with the more general test. Therefore, FDA has tentatively 
    concluded that an MPN value less than or equal to 3.05 in the fecal 
    coliform test be classified as nonviolative. FDA also has tentatively 
    concluded that an MPN value greater than 3.05 in the fecal coliform 
    test is a valid quality indicator demonstrating that the formula 
    contains fecal coliforms such as E. coli and, therefore, is adulterated 
    under sections 402(a)(4) and 412 of the act. The agency is proposing 
    that powdered infant formula that results in an MPN value greater than 
    3.05 in the fecal coliform test be classified as violative.
        If the E. coli test was performed, the sample inoculum would be the 
    cultured bacteria from positive tubes in the fecal coliforms test. 
    However, the agency is not proposing to require specific testing for 
    the presence of E. coli, or to set a specification for an M value for 
    E. coli, because the specification of less than or equal to 3.05 MPN/g 
    in the fecal coliforms test is sufficient to ensure that nonviolative 
    samples do not contain E. coli since E. coli is a type of fecal 
    coliform. Moreover, FDA has tentatively concluded that an MPN value 
    greater than 3.05 in the fecal coliform test is a sufficient quality 
    indicator of fecal contamination that the agency need not propose, as 
    an option, that a manufacturer may conduct an additional specific test 
    for the presence of E. coli. The agency requests comments on the 
    proposed requirements for sequential testing for coliforms and fecal 
    coliforms, with no testing for E. coli.
        c. Salmonella. Tests for the presence of Salmonella involve the 
    enrichment in a broth of the entire analytical unit followed by plating 
    onto culture plates rather than the culture of a series of dilutions 
    that is performed in tests for coliforms. A positive result in a test 
    for Salmonella is based on the detectable presence of the microorganism 
    on the culture plate rather than on the mathematical calculations that 
    result in a MPN.
        Proposed Sec. 106.55(c) requires that powdered infant formula be 
    tested for Salmonella and provides that the formula is adulterated if 
    any Salmonella is found. All serotypes of this genus of bacteria can 
    cause illness (often gastrointestinal) in infants and adults (Refs. 33 
    and 34). The presence of any Salmonella in infant formula could render 
    it injurious to an infant who consumes it because the infectious dose 
    of these bacteria is low (Ref. 35). Therefore, FDA has tentatively 
    concluded that the risk from Salmonella is of such significance that an 
    M value of zero (i.e., none detectable) for Salmonella in infant 
    formula is necessary to protect the health of infants.
        d. Listeria monocytogenes. Tests for the presence of L. 
    monocytogenes are similar to those for Salmonella and a positive result 
    is based on the detectable presence of the microorganism on the culture 
    plate rather than on the mathematical calculations that result in a 
    MPN.
        Proposed Sec. 106.55(c) requires that powdered infant formula be 
    tested for L. monocytogenes and provides that the formula is 
    adulterated if any L. monocytogenes is found. Individuals with immune 
    systems that make them susceptible to infections, such as newborns and 
    infants with incompletely developed immune systems, are susceptible to 
    infection with L. monocytogenes which may cause severe illness or death 
    (Ref. 37). The infectious dose of this bacterium is believed to be low 
    (Ref. 38). Because the specific dose of this bacterium that may cause 
    illness is not known but is believed to be low, FDA has tentatively 
    concluded that the risk from L. moncytogenes is of such significance 
    that an M value of zero (i.e., none detectable) for L. monocytogenes in 
    powdered infant formula is necessary to protect the health of infants. 
    The agency requests comment on this proposed specification for L. 
    monocytogenes.
        e. Staphylococcus aureus. S. aureus is harmful to infants because 
    some strains of this microorganism produce an enterotoxin that causes 
    acute gastrointestinal illness (nausea,
    
    [[Page 36173]]
    
    vomiting, cramps) soon after the food is ingested (Ref. 39). Tests for 
    S. aureus involve liquid culture of series of dilutions as was 
    discussed previously in reference to coliform and fecal coliform 
    testing and results are calculated as MPN based on tables in the BAM. 
    Proposed Sec. 106.55(c) requires that powdered infant formula be tested 
    for S. aureus and establishes an M value of 3.05 for this 
    microorganism. FDA has tentatively concluded that the risk from S. 
    aureus is of such significance that an M value of 3.05 is necessary to 
    protect the health of infants.
        f. Bacillus cereus. Tests for B. cereus involve liquid culture of a 
    series of dilutions as was discussed previously in reference to 
    coliform and fecal coliform testing and results are calculated as MPN 
    based on tables in the BAM. Proposed Sec. 106.55(c) requires that 
    powdered infant formula be tested for B. cereus when the APC exceeds 
    100 CFU/g and establishes an M value for B. cereus of 100 MPN/g or 100 
    CFU/g. This proposed M value for B. cereus is lower than the M value of 
    1,000 MPN/g or 1,000 CFU/g in the current recommended infant formula 
    microbiological guidelines (54 FR 3783). B. cereus can produce diarrhea 
    and vomiting in adult humans (Ref. 40) when food contaminated with at 
    least 105 B. cereus cells is consumed. The infectious dose of B. 
    cereus for infants is not known; however, because the immune systems of 
    infants are not fully developed, infants are more susceptible to 
    bacterial infections than are healthy adults and older children. In the 
    absence of data on the dose of B. cereus capable of causing disease in 
    infants, the agency is concerned that a safety standard of 1,000 MPN/g 
    or 1,000 CFU/g poses a potential risk to infants who consume rehydrated 
    formula because B. cereus in rehydrated powdered infant formula is 
    capable of rapid growth and can reach 4.9 x 106 cells/g within 24 
    hours at 26  deg.C (Ref. 48), a level sufficient to cause disease. 
    Therefore, FDA has tentatively concluded that the risk from B. cereus 
    is of such significance that an M valve that is lower than the current 
    standard of 1,000 MPN/g or 1,000 CFU/g is necessary to protect the 
    health of infants.
        Powdered infant formulas and similar products (e.g., powdered milk) 
    produced under CGMP contain less than 100 MPN/g or 100 CFU/g of B. 
    cereus (Refs. 43 and 48). Additionally, an FDA survey of different 
    production lots of milk-, soy-, and protein hydrolysate-based powdered 
    infant formulas (Ref. 49) showed that the maximum APC was 103 CFU/g, 
    and that the proportion of B. cereus in the samples ranged from 1.2 to 
    63.9 percent of the APC. Therefore, FDA has tentatively concluded that 
    an M value of 100 MPN/g or 100 CFU/g for B. cereus will adequately 
    protect the health of infants. Moreover, because this M value is higher 
    than the B. cereus levels typically found in infant formula currently 
    being produced (Refs. 43, 48, and 49), the proposed M value of 100 MPN/
    g or 100 CFU/g will not be overly burdensome.
        g. Methods. Proposed Sec. 106.55(c) states that the agency intends 
    to determine compliance with the proposed M values using the methods in 
    the BAM. These methods provide reproducible, consistent, and accurate 
    results at different laboratories. The agency proposes to incorporate 
    the BAM by reference in Sec. 106.55(c) in accordance with 5 U.S.C. 
    552(a) and 1 CFR part 51. While manufacturers may use other equivalent 
    methods, a manufacturer who uses methods that do not provide results 
    that are consistent with the results obtained by methods approved by 
    FDA will bear the risk that the firm's product is not in compliance 
    with the law.
        The agency intends to test for Salmonella using the method 
    described in Chapter 5, BAM, including the sample preparation 
    procedures described in section C, paragraph 1 and the sampling plan 
    described in Chapter 1, BAM; for L. monocytogenes using the method 
    described in Chapter 10, BAM and the sampling plan described in Chapter 
    1, BAM; for coliforms, fecal coliforms, and E. coli using the MPN 
    method described in Chapter 4, BAM; for S. aureus using the MPN method 
    described in Chapter 12, BAM; for B. cereus using the MPN or plate 
    count method described in Chapter 14, BAM. The agency intends to 
    determine the APC using the method described in Chapter 3, BAM. All 
    chapter references are to the 8th ed. BAM. FDA intends to update the 
    reference to reflect the most recent edition of the BAM at the time the 
    final rule based on this proposed rule is issued.
        h. Records. Proposed Sec. 106.55(d) requires that manufacturers 
    make and retain records, in accordance with proposed Sec. 106.100 
    (e)(5)(ii) and (f)(7) on the testing of infant formula for 
    microorganisms. As discussed in the description of the revisions to 
    proposed subpart F of part 106, FDA has the authority to require such 
    records under section 412(b)(4)(A)(i) of the act. These records will 
    document whether the batch of powdered infant formula meets the 
    microbiological quality standards of proposed Sec. 106.55(c) and is 
    therefore not adulterated. Records that describe the full methodology 
    for testing powdered infant formula for microbiological quality will 
    provide consistency in the testing of the microbiological quality of 
    the formula, even if different laboratory personnel conduct the tests. 
    The accuracy and reproducibility of microbiological quality testing 
    depend on the procedure used to conduct the test. In addition, the 
    records will provide the manufacturer with data to evaluate any 
    complaints received associated with a particular batch of infant 
    formula by showing whether microbiological contamination could have 
    contributed to the adverse event.
    10. Controls to Prevent Adulteration During Packaging and Labeling of 
    Infant Formula
        Because consumers rely on correct labels to select a formula to 
    meet their childrens' individual needs and to have proper instructions 
    for the use of the formula, FDA is proposing Sec. 106.60(a) which 
    requires manufacturers examine packaged and labeled infant formula to 
    ensure that containers and packages bear the correct labels, use-by 
    dates, and traceability codes. The proposal also requires that labels 
    be designed, printed, and applied so that they remain attached and 
    legible during processing, handling, storage, and use (proposed 
    Sec. 106.60(b)), and that all formula held in a single package be the 
    same product bearing the same traceability code, and that the package 
    carry the product name, name of the manufacturer, and the code 
    (proposed Sec. 106.60(c)).
        These proposed requirements will ensure that infants who have 
    allergies will not be placed at risk by consuming formula containing 
    ingredients to which they are allergic, and that consumers will be 
    aware of the date when the product may no longer be appropriate for 
    use. In addition, the traceability codes will show the origin of the 
    product if there were a recall, and the packaging requirements will 
    make it more difficult for counterfeit formula, or formula with 
    counterfeit labels, to be shipped in interstate commerce. There have 
    been cases of counterfeit shipments in which a single package held more 
    than one product, or held a single product which bore more than one 
    code. The proposed regulations are not only intended to reduce the 
    incidence of counterfeit activities, but to ensure that firms that 
    receive the formula are aware that only one product should be in the 
    packaging, and that all containers should be identified with the code 
    shown on the package. This requirement will not impose an additional 
    burden on industry because manufacturers routinely package a
    
    [[Page 36174]]
    
    single infant formula product bearing the same code.
    11. Controls on the Release of Finished Infant Formula
        Proposed Sec. 106.70(a) requires that the manufacturer determine 
    that each batch of formula meets all of the manufacturer's 
    specifications before releasing the batch for distribution. 
    Specifically, each batch must meet the requirements of Sec. 106.55 on 
    microbiological contamination to ensure that the infant formula does 
    not contain microorganisms at levels that may be injurious to the 
    health of infants and render the formula adulterated and must meet the 
    requirements of Sec. 106.91(a) on quality control procedures to ensure 
    that the infant formula provides the required nutrients at the required 
    levels, and that it provides any nutrient added by the manufacturer. 
    Proposed Sec. 106.70(a) is designed to ensure that any infant formula 
    that fails to meet the manufacturer's specifications, or that is 
    adulterated for any reason, will not be introduced into interstate 
    commerce.
        Proposed Sec. 106.70(b) requires that each batch of infant formula 
    that fails to meet the manufacturer's specifications be rejected. 
    Although proposed Sec. 106.70(b) recognizes that the formula may be 
    reprocessed, it requires that the reprocessed product be shown to meet 
    the requirements of Sec. 106.70(a) before the product is released. FDA 
    has tentatively concluded that this proposed requirement is necessary 
    to ensure that any defect that caused a batch of infant formula to be 
    rejected is corrected before the formula is released into commerce.
        Proposed Sec. 106.70(c) requires that an individual qualified by 
    training or experience conduct an investigation of a finding that a 
    batch of infant formula fails to meet any manufacturer's 
    specifications. This investigation is necessary to determine why such a 
    failure occurred and to assist the manufacturer in developing controls 
    to ensure that such a failure does not reoccur. FDA has proposed to 
    require that the individual who conducts the investigation be qualified 
    to ensure that the investigation is properly conducted.
    12. Traceability
        Section 412(g)(1) of the act requires that each manufacturer make 
    and retain such distribution records as may be necessary to effect and 
    monitor recalls of the formula, and section 412(b)(4)(A)(vi) requires 
    that each manufacturer retain all complaints concerning infant formulas 
    that may reveal the possible existence of a hazard to health. 
    Therefore, infant formulas must be traceable to permit identification 
    of the product that is the subject of a complaint and to make it 
    possible to determine whether that batch of infant formula presents a 
    possible hazard to health. Traceability of an infant formula is also 
    necessary so that the recall requirements of the act can be met.
        The agency's view, based on its experience, is that coding is the 
    most effective method for ensuring traceability. It provides a uniform 
    system that is able to identify large numbers of batches of infant 
    formula with a distinctive code that is easily understood and that can 
    be used by manufacturers, retailers, and consumers. A code also allows 
    a large amount of information to be presented on the container of 
    infant formula in a very small space. Therefore, the agency is 
    proposing, under sections 412 (b)(4)(A)(vi) and (g)(1) and 701(a) of 
    the act that batches of infant formula be identified with a distinctive 
    code that will allow the traceability of an infant formula.
        Current Sec. 106.90 requires that manufacturers ensure traceability 
    by coding all infant formulas in conformity with the coding 
    requirements in Sec. 113.60(c) for thermally processed low- acid foods 
    packaged in hermetically sealed containers. Section 113.60(c) requires 
    that the code identify the establishment where the product is packed, 
    the product contained therein, the year packed, the day packed, and the 
    period during which packed, and that the packing period code be changed 
    with sufficient frequency to permit ready identification of lots during 
    their sale and distribution. FDA is proposing to carry the requirement 
    that manufacturers code their product in accordance with Sec. 113.60(c) 
    forward in proposed Sec. 106.80(a).
        FDA has tentatively determined that it is appropriate to code 
    liquid infant formulas in this manner because they are thermally 
    processed low-acid foods, and a batch is produced in a relatively short 
    period of time, usually a day. It also may be appropriate for coding 
    some powdered infant formulas in this manner if they are processed in a 
    short enough time to make the day packed and the period during which 
    packed meaningful information.
        Proposed Sec. 106.80(b) allows for alternative coding of batches of 
    powdered infant formula. Powdered infant formula is usually 
    manufactured in stages over a longer period of time than liquid infant 
    formula. Some powdered infant formulas are dry mixed in a number of 
    stages over an extended period of time. In other cases, powdered infant 
    formula is mixed in liquid form at one manufacturing facility and 
    shipped to a second site for spray drying and packaging. Powdered 
    infant formula manufacturing is often not completed in a short enough 
    period of time for coding based on the date packed or the period of 
    time in which it was packed to be meaningful information. Therefore, 
    under the alternate method that FDA is proposing, a sequential code 
    would be assigned so that all the essential information needed to track 
    any problems with the infant formula could be determined.
    13. Audits of CGMP
        Proposed Sec. 106.90 requires that manufacturers (or their agents) 
    conduct regularly scheduled audits to determine whether they are 
    complying with CGMP. This provision derives from section 
    412(b)(2)(B)(iv) of the act, which requires that the CGMP include ``the 
    conduct by the manufacturer of an infant formula or an agent of such 
    manufacturer of regularly scheduled audits to determine that such 
    manufacturer has complied with the regulations prescribed under'' 
    section 412(b)(2)(A) of the act. Section 412(b)(2)(A) requires that the 
    Secretary (and by delegation FDA) establish CGMP's by regulation.
        FDA is proposing to require that regularly scheduled audits be part 
    of CGMP because such audits are the best way to ensure overall 
    compliance with CGMP and to identify recurring problems that may 
    dictate an alteration in the master manufacturing order. For example, 
    regularly scheduled audits of all deviations from the manufacturer's 
    specifications or procedures will accentuate deviations that occur 
    repeatedly and will enable the manufacturer to identify specifications 
    or procedures that should be reassessed.
        Section 412(b)(2)(B)(iv) of the act also specifies that such audits 
    are to ``be conducted by appropriately trained individuals who do not 
    have any direct responsibility for the manufacture or production of 
    infant formula.'' FDA is therefore proposing that an individual be 
    knowledgeable in all aspects of infant formula production perform the 
    audit. Without such broad knowledge, the individual conducting the 
    audit will not be able to adequately evaluate the manufacturer's 
    production and in-process control procedures. In addition, because the 
    purpose of the audit is to determine whether the manufacturer is 
    complying with the CGMP regulations issued under section 412(b)(2)(A) 
    of the act, the agency has tentatively concluded that the person 
    conducting the audit needs to be knowledgeable in
    
    [[Page 36175]]
    
    these regulations. Without such knowledge, the person would be unable 
    to make the determinations that are the very purpose of the audit.
        The requirement that the audit be performed by an individual who 
    has no direct responsibility for the matters being audited is one way 
    to ensure the objectiveness of the audit process. The person should be 
    free of any past involvement in the activities being audited because 
    the audit is intended to uncover any problems or shortcomings in the 
    manufacturer's procedures. A person who has been involved may feel that 
    finding problems will reflect poorly on his or her work. Therefore, FDA 
    has tentatively concluded that the audit must be conducted by someone 
    who has no direct interest in the outcome of the audit.
    
    C. Quality Control Procedures
    
    1. Introduction
        FDA is proposing to redesignate and revise subpart B of part 106 as 
    subpart C of part 106. Under this proposal, several sections of the 
    current regulations will be revoked, and several sections will be 
    redesignated without change. The latter sections are being recodified, 
    however, to fit the organization of the proposed regulations. Table II 
    describes the current and proposed regulations as follows:
    
                                    Table II                                
    ------------------------------------------------------------------------
                Current regulation                   Proposed regulation    
    ------------------------------------------------------------------------
                               INGREDIENT CONTROL                           
    ------------------------------------------------------------------------
    Sec.  106.20(a), Sec.  106.20(b)(1), Sec.   Changed by Secs.            
     106.20(b)(2).                               106.91(a)(1) and 106.40(d).
    ------------------------------------------------------------------------
                               IN-PROCESS CONTROL                           
    ------------------------------------------------------------------------
    Sec.  106.25(a)...........................  Sec.  106.50(a)(1).         
    Sec.  106.25(b)(1)........................  Omitted.                    
    Sec.  106.25(b)(2)........................  Sec.  106.91(a)(4).         
    Sec.  106.25(b)(3)........................  Sec.  106.91(a)(2).         
    Sec.  106.25(b)(4)........................  Sec.  106.91(a)(4) with     
                                                 modification.              
    Sec.  106.25(b)(5)........................  Sec.  106.91(a)(3) with     
                                                 modification.              
    ------------------------------------------------------------------------
                           FINISHED PRODUCT EVALUATION                      
    ------------------------------------------------------------------------
    Sec.  106.30(a)...........................  Sec.  106.91(a).            
    Sec.  106.30(b)(1)(i).....................  Sec.  106.91(a)(3).         
    Sec.  106.30(b)(1)(ii)....................  Sec.  106.91(a) with        
                                                 modification.              
    Sec.  106.30(b)(2), Sec.  106.30(b)(3)....  Sec.  106.91(b) with        
                                                 modification.              
    Sec.  106.30(c)(1)........................  Omitted.                    
    Sec.  106.30(c)(2)........................  Sec.  106.3(i)              
                                                Secs.  106.91(b)(1) and     
                                                 106.97(b)(1) with          
                                                 elimination of the         
                                                 osmolality and vitamin D   
                                                 assay.                     
    Sec.  106.30(d)...........................  Omitted.                    
    ------------------------------------------------------------------------
    
        FDA is proposing quality control procedures under the authority 
    granted by section 412(b)(2), (b)(3), and (b)(4) of the act, which 
    direct the Secretary (and by delegation, FDA) to establish by 
    regulation the quality control procedures that he or she determines are 
    necessary to ensure that an infant formula provides the required 
    nutrients at the required levels. In the Congressional Record of 
    September 27, 1986, Senator Metzenbaum stated: ``The most important 
    provision of this amendment is the simple requirement that each batch 
    of formula must be tested for each essential nutrient that must be 
    contained in the formula'' (Ref. 1). The quality control procedures in 
    proposed subpart C of part 106 are the minimum practices that 
    manufacturers must implement to ensure that the infant formula that 
    they produce contains the required nutrients at the required levels 
    throughout the shelf life of the product. Under section 412(a)(3) of 
    the act, an infant formula is deemed to be adulterated if the 
    processing of the formula does not comply with quality control 
    procedures prescribed by the Secretary.
    2. Nutrient Testing
        Proposed Sec. 106.91(a) describes the testing that FDA has 
    tentatively concluded each manufacturer must conduct on each batch of 
    infant formula to ensure that it provides the required nutrients at the 
    required levels and provides any nutrient added by the manufacturer. 
    FDA is proposing these requirements under the authority of two sections 
    of the act. Section 412(b)(2)(B)(i) of the act provides that the 
    quality control procedures shall include requirements for testing, in 
    accordance with section 412(b)(3), of each batch of infant formula for 
    each required nutrient, before distribution of such batch. Section 
    412(b)(3)(D) of the act states that if the Secretary adds a required 
    nutrient, the Secretary must require that the manufacturer of the 
    infant formula test each batch of such formula for that nutrient in 
    accordance with section 412(b)(3)(A), (b)(3)(B), and (b)(3)(C) of the 
    act.
        Current Sec. 106.20(a) and (b)(2), which FDA is proposing to 
    replace with Sec. 106.91(a)(1), do not require that manufacturers 
    analyze nutrient premixes if the premixes come with a supplier's 
    guarantee or certification. Proposed Sec. 106.91(a)(1), however, 
    requires that each nutrient premix used in the manufacture of an infant 
    formula be tested by the formula manufacturer for each nutrient that 
    the manufacturer is relying on the premix to provide to ensure that the 
    premix complies with the manufacturer's specification. This change is 
    required by section 412(b)(3)(B) of the act. Section 412(b)(3)(B) was 
    included in the 1986 amendments because infant formula manufacturers 
    were increasingly relying on the use of formula premixes, and Congress 
    felt that relying on a premix supplier's written assurance that its 
    premix product was properly tested was inadequate (Ref. 1). In 1985, 
    the Department of Justice sought an injunction against a premix 
    supplier because, ``as a result of inadequate quality control, numerous 
    * * * vitamin and mineral mixes--used in infant formula--have been 
    misbranded and adulterated'' (Ref. 3). The premix supplier entered into 
    a consent decree of permanent injunction that enjoined it from shipping 
    any of its vitamin/mineral premixes for use in infant formulas until it 
    completed a number of specific acts that were designed to improve its 
    quality control (Ref. 50).
        FDA is proposing to redesignate current Sec. 106.25(b)(3) as 
    Sec. 106.91(a)(2), which requires that after the addition of the 
    premix, or at the final-product stage but before distribution, each 
    batch of infant formula be tested to confirm that the nutrients 
    contained in any nutrient premix used in such infant formula are 
    present in each batch of infant formula in the proper concentration. 
    This requirement implements section 412(b)(3)(C)(ii) of the act, which 
    requires that infant formula be tested to ensure that any nutrient 
    premixes used by the manufacturer are actually included in the batch of 
    infant formula in the proper amount. Without this check, inadvertent 
    failure to include the premix could go undetected, and infant formula 
    that is deficient in the nutrients that were to be provided by the 
    premix would be introduced into the market.
        Current Sec. 106.30(b)(1)(i) requires that the manufacturer analyze 
    representative samples of each batch of finished infant formula for 
    specific nutrients to assess process degradation. FDA is carrying 
    forward a modified version of this requirement in proposed 
    Sec. 106.91(a)(3), which requires that each batch of infant formula be 
    tested for vitamins A, C, and
    
    [[Page 36176]]
    
    E and thiamin at the final-product stage, before distribution. This 
    regulation is proposed under section 412(b)(3)(A) of the act, which 
    states: ``At the final product stage, each batch of infant formula 
    shall be tested for vitamin A, vitamin B1, vitamin C, and vitamin E * * 
    *.'' In the Congressional Record, Senator Metzenbaum stated that 
    testing for these vitamins is required at the final-product stage 
    because they are vulnerable to degradation (Ref. 1). Testing at the 
    final-product stage will ensure that these nutrients are present in the 
    infant formula at the end of all the processing steps that may destroy 
    them.
        Proposed Sec. 106.91(a)(4) requires that, before distribution, each 
    batch of infant formula be tested for all nutrients required to be 
    included, and any others that have been included, but for which testing 
    to comply with Sec. 106.91(a)(1) or (a)(3) was not conducted. This 
    proposed provision takes a markedly different tack than current 
    Sec. 106.30(b)(1)(ii), which states that no analyses are needed for 
    linoleic acid, vitamin D, vitamin K, choline, inositol, and biotin 
    before release of a batch of infant formula for commercial or 
    charitable distribution. This change in approach is necessary because 
    section 412(b)(3)(C) of the act, which was added by the 1986 
    amendments, states that each batch of formula must be tested for each 
    nutrient required by the law to be present in an infant formula. Also, 
    manufacturers are adding nutrients not required by Sec. 107.100, such 
    as selenium, to infant formulas. These nutrients meet the definition 
    for ``nutrient'' in proposed Sec. 106.3(m) because they have been 
    identified as essential for infants by NAS through its development of a 
    Recommended Dietary Allowance or an Estimated Safe and Adequate Daily 
    Dietary Intake range. The agency has not objected to the addition of 
    nutrients not required by Sec. 107.100 to infant formulas. However, it 
    is important that the level of these added nutrients be controlled, and 
    that the level of the added nutrient be consistent from batch to batch 
    and be uniform throughout the batch of infant formula.
        The level of a nutrient needs to be controlled because some 
    nutrients can be toxic to an infant if given at too high a level. 
    Controlling the level of the added nutrient for consistency from batch 
    to batch and in a particular batch of infant formula will ensure that 
    the infant receives the essential nutrient on a consistent basis and 
    will also ensure that the infant does not receive too high, or too low, 
    a level of the nutrient because the nutrient was not uniform throughout 
    the batch of infant formula.
    3. Stability Testing
        Current Sec. 106.30(c) requires that the manufacturer, using 
    representative samples collected from finished product batches, conduct 
    stability analysis for selected nutrients with sufficient frequency to 
    substantiate the maintenance of nutrient content throughout the shelf 
    life of the product. The 1986 amendments added subsection 
    412(b)(2)(B)(ii) to the act, which requires ``regularly scheduled 
    testing, by the manufacturer of an infant formula or an agent of such 
    manufacturer, of samples of infant formula during the shelf life of 
    such formula to ensure that such formulas are in compliance with'' 
    section 412 of the act. To implement this section of the act, the 
    agency is redesignating and revising current Sec. 106.30(b)(3) as 
    proposed Sec. 106.91(b), which requires quarterly collection of samples 
    of infant formula for stability testing to provide a check on nutrient 
    stability. This periodic check will alert the manufacturer if nutrient 
    stability has changed in some unpredicted way so that the formula no 
    longer complies with section 412 of the act. Quarterly testing of 
    infant formulas for nutrient stability is currently conducted by the 
    industry (Refs. 51 and 52), and the agency is not aware of any problems 
    that have resulted from this frequency of testing. The agency requests 
    comment on whether this proposed frequency of sample collection for 
    stability testing is appropriate.
        The agency has tentatively concluded that this periodic sample 
    collection to check on nutrient stability must be performed on a batch 
    of each physical form (powder, ready-to-feed, or concentrate) of each 
    infant formula, at each different manufacturing facility, because 
    different forms of the product may contain different ingredients, and 
    different forms of infant formula are subjected to different processing 
    procedures. Therefore, ensuring the nutrient stability of one form of 
    the product, such as the powder, will not answer questions about the 
    nutrient stability of other forms of the product. Thus, the agency has 
    tentatively concluded that each form of the infant formula must be 
    sampled on a periodic basis for nutrient stability. Also, the agency 
    has tentatively concluded that the sampling of one batch of each 
    physical form of each infant formula must be conducted at each 
    manufacturing facility. This proposed requirement is necessary because 
    manufacturers may produce the same infant formula at more than one 
    facility, and the manufacturing conditions at one facility may not be 
    the same as the conditions at another facility. The differences in 
    conditions cannot be allowed to affect the quality of the formula.
        Proposed Sec. 106.91(b) further requires testing at the beginning, 
    midpoint, and end of the shelf life of the infant formula. Testing at 
    the beginning of the shelf life shows that the formula is in compliance 
    with the nutrient requirements of the act when it is released for 
    distribution. Testing at the midpoint of the shelf life will alert the 
    manufacturer if any nutrient is deteriorating at a rate different from 
    that predicted, so that the nutrient may not be in the formula at a 
    level to comply with the act throughout the formula's shelf life. 
    Testing at the end of shelf life will ensure that the formula contained 
    all the nutrients needed to comply with the act throughout its shelf 
    life and will provide continued justification for the predicted shelf 
    life.
        Additional testing may be necessary to ensure that a formula 
    complies with section 412 of the act throughout its shelf life. Such 
    testing is likely to focus on a particular nutrient and its stability 
    within the matrix of the formulation. This additional testing will 
    ensure that, if there is a significant deterioration in the level of 
    the nutrient in the formula, the manufacturer will be aware of this 
    fact and will be able to take steps promptly to have the product 
    removed from the market, before a significant number of infants are 
    exposed to a deficient product.
        The agency is not proposing to specify what frequency is required 
    because manufacturers have experience with the nutrient stability of 
    the infant formula matrices that they produce and are thus in a 
    position to determine how frequently testing is necessary. For example, 
    the manufacturer is in a position to know whether the nutrient levels 
    of a milk-based infant formula need to be tested on a different basis 
    than that of a soy-based product, or whether the nutrient levels of an 
    infant formula that contains hydrolyzed protein needs to be tested more 
    frequently than that of an infant formula that contains non-hydrolyzed 
    protein. Manufacturers will be able to comply with section 
    412(b)(2)(B)(ii) of the act by testing different nutrients at different 
    frequencies. For example, unstable nutrients, such as vitamins, may 
    require testing on a more frequent basis than more stable nutrients, 
    such as minerals. Proposed Sec. 106.91(b) allows the manufacturers the 
    discretion to determine the necessary frequency of testing to ensure 
    that their infant formula complies with the nutrient
    
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    requirements of the act, as long as the minimum testing (i.e., at the 
    beginning, middle, and end of the shelf life) required by proposed 
    Sec. 106.91(b) is accomplished.
        Proposed Sec. 106.91(b)(1) provides for an addition to the 
    stability testing required under Sec. 106.91(b). FDA is proposing that 
    the first batch of each form of a new infant formula be subjected to 
    such testing to ensure that the product complies with the nutrient 
    requirements of section 412 of the act throughout its shelf life.
        Proposed Sec. 106.91(b)(2) requires the sampling of the first batch 
    of an infant formula in which there has been a change in formulation or 
    in processing that could affect whether the formula is adulterated 
    under section 412(a) of the act and requires testing of these samples 
    for each nutrient that has been, or may have been, affected by the 
    change. The change in formulation or processing referred to here would 
    not be a ``major change'' because a ``major change'' would mean that 
    the formula is a ``new infant formula.'' Examples of the types of 
    changes that are subject to proposed Sec. 106.91(b)(2) are: (1) 
    Reducing a ``required nutrient'' in a minor way or increasing a 
    ``required nutrient'' that is subject to maximum limits in Sec. 107.100 
    in a minor way; (2) replacing one nutrient form with another form, such 
    as replacing vitamin A acetate with vitamin A palmitate or replacing 
    calcium carbonate with tricalcium phosphate; (3) changing a time-
    temperature condition of preheating, handling, mixing, or sterilizing 
    an in-process product; or (4) changing the oxygen content of a packaged 
    product that might have a minimal effect on the level of nutrients. 
    Requiring sample collection for stability testing when a manufacturer 
    makes changes such as these in the manufacture of the product will 
    ensure that the manufacturer can verify the predicted shelf life of the 
    changed formula.
        Proposed Sec. 106.91(b)(2) requires that the manufacturer ensure 
    that the infant formula meets all the nutrient requirements of section 
    412 of the act. This provision is proposed under the authority of 
    section 412(b)(2)(A) of the act, which provides for the establishment 
    of CGMP's for infant formulas, including quality control procedures 
    that are necessary to assure that the infant formula provides nutrients 
    in accordance with section 412 (b) and (i) of the act, as well as 
    section 412(b)(2)(B)(ii). If the formulation or processing of the 
    infant formula has been changed, the manufacturer must consider what 
    nutrients may have been affected by the change and test for each of 
    these nutrients in the final-product stage of the first batch of the 
    changed formula. For example, if the manufacturer makes a change in the 
    amount of a protein source used in the infant formula, the firm must 
    test the formula for protein content and for any nutrients provided 
    endogenously to the formula by the protein, such as minerals like 
    calcium and phosphorus. The manufacturer is aware of how much of each 
    mineral it is relying on the protein source to provide to the formula. 
    When the amount of the protein source used in the formula is changed, 
    the manufacturer must test for the level of all nutrients it relies on 
    the protein source to provide to the formula to ensure that all 
    nutrients in the formula meet the requirement of Sec. 107.100.
    4. Quality Control Records
        Proposed Sec. 106.91(c) requires that manufacturers make and retain 
    records of the results of all testing performed on the batch of infant 
    formula in accordance with proposed Sec. 106.100(e)(5)(i) and a full 
    description of the methodology used in accordance with proposed 
    Sec. 106.100(f)(7). As discussed in the description of the proposed 
    revisions to subpart F of part 106, FDA has authority to require these 
    records under section 412(b)(4)(A)(i) of the act. Providing a record of 
    the results of quality control testing will verify that each nutrient 
    required by Sec. 107.100 is present in each batch of infant formula at 
    the required level, and that any nutrients added by the manufacturer 
    are present at the appropriate level. These records will show the 
    levels of nutrients in the formula and will provide data needed to 
    evaluate a batch of infant formula if problems, such as adverse events 
    in infants, occur later with that particular batch. Records that 
    describe the full methodology used to conduct the quality control 
    testing will provide consistency in the procedure that the manufacturer 
    is using to test for the nutrients in each batch of infant formula, 
    even when different laboratory personnel are conducting the testing. 
    The accuracy and reproducibility of quality control testing depend on 
    the procedure used to conduct the test.
    5. Audits of Quality Control Procedures
        Proposed Sec. 106.92 requires that the manufacturer of an infant 
    formula, or an agent of such a manufacturer, conduct regularly 
    scheduled quality control audits to ensure that an infant formula 
    provides required nutrients and has been manufactured in a manner 
    designed to prevent adulteration. Proposed Sec. 106.92 derives from 
    section 412(b)(2)(B)(iv) of the act, which requires that the quality 
    control procedures prescribed by the Secretary include ``the conduct by 
    the manufacturer of an infant formula or an agent of such manufacturer 
    of regularly scheduled audits to determine that such manufacturer has 
    complied with the regulations prescribed under'' section 412(b)(2)(A) 
    of the act (stating that the Secretary (and FDA by delegation) 
    establish by regulation ``quality control procedures that the Secretary 
    determines are necessary to assure that an infant formula provides 
    nutrients in accordance with'' section 412 (b) and (i) and ``is 
    manufactured in a manner designed to prevent adulteration of the 
    formula''. FDA is proposing to require that regularly scheduled audits 
    be part of quality control procedures because such audits will document 
    compliance with the quality control procedures and will identify 
    recurring problems that may dictate an alteration in the master 
    manufacturing order. For example, regularly scheduled audits of the 
    results of tests of nutrient levels in infant formulas and of any 
    deviations from the manufacturer's specifications or procedures for 
    acceptable nutrient levels will reveal deviations that occur on a 
    repeated basis and will enable the manufacturer to identify 
    specifications or procedures that should be reassessed.
        Proposed Sec. 106.92 further requires that the audits be performed 
    by an individual who, as a result of education, training, and 
    experience, is knowledgeable in all aspects of infant formula 
    production and of the agency's regulations concerning quality control 
    procedures, but who has no direct responsibilities for the matters 
    being audited. The legal authority for this provision, the importance 
    of the responsible individual's knowledge in all aspects of infant 
    formula production and the agency's regulations, and the need for the 
    audit to be performed by an individual who has no direct responsibility 
    for the matters being audited were discussed previously under the 
    proposed CGMP regulations in Sec. 106.90.
        By proposing different regulations (proposed Secs. 106.90 and 
    106.92) that require audits of CGMP and of quality control procedures, 
    the agency is not suggesting that it will require that separate audits 
    be conducted. These regulations are being proposed separately to make 
    clear that the regularly scheduled audits required by section 
    412(b)(2)(B)(iv) of the act are an aspect both of CGMP and of quality 
    control procedures. The agency would have no objection to a combined 
    audit
    
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    of CGMP and of quality control procedures.
    6. Revocation of the Requirement for Determination of Vitamin D by the 
    Rat Bioassay Method
        FDA is proposing to revoke the requirement in current 
    Sec. 106.30(c)(2) for the determination of vitamin D by a rat bioassay 
    method. This rat bioassay for vitamin D is no longer a viable assay 
    because appropriate animals for conducting this test are difficult to 
    acquire (Ref. 53), and an alternate analytical method for the 
    determination of vitamin D in infant formulas has been approved by the 
    Association of Official Analytical Chemists (Ref. 54).
    
    D. Conduct of Audits
    
        Section 412(b)(2)(B)(iv) of the act provides that CGMP and quality 
    control procedures include regularly scheduled audits to determine 
    whether the manufacturer is complying with CGMP, including following 
    the quality control procedures that are necessary to ensure that an 
    infant formula provides the required nutrients at the required levels, 
    and whether it is operating in a manner designed to prevent 
    adulteration of the formula. FDA is proposing to require in 
    Sec. 106.94(a) that manufacturers develop and follow a written audit 
    plan that is available at the manufacturing facility for FDA 
    inspection. A written audit plan is necessary to provide consistency in 
    how audits are conducted and to ensure that the auditor can determine 
    whether the facility is operating in compliance with the applicable 
    procedures.
        Proposed Sec. 106.94(b) requires that the audit plan include the 
    procedures that the manufacturer uses to determine whether the facility 
    is operating in accordance with CGMP, with the applicable quality 
    control procedures, and in a manner designed to prevent adulteration of 
    the infant formula it produces. This proposed requirement derives from 
    current Sec. 106.100(j), which defines audit procedures as the methods 
    used to review the manufacturing and quality control procedures and is 
    intended to direct the manufacturer's attention to the fundamental 
    goals of the manufacturing process in formulating its audit plan.
        Proposed Sec. 106.94(c) sets out the minimum requirements for the 
    audit procedures that are to be employed by manufacturers. Under 
    proposed Sec. 106.94(c)(1) these procedures are to include a review of 
    how the production and in-process control system established under 
    Sec. 106.6(b) is operating. In particular, proposed 
    Sec. 106.94(c)(1)(i) specifies that the evaluation of the production 
    and in-process control system include observation of the production of 
    infant formula and a comparison of the observed process to the written 
    production and in-process control plan required under proposed 
    Sec. 106.6(b). FDA has tentatively concluded that such observations 
    will show whether the production and in-process control system is being 
    followed appropriately, and, if not, they will identify any deviations 
    from the production and in-process control system, so that the 
    manufacturer can take corrective actions to ensure that infant formula 
    is produced in compliance with the production and in-process control 
    system.
        Proposed Sec. 106.94(c)(1)(ii) requires that the evaluation of the 
    production and in-process control system include a review of records of 
    the monitoring of points, steps, or stages where control is deemed 
    necessary to prevent adulteration. As discussed below, proposed 
    Sec. 106.100(e)(3) requires that the batch production and control 
    records document the monitoring of all points where control is deemed 
    necessary to prevent adulteration in the manufacturing of the batch. 
    FDA has tentatively concluded that proposed Sec. 106.94(c)(1)(ii) is 
    necessary because the auditor can observe the production of only a 
    limited number of batches of infant formula. A review of the production 
    and in-process control records of all batches produced in a given 
    period of time will ensure that the production and in-process control 
    system is working appropriately on a continuous basis, will identify 
    any point that monitoring reveals is out of control on a recurring 
    basis, and will identify where the production and in-process control 
    system needs improvement.
        Proposed Sec. 106.94(c)(1)(iii) requires that the evaluation of the 
    production and in-process control system include a review of records of 
    how deviations from any standard or specification at points, steps, or 
    stages where control is deemed necessary to prevent adulteration were 
    handled. As discussed below, proposed Sec. 106.100(e)(4)(iii) requires 
    that the batch records include the conclusions and followup of an 
    investigation of the failure to meet any specification or standard at 
    any point where control is deemed necessary to prevent adulteration. A 
    review of these records as a part of the audit will identify failures 
    that occur on a repeated basis and will show how these failures are 
    handled by the manufacturer. The auditor will be able to evaluate 
    whether the conclusions and followup of these investigations are 
    appropriate for each failure to meet the specification or standard.
        Proposed Sec. 106.94(c)(2) requires that the audit procedures 
    include a review of a representative sample of all records maintained 
    in accordance with proposed Sec. 106.100 (e) and (f). As discussed 
    below, proposed Sec. 106.100(e) sets out the requirements for the batch 
    production and control records, and proposed Sec. 106.100(f) sets out 
    the requirements for records related to observance of CGMP. A review of 
    a representative sample of these records will show the auditor whether 
    there has been compliance with the appropriate regulations in producing 
    the batches of product so that the formula is not adulterated. Section 
    412(b)(2)(B)(iv) of the act states that the audit is conducted to 
    determine whether the manufacturer has complied with the regulations 
    establishing CGMP for infant formulas, including quality control 
    procedures. FDA has tentatively concluded that review of a 
    representative sample of the records maintained in accordance with 
    Sec. 106.100 (e) and (f) is necessary to determine whether the 
    manufacturer is complying with these regulations.
    
    E. Quality Factors for Infant Formulas
    
    1. What Are Quality Factors?
        The agency is proposing to create a new subpart E to implement the 
    quality factor requirements of sections 412 (a)(2) and (b)(1) of the 
    act. Section 412(a)(2) of the act states that an infant formula is 
    adulterated unless it meets the quality factor requirements that are 
    established under section 412(b)(1). Section 412(b)(1) of the act 
    states that the Secretary shall by regulation establish requirements 
    for quality factors, including quality factor requirements for required 
    nutrients for infant formulas to the extent possible consistent with 
    current scientific knowledge. Therefore, it is incumbent on 
    manufacturers to establish that the infant formula that they produce 
    meets the minimum quality factor requirements that FDA adopts.
        What Congress meant by ``quality factors'' is discussed in the 
    report of the House Committee on Interstate and Foreign Commerce that 
    accompanied the 1980 act. The report states that quality factors 
    ``pertain to the bioavailability of a nutrient and the maintenance of 
    levels or potency of nutrients during the expected shelf life of the 
    product'' (Ref. 5). FDA, in proposed Sec. 106.3(o), has defined 
    ``quality factors'' in a manner that encompasses several basic 
    concepts, including the concepts of
    
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    ``bioavailability'' and of ``healthy growth.''
        The concept of ``healthy growth'' was discussed in the report of 
    the House Committee on Interstate and Foreign Commerce that accompanied 
    the 1980 act. The report states that infant formulas are often the sole 
    source of nutrition for infants, and that ``the growth of infants 
    during the first few months of life often determines the pattern of 
    development and quality of health in adult life'' (Ref. 5). FDA 
    considers the concept of ``healthy growth'' to be broad, encompassing 
    all aspects of physical growth and normal maturational development, 
    including maturation of organ systems and achievement of normal 
    functional development of motor, neurocognitive, and immune systems. 
    All of these growth and maturational developmental processes are major 
    determinants of an infant's ability to achieve his/her biological 
    potential, and all can be affected by the nutritional status of an 
    infant.
        ``Bioavailability'' of a nutrient for an infant means that the 
    nutrient is physiologically available in sufficient quantities to 
    perform its metabolic functions (Ref. 55). In a formula product, 
    bioavailability of individual nutrients is affected by the net effect 
    of the formulation and processing of the product on the chemical form 
    of the nutrient. These processes are influenced by such factors as the 
    chemical form of the nutrient in the ingredient source, the chemical 
    form of the nutrient after processing, and the net effect of various 
    inhibitors and enhancers in a food or meal on the chemical form of the 
    nutrient and its ability to be absorbed and utilized by the infant. In 
    the infant, the bioavailability of a nutrient is determined by the net 
    effect of the amount of nutrient that is converted during digestion to 
    an absorbable form, the proportion of the nutrient that is absorbed 
    into the bloodstream, the proportion of the absorbed nutrient that is 
    converted to its biologically useful form, and the proportion that is 
    lost through excretory processes (Ref. 55). Bioavailability varies 
    among nutrients within a given food product and, for a given nutrient, 
    among foods. The factors affecting nutrient bioavailability are complex 
    and can be difficult to predict based on analyzed nutrient values 
    alone.
        Bioavailability issues are particularly critical for infants during 
    the first few months of life, where a single food (infant formula) 
    serves as the sole source of all nutrients at a period when rapid 
    physical growth and development and maturation of various organ systems 
    makes the infant particularly vulnerable to harm by nutritional 
    insults. Unlike the mixed diet of persons beyond infancy where poor 
    bioavailability in one food can be compensated for by other foods in 
    the diet, a problem with bioavailability in an infant formula affects 
    the total amount of nutrient available to that infant for several 
    months after birth. Furthermore, requirements for nutrients are higher 
    per kilogram body weight during early infancy than at any other time 
    during the life cycle. Because numerous critical developmental 
    milestones (e.g., neurocognitive or immune functions) must be achieved 
    by young infants, a nutrient insufficiency during infancy can quickly 
    develop into serious, and in some cases, permanent adverse effects on a 
    range of developmental processes, including physical growth and organ 
    maturation. Thus, a problem with bioavailability is far more critical 
    for a food such as infant formula than it is for foods that are used as 
    part of a mixed diet by the general population.
        Furthermore, the rapidly changing and increasingly complex 
    physical, chemical, and biologically significant characteristics of 
    ingredients used in new and reformulated infant formulas make it 
    important to continually ensure that quality factor requirements are 
    met. Changes in formulation of infant formulas are made by 
    manufacturers for a variety of reasons, including enhancing the 
    functional characteristics of the formula (e.g., to prevent separation 
    of ingredients or to prevent clumping that will plug nipples on 
    bottles), to enhance digestibility of the formula (e.g., different 
    sources or blends of fats), or to improve the nutritional quality 
    (e.g., a different source of protein or of a vitamin or mineral, or 
    adding a nonrequired nutrient such as selenium). For example, in some 
    formulas, novel sources of vegetable oils (e.g., fractions of plant 
    oils that are particularly rich in certain types of fatty acids) have 
    partially or fully replaced cow's milk fat as the fat source (Refs. 56 
    and 57). Whey proteins or highly processed proteins (e.g., hydrolyzed 
    proteins) are now frequently used as partial or complete replacements 
    for more traditional cow's milk protein sources. In other cases, 
    nutrient/nutrient interactions (e.g., high iron inhibiting absorption 
    of zinc) or nutrient/ingredient interactions (e.g., phytates from soy 
    protein isolates inhibiting absorption of zinc, or the replacing of the 
    milk sugar (lactose) that enhances absorption of calcium with a sugar 
    source that does not have this ability) can adversely affect nutrient 
    availability.
        New processing methods may also have unintended consequences when 
    used with established ingredients or formulations. For example, a new 
    processing method that subjects the formula to conditions that are less 
    denaturing to cow's milk proteins than traditional heat treatments 
    could produce a formula that is less digestible and that causes 
    reactivity of the gastrointestinal wall, such as has been seen with 
    whole cow's milk (Ref. 58).
        In summary, consideration of quality factors goes beyond analytical 
    measures of the presence or absence of a nutrient in the formula 
    product and is needed to provide assurance that adverse effects on the 
    nutritional value of the formula for the infant do not unintentionally 
    or unknowingly occur as a result of the formulation or the processing 
    of an infant formula. Chemical analysis of the formula product to 
    define its nutrient composition often overestimates the amount of 
    nutrient that is bioavailable for physiological use by the infant. The 
    quality factors, therefore, provide a means of evaluating whether a 
    nutrient has become less bioavailable than would be expected, so that 
    it is not sufficiently effective to meet its normal nutritive 
    functions, or whether its bioavailability has been enhanced to a level 
    that raises safety concerns.
        Quality factor requirements are distinctly different from quality 
    control procedures. While ``quality control procedures are intended to 
    insure that the safety and nutritional potency of a formula is built 
    into the manufacturing process'' (Ref. 5), quality factors are intended 
    to ensure that an infant formula contains an adequate amount of each 
    nutrient in a form that can be digested, absorbed, and utilized so that 
    the infant's physiological needs for these nutrients will be met (Ref. 
    5). Changes in ingredient sources and processing can affect the 
    chemical forms of nutrients in the formula product. Such changes can 
    affect the digestion and absorption of food nutrients such that: (1) 
    Absorption is incomplete, (2) absorbed nutrients are not in a form that 
    allows use by metabolic pathways, or (3) the nutrient may interact with 
    other dietary substances to cause excessive excretion. Thus, the amount 
    of nutrients (i.e., the analyzable amounts) in formulas must generally 
    be higher than the physiological requirements of infants (i.e., the 
    amounts of nutrients needed by the body to meet metabolic and growth 
    needs of infants). Although these inefficiencies are generally taken 
    into account when recommending nutrient levels for infant formulas, 
    there
    
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    is always the potential for affecting nutrient bioavailabilities in 
    unexpected ways.
        In summary, a demonstration that both the quantitative and quality 
    factor requirements for essential nutrients in an infant formula are 
    met is necessary to ensure that the infant formula is likely to meet 
    all of the known physiological nutritional needs of infants and to 
    ensure that healthy growth and nutritional well-being will be achieved 
    by an infant consuming the infant formula as the sole source of 
    nutrition.
    2. Identification of Quality Factors
        In testimony before the passage of the 1986 amendments, the agency 
    informed the Senate that the state of knowledge and science with 
    respect to quality factors was still evolving, and that, therefore, 
    there was a basis for only one quality factor for a nutrient. (Although 
    the testimony to the Senate does not specify the identity of the 
    nutrient for which there was a basis for a quality factor, the quality 
    factor was the protein efficiency ratio used for assessing protein 
    quality (Ref. 1).) Senator Metzenbaum stressed that the amendments 
    contemplated that additional quality factors would emerge, and that the 
    Secretary should implement requirements for such factors as quickly as 
    scientific advances would allow.
        The agency subsequently took a major step toward establishing 
    quality factors through a contract in 1986 with the CON/AAP. The AAP 
    earlier had published recommendations regarding the quantities of 
    nutrients needed in infant formulas (Ref. 59). These recommendations 
    were relied upon during the development of the nutrient specifications 
    of the act (Ref. 60). In its report to FDA, ``Clinical Testing of 
    Infant Formulas with Respect to Nutritional Suitability for Term 
    Infants'' (Ref. 6), the CON/AAP identified those conditions in which 
    changes in formula composition warranted clinical testing. The CON/AAP 
    stated that ``clinical testing is primarily useful for determining (1) 
    acceptability of the formula, (2) ability of the formula to support 
    normal growth, and (3) availability of selected nutrients.'' The CON/
    AAP also discussed the limitations of the available measurements, 
    providing an assessment of the limits of scientific knowledge.
        The agency has considered the CON/AAP report carefully and has also 
    considered new scientific information published since the release of 
    that report to determine what quality factors are appropriate for 
    nutrients in infant formula. Based on its consideration, FDA is 
    proposing to adopt Sec. 106.96. This section, if adopted, will require 
    that all infant formula be of sufficient quality that it meets the 
    nutritional requirements of infants for healthy growth when fed as the 
    sole source of nutrition, as indicated by a general quality factor for 
    physical growth, assessed using anthropometric measures of infants 
    consuming the formula, and by a nutrient-specific quality factor for 
    protein biological quality, assessed by an animal bioassay using the 
    formula.
        The agency is not proposing to require that manufacturers measure, 
    individually, the absorption, metabolism, metabolic transformation, or 
    utilization of any of the other essential nutrients. These measures are 
    often technically difficult or unavailable, difficult to interpret, or 
    invasive, thus causing unnecessary testing of infants without potential 
    for providing meaningful results. Rather, the agency has tentatively 
    concluded that current scientific knowledge and ethical and practical 
    considerations are supportive only of requiring two quality factor 
    measures: (1) Physical growth of infants consuming the formula as an 
    integrative indicator of the net effect of the overall nutritional 
    quality of the formula, and (2) a rat bioassay of protein quality in 
    the formula product to ensure that the infant's needs for individual 
    amino acids will be met.
        The agency has tentatively determined that these are minimum 
    requirements. The agency recognizes that, on a case-by-case basis as 
    warranted by the formulation and intended use of a particular infant 
    formula, demonstration of additional quality factors may be necessary. 
    For example, a formula intended for use by premature infants who are at 
    a particularly vulnerable developmental stage relative to nutritional 
    needs to support neurocognitive development may need to be subject to 
    testing that includes measurement of this endpoint to ensure that the 
    formula supports healthy growth. In addition, a formula in which a 
    novel fatty acid has been added to enhance the formula's ability to 
    meet nutritional needs for supporting visual development may need to be 
    evaluated to determine whether it has adverse nutritional effects on 
    other aspects of healthy growth (e.g., on development of immune 
    function).
    3. The Regulation
        Proposed Sec. 106.96(a) sets forth quality factor requirements that 
    reflect the minimum measures needed to evaluate the nutritional quality 
    of an infant formula product, taking into account current scientific 
    knowledge and the usefulness of the outcome measures for evaluating 
    quality factors, while minimizing unnecessary testing of infants 
    serving as subjects in clinical trials. Infant formula is defined in 
    the act as a complete or partial substitute for human milk (section 
    201(aa) of the act). Obviously, the greatest need for a nutritionally 
    complete formula that meets all quality factors is when the formula is 
    used as a complete substitute for human milk. When no other form of 
    nutriture is available to the infant, the formula must provide all of 
    the nutrients needed for the healthy growth of the infant. There is no 
    room for error or miscalculation. The absence or an inadequate level of 
    an essential nutrient will be evidenced by growth failure and other 
    signs or symptoms resulting from nutritional insufficiencies. FDA has 
    tentatively concluded, therefore, that an evaluation of the ability of 
    a formula to support healthy growth must be made under its most 
    demanding conditions of use, i.e., when it is used as the sole source 
    of nutrition, because other foods may mask or compensate for 
    deficiencies in the formula that would occur if the formula were used 
    as a complete substitute for human milk, which would produce results 
    that cannot be meaningfully interpreted.
        Proposed Sec. 106.96(b) identifies ``normal physical growth'' as a 
    quality factor. This quality factor reflects the CON/AAP recommendation 
    that the determination of physical growth rate is the most valuable 
    component of the clinical evaluation of an infant formula (Ref. 6). 
    Physical measures of growth such as weight gain are the most widely 
    accepted and used markers of a young infant's overall ability to digest 
    and utilize those nutrients provided by the formula. The very rapid 
    rate of growth in early infancy means that abnormalities in growth rate 
    can be detected in a few months, providing an easily measured and 
    sensitive, although nonspecific, indication of nutritional 
    insufficiencies (Ref. 4). Physical measures of growth rate are easily 
    done, are familiar to both parents and health professionals, and are a 
    normal part of routine office visits. They are noninvasive and pose 
    little or no risk to infants and provide meaningful results for 
    evaluating the ability of an infant formula to support physical growth 
    in very young infants. Thus, the agency has tentatively concluded that 
    the ability of the formula, when fed as a sole source of nutrition, to 
    meet the nutritional requirements of young infants for normal physical 
    growth is a
    
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    necessary indicator of the overall nutritional quality of the formula.
        Proposed Sec. 106.96(c) requires that the protein in infant 
    formulas be of sufficient biological quality to meet the protein 
    nutritional requirements of infants. Protein, while generally discussed 
    as a single nutrient, depends for its nutritive value on the inclusion 
    of all essential amino acids at levels and relative proportions needed 
    to support healthy growth. The protein requirement is really the sum of 
    different requirements for 10 essential amino acids that occur at 
    different levels and proportions in various food protein sources. 
    Protein quality is also affected by differences in digestibility of 
    different protein sources, by factors that modify digestion, and by 
    chemical reactions that affect the ability of enzymes in the infant's 
    gastrointestinal tract to digest and absorb the amino acids in the 
    protein source. Once absorbed, the relative proportions of the amino 
    acids can affect their uptake by body tissues because of competition 
    for receptors and transport systems. Thus, protein quality depends on a 
    number of complex interactions and conditions that can be difficult to 
    predict.
        Chemical analysis of foods generally only measures the amount of 
    total protein present and does not identify specific amino acids or 
    their ability to meet the physiological needs of infants for the 
    essential amino acids. Chemical analysis alone, therefore, is not 
    capable of predicting whether adequate amounts of all essential amino 
    acids are present, or whether the amino acids present are able to 
    support healthy growth in infants. Yet ensuring that the protein in an 
    infant formula's is of high biological value is critical to an infant's 
    health. For example, during the first year of life, the protein content 
    of an infant's body increases from 11 to 15 percent at the same time 
    that the infant's body weight increases by 7 kg. The average increase 
    in body protein is about 3.5 g/day for the first 4 months of life and 
    about 3.1 g/day for the next 8 months. These protein requirements must 
    be met by a formula that not only contains adequate protein but also 
    contains protein of high biological quality in a form that can be 
    utilized by the infant. Because biological quality varies among protein 
    sources and may be adversely affected by processing methods and other 
    constituents present in the formula, the agency has tentatively 
    concluded that the biological quality of the protein in an infant 
    formula is a necessary quality factor. This quality factor will require 
    an evaluation of whether the formula contains the essential amino acids 
    and total nitrogen in the amounts and proportions necessary to permit 
    normal tissue and organ growth and development. As discussed later in 
    this document, the agency is proposing in Sec. 106.97(b) that the 
    biological quality of the test protein be measured by the Protein 
    Efficiency Ratio (PER) rat bioassay and be comparable to the biological 
    quality of the milk protein casein.
        Proposed Sec. 106.96 does not include quality factor requirements 
    for all nutrients required by infants because methods to determine 
    whether these requirements are met are not available or are not 
    practical for most nutrients (e.g., results cannot be meaningfully 
    interpreted, or methods are invasive, thus causing unnecessary testing 
    of infants). Nonetheless, FDA has tentatively concluded that, as the 
    science evolves, establishing quality factor requirements for other 
    nutrients needed by infants would provide assurance, beyond that 
    provided by the general quality factor of physical growth in proposed 
    Sec. 106.96(b) and the specific protein quality factor in 
    Sec. 106.96(c), that a formula will meet the overall nutritional needs 
    of infants. As the science evolves, FDA anticipates being able to 
    progress beyond generalized, nonspecific indicators of overall 
    nutritional intakes (e.g., measures of physical growth), to more 
    specific and sensitive measures of biochemical and functional 
    nutritional status. FDA also has tentatively concluded that, on a case-
    by-case basis, additional quality factors may be needed for a specific 
    formula product if formulation or processing concerns raise sufficient 
    quality factor questions such that additional measures are necessary to 
    adequately ensure that the nutritional quality of the formula supports 
    healthy growth. FDA asks for comment on criteria as to when such 
    measures are required.
    4. Request for Comment on Need for Establishing Requirements for Other 
    Quality Factors
        Proposed Sec. 106.96(b) and (c) set forth minimum requirements for 
    quality factors (physical growth and protein quality) that all infant 
    formulas should meet. FDA has tentatively concluded that these quality 
    factors are consistent with current state-of- the-art science and 
    provide significant information on the nutritional quality of the 
    infant formula without requiring unnecessary or meaningless testing of 
    infant enrollees in studies.
        As discussed above, the 1986 amendments contemplated that when 
    scientific research identified criteria that could be used to establish 
    quality factors for specific nutrients in infant formula, the agency 
    would establish quality factor requirements for those nutrients. 
    Proposed Sec. 106.96 will establish two quality factors (physical 
    growth and protein quality) because the agency has tentatively 
    concluded that there is sufficient scientific evidence of the 
    importance of these quality factors, and because adequate methods exist 
    to meaningfully and ethically measure these factors.
        However, the CON/AAP report discussed other nutrients necessary for 
    healthy growth of infants and for which the report recommended 
    establishing quality factor requirements (Ref. 6). The agency has 
    studied the evidence supporting the establishment of quality factor 
    requirements for these other nutrients, and the methods available for 
    determining whether an infant formula meets quality factor requirements 
    for these nutrients. FDA has tentatively concluded that establishing 
    quality factor requirements for the three additional nutrients 
    recommended by CON/AAP (i.e., (a) fat, as measured by fat balance; (b) 
    calcium and phosphorus, as measured by calcium and phosphorus balance; 
    and (c) iron as measured by iron bioavailability) is not warranted at 
    this time. FDA, however, solicits additional information that it will 
    consider before reaching a final decision on whether the scientific 
    evidence and usefulness of results are sufficient to support 
    establishing these additional quality factor requirements. Therefore, 
    the agency requests comments and information on: (1) The scientific 
    evidence on the importance of the amount, type, and sources of fat, 
    calcium and phosphorus, and iron in infant formula, and (2) the 
    appropriate methods and interpretative criteria to determine whether an 
    infant formula meets the nutritional requirements for fat, calcium and 
    phosphorus, and iron of infants consuming the formula as the sole 
    source of nutrition. The basis upon which the agency is considering 
    establishing quality factor requirements for these nutrients is 
    discussed below.
        a. Fat. The agency requests comment on a quality factor for fat 
    balance that would require that all infant formulas be formulated and 
    manufactured to provide fat in a manner that allows the fat to be 
    absorbed and retained by infants at a level that the energy and other 
    nutritional requirements of the infant are not adversely affected (Ref. 
    6). Normal, healthy, full-term infants fed various mixtures of the fats 
    traditionally used in infant formulas in the United States rarely 
    excrete more than 15 percent of their fat intake (Ref. 6). This level 
    of fat excretion is an indication
    
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    that the fat is highly digestible. The use of a fat with lower 
    digestibility would adversely affect energy balance, could reduce the 
    absorption of fat-soluble vitamins and other nutrients, and could have 
    a negative impact on healthy growth of the infants.
        b. Iron. The agency solicits comment on a quality factor that would 
    require that all infant formula be formulated and manufactured such 
    that the iron used is bioavailable and meets the iron requirements of 
    the growing infant. The maintenance of adequate iron status in the 
    infant is important because iron is required to transport oxygen in the 
    red blood cells to body tissues (as a component of hemoglobin), to 
    supply oxygen to muscle tissue (as a component of myoglobin), and to 
    support normal mental development. Full-term infants are generally born 
    with adequate iron stores to meet their iron needs for the first few 
    months of life, but the iron needs of premature infants and older 
    infants must be met by the diet.
        Iron bioavailability from infant formulas is low compared to the 
    iron bioavailability from human milk (Refs. 61 and 62).
        Nutrient sources and other ingredients, such as protein sources, 
    can affect the chemical form of iron, thus interfering with its 
    potential for absorption (Ref. 63). Furthermore, factors that enhance 
    iron bioavailability from human breast milk are poorly understood and 
    currently are not present in commercial formulas. Consequently, infant 
    formulas are fortified with up to 10 times the amount of iron found in 
    human milk. If, however, the bioavailability of the iron in the infant 
    formula is substantially improved by a change in the formulation or 
    processing of the formula, then reductions in the amounts of iron added 
    to the infant formula may be necessary to prevent the infant from 
    absorbing excessive amounts of iron which could be unsafe because high 
    dietary intakes of iron can adversely interfere with the 
    bioavailabilities of other nutrients (59 FR 51030, October 6, 1994). 
    If, however, the iron was bound to another ingredient such that it 
    interfered with absorption, the infant's physiological needs for iron 
    might not be met. Infant formula iron levels and iron bioavailability, 
    thus, represent a delicate balance between effectiveness and safety 
    that cannot be adequately predicted by chemical analysis of the iron 
    content of the formula, but can best be assessed by measurement of 
    clinical indicators of iron status.
        Early changes in iron nutritional status are not likely to be 
    detected by the general quality factor of physical growth. Therefore, a 
    quality factor requirement for an infant formula to meet the iron 
    requirements of infants, and to contain sufficient bioavailable iron 
    for this purpose, may be needed. The agency, however, is concerned that 
    clinical studies, as described in proposed Sec. 106.97(a), in which 
    selection criteria include requirements that enrollees be healthy, 
    full-term infants aged 0 to 4 and 5 months, may not be sensitive enough 
    to detect significant differences in iron bioavailability of a formula 
    product. Healthy, full-term infants are usually born with adequate iron 
    stores to maintain normal iron status for the first 3 to 4 months of 
    life--the period of time that a clinical trial would be conducted. 
    Without assurance that the test results are meaningful, the agency has 
    tentatively decided not to require a specific quality factor for iron 
    bioavailability.
        c. Calcium and phosphorus. The agency also requests comment on a 
    quality factor that would require that all infant formulas be 
    formulated and manufactured such that the calcium and phosphorus are 
    bioavailable and meet the calcium and phosphorus needs of infants. 
    Calcium and phosphorus are essential for healthy bone mineralization 
    and growth in infants. Calcium bioavailability is of particular concern 
    because inadequate intakes of calcium impair bone mineralization and 
    can cause rickets in severe cases (Refs. 64 and 65).
        Interactions with other ingredients and manufacturing processes can 
    reduce calcium and phosphorus bioavailability. High concentrations of 
    calcium and phosphorus can interact to form insoluble complexes that 
    may be unavailable (Ref. 66). Calcium can interact with free fatty 
    acids and form soaps that are not absorbed (Ref. 66). Lactose-free 
    formulas have been found to have lower calcium absorption than formulas 
    containing this sugar (Refs. 67 and 68).
        Some phosphorus compounds, such as the phytates found in plant 
    protein sources, may not be readily digested and absorbed by infants 
    (Ref. 69). Inadequate dietary phosphorus can cause a loss of calcium 
    from the body as a result of bone resorption (i.e., loss of bone mass) 
    (Ref. 70). Formulation or processing changes that affect other formula 
    ingredients that influence calcium and phosphorus absorption require 
    careful consideration of their potential effects on calcium and 
    phosphorus bioavailability and the calcium and phosphorus status of the 
    infant.
        A dietary insufficiency of calcium and phosphorus of a magnitude 
    that decreases bone formation may not be detected by physical measures 
    of growth (Ref. 71). Therefore, a quality factor requirement for an 
    infant formula to ensure that it meets the calcium and phosphorous 
    requirements of infants, and to ensure that it contains sufficient 
    bioavailable calcium and phosphorus for this purpose, may be needed. 
    FDA is concerned, however, that meaningful measures for assessing the 
    bioavailability of calcium and phosphorus may not be available.
        d. Summary. FDA has tentatively concluded that the clinical and 
    nutritional sciences have not reached a state where specific tests are 
    available that would permit manufacturers to establish that they meet 
    quality factors for each of the essential nutrients listed in 
    Sec. 107.100, except for protein. Therefore, except for the quality 
    factor requirements for physical growth and protein quality discussed 
    above and set forth in proposed Sec. 106.96 (b) and (c), the agency has 
    tentatively concluded that it is not useful to propose quality factor 
    requirements for specific nutrients at this time.
        Thus, to meet the nutritional needs of infants consuming formula, 
    manufacturers must use forms or sources of essential nutrients that are 
    bioavailable. The agency is concerned that manufacturers could 
    unintentionally or unknowingly use forms of nutrients that have a 
    relatively low bioavailability or ingredients or processing methods 
    that will produce interactions that adversely affect the 
    bioavailability of nutrients, thereby adulterating the formula because 
    it no longer meets the nutritional needs of the infant. However, at 
    this time, FDA is not aware of a means to systematically identify those 
    circumstances that could adversely affect all nutrient 
    bioavailabilities. FDA does not believe that it is ethical to 
    unnecessarily subject infants to testing protocols when meaningful 
    results cannot be assured. However, because of the potential 
    seriousness of the public health impact of not meeting quality factors, 
    FDA also believes that it is desirable to establish additional quality 
    factors, as soon as they are warranted by evolving scientific 
    knowledge, to ensure adequate nutrient bioavailability.
        FDA, therefore, requests comment on the: (a) Need for routine 
    testing of quality factors, in addition to measures of physical growth 
    and protein quality; (b) criteria to be used in determining that such a 
    need can be meaningfully implemented, and (c) if a need is established, 
    the type of qualitative and quantitative measurements that could be 
    used by manufacturers to demonstrate
    
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    that an infant formula meets with those quality factors. If FDA 
    receives information demonstrating the need for additional quality 
    factors, it will consider including them in any final rule that results 
    from this proceeding.
    5. Assurances for Quality Factors
        a. Quality factor--physical growth of infants. Proposed 
    Sec. 106.97(a)(1) requires that the manufacturer conduct an adequate 
    and well-controlled clinical study to determine whether the formula 
    supports normal physical growth in infants when it is fed as the sole 
    source of nutrition. The CON/AAP Task Force on Clinical Testing of 
    Infant Formulas (Ref. 6) concluded that the capability to support 
    physical growth is the most widely accepted and used measurement 
    available of the nutritional adequacy of an infant formula. Gains in 
    weight and length of young infants reflect the long-term, integrative 
    physiological processes that can only be achieved if the infant's 
    nutritional needs are met.
        A randomized, controlled study represents the most sensitive type 
    of study to measure the nutritional adequacy of infant formula. The use 
    of concurrent treatment and control groups is in agreement with the 
    CON/AAP Task Force recommendations (Ref. 6) and with the agency's 
    recommendations for human bioavailability studies of drugs (21 CFR 
    320.25). Although comparisons to historical controls (e.g., population 
    reference standards) have been used by some investigators to evaluate 
    growth of infants consuming a particular formula product, this type of 
    study lends itself to misleading results because population reference 
    standards are generally for the total population of infants (regardless 
    of birth weight, health status, socioeconomic status, or other factors 
    that can affect growth unrelated to nutritional components). In a study 
    to evaluate the nutritional adequacy of a formula, on the other hand, 
    selection criteria are usually used to limit enrollment to healthy, 
    full-term infants. Thus, differences or similarities in growth between 
    study infants and population reference standards cannot be meaningfully 
    interpreted. Therefore, the agency is proposing to require that 
    adequate and well-controlled clinical studies be conducted to collect 
    the data needed to determine whether a formula satisfies the quality 
    factor requirements for physical growth. To assist manufacturers in 
    understanding the general principles for adequate and well-controlled 
    clinical studies, FDA has prepared the ``Guideline for the Format and 
    Content of the Clinical and Statistical Sections of New Drug 
    Applications,'' U.S. Department of Health and Human Services, July, 
    1988 (Ref. 72).
        FDA has tentatively concluded that it is necessary to enroll 
    infants into a clinical study shortly after birth, and that the studies 
    be at least 4 months in duration (see proposed 
    Sec. 106.97(a)(1)(i)(A)), to ensure that the study focuses on the 
    period during which infant formula generally serves as the sole source 
    of nutrition, and, thus, the infant is most vulnerable to a problem 
    with a formula since the infant is not consuming other foods that could 
    mask or compensate for a deficiency in the formula. Also, the 
    sensitivity of growth studies for identifying nutritional problems with 
    an infant formula is highest during early infancy. Young infants, those 
    less than 4 to 5 months, allocate a substantially higher percentage of 
    the intakes of energy, protein, and other nutrients for growth than do 
    older infants. After this early period of rapid growth, the rate of 
    physical growth slows, and the allocation of nutrient intakes for 
    growth is lower. Thus, early infancy is the period of greatest 
    nutritional risk and is the age associated with the most sensitive 
    growth phase.
        Because of the rapid rate of growth in infants less than 4 months 
    of age, adverse nutritional impacts that affect growth rate can be 
    detected within a few months (Ref. 4). Growth studies in older infants, 
    where growth rates are of smaller magnitude and where solid foods are 
    also consumed, are not sensitive enough to provide a meaningful 
    evaluation of the ability of the formula to support healthy growth.
        The CON/AAP Task Force (Ref. 6) also recommended that clinical 
    studies be conducted for a period of 3 to 4 months, and that growth be 
    examined at least during the first 8 weeks of life, because nutrient 
    requirements per kg body weight are greatest during this period. It 
    also pointed out that such a study will cover a period when the infant 
    is not consuming solid foods, and the infant formula is fed as a sole 
    source of nutrition.
        Therefore, FDA has tentatively concluded that a clinical trial that 
    lasts at least 4 months will be long enough to detect adverse effects 
    of nutritional inadequacies on growth rate. FDA also has tentatively 
    concluded that a clinical trial must be conducted with infants less 
    than 1 month of age at the time of their entry into the study (see 
    proposed Sec. 106.97(a)(1)(i)(A)) to ensure that the formula is tested 
    during the period of time when growth rate and nutrient requirements 
    are proportionately greatest, and when the infant formula serves as the 
    sole source of nutrition. These requirements are intended to ensure 
    that the study assesses the nutritional adequacy of the formula for 
    supporting normal physical growth in the young infant.
        Under proposed Sec. 106.97(a)(1)(i)(B), the manufacturer will be 
    required to collect and maintain individual and group summary data on 
    anthropometric measures of physical growth and plot the data on 
    National Center for Health Statistics (NCHS) reference percentile body 
    weight and body length curves, which are standard measurements of 
    infant physical growth (Refs. 73, 74, and 75) and provide the most 
    widely accepted assessment of infant growth (Ref. 6).
        Plotting each infant's anthropometric data on NCHS reference 
    percentile body weight and body length curves, and providing individual 
    data on increments of weight gain, provide a means to make a 
    quantitative assessment of the growth pattern over the 4 months 
    duration of the study for individual infants. There is normally wide 
    variation in body weights and lengths among healthy infants, with some 
    being smaller than average and others average or above average. Single 
    point measures of weight or length are difficult to interpret relative 
    to a given infant because one does not know whether, for example, a 
    smaller than average weight is attributable to inadequate nutrition or 
    to a healthy and thriving infant whose body size is smaller than 
    average.
        Over time, young infants tend to individualize their track within a 
    given percentile on population reference growth standards. An infant at 
    the 25th percentile level for weight shortly after birth tends to stay 
    at or near the 25th percentile for weight throughout the first few 
    months of life. When multiple longitudinal measures of weight (or 
    length) of an infant are plotted on a weight-for-age reference chart, a 
    reviewer can make a quick assessment as to whether an infant's pattern 
    of weight or length gain is similar to that expected for healthy 
    infants of the same age, taking into account the range of normal 
    individual variation in body weights and lengths and that infant's 
    percentile track. Similar comparisons can be made with a given infant's 
    weight or length incremental gain data relative to population reference 
    standards. These data allow for identification of infants with 
    unusually slow or rapid growth, an observation that is masked by 
    grouped data.
        Thus, plots of changes in individual infant's weight and length in 
    conjunction with comparisons of increments per unit time of weight or 
    length gains against population
    
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    reference standards allow researchers and reviewers to identify those 
    infants whose growth is not following expected longitudinal patterns 
    and, therefore, for whom a more thorough review of their medical and 
    dietary histories is necessary to assess the possibility that the 
    infant formula is responsible for reduced growth rates in a subgroup of 
    infants. This careful review of individual infant growth patterns in 
    addition to group summary data is particularly important because 
    studies, while adequate to evaluate differences in group means between 
    test and control formulas, often lack the statistical power to detect 
    subgroups of infants whose growth patterns deviate from normal. These 
    data will also provide useful information on possible trends towards 
    failure to thrive or obesity, or on catchup growth in infants who 
    experienced transient adverse effects relative to expected growth 
    rates.
        FDA has tentatively concluded that a comparison of a manufacturer's 
    data to well-established population reference standards can provide the 
    basis for an evaluation of the growth patterns of individual infants to 
    identify, and to provide the basis for an investigation of, possible 
    causes of unusually slow or fast rates of gain. Thus, the agency is 
    proposing that the NCHS growth charts for individuals and for grouped 
    data be incorporated by reference into the regulation (proposed 
    Sec. 106.97(a)(1)(i)(B)).
        Proposed Sec. 106.97(a)(1)(i)(C) requires that the manufacturer 
    collect the anthropometric measurements at the beginning of the 
    clinical study, at 2 weeks and at 4 weeks of the study, at least 
    monthly thereafter, and at the conclusion of the study. These 
    measurements will permit the calculation of incremental gains in the 
    different measurements. Incremental gains, such as weight gain per unit 
    of time, are generally considered the most sensitive indicator of the 
    ability of a formula to support the physical growth of individual 
    infants over time (Ref. 4). Also, because growth rate and nutritional 
    requirements are curvilinear rather than linear during early infancy, 
    multiple measurements help in assessing whether the formula meets the 
    nutritional needs throughout the period of the clinical study and aids 
    in more accurately placing infants in their ``correct'' reference 
    percentile tract, particularly since age of enrollment varies somewhat 
    among infants (although, if adopted, this regulation should serve to 
    minimize that variation). Additionally, measures of an infant's body 
    weight, the most critical anthropometric measure, are subject to a 
    number of measurement errors unrelated to the nutritional value of the 
    formula (e.g., timing of weighing of infant relative to feeding or 
    defecation or urination).
        For these reasons, multiple measures over a relatively long period 
    (e.g., 4 months) provide a more accurate picture of the pattern of 
    growth of infants than do one or two point measures. The agency has 
    tentatively concluded that the requirement of four measurements taken 1 
    month apart will provide a sufficient number of measurements to permit 
    evaluation of whether the formula meets the nutritional needs for 
    physical growth of the infant throughout the study period. However, the 
    agency requests comment, supported by data, on which measurements are 
    needed to provide evidence that the formula meets the nutritional needs 
    for physical growth of infants.
        FDA has tentatively concluded that more frequent measurements are 
    needed during the early stages of the study because variations in 
    measured body weight that are a result of factors unrelated to the 
    nutritional quality of the formula can be particularly serious in early 
    infancy. For example, during the first week of life, there is a normal 
    loss of body weight by the infant because of fluid loss that may reach 
    6 to 10 percent of body weight (Ref. 76). This weight loss will reduce 
    the apparent growth of the infant as measured by body weight. This 
    reduction may affect the ability to evaluate and interpret the weight 
    gain data collected early in the study. FDA has tentatively concluded 
    that requiring more frequent anthropometric measurements, especially 
    for weight, early in the study, increases the ability to accurately 
    place individual infants in the correct percentile track for monitoring 
    their growth patterns in relation to the population reference curves 
    and for monitoring physical growth during the most sensitive part of 
    their growth phase.
        To minimize the burdens of this regulation, FDA has not proposed to 
    require that blood samples obtained from infants during the time period 
    of their enrollment in the clinical study, or at completion of the 
    study, be analyzed for biochemical and clinical indicators of 
    nutritional and growth status. However, the CON/AAP Task Force (Ref. 6) 
    recommended that some blood tests be conducted at the conclusion of 
    required clinical studies to provide a more comprehensive evaluation of 
    the nutritional adequacy of a formula. Thus, the agency requests 
    comments on whether it would be useful for the manufacturer to collect 
    and maintain data on standard laboratory measures, including complete 
    blood count (white blood cell count and red blood cell count), 
    hemoglobin concentration or hematocrit percentage, and serum or plasma 
    concentrations of albumin, urea nitrogen, electrolytes (sodium, 
    potassium, and chloride), alkaline phosphatase, and creatinine. These 
    measurements are standard practice when infants are seen clinically and 
    can be made with very small quantities of blood. The maintenance of 
    these indicators within normal limits at the end of the study provides 
    additional assurance over and above measures of physical growth that 
    the infant's general state of well-being is healthy and ``normal,'' 
    particularly because changes in biochemical measures may occur before 
    detectable differences in physical growth are identified or may not be 
    detected by measures of physical growth. General anthropometric 
    measurements of physical growth provide indirect, although very 
    important, evidence that the formula is able to help the infant 
    maintain overall good health, but they are not as specific, and may not 
    be as sensitive, as are biochemical indicators of health.
        FDA also requests comment on whether requiring some, or all, of the 
    biochemical and clinical tests described above would provide useful and 
    necessary information for determining whether a formula causes adverse 
    consequences that may not be reflected in the quality factor 
    requirements for measurements of physical growth in proposed 
    Sec. 106.97(a)(1)(i).
        The identification of deviations from expected values for these 
    biochemical and clinical measurements, throughout the duration of the 
    clinical study, could serve as an early warning of unexpected risk to 
    infants enrolled in the study and, therefore, result in early actions 
    to prevent undue risk to infant enrollees in the study. Conversely, 
    collection of blood samples throughout the study could discourage 
    parents from continuing their infants in the study, thus causing a high 
    attrition rate and producing final study results that are difficult to 
    interpret.
        Proposed Sec. 106.97(a)(1)(ii) sets forth guidelines for the design 
    of clinical study protocols. A comprehensive clinical study protocol 
    will ensure that individual investigators understand and follow 
    generally accepted scientific principles for the design and conduct of 
    clinical trials, thus enhancing the likelihood of interpretable results 
    while maintaining minimal or no risk to infants enrolled in the 
    studies. In the conduct of all studies, manufacturers should use the 
    general principles,
    
    [[Page 36185]]
    
    described in Sec. 314.126 (21 CFR 314.126) for adequate and well-
    controlled clinical studies to ensure that the design and conduct of 
    the study are adequate to permit scientific review and interpretation 
    of the study's results. Studies that cannot produce meaningful results 
    because of poor or inadequate study design and conduct mean that 
    infants will be subjected to unnecessary testing. Such a situation 
    places infant enrollees at undue risk and is clearly unethical.
        In this section, FDA is not establishing mandatory elements for 
    inclusion in a protocol, nor requiring that manufacturers provide the 
    agency with the protocol used for a study intended to provide data to 
    show that an infant formula meets the quality factor requirements. 
    However, as discussed above, a protocol is an essential part of the 
    design and execution of a well- controlled scientific study. 
    Furthermore, a protocol often provides invaluable information that 
    assists in the analysis and interpretation of the study data. 
    Consequently, the agency strongly encourages manufacturers to develop 
    and use protocols that incorporate the specific elements in proposed 
    Sec. 106.97(a)(1)(ii) in all research studies using infants because 
    these elements will ensure that the study is designed and conducted in 
    a manner that will produce results that will permit meaningful 
    evaluation of the usefulness of the infant formula.
        The steps outlined in proposed Sec. 106.97(a)(1)(ii)(A) represent 
    standard practice in the design and conduct of clinical studies (Ref. 
    72). Proposed Sec. 106.97(a)(1)(ii)(B) states that the clinical study 
    protocol should describe the necessary qualifications and experience of 
    the investigators. It is essential that clinical studies be conducted 
    by personnel with sufficient experience and training to ensure that 
    their work will yield interpretable and meaningful results. If a study 
    is conducted by an investigator who is not qualified, it increases the 
    likelihood that the study will have to be redone, and that more infants 
    will be exposed to risk. Therefore, it is important that in the 
    protocol, the manufacturer define the requisite qualifications to 
    conduct the study it is designing.
        Proposed Sec. 106.97(a)(1)(ii)(C) states that the protocol should 
    be reviewed and approved by an Institutional Review Board (IRB) in 
    accordance with part 56 (21 CFR part 56), and that the manufacturer 
    should establish procedures to obtain written informed consent from the 
    parents or legal representatives of the infants enrolled in the study 
    in accordance with part 50 (21 CFR part 50). These steps are necessary 
    to protect the rights and safety of subjects involved in the studies.
        Proposed Sec. 106.97(a)(1)(ii)(D) states that the clinical study 
    protocol should explain how the study population represents the 
    population for which the new infant formula is intended. FDA has 
    tentatively concluded that such an explanation is necessary so that if 
    questions about the relevance of the study population arise, the answer 
    is readily available and free of any taint that it is a post hoc 
    rationalization. For example, FDA has recently had questions about a 
    study that involved hospitalized infants that were offered to support 
    use of the product on post-discharge infants. If there had been the 
    type of explanation available that FDA is proposing in this guideline, 
    it would have greatly minimized the questions about this product.
        Proposed Sec. 106.97(a)(1)(ii)(D) also states that the clinical 
    study protocol should explain how the study addresses the intended 
    conditions of use of the formula. FDA has tentatively concluded that, 
    by having manufacturers consider this question before the study is 
    conducted, this guideline will prevent clinical studies that are 
    conducted under conditions of use that do not accurately reflect the 
    proposed conditions of use. For example, a clinical study protocol for 
    testing a formula designed to be used by premature infants throughout 
    infancy should explain how the study design will provide information to 
    support the claim that the formula supports healthy growth under these 
    conditions.
        Proposed Sec. 106.97(a)(1)(ii)(E) states that the clinical study 
    protocol should describe the sample size calculations and the power 
    calculations and the basis for selecting the sample size and study 
    design. This information is necessary to establish the likelihood that 
    the study will not fail to detect a real difference, should there be a 
    difference for the measurements of interest, between the infant formula 
    being tested and the control. For example, a study might not find a 
    difference in incremental rate of weight gain between infants consuming 
    two formulas because too few infants were enrolled in the study to 
    provide sufficient statistical power to detect this difference. 
    Inadequate statistical power could mask the nutritional inferiority of 
    a product and could result in the marketing of a formula that does not 
    meet the quality factor requirements and, therefore, is not safe for 
    its intended use. Therefore, FDA has tentatively concluded that this 
    guideline is needed to ensure that manufacturers design their growth 
    studies to be capable of detecting biologically meaningful differences 
    for the endpoints of interest between the two formulas. Identification 
    of differences would raise safety concerns or serious questions of 
    nutritional quality of the test formula product.
        Proposed Sec. 106.97(a)(1)(ii)(F) states that the clinical study 
    protocol should include a plan to identify and evaluate any adverse 
    events. This proposed guideline is necessary to document that 
    appropriate attention is given to the systematic evaluation and 
    recording of any adverse events that may occur during the course of the 
    study. Inadequate planning for and conduct of the monitoring of adverse 
    events may result in an erroneous conclusion that the formula is safe 
    and suitable, when in fact the formula is not safe and suitable for 
    infants under intended conditions of use.
        Proposed Sec. 106.97(a)(1)(ii)(G) states that the clinical study 
    protocol should describe the quality control procedures that the 
    investigator will use to ensure the validity and reliability of the 
    measurements collected. This proposed guideline represents standard 
    practice in the design and conduct of clinical studies and is necessary 
    to allow a meaningful interpretation of study results. Data obtained 
    with unreliable measures, or with indicators that do not accurately or 
    meaningfully measure identified endpoints, may produce misleading study 
    results that are uninterpretable and that suggest that a formula is 
    safe and suitable, when more valid or reliable measures would not have 
    supported this conclusion. The institution of adequate quality control 
    procedures before beginning a study provides a mechanism for 
    manufacturers to ensure that the data collected are reliable, and that 
    the study provides interpretable results.
        Proposed Sec. 106.97(a)(1)(ii)(H) states that the clinical study 
    protocol should describe and compare the composition of the control and 
    test formulas. These descriptions of the control and the test formulas 
    are necessary to establish that the formula used as the control 
    provides an adequate comparison for evaluating the quality factors of 
    the test formula. If the control formula is not comparable to (i.e., 
    bioequivalent to) formulas in current use, differences between the test 
    and control formulas have no meaning. They cannot be generalized to 
    projected conditions of use. For example, comparable or enhanced 
    physical growth in infants consuming a test formula as compared to 
    infants consuming a control formula when the control formula does not 
    meet
    
    [[Page 36186]]
    
    requirements in Sec. 107.100 for nutrients, or is not bioequivalent 
    relative to quality factors to currently marketed formulas in the 
    United States, cannot be interpreted as supporting healthy growth 
    because it is not possible to determine whether the apparent ``equal'' 
    or ``enhanced'' physical growth is attributable to the fact that the 
    formula is nutritionally adequate, or whether the formula looks 
    adequate because it is being compared to a nutritionally inadequate 
    formula. The nature of the differences between control and test 
    formulas will also affect sample size and measurement (endpoint) 
    considerations.
        FDA's experience in reviewing clinical data submitted with 90-day 
    notifications has been that the absence of information on control 
    formulas is not uncommon. Thus, FDA has tentatively concluded that a 
    guideline on the information that needs to be considered in selecting a 
    control formula is necessary to ensure that study results are 
    meaningful and interpretable.
        If the test formula used in a study is not identical to the formula 
    that is intended to be marketed in the United States, proposed 
    Sec. 106.97(a)(1)(ii)(I) states that the clinical protocol should 
    describe the basis upon which the manufacturer has decided that the 
    test formula is appropriate for use in the study. This proposed 
    guideline is necessary to ensure that the manufacturer considers such 
    factors as the bioequivalence of the studied (test) formula relative to 
    the formula that is to be marketed in this country and can document why 
    its choice of test formulas is appropriate. Without this documentation, 
    it would not be possible to determine whether the marketed formula 
    meets the quality factor requirement in proposed Sec. 106.96(b).
        FDA has had experience under the 1986 amendments in which 
    manufacturers have submitted data on test formulas that were 
    significantly different (e.g., in calorie levels) from the formula that 
    they intended to market as evidence of the safety and suitability of 
    the latter formula. In these instances, the agency has had considerable 
    difficulty in interpreting study results. Therefore, if the guidance in 
    proposed Sec. 106.97(a)(1)(ii)(I) is followed, this significant study 
    design issue will be critically reviewed by manufacturers before they 
    initiate their studies, and, as a result, they will be more likely to 
    design and conduct a study that will produce data that can be 
    meaningfully interpreted as evidence that an infant formula is safe, 
    and that it supports healthy growth.
        As provided in proposed Sec. 106.97(a)(2), however, FDA recognizes, 
    that while changes in ingredients or in the processes used in the 
    manufacture of infant formulas can have a significant adverse impact on 
    the levels or availability of nutrients that affect healthy growth of 
    infants, other changes may not be likely to do so. In the latter 
    circumstances, it may be possible to demonstrate that the quality 
    factor requirements are met by means of measures or data that do not 
    involve the use of clinical trials. If such assurances can be provided 
    without clinical trials, then infants will not be subjected to 
    unnecessary testing. Therefore, FDA sets out in proposed 
    Sec. 106.97(a)(2), the circumstances in which a manufacturer can 
    request an exemption from the clinical study requirement.
        Proposed Sec. 106.97(a)(2)(i) provides for an exemption if the 
    manufacturer can cite experience that shows that the ingredient, 
    ingredient mixture, or processing method has been used to make an 
    infant formula that meets the quality factor requirements in proposed 
    Sec. 106.96(a). For example, if the manufacturer has previously 
    submitted information to FDA in response to the quality factor 
    requirements of the act that showed that an infant formula that 
    contains the ingredient or ingredient mixture, or that was produced by 
    the processing method, in question supported adequate physical growth, 
    this information could form the basis on which the new infant formula 
    could qualify for an exemption from this quality factor requirement. 
    Under this provision, FDA will evaluate the experience cited in support 
    of an exemption on a case-by-case basis. FDA requests comment on this 
    proposed provision.
        Proposed Sec. 106.97(a)(2)(ii) provides for an exemption if a 
    manufacturer that markets a formulation in more than one form (such as 
    liquid and powdered forms) can demonstrate that the quality factor 
    requirements are met by the form of the formula that is processed using 
    the method that has the greater potential for adversely affecting the 
    formula's nutrient content and bioavailability. For example, the 
    temperatures used to retort liquid formulas during processing can cause 
    a loss of protein quality compared to powdered forms processed at lower 
    temperatures (Refs. 77 and 78). Thus, if the liquid formula is tested 
    and shown to meet the quality factors requirements, it will provide 
    reasonable assurance that the powdered form of the formula, that is, 
    the less processed form is of appropriate nutritional quality. Thus, 
    FDA tentatively concludes that it would be unnecessary to test the less 
    processed form.
        Proposed Sec. 106.97(a)(2)(iii) provides for an exemption if the 
    manufacturer can demonstrate that the requirements of proposed 
    Sec. 106.97(a)(1) are not appropriate for the formula, and an 
    alternative method or study design for showing that the formula 
    supports healthy growth in infants fed the formula as a sole source of 
    nutrition is available. As stated above, double- blind, well-
    controlled, clinical studies are generally the most powerful and 
    sensitive method for demonstrating that an infant formula will support 
    physical growth. Nonetheless, the agency anticipates that there will be 
    circumstances in which a clinical study of a new infant formula would 
    not be appropriate. For example, double-blind clinical studies would 
    not be appropriate in situations such as those involving some exempt 
    infant formulas in which they would cause withholding of conventional 
    treatment and, therefore, would be unethical. Other situations that may 
    not be amenable to double-blind clinical trials are those in which it 
    would be difficult to enroll an adequate number of infants (e.g., for 
    exempt infant formulas where the formula is intended for a rare 
    disease). Alternative study designs may also be appropriate in 
    situations in which a manufacturer has access to extensive reference 
    data, such as a database on many similarly conducted clinical studies 
    using infants from the same potential study population, provided that 
    the manufacturer can demonstrate that the reference data apply to the 
    new infant formula, its intended use, and its study population. FDA has 
    tentatively concluded that such an exemption will permit flexibility in 
    the design of suitable experimental protocols but still provide 
    reasonable and documentable assurance that the study design can 
    demonstrate the safety and suitability of the infant formula.
        b. Specific quality factors. Proposed Sec. 106.97(b) establishes 
    requirements for demonstrating that a formula meets the protein quality 
    factor requirement in proposed Sec. 106.96(c) and requires that the 
    manufacturer collect and maintain data that establish that the 
    biological quality of protein in an infant formula is sufficient to 
    meet the protein requirements of infants by demonstrating that the 
    protein source supports adequate growth using the PER rat bioassay, 
    which the agency proposes to incorporate by reference. The PER provides 
    an estimate of the bioavailability and relative proportion of the 
    essential amino acids in the protein-containing ingredient.
    
    [[Page 36187]]
    
        A chemical analysis of the protein can identify the amino acids 
    contained in a protein source but does not measure their 
    bioavailability. A protein source may contain the necessary amino 
    acids, but they may be in a form that the infant cannot digest and 
    absorb. Furthermore, processing methods may alter the chemical nature 
    of the protein source, possibly making the protein more resistant to 
    digestion by the infant. FDA has tentatively concluded that the rat 
    bioassay is necessary to establish that the amino acids in a protein 
    source are present, and that adequate amounts and proportions of all 
    essential amino acids are capable of being digested by an infant. Such 
    a showing is particularly important when a manufacturer is using a 
    novel protein source (e.g., a hydrolyzed protein), a new protein 
    mixture, a new processing method that could affect the chemical form or 
    bonding of amino acids, or a formulation that provides an amount of 
    protein near the minimum required level (<2.0 g/100="" kilocalorie="" (kcal))="" specified="" in="" sec.="" 107.100.="" proposed="" sec.="" 106.97(b)(1)="" also="" provides="" that="" if="" the="" manufacturer="" is="" unable="" to="" conduct="" a="" per="" rat="" bioassay,="" it="" must="" demonstrate="" that="" the="" amino="" acid="" composition="" of="" the="" protein="" meets="" the="" known="" amino="" acid="" requirements="" of="" infants="" for="" whom="" the="" formula="" is="" intended.="" for="" example,="" fda="" is="" aware="" that="" a="" per="" would="" not="" provide="" useful="" data="" for="" an="" exempt="" infant="" formula="" intended="" for="" use="" in="" infants="" that="" cannot="" metabolize="" a="" specific="" amino="" acid="" and="" from="" which="" that="" amino="" acid="" has="" been="" purposefully="" omitted="" or="" is="" limited="" to="" a="" level="" inadequate="" to="" support="" healthy="" growth.="" the="" lack="" of="" that="" amino="" acid="" is="" necessary="" for="" the="" dietary="" management="" of="" the="" intended="" infant="" population="" but="" would="" result="" in="" an="" incomplete="" protein="" and="" would="" reduce="" the="" growth="" rate="" of="" the="" rat,="" invalidating="" the="" conditions="" upon="" which="" the="" per="" rat="" bioassay="" is="" based.="" fda="" is="" not="" aware="" of="" alternative="" methods="" for="" ensuring="" bioavailability="" of="" such="" a="" protein="" source.="" in="" these="" circumstances,="" proposed="" sec.="" 106.97(b)(1)="" will="" provide="" an="" alternate="" means="" of="" evaluating="" whether="" the="" protein="" at="" least="" contains="" adequate="" amounts="" of="" essential="" amino="" acids="" to="" meet="" the="" known="" amino="" acid="" requirements="" of="" the="" infant,="" even="" though="" the="" bioavailability="" of="" these="" amino="" acids="" cannot="" be="" assured="" using="" available="" methods.="" proposed="" sec.="" 106.97(b)(2)="" establishes="" the="" circumstances="" in="" which="" a="" manufacturer="" may="" request="" an="" exemption="" from="" the="" requirements="" of="" proposed="" sec.="" 106.97(b)(1).="" proposed="" sec.="" 106.97(b)(2)(i)="" provides="" that="" if="" the="" protein="" source="" (including="" the="" processing="" method="" used="" to="" produce="" it)="" is="" already="" used="" in="" another="" of="" the="" infant="" formulas="" marketed="" by="" its="" manufacturer="" in="" the="" united="" states,="" the="" manufacturer="" may="" request="" an="" exemption="" if="" it="" can="" demonstrate="" that="" such="" other="" infant="" formula="" meets="" the="" quality="" factor="" requirements="" prescribed="" in="" sec.="" 106.96(b)(1).="" the="" purpose="" of="" the="" per="" or="" amino="" acid="" analyses="" is="" to="" estimate="" the="" quality="" of="" the="" protein="" in="" the="" proposed="" formula.="" once="" a="" manufacturer="" has="" established="" standard="" sources="" and="" processing="" of="" protein="" in="" a="" formula,="" and="" has="" demonstrated="" that="" the="" technology="" is="" effective,="" in="" its="" hands,="" in="" producing="" a="" formula="" that="" meets="" the="" quality="" factor="" requirement="" for="" protein,="" other="" formulation="" changes="" would="" not="" be="" expected="" to="" markedly="" affect="" protein="" quality.="" thus,="" the="" quality="" of="" the="" processed="" protein="" would="" be="" retained="" in="" other="" formulas.="" however,="" under="" proposed="" 106.97(b)(2)(i),="" it="" will="" be="" incumbent="" on="" the="" manufacturer="" to="" demonstrate="" that="" the="" quality="" of="" the="" protein="" is="" not="" affected.="" proposed="" sec.="" 106.97(b)(2)(ii)="" provides="" for="" an="" exemption="" if="" the="" protein="" source,="" or="" the="" processing="" method="" used="" to="" produce="" the="" protein="" source,="" in="" the="" infant="" formula="" does="" not="" constitute="" a="" major="" change="" from="" the="" infant="" formula="" that="" it="" replaces,="" and="" the="" manufacturer="" can="" demonstrate="" that="" the="" infant="" formula="" that="" it="" replaces="" meets="" the="" quality="" factor="" requirements="" prescribed="" in="" sec.="" 106.96(b).="" fda="" is="" proposing="" to="" allow="" this="" exemption="" because="" it="" is="" unlikely="" that="" the="" methods="" for="" assessing="" protein="" quality="" prescribed="" are="" sensitive="" enough="" to="" measure="" any="" change="" in="" protein="" quality="" that="" is="" not="" a="" major="" change.="" because="" fda="" has,="" as="" a="" matter="" of="" policy,="" been="" requesting="" that="" infant="" formula="" manufacturers="" submit="" data="" from="" a="" per="" or="" amino="" acid="" analysis="" as="" part="" of="" their="" submission="" 90="" days="" prior="" to="" marketing="" infant="" formula,="" many="" infant="" formulas="" that="" are="" on="" the="" market="" have="" been="" shown="" to="" meet="" the="" proposed="" quality="" factor="" requirement="" for="" protein.="" therefore,="" if="" the="" proposed="" exemption="" criteria="" in="" sec.="" 106.97(b)(2)="" are="" adopted,="" those="" formulas="" that="" contain="" protein="" sources,="" or="" proteins="" which="" were="" produced="" using="" processing="" methods,="" that="" were="" the="" subject="" of="" a="" submission="" to="" fda="" in="" response="" to="" the="" quality="" factor="" requirements="" of="" the="" act="" may="" qualify="" for="" an="" exemption.="" 6.="" request="" for="" comment="" on="" establishing="" assurances="" for="" other="" quality="" factors="" as="" discussed="" above,="" fda="" has="" solicited="" comment="" on="" whether="" to="" establish="" quality="" factor="" requirements="" for="" fat,="" iron,="" and="" calcium="" and="" phosphorus.="" if="" such="" quality="" factors="" are="" adopted,="" appropriate="" methods="" will="" be="" needed="" to="" provide="" assurance="" that="" an="" infant="" formula="" meets="" these="" nutrient-specific="" quality="" factors.="" therefore,="" fda="" discusses="" below="" measurements="" of="" fat="" balance="" and="" of="" calcium="" and="" phosphorus="" balance,="" as="" well="" as="" measurements="" that="" reflect="" iron="" bioavailability.="" the="" agency="" requests="" comments="" and="" information="" on="" these="" or="" other="" methods="" for="" these="" three="" quality="" factors:="" a.="" apparent="" fat="" absorption.="" apparent="" digestibility="" and="" apparent="" absorption="" measure="" the="" amount="" of="" fat="" that="" was="" able="" to="" be="" digested="" and="" absorbed="" by="" the="" infant.="" apparent="" digestibility="" is="" expressed="" as="" a="" percentage="" of="" intake,="" while="" apparent="" absorption="" is="" expressed="" in="" units="" of="" fat="" (e.g.,="" g)="" absorbed="" per="" day.="" if="" a="" quality="" factor="" for="" fat="" were="" established,="" manufacturers="" would="" be="" required="" to="" collect="" and="" maintain="" data="" establishing="" that="" the="" apparent="" digestibility="" or="" apparent="" absorption="" by="" the="" infant="" of="" the="" fat="" in="" an="" infant="" formula="" is="" adequate="" to="" meet="" the="" infant's="" energy="" requirements.="" these="" data="" would="" be="" necessary="" because="" fat="" represents="" the="" major="" dietary="" source="" of="" energy="" for="" the="" infant="" and="" must="" be="" readily="" digested="" and="" absorbed="" if="" the="" formula="" is="" to="" support="" healthy="" growth.="" the="" con/aap="" task="" force="" (ref.="" 6)="" recommended="" that="" studies="" that="" are="" conducted="" to="" determine="" whether="" a="" formula="" meets="" the="" quality="" factor="" for="" fat="" should="" use="" a="" cross-over="" experimental="" design.="" this="" type="" of="" study="" requires="" that="" the="" manufacturer="" compare="" apparent="" fat="" absorption="" of="" infants="" fed="" the="" test="" formula="" at="" one="" time="" and="" a="" currently="" marketed="" formula="" at="" another="" time.="" an="" experiment="" using="" this="" design="" would="" enable="" a="" manufacturer="" to="" make="" measurements="" of="" apparent="" fat="" absorption="" using="" a="" small="" number="" of="" infants,="" since="" the="" variance="" in="" fat="" excretion="" of="" infants="" fed="" most="" fat="" sources="" currently="" available="" is="" less="" than="" 5="" percent.="" furthermore,="" the="" method="" is="" noninvasive,="" is="" easily="" implemented,="" and="" does="" not="" require="" costly="" or="" sophisticated="" equipment="" to="" conduct.="" other="" experimental="" designs="" could="" be="" used="" but="" would="" require="" larger="" numbers="" of="" infants="" and="" would="" be="" more="" expensive.="" thus,="" fda="" asks="" for="" comments="" on="" whether="" there="" should="" be="" a="" specific="" requirement="" that="" manufacturers="" measure="" apparent="" fat="" absorption="" using="" cross-over="" studies.="" the="" con/aap="" task="" force="" (ref.="" 6)="" recommended="" that="" studies="" that="" are="" conducted="" to="" determine="" the="" apparent="" absorption="" of="" fat="" be="" conducted="" such="" that="" measurements="" are="" made="" using="" infants="" fed="" each="" formula="" for="" at="" least="" 72="" hours.="" the="" task="" force="" report="" suggested="" that="" measurements="" of="" apparent="" fat="" absorption="" for="" this="" length="" of="" time="" would="" accurately="" reflect="" the="" apparent="" [[page="" 36188]]="" absorption="" of="" the="" fat="" in="" the="" formula="" being="" tested.="" fda="" is="" considering="" requiring="" that="" a="" study="" of="" at="" least="" 72="" hours="" for="" each="" formula="" tested="" be="" conducted="" and="" requests="" comment="" on="" what="" duration="" would="" be="" appropriate.="" fda="" also="" is="" considering="" whether="" to="" require="" that="" the="" manufacturer="" document="" the="" method="" that="" it="" used="" to="" analyze="" for="" fat="" and="" explain="" the="" reason="" for="" choosing="" that="" method.="" the="" agency="" believes="" that="" this="" information="" is="" important="" because="" the="" method="" used="" to="" analyze="" the="" excreted="" fat="" must="" be="" appropriate="" for="" the="" specific="" type="" of="" fat="" in="" the="" formula.="" fda="" also="" is="" considering="" whether="" circumstances="" exist="" that="" would="" justify="" establishing="" an="" exemption="" from="" the="" requirements="" to="" measure="" fat="" balance.="" fda="" has="" tentatively="" concluded="" that="" the="" reasons="" and="" justification="" for="" such="" an="" exemption="" are="" essentially="" those="" set="" forth="" above="" in="" the="" discussion="" of="" proposed="" sec.="" 106.97(b)(2).="" fda="" requests="" comment="" on="" whether,="" if="" the="" agency="" adopts="" a="" quality="" factor="" for="" fat,="" it="" should="" provide="" for="" exemptions="" from="" testing,="" to="" show="" that="" the="" formula="" meets="" that="" quality="" factor,="" such="" as="" those="" set="" forth="" in="" proposed="" sec.="" 106.97(b)(2),="" and="" to="" allow="" manufacturers="" to="" assure="" the="" agency="" that="" their="" products="" meet="" that="" quality="" factor="" requirement="" without="" subjecting="" infants="" to="" unnecessary="" testing.="" b.="" calcium="" and="" phosphorus="" balance.="" if="" fda="" were="" to="" establish="" a="" quality="" factor="" for="" calcium="" and="" phosphorus,="" manufacturers="" would="" be="" required="" to="" collect="" and="" maintain="" data="" from="" clinical="" studies="" conducted="" in="" infants="" to="" show="" that="" the="" calcium="" and="" phosphorus="" contained="" in="" the="" infant="" formula="" are="" sufficient="" to="" meet="" the="" infant's="" requirements.="" there="" are="" currently="" no="" satisfactory="" clinical="" laboratory="" measurements="" that="" are="" practical="" for="" directly="" assessing="" calcium="" and="" phosphorus="" nutritional="" status="" in="" infants="" (ref.="" 79).="" furthermore,="" there="" are="" no="" accurate="" indirect="" measurements="" that="" could="" be="" made="" on="" the="" infant="" formula="" itself="" that="" would="" be="" useful="" in="" predicting="" how="" effective="" the="" amount="" and="" the="" sources="" of="" calcium="" and="" phosphorus="" in="" the="" formula="" would="" be="" in="" meeting="" the="" needs="" of="" infants="" consuming="" that="" formula.="" therefore,="" fda="" is="" considering="" requiring="" that="" manufacturers="" implement="" the="" recommendations="" of="" the="" con/aap="" task="" force="" and="" make="" a="" measurement="" that="" provides="" a="" reasonable="" estimate="" of="" the="" amount="" of="" calcium="" and="" phosphorus="" that="" is="" capable="" of="" being="" absorbed="" and="" retained="" for="" use="" by="" infants="" (i.e.,="" calcium="" and="" phosphorus="" balance)="" from="" the="" formula.="" fda="" asks="" for="" comment="" concerning="" the="" appropriateness="" and="" usefulness="" of="" a="" measurement="" of="" calcium="" and="" phosphorus="" balance="" as="" one="" that="" reflects="" both="" the="" bioavailability="" of="" the="" calcium="" and="" phosphorus="" in="" the="" formula="" and="" how="" well="" the="" diet="" meets="" the="" metabolic="" requirements="" for="" these="" two="" minerals.="" as="" discussed="" above="" with="" regard="" to="" the="" conduct="" of="" trials="" to="" measure="" apparent="" fat="" absorption,="" fda="" requests="" comment="" on="" whether="" it="" is="" necessary="" to="" require="" that="" a="" cross-over="" study="" design="" be="" used="" for="" clinical="" studies="" to="" measure="" calcium="" and="" phosphorus="" balance.="" fda="" also="" requests="" comment="" on="" what="" would="" be="" an="" appropriate="" duration="" for="" studies="" to="" measure="" calcium="" and="" phosphorus="" balance.="" the="" con/aap="" task="" force="" suggested="" that="" calcium="" and="" phosphorus="" balance="" studies="" be="" conducted="" for="" a="" 72-hour="" balance="" period="" after="" an="" 11-day="" adaptation="" period.="" fda="" requests="" comment="" on="" whether="" these="" time="" periods="" are="" appropriate,="" both="" to="" minimize="" the="" effects="" of="" previous="" dietary="" intake="" on="" the="" availability="" of="" calcium="" from="" the="" formula="" being="" tested="" (ref.="" 6)="" and="" to="" ensure="" that="" the="" results="" of="" the="" balance="" study="" are="" reliable="" and="" interpretable,="" and="" on="" whether="" they="" provide="" a="" meaningful="" basis="" on="" which="" to="" determine="" that="" a="" formula="" meets="" the="" quality="" factor="" requirement="" for="" calcium="" and="" phosphorus.="" fda="" is="" considering="" requiring="" that="" the="" formula="" used="" as="" the="" control="" in="" any="" clinical="" studies="" to="" measure="" calcium="" and="" phosphorus="" balance="" contain="" approximately="" the="" same="" calcium="" and="" phosphorus="" levels="" as="" the="" test="" formula="" because="" the="" absolute="" amounts="" of="" these="" nutrients="" absorbed="" and="" retained="" by="" infants="" may="" be="" different="" between="" formulas="" with="" different="" calcium="" and="" phosphorus="" levels.="" fda="" is="" asking="" for="" comment="" on="" requirements="" for="" appropriate="" control="" formulas="" for="" calcium="" and="" phosphorus="" balance="" studies.="" amounts="" of="" calcium="" and="" phosphorus="" in="" urine="" and="" feces,="" along="" with="" calculated="" amounts="" absorbed="" and="" retained="" expressed="" in="" milligrams="" per="" kilogram="" and="" as="" percentages="" of="" intake,="" provide="" evidence="" of="" the="" rates="" of="" absorption="" and="" retention="" of="" these="" nutrients="" but="" do="" not="" specifically="" measure="" the="" ability="" of="" the="" formula="" to="" provide="" adequate="" calcium="" and="" phosphorus="" for="" proper="" bone="" mineralization,="" the="" most="" important="" need="" for="" these="" minerals="" in="" the="" infant.="" fda="" is="" considering="" requiring="" that="" serum="" alkaline="" phosphatase="" be="" measured="" in="" situations="" in="" which="" calcium="" and="" phosphorus="" balance="" studies="" are="" required="" in="" order="" to="" assess="" the="" adequacy="" of="" formula="" minerals="" to="" support="" normal="" bone="" mineralization.="" alkaline="" phosphatase="" is="" an="" enzyme="" involved="" in="" bone="" remodeling="" and="" in="" maintaining="" serum="" calcium="" concentration="" (ref.="" 64).="" increased="" serum="" alkaline="" phosphatase="" activity="" may="" be="" a="" marker="" of="" reduced="" bone="" mineralization="" (ref.="" 80)="" and="" therefore="" may="" be="" useful="" in="" determining="" whether="" a="" formula="" meets="" a="" quality="" factor="" requirement="" for="" calcium="" and="" phosphorus.="" because="" of="" the="" limits="" of="" metabolic="" balance="" studies,="" including="" short="" duration,="" dependence="" on="" previous="" diet,="" and="" expense,="" the="" agency="" is="" considering="" the="" appropriateness="" of="" alternative="" methods="" for="" the="" assessment="" of="" bone="" mineral="" accretion.="" the="" agency="" is="" aware="" that="" sophisticated="" instruments,="" such="" as="" single-photon="" absorptiometry="" and="" dual-energy="" x-ray="" absorptiometry,="" have="" been="" tested="" for="" measuring="" bone="" mineral="" content="" in="" infants="" (refs.="" 81="" through="" 84),="" and="" that="" some="" authorities="" recommend="" them="" for="" determining="" bone="" mineralization="" in="" infants="" (ref.="" 85).="" these="" types="" of="" measurements="" have="" the="" potential="" to="" provide="" an="" accurate="" measure="" of="" bone="" mineral="" accretion="" over="" the="" duration="" of="" use="" of="" the="" formula,="" while="" at="" the="" same="" time="" reducing="" many="" sources="" of="" variation="" inherent="" in="" balance="" studies.="" the="" agency="" is="" concerned,="" however,="" that="" these="" methods="" have="" not="" been="" adequately="" validated="" in="" infants,="" and="" that="" reference="" standards="" for="" mineralization="" in="" infants="" have="" not="" been="" established="" to="" support="" a="" requirement="" for="" manufacturers="" to="" measure="" bone="" mineralization="" in="" order="" to="" provide="" assurance="" that="" a="" formula="" satisfies="" a="" quality="" factor="" requirement="" for="" calcium="" and="" phosphorus.="" the="" agency="" asks="" for="" comment="" on="" the="" usefulness="" of="" these="" methods="" of="" analysis="" of="" bone="" mineral="" accretion="" in="" infants,="" and="" on="" whether="" they="" should="" be="" used="" in="" lieu="" of="" calcium="" and="" phosphorus="" balance="" studies="" as="" measurements="" of="" whether="" an="" infant="" formula="" meets="" the="" quality="" factor="" requirements="" for="" calcium="" and="" phosphorus="" assuming="" that="" the="" agency="" adopts="" such="" a="" quality="" factor.="" the="" agency="" also="" asks="" for="" comment="" on="" the="" criteria="" that="" it="" should="" use,="" on="" a="" case-by-case="" basis,="" in="" deciding="" whether="" to="" require="" these="" types="" of="" measures="" when="" there="" is="" particular="" reason="" to="" be="" concerned="" that="" calcium="" and="" phosphorus="" bioavailability="" may="" be="" problematic.="" fda="" also="" is="" considering="" whether="" circumstances="" exist="" that="" would="" justify="" establishing="" an="" exemption="" from="" a="" requirement="" to="" measure="" calcium="" and="" phosphorus="" balance.="" fda="" has="" tentatively="" concluded="" that="" the="" reasons="" and="" justification="" for="" such="" an="" exemption="" are="" essentially="" those="" set="" forth="" above="" in="" the="" discussion="" of="" proposed="" sec.="" 106.97(b)(2),="" and="" requests="" comment="" on="" whether,="" if="" it="" adopts="" a="" quality="" factor="" for="" calcium="" and="" phosphorus,="" it="" should="" provide="" for="" exemptions="" from="" testing="" to="" show="" that="" the="" formula="" meets="" the="" quality="" [[page="" 36189]]="" factor="" similar="" to="" those="" in="" proposed="" sec.="" 106.97(b)(2)="" and="" allow="" manufacturers="" to="" assure="" the="" agency="" that="" their="" products="" meet="" that="" requirement="" without="" requiring="" redundant="" testing.="" c.="" iron="" status.="" if="" fda="" were="" to="" adopt="" a="" quality="" factor="" for="" iron,="" manufacturers="" would="" be="" required="" to="" collect="" and="" maintain="" data="" that="" establish="" that="" the="" iron="" in="" an="" infant="" formula="" is="" bioavailable="" and="" maintains="" the="" iron="" status="" of="" infants="" that="" consume="" the="" formula.="" these="" data="" would="" be="" necessary="" to="" demonstrate="" that="" an="" infant="" formula="" provides="" enough="" iron="" to="" prevent="" iron="" deficiency="" and="" anemia.="" alterations="" in="" a="" number="" of="" biochemical="" measurements="" are="" useful="" signs="" associated="" with="" inadequate="" iron="" intake="" or="" the="" development="" of="" iron="" deficiency.="" early="" signs="" of="" inadequate="" iron="" intake,="" which="" reflect="" the="" depletion="" of="" iron="" storage="" sites,="" are="" reductions="" in="" serum="" ferritin="" concentration="" and="" transferrin="" saturation="" (ref.="" 86).="" if="" the="" dietary="" intake="" of="" iron="" remains="" inadequate,="" impaired="" erythropoiesis="" (i.e.,="" the="" process="" whereby="" the="" body="" produces="" new="" red="" blood="" cells)="" may="" be="" reflected="" in="" alterations="" in="" erythrocyte="" maturation="" and="" increases="" in="" erythrocyte="" size,="" erythrocyte="" protoporphyrin="" concentration,="" or="" serum="" transferrin="" receptor="" levels.="" if="" the="" period="" of="" inadequate="" iron="" intake="" continues,="" erythropoiesis="" is="" further="" impaired,="" and="" hemoglobin="" concentration,="" hematocrit,="" and="" mean="" corpuscular="" volume="" decrease.="" iron="" deficiency="" without="" anemia="" should="" be="" considered="" to="" be="" a="" risk="" factor="" for="" iron-deficiency="" anemia,="" which="" may="" be="" associated="" with="" long-="" lasting,="" adverse="" effects="" in="" infants="" (ref.="" 86).="" therefore,="" fda="" is="" considering="" requiring="" one="" measurement="" of="" iron="" status="" that="" is="" sensitive="" to="" each="" of="" the="" three="" stages="" of="" inadequate="" iron="" intake="" (stage="" 1,="" decreased="" stores,="" normal="" erythropoiesis;="" stage="" 2,="" decreased="" stores="" and="" early="" stage="" impaired="" erythropoiesis;="" and="" stage="" 3,="" decreased="" stores="" and="" late="" stage="" impaired="" erythropoiesis).="" for="" example,="" fda="" is="" considering="" requiring="" that="" manufacturers="" measure:="" (1)="" serum="" ferritin="" concentration,="" because="" such="" a="" measurement="" is="" sensitive="" to="" decreased="" iron="" stores="" and="" normal="" erythropoiesis;="" (2)="" transferrin="" saturation="" or="" erythrocyte="" protoporphyrin="" concentration,="" because="" such="" measures="" are="" sensitive="" to="" decreased="" iron="" stores="" and="" early="" stage="" impaired="" erythropoiesis;="" and="" (3)="" hematocrit="" percentage,="" hemoglobin="" concentration,="" or="" mean="" corpuscular="" volume,="" because="" such="" measurements="" are="" sensitive="" to="" decreased="" iron="" stores="" and="" late="" stage="" impaired="" erythropoiesis.="" this="" approach="" would="" be="" consistent="" with="" the="" recommendations="" of="" the="" con/aap="" task="" force="" (ref.="" 6).="" it="" would="" also="" provide="" reasonable="" assurance="" that="" low="" iron="" availability="" in="" an="" infant="" formula="" would="" be="" detected,="" and="" that="" an="" infant="" formula="" that="" does="" not="" provide="" sufficient="" iron="" to="" meet="" the="" infant's="" requirement,="" and="" thereby="" does="" not="" meet="" the="" quality="" factor="" requirement="" for="" iron,="" will="" not="" be="" marketed.="" fda="" also="" is="" considering="" whether="" circumstances="" exist="" that="" would="" justify="" establishing="" an="" exemption="" from="" the="" requirements="" to="" determine="" iron="" status.="" fda="" has="" tentatively="" concluded="" that="" the="" reasons="" and="" justification="" for="" such="" an="" exemption="" are="" essentially="" those="" set="" forth="" above="" in="" the="" discussion="" of="" proposed="" sec.="" 106.97(b)(2).="" fda="" requests="" comment="" on="" whether,="" if="" it="" adopts="" a="" quality="" factor="" for="" iron,="" it="" should="" provide="" for="" exemptions="" from="" testing="" similar="" to="" those="" set="" forth="" in="" proposed="" sec.="" 106.97(b)(2)="" to="" show="" that="" the="" formula="" meets="" that="" factor="" and="" allow="" manufacturers="" to="" assure="" the="" agency="" that="" their="" products="" meet="" that="" quality="" factor="" requirement="" without="" requiring="" redundant="" testing.="" f.="" records="" and="" reports="" 1.="" introduction="" under="" subpart="" c="" of="" part="" 106,="" fda="" is="" proposing="" to="" revise="" the="" requirements="" on="" the="" records="" that="" must="" be="" made="" and="" retained.="" fda="" is="" proposing="" requirements="" on="" batch="" records;="" records="" on="" cgmp="" and="" quality="" control="" procedures;="" maintenance="" of="" distribution="" records="" on="" formulas="" for="" export="" only;="" audits;="" and="" notifications="" to="" fda.="" these="" proposed="" changes="" to="" current="" sec.="" 106.100="" are="" outlined="" in="" table="" iii="" below:="" table="" iii="" ------------------------------------------------------------------------="" current="" regulation="" proposed="" regulation="" ------------------------------------------------------------------------="" sec.="" 106.100(a)..........................="" no="" change.="" sec.="" 106.100(b)..........................="" no="" change.="" sec.="" 106.100(c)..........................="" no="" change.="" sec.="" 106.100(d)..........................="" no="" change.="" sec.="" 106.100(e),="" (f),="" and="" (h)............="" current="" sec.="" 106.100(e),="" (f),="" and="" (h)="" will="" be="" incorporated="" into="" proposed="" sec.="" 106.100(e).="" new="" sec.="" 106.100(f)="" will="" codify="" the="" records="" required="" for="" the="" cgmp="" regulations="" found="" in="" proposed="" subpart="" b.="" sec.="" 106.100(g)..........................="" current="" sec.="" 106.100(g)="" with="" modification.="" sec.="" 106.100(h)..........................="" current="" sec.="" 106.100(h)="" is="" incorporated="" into="" sec.="" 106.100(e).="" sec.="" 106.100(h)="" reserved.="" sec.="" 106.100(i)..........................="" no="" change.="" sec.="" 106.100(j)..........................="" current="" sec.="" 106.100(j)="" with="" modification.="" sec.="" 106.100(k)..........................="" current="" sec.="" 106.100(k)="" with="" modification.="" sec.="" 106.100(l)..........................="" no="" change.="" sec.="" 106.100(m)..........................="" no="" change.="" sec.="" 106.100(n)..........................="" no="" change.="" sec.="" 106.100(o)..........................="" no="" change.="" ------------------------------------------------------------------------="" 2.="" batch="" production="" and="" control="" records="" proposed="" sec.="" 106.100(e)="" requires="" that="" manufacturers="" make="" and="" retain="" records="" (hereafter="" referred="" to="" as="" ``batch="" records'')="" that="" include="" complete="" information="" relating="" to="" the="" production="" and="" control="" of="" each="" batch="" of="" infant="" formula.="" section="" 412(b)(4)(a)(i)="" of="" the="" act="" requires="" the="" establishment,="" by="" regulation,="" of="" requirements="" for="" the="" retention="" of="" all="" records,="" including="" records="" containing="" the="" results="" of="" all="" testing="" required="" under="" section="" 412(b)(2)(b)="" of="" the="" act,="" necessary="" to="" demonstrate="" compliance="" with="" the="" cgmp="" requirements="" and="" quality="" control="" procedures="" prescribed="" under="" section="" 412(b)(2).="" in="" proposed="" sec.="" 106.100(e)="" fda="" is="" proposing="" to="" require="" that="" manufacturers="" prepare="" and="" maintain="" records="" that="" include="" complete="" information="" relating="" to="" the="" production="" and="" control="" of="" the="" batch="" to="" ensure="" that="" the="" complete="" history="" of="" each="" batch="" of="" infant="" formula="" is="" available="" for="" review="" in="" the="" event="" that="" a="" problem="" arises="" with="" a="" particular="" batch.="" proposed="" sec.="" 106.100(e)(1)="" requires="" that="" the="" batch="" records="" include="" the="" appropriate="" master="" manufacturing="" order.="" as="" discussed="" above,="" proposed="" sec.="" 106.50(a)="" requires="" that="" manufacturers="" produce="" each="" infant="" formula="" in="" accordance="" with="" a="" master="" manufacturing="" order="" that="" has="" been="" approved="" by="" a="" responsible="" official="" of="" the="" company.="" the="" master="" manufacturing="" order="" thus="" provides="" fundamental="" information="" about="" the="" batch.="" having="" all="" the="" information="" concerning="" the="" production="" of="" a="" batch="" of="" infant="" formula,="" including="" the="" master="" manufacturing="" order,="" in="" one="" place="" as="" a="" part="" of="" a="" batch="" record="" will="" ensure="" that="" there="" is="" a="" document="" available="" that="" makes="" readily="" apparent="" whether="" a="" batch="" was="" properly="" produced.="" it="" will="" also="" ensure="" that="" all="" the="" information="" needed="" to="" evaluate="" the="" cause="" of="" any="" problem="" that="" may="" develop="" with="" a="" batch="" of="" infant="" formula="" is="" readily="" available.="" thus,="" fda="" has="" tentatively="" concluded="" that="" the="" master="" manufacturing="" order="" is="" an="" essential="" part="" of="" the="" batch="" record.="" proposed="" sec.="" 106.100(e)(1)(i)="" requires="" that="" the="" master="" manufacturing="" order="" include="" the="" significant="" steps="" in="" the="" production="" of="" the="" batch="" of="" infant="" formula="" and="" the="" date="" on="" which="" each="" [[page="" 36190]]="" significant="" step="" occurred.="" thus,="" the="" master="" manufacturing="" order="" will="" include="" a="" list="" of="" the="" significant="" steps="" for="" the="" production="" of="" each="" infant="" formula="" and="" a="" space="" to="" write="" in="" the="" date="" the="" step="" was="" performed.="" thus,="" it="" will="" provide="" both="" a="" check="" that="" the="" step="" was="" performed="" and="" a="" record="" of="" when="" it="" was="" performed.="" fda="" has="" tentatively="" concluded="" that="" this="" information="" is="" necessary="" because="" all="" production="" activities="" for="" a="" specific="" batch="" of="" infant="" formula="" may="" not="" be="" accomplished="" in="" one="" day="" but="" may="" occur="" over="" a="" number="" of="" days,="" and="" people="" who="" begin="" work="" the="" second="" day="" will="" know="" what="" work="" has="" been="" completed,="" and="" what="" has="" not="" been.="" moreover,="" each="" date="" is="" needed="" so="" that="" a="" batch="" of="" formula="" can="" be="" traced="" if,="" at="" a="" later="" date,="" a="" problem="" that="" may="" adversely="" affect="" an="" infant="" formula="" is="" identified="" at="" a="" specific="" production="" stage.="" having="" the="" date="" available="" will="" allow="" the="" manufacturer="" to="" identify="" all="" batches="" that="" may="" have="" been="" affected="" by="" the="" problem.="" proposed="" sec.="" 106.100(e)(1)(ii)="" requires="" that,="" if="" the="" manufacturer="" has="" more="" than="" one="" line="" or="" set="" of="" equipment="" in="" the="" plant="" in="" which="" the="" formula="" is="" made,="" the="" master="" manufacturing="" order="" include="" the="" identity="" of="" equipment="" and="" processing="" lines="" used="" in="" producing="" the="" batch="" of="" infant="" formula.="" this="" information="" will="" allow="" the="" manufacturer="" to="" ensure="" that="" the="" equipment="" on="" which="" the="" formula="" was="" produced="" met="" the="" requirements="" of="" sec.="" 106.30.="" this="" information="" also="" will="" facilitate="" the="" identification="" of="" all="" batches="" of="" formula="" that="" may="" be="" affected="" by="" equipment="" malfunctions="" or="" that="" were="" produced="" on="" the="" same="" equipment="" as="" a="" batch="" that="" is="" discovered="" to="" be="" microbiologically="" contaminated.="" proposed="" sec.="" 106.100(e)(1)(iii)="" requires="" that="" the="" master="" manufacturing="" order="" include="" the="" identity="" of="" each="" batch="" or="" lot="" of="" ingredients,="" containers,="" and="" closures="" used="" in="" producing="" the="" batch="" of="" infant="" formula.="" all="" materials="" used="" in="" infant="" formula="" will="" have="" to="" meet="" the="" specifications="" of="" proposed="" sec.="" 106.40(d)="" and="" be="" identified="" by="" a="" batch="" or="" lot="" number="" as="" specified="" in="" proposed="" sec.="" 106.40(c).="" fda="" has="" tentatively="" concluded="" that="" it="" is="" necessary="" to="" propose="" that="" the="" identity="" of="" each="" batch="" or="" lot="" of="" ingredients,="" containers,="" and="" closures="" used="" in="" producing="" the="" batch="" of="" infant="" formula="" be="" recorded="" in="" the="" master="" manufacturing="" order="" to="" enable="" the="" manufacturer="" to="" ensure="" that="" all="" of="" those="" materials="" met="" the="" requirements="" of="" sec.="" 106.40,="" particularly="" the="" standards="" for="" acceptance="" or="" rejection="" of="" the="" materials.="" recording="" this="" information="" also="" will="" allow="" the="" manufacturer="" to="" evaluate="" the="" contribution="" of="" specific="" ingredients,="" containers,="" and="" closures="" to="" any="" problem="" with="" a="" batch="" of="" infant="" formula="" that="" may="" develop.="" fda="" is="" not="" proposing="" to="" require="" that="" the="" batch="" records="" contain="" the="" results="" of="" any="" tests="" conducted="" on="" ingredients,="" containers,="" and="" closures="" in="" accordance="" with="" proposed="" sec.="" 106.40(d)="" because="" the="" same="" lot="" of="" raw="" materials="" may="" be="" used="" in="" multiple="" batches.="" the="" identification="" of="" the="" batch="" or="" lot="" of="" all="" ingredients,="" containers,="" and="" closures="" in="" the="" master="" manufacturing="" order="" should="" be="" sufficient="" to="" allow="" the="" manufacturer="" to="" locate="" and="" review="" relevant="" test="" results="" if="" problems="" arise="" with="" a="" particular="" batch="" of="" infant="" formula.="" proposed="" sec.="" 106.100(e)(1)(iv)="" requires="" that="" the="" master="" manufacturing="" order="" include="" the="" amount="" of="" each="" ingredient="" to="" be="" added="" to="" the="" batch="" of="" infant="" formula="" and="" a="" check="" (verification)="" that="" the="" correct="" amount="" was="" added.="" as="" discussed="" above,="" proposed="" sec.="" 106.50(b)="" requires="" that="" the="" manufacturer="" establish="" controls="" to="" ensure="" that="" raw="" and="" in-process="" ingredients="" required="" by="" the="" master="" manufacturing="" order="" are="" examined="" by="" one="" person="" and="" checked="" by="" a="" second="" person="" or="" system="" to="" ensure="" that="" the="" correct="" weight="" or="" measure="" of="" the="" ingredient="" is="" added="" to="" the="" batch.="" the="" agency="" has="" tentatively="" concluded="" that="" recording="" in="" the="" master="" manufacturing="" order="" the="" amount="" of="" each="" ingredient="" added="" to="" the="" batch="" of="" formula,="" and="" a="" check="" (verification)="" that="" the="" correct="" amount="" was="" added,="" are="" appropriate="" controls="" to="" ensure="" that="" the="" correct="" weight="" or="" measure="" of="" the="" ingredient="" is="" added="" to="" the="" batch.="" this="" proposed="" requirement="" is="" necessary="" to="" ensure="" that="" there="" is="" compliance="" with="" proposed="" sec.="" 106.50(b),="" to="" provide="" a="" record="" that="" the="" batch="" of="" infant="" formula="" includes="" all="" of="" the="" ingredients="" in="" the="" amounts="" specified="" in="" the="" master="" manufacturing="" order,="" and="" to="" provide="" assurance="" that="" the="" product="" contains="" all="" of="" the="" required="" nutrients.="" proposed="" sec.="" 106.100(e)(1)(v)="" requires="" that="" the="" master="" manufacturing="" order="" include="" copies="" of="" all="" labeling="" used="" and="" the="" results="" of="" the="" examinations="" conducted="" during="" the="" finishing="" operations="" to="" ensure="" that="" containers="" and="" packages="" in="" the="" batch="" are="" correctly="" labeled.="" (the="" importance="" of="" ensuring="" that="" containers="" are="" correctly="" labeled="" was="" discussed="" in="" conjunction="" with="" proposed="" sec.="" 106.60(b).)="" the="" inclusion="" in="" the="" batch="" records="" of="" copies="" of="" the="" labeling="" used="" on="" each="" batch="" of="" infant="" formula="" will="" provide="" a="" record="" of="" such="" labeling="" and="" will="" document="" that="" the="" finishing="" operation="" examinations,="" required="" by="" proposed="" sec.="" 106.60(b),="" are="" conducted.="" proposed="" sec.="" 106.100(e)(2)="" requires="" that="" the="" batch="" record="" include="" any="" deviations="" from="" the="" master="" manufacturing="" order="" and="" any="" corrective="" actions="" taken.="" while="" the="" manufacturer's="" goal="" should="" be="" to="" produce="" the="" infant="" formula="" in="" accordance="" with="" the="" master="" manufacturing="" order,="" on="" occasion="" deviations="" may="" occur.="" on="" these="" occasions,="" the="" deviations,="" and="" any="" corrective="" actions="" taken="" because="" of="" the="" deviations,="" should="" become="" a="" part="" of="" the="" batch="" record.="" for="" example,="" if="" a="" batch="" of="" liquid="" infant="" formula="" was="" thermally="" processed="" at="" a="" different="" temperature="" than="" the="" temperature="" specified="" in="" the="" master="" manufacturing="" order,="" the="" batch="" record="" would="" state="" the="" actual="" processing="" temperature.="" the="" record="" would="" also="" state="" any="" corrective="" actions="" taken="" because="" of="" this="" processing="" temperature,="" such="" as="" a="" change="" in="" processing="" time.="" a="" record="" of="" deviations="" from="" the="" master="" manufacturing="" order="" and="" of="" the="" corrective="" actions="" taken="" by="" the="" manufacturer="" will="" allow="" the="" manufacturer="" to="" quickly="" determine="" whether="" all="" deviations="" have="" been="" appropriately="" addressed,="" and="" if="" they="" have="" not="" been,="" whether="" the="" actions="" needed="" to="" correct="" the="" deviations="" have="" been="" identified.="" it="" will="" also="" provide="" relevant="" information="" if="" a="" problem="" arises="" with="" that="" batch="" of="" infant="" formula.="" proposed="" sec.="" 106.100(e)(3)="" requires="" that="" the="" batch="" records="" include="" documentation="" of="" the="" monitoring="" at="" any="" production="" and="" in-process="" control="" point,="" step,="" or="" stage="" where="" control="" is="" deemed="" necessary="" to="" prevent="" adulteration.="" as="" discussed="" above,="" proposed="" sec.="" 106.6(c)(2)="" requires="" this="" monitoring.="" fda="" is="" proposing="" that="" the="" documentation="" that="" the="" monitoring="" required="" by="" proposed="" sec.="" 106.6(c)(2)="" is="" occurring="" be="" included="" in="" the="" batch="" records="" to="" ensure="" that="" a="" measurement="" or="" observation="" made="" at="" one="" particular="" point="" in="" time="" can="" be="" related="" to="" a="" particular="" batch.="" the="" linkage="" of="" the="" record="" to="" the="" batch="" is="" especially="" important="" when="" a="" standard="" or="" specification="" is="" not="" met.="" it="" will="" enable="" the="" manufacturer="" to="" determine="" what="" batches="" may="" have="" been="" affected="" by="" a="" deviation="" and="" to="" take="" appropriate="" action,="" such="" as="" withholding="" a="" batch="" from="" distribution.="" proposed="" sec.="" 106.100(e)(3)(i)="" requires="" that="" the="" batch="" records="" include="" a="" list="" of="" the="" standards="" or="" specifications="" established="" at="" each="" point,="" step,="" or="" stage="" in="" the="" production="" process="" where="" control="" is="" deemed="" necessary="" to="" prevent="" adulteration,="" and="" that="" it="" include="" documentation="" of="" the="" scientific="" basis="" for="" each="" standard="" or="" specification.="" as="" discussed="" above,="" proposed="" sec.="" 106.6(c)(1)="" requires="" the="" establishment="" of="" such="" standards="" or="" specifications.="" the="" agency="" has="" tentatively="" concluded="" that="" a="" list="" of="" these="" standards="" or="" specifications="" must="" be="" a="" part="" of="" the="" batch="" record="" so="" that="" the="" manufacturer="" will="" have="" them="" readily="" [[page="" 36191]]="" available="" to="" compare="" to="" the="" actual="" values="" obtained="" during="" the="" monitoring="" operation="" of="" the="" production="" and="" in-process="" control="" system.="" also,="" the="" documentation="" of="" the="" scientific="" basis="" for="" each="" standard="" or="" specification="" will="" verify="" that="" each="" was="" established="" by="" trained="" and="" experienced="" sources.="" such="" documentation="" will="" summarize="" the="" work="" performed="" to="" establish="" the="" standard="" or="" specification="" and="" will="" establish="" the="" source="" used.="" if="" changes="" to="" the="" standard="" or="" specification="" become="" necessary,="" this="" documentation="" of="" the="" scientific="" basis="" for="" each="" standard="" or="" specification="" will="" assist="" the="" manufacturer="" in="" making="" such="" changes.="" proposed="" sec.="" 106.100(e)(3)(ii)="" requires="" that="" the="" batch="" records="" include="" the="" actual="" values="" obtained="" during="" the="" monitoring="" (such="" as="" the="" actual="" temperatures="" and="" actual="" times="" that="" the="" measurements="" were="" taken),="" any="" deviations="" from="" the="" established="" standards="" or="" specifications,="" and="" any="" corrective="" actions="" taken.="" for="" example,="" notations="" that="" refrigeration="" temperatures="" are="" satisfactory="" or="" unsatisfactory,="" without="" a="" record="" of="" the="" actual="" temperatures,="" are="" subject="" to="" varying="" interpretation="" and="" thus="" will="" not="" ensure="" that="" preventive="" controls="" are="" working.="" it="" is="" important="" that="" the="" actual="" values="" be="" recorded.="" in="" addition,="" actual="" values="" are="" necessary="" to="" discern="" trends="" or="" to="" pinpoint="" the="" onset="" of="" a="" problem.="" the="" record="" of="" any="" corrective="" actions="" taken="" will="" show="" what="" the="" manufacturer="" did="" when="" a="" standard="" or="" specification="" was="" violated,="" and="" how="" the="" manufacturer="" is="" ensuring="" that="" the="" infant="" formula="" is="" not="" adulterated.="" entry="" of="" information="" on="" the="" records="" at="" the="" time="" of="" the="" monitoring="" ensures="" that="" the="" record="" does="" not="" rely="" on="" the="" memory="" of="" the="" observer="" and="" thus="" is="" as="" accurate="" and="" valid="" as="" possible.="" proposed="" sec.="" 106.100(e)(3)(iii)="" requires="" that="" the="" batch="" records="" identify="" the="" person="" monitoring="" each="" point="" where="" control="" is="" deemed="" necessary="" to="" prevent="" adulteration.="" fda="" has="" tentatively="" concluded="" that="" it="" is="" important="" that="" the="" responsible="" individuals="" be="" identified="" in="" the="" batch="" record="" so="" that="" the="" manufacturer="" can="" check="" that="" a="" qualified="" person="" is="" actually="" monitoring="" the="" point,="" step,="" or="" stage="" where="" control="" is="" deemed="" necessary="" to="" prevent="" adulteration,="" and="" so="" that="" such="" individual="" can="" be="" contacted="" if="" a="" problem="" with="" a="" batch="" of="" infant="" formula="" is="" identified="" at="" a="" later="" date.="" these="" individuals="" are="" in="" the="" best="" position="" to="" know="" of="" any="" other="" information="" that="" may="" not="" have="" seemed="" pertinent="" at="" the="" time="" but,="" in="" retrospect,="" could="" be="" important="" in="" identifying="" the="" cause="" of="" the="" problem="" and="" initiating="" actions="" to="" prevent="" it="" from="" recurring.="" proposed="" sec.="" 106.100(e)(4)="" requires="" that="" the="" batch="" records="" include="" the="" conclusions="" and="" followup,="" along="" with="" the="" identity,="" of="" the="" qualified="" individual="" who="" investigated="" any="" deviations,="" or="" failures="" to="" meet="" specifications,="" that="" occurred="" during="" the="" production="" of="" the="" batch.="" under="" these="" proposed="" regulations,="" individuals="" qualified="" by="" training="" or="" experience="" must="" conduct="" an="" investigation="" of="" any="" deviation="" from="" the="" master="" manufacturing="" order="" and="" of="" the="" corrective="" actions="" taken="" (sec.="" 106.50(a)(2));="" conduct="" an="" investigation="" of="" a="" finding="" that="" a="" batch="" or="" any="" of="" its="" ingredients="" failed="" to="" meet="" any="" manufacturer's="" specifications="" (secs.="" 106.40(d)="" and="" 106.70(c));="" and="" conduct="" an="" investigation="" of="" a="" failure="" to="" meet="" any="" specification="" or="" standard="" at="" any="" point="" where="" control="" is="" deemed="" necessary="" to="" prevent="" adulteration="" (sec.="" 106.6(c)(4)).="" fda="" has="" tentatively="" concluded="" that="" the="" record="" of="" the="" conclusions="" and="" followup="" of="" these="" investigations="" is="" necessary="" to="" enable="" the="" manufacturer="" to="" ensure="" that="" it="" has="" complied="" with="" proposed="" secs.="" 106.6(c)(4),="" 106.40(d),="" 106.50(a)(2),="" and="" 106.70(c).="" such="" records="" will="" provide="" information="" on="" how="" the="" production="" of="" the="" batch="" of="" infant="" formula="" deviated="" from="" established="" standards="" or="" specifications="" and="" on="" the="" cause="" of="" any="" problem="" with="" the="" formula,="" if="" infants="" are="" reported="" to="" have="" been="" adversely="" affected="" by="" the="" product="" at="" a="" later="" date.="" identification="" of="" the="" qualified="" individual="" who="" conducted="" the="" investigations="" will="" ensure="" that="" there="" is="" responsibility="" and="" accountability="" for="" the="" investigation="" and="" will="" allow="" the="" responsible="" individuals="" to="" be="" contacted,="" if="" necessary.="" these="" individuals="" will="" be="" in="" the="" best="" position="" to="" provide="" information="" if="" additional="" details="" about="" the="" record="" are="" needed.="" proposed="" sec.="" 106.100(e)(5)="" requires="" that="" the="" batch="" records="" include="" the="" results="" of="" all="" testing="" performed="" on="" the="" batch="" of="" infant="" formula,="" including="" testing="" on="" the="" in-process="" batch,="" at="" the="" final-product="" stage,="" and="" on="" finished="" product="" throughout="" the="" shelf="" life="" of="" the="" product.="" section="" 412(b)(2)(b)="" of="" the="" act="" requires="" that="" manufacturers="" conduct="" such="" testing.="" fda="" has="" tentatively="" concluded="" that="" the="" assembly="" of="" such="" records="" in="" one="" place="" will="" enable="" the="" manufacturer="" to="" ensure="" that="" the="" batch="" of="" infant="" formula="" complies="" with="" proposed="" secs.="" 106.55="" and="" 106.91="" and="" will="" facilitate="" the="" review="" of="" the="" test="" results="" in="" the="" event="" that="" a="" problem="" arises="" with="" the="" batch.="" proposed="" sec.="" 106.100(e)(5)(i)="" states="" that="" the="" batch="" records="" are="" to="" include="" the="" results="" of="" any="" quality="" control="" testing="" conducted,="" in="" accordance="" with="" proposed="" sec.="" 106.91(a)="" and="" (b),="" to="" verify="" that="" each="" nutrient="" required="" by="" sec.="" 107.100="" is="" present="" at="" the="" required="" level,="" and="" that="" any="" nutrient="" added="" by="" the="" manufacturer="" is="" present="" at="" the="" appropriate="" level.="" including="" the="" results="" of="" this="" testing="" in="" the="" batch="" records="" will="" provide="" data="" needed="" to="" evaluate="" compliance="" of="" the="" batch="" of="" infant="" formula="" with="" proposed="" sec.="" 106.91,="" and="" provide="" data="" needed="" to="" evaluate="" a="" batch="" of="" infant="" formula="" if="" problems,="" such="" as="" adverse="" events="" in="" infants,="" occur="" later="" with="" that="" particular="" batch.="" these="" records="" will="" show="" the="" levels="" of="" nutrients="" in="" the="" formula="" and="" will="" provide="" information="" to="" help="" the="" manufacturer="" determine="" whether="" any="" problems="" associated="" with="" the="" formula="" are="" attributable="" to="" the="" nutrient="" levels="" in="" the="" product.="" proposed="" sec.="" 106.100(e)(5)(i)(a)="" requires="" that="" manufacturers="" maintain="" a="" summary="" table="" in="" the="" batch="" record="" that="" identifies="" the="" stages="" of="" the="" manufacturing="" process="" at="" which="" the="" nutrient="" analysis="" is="" conducted="" for="" each="" nutrient,="" in="" accordance="" with="" proposed="" sec.="" 106.91(a).="" as="" discussed="" above,="" proposed="" sec.="" 106.91(a)="" provides="" flexibility="" in="" the="" stage="" at="" which="" many="" of="" the="" nutrients="" are="" tested.="" a="" summary="" table="" will="" facilitate="" the="" manufacturer's="" compliance="" with="" quality="" control="" procedures="" because="" it="" will="" allow="" a="" manufacturer="" to="" quickly="" verify="" that="" it="" has="" tested="" for="" all="" the="" nutrients="" required="" by="" sec.="" 107.100="" during="" the="" production="" of="" the="" infant="" formula.="" proposed="" sec.="" 106.100(e)(5)(i)(b)="" requires="" that="" the="" quality="" control="" records="" in="" the="" batch="" record="" include="" a="" summary="" table="" on="" the="" stability="" testing="" program,="" conducted="" in="" accordance="" with="" proposed="" sec.="" 106.91(b),="" including="" the="" nutrients="" tested="" and="" the="" frequency="" of="" testing="" of="" nutrients="" throughout="" the="" shelf="" life="" of="" the="" product.="" as="" discussed="" above,="" proposed="" sec.="" 106.91(b)="" requires="" that="" manufacturers="" test="" infant="" formula="" at="" the="" beginning,="" midpoint,="" and="" end="" of="" the="" shelf="" life,="" and="" with="" sufficient="" frequency="" to="" ensure="" that="" the="" manufacturer="" is="" aware="" if="" there="" is="" a="" significant="" deterioration="" in="" the="" required="" level="" of="" a="" nutrient.="" therefore,="" proposed="" sec.="" 106.91(b)="" provides="" flexibility="" in="" the="" testing="" frequency,="" depending="" on="" the="" shelf="" life="" and="" the="" characteristics="" of="" the="" product.="" a="" summary="" table="" will="" facilitate="" the="" manufacturer's="" compliance="" with="" quality="" control="" procedures="" because="" it="" will="" allow="" a="" manufacturer="" to="" quickly="" determine="" whether="" it="" has="" tested="" for="" all="" the="" nutrients="" required="" by="" sec.="" 107.100="" with="" sufficient="" frequency="" to="" verify="" that="" the="" ``use="" by''="" date="" on="" the="" formula="" is="" appropriate.="" proposed="" sec.="" 106.100(e)(5)(ii)="" requires="" that="" the="" batch="" records="" for="" powdered="" infant="" formula="" include="" the="" results="" of="" any="" testing="" conducted="" in="" accordance="" with="" proposed="" sec.="" 106.55(b)="" to="" document="" that="" the="" tests="" were="" done="" and="" to="" verify="" compliance="" with="" the="" microbiological="" [[page="" 36192]]="" quality="" standards="" in="" proposed="" sec.="" 106.55(c).="" as="" discussed="" above,="" proposed="" sec.="" 106.55(b)="" requires="" that="" manufacturers="" test="" representative="" samples="" of="" each="" batch="" of="" powdered="" infant="" formula="" to="" ensure="" that="" the="" batch="" meets="" the="" microbiological="" quality="" standards="" in="" proposed="" sec.="" 106.55(c)="" and="" therefore="" is="" not="" adulterated.="" this="" record="" will="" also="" provide="" the="" manufacturer="" with="" data="" to="" evaluate="" adverse="" events="" that="" infants="" may="" have="" experienced="" after="" consuming="" this="" batch="" of="" infant="" formula="" by="" showing="" whether="" microbiological="" contamination="" could="" have="" contributed="" to="" the="" adverse="" event.="" 3.="" cgmp="" records="" proposed="" sec.="" 106.100(f)="" identifies="" the="" records="" that="" manufacturers="" must="" make="" and="" retain="" pertaining="" to="" cgmp="" described="" in="" proposed="" subpart="" b="" of="" part="" 106.="" section="" 412(b)(4)(a)(i)="" of="" the="" act="" requires="" the="" establishment="" by="" regulation="" of="" requirements="" for="" the="" retention="" of="" all="" records="" necessary="" to="" demonstrate="" compliance="" with="" the="" cgmp,="" including="" testing="" designed="" to="" prevent="" the="" adulteration="" of="" infant="" formula.="" fda="" has="" already="" discussed="" proposed="" regulations="" (proposed="" sec.="" 106.100(e))="" respecting="" the="" retention="" of="" records="" relating="" to="" each="" batch="" of="" infant="" formula.="" fda="" also="" is="" proposing="" regulations="" respecting="" the="" retention="" of="" records="" relating="" to="" the="" overall="" operation="" of="" the="" plant="" and="" the="" maintenance="" of="" equipment,="" because="" these="" records="" are="" necessary="" to="" demonstrate="" that="" the="" infant="" formula="" was="" manufactured="" in="" a="" manner="" designed="" to="" prevent="" adulteration.="" maintenance="" of="" these="" records="" will="" help="" manufacturers="" identify="" trends="" in="" the="" processing="" of="" the="" infant="" formula,="" in="" particular="" trends="" that="" show="" when="" the="" process="" is="" breaking="" down="" in="" a="" way="" that="" will="" lead="" to="" the="" production="" of="" adulterated="" product.="" these="" records="" also="" will="" provide="" information="" to="" assist="" the="" manufacturer="" in="" tracking="" the="" cause="" of="" adverse="" events="" to="" a="" formula,="" if="" such="" events="" are="" reported.="" proposed="" sec.="" 106.100(f)(1)="" requires="" that="" manufacturers="" make="" and="" retain="" records="" of="" the="" frequency="" and="" results="" of="" the="" testing="" of="" water="" used="" in="" the="" production="" of="" infant="" formula.="" these="" records="" will="" show="" if="" problems="" are="" starting="" to="" develop="" with="" the="" water="" supply="" so="" that="" manufacturers="" can="" take="" corrective="" actions="" before="" the="" water="" is="" inappropriate="" for="" use="" in="" infant="" formula.="" proposed="" sec.="" 106.100(f)(2)="" requires="" that="" manufacturers="" make="" and="" retain="" records,="" in="" accordance="" with="" sec.="" 106.30(d),="" of="" accuracy="" checks="" on="" instruments="" and="" controls.="" under="" this="" proposal,="" these="" records="" must="" include="" a="" certification="" of="" the="" accuracy="" of="" any="" known="" reference="" standard="" used="" and="" a="" history="" of="" its="" recertification.="" as="" discussed="" previously,="" the="" accuracy="" of="" the="" reference="" standard="" must="" be="" ensured="" before="" it="" can="" be="" used="" to="" ensure="" that="" the="" production="" instruments="" are="" properly="" calibrated.="" these="" records="" also="" will="" provide="" information="" to="" assist="" the="" manufacturer="" in="" tracing="" the="" source="" of="" a="" problem,="" if="" one="" arises,="" with="" a="" batch="" of="" infant="" formula.="" for="" example,="" if="" infants="" have="" adverse="" events="" to="" a="" batch="" of="" infant="" formula,="" records="" containing="" a="" certification="" of="" accuracy="" of="" the="" reference="" standards="" used="" and="" a="" history="" of="" their="" recertification="" would="" assist="" the="" manufacturer="" in="" determining="" whether="" the="" problem="" was="" created="" because="" a="" production="" instrument="" was="" calibrated="" with="" an="" inaccurate="" reference="" instrument.="" fda="" is="" proposing="" to="" require="" that,="" at="" a="" minimum,="" the="" records="" specify="" the="" instrument="" or="" control="" being="" checked,="" the="" date="" of="" the="" accuracy="" check,="" the="" standard="" used,="" the="" calibration="" method="" used,="" the="" results="" found,="" any="" actions="" taken="" if="" the="" instrument="" is="" found="" to="" be="" out="" of="" calibration,="" and="" the="" initials="" or="" name="" of="" the="" individual="" performing="" the="" test.="" these="" records="" will="" enable="" the="" manufacturer="" to="" determine,="" based="" on="" the="" performance="" of="" the="" instrument,="" whether="" the="" calibration="" schedule="" is="" sufficient="" to="" ensure="" the="" accuracy="" of="" the="" instrument.="" these="" records="" also="" will="" provide="" information="" on="" when="" and="" how="" the="" instruments="" were="" calibrated="" to="" assist="" the="" manufacturer="" in="" identifying="" the="" cause="" of="" a="" problem,="" if="" one="" arises,="" with="" a="" batch="" of="" infant="" formula.="" including="" the="" date="" of="" the="" accuracy="" check="" in="" the="" record="" will="" permit="" a="" determination="" of="" the="" accuracy="" of="" the="" instrument="" or="" control="" over="" time;="" including="" the="" standard="" used="" will="" allow="" the="" manufacturer="" to="" verify="" that="" the="" standard="" was="" properly="" calibrated;="" and="" including="" the="" calibration="" method="" used="" will="" ensure="" that="" the="" instrument="" is="" being="" calibrated="" free="" from="" the="" variability="" that="" can="" occur="" when="" different="" laboratory="" personnel="" perform="" the="" same="" calibration.="" the="" results="" of="" the="" accuracy="" check="" in="" the="" record="" will="" show="" whether="" the="" instrument="" or="" control="" is="" accurate,="" or="" whether="" a="" correction="" was="" necessary.="" documenting="" the="" actions="" taken="" if="" the="" instrument="" is="" found="" to="" be="" out="" of="" calibration="" will="" enable="" the="" manufacturer="" to="" ensure="" that="" a="" correction="" was="" made.="" requiring="" that="" the="" individual="" performing="" the="" test="" note="" his="" or="" her="" initials="" or="" name="" in="" the="" record="" will="" document="" who="" was="" last="" responsible="" for="" ensuring="" the="" accuracy="" of="" the="" instrument="" or="" control="" and="" will="" allow="" the="" manufacturer="" to="" discuss="" questions="" that="" may="" arise="" about="" the="" record="" with="" the="" person="" in="" the="" best="" position="" to="" know="" additional,="" but="" unrecorded,="" details="" about="" the="" record.="" if="" calibration="" of="" an="" instrument="" shows="" that="" a="" specification="" or="" standard,="" at="" a="" point,="" step,="" or="" stage="" in="" the="" production="" process="" where="" control="" is="" deemed="" necessary="" to="" prevent="" adulteration,="" has="" not="" been="" met,="" a="" written="" evaluation="" of="" all="" affected="" product,="" and="" of="" any="" actions="" that="" need="" to="" be="" taken="" with="" respect="" to="" that="" product,="" needs="" to="" be="" made.="" for="" example,="" if="" the="" manufacturer="" is="" monitoring="" temperature="" to="" ensure="" that="" a="" specification="" or="" standard="" of="" 250="" deg.f="" is="" maintained="" as="" a="" minimum="" temperature,="" and="" calibration="" of="" the="" temperature="" indicating="" instruments="" against="" a="" reference="" standard="" reveals="" that="" it="" was="" reading="" a="" true="" temperature="" of="" 248="" deg.f,="" an="" evaluation="" of="" the="" health="" hazard="" significance="" of="" this="" temperature="" deviation="" must="" be="" made.="" this="" proposed="" requirement="" is="" necessary="" because,="" if="" an="" instrument="" is="" found="" to="" have="" been="" giving="" inaccurate="" readings,="" all="" infant="" formula="" produced="" subject="" to="" such="" inaccuracies="" must="" be="" identified="" and="" evaluated="" for="" the="" possibility="" that="" the="" inaccuracies="" caused="" the="" formula="" to="" be="" adulterated.="" in="" identifying="" the="" affected="" product="" to="" ensure="" that="" the="" health="" of="" potentially="" affected="" infants="" is="" fully="" protected,="" in="" the="" absence="" of="" evidence="" to="" the="" contrary,="" such="" evaluation="" would="" cover="" all="" product="" manufactured="" since="" the="" last="" time="" the="" instrument="" was="" calibrated="" and="" found="" to="" be="" accurate.="" proposed="" sec.="" 106.100(f)(3)="" requires="" that="" manufacturers="" make="" and="" retain="" records,="" in="" accordance="" with="" proposed="" sec.="" 106.30(e)(3)(ii),="" of="" the="" temperatures="" monitored="" for="" cold="" storage="" compartments="" and="" thermal="" processing="" equipment.="" these="" records="" are="" needed="" to="" show="" that="" the="" thermal="" processing="" equipment="" or="" cold="" storage="" compartments="" are="" being="" maintained="" at="" the="" correct="" temperatures="" to="" prevent="" adulteration="" of="" the="" product.="" the="" records="" of="" these="" temperatures="" will="" enable="" the="" manufacturer="" to="" identify="" trends="" in="" temperature="" fluctuations="" that="" can="" signal="" the="" need="" to="" perform="" nonscheduled="" maintenance.="" fda="" is="" proposing="" in="" sec.="" 106.100(f)(4)="" that="" equipment="" cleaning,="" sanitizing,="" and="" maintenance="" records,="" showing="" the="" date="" and="" time="" of="" maintenance,="" as="" well="" as="" the="" lot="" number="" of="" each="" batch="" of="" infant="" formula="" processed="" between="" equipment="" startup="" and="" shutdown="" for="" cleaning,="" sanitizing,="" and="" maintenance,="" be="" made="" and="" maintained.="" these="" records="" will="" allow="" the="" manufacturer="" to="" ensure="" that="" equipment="" and="" utensils="" are="" being="" cleaned="" and="" maintained="" regularly="" and="" to="" check="" that="" the="" frequency="" of="" such="" cleaning,="" sanitizing,="" and="" maintenance="" is="" appropriate="" in="" light="" of="" the="" actual,="" as="" [[page="" 36193]]="" opposed="" to="" planned,="" use="" of="" the="" equipment.="" for="" example,="" a="" manufacturer="" may="" need="" to="" increase="" the="" frequency="" of="" cleaning,="" sanitizing,="" and="" maintenance="" if="" actual="" rate="" of="" production="" consistently="" exceeds="" the="" predicted="" rate="" of="" production.="" these="" records="" also="" will="" allow="" the="" manufacturer="" to="" trace="" all="" formula="" that="" may="" be="" affected="" if="" evidence="" becomes="" available="" that="" a="" particular="" cleaning,="" sanitizing,="" or="" maintenance="" was="" improperly="" performed.="" proposed="" sec.="" 106.100(f)(4)="" also="" requires="" that="" the="" person="" performing="" and="" checking="" the="" cleaning,="" sanitizing,="" or="" maintenance="" date="" and="" sign="" or="" initial="" the="" record="" indicating="" that="" the="" work="" was="" performed.="" identification="" of="" the="" person="" performing="" and="" checking="" the="" cleaning,="" sanitizing,="" or="" maintenance="" will="" allow="" the="" manufacturer="" to="" ensure="" that="" a="" qualified="" person="" is="" doing="" these="" tasks="" and="" to="" discuss="" questions="" that="" may="" arise="" about="" the="" record="" with="" the="" person="" in="" the="" best="" position="" to="" know="" additional,="" but="" unrecorded,="" details="" about="" the="" record.="" proposed="" sec.="" 106.100(f)(5)="" requires="" that="" manufacturers="" make="" and="" retain="" records,="" in="" accordance="" with="" sec.="" 106.35(c),="" on="" all="" automatic="" (mechanical="" or="" electronic)="" equipment="" used="" in="" the="" production="" or="" quality="" control="" of="" infant="" formula.="" proposed="" sec.="" 106.100(f)(5)(i)="" requires="" that="" the="" automatic="" equipment="" records="" include="" a="" list="" of="" all="" systems="" used,="" with="" a="" description="" of="" computer="" files="" and="" of="" the="" inherent="" limitations="" of="" each="" system.="" the="" manufacturer="" cannot="" effectively="" operate="" the="" system,="" and="" correct="" problems="" that="" arise,="" if="" it="" does="" not="" understand="" the="" system.="" it="" is="" not="" always="" possible="" for="" the="" individuals="" who="" developed="" and="" best="" understand="" the="" system="" to="" be="" present="" when="" the="" system="" is="" operating.="" therefore,="" these="" records="" will="" enable="" the="" manufacturer="" to="" operate="" and="" troubleshoot="" the="" systems="" even="" when="" the="" individuals="" who="" best="" know="" the="" system="" are="" not="" available.="" proposed="" sec.="" 106.100(f)(5)(ii)="" requires="" that="" the="" automatic="" equipment="" records="" include="" a="" copy="" of="" all="" software="" used.="" having="" a="" copy="" of="" all="" software="" used="" will="" minimize="" the="" manufacturer's="" down="" time="" if="" problems="" occur,="" and="" parts="" of="" the="" software="" are="" lost="" from="" the="" system.="" for="" example,="" if="" a="" computer="" virus="" is="" found="" in="" the="" software="" used="" to="" run="" the="" processing="" lines,="" having="" a="" copy="" of="" the="" software="" to="" reload="" into="" the="" hardware="" will="" minimize="" the="" time="" lost.="" likewise,="" if="" there="" is="" a="" problem="" with="" the="" software="" used="" to="" perform="" quality="" control="" testing,="" having="" copies="" of="" this="" software="" will="" ensure="" that="" the="" testing="" can="" continue="" with="" a="" minimum="" amount="" of="" time="" lost.="" proposed="" sec.="" 106.100(f)(5)(iii)="" further="" requires="" that="" the="" automatic="" equipment="" records="" document="" installation,="" calibration,="" testing="" or="" validation,="" and="" maintenance="" of="" the="" systems="" used.="" these="" requirements="" are="" necessary="" for="" compliance="" with="" section="" 412(b)(4)(a)(i)="" of="" the="" act.="" as="" discussed="" more="" fully="" above="" with="" respect="" to="" proposed="" sec.="" 106.35="" (b)(1),="" (b)(2),="" and="" (b)(4)="" cgmp="" requires="" that="" all="" systems="" be="" installed,="" calibrated,="" and="" maintained="" in="" a="" manner="" necessary="" to="" ensure="" that="" they="" are="" capable="" of="" performing="" their="" intended="" function="" and="" of="" producing="" or="" analyzing="" infant="" formula="" as="" intended,="" and="" that="" all="" systems="" be="" validated="" before="" their="" first="" use="" to="" manufacture="" commercial="" product.="" in="" addition="" to="" documenting="" that="" the="" manufacturer="" is="" complying="" with="" cgmp,="" records="" documenting="" installation,="" calibration,="" testing="" or="" validation,="" and="" maintenance="" of="" systems="" are="" necessary="" to="" provide="" information="" if="" the="" manufacturer="" later="" tries="" to="" determine="" why="" a="" problem="" with="" the="" system="" is="" occurring="" or="" tries="" to="" determine="" why="" the="" system="" is="" not="" producing="" an="" infant="" formula="" that="" complies="" with="" the="" manufacturer's="" specifications="" for="" the="" product.="" proposed="" sec.="" 106.100(f)(5)(iv)="" requires="" that="" the="" automatic="" equipment="" records="" include="" a="" list="" of="" all="" persons="" authorized="" to="" create="" or="" modify="" software.="" this="" record="" will="" help="" to="" minimize="" delays="" when="" the="" name="" of="" a="" person="" with="" those="" skills="" is="" needed="" quickly.="" proposed="" sec.="" 106.100(f)(5)(v)="" requires="" that="" the="" automatic="" equipment="" records="" document="" modifications="" to="" software,="" including="" the="" identity="" of="" the="" person="" who="" modified="" it.="" this="" documentation="" will="" ensure="" that="" the="" manufacturer="" is="" aware="" of="" any="" changes="" made="" to="" the="" software,="" and="" that="" it="" has="" a="" record="" of="" how="" the="" changed="" system="" works,="" so="" that="" it="" can="" continue="" to="" operate="" the="" system="" even="" in="" the="" absence="" of="" the="" responsible="" individual="" who="" made="" the="" modification="" to="" the="" system.="" a="" record="" of="" the="" identity="" of="" the="" person="" who="" modified="" the="" software="" will="" show="" who="" was="" responsible="" for="" modifying="" the="" software="" if="" problems="" arise="" with="" the="" operation="" of="" the="" system="" and="" will="" identify="" the="" person="" in="" the="" best="" position="" to="" know="" additional,="" but="" unrecorded,="" details="" about="" the="" software="" modification="" to="" help="" in="" troubleshooting="" the="" software="" problems.="" proposed="" sec.="" 106.100(f)(5)(vi)="" requires="" that="" the="" automatic="" equipment="" records="" include="" documentation="" of="" retesting="" or="" revalidation="" of="" modified="" systems.="" this="" proposed="" requirement="" is="" necessary="" for="" compliance="" with="" section="" 412(b)(4)(a)(i)="" of="" the="" act.="" as="" discussed="" more="" fully="" above="" in="" the="" section="" on="" proposed="" sec.="" 106.35(b)(5),="" cgmp="" requires="" that="" all="" modifications="" to="" software="" be="" made="" by="" a="" designated="" individual,="" and="" that="" all="" systems="" be="" revalidated="" after="" any="" modification="" to="" ensure="" that="" infant="" formula="" produced="" or="" analyzed="" using="" the="" modified="" software="" complies="" with="" subparts="" b="" and="" c.="" fda="" has="" tentatively="" concluded="" that="" records="" on="" retesting="" or="" revalidation="" of="" the="" modified="" systems,="" just="" like="" records="" on="" the="" initial="" testing="" or="" validation="" of="" the="" system="" (sec.="" 106.100(f)(5)(iii)),="" are="" necessary="" to="" document="" that="" the="" work="" has="" been="" done="" properly="" and="" to="" provide="" information="" if="" the="" manufacturer="" later="" tries="" to="" determine="" why="" a="" problem="" with="" the="" system="" is="" occurring="" or="" tries="" to="" determine="" why="" the="" system="" isnot="" producing="" an="" infant="" formula="" that="" complies="" with="" the="" manufacturer's="" specifications="" for="" the="" product.="" proposed="" sec.="" 106.100(f)(5)(vii)="" requires="" that="" the="" manufacturer="" make="" and="" retain="" a="" backup="" file="" of="" data="" entered="" into="" a="" computer="" or="" related="" system.="" it="" also="" requires="" that="" this="" backup="" file="" consist="" of="" a="" hard="" copy="" or="" alternative="" system,="" such="" as="" duplicate="" diskettes,="" tapes,="" or="" microfilm,="" designed="" to="" ensure="" that="" backup="" data="" are="" exact="" and="" complete,="" and="" that="" they="" are="" secure="" from="" alteration,="" inadvertent="" erasures,="" or="" loss.="" this="" proposed="" requirement="" is="" necessary="" to="" ensure="" compliance="" with="" cgmp="" because="" computer="" files="" can="" be="" easily="" altered="" or="" erased.="" backup="" files="" of="" data="" will="" allow="" the="" manufacturer="" to="" readily="" reload="" the="" files="" of="" data="" if="" problems="" occur="" in="" the="" operation="" of="" the="" computer="" or="" related="" system,="" so="" that="" the="" manufacturer's="" down="" time="" is="" minimized,="" and="" so="" that="" the="" data="" entered="" into="" the="" system="" will="" be="" an="" exact="" copy="" of="" the="" data="" previously="" used="" in="" the="" system.="" proposed="" sec.="" 106.100(f)(6)="" requires="" that="" manufacturers="" make="" and="" retain="" records="" on="" ingredients,="" containers,="" and="" closures,="" including="" the="" identity="" and="" quantity="" of="" each="" lot,="" the="" name="" of="" the="" supplier,="" the="" supplier's="" lot="" number,="" the="" name="" and="" location="" of="" the="" manufacturer="" (if="" different="" from="" the="" supplier),="" the="" date="" of="" receipt,="" and="" the="" receiving="" code="" as="" specified="" (proposed="" sec.="" 106.100(f)(6)="" (i)="" through="" (vi)).="" these="" records="" will="" enable="" the="" manufacturer="" to="" document="" that="" it="" is="" complying="" with="" proposed="" sec.="" 106.40(g).="" moreover,="" this="" information="" is="" needed="" to="" enable="" the="" manufacturer="" to="" track="" the="" source="" of="" each="" ingredient,="" container,="" or="" closure="" used="" in="" infant="" formula="" if="" a="" problem="" arises.="" if="" an="" ingredient,="" container,="" or="" closure="" is="" found="" to="" cause="" adulteration="" of="" the="" formula,="" it="" is="" important="" to="" be="" able="" to="" determine="" the="" source="" of="" the="" material,="" so="" that="" use="" of="" such="" materials="" can="" be="" halted="" and="" prevented="" in="" the="" future.="" proposed="" sec.="" 106.100(f)(6)(vii)="" requires="" that="" the="" records="" on="" ingredients,="" containers,="" and="" closures="" include="" the="" results="" and="" conclusions="" of="" any="" test="" or="" examination,="" including="" retesting="" and="" [[page="" 36194]]="" reexamination,="" performed="" on="" them="" and="" their="" disposition.="" these="" records="" will="" document="" that="" appropriate="" testing="" is="" being="" conducted="" to="" ensure="" that="" the="" ingredients="" will="" not="" adulterate="" the="" infant="" formula,="" and="" that="" the="" containers="" and="" closures="" will="" protect="" the="" infant="" formula="" against="" adulteration.="" further,="" these="" records="" will="" show="" the="" basis="" on="" which="" each="" ingredient,="" container,="" and="" closure="" was="" released="" for="" use="" in="" infant="" formula="" production="" if="" questions="" about="" such="" release="" later="" arise.="" individual="" lots="" of="" ingredients,="" containers,="" and="" closures="" are="" likely="" to="" be="" used="" in="" a="" number="" of="" different="" batches="" of="" infant="" formula;="" therefore,="" the="" agency="" is="" proposing="" that="" the="" records="" on="" ingredients,="" containers,="" and="" closures="" be="" a="" part="" of="" the="" records="" pertaining="" to="" cgmp.="" retaining="" such="" records="" in="" the="" cgmp="" records,="" rather="" than="" in="" each="" batch="" record,="" will="" eliminate="" the="" duplication="" of="" records="" and="" simplify="" the="" recordkeeping.="" the="" disposition="" of="" the="" ingredients,="" containers,="" and="" closures="" will="" show="" which="" materials="" were="" destroyed="" because="" they="" did="" not="" meet="" the="" manufacturers="" specifications="" (and="" not="" used="" in="" manufacture="" in="" compliance="" with="" sec.="" 106.40(d)),="" and="" which="" batches="" of="" infant="" formula="" were="" made="" using="" each="" lot="" of="" ingredients,="" containers,="" or="" closures.="" thus,="" the="" manufacturer="" will="" know="" which="" lots="" of="" ingredients,="" containers,="" or="" closures="" were="" used="" in="" making="" infant="" formula="" and="" will="" be="" able="" to="" confirm="" that="" those="" lots="" complied="" with="" proposed="" sec.="" 106.40(d).="" moreover,="" if="" a="" batch="" of="" formula="" is="" shown="" to="" be="" adulterated,="" these="" records="" will="" help="" the="" manufacturer="" to="" identify="" the="" source="" of="" the="" adulteration.="" proposed="" sec.="" 106.100(f)(7)="" requires="" that="" manufacturers="" make="" and="" retain="" records="" that="" include="" a="" full="" description="" of="" the="" methodology="" used="" to="" test="" powdered="" infant="" formulas="" to="" verify="" compliance="" with="" proposed="" sec.="" 106.55(c)="" and="" the="" methodology="" used="" to="" conduct="" quality="" control="" testing="" in="" accordance="" with="" sec.="" 106.91="" (a)="" and="" (b).="" the="" agency="" has="" not="" specified="" in="" these="" regulations="" the="" methodologies="" that="" must="" be="" used="" to="" conduct="" microbiological="" and="" quality="" control="" testing.="" thus,="" fda="" has="" tentatively="" concluded="" that="" a="" manufacturer="" needs="" to="" maintain="" a="" record="" that="" fully="" describes="" the="" methodology="" that="" it="" has="" decided="" to="" use="" to="" test="" powdered="" infant="" formula="" for="" microorganisms="" and="" for="" quality="" control="" testing.="" such="" a="" record="" is="" necessary="" if="" there="" is="" to="" be="" consistency="" in="" the="" procedure="" that="" the="" manufacturer="" follows="" in="" testing="" each="" batch="" of="" infant="" formula,="" particularly="" in="" light="" of="" the="" fact="" that="" the="" laboratory="" personnel="" conducting="" the="" testing="" are="" likely="" to="" vary.="" the="" accuracy="" and="" reproducibility="" of="" microbiological="" and="" quality="" control="" testing="" depend="" on="" the="" procedure="" used="" to="" conduct="" the="" test.="" fda="" is="" proposing="" that="" the="" full="" description="" of="" the="" methodology="" be="" retained="" as="" part="" of="" the="" cgmp="" records,="" rather="" than="" in="" the="" batch="" record="" provided="" for="" in="" proposed="" sec.="" 106.100(e)(5),="" because="" these="" methods="" will="" be="" used="" to="" test="" multiple="" batches="" of="" infant="" formula.="" retaining="" such="" records="" in="" the="" cgmp="" records,="" rather="" than="" in="" each="" batch="" record,="" will="" mean="" that="" the="" manufacturer="" has="" to="" maintain="" only="" one="" document,="" rather="" than="" having="" to="" reproduce="" it="" each="" time="" that="" it="" runs="" a="" batch="" of="" formula.="" thus,="" the="" proposed="" approach="" will="" eliminate="" duplication="" of="" records="" and="" simplify="" recordkeeping.="" 4.="" records="" on="" distribution="" of="" infant="" formulas="" proposed="" sec.="" 106.100(g)="" adds="" to="" current="" sec.="" 106.100(g)="" a="" requirement="" that="" records="" pertaining="" to="" distribution="" of="" the="" infant="" formula="" show="" that="" products="" intended="" for="" export="" only="" are="" in="" fact="" exported.="" it="" has="" recently="" come="" to="" the="" attention="" of="" the="" agency="" that="" infant="" formulas="" produced="" for="" export="" have="" been="" diverted="" and="" sold="" in="" the="" united="" states.="" all="" persons="" introducing="" any="" new="" infant="" formula="" into="" interstate="" commerce,="" which="" includes="" persons="" exporting="" an="" infant="" formula="" to="" a="" foreign="" country,="" are="" required="" by="" section="" 412(c)="" of="" the="" act="" to="" register="" and="" make="" a="" submission="" to="" the="" agency="" 90="" days="" before="" marketing="" the="" formula.="" (see="" discussion="" of="" proposed="" secs.="" 106.110="" and="" 106.120.)="" as="" discussed="" in="" the="" section="" of="" this="" preamble="" on="" proposed="" sec.="" 106.120(c),="" the="" agency="" has="" tentatively="" concluded="" that="" it="" will="" not="" require="" manufacturers="" who="" produce="" infant="" formula="" for="" export="" only="" to="" submit="" the="" same="" information="" that="" would="" be="" required="" for="" products="" intended="" or="" offered="" for="" sale="" in="" the="" united="" states.="" in="" lieu="" of="" the="" information="" required="" by="" sec.="" 106.120(b),="" fda="" is="" proposing="" to="" allow="" manufacturers="" of="" products="" for="" export="" only="" to="" give="" assurances="" that="" the="" infant="" formula="" will="" not="" be="" sold="" or="" offered="" for="" sale="" in="" domestic="" commerce.="" this="" provision="" is="" based,="" in="" part,="" on="" section="" 801(e)="" of="" the="" act,="" which="" states="" that="" a="" food="" will="" not="" be="" deemed="" to="" be="" adulterated="" or="" misbranded="" under="" the="" act="" if,="" among="" other="" things,="" it="" is="" not="" sold="" or="" offered="" for="" sale="" in="" domestic="" commerce.="" thus,="" the="" agency="" has="" tentatively="" concluded="" that="" the="" additional="" recordkeeping="" requirement="" on="" distribution="" of="" infant="" formulas="" for="" export="" only="" in="" proposed="" sec.="" 106.100(g)="" is="" necessary="" so="" that="" verification="" that="" the="" infant="" formula="" was="" not="" in="" fact="" sold="" or="" offered="" for="" sale="" in="" domestic="" commerce="" will="" be="" readily="" available="" in="" the="" manufacturer's="" records.="" 5.="" audit="" records="" proposed="" sec.="" 106.100(j)="" carries="" forward="" the="" requirement="" in="" current="" sec.="" 106.100(j)="" that="" the="" manufacturer="" make="" and="" retain="" records,="" which="" include="" the="" audit="" plans="" and="" procedures,="" that="" pertain="" to="" regularly="" scheduled="" audits.="" as="" discussed="" above,="" the="" written="" audit="" plan,="" which="" includes="" audit="" procedures,="" is="" required="" under="" proposed="" sec.="" 106.94(a)="" and="" (b).="" the="" proposed="" section="" further="" requires="" that="" records="" of="" audits="" include="" the="" findings="" of="" the="" audit="" and="" a="" listing="" of="" any="" changes="" made="" in="" response="" to="" these="" findings.="" this="" requirement="" is="" proposed="" under="" the="" authority="" of="" section="" 412(b)(4)(a)(v)="" of="" the="" act,="" which="" requires="" that="" manufacturers="" retain="" all="" records="" of="" the="" results="" of="" regularly="" scheduled="" audits="" conducted="" under="" the="" requirements="" prescribed="" by="" the="" secretary="" (and="" by="" delegation,="" fda)="" under="" the="" authority="" of="" section="" 412(b)(2)(b)(iv).="" proposed="" sec.="" 106.100(j)="" also="" requires="" that="" the="" manufacturer="" make="" readily="" available="" for="" authorized="" inspection="" the="" audit="" plans="" and="" procedures="" and="" a="" statement="" of="" assurance="" that="" the="" regularly="" scheduled="" audits="" are="" being="" conducted.="" this="" provision="" implements="" section="" 412(b)(4)(b)(ii)="" of="" the="" act,="" which="" requires="" that="" the="" manufacturer="" provide="" written="" assurance="" that="" the="" regularly="" scheduled="" audits="" are="" being="" conducted="" by="" the="" manufacturer.="" however,="" proposed="" sec.="" 106.100(j)="" also="" provides="" that="" the="" findings="" of="" the="" audit="" and="" any="" changes="" made="" in="" response="" to="" these="" findings="" need="" not="" be="" made="" available="" to="" fda.="" this="" provision="" is="" brought="" forward="" from="" current="" sec.="" 106.100(j)="" and="" reflects="" section="" 412(b)(4)(b)(ii)="" of="" the="" act,="" which="" states="" that="" a="" ``manufacturer="" need="" only="" provide="" written="" assurances="" to="" the="" secretary="" that="" the="" regularly="" scheduled="" audits="" required="" by''="" section="" 412(b)(2)(b)(iv)="" of="" the="" act="" ``are="" being="" conducted="" by="" the="" manufacturer,="" and="" need="" not="" make="" available="" to="" the="" secretary="" the="" actual="" written="" reports="" of="" such="" audits.''="" 6.="" modification="" of="" current="" sec.="" 106.100(k)(3)="" the="" agency="" also="" is="" revising="" current="" sec.="" 106.100(k)(3)="" to="" reflect="" the="" numbering="" changes="" in="" the="" regulations="" on="" notifying="" the="" agency="" of="" a="" causal="" relationship="" between="" the="" consumption="" of="" an="" infant="" formula="" and="" an="" infant's="" death.="" the="" agency="" is="" moving="" the="" requirements="" of="" current="" sec.="" 106.120(b)="" to="" sec.="" 106.150="" to="" reflect="" the="" changes="" it="" is="" proposing="" in="" subpart="" g.="" thus,="" the="" reference="" to="" sec.="" 106.120="" in="" sec.="" 106.100="" (k)(3)="" will="" be="" changed="" to="" read="" ``sec.="" 106.150,''="" if="" the="" [[page="" 36195]]="" agency="" adopts="" the="" relevant="" proposed="" changes.="" g.="" registration,="" submission,="" and="" notification="" requirements="" 1.="" introduction="" the="" act="" provides="" for="" three="" types="" of="" notices="" that="" manufacturers="" of="" infant="" formula="" must="" provide="" to="" fda="" and="" sets="" forth="" the="" general="" information="" that="" must="" be="" included="" in="" each="" type="" of="" notice.="" first,="" manufacturers="" of="" a="" new="" infant="" formula="" must="" register="" with="" fda,="" in="" accordance="" with="" section="" 412(c)(1)(a)="" of="" the="" act,="" providing="" the="" name="" and="" address="" of="" the="" firm="" and="" all="" establishments="" that="" will="" manufacture="" the="" new="" infant="" formula.="" second,="" manufacturers="" must="" submit="" to="" fda,="" in="" accordance="" with="" section="" 412(d)="" of="" the="" act,="" certain="" information="" concerning="" a="" new="" infant="" formula="" or="" an="" infant="" formula="" in="" which="" there="" is="" a="" change="" in="" formulation="" or="" processing="" that="" may="" affect="" whether="" the="" formula="" is="" adulterated="" under="" section="" 412(a)="" of="" the="" act.="" third,="" manufacturers="" must="" notify="" fda,="" in="" accordance="" with="" section="" 412(e)="" of="" the="" act,="" of="" any="" adulterated="" or="" misbranded="" infant="" formula="" that="" has="" left="" their="" control.="" the="" agency="" has="" not="" specified="" the="" information="" that="" must="" be="" included="" in="" an="" infant="" formula="" registration,="" submission,="" or="" notification.="" while="" firms="" have="" been="" able="" to="" function="" under="" these="" requirements="" since="" the="" 1986="" amendments="" were="" enacted="" with="" respect="" to="" the="" notice="" that="" manufacturers="" must="" provide="" to="" the="" agency="" under="" section="" 412(c)="" and="" (d)="" of="" the="" act,="" inquiries="" from="" industry="" suggest="" that="" manufacturers="" are="" uncertain="" about="" the="" information="" that="" they="" must="" provide.="" some="" manufacturers="" have="" needed="" to="" make="" multiple="" submissions="" for="" a="" new="" infant="" formula="" because="" of="" deficiencies="" in="" the="" initial="" submission.="" for="" example,="" some="" submissions="" have="" contained="" information="" concerning="" more="" than="" one="" formula="" without="" clearly="" identifying="" which="" information="" applied="" to="" which="" formula.="" some="" submissions="" have="" not="" contained="" the="" information="" required="" by="" section="" 412(d)(1)="" of="" the="" act.="" therefore,="" fda="" recognizes="" that="" it="" will="" be="" useful="" both="" to="" manufacturers="" and="" to="" the="" agency="" to="" issue="" regulations="" to="" ensure="" that="" registrations="" and="" submissions="" required="" by="" the="" act="" follow="" a="" consistent="" format="" and="" contain="" the="" necessary="" information="" for="" the="" agency="" to="" determine="" whether="" there="" is="" a="" basis="" to="" object="" to="" the="" marketing="" of="" a="" new="" infant="" formula.="" such="" regulations="" will="" facilitate="" the="" manufacturer's="" preparation="" of="" the="" notice="" and="" also="" will="" facilitate="" the="" agency's="" review="" of="" the="" notice="" once="" fda="" receives="" it.="" these="" proposed="" regulations="" also="" will="" make="" clear="" when="" a="" registration,="" notification,="" or="" submission="" to="" the="" agency="" is="" needed.="" for="" example,="" as="" stated="" above,="" it="" has="" recently="" come="" to="" the="" attention="" of="" the="" agency="" that="" some="" firms="" that="" manufacture="" infant="" formula="" intended="" only="" for="" export="" are="" not="" aware="" of="" their="" registration="" and="" submission="" responsibilities.="" section="" 412(c)(1)="" of="" the="" act="" requires="" that="" a="" person="" introducing="" a="" new="" infant="" formula="" into="" interstate="" commerce="" (which="" includes="" export="" to="" a="" foreign="" country)="" must="" register="" the="" infant="" formula="" and="" make="" the="" proper="" submission="" 90="" days="" before="" marketing="" it.="" these="" proposed="" regulations="" make="" clear="" that="" registration="" and="" submission="" requirements="" apply="" to="" infant="" formulas="" intended="" only="" for="" export="" as="" well="" as="" to="" infant="" formula="" intended="" for="" the="" domestic="" market.="" finally,="" for="" completeness,="" fda="" has="" decided="" that="" it="" would="" be="" useful="" to="" both="" manufacturers="" and="" the="" agency,="" to="" carry="" forward="" current="" sec.="" 106.240,="" concerning="" notification="" of="" a="" violative="" infant="" formula,="" as="" sec.="" 106.150.="" doing="" so="" will="" consolidate="" in="" one="" place="" in="" the="" agency's="" regulations="" all="" requirements="" concerning="" notice="" to="" the="" agency="" to="" meet="" the="" requirements="" of="" section="" 412(c),="" (d),="" and="" (e)="" of="" the="" act.="" 2.="" new="" infant="" formula="" registration="" proposed="" sec.="" 106.110(a)="" requires="" that="" a="" manufacturer="" of="" a="" new="" infant="" formula="" register="" with="" fda="" before="" introducing="" the="" formula,="" or="" delivering="" it="" for="" introduction,="" into="" interstate="" commerce.="" because="" ``interstate="" commerce''="" is="" defined="" in="" section="" 201(b)="" of="" the="" act="" as="" ``(1)="" commerce="" between="" any="" state="" or="" territory="" and="" any="" place="" outside="" thereof,="" and="" (2)="" commerce="" within="" the="" district="" of="" columbia="" or="" within="" any="" other="" territory="" not="" organized="" with="" a="" legislative="" body,''="" under="" this="" provision,="" a="" manufacturer="" is="" required="" to="" register="" with="" fda="" before="" introducing="" a="" new="" infant="" formula="" into="" the="" united="" states="" market="" or="" before="" beginning="" exporting="" the="" formula.="" proposed="" sec.="" 106.110(a)="" sets="" out="" how="" to="" comply="" with="" section="" 412(c)(1)(a)="" of="" the="" act.="" failure="" to="" provide="" the="" notice="" required="" by="" section="" 412(c)(1)(a)="" of="" the="" act="" is="" a="" prohibited="" act="" under="" section="" 301(s).="" under="" section="" 412(c)(1)(a)="" of="" the="" act,="" proposed="" sec.="" 106.110(b)="" sets="" out="" the="" information="" required="" in="" a="" new="" infant="" formula="" registration.="" while="" manufacturers="" may="" register="" at="" any="" time="" before="" introducing="" a="" new="" formula="" into="" interstate="" commerce,="" fda="" urges="" that="" they="" do="" so="" at="" the="" same="" time="" that="" they="" submit="" notice="" of="" their="" intent="" to="" market="" a="" new="" infant="" formula="" in="" accordance="" with="" section="" 412(c)(1)(b)="" and="" (d)(1)="" of="" the="" act.="" receiving="" registration="" and="" the="" 90="" day="" submission="" at="" the="" same="" time="" will="" facilitate="" the="" agency's="" review.="" 3.="" new="" infant="" formula="" submission="" section="" 412(c)(1)(b)="" of="" the="" act="" requires="" that="" manufacturers="" of="" a="" new="" infant="" formula="" submit="" to="" fda="" a="" notice="" of="" their="" intent="" to="" market="" the="" new="" formula="" that="" complies="" with="" section="" 412(d)(1)="" of="" the="" act.="" the="" notice="" must="" be="" submitted="" at="" least="" 90="" days="" before="" the="" infant="" formula="" is="" introduced="" or="" delivered="" for="" introduction="" into="" interstate="" commerce="">6. Proposed Sec. 106.120 implements this requirement.
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        \6\ While section 412(c)(1) and (c)(1)(B) of the act state ``No 
    person shall introduce or deliver for introduction into interstate 
    commerce any new infant formula unless--such person has at least 90 
    days before marketing such new infant formula, made the submission 
    to the Secretary required by'' section 412(c)(1) of the act, FDA has 
    recognized since 1986 that this citation is in error (see 
    ``Requirements for Infant Formulas'' published by FDA's Industry 
    Programs Branch, CFSAN), and that the correct citation is section 
    412(d)(1). This correction agrees with the language of section 
    412(d)(1) of the act, which states what a submission about any 
    infant formula subject to section 412(c) of the act should include. 
    It is also consistent with the rules of statutory construction. See 
    Colonial Life & Accident Insurance Co. v. American Family Life 
    Assurance Co., 846 F. Supp. 454, 463 n. 14(D.S.C. 1994) (where the 
    legislature has made a mistake in reference, and its intent is 
    manifest, the statute may be read as corrected in order to give 
    effect to the legislative intent).
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        Proposed Sec. 106.120(a) sets out the requirement that a 
    manufacturer submit a notice of its intent to market a new infant 
    formula and provides the address to which such notices are to be 
    submitted.
        Proposed Sec. 106.120(b) sets forth the information that 
    manufacturers must include in their new infant formula submission. This 
    proposed regulation implements and specifies the information called for 
    in section 412(d)(1) of the act.
        a. General information required in a 90-day submission. Because the 
    registration of a new infant formula (proposed Sec. 106.110) need not 
    accompany the new infant formula submission (proposed Sec. 106.120), 
    and because a third submission on a newinfant formula that verifies 
    that the new infant formula, as produced, contains all required 
    nutrients (see proposed Sec. 106.130) will be submitted separately, FDA 
    has tentatively concluded that the name of the infant formula is needed 
    to ensure that all information on a particular infant formula is filed 
    together and is available to determine whether the agency should object 
    to the marketing of the formula. Information on the form of the product 
    is necessary for an accurate evaluation of the product because 
    different
    
    [[Page 36196]]
    
    requirements may apply to different forms of a formula. For example, 
    powdered infant formula must meet the microbiological quality 
    requirements in proposed Sec. 106.55, whereas liquid forms of a formula 
    do not. Therefore, FDA is proposing to require this information in 
    Sec. 106.120(b)(1), under the authority of sections 412(d)(1) and 
    701(a) of the act, even though it is not explicitly required in section 
    412(d)(1).
        Proposed Sec. 106.120(b)(2) requires that the submission include an 
    explanation of why the formula is a new infant formula to facilitate a 
    determination by the agency as to the type of evaluation the new infant 
    formula requires. For example, if the formula is a new infant formula 
    because a new manufacturing plant will be used to produce it, but the 
    formulation of the product is not changed, FDA will evaluate the 
    processing and arrange to inspect the new facility but may conclude 
    that testing to provide assurance that quality factor requirements have 
    been met is not necessary. Thus, FDA is proposing to require the 
    submission of this information, even though, like the information 
    required under proposed Sec. 106.120(b)(1), submission of this 
    information is not specifically provided for in the act. The agency 
    tentatively concludes that this information is necessary for the 
    efficient enforcement of sections 412(c)(1)(B) and (d)(1) of the act.
        b. Formulation and processing information required in a 90-day 
    submission. Pursuant to section 412(d)(1)(A) of the act, proposed 
    Sec. 106.120(b)(3) requires that the submission include the 
    quantitative formulation of the infant formula. The agency is proposing 
    that, if the notice concerns more than one form of the formula, the 
    submission include quantitative information on each form of the formula 
    that is the subject of the notice. FDA is proposing to require that 
    manufacturers submit the formulation in units per volume (for liquid 
    formulas) or units per dry weight (for powdered formulas) because 
    formulations expressed in these units will facilitate agency 
    understanding of the formula. Manufacturers already will have the 
    formulation available in these units as a part of the master 
    manufacturing order, and submitting the formulations in these units 
    should not require additional calculations by the manufacturer.
        Proposed Sec. 106.120(b)(3) also requires, under section 
    412(d)(1)(B) of the act, that the submission include a description of 
    any reformulation of the infant formula, including a listing of each 
    new or changed ingredient and a discussion of the effect of such 
    changes on the nutrient levels in the formulation. For example, if the 
    protein source in an infant formula is replaced with a protein source 
    that contains a different amount of protein (e.g., from casein to a 
    mixture of casein and whey), it is important to ensure that the amount 
    of the new protein source used will provide the amount of protein 
    required by Sec. 107.100. As another example, if an ingredient such as 
    sodium selenite is added to the formula for the first time, it is 
    important to ensure that the level of the ingredient provides selenium 
    (in the form of selenite) at a level that is consistent with the 
    infant's needs and yet within the safe range of selenium intake.
        Proposed Sec. 106.120(b)(4) requires that the submission include a 
    description, when applicable, of any change in processing of the infant 
    formula, and that such description identify the specific change in 
    processing, including side-by-side, detailed schematic diagrams 
    comparing the new processing to the previous processing (including 
    processing times and temperatures). This proposed requirement 
    implements section 412(d)(1)(B) of the act, which states that the 
    submission must include a description of any change in the processing 
    of an infant formula. FDA is proposing that the description of the 
    change in processing include detailed schematic diagrams comparing the 
    new processing to the previous processing because schematic diagrams 
    are efficient tools for identifying the nature and significance of 
    changes in processing.
        c. Assurance that the infant formula will not be marketed unless it 
    meets quality factor and nutrient requirements of the act. Pursuant to 
    section 412(d)(1)(C) of the act, proposed Sec. 106.120(b)(5) requires 
    that the submission include an assurance that the infant formula will 
    not be marketed unless it meets the quality factor requirements of 
    section 412(b)(1) of the act and the nutrient content requirements of 
    section 412(i) of the act.
        Proposed Sec. 106.120(b)(5)(i) requires that the assurance that the 
    formula meets the quality factor requirements, which are set forth in 
    subpart E of part 106, be provided by a submission that complies with 
    Sec. 106.121. Section 412(d)(1)(C) of the act requires that, 90 days 
    before marketing a new infant formula, a manufacturer submit assurances 
    that the infant formula will not be marketed unless it meets the 
    quality factor requirements established by regulations under section 
    412(b)(1). Section 412(d)(2) of the act requires that, after the first 
    production of a new infant formula and before introduction into 
    interstate commerce of such formula, the manufacturer submit a written 
    verification that summarizes test results and records demonstrating 
    that such formula complies with the quality factor requirements. 
    However, FDA has tentatively concluded that to implement sections 412 
    (d)(1) and (d)(2) of the act in a way that ensures that the statutory 
    goals are achieved--that is, to ensure that the agency has all the 
    relevant information for a sufficient period of time to conduct a 
    meaningful review of the nutritional adequacy of the formula while 
    enabling the infant formula manufacturer to market its product as 
    expeditiously as possible--it is appropriate to require that the 
    assurances that the quality factors will be met be provided by means of 
    data that would otherwise be required as part of the verification 
    submission. FDA notes that such a requirement would only codify current 
    practice. Since passage of the 1986 amendments, infant formula 
    manufacturers have been providing data demonstrating that a new infant 
    formula meets the quality factor requirements as a part of the 
    submission made 90 days before marketing.
        Proposed Sec. 106.120(b)(5)(ii) requires that the assurance that 
    the formula complies with the nutrient content requirements, which are 
    set forth in Sec. 107.100, be provided by a statement assuring that the 
    formula will not be marketed unless it meets the nutrient requirements 
    of Sec. 107.100, as demonstrated by testing required under subpart C of 
    part 106.
        The agency acknowledges that there is an apparent inconsistency in 
    how it interprets the word ``assurance'' in section 412(d)(1)(C) of the 
    act as it relates to assurance that the infant formula meets the 
    quality factor requirements and assurance that the infant formula meets 
    nutrient content requirements. FDA has tentatively concluded, however, 
    that assurance that the formula will meet the quality factor 
    requirements is a threshold question that must be answered 
    affirmatively before the effort in setting up the line for first 
    production of the infant formula would be justified. Therefore, the 
    agency is proposing to require that the assurance that the infant 
    formula will meet the quality factor requirements be provided by data 
    submitted 90 days before marketing the formula.
        On the other hand, the agency is proposing that the assurance that 
    the formula will not be marketed unless it meets the nutrient 
    requirements of Sec. 107.100 can be provided by a statement to that 
    effect (as opposed to data) submitted 90 days before marketing of the 
    formula because the
    
    [[Page 36197]]
    
    data and records demonstrating that the formula complies with the 
    nutrient requirements of Sec. 107.100 will not be available until the 
    production line is set up, and the first production of the infant 
    formula has occurred. FDA will receive verification that the formula 
    meets the nutrient requirements as a part of the submission required by 
    section 412(d)(2) of the act (see proposed Sec. 106.130(b)(3), below). 
    Therefore, FDA has tentatively concluded that it is adequate to receive 
    a commitment from the manufacturer, 90 days before marketing, that the 
    infant formula will not be marketed unless it meets the nutrient 
    requirements of Sec. 107.100.
        d. Assurance that the processing of the infant formula complies 
    with the CGMP and quality control procedures of the act. Under section 
    412(d)(1)(D) of the act, proposed Sec. 106.120(b)(6) requires that the 
    submission include assurance that the processing of the infant formula 
    complies with section 412(b)(2) of the act (CGMP, including quality 
    control procedures).
        Proposed Sec. 106.120(b)(6)(i) requires that the assurance that the 
    processing of the infant formula complies with section 412(b)(2) of the 
    act include a statement that the formula will be produced in accordance 
    with subparts B and C of part 106. This proposed requirement is a 
    necessary element of the assurance required by section 412(d)(1)(D) of 
    the act because the requirements for CGMP are set forth in subpart B 
    and the requirements for quality control procedures are set forth in 
    subpart C. In the Congressional Record (Ref. 1), Senator Metzenbaum 
    stated that the amendments to the Infant Formula Act set up 
    requirements ``which will prevent our Nation's Children from ever again 
    being threatened by defective baby formula. The most important 
    provision of this amendment is the simple requirement that each batch 
    of formula must be tested for each essential nutrient that must be 
    contained in the formula'' (Ref. 1).
        Proposed Sec. 106.120(b)(6)(ii) requires that the assurance that 
    the processing of the infant formula complies with section 412(b)(2) of 
    the act include the basis on which the manufacturer has concluded that 
    each ingredient meets the requirement of proposed Sec. 106.40(a), i.e., 
    that the ingredient is an approved food additive, is authorized by a 
    prior sanction issued by the agency, or is GRAS for its intended use. 
    The statute provides that the manufacturer submit, 90 days before 
    marketing a new infant formula, assurance that the processing of the 
    formula complies with the CGMP regulations, and that the formula is 
    manufactured in a way that is designed to prevent its adulteration. FDA 
    has tentatively concluded that, to implement the act in a way that will 
    ensure that the statutory goals are achieved, that is, to ensure that 
    the agency has all the relevant information for a sufficient period of 
    time to conduct a meaningful review of the formula while enabling the 
    manufacturer to market its product as expeditiously as possible, it is 
    appropriate to require that the assurance that none of the ingredients 
    will adulterate the formula be provided by an explanation of how each 
    ingredient meets proposed Sec. 106.40(a). FDA has tentatively concluded 
    that this approach is appropriate because, like the evidence that the 
    formula meets the quality factors, evidence that all the ingredients in 
    the infant formula are safe goes to a threshold question that must be 
    answered affirmatively before the effort in setting up the production 
    line for the first production of the infant formula would be justified. 
    Moreover, an infant formula manufacturer would want to have information 
    demonstrating that each of the ingredients in the formula is safe 
    before marketing the formula, because without such information, a 
    responsible manufacturer would not include the ingredient in its 
    product.
        FDA will review the new infant formula submission to ensure that a 
    safe product will be produced (sections 201(s), 402(a)(1) and (a)(2), 
    and 409 of the act). If the agency is not presented with basis on which 
    it can be satisfied that the use of an ingredient in an infant formula 
    will be safe, FDA will not be able to acquiesce in the marketing of the 
    formula. The legislative history of the 1986 amendments supports that 
    Congress anticipated that FDA would provide this type of review. In the 
    Congressional Record of September 27, 1986, Senator Metzenbaum stated:
    
        I continue to be concerned, however, that our food and drug laws 
    do not differentiate between foods and infant formulas. But they are 
    fundamentally different. An infant formula is designed as the sole 
    source of nutrition for a baby. An infant formula is used daily. A 
    baby must thrive from its content for the first and most formative 
    months of his or her life. I expect the Secretary to look closely at 
    whether or not our standards in this area for foods are adequate 
    standards for infant formula. I have no reason at this time to 
    suspect that there is a problem here. But I continue to urge the 
    Secretary to give thorough consideration to the important 
    distinctions between infant formula and other foods, as well as food 
    additives which may be used with infant formulas. (Ref. 1)
    
        One way for a manufacturer to satisfy the agency that proposed 
    Sec. 106.40(a) is met would be for the manufacturer to use only 
    ingredients that are: (1) Listed as GRAS for such use in 21 CFR part 
    182 or affirmed as GRAS for such use in 21 CFR part 184 or otherwise 
    GRAS for such use under the regulations included in those parts; (2) 
    approved for such use by a food additive regulation; or (3) authorized 
    by a prior sanction issued by FDA.
        Alternatively, the requirements of proposed Sec. 106.40(a) can be 
    met by a showing that the substance is GRAS within the meaning of 
    Sec. 170.30 (21 CFR 170.30), which states that ``general recognition of 
    safety may be based only on the view of experts qualified by scientific 
    training and experience to evaluate the safety of substances directly 
    or indirectly added to foods'' (Sec. 170.30(a)). To clarify this point, 
    Sec. 170.30(a) states that ``[g]eneral recognition of safety requires 
    common knowledge about the substance throughout the scientific 
    community knowledgeable about the safety of substances directly or 
    indirectly added to food.'' The qualified experts can base their views 
    on either: (1) Scientific procedures, or (2) in the case of a substance 
    used in food prior to January 1, 1958, through experience based on 
    common use in food (section 201(s) of the act).
        Under Sec. 170.30(b), general recognition of safety based upon 
    scientific procedures requires the same quantity and quality of 
    scientific evidence as is required to obtain approval of the ingredient 
    as a food additive, and it must ordinarily be based on published 
    studies, which may be corroborated by unpublished studies and other 
    data and information. If the manufacturer of an infant formula wishes 
    to use an ingredient because there is general recognition of safety 
    based upon scientific procedures, FDA is proposing to require in 
    Sec. 106.120(b)(6)(ii) that the manufacturer include as a part of its 
    new infant formula 90-day submission the rationale for why the 
    ingredient is GRAS and the evidence that demonstrates that there is 
    common knowledge about the safety of the substance throughout the 
    scientific community knowledgeable about the safety of such substance. 
    FDA is proposing that this evidence include a bibliography of published 
    studies, copies of those scientific publications about the substance, 
    and an explanation as to why, based on the published studies, the use 
    of the substance in infant formula is GRAS.
        Under Sec. 170.30(c)(1), if a substance is GRAS based on common use 
    in food prior to January 1, 1958, this determination must be based 
    solely on
    
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    food use of the substance before January 1, 1958, and must ordinarily 
    be based upon generally available data and information. Thus, GRAS 
    based on common use in food prior to January 1, 1958, may be determined 
    without the quantity or quality of scientific procedures required for 
    approval of a food additive regulation. If the manufacturer of an 
    infant formula wishes to use an ingredient based solely on food use of 
    the substance prior to January 1, 1958, it should provide as a part of 
    the new infant formula 90-day submission the evidence supporting that 
    the ingredient was in common use in infant formula prior to January 1, 
    1958, and an explanation of why that use provides the basis for general 
    recognition of the safety of the substance.
        FDA has recognized that it is impractical to list all substances 
    that are GRAS for their intended use based on their common use in food 
    prior to 1958 (see 21 CFR 182.1(a)). The agency regards such common 
    food ingredients as salt, pepper, vinegar, and baking powder as safe 
    for their intended use. Also, current Sec. 170.30(d) provides that a 
    ``food ingredient of natural biological origin that has been widely 
    consumed for its nutrient properties in the United States prior to 
    January 1, 1958, without known detrimental effects, which is subject 
    only to conventional processing as practiced prior to January 1, 1958, 
    and for which no known safety hazard exists, will ordinarily be 
    regarded as GRAS * * *.'' Some ingredients are used in infant formulas 
    even though they are not listed or affirmed as GRAS by the agency for 
    their intended use. Vitamin K, for example, is required to be a part of 
    an infant formula under section 412(i) of the act and, in the form of 
    phylloquinone, is considered to be safe and suitable for infant 
    formulas when used in accordance with prescribed levels in 
    Sec. 107.100, although no source of vitamin K, such as phytonadione or 
    phylloquinone, has been listed or affirmed as GRAS by the agency. 
    Likewise, sodium selenite has been added to infant formulas to provide 
    the amount of selenium that has been determined to be essential for 
    infants by NAS (Ref. 19). Published experimental and clinical data 
    provide a basis upon which experts qualified by scientific training and 
    experience could evaluate the safety of sodium selenite as a source of 
    selenium for use in infant formula and could conclude that it is safe. 
    The agency anticipates that other ingredients may be shown to be GRAS 
    because they are generally accepted sources of substances that are 
    established as essential for infants by an authoritative body such as 
    NAS. However, manufacturers should not take this acknowledgment to mean 
    that they are free to declare that the use of any ingredient they want 
    to use is GRAS. Any ingredient that cannot meet the standard of 
    Sec. 170.30 for a GRAS determination will be viewed by the agency as a 
    food additive, and any infant formula that contains a food additive 
    that the agency has not approved for use in infant formula is subject 
    to being acted against by the agency.
        If the safety of an ingredient is not expressly recognized in an 
    FDA regulation, the burden will rest on the manufacturer of the infant 
    formula to include in its new infant formula submission an explanation 
    of why the substance is GRAS under Sec. 170.30, along with the 
    published and other information that provides the basis for that 
    explanation, in accordance with proposed Sec. 106.120(b)(6)(ii). If the 
    agency adopts this approach, a failure of the agency to object to a 
    manufacturer's determination that an ingredient is GRAS in a new infant 
    formula submission will not constitute a GRAS affirmation by the 
    agency. However, if FDA knows of no reason to question the safety of an 
    ingredient to be used in infant formula, the agency will not object to 
    the manufacturer's relying on its own determination that use of the 
    substance is GRAS.
        e. Submission 90 days before marketing a new infant formula 
    intended only for export. When a new infant formula is intended only 
    for export, proposed Sec. 106.120(c) provides that manufacturers may 
    submit, in lieu of the information required under proposed 
    Sec. 106.120(b), a statement that the infant formula meets the 
    specifications of the foreign purchaser, does not conflict with the 
    laws of the country to which it is to be exported, is labeled on the 
    outside of the shipping package to indicate that it is intended for 
    export only, and will not be sold or offered for sale in domestic 
    commerce. This proposed requirement recognizes that under section 
    801(e) of the act, in certain limited circumstances, manufacturers may 
    lawfully export products that are adulterated or misbranded. The 
    information required under proposed Sec. 106.120(c) will demonstrate 
    that those limited circumstances exist. FDA has tentatively concluded 
    that proposed Sec. 106.120(c) will provide manufacturers with the 
    flexibility allowed under section 801(e) of the act while meeting the 
    requirements of sections 412(c) and (d) of the act.
        f. Submission 90 days before marketing--administrative procedures. 
    Proposed Sec. 106.120(d) states that the submission will not constitute 
    notice under section 412 of the act unless it complies fully with 
    Sec. 106.120(b), and the information that it contains is set forth in a 
    manner that is readily understandable, so that FDA can complete its 
    review in a timely manner and advise the manufacturer if it has any 
    concerns about the marketing of the formula before the 90 days is up. 
    Proposed Sec. 106.120(d) makes clear that the agency will notify the 
    submitter if the notice is not adequate because it does not meet the 
    requirements of sections 412(c) and (d) of the act.
        Proposed Sec. 106.120(e) provides that if a new infant formula 
    submission contains all the information required by proposed 
    Sec. 106.120(b), FDA will acknowledge its receipt and notify the 
    manufacturer of the date of receipt, which will be the filing date for 
    the submission (and the manufacturer will be able to plan those actions 
    necessary to begin marketing the new formula in reliance on that date). 
    Further, pursuant to section 412(c)(1)(B) of the act, proposed 
    Sec. 106.120(e) also requires that the manufacturer not market the new 
    infant formula until 90 days after the filing date. Congress provided 
    for 90-day notice so that the agency would have sufficient time to 
    examine all of the material submitted and decide whether there is any 
    basis for concern about the marketing of the formula.
        Proposed Sec. 106.120(f) makes clear that if the manufacturer 
    provides additional information in support of a new infant formula 
    submission, FDA will determine whether it represents a substantive 
    amendment to the submission, and that, if it does, FDA will assign the 
    new infant formula submission a new filing date. FDA is proposing to 
    adopt Sec. 106.120(f) to clarify how it will treat amendments to infant 
    formula notifications. In the 9 years since the passage of the 1986 
    amendments, the treatment of additional submissions has been the source 
    of some confusion. FDA has tentatively concluded that it is necessary 
    to give a new filing date to a new infant formula submission when a 
    substantive amendment is made to it so that the agency has time to 
    examine all of the material submitted and to determine whether there is 
    any basis for concern about the marketing of the formula.
    4. Quality Factor Submission
        Proposed Sec. 106.121 sets forth the requirements for specific 
    information that a manufacturer must submit to
    
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    FDA, in accordance with proposed Sec. 106.120(b)(5), to provide 
    assurance that the infant formula meets the quality factor requirements 
    set forth in subpart E of part 106. FDA has tentatively concluded that 
    agency access to study records and data are necessary so that it can 
    ensure that study results are meaningfully interpretable, and that the 
    manufacturer's conclusion that the infant formula meets the quality 
    factor requirements withstands scientific scrutiny and evaluation. 
    Failure to adequately document study results and interpretation raises 
    questions as to the validity of conclusions and could mean that infants 
    have been unnecessarily subjected to testing procedures.
        Proposed Sec. 106.121(a) requires that the manufacturer submit an 
    explanation, in narrative form, setting forth its conclusions on how 
    all quality factor requirements of subpart E of part 106 have been met. 
    This narrative will facilitate the agency's review by summarizing the 
    results, and their interpretation, that provide the basis on which the 
    manufacturer has concluded that the quality factor requirements have 
    been met, or that the subject infant formula is eligible for the 
    exemptions described in proposed Sec. 106.97(a)(2) and (b)(2).
        Proposed Sec. 106.121(b) requires that the manufacturer submit 
    records that contain the information collected during the study for 
    each infant enrolled in the study. The measurements and information 
    collected for each infant enrolled in the study are necessary to an 
    evaluation of whether the infant formula supported healthy growth. 
    Proper identification of the records is necessary for proper use and 
    analysis of the records.
        Proposed Sec. 106.121(c)(1) requires that the manufacturer submit a 
    statistical evaluation of the data from the clinical study, including 
    group means, group standard deviations, and measures of statistical 
    significance for all measurements for each feeding group at the 
    beginning of the study and at every point where measurements were made 
    throughout the study. This evaluation forms the basis for the 
    manufacturer's conclusion as to whether the formula meets the quality 
    factor requirements. Without knowledge of the statistical basis upon 
    which the manufacturer drew its conclusions, FDA would not have 
    sufficient information to evaluate the conclusions reported by the 
    manufacturer.
        Proposed Sec. 106.121(c)(2) requires that the manufacturer submit a 
    calculation of the statistical power of the study at its completion. 
    Proposed Sec. 106.97(a)(1)(ii)(E) recommends that the power calculation 
    used to design the study be included in the study protocol. FDA is 
    aware that circumstances (e.g., attrition, difficulty in recruiting 
    sufficient numbers of infants, unexpectedly high measurement error in a 
    particular variable) may unintentionally result in sample sizes and 
    feeding group assignments that lack adequate statistical power for 
    detecting differences between treatment and control groups, regardless 
    of the apparent adequacy in planning for the study protocol. Reviewers 
    must be aware of changes in the statistical power of a study so that 
    they do not inadvertently misinterpret the absence of differences that 
    occur between different formulas as meaning there are no differences. 
    Failure to detect differences, if they are real, could result in 
    erroneously concluding that a formula is safe and suitable for its 
    intended use when, in fact, it is not. The agency is proposing to 
    require that the manufacturer submit this calculation to FDA so that 
    the agency can meaningfully review and interpret the data and study 
    results contained in the submission.
        Proposed Sec. 106.121(d) requires that the manufacturer submit 
    reports on attrition and on all occurrences of adverse events during 
    the study.
        FDA has tentatively found that information on the occurrence of 
    adverse events is a critical element of the data that must be evaluated 
    to determine whether a formula meets quality factor requirements and is 
    safe and suitable for infants. Adverse events associated with the use 
    of an infant formula, although unexpected, can be a sign or symptom of 
    a nutritional inadequacy or of a safety problem with the infant 
    formula, and failure to use these results could result in inadvertent 
    release of an unsafe product. Conversely, adverse events can be 
    unrelated to a formula product (e.g., flu), but their occurrence can 
    affect the way in which results are interpreted and used. For example, 
    illnesses can influence the interpretation of growth data and of the 
    laboratory measurements collected to evaluate the infant formula.
        For these reasons, FDA has tentatively concluded that complete 
    reports, including the results of followup investigations, on the 
    occurrence of all adverse events during the study, regardless of 
    whether the adverse events are attributable to the use of the new 
    infant formula or to some other illnesses, are necessary to properly 
    evaluate the conclusions drawn from a clinical study (proposed 
    Sec. 106.121(d)(1)). FDA has tentatively concluded that a complete 
    report on the occurrence of an adverse event must include 
    identification of the infant by subject number to permit evaluation of 
    infant growth measurements; identification of the feeding group to show 
    whether there is a pattern of adverse events in one feeding group 
    versus another; and a complete description of the adverse event, 
    including comparisons of the frequency of occurrence in each feeding 
    group and information on the health of the infants during the course of 
    the study, including the occurrence and duration of any illness, that 
    occurred during the trial, so that it is possible to evaluate the 
    significance of the illness.
        As discussed above, it is very important to be able to evaluate 
    whether the adverse event is a result of a nutritional quality factor 
    problem with the formula product. The results and evaluation of the 
    infant's clinical status are essential to make this evaluation, and the 
    health of the infant is also relevant to interpreting study endpoints, 
    for example, growth data. Therefore, knowledge of the infant's health 
    status is an essential piece of information in evaluating the 
    circumstances surrounding an observed adverse event associated with use 
    of a formula product. Thus, FDA has tentatively concluded that 
    evaluations by a health care professional are necessary to provide the 
    agency with relevant information on the circumstances surrounding the 
    adverse event (see Sec. 106.121(d)(2)) to assist the agency in 
    evaluating the nutritional adequacy and safety of the formula product 
    for supporting healthy growth in infants. In some cases, this clinical 
    assessment may be carried out by the infant's health care provider, 
    rather than the investigators conducting this clinical study, because 
    some parents will contact the infant's health care provider if the 
    infant experiences any adverse event during the course of the study. 
    The agency expects that the study investigators will take sufficient 
    measures to obtain all available information to enhance the likelihood 
    of being able to meaningfully interpret the likely relationship of the 
    adverse event to the formula product and its impact on study 
    conclusions.
        Attrition of infants from a study can result not only from adverse 
    events and illnesses but also from a variety of reasons having no 
    bearing on whether the new infant formula meets the quality factor 
    requirements. For example, an infant enrolled in the study may be 
    withdrawn from the study because the parents moved from the area. The 
    effect of attrition on study results, however, must be evaluated in 
    order to be able to meaningfully
    
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    interpret those results. To properly evaluate the impact of attrition 
    on study results, FDA must have information that permits it to evaluate 
    the likely cause of the attrition and its relationship to product use 
    and study measurements. Therefore, the agency is proposing to require 
    the submission of this information on attrition under 
    Sec. 106.121(d)(3).
        Proposed Sec. 106.121(e) requires that the manufacturer submit the 
    results of the Protein Efficiency Ratio. This proposed submission 
    requirement is necessary to provide assurance that the manufacturer has 
    complied with proposed Sec. 106.97(b) and to provide assurance that the 
    infant formula meets the specific quality factor for protein quality.
        Under proposed Sec. 106.121(f), the manufacturer is required to 
    submit a statement certifying that it has collected and considered all 
    information and data on the ability of the infant formula to meet the 
    quality factor requirements, and that it is not aware of anything that 
    would show that the formula does not meet the quality factors. This 
    proposed requirement is necessary to provide assurance that the 
    manufacturer has complied with the regulations and considered all 
    information and data of which it is aware, and that it has not made a 
    selective submission of information that gives a false impression of 
    the degree or extent to which a formula meets the quality factor 
    requirements.
    5. Verification Submissions
        Proposed Sec. 106.130(a) requires that manufacturers, after the 
    first production, but before the introduction into interstate commerce, 
    of a new infant formula, verify in a written submission that the infant 
    formula complies with the requirements of the act and is not 
    adulterated. This proposed requirement implements section 412(d)(2) of 
    the act, which requires the submission of a written verification that 
    summarizes test results and records demonstrating that a formula meets 
    the requirements of section 412(b)(1), (b)(2)(A), (b)(2)(B)(i), 
    (b)(2)(B)(iii), (b)(3)(A), (b)(3)(C), and (i) of the act. The failure 
    to provide the notice required by section 412(d) of the act is a 
    prohibited act under section 301(s) of the act.
        Proposed Sec. 106.130(b)(1) requires that the verification 
    submission include the name of the new infant formula, the filing date 
    for the new infant formula submission required under proposed 
    Sec. 106.120, and the identification number assigned by FDA to the new 
    infant formula submission, so that FDA is able to match the 
    verification submission with the appropriate new infant formula 
    submission.
        Proposed Sec. 106.130(b)(2) requires that the verification 
    submission include a statement that the infant formula to be introduced 
    into interstate commerce is the same as that which was the subject of 
    the new infant formula submission and for which the manufacturer 
    provided assurances in accordance with the requirements of proposed 
    Sec. 106.120. FDA has tentatively concluded that if this statement can 
    be made by the manufacturer, it means that the assurances that the 
    manufacturer provided in the new infant formula submission with respect 
    to the quality factor requirements and the safety of the ingredients 
    remain relevant and applicable to the product. Thus, no additional 
    information need be included in the verification to demonstrate 
    compliance, in accordance with section 412(d)(2) of the act, with 
    section 412(b)(1) or with this aspect of section 412(b)(2)(A).
        Proposed Sec. 106.130(b)(3) requires a summary of test results that 
    show the levels of each nutrient required by Sec. 107.100 in the 
    formula and of any nutrient added by the manufacturer. This proposed 
    requirement is necessary to demonstrate compliance with section 412(i) 
    of the act. Section 412(i) of the act sets forth those nutrients that 
    an infant formula must contain in order not to be adulterated, and the 
    submission of a summary of test results as required by section 
    412(d)(2), and implemented by Sec. 106.130(b)(3), is necessary to show 
    that an infant formula, after the first production, contains all of the 
    required nutrients at the required levels.
        FDA has tentatively concluded that it is not necessary to require 
    that the verification submission summarize test results or records 
    demonstrating compliance with sections 412(b)(2)(A) and (b)(2)(B)(iii) 
    of the act because the underlying records will be available for 
    inspection by FDA. FDA has tentatively concluded that to require the 
    manufacturer to create a report based on these records would be to 
    require an unnecessary expenditure of effort. However, the agency is 
    proposing to require (under Sec. 106.130(b)(4)) that the manufacturer 
    certify as a part of its verification submission that it has 
    established procedures that comply with sections 412(b)(2)(A) and 
    (b)(2)(B)(iii) of the act.
        FDA has tentatively concluded that requiring additional test 
    results or records demonstrating compliance with section 
    412(b)(2)(B)(i), (b)(3)(A), and (b)(3)(C) of the act would be 
    unnecessary because such showings would be subsumed in the testing to 
    show whether the formula meets the requirements of Sec. 107.100 (under 
    Sec. 106.130(b)(3)).
        Proposed Sec. 106.130(c) makes clear the consequences of failing to 
    comply with Sec. 106.130 and that in such circumstances, the agency 
    will notify the submitter that the notice is not adequate, and that the 
    manufacturer has not met the requirements of section 412(d)(2) of the 
    act.
    6. Submissions Concerning a Change in Infant Formula That May 
    Adulterate the Product
        Proposed Sec. 106.140(a) provides that, when a manufacturer makes a 
    change in the formulation or processing of the formula that may affect 
    whether the formula is adulterated under section 412(a) of the act, it 
    shall make a submission to FDA before the first processing of such 
    formula. This proposed requirement implements section 412(d)(3) of the 
    act, which requires that manufacturers make the submission to FDA 
    required by section 412(d)(1) of the act before first processing when 
    they determine that a change in formulation or in the processing of an 
    infant formula may affect whether the formula is adulterated under 
    section 412(a) of the act. Examples of changes that may affect whether 
    a formula is adulterated under section 412(a) of the act include, but 
    are not limited to:
        (1) A change in the level of an ingredient that does not constitute 
    a major change but that may affect whether the formula meets the 
    requirements of section 412(i) of the act (for example, decreasing the 
    amount of an ingredient such as sodium chloride could affect whether 
    the formula provides two nutrients required by Sec. 107.100);
        (2) A change in an ingredient in an infant formula that does not 
    constitute a major change but that may affect whether the formula meets 
    the quality factor requirements of subpart E of part 106 (for example, 
    a change in the level of an emulsifier could result in a change in the 
    bioavailability of fat because the emulsifier may interfere with fat 
    digestion); or
        (3) A change in the processing of the infant formula that does not 
    constitute a major change but that may affect whether the CGMP 
    requirements or the quality control procedures of subparts B and C of 
    part 106 are met (for example, a change in the processing of the infant 
    formula may affect whether a specification or a standard for a 
    particular point in the manufacturing process where control is deemed
    
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    necessary to prevent adulteration is met; a change in a processing 
    temperature or holding time may allow microorganisms to develop in 
    violation of Sec. 106.55; or a change in a processing temperature may 
    affect the level of a labile (temperature sensitive) nutrient in the 
    formula).
        Proposed Sec. 106.140(b)(1) requires that the submission include 
    information on the name and physical form of the product, so that the 
    change in the formula can be evaluated with other information that the 
    agency has received on the formula, and so that an accurate evaluation 
    of the product can be made because different requirements may apply to 
    different forms of a formula.
        Proposed Sec. 106.140(b)(2) requires an explanation of why the 
    change in formulation or processing may affect whether the formula is 
    adulterated, so that the agency can determine what type of evaluation 
    the submission requires. For example, if a change in formulation may 
    affect nutrient levels, the agency needs to evaluate the nutrient 
    content of the formula to be assured that this formulation change will 
    not lead to production of a formula that will not provide a required 
    nutrient at the required amount. Likewise, if a change in processing 
    may affect whether the formula is adulterated, the agency will need to 
    evaluate the formula's processing to be assured that the processing of 
    the formula will still comply with the CGMP regulations in subpart B of 
    part 106.
        Proposed Sec. 106.140(b)(3) requires that the submission comply 
    with Sec. 106.120(b)(3), (b)(4), (b)(5), and (b)(6). This proposed 
    requirement implements section 412(d)(3) of the act, which provides 
    that manufacturers make the submission required by section 412(d)(1). 
    FDA has tentatively concluded that requiring that the submission comply 
    with these aspects of Sec. 106.120(b) will promote consistency in the 
    form and substance of the information that industry must submit, and 
    FDA must review. If the information required on processing by 
    Sec. 106.120(b)(4) has already been provided in compliance with 
    Sec. 106.140(b)(2) as a part of the explanation of why the change in 
    processing may affect whether the formula is adulterated, the same 
    information does not need to be repeated in the submission. To avoid 
    redundant submissions, proposed Sec. 106.140(b)(3) further provides 
    that if the information required by Sec. 106.120(b)(3), (b)(4), (b)(5), 
    or (b)(6) has been provided to the agency previously, and that 
    information is not affected by the change that is the subject of the 
    submission, a statement to that effect, together with the 
    identification number assigned by the agency to the relevant infant 
    formula submission, can be provided in lieu of a new submission.
        Proposed Sec. 106.140(b)(3) requires inclusion of the 
    identification number assigned by the agency to the infant formula 
    submission so that the agency can have ready access to the relevant 
    information that was previously submitted. For example, if the 
    manufacturer makes a submission as a result of a change in processing, 
    but the formulation will remain the same, the manufacturer need not 
    provide the information required by Sec. 106.120(b)(3). Likewise, if 
    the manufacturer makes a submission as a result of a change in 
    formulation, but the processing of the formula remains the same, the 
    manufacturer need not submit the information required by 
    Sec. 106.120(b)(4).
        A determination of whether the assurances required by 
    Sec. 106.120(b)(5) and (b)(6) need to be given is based on the 
    manufacturer's reason for providing the submission. For example, if the 
    submission is provided because a change in formulation or processing 
    may affect whether the formula is adulterated because it does not meet 
    the quality factors set forth in subpart E of part 106, the assurance 
    required by Sec. 106.120(b)(5)(i) would have to be provided. Likewise, 
    if the submission is provided because a change in formulation or 
    processing may affect whether the formula is adulterated because it 
    does not meet the nutrient requirements of Sec. 107.100, the assurance 
    required by Sec. 106.120(b)(5)(ii) would have to be provided. Further, 
    if the submission is provided because a change in processing may affect 
    whether the formula is adulterated because the processing of such 
    formula may no longer be in compliance with CGMP or with appropriate 
    quality control, as set forth in subparts B and C of part 106, or 
    whether the formula is manufactured in a manner designed to prevent 
    adulteration, the assurance required by Sec. 106.120(b)(6) would have 
    to be provided.
        In proposed Sec. 106.140(c), the agency sets forth requirements 
    necessary to ensure that the data and other information provided in the 
    submission are in a form that will allow FDA to complete its review in 
    a timely manner and to advise the manufacturer if the agency has any 
    concerns about the marketing of the formula. Proposed Sec. 106.140(c) 
    also makes clear that the agency will notify the submitter if the 
    notice is not adequate because it does not meet the requirements of 
    section 412(d)(3) of the act.
    7. Notification of an Adulterated or Misbranded Infant Formula
        If FDA adopts the other regulations that it has proposed, it will 
    redesignate current Secs. 107.240(a) and (b) as Sec. 106.150 so that 
    all notification requirements on infant formulas can be found in one 
    place in the agency's regulations. In Sec. 106.150(b), FDA has revised 
    the address to reflect the reorganization of CFSAN.
    
    H. Conforming and Editorial Changes to Part 107--Infant Formula
    
        The agency is making conforming and editorial changes to part 107 
    to reflect the changes made by the 1986 amendments and the regulations 
    that FDA is proposing to adopt in part 106. The references in part 107 
    to the Division of Regulatory Guidance are being changed to the 
    Division of Enforcement to reflect the reorganization of CFSAN in 
    November 1992.
    1. Changes in Subpart A
        The agency is proposing to add a new Sec. 107.1 which will parallel 
    proposed Sec. 106.1. Proposed Sec. 107.1 describes the authority for 
    each of the proposed subparts and the consequences under the act of 
    failure to comply with any of the regulations in the proposed subparts.
    2. Changes in Subpart B of Part 107--Labeling
        The agency is proposing to amend Sec. 107.10 to require a statement 
    of the amount, supplied by 100 kcal, of each of any nutrient added by 
    the manufacturer as well as of the listed nutrients. As discussed 
    previously in the quality control section of this document, infant 
    formula manufacturers are adding ingredients to infant formula to 
    provide nutrients, such as selenium, that are not required by 
    Sec. 107.100 to be in infant formulas. The proposed change to 
    Sec. 107.10 requires that the amount of the added nutrients supplied by 
    100 kcal of the formula be declared on the label of the infant formula. 
    This proposed requirement is necessary to inform the consumer on a 
    consistent basis of the level of all nutrients included in an infant 
    formula.
    3. Subpart C of Part 107--Exempt Infant Formulas
        At this time the agency is not proposing to revise the regulations 
    in Sec. 107.50 pertaining to infant formulas that are subject to 
    section 412(h) of the act. These regulations were finalized in 1985 (50 
    FR 48183), before passage of the 1986 amendments. In the near future, 
    the agency intends to reevaluate
    
    [[Page 36202]]
    
    the exempt infant formula regulations and the effect of the 1986 
    amendments on exempt infant formulas and to issue a proposed rule to 
    reflect the results of this reevaluation. The agency also plans to 
    evaluate the effect of the Nutrition Labeling and Education Act of 1990 
    (Pub. L. 101-535) (the 1990 amendments) on the regulations for exempt 
    infant formulas. Exempt infant formulas are specifically exempted from 
    requirements for health claims and nutrient content claims by section 
    403(r)(5)(A) of the act. The basis for being an exempt infant formula, 
    according to section 412(h)(1) of the act, is how the product is 
    represented and labeled for use. This category of infant formula 
    recognizes that infants who suffer from special medical disorders, such 
    as maldigestion and malabsorption, inborn errors of metabolism such as 
    phenylketonuria or maple syrup urine disease, or severe kidney disease, 
    require formulas tailored specifically to their medical needs. 
    Therefore, it is important that any claims made for these products be 
    truthful, not misleading, and adequately substantiated because these 
    infants make up a vulnerable population and must receive the 
    appropriate nutrients for their medical condition. Because these 
    formulas are exempt from the regulations governing claims that were 
    developed under the 1990 amendments, the agency plans to evaluate how 
    claims for these products need to be substantiated to ensure that 
    infants with special nutritional needs are receiving appropriate infant 
    formulas.
    4. Subpart E--Infant Formula Recalls
        Current Sec. 107.240(a) sets out the requirements for notification 
    of a violative infant formula, and current Sec. 107.240(b) sets out the 
    method of notification. As stated above, the agency is moving the 
    provisions of current Sec. 107.240(a) and (b) to Sec. 106.150, so that 
    all of the agency's notification requirements are in one place. The 
    agency is renumbering current Sec. 107.240(c)(1), (c)(2), and (c)(3) as 
    Sec. 107.240(a), (b), and (c).
        Section 107.250 gives directions on the termination of an infant 
    formula recall. The agency is changing the reference to the Division of 
    Regulatory Guidance to the Division of Enforcement in Sec. 107.250 to 
    reflect the 1992 reorganization of CFSAN.
    
    V. Environmental Impact
    
        The agency has carefully considered the potential environmental 
    effects of this action. FDA has concluded that the action will not have 
    a significant impact on the human environment, and that an 
    environmental impact statement is not required. The agency's finding of 
    no significant impact and the evidence supporting that finding, 
    contained in an environmental assessment, may be seen in the Dockets 
    Management Branch (address above) between 9 a.m. and 4 p.m., Monday 
    through Friday.
    
    VI. Analysis of Impacts
    
        FDA has examined the impacts of the proposed rule under Executive 
    Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354). 
    Executive Order 12866 directs agencies to assess all costs and benefits 
    of available regulatory alternatives and, when regulation is necessary, 
    to select regulatory approaches that maximize net benefits (including 
    potential economic, environmental, public health and safety, and other 
    advantages; distributive impacts; and equity). According to Executive 
    Order 12866, a regulatory action is ``economically significant'' if it 
    meets any one of a number of specified conditions, including having an 
    annual effect on the economy of $100 million or adversely affecting in 
    a material way a sector of the economy, competition, or jobs. A 
    regulation is considered ``significant'' under Executive Order 12866 if 
    it raises novel legal or policy issues.
        The Regulatory Flexibility Act requires Federal agencies to 
    minimize the economic impact of their regulations on small businesses. 
    FDA finds that this proposed rule is neither an economically 
    significant nor a significant regulatory action as defined by Executive 
    Order 12866. In compliance with the Regulatory Flexibility Act, the 
    agency certifies that this proposed rule, if issued, will not have a 
    significant impact on a substantial number of small businesses. 
    Therefore, under the Regulatory Flexibility Act, no further analysis is 
    required. The agency examined three options in determining the economic 
    impact of this proposed regulations. A summary of the options follow:
    
    A. Options
    
        FDA has three primary options: (1) Adopt regulations with more 
    stringent requirements than the proposed regulations; (2) adopt the 
    proposed regulations; or (3) adopt regulations with less stringent 
    requirements than the proposed regulations.
    1. Option 1--Adopt Regulations More Stringent Than the Proposed 
    Regulations
        FDA believes infant formula manufacturers already comply with most 
    of the requirements of this proposed rule. One option would be to add 
    provisions to this proposed rule that would require activity beyond 
    that which is currently engaged in by infant formula manufacturers or 
    that is likely to be engaged in by manufacturers entering the infant 
    formula industry. Potential requirements of this type include specific 
    production and in- process control systems, specific equipment or types 
    of personnel, and additional testing and recordkeeping.
        Under this option, incumbent manufacturers would face higher 
    production costs and would pass most of the costs on to consumers of 
    infant formula. In addition, the startup and operating costs would 
    increase, and thus discourage entry into the infant formula industry. 
    The ability of new firms to enter an industry is an important element 
    in promoting price competition and innovation. These additional 
    requirements would reduce price competition in the infant formula 
    industry.
        The price of infant formula is probably linked to certain risky 
    infant feeding practices. With very high infant formula prices, some 
    consumers may increase risks to infants by improperly diluting formula 
    with water or other substances; using inappropriate substitutes for 
    formula or breast milk; or prematurely switching from formula to cow's 
    milk. For example, preliminary results of an FDA study on infant 
    formula feeding practices showed that approximately 20 percent of 
    infants (younger than 2 months) had their formula diluted by cereal, 
    which is cheaper than infant formula.
    2. Option 2--Adopt the Proposed Regulations
        There are two types of costs associated with this option: precluded 
    future cost cutting behavior and direct compliance costs.
        a. Future cost cutting behavior. This type of cost may arise 
    because the proposed rule precludes cost cutting behavior by either 
    incumbent firms or firms entering the infant formula industry. Infant 
    formula manufacturers currently undertake a considerable amount of 
    activity, such as infant growth studies, that is designed to ensure the 
    safety of infant formula but is not explicitly required by either 
    current law or regulation. In the absence of this regulation, which 
    mandates this activity, either incumbent or future manufacturers may 
    choose not to undertake this activity in the future. However, because 
    of reputation effects and liability laws, these costs are likely to be 
    low.
    
    [[Page 36203]]
    
        b. Direct compliance costs. (i). CGMP. FDA believes that infant 
    formula manufacturers already comply with most of the proposed CGMP's. 
    These CGMP's include those dealing with: (1) Production and in-process 
    control systems, including the evaluation of any deviation from these 
    procedures or from established standards or specifications; (2) 
    controls designed to prevent adulteration of infant formula by workers, 
    by facilities, and during packaging and labeling; (3) controls to 
    prevent adulteration during manufacturing, including recording and 
    justifying deviations from the master manufacturing order and 
    evaluating deviations from processing times; (4) controls on the 
    release and storage of finished infant formula; (5) all requirements 
    relating to batch production and control records, and to coding; and 
    (6) all requirements dealing with general quality control procedures, 
    including the testing of one batch of each physical form of infant 
    formula at least once every 3 months.
        If all manufacturers already comply with these proposed CGMP's, 
    then no compliance costs will result from them. FDA requests comments 
    on whether all infant formula manufacturers are already in compliance 
    with the proposed CGMP's listed above.
        FDA believes that all infant formula manufacturers already comply 
    with the proposed CGMP's dealing with controls to prevent adulteration 
    caused by ingredients, containers, and closures. The provision that FDA 
    may object to the use of a particular substance in an infant formula 
    during its prenotification review of ingredients used in a formula 
    because it believes that the substance is not safe and suitable for 
    that use does not represent a change in the way FDA reviews infant 
    formula ingredients. This provision recognizes the fact that 
    manufacturers may make independent GRAS determinations about 
    ingredients. When a manufacturer makes such a determination, that 
    manufacturer is not necessarily required to have the relevant 
    ingredient affirmed as GRAS by FDA. However, FDA is reserving the right 
    to review infant formula ingredient lists and documentation concerning 
    whether particular ingredients are safe and suitable for use in infant 
    formula. Theoretically, this provision could lead to a reduction in the 
    number of ingredients that are independently determined to be GRAS and 
    a corresponding increase in the number of ingredients for which food 
    additive petitions are required. Petitions for direct food additives 
    can take between 1 to 6 years to complete and cost approximately $1 
    million per year. However, because manufacturers of infant formula 
    generally obtain FDA concurrence on the safety and suitability of 
    ingredients used in infant formula before making these determinations, 
    FDA believes no additional compliance costs will be generated by this 
    provision.
        FDA also believes that infant formula manufacturers already comply 
    with many of the other proposed CGMP's. Provisions of CGMP's that some 
    infant formula manufacturers may not currently be in compliance include 
    the following:
        (1) Controls to prevent adulteration caused by equipment or 
    utensils. Some manufacturers may not repair or replace instruments and 
    controls when those instruments and controls cannot be adjusted to 
    within essential agreement with the reference standard. In addition, 
    most manufacturers probably do not perform a written evaluation of all 
    affected product, or of actions taken when calibration results indicate 
    that a specification or standard for a point where control is deemed 
    necessary to prevent adulteration has not been met. FDA cannot estimate 
    the repair or replacement costs of instruments and controls at this 
    time. Written evaluations will take a supervising technician an 
    estimated 2 hours to complete, which will generate some small 
    compliance costs.
        (2) Controls to prevent adulteration because of automatic, 
    mechanical, and electronic equipment. Most manufacturers will probably 
    have to perform additional analysis of software modifications. FDA 
    preliminarily estimates this analysis will add approximately 1 month to 
    the time required to analyze programming and software modifications. 
    One or two software modifications are probably made each year at each 
    of the fifteen plants that produce infant formula. Assuming that a 
    single computer scientist works on the additional activity required, 
    compliance costs are estimated to be about $100,000 per year.
        ii. Audits, Quality factors, registration and notification 
    requirements, and infant formula recalls. FDA believes that infant 
    formula manufacturers already comply with the following provisions: (1) 
    Regularly scheduled audits to determine compliance with CGMP's and 
    Quality Control Procedures (QCP's), (2) growth and development studies 
    to be submitted under certain conditions and new notification 
    requirements (FDA already requests and receives these quality factor 
    growth and development studies and notification material based on FDA's 
    interpretation of the language of the 1986 amendments), and (3) all 
    provisions involving registration and notification requirements.
        If infant formula manufacturers are already complying with these 
    provisions, then no compliance costs will be generated by these 
    provisions.
        FDA requests information on whether all infant formula 
    manufacturers already comply with all provisions listed above, 
    particularly those provisions dealing with quality factors.
        iii. Records. Under the current proposal, the records produced and 
    maintained by infant formula manufacturers to establish compliance with 
    FDA regulations will have to be expanded to include all new CGMP's and 
    QCP's. FDA believes most of the specified records are already being 
    kept by all firms; however, some records may not be. A plausible 
    assumption is that current annual industry expenditures on 
    recordkeeping may increase by about 10 percent, or $450,000 per year 
    based on information received from industry on current recordkeeping 
    costs. FDA requests information on the cost of increased recordkeeping.
        iv. Administrative costs. Interpreting and implementing changes in 
    CGMP and QCP regulations generate administrative costs even when all 
    activity required in those CGMP's and QCP's is already being done. FDA 
    does not have information on the administrative costs involved in 
    interpreting and implementing changes in CGMP and QCP regulations; 
    however, it is plausible to suppose that 20 percent of the total 
    compliance costs other than administrative costs may be used to reflect 
    administrative costs.
        Administrative costs under this assumption would be approximately 
    $100,000 and would accrue in the first year only. FDA requests 
    information on administrative costs.
    3. Option 3--Adopt Regulations Less Stringent Than the Proposed 
    Regulations
        Another option is to limit the activity required by this proposed 
    rule to activity already engaged in by all incumbent infant formula 
    manufacturers. In this case, there would be no compliance costs based 
    on current behavior. However, in the absence of this proposed rule, 
    incumbent or new manufacturers might choose not to undertake all 
    activity specified in this proposed rule. Therefore, the only costs 
    associated with this option are the costs associated with precluded 
    potential future behavior on the part of incumbent or new 
    manufacturers.
    
    [[Page 36204]]
    
    B. Benefits
    
    1. Option 1--Adopt Regulations More Stringent Than the Proposed 
    Regulations
        More stringent regulations for infant formula would cause infant 
    formula manufacturers to undertake further activity to ensure the 
    safety of infant formula. If there were identifiable risks from infant 
    formula that were not addressed by this proposal, then this additional 
    activity might decrease those health risks. However, FDA is not aware 
    of identifiable health risks from infant formula that are not addressed 
    by this proposal.
    2. Option 2--Adopt the Proposed Regulations
        The proposed regulation has two primary benefits: A potential 
    direct reduction in the health risks posed by infant formula, and a 
    potential reduction in the cost of entering the infant formula 
    industry. The latter effect could lead to an increase in the 
    competitiveness of the infant formula industry, resulting in lower 
    infant formula prices and a reduction in the incidence of risky infant 
    feeding practices linked to high infant formula prices.
        One example of a current activity that can be linked to a direct 
    reduction in health risks but that is not explicitly required by 
    current law or regulation is the performance of growth studies for new 
    infant formulas. FDA currently requests and receives these studies to 
    demonstrate that the infant formula meets the quality factor 
    requirements of section 412(b)(1) of the act. However, because section 
    412(b)(1) of the act does not list specific quality factors that infant 
    formulas must meet, a quality factor for healthy growth currently is 
    not expressly stipulated. In the absence of this proposed rule, 
    manufacturers could decline to perform these growth studies in the 
    future with a potential consequence that products that do not support 
    normal growth would be marketed. Low growth rates would not be detected 
    by existing regulatory and legal requirements that measure only the 
    levels of required nutrients because the required nutrients may be 
    present but not be bioavailable, and there is no mechanism for testing 
    bioavailability other than the proposed studies.
        An example of a formula associated with low growth rates that would 
    not have been detected in the absence of growth studies was an 
    experimental formula that contained a source of fatty acids not 
    previously used in infant formula. Because only a small amount of the 
    new fat source was added to a commercial formula, it is reasonable to 
    assume that all required nutrients were present within legal 
    specifications. Consequently, it would likely have met all current 
    regulations. Nonetheless, this formula was found to result in low 
    infant growth rates (Ref. 87). In this case, the manufacturer undertook 
    the necessary growth studies and detected the problem on its own. 
    However, manufacturers might not undertake these studies on their own 
    in the future. In addition, even if manufacturers continue to undertake 
    these studies in the absence of this regulation, they may not do these 
    studies correctly.
        In general, low rates of infant growth are associated with higher 
    than normal levels of infant morbidity. If a problem of this type were 
    to occur, a large number of infants could potentially be affected.
        Other types of current activity can also be linked to a direct 
    reduction in health risks and also are not explicitly required by 
    current law or regulation. In the absence of this regulation, incumbent 
    or new manufacturers may not undertake this activity in the future. 
    However, as explained earlier, because of reputation effects and legal 
    liability, such a refusal seems unlikely.
        An example of a health risk from infant formula is the 1978 
    incident, discussed elsewhere in this document, in which a required 
    nutrient was missing from an infant formula. Recurrence of this 
    particular problem is unlikely because section 412(d)(1)(A) of the act 
    already explicitly requires the submission of the quantitative 
    formulation of an infant formula as part of the mandatory FDA 
    notification of a new infant formula. Recurrence of this problem is 
    also made unlikely because section 412(b)(2) of the act already 
    explicitly requires the testing of infant formula for all required 
    nutrients. However, the risk of a formula being sold without a required 
    nutrient is minimized to the extent possible by specifically clarifying 
    this part of the infant formula law in the regulation.
        Another example of a health risk associated with infant formula is 
    an incident in which infant formula was found to contain Salmonella. It 
    appears that the manufacturer was testing for Salmonella in a manner 
    consistent with the testing requirements of this proposed rule, and 
    therefore it is not clear that this particular incident would have been 
    avoided if the proposed rule had been in effect. This proposed rule 
    will reduce the risk of microbiological contamination, however, because 
    it requires manufactures to institute a production and in-process 
    control system. The production and in-process control system 
    establishes standards or specifications to be met throughout the 
    production of their product. Other provisions of the proposed 
    regulation that will also help to prevent microbiological contamination 
    of infant formulas are controls to prevent adulteration by workers 
    (proposed Sec. 106.10), controls on the required temperature of cold 
    storage compartments used for storing ingredients and uncanned infant 
    formula (proposed Sec. 106.30(e)(2)), controls on the monitoring of the 
    temperature of both cold storage and thermal processing equipment 
    (proposed Sec. 106.30(e)), controls on the spray-drying process for 
    powdered infant formula including the filtering of the intake air 
    before heating to prevent microbial growth (proposed 
    Sec. 106.50(d)(2)), and controls to ensure that each container of 
    finished product is properly sealed (proposed Sec. 106.50(d)(4)).
        The incident in which infant formula was found to contain 
    Salmonella resulted in two reported cases of salmonellosis in infants. 
    The average value of preventing a single case of salmonellosis is 
    estimated to be about $2,000 (Ref. 88). If an incident like this is 
    avoided in the future because of this proposed rule, the value of the 
    adverse health effects avoided would be a benefit of this proposed 
    rule.
        This incident also resulted in two recalls. FDA estimates a 
    combined cost, including costs that accrued to both the manufacturer 
    and FDA of approximately $0.7 million per recall. If an incident like 
    this is avoided in the future because of this proposed rule, the recall 
    costs that would otherwise have been associated with this incident 
    would also be a benefit of this proposed rule.
        Another benefit of the proposed regulations is a potential 
    reduction in the administrative and time costs of entering the infant 
    formula industry. Currently, infant formula manufacturers must analyze 
    and interpret the relevant laws to determine the legal requirements 
    involved in the manufacture of infant formula. Incumbent firms have 
    tended to accept FDA's interpretations of these laws and have received 
    information on this interpretation incrementally over time, chiefly 
    through direct contact with FDA on various issues.
        It is reasonable to expect that potential entrants into the infant 
    formula industry would also prefer to rely on FDA's interpretations of 
    the relevant laws. However, considerable time and administrative costs 
    are involved in obtaining this information because there is no 
    established
    
    [[Page 36205]]
    
    mechanism by which manufacturers can obtain this information other than 
    direct communication with FDA on various particular issues. By 
    providing an explicit specification of the activities that are required 
    by the relevant laws, the proposed regulations, if adopted, will reduce 
    the time and administrative costs involved in entering this industry.
        In order to determine the net effect of the proposed rule on the 
    cost of entering the infant formula industry, the reduction in time and 
    administrative costs must be weighed against the additional compliance 
    costs imposed by this proposed rule on new firms. These countervailing 
    compliance costs are probably low because new firms will probably 
    undertake voluntarily the same activity that is currently undertaken 
    voluntarily by incumbent manufacturers. Therefore, the net effect of 
    this proposed rule is likely to be the reduction in the cost of 
    entering the infant formula industry. Publication of the proposed and 
    final regulations will provide a means of expedited entry for new firms 
    into the infant formula market.
        A reduction in the cost of entering the infant formula industry 
    will promote both price competition and innovation in this industry. 
    Increased price competition may lead to health benefits because, as 
    stated above, high infant formula prices may encourage some consumers 
    to: (1) Improperly dilute infant formula to reduce the cost per 
    serving; (2) prematurely switch from infant formula to cow's milk; or 
    (3) use inappropriate substitutes for breast milk and infant formula.
        A final benefit of this proposed rule is the cost savings generated 
    by the elimination of the current FDA requirement that a vitamin D rat 
    bioassay be performed for all major changes in infant formula. In 1992, 
    there were approximately 50 major changes. The cost of a rat bioassay 
    for vitamin D for infant formula at a private lab is about $1,070 (Ref. 
    89). Infant formula manufacturers should therefore save approximately 
    $54,000 in testing costs per year.
    3. Option 3--Adopt Regulations Less Stringent than the Proposed 
    Regulations
        Except for the value of the risk reductions resulting from 
    requirements that go beyond activity currently undertaken by infant 
    formula manufacturers the benefits of this option are identical to 
    those of Option 2.
    
    C. Conclusions
    
        In accordance with Executive Order 12286, FDA has analyzed the 
    economic effects of this proposed rule and has determined that this 
    rule, if issued, will not be a significant rule as defined by that 
    order. In accordance with the Regulatory Flexibility Act, FDA certifies 
    that the proposed rule will not have a significant impact on a 
    substantial number of small businesses.
        The primary compliance costs of Option 2 include both direct costs 
    of new requirements and precluded production cost reductions which may 
    occur without this regulation. FDA has estimated direct costs to 
    incumbent manufacturers to be approximately $0.7 million in the first 
    year and $0.6 million each additional year. An additional cost to 
    incumbent manufacturers is the cost of repairing or replacing 
    instruments and controls when those instruments and controls cannot be 
    adjusted to agreement with the reference standard. FDA has insufficient 
    information to estimate this cost. FDA does not expect compliance with 
    the proposed regulations to cause any significant increase in the price 
    of infant formula products. However, the agency requests comments about 
    any potential effects of the proposed regulations on the price of 
    infant formula products.
        The primary benefit of Option 2 is the reduction in the risk that 
    defective infant formula will be produced, go undetected, and reach the 
    market. FDA has insufficient information to estimate this potential 
    benefit. In addition, this proposed rule is also expected to reduce the 
    time and administrative costs of entering the infant formula industry. 
    This benefit may increase price competition in the infant formula 
    industry and reduce the health risks associated with high infant 
    formula prices. FDA also has insufficient information to estimate these 
    benefits.
        Except for the costs and benefits associated with activity required 
    by this proposed rule that some incumbent manufacturers do not 
    currently undertake, the costs and benefits of Option 3 are identical 
    to those of Option 2. FDA has insufficient information to estimate 
    either the costs or benefits of this option.
        Option 1 is expected to have higher costs and lower benefits than 
    either Option 2 or Option 3.
    
    VII. Paperwork Reduction Act of 1995
    
        This proposed rule contains information collection provisions that 
    are subject to review by the Office of Management and Budget (OMB) 
    under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The 
    title, description, and respondent description for the proposed 
    collection of information are shown below, along with an estimate of 
    the annual recordkeeping and periodic reporting burden. Included in the 
    estimate is the time for reviewing instructions, searching existing 
    data sources, gathering and maintaining the necessary information, and 
    completing and submitting the registrations, notifications, and other 
    submissions that would be required under the proposed regulations.
        FDA solicits public comment in order to: (1) Evaluate whether the 
    proposed collection of information is necessary for the proper 
    performance of the functions of the agency, including whether the 
    information will have practical utility; (2) evaluate the accuracy of 
    the agency's estimate of the burden of the proposed collection of 
    information, including the validity of the methodology and assumptions 
    used; (3) enhance the quality, utility, and clarity of the information 
    to be collected; and (4) minimize the burden of the collection of 
    information on those who are to respond, including through the use of 
    automated collection techniques, where appropriate or other forms of 
    information technology.
        Title: Current Good Manufacturing Practice, Quality Control 
    Procedures, Quality Factors, Notification Requirements, and Records and 
    Reports, for the Production of Infant Formula.
        Description: FDA is proposing regulations on recordkeeping 
    requirements that include: (1) Records pertaining to batch production 
    and control; (2) records pertaining to current good manufacturing 
    practice and quality control; (3) records pertaining to distribution of 
    the infant formula; and (4) records pertaining to regularly scheduled 
    audits. FDA is also proposing regulations on reporting requirements 
    pertaining to: (1) Registration of a new infant formula; (2) submission 
    requirements for a new infant formula; (3) submission requirements to 
    provide assurance that an infant formula meets the quality factor 
    requirements; (4) submission requirements when there is a change in the 
    formulation or processing of the formula that may affect whether the 
    formula is adulterated; and (5) submission requirements to provide 
    assurance that the infant formula complies with the requirements of the 
    Federal Food, Drug, and Cosmetic Act and is not adulterated.
        Description of Respondents: Infant Formula Manufacturers.
    
    [[Page 36206]]
    
    
    
                                          Estimated Annual Recordkeeping Burden                                     
    ----------------------------------------------------------------------------------------------------------------
                                                                  Annual        Total                               
                      21 CFR                       No. of      frequency of     annual      Hours per    Total hours
                                               recordkeepers  recordkeeping    records    recordkeeping             
    ----------------------------------------------------------------------------------------------------------------
    106.6....................................             5              1             5           200         1,000
    106.20(f)(4) and 106.100(f)(1)...........             5             52           260             3           780
    106.30(d) and 106.100(f)(2)..............             5             25           125             4           500
    106.30(e)(3)(ii) and 106.100(f)(3).......             5            365         1,825             2         3,650
    106.30(f) and 106.100(f)(4)..............             5            365         1,825             3         5,475
    106.35(c) and 106.100(f)(5)..............             5              2            10           500         5,000
    106.40(d)................................             5             20           100            30         3,000
    106.40(g) and 106.100(f)(6)..............             5            122           610             4         2,440
    106.50...................................             5              1             5           200         1,000
    106.55(d) 106.100(e)(5)(ii), and                                                                                
     106.100(f)(7)...........................             5            182           910             3         2,730
    106.60(c)................................             5              1             5            40           200
    106.91(c), 106.100(e)(5)(i), and                                                                                
     106.100(f)(7)...........................             5            365         1,825             4         7,300
    106.94...................................             5              1             5            88           440
    106.97...................................             5            0.6             3           225           675
    106.100(e)...............................             5            365         1,825             9        16,425
                                                                                                        ------------
        Total................................  .............  .............  ...........  .............       50,615
    ----------------------------------------------------------------------------------------------------------------
    
    
                                            Estimated Annual Reporting Burden                                       
    ----------------------------------------------------------------------------------------------------------------
                                                                     Annual                                         
                                                        No of      frequency      Total      Hours per              
                         21 CFR                      respondents      per         annual      response   Total hours
                                                                    response    responses                           
    ----------------------------------------------------------------------------------------------------------------
    106.110........................................            3           NA           20            1           20
    106.120........................................            3           NA           20           49          980
    106.121........................................            3           NA           10           50          500
    106.130........................................            3           NA           20            2           40
    106.140........................................            3           NA           25         5-10      125-250
                                                                                                        ------------
        Total......................................  ...........  ...........  ...........  ...........        1,790
                                                                                                        ============
        Total Recordkeeping and Reporting Burden...       52,405                                                    
    ----------------------------------------------------------------------------------------------------------------
    
        FDA tentatively concludes that there are no capital costs or 
    operating and maintenance costs associated with the reporting and 
    recordkeeping provisions of this proposed rule. However, the agency 
    welcomes comments on any such anticipated costs.
        As required by section 3507(d) of the Paperwork Reduction Act of 
    1995, FDA has submitted a copy of this proposed rule to OMB for its 
    review of the information collection requirements. Other organizations 
    and individuals interested in submitting comments regarding this burden 
    estimate or any aspect of these information collection requirements, 
    including suggestions for reducing the burden, should direct them to 
    the Office of Information and Regulatory Affairs, OMB, New Executive 
    Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, ATTN: 
    Desk Officer for FDA. Written comments on the information collection 
    should be submitted by August 8, 1996.
    VIII. Requests for Comments
        Interested persons may, on or before October 7, 1996, submit to the 
    Dockets Management Branch (address above) written comments regarding 
    this proposal. Two copies of any comments are to be submitted, except 
    that individuals may submit one copy. Comments are to be identified 
    with the docket number found in brackets in the heading of this 
    document. Received comments may be seen in the office above between 9 
    a.m. and 4 p.m., Monday through Friday.
    IX. References
        The following references have been placed on display in the Dockets 
    Management Branch (address above) and may be seen by interested persons 
    between 9 a.m. and 4 p.m., Monday through Friday.
    1. Congressional Record--Senate S 14042-14047, September 27, 1986.
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    [[Page 36207]]
    
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    Foods, ``Listeria monocytogenes,'' International Journal of Food 
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    39. Benenson, A. S., ed., ``Control of Communicable Diseases in 
    Man,'' 15th ed., American Public Health Association, pp. 170-177, 
    1991.
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    Poisoning'' in Laboratory Diagnosis of Infectious Diseases: 
    Principles and Practice; vol. 1, Bacterial, Mycotic, and Parasitic 
    Diseases; edited by Balows, A., W. J. Hausler, Jr., M. Ohashi, and 
    A. Turano, vol. 1, pp. 83-93, Springer-Verlag, New York, 1988.
    41. The International Commission on Microbiological Specifications 
    for Foods (ICMSF) of the International Association of 
    Microbiological Societies, Chapter 12: Sampling Plans for Milk and 
    Milk Products in Microorganisms in Foods 2. Sampling for 
    Microbiological Analysis: Principles and Specific Applications, 
    University of Toronto Press, Toronto, Canada; 1974.
    42. Schwab, A. H., A. Swartzentruber, B. A. Wentz, R. B. Read, Jr., 
    ``Microbiological Quality of Dry-milk Mixes and Milk Substitute 
    Infant Formulas,'' Applied and Environmental Microbiology, 43:389-
    391, 1982.
    43. Collins-Thompson, D. L., K. F. Weiss, G. W. Riedel, and S. 
    Charbonneau, ``Microbiological Guidelines and Sampling Plans for 
    Dried Infant Cereals and Powdered Infant Formula from a Canadian 
    National Microbiological Survey,'' Journal of Food Protection, 
    43(8):613-616, 1980.
    44. FDA Enforcement Report, July 14, 1993.
    45. Jackson, G. J., C. F. Langford, and D. L. Archer, ``Control of 
    Salmonellosis and Similar Foodborne Infections,'' Food Control, 
    2(1), pp. 26-34, 1991.
    46. Food and Drug Administration Bacteriological Analytical Manual, 
    7th ed., AOAC International, Gaithersburg, MD, 1992.
    47. Flowers, R. S., W. Andrews, C. W. Donnelly, and E. Koenig, 
    ``Pathogens in Milk and Milk Products'' in Standard Methods for the 
    Examination of Dairy Products, 16th ed., edited by Marshall, R. T., 
    American Public Health Association, Washington, DC 20005, 1992.
    48. Harmon, S. M., D. A. Kautter, ``Incidence and Growth Potential 
    of Bacillus cereus in Ready-to-Serve Foods,'' Journal of Food 
    Protection, 54(5):372-374, 1991.
    49. Golden, D. A., ``Microbiological Evaluation of Powdered Infant 
    Formula,'' Report submitted to the U.S. Food and Drug 
    Administration, Center for Food Safety and Applied Nutrition.
    50. FDA Consumer, Defendants: Watson Foods Co., Inc., Civil No. CV-
    85-4659, p. 40, October 1988.
    51. Memorandum of Records from Nicholas Dvy, FDA, dated June 25, 
    1996.
    52. Establishment Inspection Report, 1992.
    53. Memo from Alan J. Sheppard to Carolyn W. Miles, on Status of 
    Vitamin D Rat Bioassay, May 12, 1994.
    54. Tanner, J. T., S. A. Barnett, and M. K. Mountford, ``Analysis of 
    Milk-based Infant Formula,'' Phase IV. Iodine, Linoleic Acid, and 
    Vitamins D and K: U.S. Food and Drug Administration-Infant Formula 
    Council: Collaborative Study, Journal of the Association of Official 
    Analytical Chemists International, 76:1042-1056, 1993.
    55. Southgate, D. A. T., ``Conceptual Issues Concerning the 
    Assessment of Nutrient Bioavailability,'' in Nutrient Availability: 
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    56. Jensen, R. G., M. M. Hagerty, and K.E. McMahon, ``Lipids of 
    Human Milk and Infant Formulas: A Review,'' American Journal of 
    Clinical Nutrition, 31:990-1016, 1978.
    57. Jenson, R. G., and G. L. Jensen, ``Specialty Lipids for Infant 
    Nutrition, I. Milks and Formulas,'' Journal of Pediatric 
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    [[Page 36208]]
    
    58. Ziegler, E. E., S. J. Fomon, S. E. Nelson et al., ``Cow Milk 
    Feeding in Infancy: Further Observations on Blood Loss From the 
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    59. American Academy of Pediatrics, ``Commentary on Breast-Feeding 
    and Infant Formulas, with Proposed Standards for Formulas,'' 
    Pediatrics, 57:278-285, 1976.
    60. Committee on Labor and Human Resources Report (Senate) August 
    26, 1980.
    61. Saarinen, U. M., M. A. Siimes, P. R. Dallman, ``Iron Absorption 
    in Infants: High Bioavailability of Breast Milk Iron as Indicated by 
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    ``Bioavailability in Man of Iron in Human Milk and Cow's Milk in 
    Relation to Their Calcium Contents,'' Pediatric Research, 31:524-
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    63. Derman, D. P., D. Ballot, T. H. Bothwell, B. J. MacFarlane, R. 
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    Bezwoda, ``Factors Influencing the Absorption of Iron From Soya-Bean 
    Protein Products,'' British Journal of Nutrition, 57:345-353. 1987.
    64. Koo, W. W. K., and R. G. Tsang, ``Calcium, Magnesium, 
    Phosphorus, and Vitamin D,'' In Nutrition Needs of the Preterm 
    Infant, edited by Tsang, R. C., et al., Academic Press, 1993
    65. Steichen, J. J., T. L. Gratton, and R. C. Tsang, ``Osteopenia of 
    Prematurity: The Cause and Possible Treatment,'' Journal of 
    Pediatrics, 96:528-34, 1980.
    66. Koletzko, B., R. Tangerman, R. Von Kries, et al. ``Intestinal 
    Milk-Bolus Obstruction in Formula-Fed Premature Infants Given High 
    Doses of Calcium,'' Journal of Pediatric Gastroenterology and 
    Nutrition 7:548-553, 1988.
    67. Ziegler, E. E., and S. J. Fomon, ``Lactose Enhances Mineral 
    Absorption in Infancy,'' Journal of Pediatric Gastroenterology and 
    Nutrition, 2:288-294, 1983.
    68. Moya, M., E. Cortes, M. I. Ballester et al., ``Short-term 
    Polycose Substitution for Lactose Reduces Calcium Absorption in 
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    Nutrition, 14:57-61, 1992.
    69. Shenai, J. P., B. M. Jhaveri, J. W. Reynolds et al., 
    ``Nutritional Balance Studies in Very Low Birth Weight Infants: Role 
    of Soy Formula,'' Pediatrics, 67:631-637, 1981.
    70. Lindroth, M., U. Westgren, and S. Laurin, ``Rickets in Very Low 
    Birth Weight Infants; Influence of Supplementation with Vitamin D, 
    Phosphorus, and Calcium,'' Acta Pediatrica Scandinavica, 75:927-931, 
    1986.
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    Diseases in Childhood, 139:896-8, 1985.
    72. Food and Drug Administration, Public Health Service, U.S. 
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    and Content of the Clinical and Statistical Sections of New Drug 
    Applications July, 1988.
    73. American Academy of Pediatrics. Pediatric Nutrition Handbook, 3d 
    ed., 1993.
    74. Roche, A. F., S. Guo, and W. M. Moore, ``Weight and Recumbent 
    Length From 1 to 12 Mo of Age: Reference Data for 1-Mo Increments,'' 
    American Journal of Clinical Nutrition, 49:599-607, 1989.
    75. Moore, W. M., and A. F. Roche, ``Pediatric Anthropometry,'' Ross 
    Laboratories.
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    Saunders Co., Philadelphia, 1992.
    77. Sarwar, G., R. W. Peace, and H. G. Botting, ``Differences in 
    Protein Digestibility and Quality of Liquid Concentrate and Powder 
    Forms of Milk-Based Infant Formulas Fed to Rats,'' American Journal 
    of Clinical Nutrition, 49:806-13, 1989.
    78. Rudloff, S., and B. Lonnerdal, ``Solubility and Digestibility of 
    Milk Proteins in Infant Formulas Exposed to Different Heat 
    Treatments,'' Journal of Pediatric and Gastroenterology and 
    Nutrition, 15:25-32, 1992.
    79. Fomom, S. J., and S. E. Nelson, Chapter 11, Calcium, Phosphorus, 
    Magnesium, and Sulfur in Nutrition of Normal Infants, edited by 
    Fomon, S. J., Mosby-Year Book, Inc., St. Louis, MO, 1993.
    80. Ryan, S. A., J. Truscott, M. Simpson, and J. James, ``Phosphate, 
    Alkaline Phosphatase and Bone Mineralization in Preterm Neonates,'' 
    Acta Pediatrica, 82:518-521, 1993.
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    Content in Term and Preterm Appropriate-for-Gestational-Age 
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    82. Steichen, J. J., P. A. Steichen Asch, and R. C. Tsang, ``Bone 
    Mineral Content Measurement in Small Infants by Single-photon 
    Absorptiometry: Current Methodologic Issues,'' Journal of 
    Pediatrics, 113 (suppl): 181-187, 1988.
    83. Chan, G. M., ``Performance of Dual- Energy X-ray Absorptiometry 
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    Delmas, and P. J. Meunier, ``Dual Energy X-ray Absorptiometry 
    Measurement of Bone Mineral Content in Newborns: Validation of the 
    Technique,'' Pediatric Research, 32:77-80, 1992.
    85. Salle, B. L., and F. H. Glorieux, ``Assessment of Bone Mineral 
    Content in Infants: The New Age,'' Acta Pediatrica, 82:709-10, 1993.
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    Ed Puro, FDA, March 17, 1993.
    
    List of Subjects
    
    21 CFR Part 106
    
        Food grades and standards, Infants and children, Nutrition, 
    Reporting and recordkeeping requirements, Incorporation by reference.
    
    21 CFR Part 107
    
        Food labeling, Infants and children, Nutrition, Reporting and 
    recordkeeping requirements, Signs and symbols.
        Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
    authority delegated to Commissioner of Food and Drugs, it is proposed 
    that 21 CFR parts 106 and 107 be amended as follows:
    
    PART 106--INFANT FORMULA--REQUIREMENTS PERTAINING TO CURRENT GOOD 
    MANUFACTURING PRACTICE, QUALITY CONTROL PROCEDURES, QUALITY 
    FACTORS, RECORDS AND REPORTS, AND NOTIFICATIONS
    
        1. The authority citation for 21 CFR part 106 continues to read as 
    follows:
    
        Authority: Secs. 201, 412, 701 of the Federal Food, Drug, and 
    Cosmetic Act (21 U.S.C. 321, 350a, 371).
    
        2. The heading for part 106 is revised to read as set forth above.
        3. Section 106.1 is revised to read as follows:
    
    
    Sec. 106.1  Status and applicability of the regulations in part 106.
    
        (a) The criteria set forth in subparts B, C, and D of this part 
    prescribe the steps that manufacturers must take under section 
    412(b)(2) and (b)(3) of the Federal Food, Drug, and Cosmetic Act (the 
    act) in processing infant formula. If the processing of the formula 
    does not comply with any regulation in subparts B, C, or D of this 
    part, the formula will be deemed to be adulterated under section 
    412(a)(3) of the act.
        (b) The criteria set forth in subpart E of this part prescribe the 
    quality factor requirements that infant formula must
    
    [[Page 36209]]
    
    meet under section 412(b)(1) of the act. If the formula fails to comply 
    with any regulation in subpart E of this part, it will be deemed to be 
    adulterated under section 412(a)(2) of the act.
        (c) The criteria set forth in subpart F of this part implement the 
    record retention requirements established in section 412(b)(4) of the 
    act. Failure to comply with any regulation in subpart F of this part is 
    a violation of section 301(e) of the act.
        (d) The criteria set forth in subpart G of this part describe the 
    circumstances in which infant formula manufacturers are required to 
    register with, submit to, or notify the Food and Drug Administration, 
    and the content of those registrations, submissions, or notifications, 
    under section 412(c), (d), and (e) of the act. Failure to comply with 
    any regulation in subpart G of this part is a violation of section 
    301(s) of the act.
        4. Section 106.3 is revised to read as follows:
    
    
    Sec. 106.3  Definitions.
    
        The definitions in this section and the definitions contained in 
    section 201 of the Federal, Food, Drug, and Cosmetic Act (the act) 
    shall apply to infant formula requirements in 21 CFR part 106 and part 
    107 of this chapter.
        (a) Batch means a specific quantity of an infant formula or other 
    material that is intended to have uniform character and quality, within 
    specified limits, and is produced according to a single manufacturing 
    order during the same cycle of manufacture.
        (b) Final-product-stage means the point in the manufacturing 
    process, before distribution of an infant formula, at which the infant 
    formula is homogeneous and is not subject to further degradation due to 
    processing.
        (c) Indicator nutrient means a nutrient whose concentration is 
    measured during the manufacture of an infant formula to confirm 
    complete addition and uniform distribution of a premix or other 
    substance of which the indicator nutrient is a part.
        (d) Infant means a person not more than 12 months of age.
        (e) Infant formula means a food which purports to be or is 
    represented for special dietary use solely as a food for infants by 
    reason of its simulation of human milk or its suitability as a complete 
    or partial substitute for human milk.
        (f) In-process batch means a combination of ingredients at any 
    point in the manufacturing process before packaging.
        (g) Lot means a batch, or a specifically identified portion of a 
    batch, having uniform character and quality within specified limits; 
    or, in the case of an infant formula produced by continuous process, it 
    is a specific identified amount produced in a unit of time or quantity 
    in a manner that assures its having uniform character and quality 
    within specified limits.
        (h) Lot number, control number, or batch number means any 
    distinctive combination of letters, numbers, symbols, or any 
    combination of them, from which the complete history of the 
    manufacture, processing, packing, holding, and distribution of a batch 
    or lot of infant formula or other material can be determined.
        (i) Major change in an infant formula means any new formulation, or 
    any change of ingredients or processes where experience or theory would 
    predict a possible significant adverse impact on levels of nutrients or 
    bioavailability of nutrients, or any change that causes an infant 
    formula to differ fundamentally in processing or in composition from 
    any previous formulation produced by the manufacturer. Examples of 
    infant formulas deemed to differ fundamentally in processing or in 
    composition include:
        (1) Any infant formula produced by a manufacturer who is entering 
    the U.S. market;
        (2) Any infant formula powder processed and introduced for 
    commercial or charitable distribution by a manufacturer who previously 
    only produced liquids (or vice versa);
        (3) Any infant formula having a significant revision, addition, or 
    substitution of a macronutrient (i.e., protein, fat, or carbohydrate), 
    with which the manufacturer has not had previous experience;
        (4) Any infant formula manufactured on a new processing line or in 
    a new plant;
        (5) Any infant formula manufactured containing a new constituent 
    not listed in section 412(i) of the act, such as taurine or L-
    carnitine;
        (6) Any infant formula processed by a manufacturer on new equipment 
    that utilizes a new technology or principle (e.g., a change from 
    terminal sterilization to aseptic processing); and
        (7) An infant formula for which there has been a fundamental change 
    in the type of packaging used (e.g., changing from metal cans to 
    plastic pouches).
        (j) Manufacturer means a person who prepares, reconstitutes, or 
    otherwise changes the physical or chemical characteristics of an infant 
    formula or packages or labels the product in a container for 
    distribution.
        (k) Microorganisms means yeasts, molds, bacteria, and viruses and 
    includes, but is not limited to, species having public health 
    significance.
        (l) New infant formula means:
        (1) An infant formula manufactured by a person that has not 
    previously manufactured an infant formula for the U.S. market, and
        (2) An infant formula manufactured by a person that has previously 
    manufactured infant formula and in which there is a major change in 
    processing or formulation from a current or any previous formulation 
    produced by such manufacturer.
        (m) Nutrient means any vitamin, mineral, or other substance or 
    ingredient that is required in accordance with the table set out in 
    section 412(i)(1) of the act or by regulations issued under section 
    412(i)(2) or that is identified as essential for infants by the Food 
    and Nutrition Board of the National Research Council through its 
    development of a Recommended Dietary Allowance or an Estimated Safe and 
    Adequate Daily Dietary Intake range, or that has been identified as 
    essential for infants by the Food and Drug Administration through a 
    Federal Register publication.
        (n) Nutrient premix means a combination of ingredients containing 
    two or more nutrients received from a supplier or prepared by an infant 
    formula manufacturer.
        (o) Quality factors mean those factors necessary to demonstrate 
    that the infant formula, as prepared for market, provides nutrients in 
    a form that is bioavailable and safe as shown by evidence that 
    demonstrates that the formula supports healthy growth when fed as a 
    sole source of nutrition.
        (p) Representative sample means a sample that consists of a number 
    of units that are drawn based on rational criteria, such as random 
    sampling, and intended to ensure that the sample accurately portrays 
    the material being sampled.
        (q) Shall is used to state mandatory requirements.
        (r) Should is used to state recommended or advisory procedures or 
    to identify recommended equipment.
        5. Part 106 is amended by redesignating subparts B, C, and D as 
    subparts C, F, and G, respectively, and adding new subparts B, D, and 
    E; and by revising newly redesignated subparts C and G to read as 
    follows:
    * * * * *
    
    [[Page 36210]]
    
    Subpart B--Current Good Manufacturing Practice
    
    Sec.
    106.5  Current good manufacturing practice.
    106.6  Production and in-process control system.
    106.10  Controls to prevent adulteration by workers.
    106.20  Controls to prevent adulteration caused by facilities.
    106.30  Controls to prevent adulteration caused by equipment or 
    utensils.
    106.35  Controls to prevent adulteration due to automatic 
    (mechanical or electronic) equipment.
    106.40  Controls to prevent adulteration caused by ingredients 
    containers, and closures.
    106.50  Controls to prevent adulteration during manufacturing.
    106.55  Controls to prevent adulteration from microorganisms.
    106.60  Controls to prevent adulteration during packaging and 
    labeling of infant formula.
    106.70  Controls on the release of finished infant formula.
    106.80  Traceability.
    106.90  Audits of current good manufacturing practice.
    
    Subpart C--Quality Control Procedures
    
    106.91  General quality control.
    106.92  Audits of quality control procedures.
    
    Subpart D--Conduct of Audits
    
    106.94  Audit plans and procedures.
    
    Subpart E--Quality Factors for Infant Formulas
    
    106.96  Quality factors in infant formulas.
    106.97  Assurances for quality factors.
    * * * * *
    
    Subpart G--Registration, Submission, and Notification Requirements
    
    106.110  New infant formula registration.
    106.120  New infant formula submission.
    106.121  Quality factor submission.
    106.130  Verification submission.
    106.140  Submission concerning a change in infant formula that may 
    adulterated the product.
    106.150  Notification of an adulterated or misbranded infant 
    formula.
    * * * * *
    
    Subpart B--Current Good Manufacturing Practice
    
    
    Sec. 106.5  Current good manufacturing practice.
    
        (a) The regulations set forth in this subpart and, for liquid 
    infant formulas, in part 113 of this chapter define the minimum current 
    good manufacturing practices that are to be used in, and the facilities 
    or controls that are to be used for, the manufacture, processing, 
    packing, or holding of an infant formula. Compliance with these 
    provisions is necessary to ensure that such infant formula provides the 
    nutrients required under Sec. 107.100 of this chapter and is 
    manufactured in a manner designed to prevent its adulteration.
        (b) The failure to comply with any regulation set forth in this 
    subpart or, for liquid infant formulas, in part 113 of this chapter in 
    the manufacture, processing, packing, or holding of an infant formula 
    shall render such infant formula adulterated under section 412(a)(3) of 
    the Federal Food, Drug, and Cosmetic Act (the act).
    
    
    Sec. 106.6  Production and in-process control system.
    
        (a) Manufacturers shall conform to the requirements of this subpart 
    by implementing a system of production and in-process controls. This 
    production and in-process control system shall cover all stages of 
    processing, from the receipt and acceptance of the raw materials, 
    ingredients, and components through the storage and distribution of the 
    finished product and shall be designed to ensure that all the 
    requirements of this subpart are met.
        (b) The production and in-process control system shall be set out 
    in a written plan, or set of procedures, that is designed to ensure 
    that an infant formula is manufactured in a manner that will prevent 
    adulteration of the infant formula.
        (c) At any point, step, or stage in the production process where 
    control is necessary to prevent adulteration, the manufacturer shall:
        (1) Establish standards or specifications to be met;
        (2) Monitor the production and in-process control point, step, or 
    stage;
        (3) Establish corrective action plans for use when a standard or 
    specification established in accordance with paragraph (b)(1) of this 
    section is not met;
        (4) Review the results of the monitoring required by paragraph 
    (c)(2) of this section, and review and evaluate the public health 
    significance of any deviations from standards or specifications that 
    have been established in accordance with paragraph (c)(1) of this 
    section. This review shall be conducted by an individual qualified by 
    training and experience to conduct such reviews; and
        (5) Establish recordkeeping procedures, in accordance with 
    Sec. 106.100(e)(3), that ensure that compliance with the requirements 
    of this section is documented.
    
    
    Sec. 106.10  Controls to prevent adulteration by workers.
    
        (a) There shall be sufficient personnel, qualified by training and 
    experience, to perform all operations, including all required 
    recordkeeping, in the manufacture, processing, packing, and holding of 
    each infant formula and to supervise such operations to ensure that 
    they are correctly and fully performed.
        (b) Personnel working directly with infant formula, infant formula 
    raw materials, infant formula packaging, or infant formula equipment or 
    utensil contact surfaces shall practice good personal hygiene to 
    protect the infant formula against contamination. Good personal hygiene 
    includes, but is not limited to:
        (1) Wearing clean outer garments and, as necessary, protective 
    apparel such as head, face, hands, and arm coverings; and
        (2) Washing hands thoroughly in a hand washing facility with soap 
    and running water at a suitable temperature before starting work, after 
    each absence from the work station, and at any other time when the 
    hands may become soiled or contaminated.
        (c) Any person who reports that he or she has, or appears by 
    medical examination or supervisory observation to have, an illness, 
    open lesion, including boils, sores, or infected wounds, or any other 
    source of microbial contamination that creates a reasonable possibility 
    that the safety of an infant formula may be adversely affected, shall 
    be excluded from direct contact with ingredients, containers, closures, 
    in-process materials, equipment, utensils, and infant formula product 
    until the condition is corrected or determined by competent medical 
    personnel not to jeopardize the safety of the infant formula.
    
    
    Sec. 106.20  Controls to prevent adulteration caused by facilities.
    
        (a) Buildings used in the manufacture, processing, packing, or 
    holding of infant formula shall be maintained in a clean and sanitary 
    condition and shall have space for the separation of incompatible 
    operations, such as the handling of raw materials, the manufacture of 
    the product, and packaging and labeling operations.
        (b) Separate areas shall be designated for holding raw materials, 
    in-processing materials, and final product infant formula:
        (1) Pending release for use in infant formula production or pending 
    release of the final product,
        (2) After rejection for use in infant formula and before 
    disposition, and
        (3) After release for use in infant formula production or after 
    release of the final product.
        (c) Lighting shall allow easy identification of raw materials,
    
    [[Page 36211]]
    
    packaging, labeling, in-process materials, and finished products that 
    have been released for use in infant formula production and shall 
    permit the easy reading of instruments and controls necessary in 
    processing, packaging, and laboratory analysis. Any lighting fixtures 
    directly over or adjacent to exposed raw materials, in-process 
    materials, or bulk (unpackaged) finished product shall be protected to 
    prevent glass from contaminating the product in the event of breakage.
        (d) Air filtration systems, including prefilters and particulate 
    matter air filters, shall be used on air supplies to production areas 
    where ingredients or infant formula are directly exposed to the 
    atmosphere.
        (e) All rodenticides, insecticides, fungicides, fumigating agents, 
    and cleaning and sanitizing agents shall be stored and used in a manner 
    that protects against contamination of infant formula.
        (f)(1) Potable water used in the manufacture of infant formula 
    shall meet the standards prescribed in the Environmental Protection 
    Agency's (EPA's) Primary Drinking Water Regulations set forth in 40 CFR 
    part 141, except that the fluoride level of the water used in infant 
    formula manufacturing shall be as low as possible. The water shall be 
    supplied under continuous positive pressure in a plumbing system that 
    is free of defects that could contaminate an infant formula.
        (2) Manufacturers shall test representative samples of the potable 
    water drawn at a point in the system at which the water is in the same 
    condition that it will be when it is used in infant formula 
    manufacturing.
        (3) Manufacturers shall conduct the tests required by paragraph 
    (f)(2) of this section with sufficient frequency to ensure that the 
    water meets the EPA's Primary Drinking Water Regulations but shall not 
    conduct these tests less frequently than annually for chemical 
    contaminants, every 4 years for radiological contaminants, and weekly 
    for bacteriological contaminants.
        (4) Manufacturers shall make and retain records, in accordance with 
    Sec. 106.100(f)(1), of the frequency and results of testing of the 
    water used in the production of infant formula.
        (g) There shall be no backflow from, or cross-connection between, 
    piping systems that discharge waste water or sewage and piping systems 
    that carry water for infant formula manufacturing.
        (h) When steam comes in direct contact with infant formula, it 
    shall be safe and free of rust and other particulate matter that may 
    contaminate the formula. Boiler water additives in the steam shall be 
    used in accordance with Sec. 173.310 of this chapter.
        (i) Each infant formula manufacturing site shall provide its 
    employees with readily accessible toilet facilities and hand washing 
    facilities that include hot and cold water, soap or detergent, and 
    single-service towels and that are maintained in good repair and in a 
    sanitary condition at all times, and that these facilities provide for 
    proper disposal of the sewage. Doors to the toilet facility shall not 
    open into areas where infant formula ingredients, containers, or 
    closures are stored, or where infant formula is processed or stored.
    
    
    Sec. 106.30  Controls to prevent adulteration caused by equipment or 
    utensils.
    
        (a) Equipment used in the manufacture, processing, packing or 
    holding of an infant formula shall be of appropriate design and shall 
    be installed to facilitate its intended function and its cleaning and 
    maintenance.
        (b) Equipment and utensils used in the manufacture, processing, 
    packing, or holding of an infant formula shall be constructed so that 
    surfaces that contact ingredients, in-process materials, or infant 
    formula are made of nontoxic materials and are not reactive or 
    absorptive. Such equipment and utensils shall be designed to be easily 
    cleanable and to withstand the environment of their intended use. All 
    surfaces that contact ingredients, in-process materials, or infant 
    formula shall be cleaned, sanitized, and maintained to protect infant 
    formula from being contaminated by any source. Sanitizing agents used 
    on food-contact surfaces must comply with Sec. 178.1010 of this 
    chapter.
        (c) Manufacturers shall ensure that substances, such as lubricants 
    or coolants, that are required for operation of infant formula 
    manufacturing equipment, but that would render the infant formula 
    adulterated if they contaminated the formula, do not come in contact 
    with formula ingredients, containers, closures, or in-process materials 
    or with infant formula itself.
        (d)(1) Manufacturers shall ensure that instruments used for 
    measuring, regulating, or controlling mixing time and speed, 
    temperature, pressure, moisture, water activity, or other parameters at 
    points where control is deemed necessary to prevent adulteration in the 
    processing of an infant formula are accurate, easily read, properly 
    maintained, and present in sufficient number for their intended use. 
    The instruments and controls shall be tested for accuracy (calibrated) 
    against a known reference standard before first use and thereafter at 
    routine intervals, as specified in writing by the manufacturer of the 
    instrument or control, or as otherwise deemed necessary to ensure the 
    accuracy of the instrument. The known reference standard shall be 
    certified for accuracy at routine intervals specified in writing by the 
    manufacturer of the instrument, or as otherwise deemed necessary to 
    ensure the accuracy of the instrument. Manufacturers shall make and 
    retain records of the accuracy checks in accordance with 
    Sec. 106.100(f)(2).
        (2) Instruments and controls that cannot be adjusted to agree with 
    the reference standard shall be repaired or replaced.
        (3) If calibration of an instrument (testing for accuracy against a 
    known reference standard) shows that a specification or standard for a 
    point where control is deemed necessary to prevent adulteration has not 
    been met, a written evaluation of all affected product, and of any 
    actions that need to be taken with respect to that product, shall be 
    made, in accordance with Sec. 106.100(f)(2).
        (e)(1) The temperature in cold storage compartments that are used 
    to store raw materials, in-process materials, or final product, and in 
    thermal processing equipment used at points where temperature control 
    is necessary to prevent adulteration, shall be monitored with such 
    frequency as is necessary to ensure that temperature control is 
    maintained.
        (2) Cold storage compartments shall be maintained at a temperature 
    of 40  deg.F (4.4  deg.C) or below.
        (3)(i) Cold storage compartments and thermal processing equipment 
    shall be equipped with easily readable, accurate temperature-indicating 
    devices.
        (ii) Thermal processing equipment shall be equipped with 
    temperature-recording devices that will reflect the true temperature on 
    a continuing basis. Cold storage compartments shall be equipped with 
    either temperature-recording devices that will reflect the true 
    temperature, on a continuing basis, within the compartment or, in lieu 
    of a temperature-recording device, a high temperature alarm or a 
    maximum-indicating thermometer that has been verified to function 
    properly. If the manufacturer uses either of the latter options, it 
    shall maintain a temperature log in which it notes temperature with 
    such frequency as is necessary to achieve control. Manufacturers shall 
    make and retain records, in accordance with Sec. 106.100(f)(3), of the 
    temperatures indicated or recorded by these devices.
    
    [[Page 36212]]
    
        (4) When a temperature-recording device is used, such device shall 
    not read higher than the calibrated temperature-indicating device for 
    thermal processing equipment or lower than the reference temperature-
    indicating device for cold storage compartments.
        (f) Equipment and utensils used in the manufacture of infant 
    formula shall be cleaned, sanitized, and maintained at regular 
    intervals to prevent adulteration of the infant formula. An individual 
    qualified by training or experience to conduct such a review shall 
    check all cleaning, sanitizing, and maintenance to ensure that it has 
    been satisfactorily completed. Manufacturers shall make and retain 
    records on equipment cleaning, sanitizing, and maintenance, in 
    accordance with Sec. 106.100(f)(4).
        (g) Compressed air or other gases that are mechanically introduced 
    into infant formula, that are used to clean any equipment, or that come 
    into contact with any other surface that contacts ingredients, in-
    process materials, or infant formula shall be treated in such a way 
    that their use will not contaminate the infant formula with unlawful 
    indirect food additives or other chemical, physical, or microbiological 
    contaminants. When compressed gases are used at product filling 
    machines to replace air removed from the headspace of containers, the 
    manufacturer shall install a 0.5 micrometer or smaller filter as close 
    to the end of the gas line that feeds gas into the space, as practical.
    
    
    Sec. 106.35  Controls to prevent adulteration due to automatic 
    (mechanical or electronic) equipment.
    
        (a)(1) For the purposes of this section, ``hardware'' means all 
    automatic equipment, including mechanical and electronic equipment 
    (including computers), that is used in production or quality control of 
    a infant formula.
        (2) For the purposes of this section, ``software'' means any 
    programs, procedures, rules, and associated documentation used in the 
    operation of a system.
        (3) For the purposes of this section, ``system'' means a collection 
    of components (including software and hardware) organized to accomplish 
    a specific function or set of functions in a specified environment.
        (4) For the purposes of this section, ``validation'' means 
    establishing documented evidence that provides a high degree of 
    assurance that a system will consistently produce a product meeting its 
    predetermined specifications and quality characteristics.
        (b)(1) All systems shall be designed, installed, tested, and 
    maintained in a manner that will ensure that they are capable of 
    performing their intended function and of producing or analyzing infant 
    formula in accordance with this subpart and subpart C of this part.
        (2) The infant formula manufacturer shall ensure that hardware is 
    routinely calibrated, inspected, and checked according to written 
    procedures.
        (3) The infant formula manufacturer shall check and document the 
    accuracy of input into, and output generated by, any system used in the 
    production or quality control of an infant formula. The degree and 
    frequency of input/output verification shall be based on the complexity 
    and reliability of the system and the level of risk associated with the 
    safe operation of the system.
        (4) The infant formula manufacturer shall ensure that all systems 
    are validated before their first use to manufacture commercial product.
        (5) The infant formula manufacturer shall ensure that any system 
    that is modified is revalidated after the modification and before use 
    of the modified system to manufacture commercial product. All 
    modifications to software shall be made by a designated individual and 
    shall be checked by the infant formula manufacturer to ensure that 
    infant formula that is produced or analyzed using the modified software 
    complies with this subpart and with subpart C of this part.
        (c) The infant formula manufacturer shall make and retain records, 
    in accordance with Sec. 106.100(f)(5), concerning automatic (mechanical 
    or electronic) equipment.
    
    
    Sec. 106.40  Controls to prevent adulteration caused by ingredients, 
    containers, and closures.
    
        (a) The only substances that may be used in infant formulas are 
    food ingredients whose use in infant formula is safe and suitable under 
    the applicable food safety provisions of the Federal Food, Drug, and 
    Cosmetic Act; that is, the substance is generally recognized as safe 
    (GRAS) for such use, is used in accordance with the agency's food 
    additive regulations, or is authorized by a prior sanction.
        (b) Infant formula containers and closures shall not be reactive or 
    absorptive so as to affect the safety of the infant formula, and all 
    packaging material that comes in contact with infant formula shall be 
    composed of substances that are GRAS for use in or on food, GRAS for 
    their intended use in food packaging, authorized by a prior sanction 
    issued by the agency, or authorized for use as an indirect food 
    additive. Any packaging material that comes in contact with infant 
    formula shall be used in accordance with any prescribed limitations.
        (c) Ingredients, containers, and closures used in the manufacture 
    of infant formula shall be identified with a batch or lot number to be 
    used in recording their disposition.
        (d) Infant formula manufacturers shall develop written 
    specifications for their acceptance or rejection of ingredients, 
    containers, and closures used in infant formula manufacture. These 
    specifications shall stipulate the standards for acceptance or 
    rejection of such ingredients, containers, and closures as well as the 
    procedures for determining whether the ingredients, containers, and 
    closures meet that standard. An individual qualified by training or 
    experience shall conduct an investigation of a finding that any 
    ingredients, containers, or closures used in a batch of infant formula 
    failed to meet any of the manufacturer's specifications.
        (e) Ingredients, containers and closures shall be stored in areas 
    clearly designated for:
        (1) Materials pending release for use,
        (2) Materials released for use, or
        (3) Materials rejected for use in infant formula production. Any 
    lot of ingredients, containers, or closures that does not meet the 
    manufacturer's specifications shall be rejected and controlled under a 
    quarantine system designed to prevent its use in the manufacture of 
    infant formula.
        (f) If an ingredient, a container, or a closure that has been 
    tested and examined is exposed to air, heat, or other conditions that 
    may adversely affect it, the ingredient, container, or closure shall be 
    retested or reexamined to ensure that it still meets the manufacturer's 
    specifications.
        (g) Manufacturers shall make and retain records, in accordance with 
    Sec. 106.100(f)(6), on the ingredients, containers, and closures used 
    in the manufacture of infant formula.
    
    
    Sec. 106.50  Controls to prevent adulteration during manufacturing.
    
        (a)(1) Manufacturers shall prepare and follow a written master 
    manufacturing order that establishes controls and procedures for the 
    production of an infant formula.
        (2) The manufacturer shall make and retain records, in accordance 
    with Sec. 106.100(e), that include complete information relating to the 
    production and control of the batch. An individual qualified by 
    training or experience shall conduct an investigation of any
    
    [[Page 36213]]
    
    deviations from the master manufacturing order and any corrective 
    actions taken.
        (3) Changes made to the master manufacturing order shall be 
    drafted, reviewed, and approved by a responsible official and include 
    an evaluation of the effect of the change on the nutrient content and 
    the suitability of the formula for infants.
        (b) The manufacturer shall establish controls to ensure that each 
    raw or in-process ingredient required by the master manufacturing order 
    is examined by one person and checked by a second person or system. 
    This checking will ensure that the correct ingredient is added during 
    the manufacturing process, that the ingredient has been released for 
    use in infant formula, and that the correct weight or measure of the 
    ingredient is added to the batch.
        (c) The manufacturer shall identify the contents, including the 
    processing stage and the lot or batch number of a batch of infant 
    formula, of all compounding and storage containers, processing lines, 
    and major equipment used during the production of a batch of an infant 
    formula.
        (d) The manufacturer shall establish controls to ensure that the 
    nutrient levels required by Sec. 107.100 of this chapter are maintained 
    in the formula, and that the formula is not contaminated with 
    microorganisms or other contaminants. Such controls shall include but 
    not be limited to:
        (1) The mixing time; the speed, temperature, and flow rate of 
    product; and other critical parameters necessary to ensure the addition 
    of required ingredients to, and the homogeneity of, the formula;
        (2) The spray-drying process for powdered infant formula, including 
    the filtering of the intake air before heating, to prevent microbial 
    and other contamination;
        (3) The removal of air from the finished product to ensure that 
    nutrient deterioration does not occur;
        (4) Ensuring that each container of finished product is properly 
    sealed. Such controls shall involve use of established procedures, 
    specifications, and intervals of examination that are designed by 
    qualified individuals and are sufficient to:
        (i) Detect visible closure or seal defects, and
        (ii) Determine closure strength through destructive testing. 
    Manufacturers of liquid infant formulas, which are thermally processed 
    low-acid foods packaged in hermetically sealed containers, shall 
    perform such closure integrity testing in accordance with 
    Sec. 113.60(a) of this chapter.
        (e) The manufacturer shall establish controls that ensure that the 
    equipment used at points where control is deemed necessary to prevent 
    adulteration is monitored, so that personnel will be alerted to 
    malfunctions.
        (f) The manufacturer shall establish controls that ensure that 
    rejected in-process materials:
        (1) Are clearly identified as having been rejected for use in an 
    infant formula;
        (2) Are controlled under a quarantine system designed to prevent 
    their use in manufacturing or processing operations for which they are 
    unsuitable;
        (3) Meet the appropriate specifications, if reprocessed, before 
    being released for use in infant formula.
    
    
    Sec. 106.55  Controls to prevent adulteration from microorganisms.
    
        (a) Manufacturers of liquid infant formula shall comply with the 
    procedures specified in part 113 of this chapter for liquid infant 
    formula.
        (b) Manufacturers of powdered infant formula shall test 
    representative samples of every batch of the formula at the final 
    product stage, before distribution, to ensure that the infant formula 
    meets the microbiological quality standards listed in paragraph (c) of 
    this section.
        (c) Any powdered infant formula that contains any microorganism 
    that exceeds the M value listed for that microorganism in Table 1 of 
    this section will be deemed to be adulterated under sections 402 and 
    412 of the Federal Food, Drug, and Cosmetic Act (the act). FDA will 
    determine compliance with the M values listed below using the 
    Bacteriological Analytical Manual (BAM), 8th ed. (1995), published by 
    the AOAC International Association of Official Analytical Chemists, 
    which is incorporated by reference in accordance with 5 U.S.C. 552(a) 
    and 1 CFR part 51. Copies are available from the Association of 
    Official Analytical Chemists, 481 North Frederick Ave., suite 500, 
    Gaithersburg, MD 20877, or may be examined at the Center for Food 
    Safety and Applied Nutrition's Library, 200 C St. SW., rm. 3321, 
    Washington, DC, or may be examined at the Office of the Federal 
    Register, 800 North Capitol St. NW., suite 700, Washington, DC.
    
    ------------------------------------------------------------------------
                   Microorganism                         M value \1\        
    ------------------------------------------------------------------------
    Aerobic Plate Count (APC).................  10,000 CFU/gram (g). \2\    
    Coliforms \3\.............................  3.05 MPN/g. 4,5             
    Fecal coliforms \6\.......................  3.05 MPN/g.                 
    Salmonella................................  0. \7\                      
    Listeria monocytogenes....................  0. \7\                      
    Staphylococcus aureus.....................  3.05 MPN/g.                 
    Bacillus cereus \8\.......................  100 MPN/g or CFU/g.         
    ------------------------------------------------------------------------
    \1\ The M value is the maximum allowable number of microorganisms       
      present in 1 g of dry infant formula.                                 
    \2\ CFU/g, colony forming units per g.                                  
    \3\ M values for coliforms greater than 3.05 are not violative if       
      testing for fecal coliforms results in an M value equal to or less    
      than 3.05.                                                            
    \4\ MPN/g, most probable number per g.                                  
    \5\ The MPN value of 3.05 in this table is derived from the tables of   
      calculated MPN values that appear in the 8th ed. of the BAM when using
      an inoculation series of 0.1, 0.01, and 0.001g (or ml) of the infant  
      formula sample.                                                       
    \6\ No testing for fecal coliforms is required when the M value for     
      coliforms is less than or equal to 3.05.                              
    \7\ None detected.                                                      
    \8\B. cereus testing must be performed only if the APC exceeds 100 CFU/ 
      g.                                                                    
    
        (d) Manufacturers shall make and retain records, in accordance with 
    Sec. 106.100(e)(5)(ii) and (f)(7), on the testing of infant formulas 
    for microorganisms.
    
    
    Sec. 106.60  Controls to prevent adulteration during packaging and 
    labeling of infant formula.
    
        (a) Manufacturers shall examine packaged and labeled infant formula 
    during finishing operations to ensure that containers and packages in 
    the lot have the correct label, the correct use-by date, and the 
    correct code established under Sec. 106.80.
        (b) Labels shall be designed, printed, and applied so that the 
    labels remain legible and attached during the conditions of processing, 
    storage, handling, distribution, and use.
        (c) All infant formula held in a single package shall be the same 
    product bearing the same code, established under Sec. 106.80. Packaging 
    used to hold multiple containers of infant formula shall be labeled 
    with the product name, the name of the manufacturer or shipper, and the 
    code.
    
    
    Sec. 106.70  Controls on the release of finished infant formula.
    
        (a) The manufacturer shall hold, or maintain under its control, 
    each batch of infant formula until it determines that the batch meets 
    all of its specifications, including those adopted to meet the 
    requirements of Sec. 106.55 on microbiological contamination and 
    Sec. 106.91(a) on quality control procedures, and releases the batch 
    for distribution.
        (b) Each batch of infant formula that fails to meet the 
    manufacturer's specifications shall be rejected. Although the batch may 
    be reprocessed, any batch of infant formula that is reprocessed shall 
    be shown to meet the
    
    [[Page 36214]]
    
    requirements of Sec. 106.70(a) before it is released.
        (c) An individual qualified by training or experience shall conduct 
    an investigation of a finding that a batch of infant formula fails to 
    meet any manufacturer's specifications.
    
    
    Sec. 106.80  Traceability.
    
        (a) Manufacturers shall ensure traceability by coding infant 
    formulas in conformity with the coding requirements prescribed in 
    Sec. 113.60(c) of this chapter for thermally processed low-acid foods 
    packaged in hermetically-sealed containers, except as provided in 
    paragraph (b) of this section.
        (b) Batches of powdered infant formula that are manufactured in 
    stages over more than 1 day, in lieu of being coded in accordance with 
    Sec. 113.60(c) of this chapter, may be coded with a sequential number 
    that identifies the product and the establishment where the product was 
    packed and that permits tracing of all stages of manufacture of that 
    batch, including the year, the days of the year, and the period during 
    those days that the product was packed, and the receipt and handling of 
    raw materials used.
    
    
    Sec. 106.90  Audits of current good manufacturing practice.
    
        Manufacturers of an infant formula, or an agent of such 
    manufacturers, shall conduct regularly scheduled audits to determine 
    whether the manufacturer has complied with the current good 
    manufacturing practice regulations in this subpart. These audits shall 
    be performed by an individual who, as a result of education, training, 
    and experience, is knowledgeable in all aspects of infant formula 
    production and of the agency's regulations concerning current good 
    manufacturing practice but who has no direct responsibility for the 
    matters being audited.
    
    Subpart C--Quality Control Procedures
    
    
    Sec. 106.91  General quality control.
    
        (a) Nutrient testing to ensure that each batch of infant formula 
    provides nutrients in accordance with Sec. 107.100. Manufacturers shall 
    test each batch as follows:
        (1) Each nutrient premix used in the manufacture of an infant 
    formula shall be tested for each nutrient that the manufacturer is 
    relying on the premix to provide to ensure that the premix is in 
    compliance with the manufacturer's specifications;
        (2) During the manufacturing process, after the addition of the 
    premix, or at the final-product-stage but before distribution, each 
    batch of infant formula shall be tested for at least one indicator 
    nutrient for each of the nutrient premixes used in the infant formula 
    to confirm that the nutrients supplied by each of the premixes are 
    present, in the proper concentration, in the batch of infant formula.
        (3) At the final-product-stage, before distribution of an infant 
    formula, each batch shall be tested for vitamins A, C, E, and thiamin.
        (4) During the manufacturing process or at the final-product-stage, 
    before distribution, each batch shall be tested for all nutrients 
    required to be included in such formula under Sec. 107.100 of this 
    chapter and for any nutrient added by the manufacturer for which 
    testing is not conducted for compliance with paragraphs (a)(1) or 
    (a)(3) of this section.
        (b) Stability testing. Every 3 months, manufacturers shall collect 
    representative samples from the final-product-stage of one batch of 
    each physical form (powder, ready-to-feed, or concentrate) of each 
    infant formula, at each manufacturing facility. The manufacturer shall 
    test these samples for each nutrient required under Sec. 107.100 of 
    this chapter and for any nutrient added by the manufacturer. The 
    frequency of such testing shall be at the beginning, midpoint, and end 
    of the shelf life of the infant formula and, depending on the nutrient 
    and its stability within the matrix of the formulation, with additional 
    frequency as is necessary to ensure that such formula complies with 
    section 412 of the Federal Food, Drug, and Cosmetic Act (the act) 
    throughout the shelf life of the infant formula; except that:
        (1) If the infant formula is a new infant formula, manufacturers 
    shall collect a representative sample from the final-product-stage of 
    each physical form (powder, ready-to-feed, or concentrate) of the first 
    batch of the new infant formula and test these samples according to the 
    requirements of this section; and
        (2) If an infant formula has been changed in formulation or in 
    processing in a way that does not make it a new infant formula but that 
    may affect whether it is adulterated under section 412(a) of the act, 
    the manufacturer shall collect a representative sample from the final-
    product-stage of each physical form (powder, ready-to-feed, or 
    concentrate) of the first batch of the infant formula and shall test 
    these samples according to the frequency required by this section for 
    each nutrient that has been or may have been affected by the change.
        (c) Quality control records. Manufacturers shall make and retain 
    quality control records in accordance with Sec. 106.100(e)(5)(i) and 
    (f)(7).
    
    
    Sec. 106.92  Audits of quality control procedures.
    
        A manufacturer of an infant formula, or an agent of such a 
    manufacturer, shall conduct regularly scheduled audits to determine 
    whether the manufacturer has complied with the quality control 
    procedures that are necessary to ensure that an infant formula provides 
    nutrients in accordance with section 412(b) and (i) of the Federal 
    Food, Drug, and Cosmetic Act and is manufactured in a manner designed 
    to prevent adulteration of the infant formula under section 412(a)(1) 
    and (a)(3) of the Federal Food, Drug, and Cosmetic Act. These audits 
    shall be performed by an individual who, as a result of education, 
    training, and experience, is knowledgeable in all aspects of infant 
    formula production and of the agency's regulations concerning quality 
    control procedures but who has no direct responsibility for the matters 
    being audited.
    
    Subpart D--Conduct of Audits
    
    
    Sec. 106.94  Audit plans and procedures.
    
        (a) Manufacturers shall develop and follow a written audit plan 
    that is available at the manufacturing facility for FDA inspection.
        (b) The audit plan shall include audit procedures that set out the 
    methods the manufacturer uses to determine whether the facility is 
    operating in accordance with current good manufacturing practice, with 
    the quality control procedures that are necessary to assure that an 
    infant formula provides nutrients in accordance with section 412(b) and 
    (i) of the Federal Food, Drug, and Cosmetic Act, and in a manner 
    designed to prevent adulteration of the infant formula.
        (c) The audit procedures shall include, but not be limited to:
        (1) An evaluation of the production and in-process control system 
    established under Sec. 106.6(b) by:
        (i) Observing the production of infant formula and comparing the 
    observed process to the written production and in-process control plan 
    required under Sec. 106.6(b);
        (ii) Reviewing records of the monitoring of points, steps, or 
    stages where control is deemed necessary to prevent adulteration; and
        (iii) Reviewing records of how deviations from any standard or 
    specification at points, steps, or stages where control is deemed 
    necessary to prevent adulteration were handled; and
    
    [[Page 36215]]
    
        (2) A review of a representative sample of all records maintained 
    in accordance with Sec. 106.100(e) and (f).
    
    Subpart E--Quality Factors for Infant Formulas
    
    
    Sec. 106.96  Quality factors in infant formulas.
    
        (a) All infant formulas shall, when fed to infants as a sole source 
    of nutrition, be of sufficient quality to meet the nutritional 
    requirements for healthy growth. The regulations set forth in this 
    subpart define the minimum quality factors for infant formulas.
        (b) All infant formulas shall be capable of supporting normal 
    physical growth of infants.
        (c) All infant formulas shall be formulated and manufactured such 
    that the protein is of sufficient biological quality to meet the 
    protein requirements of infants.
    
    
    Sec. 106.97  Assurances for quality factors.
    
        (a) General quality factor of normal physical growth. (1) The 
    manufacturer shall conduct an adequate and well-controlled clinical 
    study, in accordance with good clinical practice, to determine whether 
    an infant formula supports normal physical growth in infants when the 
    formula is fed as the sole source of nutrition.
        (i) The manufacturer shall:
        (A) Conduct a clinical study that is no less than 4 months in 
    duration, enrolling infants no more than 1 month old at time of entry 
    into the study.
        (B) Collect and maintain data in the study on anthropometric 
    measures of physical growth, including body weight, recumbent length, 
    head circumference, and average daily weight increment, and plot the 
    data on National Center for Health Statistics (NCHS) reference 
    percentile body weight and body length curves. The NCHS growth charts 
    are incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 
    CFR part 51. Copies are available from the Office of Constituent 
    Operations (HFS-565), Center for Food Safety and Applied Nutrition, 
    Food and Drug Administration, 200 C St. SW., Washington, DC 20204, may 
    be examined at the Office of Special Nutritionals (HFS-456), Center for 
    Food Safety and Applied Nutrition, Food and Drug Administration, 200 C 
    St. SW., Washington, DC 20204, or the Office of the Federal Register, 
    800 North Capitol St. NW., suite 700, Washington, DC.
        (C) Collect anthropometric measurements at the beginning of the 
    clinical study, at 2 weeks, at 4 weeks, at least monthly thereafter, 
    and at the conclusion of the study.
        (ii) The clinical study protocol should:
        (A) Describe the scientific basis and objectives of the study, the 
    planned control and treatment feeding regimens, the entrance criteria 
    used to enroll infants in the study, the method of randomization used 
    for the assignment of infants to feeding groups, the collection of 
    specific measurements and other data, the methods used to limit sources 
    of bias, and the planned methods of statistical analysis;
        (B) Describe the necessary qualifications and experience of 
    investigators;
        (C) Be reviewed and approved by an Institutional Review Board (IRB) 
    in accordance with part 56 of this chapter. The manufacturer shall 
    establish procedures to obtain written informed consent from parents or 
    legal representatives of the infants enrolled in the study in 
    accordance with part 50 of this chapter;
        (D) Explain how the study population represents the population for 
    which the new infant formula is intended and how the study addresses 
    the intended conditions of use of the formula.
        (E) Describe the sample size calculations and the power 
    calculations and the basis for selecting the sample size and study 
    design;
        (F) Describe the plan to identify and evaluate any adverse effects;
        (G) Describe the quality control procedures used to ensure the 
    validity and reliability of the measurements collected.
        (H) Describe and compare the composition of the test and control 
    formulas.
        (I) Describe the basis upon which the test formula is appropriate 
    for use in evaluating the formula that the manufacturer intends to 
    market, if the test formula used in a study is not identical to the 
    formula that is intended to be marketed in the United States.
        (2) The manufacturer may request an exemption from the requirements 
    of paragraph (a)(1) of this section if:
        (i) The manufacturer has similar experience using an ingredient, an 
    ingredient mixture, or a processing method in the production of an 
    infant formula marketed in the United States and can demonstrate that 
    infant formula made with that ingredient, ingredient mixture, or 
    processing method meets the quality factor requirements in Sec. 106.96;
        (ii) The manufacturer markets a formulation in more than one form 
    (e.g., liquid and powdered forms) and can demonstrate that the quality 
    factor requirements are met by the form of the formula that is 
    processed using the method that has the greatest potential for 
    adversely affecting nutrient content and bioavailability;
        (iii) The manufacturer can demonstrate that the requirements of 
    paragraph (a)(1) of this section are not appropriate for evaluation of 
    a specific infant formula, and that an alternative method or study 
    design for showing that the formula supports healthy growth in infants 
    fed it as their sole source of nutrition is available.
        (b) Specific quality factor for protein quality of infant formula. 
    (1) The manufacturer shall collect and maintain data that establish 
    that the biological quality of protein in an infant formula is 
    sufficient to meet the protein requirements of infants. The 
    manufacturer shall establish the biological quality of the protein in 
    its infant formula by demonstrating that the protein source supports 
    adequate growth using the Protein Efficiency Ratio (PER) rat bioassay 
    described in the ``Official Methods of Analysis of the Association of 
    Official Analytical Chemists,'' 16th ed., sections 43.3.04 and 43.3.05, 
    ``AOAC Official Method 960.48 Protein Efficiency Ratio Rat Bioassay'' 
    which is incorporated by reference in accordance with 5 U.S.C. 552(a) 
    and 1 CFR part 51. Copies are available from the Association of 
    Official Analytical Chemists, 481 North Frederick Ave., suite 500, 
    Gaithersburg, MD 20857, or the Office of Special Nutritionals (HFS-
    456), Center for Food Safety and Applied Nutrition, Food and Drug 
    Administration, 200 C St. SW., Washington, DC 20204, or may be examined 
    at the Office of the Federal Register, 800 North Capitol St. NW., 
    Washington, DC. If the manufacturer is unable to conduct a PER rat 
    bioassay because of the composition of the protein in the formula, then 
    it shall demonstrate that the amino acid composition of the protein 
    meets the known amino acid requirements of infants for whom the formula 
    is intended.
        (2) The manufacturer may request an exemption from the requirements 
    of paragraph (b)(1) of this section if:
        (i) The protein source, including any processing method used to 
    produce the protein source, is already used in another infant formula 
    marketed in the United States, manufactured by the same manufacturer, 
    and the manufacturer can demonstrate that such infant formula meets the 
    quality factor requirements prescribed in Sec. 106.96;
        (ii) The protein source, including any processing methods used to 
    produce the protein source, is not a major change from the infant 
    formula it replaces, and the manufacturer can demonstrate that the 
    infant formula it replaces meets the
    
    [[Page 36216]]
    
    quality factor requirements prescribed in Sec. 106.96.
        6. In newly redesignated subpart F, Sec. 106.100 is amended by 
    revising paragraphs (e), (f), (g), (j), and (k)(3), and by removing and 
    reserving paragraph (h) to read as follows:
    
    
    Sec. 106.100  Records.
    
    * * * * *
        (e) Batch production and control records. For each batch of infant 
    formula, manufacturers shall prepare and maintain records that include 
    complete information relating to the production and control of the 
    batch. These records shall include but are not limited to:
        (1) The master manufacturing order. The master manufacturing order 
    shall include but is not limited to:
        (i) The significant steps in the production of the batch and the 
    date on which each significant step occurred;
        (ii) The identity of equipment and processing lines used in 
    producing the batch, if the plant in which the formula is made includes 
    more than one set of equipment or more than one processing line;
        (iii) The identity of each batch or lot of ingredients, containers, 
    and closures used in producing the batch of formula;
        (iv) The amount of each ingredient to be added to the batch of 
    infant formula and a check (verification) that the correct amount was 
    added; and
        (v) Copies of all labeling used and the results of examinations 
    conducted during the finishing operations to provide assurance that 
    containers and packages in the lot have the correct label.
        (2) Any deviations from the master manufacturing order and any 
    corrective actions taken because of the deviations.
        (3) Documentation, in accordance with Sec. 106.6(c), of the 
    monitoring at any point, step, or stage in their production process 
    where control is deemed necessary to prevent adulteration. These 
    records shall include, but not be limited to:
        (i) A list of the standards or specifications established at each 
    point, step, or stage in their production process where control is 
    deemed necessary to prevent adulteration including documentation of the 
    scientific basis for each standard or specification;
        (ii) The actual values obtained during the monitoring operation, 
    any deviations from established standards or specifications, and any 
    corrective actions taken;
        (iii) Identification of the person monitoring each point, step, or 
    stage in their production process where control is deemed necessary to 
    prevent adulteration.
        (4) The conclusions and followup, along with the identity, of the 
    individual qualified by training or experience who investigated:
        (i) Any deviation from the master manufacturing order and any 
    corrective actions taken;
        (ii) A finding that a batch or any of its ingredients failed to 
    meet the infant formula manufacturer's specifications; and
        (iii) A failure to meet any specification or standard at any point, 
    step, or stage in the production process where control is deemed 
    necessary to prevent adulteration.
        (5) The results of all testing performed on the batch of infant 
    formula, including testing on the in-process batch, at the final-
    product stage, and on finished product throughout the shelf life of the 
    product. The results recorded shall include but are not limited to:
        (i) The results of all quality control testing conducted, in 
    accordance with Sec. 106.91(a) and (b), to verify that each nutrient 
    required by Sec. 107.100 of this chapter is present in each batch of 
    infant formula at the level required by Sec. 107.100, and that any 
    nutrient added by the manufacturer is present at the appropriate level 
    with:
        (A) A summary table identifying the stages of the manufacturing 
    process at which the nutrient analysis for each required nutrient under 
    Sec. 106.91(a) is conducted, and
        (B) A summary table on the stability testing program, including the 
    nutrients tested and the frequency of testing of nutrients throughout 
    the shelf life of the product under Sec. 106.91(b); and
        (ii) For powdered infant formula, the results of any testing 
    conducted in accordance with Sec. 106.55(b) to verify compliance with 
    the microbiological quality standards in Sec. 106.55(c).
        (f) Manufacturers shall make and retain all records pertaining to 
    current good manufacturing practice as described in subpart B of this 
    part, including but not limited to:
        (1) Records, in accordance with Sec. 106.20(f)(3), of the frequency 
    and results of testing of the water used in the production of infant 
    formula;
        (2) Records, in accordance with Sec. 106.30(d), of accuracy checks 
    of instruments and controls. A certification of accuracy of any known 
    reference standard used and a history of recertification shall be 
    maintained. At a minimum, such records shall specify the instrument or 
    control being checked, the date of the accuracy check, the standard 
    used, the calibration method used, the results found, any actions taken 
    if the instrument is found to be out of calibration, and the initials 
    or name of the individual performing the test. If calibration of an 
    instrument (testing for accuracy against a known reference standard) 
    shows that a specification or standard at a point, step, or stage in 
    the production process where control is deemed necessary to prevent 
    adulteration has not been met, a written evaluation of all affected 
    product, and any actions that need to be taken with respect to that 
    product, shall be made.
        (3) Records, in accordance with Sec. 106.30(e)(3)(ii), of the 
    temperatures monitored for cold storage compartments and thermal 
    processing equipment.
        (4) Records, in accordance with Sec. 106.30(f), on equipment 
    cleaning, sanitizing, and maintenance that show the date and time of 
    such cleaning, sanitizing, and maintenance and the lot number of each 
    batch of infant formula processed between equipment startup and 
    shutdown for cleaning, sanitizing, and maintenance. The person 
    performing and checking the cleaning, sanitizing, and maintenance shall 
    date and sign or initial the record indicating that the work was 
    performed.
        (5) Records, in accordance with Sec. 106.35(c), on all automatic 
    (mechanical or electronic) equipment used in the production or quality 
    control of infant formula. These records shall include but not be 
    limited to:
        (i) A list of all systems used with a description of computer files 
    and the inherent limitations of each system;
        (ii) A copy of all software used;
        (iii) Records that document installation, calibration, testing or 
    validation, and maintenance of the systems used;
        (iv) A list of all persons authorized to create or modify software;
        (v) Records that document modifications to software, including the 
    identity of the person who modified the software;
        (vi) Records that document retesting or revalidation of modified 
    systems; and
        (vii) A backup file of data entered into a computer or related 
    system. The backup file shall consist of a hard copy or alternative 
    system, such as duplicate diskettes, tapes, or microfilm, designed to 
    ensure that backup data are exact and complete, and that they are 
    secure from alteration, inadvertent erasures, or loss.
        (6) Records, in accordance with Sec. 106.40(g), on ingredients, 
    containers, and closures used in the manufacture of infant formula. 
    These records shall include, but are not limited to:
    
    [[Page 36217]]
    
        (i) The identity and quantity of each lot of ingredients, 
    containers, and closures;
        (ii) The name of the supplier;
        (iii) The supplier's lot numbers;
        (iv) The name and location of the manufacturer of the ingredient, 
    container, and closure, if different from the supplier;
        (v) The date of receipt;
        (vi) The receiving code as specified; and
        (vii) The results of any test or examination (including retesting 
    and reexamination) performed on the ingredients, containers, and 
    closures and the conclusions derived therefrom and the disposition of 
    all ingredients, containers, or closures.
        (7) A full description of the methodology used to test powdered 
    infant formula to verify compliance with the microbiological quality 
    standards of Sec. 106.55(c) and the methodology used to do quality 
    control testing, in accordance with Sec. 106.91(a) and (b).
        (g) The manufacturer shall maintain all records pertaining to 
    distribution of the infant formula, including records that show that 
    products produced for export only are exported. Such records shall 
    include, but not be limited to, all information and data necessary to 
    effect and monitor recalls of the manufacturer's infant formula 
    products in accordance with subpart E of part 107 of this chapter.
        (h) [Reserved]
    * * * * *
        (j) The manufacturer shall make and retain records pertaining to 
    regularly scheduled audits, including the audit plans and procedures, 
    the findings of the audit, and a listing of any changes made in 
    response to these findings. The manufacturer shall make readily 
    available for authorized inspection the audit plans and procedures and 
    a statement of assurance that the regularly scheduled audits are being 
    conducted. The findings of the audit and any changes made in response 
    to these findings shall be maintained for the time period required 
    under Sec. 106.100(n), but need not be made available to FDA.
        (k) * * *
        (3) When there is a reasonable possibility of a causal relationship 
    between the consumption of an infant formula and an infant's death, the 
    manufacturer shall, within 15 days of receiving such information, 
    conduct an investigation and notify the agency as required in 
    Sec. 106.150.
    * * * * *
    
    Subpart G--Registration, Submission, and Notification Requirements
    
    
    Sec. 106.110  New infant formula registration.
    
        (a) Before a new infant formula may be introduced or delivered for 
    introduction into interstate commerce, the manufacturer of such formula 
    shall register with the Food and Drug Administration, Center for Food 
    Safety and Applied Nutrition, Office of Special Nutritionals, Division 
    of Programs and Policy Enforcement (HFS-455), Infant Formula 
    Coordinator, 200 C St. SW., Washington, DC 20204. An original and two 
    copies of this registration shall be submitted.
        (b) The new infant formula registration shall include:
        (1) The name of the new infant formula,
        (2) The name of the manufacturer,
        (3) The place of business of the manufacturer, and
        (4) All establishments at which the manufacturer intends to 
    manufacture such new infant formula.
    
    
    Sec. 106.120  New infant formula submission.
    
        (a) At least 90 days before a new infant formula is introduced or 
    delivered for introduction into interstate commerce, a manufacturer 
    shall submit notice of its intent to do so to the Food and Drug 
    Administration at the address given in Sec. 106.110(a). An original and 
    two copies of the notice of its intent to do so shall be submitted.
        (b) The new infant formula submission shall include:
        (1) The name and physical form (e.g., powder, ready-to feed, or 
    concentrate) of the infant formula;
        (2) An explanation of why the formula is a new infant formula;
        (3) The quantitative formulation of each form of the infant formula 
    that is the subject of the notice in units per volume (for liquid 
    formulas) or units per dry weight (for powdered formulas). When 
    applicable, the submission shall include a description of any 
    reformulation of the infant formula, including a listing of each new or 
    changed ingredient and a discussion of the effect of such changes on 
    the nutrient levels in the formulation;
        (4) A description, when applicable, of any change in processing of 
    the infant formula. Such description shall identify the specific change 
    in processing, including side-by-side, detailed schematic diagrams 
    comparing the new processing to the previous processing (including 
    processing times and temperatures);
        (5) Assurance that the infant formula will not be marketed unless 
    the formula meets the quality factor requirements of section 412(b)(1) 
    of the Federal Food, Drug, and Cosmetic Act (the act) and the nutrient 
    content requirements of section 412(i) of the act.
        (i) Assurance that the formula meets the quality factor 
    requirements, which are set forth in subpart E of this part, shall be 
    provided by a submission that complies with Sec. 106.121.
        (ii) Assurance that the formula complies with the nutrient content 
    requirements, which are set forth in Sec. 107.100 of this chapter, 
    shall be provided by a statement assuring that the formula will not be 
    marketed unless it meets the nutrient requirements of Sec. 107.100 of 
    this chapter, as demonstrated by testing required under subpart C of 
    this part;
        (6) Assurance that the processing of the infant formula complies 
    with section 412(b)(2) of the act. Such assurance shall include but not 
    be limited to:
        (i) A statement that the formula will be produced in accordance 
    with subparts B and C of this part;
        (ii) The basis on which each ingredient meets the requirements of 
    Sec. 106.40(a), e.g., that it is an approved food additive, that it is 
    authorized by a prior sanction issued by the agency, or that it is GRAS 
    for its intended use. Any claim that an ingredient is GRAS shall be 
    supported by a citation to the agency's regulations or by an 
    explanation, including a list of published studies and a copy of those 
    publications, for why, based on the published studies, there is general 
    recognition of the safety of the use of the ingredient in infant 
    formula.
        (c) For products for export only, a manufacturer may submit, in 
    lieu of the information required under paragraph (b) of this section, a 
    statement that the infant formula meets the specifications of the 
    foreign purchaser, does not conflict with the laws of the country to 
    which it is intended for export, is labeled on the outside of the 
    shipping package to indicate that it is intended for export only, and 
    will not be sold or offered for sale in domestic commerce.
        (d) The submission will not constitute notice under section 412 of 
    the act unless it complies fully with paragraph (b) of this section, 
    and the information that it contains is set forth in a manner that is 
    readily understandable. The agency will notify the submitter if the 
    notice is not adequate because it does not meet the requirements of 
    section 412(c) and (d) of the act.
        (e) If a new infant formula submission is adequate, FDA will 
    acknowledge its receipt and notify the manufacturer of the date of 
    receipt. The date that the agency receives the new infant formula
    
    [[Page 36218]]
    
    submission is the filing date for the submission. The manufacturer 
    shall not market the new infant formula before the date that is 90 days 
    after the filing date.
        (f) If the manufacturer provides additional information in support 
    of a new infant formula submission, the agency will determine whether 
    the additional information is a substantive amendment to the new infant 
    formula submission. If the agency determines that the new submission is 
    a substantive amendment, FDA will assign the new infant formula 
    submission a new filing date. FDA will acknowledge receipt of the 
    additional information and, when applicable, notify the manufacturer of 
    the new filing date, which is the date of receipt by FDA of the 
    information that constitutes the substantive amendment to the new 
    infant formula submission.
    
    
    Sec. 106.121  Quality factor submission.
    
        To provide assurance that an infant formula meets the quality 
    factor requirements set forth in subpart E of this part, the 
    manufacturer shall submit the following data and information:
        (a) An explanation, in narrative form, setting forth how all 
    quality factor requirements of subpart E of this part have been met.
        (b) Records that contain the information required by proposed 
    Sec. 106.97 (a)(1)(i) and (a)(1)(ii) collected during the study for 
    each infant enrolled in the study. The records shall be identified by 
    subject number, age, feeding group, gender, and study day of 
    collection.
        (c)(1) Statistical evaluation for all measurements, including: 
    Group means, group standard deviations, and measures of statistical 
    significance for all measurements for each feeding group at the 
    beginning of the study and at every point where measurements were made 
    throughout the study.
        (2) Calculation of the statistical power of the study at its 
    completion.
        (d) A report on attrition and on all occurrences of adverse events 
    during the study, which shall include:
        (1) Identification of the infant by subject number and feeding 
    group and a complete description of the adverse event, including 
    comparisons of the frequency and nature of occurrence in each feeding 
    group and information on the health of the infant during the course of 
    the study, including the occurrence and duration of any illness;
        (2) A clinical assessment, by a health care provider, of the 
    infant's health during each suspected adverse event;
        (3) A complete listing of all infants who did not complete the 
    study, including the infant's subject number and the reason that each 
    infant left the study.
        (e) The results of the Protein Efficiency Ratio, in accordance with 
    Sec. 106.97(b).
        (f) A statement certifying that the manufacturer has collected and 
    considered all information and data concerning the ability of the 
    infant formula to meet the quality factor requirements, and that the 
    manufacturer is not aware of any information or data that would show 
    that the formula does not meet the quality factors requirements.
    
    
    Sec. 106.130  Verification submission.
    
        (a) Manufacturers shall, after the first production and before the 
    introduction into interstate commerce of the new infant formula, verify 
    in a written submission to FDA at the address given in Sec. 106.110(a), 
    that the infant formula complies with the requirements of the Federal 
    Food, Drug, and Cosmetic Act (the act) and is not adulterated. An 
    original and two copies of this verification shall be submitted.
        (b) The verification submission shall include the following 
    information:
        (1) The name of the new infant formula; the filing date for the new 
    infant formula submission, in accordance with Sec. 106.120, for the 
    subject formula; and the identification number assigned by the agency 
    to the new infant formula submission;
        (2) A statement that the infant formula to be introduced into 
    interstate commerce is the same as the infant formula that was the 
    subject of the new infant formula notification and for which the 
    manufacturer provided assurances in accordance with the requirements of 
    Sec. 106.120;
        (3) A summary of test results of the level of each nutrient 
    required by Sec. 107.100 of this chapter and any nutrient added by the 
    manufacturer in the formula, presented in units per 100 kilocalories at 
    the final-product-stage.
        (4) A certification that the manufacturer has established current 
    good manufacturing practices including quality control procedures and 
    in-process controls, including testing required by current good 
    manufacturing practice, designed to prevent adulteration of this 
    formula in accordance with subparts B and C of this part.
        (c) The submission will not constitute written verification under 
    section 412(d)(2) of the act when any data prescribed in paragraph (b) 
    of this section are lacking or are not set forth so as to be readily 
    understood. In such circumstances the agency will notify the submitter 
    that the notice is not adequate.
    
    
    Sec. 106.140  Submission concerning a change in infant formula that may 
    adulterate the product.
    
        (a) When a manufacturer makes a change in the formulation or 
    processing of the formula that may affect whether the formula is 
    adulterated under section 412(a) of the Federal Food, Drug, and 
    Cosmetic Act (the act), it shall, before the first processing of such 
    formula, make a submission to the Food and Drug Administration at the 
    address given in Sec. 106.110(a). An original and two copies shall be 
    submitted.
        (b) The submission shall include:
        (1) The name and physical form of the infant formula (i.e., powder, 
    ready-to-feed, or concentrate);
        (2) An explanation of why the change in formulation or processing 
    may affect whether the formula is adulterated; and
        (3) A submission that complies with Sec. 106.120(b)(3), (b)(4), 
    (b)(5), and (b)(6). When appropriate, a statement to the effect that 
    the information required by Sec. 106.120(b)(3), (b)(4), (b)(5), or 
    (b)(6) has been provided to the agency previously and has not been 
    affected by the changes that is the subject of this submission, 
    together with the identification number assigned by the agency to the 
    relevant infant formula submission, may be provided in lieu of such 
    submission.
        (c) The submission will not constitute notice under section 412 of 
    the act unless it complies fully with paragraph (b) of this section, 
    and the information that it contains is set forth in a manner that is 
    readily understandable. The agency will notify the submitter if the 
    notice is not adequate because it does not meet the requirements of 
    section 412(d)(3) of the act.
    
    
    Sec. 106.150  Notification of an adulterated or misbranded infant 
    formula.
    
        (a) A manufacturer shall promptly notify FDA in accordance with 
    paragraph (b) of this section, when the manufacturer has knowledge 
    (that is, the actual knowledge that the manufacturer had, or the 
    knowledge which a reasonable person would have had under like 
    circumstances or which would have been obtained upon the exercise of 
    due care) that reasonably supports the conclusion that an infant 
    formula that has been processed by the manufacturer and that has left 
    an establishment subject to the control of the manufacturer:
        (1) May not provide the nutrients required by section 412(i) of the 
    act or by regulations issued under section 412(i)(2); or
    
    [[Page 36219]]
    
        (2) May be otherwise adulterated or misbranded.
        (b) The notification made according to paragraph (a) of this 
    section shall be made by telephone, to the Director of the appropriate 
    Food and Drug Administration district office. After normal business 
    hours (8 a.m. to 4:30 p.m.), FDA's emergency number, 202-857-8400, 
    shall be used. The manufacturer shall send written confirmation of the 
    notification to the Food and Drug Administration, Center for Food 
    Safety and Applied Nutrition, Office of Special Nutritionals, Division 
    of Programs and Policy Enforcement (HFS-455), Infant Formula 
    Coordinator, 200 C St. SW., Washington, DC 20204, and to the 
    appropriate Food and Drug Administration district office specified in 
    Sec. 5.115 of this chapter.
    
    PART 107--INFANT FORMULA
    
        7. The authority citation for 21 CFR part 107 continues to read as 
    follows:
    
        Authority: Secs. 201, 403, 412, 701 of the Federal Food, Drug, 
    and Cosmetic Act (21 U.S.C. 321, 343, 350a, 371).
    
        8. Section 107.1 is added to subpart A to read as follows:
    
    
    Sec. 107.1  Status and applicability of the regulations in part 107.
    
        (a) The criteria set forth in subpart B of this part describes the 
    labeling requirements applicable to infant formula under section 403 of 
    the Federal Food, Drug, and Cosmetic Act (the act). Failure to comply 
    with any regulation in subpart B of this part will render an infant 
    formula misbranded under that section of the act.
        (b) The criteria set forth in subpart C of this part describes the 
    terms and conditions for the exemption of an infant formula from the 
    requirements of section 412(a), (b), and (c) of the act. Failure to 
    comply with any regulations in subpart C of this part will result in 
    the withdrawal of the exemption given under section 412(h)(1) of the 
    act.
        (c) Subpart D of this part sets forth the nutrient requirements for 
    infant formula under section 412(i) of the act. Failure to comply with 
    any regulation in subpart D of this part will render an infant formula 
    adulterated under section 412(a)(1) of the act.
        9. Section 107.10 is amended by revising the introductory text of 
    paragraph (a)(2) to read as follows:
    
    
    Sec. 107.10   Nutrient information.
    
        (a) * * *
        (2) A statement of the amount, supplied by 100 kilocalories, of 
    each of the following nutrients and of any nutrient added by the 
    manufacturer:
    * * * * *
        10. Section 107.240 is revised to read as follows:
    
    
    Sec. 107.240   Notification requirements.
    
        (a) Telephone report. When a determination is made that an infant 
    formula is to be recalled, the recalling firm shall telephone within 24 
    hours the appropriate Food and Drug Administration district office 
    listed in Sec. 5.115 of this chapter and shall provide relevant 
    information about the infant formula that is to be recalled.
        (b) Initial written report. Within 14 days after the recall has 
    begun, the recalling firm shall provide a written report to the 
    appropriate Food and Drug Administration district office. The report 
    shall contain relevant information, including the following cumulative 
    information concerning the infant formula that is being recalled:
        (1) Number of consignees notified of the recall and date and method 
    of notification, including recalls required by Sec. 107.200, 
    information about the notice provided for retail display and the 
    request for its display.
        (2) Number of consignees responding to the recall communication and 
    quantity of recalled infant formula on hand at the time it was 
    received.
        (3) Quantity of recalled infant formula returned or corrected by 
    each consignee contacted and the quantity of recalled infant formula 
    accounted for.
        (4) Number and results of effectiveness checks that were made.
        (5) Estimated timeframes for completion of the recall.
        (c) Status reports. The recalling firm shall submit to the 
    appropriate Food and Drug Administration district office a written 
    status report on the recall at least every 14 days until the recall is 
    terminated. The status report shall describe the steps taken by the 
    recalling firm to carry out the recall since the last report and the 
    results of these steps.
        11. Section 107.250 is amended by revising the introductory text to 
    read as follows:
    
    
    Sec. 107.250   Termination of an infant formula recall.
    
        The recalling firm may submit a recommendation for termination of 
    the recall to the appropriate Food and Drug Administration district 
    office listed in Sec. 5.115 of this chapter for transmittal to the 
    Division of Enforcement (HFS-605), Office of Field Programs, Center for 
    Food Safety and Applied Nutrition, for action. Any such recommendation 
    shall contain information supporting a conclusion that the recall 
    strategy has been effective. The agency will respond within 15 days of 
    receipt by the Division of Enforcement (HFS-605), Office of Field 
    Programs, Center for Food Safety and Applied Nutrition, of the request 
    for termination. The recalling firm shall continue to implement the 
    recall strategy until it receives final written notification from the 
    agency that the recall has been terminated. The agency will send such 
    notification, unless it has information, from FDA's own audits or from 
    other sources demonstrating the recall has not been effective. The 
    agency may conclude that a recall has not been effective if:
    
    * * * * *
        Dated: April 19, 1996.
    David A. Kessler,
    Commissioner of Food and Drugs.
    Donna E. Shalala,
    Secretary of Health and Human Services.
    [FR Doc. 96-17058 Filed 7-8-96; 8:45 am]
    BILLING CODE 4160-01-P
    
    
    

Document Information

Published:
07/09/1996
Department:
Food and Drug Administration
Entry Type:
Proposed Rule
Action:
Proposed rule.
Document Number:
96-17058
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.
Pages:
36154-36219 (66 pages)
Docket Numbers:
Docket No. 95N-0309
RINs:
0910-AA04: Infant Formula: Requirements Pertaining to Good Manufacturing Practice, Quality Control Procedures, Quality Factors, Notification Requirements, and Records and Reports
RIN Links:
https://www.federalregister.gov/regulations/0910-AA04/infant-formula-requirements-pertaining-to-good-manufacturing-practice-quality-control-procedures-qua
PDF File:
96-17058.pdf
CFR: (149)
21 CFR 107.10(a)(2)
21 CFR 106.35(a)(1)
21 CFR 106.50(a)(3)
21 CFR 106.20(a)
21 CFR 106.25(a)
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