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

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Information about this document as published in the Federal Register.

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AGENCY:

Food and Drug Administration, HHS.

ACTION:

Interim final rule; request for comments.

SUMMARY:

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

DATES:

Effective date: This interim final rule is effective July 10, 2014.

Comment date: Interested persons may submit either electronic or written comments on this interim final rule by March 27, 2014.

Paperwork Reduction Act date: Submit comments on information collection issues under the Paperwork Reduction Act of 1995 by March 12, 2014, (see the “Paperwork Reduction Act of 1995” section of this document). The incorporation by reference of certain publications listed in the rule is approved by the Director of the Federal Register as of July 10, 2014.

ADDRESSES:

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

Electronic Submissions

Submit electronic comments in the following way:

Submit written submissions in the following ways:

  • Mail/Hand delivery/Courier (for paper or CD-ROM submissions): Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

Instructions: All submissions received must include the Agency name and Docket No. FDA-1995-N-0036 (formerly 95N-0309) and RIN 0910-AF27 for this rulemaking. All comments received may be posted without change to http://www.regulations.gov, including any personal information provided. For additional information on submitting comments, see the “Comments” heading of the SUPPLEMENTARY INFORMATION section of this document.

Docket: For access to the docket to read background documents or comments received, go to http://www.regulations.gov and insert the docket number(s), found in brackets in the heading of this document, into the “Search” box and follow the prompts and/or go to the Division of Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

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FOR FURTHER INFORMATION CONTACT:

Benson M. Silverman, Office of Nutrition, Labeling, and Dietary Supplements (HFS-850), Center for Food Safety and Applied Nutrition, Food and Drug Administration, 5100 Paint Branch Parkway, College Park, MD 20740, 240-402-1450.

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SUPPLEMENTARY INFORMATION:

Executive Summary

Purpose of the Interim Final Rule

FDA is issuing this interim final rule to fulfill the statutory mandate set forth in section 412 of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 350a) for the Secretary of Health and Human Services (the Secretary), and by delegation FDA, to establish requirements for quality factors for infant formulas and good manufacturing practices, including quality control procedures. The requirements in this interim final rule will prevent the manufacture of adulterated infant formula and ensure that the nutrients in the infant formula are present in a form that is bioavailable and safe. Congress passed the Infant Formula Act of 1980 (the Infant Formula Act) (Pub. L. 96-359), which amended the FD&C Act to include section 412. In 1986, Congress, as part of the Anti-Drug Abuse Act of 1986 (Pub. L. 99-570) (the 1986 amendments), amended section 412 of the FD&C Act to address concerns related to the sufficiency of quality control testing, current good manufacturing practice (CGMP), recordkeeping, and recall requirements for infant formula. The requirements in this interim final rule improve protection of infants consuming infant formula products by establishing greater regulatory control over the formulation and production of infant formula.

We previously implemented certain of the provisions in the Infant Formula Act and 1986 amendments. This interim final rule implements the remaining provisions of the 1986 amendments, including provisions for CGMPs and quality factor requirements.

Summary of Legal Authority

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

Sections 701(a) and 402 of the FD&C Act (21 U.S.C. 371(a) and 342) provide additional authority to establish requirements to prevent adulteration.

Summary of the Major Provisions of the Interim Final Rule

Current Good Manufacturing Practice

This interim final rule issues comprehensive CGMP requirements for Start Printed Page 7935the manufacture of infant formula by establishing a framework in which specific process and control decisions are assigned to the formula manufacturer; i.e., it specifies the result to be achieved and does not prescriptively mandate how the manufacturer must achieve the result.

Under § 106.6, the interim final rule requires manufacturers to implement a system of production and in-process controls that covers all stages of processing. The system must be set out in a written plan or set of procedures that includes establishment of specifications and corrective action plans, documented reviews and material disposition decisions for articles not meeting a specification, and the quarantine of any article that fails to meet a specification pending completion of a documented review and material disposition decision.

The interim final rule also includes specific controls to prevent adulteration by workers (§ 106.10), facilities (§ 106.20), equipment or utensils (§ 106.30), automatic (mechanical or electronic) equipment (§ 106.35), and ingredients, containers, and closures (§ 106.40). Under § 106.50, manufacturers are required to prepare and follow a written master manufacturing order that establishes controls and procedures for the production of an infant formula. In addition, controls are specified to prevent adulteration during packaging and labeling (§ 106.60) and on the release of finished infant formula (§ 106.70). The interim final rule also requires that infant formula be coded with a sequential number that permits identification of the product including the location where it was packed and tracing of all stages of manufacture (§ 106.80).

Controls are also required to prevent adulteration of infant formula from microorganisms (§ 106.55). Because powdered infant formulas are not sterile products, the interim final rule requires testing of representative samples of powdered infant formula at the final product stage, before distribution, and establishes values for two microorganisms, Cronobacter spp. and Salmonella spp.

Quality Control Procedures

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

Audits

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

Quality Factors

The interim final rule identifies two infant formula quality factors, normal physical growth and sufficient biological quality of the formula's protein component, and establishes requirements for the two quality factors in § 106.96. Under the interim final rule, quality factors are defined as those factors necessary to demonstrate the bioavailability and safety of a formula, including the bioavailability of individual nutrients, to ensure healthy growth (§ 106.3).

To establish that an infant formula supports normal physical growth, the interim final rule requires under § 106.96(b) that a manufacturer conduct a growth monitoring study (GMS) of the formula (unless the formula qualifies for an exemption). To establish biological protein quality, the interim final rule requires under § 106.96(f) that a manufacturer conduct a Protein Efficiency Ratio (PER) rat bioassay.

The interim final rule's quality factor requirements apply to all infant formulas. Because, prior to this interim final rule, there were no established quality factors and no quality factor requirements, a formula manufacturer was not required to demonstrate to FDA that the formula supports normal physical growth or that its protein was of sufficient biological quality. Therefore, we provide a more flexible means for a manufacturer of a formula that is “not new” (i.e., a currently marketed or previously marketed formula) to demonstrate satisfaction of the two quality factors (§ 106.96(i)). The more flexible standards will allow manufacturers, as appropriate, to rely on existing scientific data and information and to voluntarily submit quality factor data and information on a specific infant formula formulation to FDA for evaluation.

Records and Reports

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

Registration, Submission, and Notification Requirements

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

Costs and Benefits

The estimated cost of the interim final rule is $7.29 million in the first year and $4.06 million in subsequent years. The estimated benefit to public health from this interim final rule is $10.00 million annually, resulting in total net benefits of $2.71 million in the first year and $5.94 million in subsequent years.Start Printed Page 7936

Benefit and Cost Overview

[In millions]

BenefitsCostsNet Benefits
Total First Year$10.00$7.29$2.71
Annual Total After the First Year$10.00$4.06$5.94

Table of Contents

I. Background

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

III. Legal Authority

IV. General Comments and Subpart A—General Provisions

A. General Comments

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

C. Definitions (Proposed § 106.3)

V. Subpart B—Current Good Manufacturing Practice

A. General Comments

B. Current Good Manufacturing Practices (Proposed § 106.5)

C. Production and In-Process Control System (Proposed § 106.6)

D. Controls to Prevent Adulteration by Workers (Proposed § 106.10)

E. Controls to Prevent Adulteration Caused by Facilities (Proposed § 106.20)

F. Controls to Prevent Adulteration Caused by Equipment or Utensils (Proposed § 106.30)

G. Controls to Prevent Adulteration Due to Automatic (Mechanical or Electronic) Equipment (Proposed § 106.35)

H. Controls to Prevent Adulteration Caused by Ingredients, Containers, and Closures (Proposed § 106.40)

I. Controls to Prevent Adulteration During Manufacturing (Proposed § 106.50)

J. Controls to Prevent Adulteration From Microorganisms (Proposed § 106.55)

K. Controls to Prevent Adulteration During Packaging and Labeling (Proposed § 106.60)

L. Controls on the Release of Finished Infant Formula (Proposed § 106.70)

M. Traceability (Proposed § 106.80)

N. Audits of Current Good Manufacturing Practice (Proposed § 106.90)

VI. Subpart C—Quality Control Procedures

A. General Quality Control (Proposed § 106.91)

B. Audits of Quality Control Procedures (Proposed § 106.92)

VII. Subpart D—Conduct of Audits

VIII. Subpart E—Quality Factors

A. Quality Factors: Legal Authority

B. Quality Factors for Infant Formulas

C. Quality Factor: Normal Physical Growth

D. Exemptions From Quality Factor Requirements for Normal Physical Growth

E. Quality Factor: Protein Quality

F. Exemption From the Quality Factor of Protein Quality Sufficiency

G. Miscellaneous Comments on the Quality Factor for Sufficient Biological Quality of Protein

H. Application of Quality Factors to Currently Marketed and Previously Marketed Formulas

I. Records Demonstrating Compliance with the Quality Factor Requirements for Infant Formulas That Are Not Eligible Infant Formulas

J. Establishment of Other Quality Factors

K. Miscellaneous Comments on Quality Factors

IX. Subpart F—Records and Reports

A. General Comments on Records (Proposed § 106.100)

B. Production Aggregate Production and Control Records (Proposed § 106.100(e))

C. Records of CGMP (Proposed § 106.100(f))

D. Records on Infant Formula for Export Only (Proposed § 106.100(g))

E. Means of Recordkeeping (§ 106.100(m))

F. Records of Quality Factors (§ 106.100(p) and (q))

G. Adulteration as a Consequence of the Failure to Keep Records (§ 106.100(r))

X. Subpart G—Registration, Submission, and Notification Requirements

A. General Comments

B. New Infant Formula Registration (Proposed § 106.110)

C. New Infant Formula Notifications (Proposed § 106.120)

D. Quality Factor Submissions for Infant Formula (Proposed § 106.121)

E. Verification Submissions (Proposed § 106.130)

F. Submission Concerning a Change in Infant Formula That May Adulterate the Product (Proposed § 106.140)

G. Notification of an Adulterated or Misbranded Infant Formula (Proposed § 106.150)

H. Incorporation by Reference

XI. Conforming Amendments to Part 107

XII. Environmental Impact

XIII. Federalism

XIV. Regulatory Impact Analysis for Interim Final Rule

XV. Paperwork Reduction Act of 1995

XVI. Comments

XVII. References

I. Background

The Infant Formula Act amended the FD&C Act to include section 412. This law was intended to improve protection of infants consuming infant formula products by establishing greater regulatory control over the formulation and production of infant formula. In 1982, FDA adopted infant formula recall procedures in subpart D of part 107 (21 CFR part 107, subpart D) of its regulations (47 FR 18832, April 30, 1982), and infant formula quality control procedures in subpart B of part 106 (21 CFR part 106, subpart B) (47 FR 17016, April 20, 1982). In 1985, FDA further implemented the Infant Formula Act by establishing subparts B, C, and D in part 107 regarding the labeling of infant formula, exempt infant formulas, and nutrient requirements for infant formula, respectively (50 FR 1833, January 14, 1985; 50 FR 48183, November 22, 1985; and 50 FR 45106, October 30, 1985).

In 1986, Congress, as part of the Anti-Drug Abuse Act of 1986 (Pub. L. 99-570) (the 1986 amendments), amended section 412 of the FD&C Act to address concerns that had been expressed by Congress and consumers about the Infant Formula Act and its implementation related to the sufficiency of quality control testing, CGMP, recordkeeping, and recall requirements. The 1986 amendments: (1) Provide that an infant formula is deemed to be adulterated if it fails to provide certain required nutrients, fails to meet quality factor requirements established by the Secretary (and, by delegation, FDA), or if it is not processed in compliance with the CGMP and quality control procedures established by the Secretary; (2) require the Secretary to issue regulations establishing requirements for quality factors and CGMP, including quality control procedures; (3) require infant formula manufacturers to audit their operations regularly to ensure that those operations comply with CGMP and quality control procedure regulations; (4) require a manufacturer to make a submission to FDA when there is a major change in an infant formula or a change that may affect whether the formula is adulterated; (5) specify the required nutrient quality control testing for each batch of infant formula; (6) modify the infant formula recall requirements; and (7) authorize the Secretary to establish requirements for records retention, including records necessary to demonstrate compliance with CGMP and quality control procedures. In 1989, the Agency implemented the provisions on recalls (sections 412(f) and (g) of the FD&C Act) by establishing subpart E in part 107 (54 FR 4006, January 27, 1989). In 1991, the Agency implemented the provisions on records and record retention requirements by revising § 106.100 (56 FR 66566, December 24, 1991).Start Printed Page 7937

On July 9, 1996, FDA published a notice of proposed rulemaking (the 1996 proposal) to implement the remaining provisions of the 1986 amendments (61 FR 36154). Specifically, FDA proposed to amend the infant formula regulations in parts 106 and 107 to: (1) Establish good manufacturing practices, including microbiological testing, to minimize production of adulterated infant formula; (2) revise the quality control procedures in part 106 to ensure that an infant formula contains the level of nutrients necessary to support infant growth and development, both when the formula enters commerce and throughout its shelf life; (3) specify the audit procedures necessary to ensure that operations comply with CGMP and quality control procedure regulations; (4) establish requirements for quality factors to ensure that the required nutrients will be in a bioavailable form; (5) establish batch and good manufacturing recordkeeping requirements; (6) specify the submission requirements for registration and notification to the Agency before the introduction of an infant formula into interstate commerce; and (7) update part 107 to reflect the 1986 amendments and the November 1992 reorganization of the Center for Food Safety and Applied Nutrition (CFSAN).

FDA initially opened the comment period for the 1996 proposal for 90 days and subsequently extended it upon request for another 60 days (61 FR 49714, September 23, 1996).

Following publication of the proposed rule in September 1996, FDA convened three meetings of FDA's Food Advisory Committee (FAC) or subcommittees of the FAC to address issues related to the regulation of infant formula. On April 4 and 5, 2002, the FAC met to discuss general scientific principles related to quality factors for infant formula. The FAC also discussed the scientific issues related to the generalization of findings from a clinical study using preterm infant formula consumed by preterm infants to a different formula in a different population (a term infant formula intended for use by term infants). At a meeting on November 18 and 19, 2002, the Infant Formula Subcommittee (IFS) of the FAC discussed the scientific issues and principles involved in assessing and evaluating whether a “new” infant formula supports normal physical growth in infants when consumed as a sole source of nutrition. Finally, the Contaminants and Natural Toxicants Subcommittee (CNTS) of the FAC met on March 18 and 19, 2003, and discussed the scientific issues and principles involved in assessing and evaluating Enterobacter sakazakii contamination in powdered infant formula, risk reduction strategies based on available data, and research questions and priorities. (The organism E. sakazakii was reclassified in 2008 to a new genus, Cronobacter spp.) (Ref. 1).

In the Federal Register of April 28, 2003 (68 FR 22341) (the 2003 reopening), FDA reopened the comment period for the proposed rule to update comments generally and to receive new information based on the three FAC meetings held in 2002 and 2003. FDA specifically requested comment on the following issues related to these meetings: (1) Whether there is a need for a microbiological requirement for E. sakazakii, and if so, what requirement the Agency should consider to ensure safety and whether a stricter standard was needed for powdered infant formula to be consumed by premature and newborn infants; (2) what changes, if any, in the proposed microbiological requirements would be needed to ensure the safety of powdered infant formula to which microorganisms are intentionally added; (3) which provisions in the proposed rule would require changes to manufacturers' current activities, and a request for information on the types of control systems used to separate materials and types of air filtration systems and associated costs of making changes in each case; (4) current quality control activities by manufacturers related to validation of automated systems and FDA's proposed validation requirements; (5) current frequency and conditions of calibration of instruments and controls by manufacturers and the adequacy of such procedures; (6) quality factor issues, including sufficiency of protein quality and normal physical growth as quality factors, and when clinical growth studies are required for a new or reformulated infant formula; which growth reference should be the standard of comparison for infant growth; and duration of study and enrollment age; and (7) removal of the reference to Institutional Review Board (IRB) review and informed consent from the proposed rule as the requirements are now codified in 21 CFR parts 50 and 56, and removal of the other clinical study protocol provisions from the proposed rule for consideration in a future guidance document.

Interested persons were originally given until June 27, 2003, to comment on these issues and the 1996 proposal. However, in response to a request, the comment period was extended to August 26, 2003 (68 FR 38247, June 27, 2003).

Based on three reports published after the 2003 reopening, FDA again reopened the comment period on August 1, 2006 (71 FR 43392) (the 2006 reopening), for 45 days to accept comment on a limited set of issues related to these reports. Two reports address microbiological standards for E. sakazakii and other microbes; the third report addresses, in part, clinical studies as a means to assess the growth and development of infants. The reports addressing microbiological standards are products of a series of expert consultations related to the efforts of the Codex Committee on Food Hygiene (CCFH) of the Codex Alimentarius Commission to update the 1979 Recommended International Code of Hygienic Practice for Foods for Infants and Children (the 1979 Code). These reports (“Enterobacter sakazakii and Salmonella in Powdered Infant Formula: Meeting Report” (the 2004 FAO/WHO Report) (Ref. 2) and “E. sakazakii and Salmonella spp . in Powdered Infant Formula” (the 2006 FAO/WHO Report) (Ref. 3)) were issued by the Food and Agriculture Organization of the United Nations, World Health Organization (WHO), in 2004 and 2006 and provide scientific advice concerning E. sakazakii, Salmonella spp, and other microorganisms in powdered infant formula. The third report is from the Committee on the Evaluation of the Addition of Ingredients New to Infant Formula, which the Institute of Medicine (IOM) of the National Academy of Sciences (NAS) convened at the request of FDA and Health Canada, FDA's Canadian counterpart. The purpose of the report was, in part, to evaluate the performance of a new infant formula. The committee made several recommendations regarding growth studies, including the recommendation that “Growth studies should include precise and reliable measurements of weight and length velocity and head circumference. Duration of measurements should cover at least the period when infant formula remains the sole source of nutrients in the infant diet.” (Ref. 4, p. 108).

In reopening the comment period in August 2006, FDA requested comment on the following issues:

  • Whether FDA should require a microbiological standard for E. sakazakii for powdered infant formula of negative in 30 x 10 gram (g) samples;
  • Whether FDA should require microbiological standards for aerobic plate count, coliforms, fecal coliforms, Listeria monocytogenes, Bacillus cereus, and Staphylococcus aureus; Start Printed Page 7938
  • Whether FDA should require measurements of healthy growth beyond the two proposed quality factors of normal physical growth (as measured by body weight, recumbent length, head circumference, and average daily weight increment) and protein quality;
  • Whether FDA should require a measure for body composition as an indicator of normal physical growth, and if so, what measure; and
  • Whether FDA should require that the duration for a clinical study, if required, be no less than 15 weeks, and commence when infants are no older than 2 weeks of age.

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

The highlights of this interim final rule are as follows:

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

III. Legal Authority

FDA's authority to issue regulations that establish requirements for quality factors, current good manufacturing practices, quality control procedures, registration, submission, notification, and records and reports is derived from section 412 of the FD&C Act. FDA also relies on other sections of the FD&C Act, including sections 701(a) and 402 (21 U.S.C. 371(a) and 342). The regulations in this interim final rule are consistent with FDA's explicit statutory mission, which is, in part, to protect the public health by ensuring that foods (including infant formula) are safe, wholesome, sanitary, and properly labeled (section 903(b)(2)(A) of the FD&C Act (21 U.S.C. 393(b)(2)(A))). The regulations are also consistent with the overall purpose of section 412 of the FD&C Act (see Pub. L. 96-359, 94 Stat. 1190, 1190 (1980) (stating the purpose of the Infant Formula Act is to provide for the “safety and nutrition” of infant formula)).

FDA's authority to establish requirements for quality factors is explicit in section 412(b)(1) of the FD&C Act, which states that the “Secretary shall by regulation establish requirements for quality factors.” Infant formulas that are not in compliance with the quality factor requirements are adulterated under section 412(a)(2) of the FD&C Act. In section IV of this interim final rule FDA defines “quality factors,” and in section VIII FDA establishes specific quality factor requirements.

Similarly, FDA's authority to establish current good manufacturing practices and quality control procedure requirements is explicit in section 412(b)(2) of the FD&C Act. Section 412(b)(2) of the FD&C Act specifies certain overarching requirements that must be included as part of CGMP and quality control procedure requirements. Specifically, the section states that the “Secretary shall by regulation establish good manufacturing practices for infant formulas, including quality control procedures that the Secretary determines are necessary to assure that an infant formula . . . is manufactured in a manner designed to prevent adulteration of the infant formula.” Infant formulas that are not in compliance with the CGMP and quality control procedure requirements are adulterated under section 412(a)(3) of the FD&C Act. In addition, the failure to comply with certain CGMP requirements will result in the infant formula being adulterated under sections 402(a)(1), (a)(2), (a)(3), or (a)(4) of the FD&C Act. Although Congress has identified specific provisions that must be included as CGMP and quality control procedure requirements (see section 412(b)(2) and (b)(3) of the FD&C Act), it did not prescribe all such requirements. Rather, Congress left a gap for FDA to prescribe, by regulation, such other practices and procedures necessary to ensure the nutrient content of infant formula and prevent adulteration under section 412(b)(2) of the FD&C Act.

In addition, FDA has explicit authority under sections 412(c), (d), and (e) of the FD&C Act to establish registration, submission, and notification requirements, respectively. Section 412(c)(1)(A) of the FD&C Act states that no person may introduce a new infant formula into interstate commerce, unless the person has “registered with the Secretary the name of such person, the place of business of such person, and all establishments at which such person intends to manufacturer such infant formula.” The registration requirements in the interim final rule set forth the information that must be included in a new infant formula registration sent to FDA.

Further, the interim final rule sets forth the information that must be included in a new infant formula submission to FDA. Section 412(d) of the FD&C Act requires that a manufacturer make an infant formula submission and describes the type of information that must be included in such submission. For example, section 412(d)(1)(A) of the FD&C Act requires that the submission include the quantitative formulation of the formula. Additionally, section 412(d)(1)(C) of the FD&C Act requires, in part, assurances that the infant formula will not be marketed unless it meets the requirements of section 412(b)(1) of the FD&C Act (quality factor requirements). Section 412(d)(1)(D) of the FD&C Act requires assurances that the formula will not be marketed unless the processing of the formula complies with section 412(b)(2) of the FD&C Act (the CGMP and quality control procedure requirements). The interim final rule prescribes requirements for the assurances required by these sections of the FD&C Act.

The notification requirements in the interim final rule describe when a notification must be provided to FDA, as required by section 412(e) of the FD&C Act. Section 412(e) of the FD&C Act sets forth the circumstances in which a manufacturer must notify FDA that an infant formula processed by the manufacturer has left an establishment under the manufacturer's control and may be adulterated or misbranded.

FDA also has authority to establish requirements for records under section 412(b)(4)(A) of the FD&C Act. This interim final rule includes record requirements for CGMP and quality control procedures and for the conduct of audits. For example, under section 412(b)(4)(A)(i) of the FD&C Act, FDA has authority to establish recordkeeping requirements necessary to demonstrate compliance with CGMP and quality control procedure requirements, including records containing the results of all testing designed to prevent the adulteration of infant formula. Thus, FDA is establishing requirements in this interim final rule for manufacturers to make and retain records that include complete information relating to the production and control of each production aggregate (for discussion of this term see section IV.C.1 of this document) of infant formula to ensure Start Printed Page 7939compliance with the CGMP and quality control procedure requirements related to the production aggregate. Specifically, § 106.100(e) requires manufacturers to make and retain records that include complete information relating to the production and control of the production aggregate. Information about the processing of the production aggregate is important to the manufacturer, which must ensure that it is producing the formula it intends to produce under the master manufacturing order. In addition, if a problem arises from a particular production aggregate of formula, such records will assist the manufacturer and FDA in identifying the source of the problem and what action may be necessary to correct it. For example, § 106.100(e)(3) requires documentation of the monitoring at any point, step, or stage in the production process where control is deemed necessary to prevent adulteration.

Moreover, FDA has authority to establish record requirements under other provisions of section 412 of the FD&C Act, as well as section 701(a) of the FD&C Act. For example, as is discussed in greater detail in section VIII, it is necessary for manufacturers to create records pertaining to a growth monitoring study in order to determine whether their infant formula meets the quality factor requirement of normal physical growth established under section 412(b)(1) of the FD&C Act. It is also necessary for the enforcement of section 412(a)(2) of the FD&C Act, with respect to meeting quality factor requirements, for FDA to require records pertaining to a growth monitoring study, when such a study is required. Without such records, FDA cannot determine whether the quality factor requirements have been met. Additionally, FDA has authority under section 701(a) of the FD&C Act, when coupled with the specific authorities granted to FDA under section 412 of the FD&C Act, to establish record requirements that are necessary for the efficient enforcement of the FD&C Act.

IV. General Comments and Subpart A—General Provisions

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

A. General Comments

The general comments discussed in this section are those that addressed the rule in its entirety.

(Comment 1) One comment stated that many provisions of the infant formula proposal are “overly redundant” with other FDA laws and regulations, such as the food CGMP and food additive regulations. These redundancies include personnel requirements and the permitted use of food ingredients and food contact materials. The comment claims that these redundancies do not provide the public with greater protection, but serve only to create unnecessary confusion in those plants manufacturing both infant formulas and similar products not intended for use by infants. The comment noted that FDA's stated intent in promulgating the food CGMP regulations was to have those regulations function as “umbrella” regulations, to which FDA would add additional regulations targeted at specific industries.

(Response) As stated in the proposed rule, the CGMP requirements for infant formula are based, in part, on FDA's existing regulations concerning CGMP for foods (61 FR 36154 at 36157). Infant formulas are food, and thus, the Agency would expect that certain CGMP requirements for infant formula would parallel the CGMP provisions in part 110 (21 CFR part 110).

FDA disagrees, however, that many provisions of the infant formula rule are overly redundant with other FDA laws and regulations. The food CGMP regulations (part 110) predate the 1986 amendments. Thus, Congress was aware of these regulations at the time of the 1986 amendments when it established an explicit mandate for infant formula CGMP. By mandating that FDA establish good manufacturing practices, including quality control procedures, Congress recognized that requirements in addition to the food CGMP were necessary for infant formula. The CGMP regulations established by this interim final rule implement Congress' express mandate. As noted, section 412(b)(2)(A) of the FD&C Act specifically mandates that FDA establish CGMP for infant formula: “The Secretary shall, by regulation, establish good manufacturing practices for infant formulas, including quality control procedures that the Secretary determines are necessary to assure that an infant formula provides nutrients in accordance with [section 412] and is manufactured in a manner designed to prevent adulteration of the infant formula.” In addition, section 412(a)(3) of the FD&C Act provides that an infant formula is deemed to be adulterated if “the processing of such infant formula is not in compliance with the good manufacturing practices and the quality control procedures prescribed by the Secretary” under section 412(b)(2). This provision of section 412 of the FD&C Act underscores the Congressional determination that product-specific CGMP requirements are necessary for infant formula.

Moreover, the purpose of section 412 of the FD&C Act is to ensure product safety for the vulnerable population that consumes infant formula. To this end, FDA may include CGMP requirements in this interim final rule that are the same or similar to those found in 21 CFR part 110 for foods in general. FDA has included in this interim final rule the part 110 requirements that are common to most or all infant formula manufacturing. The Agency recognizes that there may be aspects of infant formula manufacturing operations for which certain provisions in part 110 apply, but that FDA did not determine to be common to most infant formula manufacturing operations. Infant formula manufacturers are responsible for understanding and following all of the regulations that govern their products even if the regulations are not in parts 106 and 107.[1] Thus, a manufacturer is subject to the regulations in part 110 in addition to the regulations in part 106. To the extent that the regulations conflict, the infant formula manufacturer must comply with part 106.

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In addition, FDA may include CGMP requirements in this interim final rule concerning the use of lawful ingredients and food packaging materials. Section 106.40(a) states that only substances that are safe and suitable under the applicable food safety provisions of the FD&C Act may be used in infant formulas. Section 106.40(b) requires that packaging material that comes in contact with infant formula be composed of substances that are safe and lawful for such use. FDA disagrees such requirements are “overly redundant.” The statute contains express authority to establish by regulation CGMP requirements for infant formula to prevent adulteration, in general (see section 412(b)(2)(A) of the FD&C Act) and to prevent adulteration of each production aggregate of infant formula, specifically (see section 412(b)(2)(B)(iii) of the FD&C Act). The use of ingredients in the formula, and of substances in food packaging materials that would come into contact with the formula, that are safe and lawful is important to ensuring that each production aggregate of infant formula is not adulterated. Sections 106.40(a) and (b) help to ensure that appropriate manufacturing processes are in place such that only safe and lawful food ingredients and food packaging materials are used to manufacture infant formula, a food intended for consumption by a vulnerable population. These requirements are necessary to ensure the safety of all of the formula's ingredients and food packaging materials used in the manufacture of an infant formula to prevent adulteration of the infant formula. A failure to do so would result in the infant formula being deemed adulterated under section 412 of the FD&C Act.

For the reasons set forth previously in this document, the Agency is making no changes to the language set forth in the proposed rule in response to this comment.

(Comment 2) One comment stated that since the proposed rule was published, FDA's Center for Drug Evaluation and Research (CDER) announced a new initiative on August 21, 2002, “Pharmaceutical CGMP for the 21st Century: A Risk Based Approach” (Ref. 5) that involves significant examination and reevaluation of FDA's drug CGMP. The comment suggested that the infant formula CGMP may benefit from using this risk-based drug CGMP initiative as a model and that the infant formula industry partner with CFSAN in the same way that CDER and other FDA Centers are partnering with the industries they regulate.

(Response) In developing this interim final rule, FDA did consider the drug CGMPs and those for other FDA-regulated products. FDA has on many occasions held discussions with, solicited comments from, and partnered with the infant formula industry to work toward a risk-based philosophy that provides for process control that is scientifically validated, rather than on a system that is overly reliant on testing. In addition to the three FAC meetings described previously in this document, the Agency and the infant formula industry have worked collaboratively to provide input for the WHO expert consultation on testing for microorganisms of public health significance in powdered infant formula, and to provide input on the revision of the Codex hygienic practices for production of powdered infant formula. In addition, the Agency has provided opportunities for the public, including the infant formula industry, to communicate with FDA by reopening the comment period on the proposed rule on two occasions, and again by accepting comments upon publication of this interim final rule. Thus, this rulemaking has been a collaborative process that has resulted in a sound, risk-based approach to process control for infant formula manufacture.

An example of the Agency's risk-based approach is the resolution in the interim final rule of the requirements for microbiological testing. As discussed in more detail in section V, in the 1996 proposed rule, FDA proposed broad microbiological testing requirements for powdered formula. Upon further evaluation, the Agency determined that most of the pathogens originally proposed for testing have not been associated with infant formula. Instead, relying on the WHO risk assessment model set out in the 2006 FAO/WHO Report (Ref. 3), FDA determined that Cronobacter spp. (formerly classified as E sakazakii) and Salmonella spp. are the only two pathogens of concern for powdered infant formula. Thus, the interim final rule replaces the broad microbiological testing mandate in the proposal with more narrow, risk-based requirements.

(Comment 3) One comment asked FDA to acknowledge in the preamble to the final rule that under the FD&C Act and § 107.50(c) of the regulations, exempt infant formulas are not subject to the CGMP, quality control, and quality factor requirements of part 106. The comment identified some logistical issues associated with the application of quality factor requirements to exempt infant formulas. The comment also requested that FDA state in the preamble that during inspections of special infant formula manufacturing plants (referring to plants that manufacture exempt infant formula), the Agency will accept quality control activities other than those articulated in part 106 provided that the manufacturer documents those activities, demonstrates that the product meets the nutrient requirements of the FD&C Act, and manufactures the product in a manner designed to prevent adulteration. The comment stated that FDA should encourage manufacturers of exempt infant formula to comply voluntarily with part 106, where practical, because exempt formulas should be manufactured to a high standard of quality.

(Response) The regulations in § 107.50 pertaining to exempt infant formula were finalized in 1985 (50 FR 48183) prior to the 1986 amendments. As FDA explained in the 1996 proposal, the Agency intends to address, in a separate rulemaking, the exempt infant formula regulations and the effect of the 1986 amendments on exempt infant formulas (61 FR 36154 at 36201-36202). In the interim, FDA encourages exempt infant formula manufacturers to use the requirements in this interim final rule as guidance because infant formulas for use by infants with inborn errors of metabolism, low birth weight, or other unusual medical or dietary problems should conform to the same standards set forth in the requirements of this interim final rule applicable to formulas for healthy term infants, unless there is a medical, nutritional, scientific, or technological rationale for a deviation from such requirements. Elsewhere in this issue of the Federal Register, FDA is issuing a notice of availability for a draft guidance document that addresses the application of new part 106 to exempt infant formulas. Manufacturers are encouraged to consult with CFSAN prior to the submission of an exempt infant formula submission to the extent a manufacturer believes there is such a rationale for a deviation from the provisions of this interim final rule.

(Comment 4) One comment stated that its review of the authorities cited in support of the 1996 proposed requirements calls into question the existence of concrete bases for a number of the proposed “requirements” and thus, appears to reflect “administrative” expertise and thinking as opposed to practical hands-on experience that the industry possesses. Another comment emphasized that the real GMP expertise rests with the infant formula industry, and further argues that reliance by FDA on Agency administrative expertise in response to comments, if unsupported Start Printed Page 7941by additional data, outside expert recommendations, or detailed explanation, may be neither good nor reasonable administrative practice.

(Response) FDA disagrees that real GMP “expertise” rests only with industry and disagrees with the comment's suggestion that the Agency does not have the expertise it needs to establish requirements. Such assertions are unfounded because FDA does have staff with “real GMP expertise” and, in addition, has consulted with experts outside the Agency through the FAC process. Moreover, FDA field and compliance personnel regularly interact with industry staff during inspections and other compliance activities. FDA has also achieved greater insight into the industry's concerns by virtue of the extensive comments submitted by the industry during this lengthy rule-making process. Further, the comment identifies no specific proposed requirement for which it questions the underlying support. Accordingly, FDA is making no changes in response to this comment.

(Comment 5) One comment stated that many of the provisions in the proposed regulation are inflexible and overly prescriptive. The comment requested that FDA establish the results to be achieved in the infant formula manufacturing process, but not prescribe or limit the ways in which the required results can be achieved.

(Response) FDA agrees in part with this comment. To the extent feasible, FDA is establishing requirements for the manufacturing process in a way that describes the result to be achieved and does not specifically mandate how to achieve that result. For example, as noted in this document, § 106.50(d)(3) mandates that the manufacturer establish controls for the removal of air from the finished product, because such controls are necessary to ensure that nutrient deterioration does not occur. The method used and extent of air removal are left to the discretion of the manufacturer. In other cases, the statutory language mandates how to achieve a result, e.g., the vitamins that must be tested at the final product stage for each batch (production aggregate) of infant formula to ensure compliance with required nutrient levels (section 412(b)(3) of the FD&C Act). Specific statutory mandates are reflected in the interim final rule.

(Comment 6) One comment submitted in 2003 states that instead of responding to comments submitted in response to the 1996 proposed rule, the 2003 comment period reopening merely requests comment again without giving any indication of FDA's current views on the rule's major issues. The comment further stated that the 2003 reopening raises new issues not covered in the proposed rule and fails to provide guidance on how FDA proposes to address these issues. The comment argued that the 2003 reopening is at odds with FDA's obligation under the Administrative Procedure Act (APA) to make its views known to the public in a concrete and focused form in order to make criticism or formulation of alternatives possible, and that this format forces industry to comment on a rule that the public does not see until it is in final form. Accordingly, this comment requests that FDA permit an additional round of notice and comment, especially to the extent that FDA intends to draft regulations addressing new substantive issues not in the proposed rule.

(Response) FDA disagrees with the comment's criticism of the 2003 reopening and suggestion that an additional round of notice and comment on the proposed rule is needed. The 2003 reopening provided a 60-day comment period that ended on June 27, 2003. FDA extended the reopened comment period for an additional 60 days to allow interested persons additional time to comment, as requested in a comment. With this extension, the public was provided with a total of 120 days to submit comments during the 2003 reopening.

As noted previously in this document, in 2003, FDA reopened the comment period to receive comments on all issues presented by the 1996 proposed rule. Thus, at the time of the 2003 reopening, the 1996 proposal identified FDA's views on the issues in the rulemaking. This interim final rule only addresses issues that are within the scope of the original proposal. In light of three meetings that occurred between the issuance of the 1996 proposal and the 2003 reopening, FDA also specifically requested in the 2003 reopening comments on a discrete set of issues that were within the scope of the original proposal. These issues were explained clearly, and opportunity to provide comments on these discrete issues, as well as the rule generally, was provided. In 2006, FDA again reopened the comment period on a specific microbiological standard it was considering for E. sakazakii (now classified as Cronobacter spp.), in addition to other specific issues.

Under the APA, in order to provide adequate notice, a proposed rulemaking, unless a specific exception applies, must include “either the terms or substance of the proposed rule or a description of the subjects and issues involved” (5 U.S.C. 553(b)(3).) In other words, the notice must be sufficient to fairly apprise interested parties of issues involved, but it does not need to specify every precise proposal which the Agency may ultimately adopt as a rule. Action for Children's Television v. FCC, 564 F.2d 458, 470 (D.C. Cir. 1977). The notice given by FDA in the original 1996 proposal, the 2003 reopening, and later in the 2006 reopening, was sufficient to fairly apprise all interested parties of the issues involved in the rulemaking. Thus, sufficient notice has been given and additional opportunity for comment is not required. Notwithstanding the adequacy of the prior comment periods, we are accepting comments on this interim final rule. For more details on the comment period, see part XVI of this document.

(Comment 7) One 2006 comment objected to the Agency's limiting the additional 2006 comment period to certain issues and expressed concern that the effect of this limitation would be to prevent the submission of information that could have a negative impact on the resolution of important issues. The comment stated that the limited 2006 reopening may result in the promulgation of a GMP regulation that does not reflect current good manufacturing practices and requested that the entire proposed regulation be reopened and that the public be given the opportunity to respond to FDA's reactions to the voluminous comments submitted since 1996.

(Response) FDA disagrees with this comment. First, the 1996 proposal provided sufficient notice of all issues in this interim final rule. Further, the 2003 reopening provided the public with a lengthy opportunity to comment on all issues raised by the 1996 proposal, and this 2006 comment does not specifically address why an opportunity in addition to that provided in 2003 is needed to comment on all issues. Finally, the 2006 reopening provided sufficient notice of the matters at issue in the reopening. In particular, FDA described the significant expert consultations held since the 2003 reopening and provided the Agency's tentative conclusions, including the basis for such conclusions, relying on the information added to the administrative record and comments received on such information from the 2003 reopening. Therefore, ample notice and opportunity for comment has been provided on all aspects of this interim final rule. As noted previously in this document, however, notwithstanding the adequacy of the prior comment periods, we are accepting comments on Start Printed Page 7942this interim final rule (see part XVI of this document).

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

Proposed § 106.1 described the authority for each subpart of the proposal and the consequences under the FD&C Act of a failure to comply with any of the proposed regulations. FDA is including § 106.1 because it is important for those in the infant formula industry to be aware of the legal consequences of failing to comply with these regulations, which are being issued to implement specific sections of the FD&C Act.

FDA did receive comments supporting § 106.1 as proposed but did not receive any adverse comments. On its own initiative, however, FDA is revising § 106.1 to clarify all of the requirements in subparts F and G of this interim final rule, and also to clarify the legal consequences of failing to comply with certain requirements in subparts F and G of the interim final rule.

Proposed § 106.1(a) stated that subparts B, C, and D prescribe the steps that shall be taken under section 412(b)(2) and (b)(3) of the FD&C Act (i.e., CGMP and quality control procedures requirements, including audit requirements) in processing infant formula, and that the failure to comply with any regulation under these subparts would adulterate the formula under section 412(a)(3) of the FD&C Act. While it is true that subparts B, C, and D describe CGMP and quality control procedures requirements issued under section 412(b)(2) and (b)(3) of the FD&C Act, these are not the only subparts of the interim final rule that contain CGMP and quality control procedures requirements. Subpart F of this interim final rule prescribes records requirements, some of which are part of the requirements for CGMP and quality control procedures issued under the authority of section 412(b)(2) of the FD&C Act. Additionally, some of the CGMP and quality control procedures requirements are codified in subpart G of this interim final rule. Subpart G describes, in part, the content of submissions. Some of the records that make up the content of these submissions are records made as part of requirements for CGMP and quality control procedures issued under the authority of section 412(b)(2).

Because subparts F and G also contain requirements that are properly classified as CGMP and quality control procedures requirements issued under the authority of section 412(b)(2) of the FD&C Act, FDA is revising proposed § 106.1(c) and (d) to include these requirements and the authority under which they are issued. FDA is also revising proposed § 106.1(c) and (d) to explain that the failure to follow these requirements issued under section 412(b)(2) of the FD&C Act will result in an infant formula that is deemed to be adulterated under section 412(a)(3) of the FD&C Act.

Furthermore, FDA is revising proposed § 106.1(c) and (d) to describe requirements in subparts F and G that are issued under the authority of section 412(b)(1) of the FD&C Act, which requires FDA to establish requirements for quality factors. Proposed § 106.1(b) stated that subpart E prescribed the quality factor requirements issued under section 412(b)(1) of the Act. As with CGMP and quality control procedures requirements, however, quality factor requirements are also contained in subparts F and G. Some of the records requirements that are codified in subpart F are records required under the authority to issue quality factor requirements in section 412(b)(1) of the FD&C Act. Likewise, some of the records that make up the content of the submissions required under subpart G of this interim final rule are required under the authority to issue quality factor requirements under section 412(b)(1) of the FD&C Act. Therefore, because subparts F and G contain records requirements that are part of the quality factor requirements, FDA is also revising proposed § 106.1(c) and (d) to explain that the failure to follow any quality factor requirements issued under section 412(b)(1) of the FD&C Act will result in an infant formula that is deemed adulterated under section 412(a)(2) of the FD&C Act.

C. Definitions (Proposed § 106.3)

Section 106.3 of the 1996 proposed rule provided definitions for the following terms: Batch; final-product-stage; indicator nutrient; infant; infant formula; in-process batch; lot; lot number, control number or batch number; major change; manufacturer; microorganism; new infant formula; nutrient; nutrient premix; quality factors; representative sample; shall; and should. In the 1996 proposed rule, each definition in proposed § 106.3 was designated as a subparagraph of the section using letters (for example, the definition of “batch” was proposed § 106.3(a)). Individual designation of definitions in a regulation is no longer standard in Federal regulations. Accordingly, these individual designations have been removed in the interim final rule and are not used in the discussion in this document. Consistent with the 1996 proposed rule, the definitions continue to be listed in alphabetical order.

No comments suggest modification of the definition of proposed § 106.3(q) for “shall” and thus, it is included, as proposed, in § 106.3 of the interim final rule. Because all of the provisions in this interim final rule are mandatory, there is no need for the definition “should” (proposed § 106.3(r)) and accordingly, this definition is deleted in this interim final rule.

The comments FDA received on the definitions of final-product-stage; indicator nutrient; infant; infant formula; nutrient premix; and representative sample supported the proposed definitions. Thus, these definitions are included, as proposed, in the interim final rule.

FDA received comments that suggested revisions to the definitions of the following terms in the proposed rule: Batch; lot; major change; manufacturer; microorganism; new infant formula; nutrient; and quality factors. Based on changes to the proposed definitions of “lot” and “batch,” FDA has made conforming changes to the proposed definitions of “in-process batch” and “lot number, control number, or batch number.” FDA also received comments that recommended that FDA include additional definitions of the following terms: Minor change; responsible party; specifications; target values; and critical. FDA responds to these comments in this interim final rule.

In addition, FDA is adding a definition for “eligible infant formula” on its own initiative. As discussed in section VIII, FDA is adding provisions to the quality factor requirements in § 106.96 that relate to a formula that could have been or was lawfully distributed in the United States on the 89th day after the publication of this interim final rule. FDA is describing these formulas as “eligible infant formulas,” and for clarity, FDA is adding a definition in § 106.3 to describe these formulas.

1. Batch (Proposed § 106.3(a) and Lot (Proposed § 106.3(g))

As described in more detail in this document, FDA believes that during the course of this rulemaking, two related terms, “batch” and “lot,” have been used in different ways, potentially causing confusion. These terms describe two volumes of formula that have significance in the production of infant formula. At the same time, FDA has come to understand that the food industry and the drug industry generally do not use these terms in the same way. This is particularly relevant because the Start Printed Page 7943definitions originally proposed were based on FDA's drug manufacturing CGMP regulations in part 210 (21 CFR part 210) and because some formula manufacturers are part of a larger drug manufacturing firm and others are part of a larger food manufacturing firm. Accordingly, in order to achieve necessary clarity, the interim final rule establishes and defines two new terms, “production unit” and “production aggregate,” which are substituted for the terms “batch” and “lot” used in the earlier stages of this rulemaking.

The discussion that follows recounts the background and history of the use of the terms “batch” and “lot” in this rulemaking.

In current industry practice, two volumes of formula have significance during the infant formula manufacturing phase: the quantity of formula that can be mixed in the production equipment at one time (the relatively smaller volume) and the amount of formula manufactured during a single production run (the relatively larger volume.) With a continuous production process (which is used by all formula manufacturers), the larger volume is necessarily somewhat co-mingled because there is no cleaning between production of each smaller volume, and in fact, may be purposefully co-mingled through the combination of several smaller volumes to create a single larger volume. Generally speaking, the larger volume is the production volume of particular interest to the formula manufacturer. At certain times, the quantity produced during a single production run may be a much smaller amount. In most cases, the production of two different larger volumes of formula (two different production runs) will be separated by an intervening cleaning of the production equipment. Manufacturers currently sample from the final volume produced from a single production run, which may include co-mingled volumes, for testing both for nutrients and for microbial contamination.

Although section 412 uses the term “batch,” the term is not defined. Specifically, section 412(b)(2)(B)(i) of the FD&C Act (21 U.S.C. 350a(b)(2)(B)(i)) requires testing of “each batch of infant formula” for nutrients prior to distribution of the “batch;” section 412(b)(3)(A) of the FD&C Act (21 U.S.C. 350a(b)(3)(A)) requires that “at the final product stage, each batch of infant formula” shall be tested for certain vitamins; and section 412(b)(3)(C) of the FD&C Act (21 U.S.C. 350a(b)(3)(C)) requires that “during the manufacturing process or at the final product stage and before distribution,” (emphasis added) the formula shall be tested for all nutrients; and section 412(b)(3)(D) (21 U.S.C. 350a(b)(3)(D)) requires that if a nutrient is added to the list in section 412(i) of the FD&C Act (21 U.S.C. (350a(i)), the Secretary shall require that the manufacturer test “each batch.” Section 412(b)(2)(E) of the FD&C Act (21 U.S.C. 350a(b)(2)(E)) defines “final product stage” as “the point in the manufacturing process, before distribution of an infant formula, at which an infant formula is homogenous and not subject to further degradation.” The fact that section 412 of the FD&C Act either requires or permits testing of each “batch” of a formula at the “final product stage” illustrates that Congress used the term “batch” to mean the relatively larger, often co-mingled portion of formula in which individually mixed portions of formula are combined.

Unlike “batch,” the term “lot” is not used in section 412 of the FD&C Act. The 1996 proposed rule included definitions for “batch” and “lot” (proposed § 106.3(a) and (g), respectively.) These definitions were derived from FDA's drug CGMP regulations in part 210. The proposed rule defined “batch” to mean “a specific quantity of an infant formula or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture.” The proposed rule defined “lot” to mean “a batch, or a specifically identified portion of a batch, having uniform character and quality within specified limits; or, in the case of an infant formula produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures its having uniform character and quality within specified limits.”

The proposed rule stated that it was important to maintain consistency throughout FDA's regulations. Therefore, where possible and appropriate, the proposed definitions relied on FDA's regulations in part 210, the CGMP for drugs. Specifically, the definitions in the proposed rule for “batch,” “lot,” “lot number, control number, or batch number,” and “representative sample” were based on the definitions in part 210.

The proposed definitions of “batch” and “lot” contemplated that infant formula would be produced in bulk, that “batch” was considered the relatively larger volume, that “lot” was the relatively smaller volume, and that more than one “lot” could comprise a “batch.” The 1996 proposed rule (§ 106.55) used the term “batch” when describing the requirements for evaluating the microbiological quality of powdered formula at the final product stage.

In 2006, following the emergence of Enterobacter sakazakii as a contaminant in powdered infant formula, FDA reopened the comment period on the 1996 proposal to receive comments on the microbiological testing scheme. (The organism E. sakazakii was reclassified in 2008 to new genus, Cronobacter spp. (Ref. 1).) In that reopening, FDA proposed a new microbiological testing scheme for powdered infant formula. The revised testing requirement proposed in the 2006 reopening was confined to testing for E. sakazakii and Salmonella ssp. This change was based on the findings of the 2006 FAO/WHO Report (Ref. 3) which provided, for the first time, a risk assessment model to describe the factors leading to E. sakazakii infection in infants and identified potential risk mitigation strategies. The 2006 FAO/WHO Report also described a microbiological standard sampling plan for E. sakazakii, of negative for E. sakazakii in 30 × 10 gram samples from each lot of powdered infant formula. The microbiological standard for Salmonella spp. of negative in 60 × 25 gram samples is well established and was not changed. Details concerning the microbiological testing required for powdered infant formula by this interim final rule are discussed in section V of this document.

In proposing to adopt this microbiological standard, FDA also proposed that the definition of “lot” be modified to be consistent with the statistical basis for the proposed microbiological testing requirements and the agreed upon international terminology. Specifically, FDA stated that the Agency was considering modifying the definition of “lot” to mean “a quantity of product, having uniform character or quality, within specified limits, or, in the case of an infant formula produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures its having uniform character and quality within specified limits” (71 FR 43392 at 43395).

Unfortunately, the terms “batch” and “lot” were used without adequate distinction in the 2006 FAO/WHO Report and in the 2006 reopening. As noted, the 2006 reopening proposed a revised definition of “lot” (71 FR 43392 at 44395; August 1, 2006.) Under this definition, “lot” would have been the relatively larger quantity of formula, a definition inconsistent with both the Start Printed Page 79441996 proposal and FDA's drug CGMP definition. Also, at the time of the 2006 reopening, the Agency did not propose a comparable modification of the definition of “batch.” As a result of this oversight, the most recently proposed definitions for “lot” and “batch” both refer to the relatively larger quantity of infant formula. Elsewhere in the 2006 reopening notice, the Agency referred to “batch testing” of microorganisms (71 FR 43392 at 43396), a reference intended to identify the relatively larger quantity of formula.

The confusion surrounding “lot” and “batch” is further illustrated by the comments FDA received on the definitions of “batch” and “lot” in response to the 1996 proposal. Specifically, comments reflected that these terms are used inconsistently and that the terms are not used in the same way in formula manufacturing and in drug manufacturing. As a result of the foregoing, FDA believes that there is significant confusion about the meaning of “batch” and “lot,” about the relationship between “batch” and “lot,” and, most significantly, about the quantity of formula under discussion for the microbial testing requirements of the interim final rule.

FDA has considered the need to resolve this confusion as well as the importance of clarifying the volume of formula associated with the master manufacturing order and the requirements for nutrient and microbiological testing and has concluded that the terms “batch” and “lot” should be replaced in the interim final rule with two new terms, “production aggregate” and “production unit.” The interim final rule defines “production aggregate” and “production unit” in a manner that clarifies the volume of formula and stage of production contemplated by each term as well as the relationship between the two volumes of formula. In addition, the definitions of the two terms reflect changes made in response to comments on “batch” and “lot.” By incorporating “production unit” and “production aggregate” into the interim final rule, however, FDA does not intend to introduce new concepts or to make significant changes. Rather, the Agency is using new descriptors to clarify the quantity of formula associated with the master manufacturing order and with the requirements for microbiological and nutrient testing.

“Production unit” represents the individually mixed portion of formula and is defined in § 106.3 as “a specific quantity of an infant formula produced during a single cycle of manufacture that has uniform composition, character, and quality, within specified limits.” “Production aggregate” is frequently a co-mingled portion of formula composed of one or more production units; it is defined in § 106.3 as “a quantity of product, or, in the case of an infant formula produced by continuous process, a specific identified amount produced in a unit of time, that is intended to have uniform composition, character, and quality, within specified limits, and is produced according to a master manufacturing order.” Thus, under this interim final rule, as a result of the revision of these definitions and the addition of these new terms:

  • “Production aggregate” represents the relatively larger volume of formula and thus, effectively replaces “batch” (the 1996 proposal) and “lot” (the 2006 reopening).
  • “Production unit” represents the relatively smaller volume of formula and effectively replaces “lot” (the 1996 proposal). (The 2006 reopening did not specifically propose a term or definition for the relatively smaller volume.)
  • A “production aggregate” may consist of one or more “production units.” This is consistent with the definition of lot proposed in 1996. (“Lot means a batch or a specifically identified portion of a batch. . . .”)
  • As with “batch” (the 1996 proposal) and “lot” (the 2006 reopening), the term “production aggregate,” the term representing the relatively larger volume of formula, incorporates the concept of being produced according to a master manufacturing order.
  • The term “production aggregate” (§ 106.3), which refers to the relatively larger volume of formula, is defined both for purposes of conventional manufacturing and continuous process manufacturing. The comparable term from the 1996 proposal did not address the application of the concept to continuous processing.
  • As discussed in section V, the requirements for controls to prevent adulteration from microorganisms (§ 106.55) stipulate that testing be conducted on each “production aggregate” of formula. Imposing the testing requirement on the relatively larger volume of formula is consistent with the FAO/WHO report and is also necessitated by the formula industry's use of continuous processing, a production method that generally does not always result in identifiable smaller volumes. Testing the relatively larger volume is consistent with the proposed rule (which would have required each “batch” to be tested), the 2006 reopening (which would have required each “lot” to be tested), and the language in section 412 (which uses the term “batch” to mean the relatively larger, often co-mingled portion of formula in which individually mixed portions of formula are combined.)

In the remainder of this preamble, FDA uses the terms “production unit” and “production aggregate,” as appropriate, to minimize confusion and misunderstanding.

(Comment 8) One comment requested that the term “composition” be added to the definition of “batch” in proposed § 106.3, so that the definition would read “uniform composition, character, and quality.” The comment stated that the word “composition” adds to the accepted concept of the characteristics of a batch.

(Response) FDA agrees with this comment, and has added the word “composition” to the definition of “production aggregate” in § 106.3. The ordinary meaning of the word “composition” is “a product of mixing or combining various elements or ingredients.” (Ref. 6, p.236) A formula with uniform composition will have the various formula components evenly distributed throughout the quantity of formula manufactured; uniform composition directly contributes to the uniform character and quality of a formula, the two other elements in the definition of “production aggregate.”

(Comment 9) One comment requested that the Agency strike the term “single” from, and substitute the word “master” in, the proposed definition of “batch.” In the proposed definition, “single” modified “manufacturing order.” The comment suggested that modifying “manufacturing order” with the word “master” would ensure that in-process adjustments, undertaken so that the batch meets nutritional requirements, would not contravene the definition.

(Response) FDA does not disagree with this comment and thus, has replaced the term “single” with “master” to describe a manufacturing order. “Master manufacturing order” is a term commonly used in the infant formula industry and is used to describe the “recipe” the manufacturer uses to prepare the production aggregate. The Agency understands the comment's underlying concern to be that the proposed definition, which referred to a “single manufacturing order,” could be interpreted to mean that a manufacturer is precluded from making in-process adjustments in what this interim final rule refers to as the “production aggregate” as defined in § 106.3. FDA recognizes that a formula manufacturer may be required to make in-process adjustments to ensure that established specifications for the in-process or final product are met. Given the potential Start Printed Page 7945confusion, FDA is making the change requested in this comment.

(Comment 10) One comment stated that the meaning of the phrase “or other material” in the proposed definition of batch was unclear and recommended that it be removed.

(Response) FDA agrees that the phrase “or other material” is not clear. Also, this phrase is not necessary and thus, it is being deleted from the definition of “production aggregate” in § 106.3.

(Comment 11) A comment requested that FDA delete the phrase “within specified limits” from the definition of “batch” asserting that the phrase creates a substantive requirement that could cause confusion. The comment also claimed that manufacturers determine some of the specifications related to the disposition of a batch on a case-by-case basis. The comment further stated that manufacturers have not identified every outer limit for every process and product parameter that would result in rejection and determination of these limits would require an overwhelming amount of technical and administrative resources.

(Response) FDA disagrees that the phrase “within specified limits” creates a substantive requirement for the identification of every outer limit for every process and product parameter that would result in product rejection. The purpose of the “within specified limits” language in this definition is to ensure that the manufactured infant formula is what the manufacturer intends, and reflects both customary practice in the formula industry as well as the requirements in § 106.6(c)(1) to establish specifications. The manufacturer establishes specifications for each production aggregate of formula, which ensures that the manufactured formula meets the nutrient requirements and applicable microbial contamination standards. Thus, the term “within specified limits” ensures that a production aggregate has the uniform composition, character, and quality intended.

As noted, the comment also requested deletion of “within specified limits” because, the comment asserted, specifications are established on a case-by-case basis. FDA disagrees with this justification because manufacturers should not be determining specifications on a case-by-case basis during production of a formula, as the comment seems to suggest. It is crucial that a manufacturer establish appropriate specifications at any point, step, or stage where control is necessary to prevent adulteration prior to manufacturing formula so that the manufacturer can ensure that its process is under control and is able to produce what is intended. Failure to meet predetermined specifications, or failure to perform necessary in-process adjustments to ensure such specifications are met, suggests that the manufacturing process is not adequately controlled to prevent adulteration.

For all of the foregoing reasons, the Agency declines to delete the phrase “within specified limits” and is retaining such phrase in the definition of “production aggregate” in § 106.3.

(Comment 12) FDA received comments on the definition of “lot” (as proposed in 1996) that were similar to comments on the definition of “batch.” In particular, these comments suggested removing the phrase “within specified limits” from the definition of “lot,” and also recommended that the definition of “lot” include the term “composition.” The comments also requested that the definition of “lot” be clarified in terms of production of infant formula by continuous process.

(Response) As explained previously in this document, the concepts of “production aggregate” and “production unit” are closely related and thus, the definitions of these terms should be consistent with one another. Accordingly, FDA agrees that the term “composition” should be added to the definition of “production unit.” In addition, in continuous processing manufacture, each production unit needs to have uniform composition, which will help to ensure that the composition of the production aggregate will be uniform and within the specified limits. Accordingly, for the reasons stated in the responses to comment 11, FDA has also added the term “composition” to the definition of “production unit” in § 106.3.

Similarly, for the reasons stated in the response to comment 11, FDA is also retaining the phrase “within specified limits” in the definition of “production unit” in § 106.3.

Finally, the definition of “production aggregate” refers to the production of infant formula by continuous process. FDA recognizes that a single production unit may also be a production aggregate where, for example, only smaller volumes of infant formula are produced.

(Comment 13) One comment stated that the phrase “or other material” is more appropriate in the definition of “lot” than in the definition of “batch” because the definition of “lot” “encompasses raw material lots better than does the definition of batch'.”

(Response) FDA disagrees with this comment. The comment is a reflection of the problem resulting from the variety of ways in which the term “lot” is used in manufacturing and also was used in the earlier stages of this rulemaking. The concept of “lots” of raw materials is separate from the concept of “lot,” which was used in the 1996 proposed rule, and “production unit,” which is the term used in this interim final rule and is defined in § 106.3. The addition of the phrase “or other material” to the definition of production unit is not appropriate because the production unit does not refer to “lots” of raw materials. Therefore, FDA has not added the phrase “or other material” to the definition for “production unit” in § 106.3.

As a result of establishing the new terms “production aggregate” and “production unit” and their definitions, FDA is also making technical revisions to two related definitions that the Agency proposed in 1996. First, FDA is revising proposed § 106.3(f), the definition of “in-process batch” and codifying the new term and definition in § 106.3 of the interim final rule as follows: “In-process production aggregate means a combination of ingredients at any point in the manufacturing process before packaging.” Similarly, the Agency is revising proposed § 106.3(h), the definition of “lot number, control number, batch number,” and codifying the new term and definition in § 106.3 of the interim final rule as follows: “Production unit number or production aggregate number means any distinctive combination of letters, numbers, symbols, or any combination of them, from which the complete history of the manufacture, processing, packing, holding, and distribution of a production aggregate or a production unit of infant formula can be determined.”

2. Major Change (Proposed § 106.3(i))

The proposed rule defined “major change in an infant formula” to mean “any new formulation, or any change of ingredients or processes where experience or theory would predict a possible significant adverse impact on levels of nutrients or bioavailability [2] of Start Printed Page 7946nutrients, or any change that causes an infant formula to differ fundamentally in processing or in composition from any previous formulation produced by the manufacturer.” The proposed definition provided seven examples of changes resulting in an infant formula that would be deemed to differ “fundamentally in processing or in composition.”

(Comment 14) One comment agreed with the proposed definition of “major change” in proposed § 106.3(i) but suggested revised language for the example in proposed § 106.3(i)(5). The comment suggested that the phrase “containing a new constituent” in proposed § 106.3(i)(5) should be changed to “containing a new nutrient” because, the comment asserted, the purpose of the Infant Formula Act is to ensure proper nutrition and the term “nutrient” is more consistent with that purpose. The comment asserted that the term “constituent” is overbroad, that its use could result in designating as a major change the addition of a wholly innocuous new constituent added at nominal levels, and that such a result is beyond the basic scope of section 412 of the FD&C Act. The comment further argued that this interpretation would require formula manufacturers to submit 90 day notifications for each of these constituents, which would require both the manufacturer and FDA to expend additional resources with no added benefit to the consumer.

(Response) FDA disagrees with this comment and, for two reasons, declines to make the suggested revision to the definition of “major change” in § 106.3 of the interim final rule. First, the use of the term “constituent” is required by the applicable statute. The definition of “major change” in proposed § 106.3(i) was based on the directive in section 412(c)(2) of the FD&C Act, which states that “the term `major change' ” has the meaning given to such term in § 106.30(c)(2) of title 21, Code of Federal Regulations (as in effect on August 1, 1986), and guidelines issued thereunder.” The guidelines referred to in section 412(c)(2) of the FD&C Act are the Guidelines Concerning Notification and Testing of Infant Formulas (“the Guidelines”) (Ref. 7). The Guidelines list seven examples of changes that cause an infant formula “to differ fundamentally in processing or in composition from any previous formulation produced by the manufacturer.” Accordingly, in proposed § 106.3(i), FDA listed the seven examples set out in the Guidelines, including, in proposed § 106.3(i)(5), “Any infant formula manufactured containing a new constituent not listed in section 412(i) of the FD&C Act, such as taurine or L-carnitine.” Thus, the language in proposed § 106.3(i)(5) was drawn directly from the definitional source identified in the applicable statute.

Second, sound policy reasons support use of the term “constituent” in the definition of “major change” in § 106.3. Constituents other than the nutrients listed in section 412(i) of the FD&C Act (“required nutrients”) are added to infant formula (e.g., intentionally added microorganisms), and a new constituent other than a required nutrient could potentially affect the bioavailability of a formula and such nutrients. The Guidelines recognize, and the definition of “major change” incorporates the recognition, that a new constituent other than a required nutrient can potentially affect the bioavailability of nutrients in the formula and the formula as a whole. Thus, from the standpoint of ensuring the bioavailability of the formula matrix as a whole, in addition to the bioavailability of individual required nutrients, use of the term “constituent” in the definition of “major change” is appropriate as a matter of policy. Therefore, FDA is not revising the definition of “major change” in response to this comment.

(Comment 15) Another comment suggested that the conjunction “and” after proposed § 106.3(i)(6) be changed to “or.” The comment argued that this revision is appropriate because each of the examples in this section is intended to stand alone and, although more than one example could be applicable in a given situation, all seven are unlikely to occur at the same time.

(Response) The Agency agrees with this comment. Proposed § 106.3(i) includes a list of examples of infant formulas, each of which differs fundamentally in processing or in composition and thus, each is a separate example of a “major change in an infant formula.” Accordingly, FDA is revising proposed § 106.3(i) by changing the conjunction “and” to “or” before the last example in the definition of “major change” in § 106.3.

On its own initiative FDA is removing the words “for commercial or charitable distribution” from proposed § 106.3(i)(2). This change is consistent with the definition of “manufacturer” as discussed in this document, in which the Agency declined to include the phrase “for commercial or charitable distribution.”

3. Manufacturer (Proposed § 106.3(j))

The proposed rule (§ 106.3(j)) defined “manufacturer” as “a person who prepares, reconstitutes, or otherwise changes the physical or chemical characteristics of an infant formula or packages or labels the product in a container for distribution.”

(Comment 16) One comment suggested that the definition of “manufacturer” be revised so that “manufacturer” means “a person who prepares, reconstitutes, or otherwise changes the physical or chemical characteristics of an infant formula or packages or labels the product in a container for commercial or charitable distribution (emphasis added)” and asserted that, by including the phrase “commercial or charitable,” parents, child care providers, hospitals, and other institutions who prepare formula for infants under their direct care would not be considered a “manufacturer.”

(Response) FDA believes that this comment raises an important issue about the breadth of the proposed definition of “manufacturer.” The Agency disagrees, however, that including the phrase “commercial or charitable” as a modifier of the word “distribution” would sufficiently clarify that those who prepare infant formula for infants under their direct care are not “manufacturers.”

The Agency recognizes that there are several groups of persons who reconstitute powdered or concentrated liquid infant formula or otherwise mix formula and provide that formula to an infant for whom these persons are providing direct care. These persons include parents, daycare providers and other caregivers, and nurses and other healthcare personnel. In addition, in some healthcare settings, there is a designated institutional unit that performs the formula mixing in place of a nurse or other healthcare provider, such as a hospital formula room; these staff mix or reconstitute formula for infants under the direct care of the hospital or healthcare institution. Whether the reconstitution is done by an individual, such as a daycare provider or staff in a hospital formula room, the preparation of the infant formula is an extension of the care-giving function. FDA does not believe that Congress intended that a person who or institution that mixes formula for a child as an extension of the care-giving function be considered a “manufacturer” subject to the requirements established under section 412. Instead, the provisions of section 412 are intended to regulate entities that prepare or reconstitute formula for further distribution because a manufacturing error by one of these entities has greater potential to cause harm by virtue of the broad distribution of its products. Also, the activities of a Start Printed Page 7947hospital formula room or comparable unit are subject to the oversight and standards of the hospital or other institution of which it is a part. Moreover, as a policy matter, FDA does not believe that it is appropriate to interfere with these care-giving relationships by requiring a person who mixes formula for an infant under his/her direct care to adhere to the types of controls the Agency is establishing in this interim final rule.

FDA affirms, however, that a person or institution that reconstitutes formula for subsequent distribution to infants not under the direct care of that person or institution is a “manufacturer” for purposes of the interim final rule. In this situation, the mixing or reconstitution and subsequent distribution are separate activities and are not simply an extension of the care-giving function.

Accordingly, FDA is revising proposed § 106.3(j) to clarify that the term “manufacturer” does not include a person or institution employing such person that prepares, reconstitutes, or mixes infant formula exclusively for an infant under his/her direct care or the direct care of the institution employing such person.

(Comment 17) One comment suggested that a definition for “responsible party” be added to § 106.3 because the proposed definition of “manufacturer” would result in overlapping responsibilities whenever co-packers are involved in the manufacturing of infant formula. This comment suggested defining “responsible party” as “the manufacturer of an infant formula when all manufacturing steps are performed by a single entity; however, when several entities are involved in the manufacture of a given formula, it means the manufacturer or other entity that has agreed to assume responsibility for ensuring that all requirements for notification and assurance under these regulations are satisfied.” The comment stated that for certain requirements, the responsible party would replace the manufacturer completely, to avoid duplication and to attribute appropriately actual responsibility for other requirements. The comment asserted that that duplicate responsibilities for the same activity do not serve any purpose in the majority of proposed requirements, and therefore, suggested that the concept of “responsible party” be introduced to eliminate duplication. The comment stated that only for “registration” (see proposed § 106.110) would duplicate responsibilities serve FDA's purpose (e.g., for inspections and counterfeit formula surveillance).

(Response) FDA disagrees that a definition for “responsible party” is needed in the interim final rule because, properly understood, the interim final rule will require no duplication of effort.

The Agency believes that the comment did not understand the responsibilities under the proposed rule. These obligations are of two types: The obligation to conduct certain activities according to the requirements of the CGMP regulation and the obligation of certain persons to ensure that there is compliance with the rule's requirements even if such person is not engaged in the specific activities covered by the rule.

In terms of activities, under the interim final rule, any person who satisfies the definition of “manufacturer” in § 106.3 must comply with all the CGMP requirements that cover activities in which such person engages. Thus, if a person conducts all the activities necessary to produce an infant formula in its final packaged form (i.e., prepares, reconstitutes, or otherwise changes the physical or chemical characteristics of a formula, packages the formula, and labels the product for distribution), that person must comply with all CGMP requirements established by this interim final rule.

FDA recognizes, however, that in the infant formula industry, a person may contract with another to perform some portion of the formula production process, such as the packaging and labeling phases of manufacture, and there is no legal prohibition to such arrangements. To the extent that a contractor performs any of the activities identified in the definition of manufacturer in § 106.3, the contractor is a “manufacturer” for purposes of those activities under this interim final rule. However, where a person (such as a contractor) performs only a part of the complete infant formula manufacturing operation, that person is obligated to adhere only to the specific parts of the CGMP rule that are relevant to such person's activities. For example, if an entity has contracted to act as a spray dryer for a powdered infant formula, the spray dryer is an infant formula manufacturer under § 106.3 and is responsible for complying with the applicable sections of subpart B (CGMPs), subpart D (Conduct of Audits), and Subpart F (Records and Reports). The specific responsibilities of a given contractor would depend on the terms of the contract. For example, a contactor whose duties under the contract are limited to spray drying infant formula generally would not be responsible for the nutrient testing required under subpart C (Quality Control Procedures), subpart E (Quality Factors), or subpart G (Registration, Submission, and Notification Requirements).

Importantly, in addition to the obligation to comply with the parts of the CGMP rule that apply to the activities of a particular person's operation, the entity who causes the infant formula to be introduced into interstate commerce in its final form for distribution to consumers has an overarching and ultimate responsibility to ensure that all phases of the production of that formula are in compliance with the final CGMP regulations and that the formula is lawful in all respects. Generally, the person who submits the notification required by section 412(c)(1)(B) of the FD&C Act is the person with this ultimate responsibility. (Under section 201(e) of the FD&C Act (21 U.S.C. 321(e)), “person” includes an individual, partnership, corporation, or association.) That is, although a firm can contract out certain parts of formula production, the firm cannot, by the same token, contract out its ultimate responsibility to ensure that the formula that such firm places into commerce (or causes to be placed into commerce) is not adulterated and is otherwise lawful. See U.S. v. Dotterweich, 320 U.S. 277, 284 (1943) (explaining that an offense can be committed under the FD&C Act by anyone who has “a responsible share in the furtherance of the transaction which the statute outlaws”); United States v. Park, 421 U.S. 658, 672 (1975) (holding that criminal liability under the FD&C Act does not turn on awareness of wrongdoing, and that “agents vested with the responsibility, and power commensurate with that responsibility, to devise whatever measures are necessary to ensure compliance with the Act” can be held accountable for violations of the FD&C Act). This overarching responsibility flows from the FD&C Act's structure. In particular, the FD&C Act prohibits a person from introducing or delivering for introduction, or causing the delivery or introduction, into interstate commerce an adulterated infant formula, 21 U.S.C. 350a(a) and 331(a). Thus, the firm that causes an infant formula to be introduced into interstate commerce is responsible for ensuring that such formula complies with all the requirements under section 412 of the FD&C Act and the interim final rule and thus, is not adulterated, regardless of Start Printed Page 7948who actually carries out the activities covered by the rule.

In terms of an infant formula firm's obligations relating to the use of contractors, FDA notes, as discussed in section X.B, that under § 106.110(b)(4), the manufacturer of a new infant formula must register with FDA and the registration must list all establishments at which the manufacturer intends to manufacture the new formula. FDA advises that the list of establishments required by § 106.110(b)(4) must include the establishments of all contractors involved in the production of the new formula.

4. Microorganisms (Proposed § 106.3(k))

The proposed rule defined “microorganisms” to mean “yeasts, molds, bacteria, and viruses and includes, but is not limited to, species having public health significance.”

(Comment 18) One comment stated that this definition of “microorganisms” is identical to the definition in the food CGMPs (21 CFR 110.3(i)), which are also applicable to the manufacture of infant formulas. Thus, the comment asserted, the definition of “microorganism” should be deleted as it represents a redundancy.

(Response) The Agency disagrees with this comment. As discussed earlier in this preamble, Congress specifically mandated in section 412(b)(2)(A) of the FD&C Act that the Secretary (and by delegation, FDA) establish regulations for “good manufacturing practices for infant formulas, including quality control procedures that the Secretary determines are necessary” to assure that an infant formula provides nutrients in accordance with the FD&C Act and is “manufactured in a manner designed to prevent adulteration of the infant formula.” Section 412(a)(3) of the FD&C Act provides that an infant formula is deemed to be adulterated if the “processing of such infant formula is not in compliance with the good manufacturing practices and the quality control procedures prescribed by the Secretary” under section 412(b)(2) of the FD&C Act. FDA is establishing a definition of “microorganisms” in this interim final rule for use with the specific requirements related to such term that have been issued under section 412 of the FD&C Act. Therefore, FDA is not deleting proposed § 106.3(k) in response to this comment, and the definition of “microorganisms” is included in § 106.3.

5. New Infant Formula (Proposed § 106.3(l))

The proposed rule defined “new infant formula” to mean “(1) An infant formula manufactured by a person that has not previously manufactured an infant formula for the U.S. market, and (2) An infant formula manufactured by a person that has previously manufactured infant formula and in which there is a major change in processing or formulation from a current or any previous formulation produced by such manufacturer.”

(Comment 19) One comment suggested that the definition of “new infant formula” in proposed § 106.3(l) be changed by replacing the word “means” with the word “includes.” The comment stated that this change would make the definition consistent with the FD&C Act and would allow for situations not described in this definition. In addition, the comment suggested removing the phrase “for the U.S. market” from the first part of this definition in proposed § 106.3(l). The comment argued that the phrase “for the U.S. market” does not appear in the FD&C Act's definition of new infant formula. Also, the comment asserted that, for purposes of proposed § 106.110 (New infant formula registration), the phrase would exclude from the definition of “new infant formula” formulas intended for export only.

(Response) FDA disagrees with the comment that the term “means” should be replaced with the term “includes” in the definition of “new infant formula.” Although the language in section 412(c)(2) of the FD&C Act allows for situations not described in the definition of “new infant formula,” the definition of “new infant formula” in this rule is limited to the situations described in the definition. An infant formula manufacturer must determine whether its formula is a “new infant formula” in order to comply with FD&C Act and its implementing regulations. A precise definition of “new infant formula” will provide these manufacturers with clarity in this area. Therefore, FDA is not revising proposed § 106.3(l) to incorporate this change.

However, FDA is removing the phrase “for the U.S. market,” from the first clause of the definition of “new infant formula” as suggested in the comment. As the comment suggests, the definition of “new infant formula” in the proposed rule could be interpreted to exclude formulas for export only from certain requirements under the FD&C Act, e.g. the registration requirements under section 412(c) of the FD&C Act. Therefore, FDA is revising proposed § 106.3(l) to remove the phrase “for the U.S. market” from the first clause of such definition.

In addition, FDA recognizes that a definition of “new infant formula” without the phrase “for the U.S. market” in the first clause of the definition could be interpreted to permit a manufacturer who has been manufacturing and marketing formula abroad to market the same formula that they have been marketing abroad in the United States without registering with FDA under section 412(c) of the FD&C Act or making a submission under section 412(d) of the FD&C Act, provided that the manufacturer made no “major change” to the formula. This is because the formula would not be a “formula manufactured by a person that has not previously manufactured an infant formula” in the proposed definition of “new infant formula.” Even without the removal of the phrase “for the U.S. market” from the proposed definition, such definition could be interpreted to permit certain manufacturers who are marketing infant formula abroad to market that formula in the United States without making a submission under section 412(c) of the FD&C Act. For example, a formula could be considered to be excluded from the “new infant formula” definition if made by a manufacturer that has been marketing that formula abroad, but has also previously marketed a different formula in the United States. To avoid any ambiguity and to ensure that an infant formula that is being marketed in the United States for the first time is classified as a “new infant formula,” FDA is revising the definition of “new infant formula” (proposed § 106.3(l)) by inserting at the end of the definition “or which has not previously been the subject of a submission under section 412(c) of the FD&C Act for the U.S. market.” With the addition of this language, any manufacturer that produces a formula that has not been the subject of such a submission will be considered a “new infant formula,” even if that manufacturer has been continuously manufacturing and marketing that formula abroad without making a major change. In addition, as explained in response to comment 328, this change is consistent with the notification requirements for a manufacturer of an infant formula for export only. Although a manufacturer of infant formula for export only must still submit a notification under section 412(c) of the FD&C Act, the formula is not for the U.S. market and the submission requirements in this interim final rule for such a formula differ from those required for an infant formula intended for the U.S. market. Therefore, the addition of the phrase “for the U.S. market” in the second clause of the definition of “new infant formula” Start Printed Page 7949makes it clear that the submission described in section 412(c) of the FD&C Act is that which is submitted for infant formula marketed in domestic commerce.

Although the phrase “or which has not previously been the subject of a submission under section 412(c) of the FD&C Act for the U.S. market” does not appear in the definition of “new infant formula” under the FD&C Act, the inclusion of such a phrase in the definition of “new infant formula” is well within FDA's authority. If the FD&C Act is silent or ambiguous with respect to the meaning of “new infant formula,” the Agency may interpret the term based on a reasonable construction of the statute. See Chevron U.S.A. Inc. v. Natural Resources Defense Council, 467 U.S. 837, 842-843; FDA v. Brown & Williamson Tobacco Corp., 529 U.S. 120, 132 (2000). There is ambiguity in the definition of “new infant formula” under section 412(c)(2) of the FD&C Act. As noted previously in this document, the word “includes” in the definition of new infant formula in section 412(c)(2) of the FD&C Act indicates that the term “new infant formula” was meant to encompass situations not described in the definition. See NORMAN J. SINGER & J.D. SHAMBIE SINGER, 2A SUTHERLAND STATUTORY CONSTRUCTION § 47:7 (7th ed. 2009) (explaining that when a statutory definition declares what it “includes,” it “conveys the conclusion that there are other items includable, though not specifically enumerated”). The situations described in the FD&C Act's definition of “new infant formula” do not encompass, for example, a situation where an infant formula manufacturer who has been manufacturing and marketing formula abroad decides to market that formula in the United States.

Because the FD&C Act's definition of “new infant formula” is ambiguous, the Agency may establish a regulation to fill any gaps in that definition so long as it is not “arbitrary, capricious, or manifestly contrary to the statute.” See Chevron, 467 U.S. at 844. Adding to the definition of “new infant formula” to account for a situation where an infant formula manufacturer who has been manufacturing and marketing formula abroad decides to market that formula in the United States is clearly consistent with the overall purpose of the Infant Formula Act. The Infant Formula Act and the 1986 Amendments were intended to ensure the “safety and nutrition” of infant formulas. See Public Law 96-359, 94 Stat. 1190, 1190 (1980). Without defining “new infant formula” as described previously in this document, however, FDA would not be able to ensure the safety and nutrition of all infant formulas imported into the United States, because a firm that had already been manufacturing and marketing a formula abroad would not need to register with FDA or make a submission to FDA demonstrating compliance with the applicable U.S. laws.

6. Nutrient (Proposed § 106.3(m))

The proposed rule defined “nutrient” to mean “any vitamin, mineral, or other substance or ingredient that is required in accordance with the table set out in section 412(i)(1) of the FD&C Act or by regulations issued under section 412(i)(2) or that is identified as essential for infants by the Food and Nutrition Board of the National Research Counsel through its development of a Recommended Dietary Allowance or an Estimated Safe and Adequate Daily Dietary Intake range, or that has been identified as essential for infants by the Food and Drug Administration through a Federal Register publication.”

(Comment 20) One comment suggested limiting the definition of “nutrient” to “any vitamin, mineral, or other substance or ingredient in infant formula that is required by the act or by regulations issued pursuant to the act.” The comment asserted that the intent of the proposed definition is to describe the ways in which nutrients can be added to the list of those already required in § 107.100. The comment stated that it interpreted both the proposed language and the suggested revision as applying to “essential” nutrients, and not to other potential or current ingredients in infant formula. On this basis, the comment stated that the regulations should not create restrictions on the ability of a manufacturer to include new ingredients that are in compliance with existing regulations, nor should the regulations affect substances that are being added currently in compliance with existing regulations.

(Response) The proposed definition of “nutrient” included “any vitamin or mineral” or “other substance or ingredient” that is (1) Required in accordance with the table in section 412(i)(1) of the FD&C Act; (2) required by FDA under section 412(i)(2) of the FD&C Act; or (3) identified as “essential” consistent with the regulations in § 107.10(b)(5). FDA believes that the comment confuses the declaration of “required nutrients” and the declaration of “essential nutrients,” with the use of “other substances or ingredients” that a manufacturer may add when producing an infant formula that are not declared as either “required” or “essential” nutrients. Thus, the Agency provides the following clarification.

The definition of “nutrient” in proposed § 106.3(m) included not only vitamins and minerals that may be considered required or essential nutrients, but includes the potential for another “substance or ingredient” that is not a vitamin or mineral to be a required or essential nutrient. In the preamble to the 1996 proposal, the Agency stated that “nutrients that are required to be in infant formula under § 107.100 will be referred to as 'required nutrients'”(61 FR 36154 at 36155). Such nutrients include those listed in the table in section 412(i) of the FD&C Act and those that FDA may require, if FDA revises such table by regulation. Importantly, there are currently several vitamins and minerals (i.e., selenium, chromium, and molybdenum) that are considered “essential” nutrients (not “required” nutrients) based on one of the following: (1) Identified as essential by NAS through its development of a recommended dietary allowance or an estimated safe and adequate daily dietary intake range; (2) identified as essential by the FDA through a Federal Register publication; or (3) identified as essential under the 10th edition of the Food and Nutrition Board's Recommended Dietary Allowances (RDA), 21 CFR 107.10(b)(5). Under the proposed definition of “nutrient,” a vitamin, or mineral, or other substance or ingredient that is “essential” may be declared on the infant formula label when provided at a level considered in the publications as having biological significance, when this level is known (§ 107.10(b)(5)(ii)). Section 107.10(b)(5) limits the label declaration of vitamins and minerals added to in an infant formula that are not otherwise required to those that are “essential.” Thus, FDA included, in the proposed definition of “nutrient,” those substances “determined to be essential by the Food and Nutrition Board of the National Research Council or by the FDA” to be consistent with § 107.10(b)(5) on labeling information (61 FR 36154 at 36157). In the preamble to the final rule implementing section § 107.10(b)(5), FDA stated that the “declaration of nutrients that are not required by the Infant Formula Act, not considered to be essential by the NAS or FDA, and not at levels considered to have biological significance is considered to be a misbranding violation under section 403(a)(1) of the FD&C Act . . . because including such nutrients in the nutrient table or declaring a nutrient at a level Start Printed Page 7950that may not have biological significance implies a level of significance or usefulness in human nutrition that has not been established” (50 FR 1833 at 1836 (January 14, 1985)). Therefore, under the proposed definition of “nutrient,” any vitamin, mineral, and other substance or ingredient that is not a “required nutrient” or an “essential nutrient,” as those terms are used in § 107.10, cannot be part of the nutrient declaration of an infant formula. Ingredients that may be considered “nutrients” but that are not “required nutrients” or “essential nutrients” may be added to infant formula provided that the use of the specific chemical form of the ingredient is in accordance with the 'Agency's food additive regulations, is generally recognized as safe (GRAS), or is authorized by a prior sanction. Thus, for these reasons, limiting the definition of “nutrient” to include only substances required under section 412(i) of the FD&C Act, or regulations issued under such section is not warranted. Accordingly, FDA is not changing the definition for “nutrient” in proposed § 106.3(m) in response to this comment.

(Comment 21) One comment questioned FDA's authority to “sub-delegate” to the Food and Nutrition Board of the National Research Council the 'Agency's authority to establ