Draft Guidance for Industry: Protein Efficiency Ratio (PER) Rat Bioassay Studies to Demonstrate that a New Infant Formula Supports the Quality Factor of Sufficient Biological Quality of Protein February 2023
Not for implementation. Contains non-binding recommendations.
This guidance is being distributed for comment purposes only.
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Guidance Issuing OfficeCenter for Food Safety and Applied Nutrition
The Infant Formula Act of 1980 (Pub. L. 96-359) amended the Federal Food, Drug, and Cosmetic Act (FD&C Act) to include section 412 (21 U.S.C. 350a). In 1986, Congress amended section 412 of the FD&C Act to require FDA to establish quality factors for infant formula and stipulated that an infant formula would be considered adulterated if it does not meet the quality factor requirements. On June 10, 2014, as part of the final rule, Current Good Manufacturing Practices, Quality Control Procedures, Quality Factors, Notification Requirements, and Records and Reports, for Infant Formula (Infant Formula Final Rule), FDA established requirements for quality factors for infant formulas (79 FR 33057), including the quality factor of sufficient biological quality of protein (21 CFR 106.96(e) and (f)).
An infant formula must meet the quality factor of sufficient biological quality of protein (21 CFR 106.96(e)). Specifically, 21 CFR 106.96(f) describes how an infant formula manufacturer must demonstrate that a formula meets this quality factor:
A manufacturer of an infant formula that is not an eligible infant formula shall demonstrate that a formula meets the quality factor of sufficient biological quality of protein by establishing the biological quality of the protein in the infant formula when fed as the sole source of nutrition using an appropriate modification of the Protein Efficiency Ratio (PER) rat bioassay described in the “Official Methods of Analysis of AOAC International,” 18th ed., sections 45.3.04 and 45.3.05, “AOAC Official Method 960.48 Protein Efficiency Ratio Rat Bioassay,” which is incorporated by reference at § 106.160 (see Appendix 1). The PER rat bioassay shall be conducted on a formula and the results evaluated prior to the initiation of a growth monitoring study of the formula that is required under 21 CFR 106.96(b).
Conducting a PER study in an animal model permits a determination of a formula’s protein quality before infants are exposed to the formula. This approach ensures that infants will not be fed a formula with inadequate or biologically unavailable protein.
We have developed this guidance to help manufacturers and laboratories in the design, conduct, evaluation, and reporting of PER studies. The guidance is intended to explain how the PER study can be used to provide assurance that a new infant formula meets the quality factor of sufficient biological quality of protein in the infant formula when fed as the sole source of nutrition using appropriate modifications of AOAC Official Method 960.48 (the AOAC Method; Reference 1) (see 21 CFR 106.96(f)).
In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
 See Anti-Drug Abuse Act of 1986, Pub. L. 99-570, § 4014.
 We support the principles of the “3Rs” to reduce, refine and replace animal use in testing when feasible. We encourage sponsors to consult with us if they wish to use a non-animal testing method they believe is suitable, adequate, and validated to demonstrate that the formula supports the quality factor for the biological quality of the protein as described in 21 CFR 106.96(g)(3). We support alternative methods by exemption in 21 CFR 106.96(f) which allows the manufacturer to request an exemption and provide certain required assurances described in 21 CFR 106.96(g). The applicability of this exemption is not the subject of this guidance.
 Current Good Manufacturing Practices, Quality Control Procedures, Quality Factors, Notification Requirements, and Records and Reports, for Infant Formula, Interim Final Rule, 79 FR 7934, at 8023, Feb. 10, 2014.