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  1. GRAS Notice Inventory

Agency Response Letter GRAS Notice No. GRN 000644

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See also Generally Recognized as Safe (GRAS).

CFSAN/Office of Food Additive Safety

October 11, 2016

Richard Kraska, Ph.D., DABT
GRAS Associates, LLC
27499 Riverview Center Parkway
Bonita Springs, FL 34134

Re: GRAS Notice No. GRN 000644

Dear Dr. Kraska:

The Food and Drug Administration (FDA) is responding to the notice, dated March 15, 2016, that you submitted on behalf of Ausnutria Hyproca B.V. (Hyproca) in accordance with the agency’s proposed regulation, proposed 21 CFR 170.36 (62 FR 18938; April 17, 1997; Substances Generally Recognized as Safe (GRAS); the GRAS proposal). FDA received the notice on March 21, 2016, filed it on May 5, 2016, and designated it as GRAS Notice No. GRN 000644. FDA received clarifying information from Hyproca on July 26, 2016.

The subject of the notice is a combination of nonfat dry goat’s milk (NFDGM) and goat whey protein concentrate (GWPC). The notice informs FDA of the view of Hyproca that the combination of NFDGM and GWPC is GRAS, through scientific procedures, for use as a source of protein in nonexempt infant formulas for term[1] infants at levels of 57% (±5%) of total protein for NFDGM and 43% (±5%) of total protein for GWPC.[2] Hyproca states that the combination of NFDGM and GWPC is intended to be the sole source of protein.

Our use of “NFDGM” and “GWPC” in this letter should not be considered an endorsement or recommendation of that term as an appropriate common or usual name for the purpose of declaring the substance in the ingredient statement of foods that contain that ingredient. Title 21 CFR 101.4 states that each ingredient must be declared by its common or usual name. In addition, 21 CFR 102.5 outlines general principles to use when establishing common or usual names for nonstandardized foods. Issues associated with labeling and the appropriate common or usual name of a food are the responsibility of the Office of Nutrition and Food Labeling in the Center for Food Safety and Applied Nutrition.

As part of its notice, Hyproca includes the statement of a panel of individuals (Hyproca’s GRAS panel) that evaluated the data and information that are the basis for Hyproca’s GRAS determination. Hyproca considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Hyproca’s GRAS panel evaluated information describing the identity, manufacturing process, product specifications, intended uses, and estimated dietary exposure for NFDGM and GWPC, as well as published studies supporting the safety of NFDGM and GWPC. Based on their review, Hyproca’s GRAS panel concludes that NFDGM and GWPC, produced in accordance with current good manufacturing practices (cGMPs) and meeting the defined specifications, is GRAS under the conditions of its intended use.

Hyproca describes the identity of NFDGM and GWPC. Hyproca describes NFDGM as a homogeneous off-white powder that is obtained by the removal of water from nonfat goat’s milk. Hyproca also describes GWPC as a homogeneous off-white powder that is produced using pasteurized goat whey.

Hyproca describes the manufacturing processes for NFDGM and GWPC. Hyproca states that NFDGM and GWPC are manufactured according to cGMPs and all other applicable manufacturing regulations and guidance for infant formulas. The method of manufacture for NFDGM starts with raw goat’s milk, which is centrifuged to remove fat. The resulting skimmed goat’s milk is pasteurized, cooled, and stored for up to 48 hours. Following storage, the skimmed goat’s milk is re-pasteurized, concentrated by evaporation, and then spray dried, resulting in the final powdered product. The method of manufacture for GWPC starts with whey obtained from pasteurized goat’s milk. Hyproca states that the whey may be concentrated by membrane filtration techniques, centrifugation, or both. The concentrated whey is then circulated along a semi-permeable membrane in a pressure-driven process to remove low molecular weight constituents (e.g., sugars and minerals) and retain high molecular weight constituents (e.g., protein and fat). When the desired protein content is achieved, Hyproca states that the retentate is concentrated by evaporation and dried.

Hyproca provides specifications for NFDGM and GWPC. Specifications for NFDGM include a minimum content of protein in milk solids (>34%), and limits for milkfat (<1.5%), moisture (<5%), lead (<0.15 milligrams (mg) per kilogram (kg)), cadmium (<0.01 mg/kg), and arsenic (< 0.1 mg/kg), as well as limits on microbial contaminants, including Cronobacter (absent in a 10 g sample). Hyproca states that specifications for NFDGM comply with those for nonfat dry milk from bovine sources that are included in FDA’s food standards for milk and cream products in 21 CFR 131.125. Specifications for GWPC include a minimum content of dry matter (>95%) and a specified range for proteins (35-80%). Specifications also include limits on ash (<6%), fat (<10%), carbohydrates (<50%), lead (<0.5 mg/kg), cadmium (<0.01 mg/kg), and arsenic (<0.1 mg/kg), as well as limits on microbial contaminants, including Cronobacter (absent in a 10 g sample). Hyproca states that specifications for GWPC are similar to specifications for bovine whey protein concentrate in the Food Chemicals Codex (FCC 8, 2013) and for whey protein concentrate in 21 CFR 184.1979c. Hyproca provides the results of three non-consecutive batch analyses of NFDGM and GWPC to demonstrate compliance with these specifications.

Hyproca provides estimates of dietary protein intake based on the intended use of NFDGM and GWPC in nonexempt infant formulas for term infants and estimates of energy requirements from the National Academy of Sciences, U.S. Dietary Reference Intakes (Institute of Medicine Panel on Micronutrients, 2005). Hyproca estimates that 6-month old male and female infants consume 16.1 g of protein per day (d) and 14.8 g/d, respectively, from NFDGM and GWPC. Hyproca provides estimates of dietary exposure to NFDGM and GWPC based on the intended use and infant formula consumption and body weight data from the U.S. National Health and Nutrition Examination Survey (Centers for Disease Control and Prevention, 2011; U.S. Department of Agriculture, 2011). The mean and 90th percentile dietary exposures to NFDGM by infants aged 0 to 6 months (users-only) are estimated at 19.3 and 27.8 g/d (3.18 and 5.12 mg/kg body weight (bw)/d), respectively. The mean and 90th percentile dietary exposures to NFDGM by infants aged 7 to 12 months (users-only) are estimated at 15.9 and 25.2 g/d (1.78 and 2.96 mg/kg bw/d), respectively. The mean and 90th percentile dietary exposures to GWPC by infants aged 0 to 6 months (users-only) are estimated at 11.8 and 17.0 g/d (1.94 and 3.12 mg/kg bw/d), respectively. The mean and 90th percentile dietary exposures to GWPC by infants aged 7 to 12 months (users-only) are estimated at 9.7 and 15.4 g/d (1.09 and 1.81 mg/kg bw/d), respectively.

Hyproca discusses published studies in animals and human infants to support the safety of NFDGM and GWPC. Hyproca provides a detailed discussion of the published study by Zhou et al. (2014). This study was a multicenter, randomized, double-blind controlled trial in which goat’s milk infant formula was fed to 101 infants and cow’s milk infant formula was fed to 99 infants for four months, with continuous feeding up to 12 months, in addition to complementary food. An exclusively breast-fed reference group of 101 infants was included in the study. The primary outcomes measured were infant weight, length, head circumference, and weights-for-lengths determined at enrollment, at 2 weeks, and at 1, 2, 3, 4, 6, and 12 months. The secondary outcomes measured at 4 months of age included blood biomarkers, such as hemoglobin, packed cell volume, serum creatinine, urea, albumin, ferritin, folate, and plasma amino acids. Hyproca states that there were no statistically significant differences in infant body weights, body lengths, head circumferences, and weights-for-lengths between the two formula-fed groups over the 12-month study period. Additionally, there were no adverse effects in the goat’s milk infant formula group with respect to the blood biomarkers. Hyproca also notes, based on published studies, that goat’s milk does not pose any increased likelihood of allergenicity compared to cow’s milk. Furthermore, Hyproca cites the publicly available scientific opinion of the European Food Safety Authority, which states that protein from goat’s milk can be a suitable protein source for infant and follow-on formulas.

Based on the data and information described above, Hyproca concludes that the combination of NFDGM and GWPC is GRAS for its intended use in nonexempt infant formulas for term infants.

Intended Use in Infant Formula

Under section 412 of the Federal Food, Drug, and Cosmetic (FD&C) Act, a manufacturer of a new infant formula must make a submission to FDA, providing required assurances about the formula, at least 90 days before the formula is marketed. Hyproca should be aware that FDA’s response to this GRAS notice does not alleviate the responsibility of any infant formula manufacturer who intends to market an infant formula that contains the combination of NFDGM and GWPC to make the submission required by section 412.

Section 301(ll) of the FD&C Act

Section 301(ll) of the FD&C Act prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FD&C Act, a biological product licensed under section 351 of the Public Health Service Act, or a drug or a biological product for which substantial clinical investigations have been instituted and their existence made public, unless one of the exemptions in section 301(ll)(1)-(4) applies. In its review of Hyproca’s notice that the combination of NFDGM and GWPC is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing the combination of NFDGM and GWPC. Accordingly, this response should not be construed to be a statement that foods that contain the combination of NFDGM and GWPC, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).

Conclusions

Based on the information provided by Hyproca, as well as other information available to FDA, the agency has no questions at this time regarding Hyproca’s conclusion that the combination of NFDGM and GWPC is GRAS for use as a source of protein in nonexempt infant formulas for term infants, provided that the ingredient statement of food products that contain the combination of NFDGM and GWPC identify the source of protein. The agency has not, however, made its own determination regarding the GRAS status of the subject use of the combination of NFDGM and GWPC. As always, it is the continuing responsibility of Hyproca to ensure that food ingredients that the firm markets are safe, and are otherwise in compliance with all applicable legal and regulatory requirements.

In accordance with proposed 21 CFR 170.36(f), a copy of the text of this letter responding to GRN 000644, as well as a copy of the information in this notice that conforms to the information in the GRAS exemption claim (proposed 21 CFR 170.36(c)(1)), is available for public review and copying at www.fda.gov/grasnoticeinventory.

Sincerely,

Dennis M. Keefe, Ph.D.
Director
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition

[1] Hyproca states that the combination of NFDGM and GWPC is intended for full-term gestation infants up to 12 months of age.

[2] Hyproca states that the intended use of the combination of NFDGM and GWPC results in a whey-to-casein ratio of 60:40 in infant formulas. Hyproca also states that the intended use levels of NFDGM and GWPC are equivalent to 22.95 and 19 grams (g) per liter (L), respectively. Hyproca notes that the finished formula (2.5 g protein/100 kcal) complies with the protein requirements of CFR 107.100 and is similar to cow’s milk-based formula.

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