Agency Response Letter GRAS Notice No. GRN 000255
CFSAN/Office of Food Additive Safety
December 24, 2008
John B. Dubeck
Keller & Heckman LLP
1001 G Street, N.W.
Suite 500 West
Washington, D.C. 20001
Re: GRAS Notice No. GRN 000255
Dear Mr. Dubeck:
The Food and Drug Administration (FDA) is responding to the notice, dated April 18, 2008, that you submitted on behalf of Proliant Health Ingredients, Inc. (Proliant), 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 April 22, 2008, filed it on June 9, 2008, and designated it as GRAS Notice No. GRN 000255.
The subject of the notice is bovine globulin. The notice informs FDA of the view of Proliant that bovine globulin is GRAS, through scientific procedures, for use as an ingredient in dairy foods, fruit juices, vegetable juices, snack foods, beverages, and meal replacement products at a maximum use level not exceeding 50 grams per kilogram (g/kg) (5 percent) in the finished food. However, Proliant expects more typical use levels to be 2 - 20 grams per kilogram (g/kg) (0.2 percent-2 percent) in the finished food.
21 CFR 101.4 states that all ingredients must be declared by their common or usual name. In addition, 21 CFR 102.5 outlines general principles to use when establishing common or usual names for nonstandardized foods. Our use of "bovine globulin" 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. Issues associated with labeling and the appropriate common or usual name of a food are the responsibility of the Office of Nutrition, Labeling and Dietary Supplements in the Center for Food Safety and Applied Nutrition.
Proliant describes the identity, method of manufacture, and provides specifications, for bovine globulin. Bovine globulin is a cream colored powder, soluble in water, with a neutral flavor and odor. The notifier states that the manufacture of bovine globulin involves two stages, namely, plasma collection and globulin production. The plasma collection is performed at the animal processing plant after a post-mortem inspection by the United States Department of Agriculture/Food Safety and Inspection Service. The plasma from centrifuged blood is cooled to 45° F, and then transported to Proliant's manufacturing facility where it is further processed to produce bovine globulin. The notifier describes bovine globulin as a purified immunoglobulin protein isolate obtained by removal of fibrin and albumin proteins from bovine plasma by chemical and mechanical processes in accordance with current good manufacturing practices (cGMP). The finished product is a spray-dried concentrate. Specifications include protein content (≥ 85 percent) of which ≥ 45 percent is immunoglobulin G, fat (≤ 1.5 percent), moisture (≤ 8 percent), ash (≤ 3 percent) and limits for microbiological counts.
Proliant calculates an estimated daily intake of bovine globulin to be 30 grams per person per day (g/p/d) based on a typical use level of 2 percent of all solid foods consumed by an average adult male.1 Proliant considers that this estimation exaggerates the expected amount of bovine globulin to be added to the diet. Proliant states that a more reasonable estimate is 2.5 to 25 g/p/d, depending on the level of consumption and the variety of food types consumed. Proliant mentions that bovine globulin has a self-limiting use level in food with levels greater than 5 percent leading to adverse, undesirable flavor profiles.
Proliant summarizes published safety studies supporting the safe use of bovine globulin in foods. Specifically, the notifier reports the results of studies conducted in weanling pigs and calves on the safety and nutritional performance of spray-dried animal plasma containing 10-25 percent of immunoglobulins. Proliant concludes that these studies show no adverse effects. Further, the notifier includes studies regarding the oral ingestion of bovine plasma and immunoglobulin in infants and children demonstrating that oral consumption is well tolerated in humans.
Proliant discusses other safety concerns traditionally associated with protein concentrates. These concerns include: 1) the possible formation of unique amino acids during processing; 2) the potential concentration of toxic impurities when evaporations or extractions are involved in the processing; and, 3) the potential for allergenicity. The notifier states that the manufacturing process for bovine globulin yields no unique amino acids. Proliant states that their process ensures that no potential impurities will be concentrated in bovine globulin. Proliant tested representative lots to demonstrate that pesticide residues, heavy metal contaminants and antibiotic residues were below levels of concern. Proliant also states that no bovine spongiform encephalopathy (BSE)-related contaminants will be present in the product due to the effectiveness of measures taken by USDA to prevent BSE. Proliant concludes that allergenicity is of no concern because bovine globulin is highly digestible2 and bovine plasma has a history of safe use in human foods such as surimi, sausage, and processed meats.3 Proliant notes that, under The Food Allergen Labeling and Consumer Protection Act of 2004, bovine globulin does not fall under the definition of a "major food allergen" as one of eight foods or food groups (i.e., milk, eggs, fish, Crustacean shellfish, tree nuts, peanuts, wheat, and soybeans) or a food ingredient that contains protein derived from one of those foods.
Potential Labeling Issues
Under section 403(a) of the Federal Food, Drug, and Cosmetic Act (FFDCA), a food is misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FFDCA lays out the statutory framework for the use of labeling claims that characterize the level of a nutrient in a food or that characterize the relationship of a nutrient to a disease or health-related condition. In describing the intended use of bovine globulin and in describing the information that Proliant relies on to conclude that bovine globulin is GRAS under the conditions of its intended use, Proliant raises a potential issue under these labeling provisions of the FFDCA. This issue consists of Proliant's intended use of bovine globulin as a protein supplement. If products that contain bovine globulin bear any claims on the label or in labeling, such claims are the purview of the Office of Nutrition, Labeling and Dietary Supplements (ONLDS) in the Center for Food Safety and Applied Nutrition (CFSAN). The Office of Food Additive Safety (OFAS) neither consulted with ONLDS on this labeling issue nor evaluated the information in your notice to determine whether it would support any claims made about bovine globulin on the label or in labeling.
Section 301(ll) of the Federal Food, Drug, and Cosmetic Act (FFDCA)
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FFDCA to, among other things, add section 301(ll). Section 301(ll) of the FFDCA prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FFDCA, 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 Proliant's notice that bovine globulin is GRAS for use as an ingredient in various foods, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing bovine globulin. Accordingly, this response should not be construed to be a statement that foods that contain bovine globulin, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Proliant, as well as other information available to FDA, the agency has no questions at this time regarding Proliant's conclusion that bovine globulin is GRAS under the intended conditions of use. The agency has not, however, made its own determination regarding the GRAS status of the subject use of bovine globulin. As always, it is the continuing responsibility of Proliant 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 000255, 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 via the FDA home page at http://www.fda.gov. To view or obtain an electronic copy of the text of the letter, follow the hyperlinks from the "Food" topic to the "Food Ingredients and Packaging" section to the "Generally Recognized as Safe (GRAS)" page where the GRAS Inventory is listed.
Laura M. Tarantino, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
1Based on FDA's default values for food consumption, a person consumes 3000 g (or 3 kg) of food per day, of which 1500 g is from solid food.
2Though bovine globulin is highly digestible, Proliant recognizes that under certain conditions, there is a low level of immunological activity in the colon. However, animal studies showed that spray-dried animal plasma does not elicit an allergic response.
3FDA is aware of publications documenting the use of bovine globulin and plasma as an ingredient in food.