CFSAN/Office of Food Additive Safety

September 21, 2016

Richard Mann
Keller and Heckman LLP
1001 G Street NW, Suite 500W
Washington, DC 20001

Re: GRAS Notice No. GRN 000633

Dear Mr. Mann:

The Food and Drug Administration (FDA) is responding to the notice, dated February 18, 2016, that you submitted on behalf of Leprino Foods Company (Leprino) 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 February 19, 2016, filed it on March 18, 2016, and designated it as GRAS Notice No. GRN 000633. FDA received clarifiying information in amendments dated July 6, August 3, and August 9, 2016.

The subject of the notice is concentrated milk protein with a ≥60:40 whey:casein ratio (cMP≥W60:C40).^[1] The notice informs FDA of the view of Leprino that cMP≥W60:C40 is GRAS, through scientific procedures, for use^[2] as an emulsifier, flavoring agent, stabilizer and thickener, texturizer, foaming agent, and protein source in several food categories except where prohibited by standards of identity, at varying use levels, depending on technical effect, as shown in Table 1.^[3] Two forms of cMP≥W60:C40 are described in the notice: (1) cMP≥W60:C40 containing not less than (NLT) 79.5% protein on a dry basis (cMP80); and (2) cMP≥W60:C40 containing NLT 89.5% protein on a dry basis (cMP90).

Our use of “concentrated milk protein with a ≥60:40 whey:casein ratio,” “cMP≥W60:C40,” “cMP80,” or “cMP90” 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 (ONFL) in the Center for Food Safety and Applied Nutrition.

Leprino compares the cMP≥W60:C40 ingredient to various ingredients that have been the subject of previous GRAS notices, noting that, in general these support the safety of a variety of milk-based ingredients. These previous GRAS notices include: GRN 000037 (whey protein isolate), GRN 000196 (bovine milk basic protein fraction), and GRN 000504 (milk protein concentrate (MPC) and milk protein isolate (MPI)).^[4] Further, Leprino notes whey and whey protein concentrate ingredients that are affirmed as GRAS (21 CFR 184.1979 and 184.1979c) for use in food generally with no limitation other than current good manufacturing practice (cGMP). Leprino considers that the cMP≥W60:C40 ingredient, obtained by isolation of proteins directly from milk, is distinct from traditional whey-based ingredients that contain ingredients and byproducts of cheesemaking, but is similar with respect to protein composition to traditional concentrated whey ingredients.

In GRN 000633, Leprino describes the method of manufacture of cMP≥W60:C40, which is obtained from milk by physical separation processes, using food-grade semi-permeable membranes that are suitable for their intended use. The fluid milk starting material is produced in accordance with good agricultural practices, and meets applicable state and federal regulations. Leprino states that membrane materials meet applicable food contact regulations, including regulations for ultrafiltration (21 CFR 177.2910) and electrodialysis/ion-exchange (21 CFR 173.25) membranes. cMP≥W60:C40 is obtained by microfiltration followed or preceded by ultrafiltration of pasteurized whole or skim milk, and optionally, by nanofiltration, evaporation, dialysis, or by any other safe and suitable process in which all or part of the lactose, minerals, and moisture may be removed. Similar processes, including ultrafiltration, microfiltration, and dialysis were previously described in GRN 000504. Leprino considers that there is substantial overlap in the manufacturing processes between cMP80 and cMP90 and the GRN 000504 ingredients (i.e., MPC and MPI). In the amendment dated July 6, 2016, Leprino states that it considers all references in GRN 000504 and amendments thereto to be applicable to GRN 000633, due to the substantial similarities of the respective ingredients. Leprino considers the key distinction to be the level of casein, which is ≤40% in cMP80 and cMP90, but between 80% and 95% casein for MPCs and MPI with the “standard casein ratio” (reflecting ratio in fluid milk) or “altered casein ratio,” respectively as described in GRN 000504.^[5]

In GRN 000633, Leprino describes the method of manufacture for the two forms of cMP≥W60:C40 (i.e., cMP80 and cMP90), both produced in accordance with cGMPs. cMP80 and cMP90 are produced from pasteurized whole or skim milk by standard filtration methods used in the dairy industry to separate milk constituents by molecular size. Microfiltration enables adjustment of casein:whey ratio (from a typical level in milk at a ratio of 80% casein:20% whey) and ultrafiltration enables removal of water, ash/minerals, non-protein nitrogen, and lactose until the desired protein concentration is reached. To produce the higher protein level, a diafiltration step is used, to facilitate removal of further quantities of minerals and lactose. With microfiltration, only the large proteins (i.e., casein micelles) and fat globules remain in the retentate. Leprino notes that nanofiltration may also be used, primarily for removal of water, as described in the published literature for concentrated milk proteins. Dialysis may be used to further reduce mineral content of cMP≥W60:C40. Once the product has reached its target protein content and whey-to-casein ratio of ≥60:40 , it is further processed by evaporation/concentration, spray drying, and packaging. The resultant cMP80 and cMP90 product forms are free-flowing, off-white to light-tan colored powders. According to Leprino, manufacturers may add additional food additives or GRAS ingredients. Such additional ingredients would be used in accordance with cGMPs and any limitations stated in respective regulations or GRAS notices. An example of an added ingredient is lecithin (21 CFR 184.1400) for use in production of instantized cMP≥W60:C40.

Leprino provide specifications and typical composition for the two forms of cMP≥W60:C40. MP80 contains a minimum of 79.5% (w/w basis) crude protein. MP90 contains a minimum of 89.55% (w/w basis) crude protein. Although cMP≥W60:C40 commonly contains 20-30% casein, Leprino has set a maximum limit of 40% casein in this ingredient. For both cMP80 and cMP90, Leprino provides specifications for fat, ash, and moisture that vary slightly with protein level, although none exceed the following: fat content (not more than (NMT) 3.0%; limit includes added lecithin), ash content (NMT 5% for cMP80 and 4.5% for cMP90), moisture (NMT 5.5%). Specifications also include limits for lead (< 0.5 milligram per kilogram (mg/kg))^[6] and microbial contaminants. Leprino provides results of batch analyses (n=5) demonstrating compliance with specifications, with fat <1% in the absence of lecithin (0.1-0.7 % for both cMP80 and cMP90) and lactose reduction with increasing protein concentration (13.9-16.8% carbohydrate in cMP80; 3.3-4 % carbohydrate in cMP90).

Leprino states that its ingredient is intended to replace other concentrated milk protein products in foods, and is not expected to increase overall dietary intake of protein. Leprino compares its estimate of intake of protein from cMP≥W60:C40 with recommendations for fluid milk intake previously cited in GRN 000504 and the recommendations of the Institute of Medicine (2005) for intake of dietary protein.^[7] However, Leprino estimates dietary exposure, using data for micellar casein, to be 0.4 grams per person per day (g/p/d). While FDA does not question Leprino’s statement that cMP≥W60:C40 would substitute for currently-used milk protein ingredients, FDA does not concur with Leprino’s use of micellar casein as a proxy for cMP≥W60:C40 in its exposure estimates. In FDA’s view, a more relevant proxy would be a product of similar composition or technical effect (i.e., MPC/MPI or whey protein concentrate). As described in GRN 000504, the estimated dietary exposure to milk protein concentrate, which is intended for uses similar to those in GRN 000633 (with the exception of the added food category of acidified sports beverages in GRN 000633), is 6.2 g/p/d based on industry poundage data and assuming only 10 percent consumers. FDA also notes the availability of per capita consumption data for dairy products from the U.S. Department of Agriculture (USDA), Economic Research Service (ERS). The USDA ERS estimate for 2013 for dry whey (including dry whey, whey protein concentrate) is 2.2 pounds per person per year^[8] (equivalent to 2.7 g/p/d). The dietary exposure estimates in GRN 000504 and the USDA ERS estimate are still within the recommendations for protein intake established by IOM (2005) for protein.

Leprino considers that the subject of its GRAS notice, cMP≥W60:C40, is similar to traditional whey proteins that have been the subject of several previous GRAS notices. Therefore, Leprino incorporates the safety overview provided in GRN 000504 into GRN 000633 and highlights the relevance of those safety data to its assessment of cMP≥W60:C40. Briefly, Leprino states that the raw material used in the manufacture of cMP≥W60:C40 is milk or skim milk. Milk and products derived from milk, such as whey, have a long history of safe consumption by humans at all ages, except for milk-allergic and lactose intolerant individuals. Leprino notes that labeling will indicate the source of the product as milk and emphasizes that the lactose content of the final product forms, cMP80 and cMP90, is lower than that of milk. Therefore, Leprino concludes that no unanticipated effects would be expected for lactose intolerant individuals who may consume cMP≥W60:C40. Leprino performed an updated literature search, through June 2016, for any toxicological studies relevant to the cMP≥W60:C40 that may have been published after submission of GRN 000504. Although studies related to potential benefits of consuming whey and casein were found, Leprino reports that no studies relevant to toxicology was found that would alter its safety conclusion.

Standards of Identity

In the notice, Leprino states its intention to use cMP≥W60:C40 in several food categories, including foods for which standards of identity exist, located in Title 21 of the Code of Federal Regulations. We note that an ingredient that is lawfully added to food products may be used in a standardized food only if it is permitted by the applicable standard of identity.

Allergen Labeling

The Federal Food, Drug, and Cosmetic Act (FD&C Act) requires that the label of a food that is or contains an ingredient that bears or contains a “major food allergen” declare the presence of the allergen (section 403(w)). The FD&C Act defines 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. cMP≥W60:C40 derived from milk requires labeling under the FD&C Act, because it contains protein derived from milk.

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 Leprino’s notice that cMP≥W60:C40 is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing cMP≥W60:C40. Accordingly, this response should not be construed to be a statement that foods that contain cMP≥W60:C40, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).

Conclusions

Based on the information provided by Leprino, as well as other information available to FDA, the agency has no questions at this time regarding Leprino’s conclusion that cMP≥W60:C40 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 cMP≥W60:C40. As always, it is the continuing responsibility of Leprino 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 000633, 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

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^[1] Leprino refers to the subject of the notice as “native whey protein” to convey that the starting material for this ingredient is not whey derived from the cheese-making process; rather, it is obtained from filtration of milk. Leprino describes two forms of the ingredient: “native whey protein concentrate” containing not less than (NLT) 79.5% protein (dry basis) and “native whey protein isolate” containing NLT 89.5% protein (dry basis), respectively. Leprino refers to these collectively as “native whey proteins.” However, FDA notes that, although the ingredient is comprised predominantly (≥60%) of whey protein, it also contains a substantial amount of casein (up to 40%). For the purpose of this letter, FDA refers collectively to the subject of the notice as concentrated milk protein (≥ 60:40 whey:casein ratio), abbreviated cMP≥W60:C40, and to the two forms of the ingredient as cMP80 and cMP90.

^[2] In describing the ingredient, Leprino lists flavor enhancer, formulation aid, and humectant among the technical effects of cMP≥W60:C40; however, Leprino did not identify any food categories (Table 4 of GRN 000633) where these technical effects would apply. When asked for clarification, Leprino, in the amendment dated July 6, 2016, states that these technical effects were “secondary and are either superseded or subsumed by the primary effects” listed in Table 4 of GRN 000633. Given Leprino’s statement, FDA considers the primary technical effects listed in Table 4 of GRN 000633 to represent the intended technical effects for cMP≥W60:C40.

^[3] Leprino states that cMP≥W60:C40 is not intended for use in infant formula, nor is it intended for use in products under the jurisdiction of the U.S. Department of Agriculture. In the amendment dated July 6, 2016, Leprino clarifies that with the exception of the added food category of acidified sports beverages in GRN 000633, the food categories are the same as those in GRN 000504.

^[4] FDA does not currently have a standard definition for “milk protein concentrate” or “milk protein isolate” but relies on the information provided in GRN 000504, as well as published information regarding the identity and specifications for the ingredients that are the subjects of GRN 000504.

^[5] FDA notes that, although chromatography was listed as an optional process step in the method of manufacture, Leprino later clarified in the amendment dated August 3, 2016, that chromatography was not currently used to produce cMP80 or cMP90. Therefore, Leprino removed chromatography from the list of optional processes in the method of manufacture. FDA notes that, chromatography has been used to produce fractionated milk proteins (e.g., bovine milk basic protein fraction, lactoferrin) that have been the subjects of previous GRAS notices.

^[6] Updated specification for lead provided in amendment dated July 6, 2016.

^[7] The IOM’s recommended dietary allowance for protein is 56 g/p/d for adult men and 46 g/p/d for non-pregnant adult women.

^[8] U.S. Department of Agriculture, Economic Research Service. Dairy Data. Dairy Products: Per capita consumption, United States (Annual). http://www.ers.usda.gov/data-products/dairy-data.aspx#48505.