Agency Response Letter GRAS Notice No. GRN 000465
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CFSAN/Office of Food Additive Safety
February 18, 2014
Claire L. Kruger, Ph.D., D.A.B.T.
Spherix Consulting, a division of ChromaDex, Inc.
11900 Parklawn Drive, Suite 200
Rockville, MD 20852
Re: GRAS Notice No. GRN 000465
Dear Dr. Kruger:
The Food and Drug Administration (FDA) is responding to the notice, dated March 1, 2013, that you submitted on behalf of Morinaga Milk Industry Co., Ltd. (Morinaga) 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 4, 2013, filed it on March 22, 2013, and designated it as GRAS Notice No. GRN 000465. Additional clarifying information was provided on September 4, October 22, November 6, and November 25, 2013.
The subject of the notice is cow’s milk-derived lactoferrin(cMDLf). The notice informs FDA of the view of Morinaga that cMDLf is GRAS, through scientific procedures, for use as an ingredient in cow’s milk-based term infant formulas at a level of 13 milligrams (mg) per 100 milliliters of formula (ready-to-feed or prepared for consumption from powder or liquid concentrate).
As part of its notice, Morinaga includes the report of a panel of individuals (Morinaga’s GRAS panel) that evaluated the data and information that are the basis for Morinaga’s GRAS determination. Morinaga considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Morinaga’s GRAS panel evaluated estimates of dietary exposure, product specifications as well as published studies. Based on this review, Morinaga’s GRAS panel concluded that cMDLf is GRAS under the conditions of its intended use.
Morinaga describes cMDLf as an iron-binding glycoprotein that has been characterized in the published literature as a single polypeptide chain of approximately 700 amino acids, with a molecular weight of approximately 75-80 kilodaltons. cMDLf can exist in an iron-free or iron-saturated state; and, in the iron-saturated form, the glycoprotein is more resistant to proteolysis and thermal denaturation. cMDLf contains four N-linked glycans, which are composed of varying amounts of N-acetyllactosaminic acid, galactose, mannose, fucose, N-acetylglucosamine, and N-acetylneuraminic acid residues.
Morinaga describes the production of cMDLf. The notifier states that cMDLf can be produced from two possible starting materials: sweet whey (a byproduct of cheese production) or unpasteurized skim milk. Morinaga notes that the resulting cMDLf is produced similarly to published methods used for the purification of whey proteins and in accordance with current good manufacturing practices. Briefly, production starts by chilling the starting material below 8 degrees Celsius (˚C) to minimize microbial growth, followed by microfilteration to remove fat and other insoluble material. The filtrate is bound to a column or resin; and, the cMDLf is eluted with sodium chloride, desalted, ultrafiltered, and pasteurized at 75 ˚C for at least 15 seconds.
The pasteurized cMDLf solution is further concentrated by ultrafiltration and then freeze-dried and pulverized before packaging. Morinaga describes cMDLf as a pink, odorless powder. Further, the notifier notes that cMDLf is stable for up to 96 months when stored in polyethylene bags and up to 102 months when stored in aluminum bags.
Morinaga states that cMDLf complies with established food grade specifications and utilizes only food grade raw materials and processing aids. Morinaga further states that cow’s milk used to obtain lactoferrin is produced in accordance with good agricultural practices and in compliance with U.S. regulations, including applicable regulations for use of agricultural pesticides and veterinary drugs. Skim milk and sweet whey are produced from food-grade cow’s milk in accordance with current good manufacturing practices.
Morinaga provides specifications for cMDLf. cMDLf contains ≥94.5% protein (of which ≥96% is lactoferrin), iron (≤35 mg/100 grams (g)), 4.2% moisture, 1.3% ash, and 0.5% fat. Specifications also include limits for lead (≤1 mg/kilogram (kg)), arsenic (≤1 mg/kg), Cronobacter sakazakii (negative/333g), Salmonella (negative/25g), polychlorinated biphenyls, pesticides, certain veterinary drugs, and aflatoxin M1. Morinaga also provides batch analyses for non-consecutive lots of cMDLf.
Morinaga estimates dietary exposure for infants consuming formulas containing cMDLf at the intended use level using the protein concentrations, whey proteins to caseins ratios in the infant formulas, the amount of cMDLf in whey, and consumption data obtained from the National Center for Health Statistics' 2007-2008 National Health and Nutrition Examination Survey (NHANES) database. Morinaga states, that in general, infants 0 to 4 months of age would consume 100.3 mg/day (d) (17.5 mg/kg body weight (bw)/d) and 145.5 mg/d (26.4 mg/kg bw/d) of cMDLf at the mean and 90th percentile, respectively. Infants aged 5 to 11 months would consume 87.4 mg/d (10.1 mg/kg bw/d) and 129.0 mg/d (14.7 mg/kg bw/d) of cMDLf at the mean and 90th percentile, respectively.
Morinaga further explains that infants are currently exposed to cMDLf with the consumption of cow’s milk-based infant formula and that with the consumption of cMDLf from the intended uses their average daily exposure will increase by approximately two-fold. Morinaga also notes, that the intended cMDLf use levels in this GRAS notice are eight times less than the levels approved for use in Europe and at least eight times less than the levels of lactoferrin in breast milk.
Morinaga discusses published information in support of the safe use of cMDLf. As part of its discussion, Morinaga considers the absorption, distribution, metabolism and elimination of cMDLf. The notifier examines a published Ames assay indicating that cMDLf was not genotoxic. In addition, the notifier reviews a published 13 week study in male and female rats exposed to cMDLf (200, 600 and 2000 mg/kg bw/d) in which no toxicologically significant treatment-related changes were observed by the study authors at any exposure level. Also, the notifier communicates a published study in which male rats (for 60 weeks) and female rats (for 65 weeks) received up to 5% cMDLf (equivalent to approximately 2,000 mg/kg bw/d) in the diet with no adverse effects noted by the study authors. Furthermore, multiple published human clinical trials in infants (consuming up to 2.9 g/d cMDLf for up to one year) are evaluated by the notifier with no significant adverse effects noted. Finally, the notifier discusses published information about immunomodulation, allergenicity, hypersensitivity and oral tolerance as it relates to cMDLf. Morinaga states that no evidence exists to conclude that cMDLf is a clinically relevant allergen or has the ability to promote the development of, or exacerbate allergenicity, hypersensitivity, immunomodulation or develop an oral tolerance.
Morinaga also cites findings from the European Food Safety Authority Expert Panel that evaluated bovine lactoferrin and determined that use in general foods is safe at levels ranging from 60 to 100 mg/serving and in infant formulas at levels ranging from 40 to 1000 mg/liter.
Based on the totality of the data and information described above, Morinaga concludes that cMDLf is well tolerated and is GRAS for its intended use in term infant formula.
Potential Labeling Issues
In describing data and information on clinical studies that Morinaga relies on to conclude that cMDLf is GRAS under the conditions of its intended use, Morinaga raises a potential issue under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act). Under section 403(a) of the FD&C Act, a food is misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FD&C Act 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. If products that contain cMDLf 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. 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 cMDLf on the label or in labeling.
Potential Requirement for a Color Additive Petition
In its notice, Morinaga describes cMDLf as a pink powder. As such, the use of cMDLf in food products may constitute the use of a color additive under section 201(t)(1) of the FD&C Act and FDA’s implementing regulations in 21 CFR Part 70. Under section 201(t)(1) and 21 CFR 70.3(f), the term color additive means a material that is a dye, pigment, or other substance made by a process of synthesis or similar artifice, or extracted, isolated, or otherwise derived from a vegetable, animal, mineral, or other source, and that is capable (alone or through reaction with another substance) of imparting color when added or applied to a food; except that such term does not include any material which the Secretary,
by regulation, determines is used (or intended to be used) solely for a purpose or purposes other than coloring. Under 21 CFR 70.3(g), a material that otherwise meets the definition of color additive can be exempt from that definition on the basis that it is used or intended to be used solely for a purpose or purposes other than coloring, as long as the material is used in a way that any color imparted is clearly unimportant insofar as the appearance, value, marketability, or consumer acceptability is concerned. Given the construct of section 201(t)(1) of the FD&C Act and 21 CFR 70.3(f) and (g), the use of a substance that is capable of imparting color may constitute use as a color additive in addition to use as a food additive or GRAS substance. For example, β-carotene is both approved for use as a color additive (21 CFR 73.95) and affirmed as GRAS for use as a nutrient supplement (21 CFR 184.1245); in some food products, β-carotene is used for both purposes. Importantly, if the use of cMDLf constitutes use as a color additive within the meaning of section 201(t)(1) of the FD&C Act and FDA’s implementing regulations in 21 CFR 70.3(f) and (g), section 721(a) of the FD&C Act requires premarket review and approval of that use by FDA. Under section 402(c) of the FD&C Act, a food product that contains an unapproved color additive would be deemed adulterated.
In its notice, Morinaga considers that the addition of cMDLf would be at sufficiently low levels that it will not impart significant color to the resulting food products and that cMDLf is not intended to function as a color additive. Importantly, FDA’s response to GRN 000465 does not include any comment by FDA about Morinaga’s view of this issue. If, after receipt of this letter, Morinaga has any specific questions about this issue, we recommend that Morinaga contact the Division of Petition Review in OFAS.
The Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) amends the FD&C Act to require 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)). FALCPA 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. cMDLf is a milk-based ingredient that requires labeling under FALCPA, because it contains protein derived from milk. Although issues associated with labeling food are the responsibility of ONLDS, issues associated with FALCPA exemptions are the responsibility of the Food Allergen Coordinator in OFAS.
Intended Use in Infant Formula
Under section 412 of the 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. Morinaga should be aware that FDA’s response to Morinaga’s GRAS notice does not alleviate the responsibility of any infant formula manufacturer who intends to market an infant formula that contains cMDLf to make the submission required by section 412.
Section 301(ll) of the FD&C Act
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FD&C Act to, among other things, add section 301(ll). 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 Morinaga’s notice that cMDLf is GRAS for the intended use, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing cMDLf. Accordingly, this response should not be construed to be a statement that foods that contain cMDLf, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Morinaga, as well as other information available to FDA, the agency has no questions at this time regarding Morinaga’s conclusion that cMDLf 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 cMDLf. As always, it is the continuing responsibility of Morinaga 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 000465, 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.
Dennis M. Keefe, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
Per Morinaga, the pasteurization conditions exceed the requirements for pasteurization of milk as described in the FDA’s Grade “A” Pasteurized Milk Ordinance (revised 2009).
ESFA Scientific panel on Dietetic Products, Nutrition and Allergies (2012).
The Secretary of the Department of Health and Human Services.
We note that section 721(b)(4) of the FD&C Act provides that a color additive shall be deemed to be safe and suitable for the purpose of listing under section 721(b) of the FD&C Act while there is in effect a published finding of the Secretary declaring that the substance is exempt from the definition of “food additive” because of its being generally recognized by qualified experts as safe for its intended use as provided in section 201(s) of the FD&C Act. Importantly, FDA’s response to GRN 000465 does not constitute a “finding of the Secretary” within the meaning of section 721(b)(4) of the FD&C Act.