Agency Response Letter GRAS Notice No. GRN 000357
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CFSAN/Office of Food Additive Safety
April 19, 2011
Robert H. Sindt
Attorney at Law
1025 Thomas Jefferson Street, NW
Washington, DC 20007
Re: GRAS Notice No. GRN 000357
Dear Mr. Sindt:
The Food and Drug Administration (FDA) is responding to the notice, dated October 20, 2010, that you submitted on behalf of Danisco USA, Inc. (Danisco) 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 October 21, 2010, filed it on October 27, 2010, and designated it as GRAS Notice No. GRN 000357.
The subject of the notice is Lactobacillus acidophilus NCFM. The notice informs FDA of the view of Danisco that L. acidophilus NCFM is GRAS, through scientific procedures, for use as an ingredient in ready-to-eat breakfast cereals; bars; cheeses, milk drinks, and milk products; bottled water and teas; fruit juices, fruit nectars, fruit “ades,” and fruit drinks; chewing gum; and confections at a level to provide 109 colony forming units per standard serving1 (cfu/serving). Danisco states that the intended uses for L. acidophilus NCFM do not include infant formula or meat and poultry products.
Our use of Lactobacillus acidophilus NCFM or L. acidophilus NCFM in this letter should not be considered an endorsement or recommendation of these terms 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 of the Code of Federal Regulations (CFR) part 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, Labeling, and Dietary Supplements (ONLDS) in the Center for Food Safety and Applied Nutrition.
As part of its notice, Danisco includes the report of a panel of individuals (Danisco’s GRAS panel) who evaluated the data and information that are the basis for Danisco’s GRAS determination. Danisco considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Danisco’s GRAS panel evaluated information on the characterization of the strain, the manufacturing process, history of use in food, potential exposure, and safety studies. Based on this review, Danisco’s GRAS panel concluded that L. acidophilus NCFM, produced according to current good manufacturing practices and meeting its food-grade specifications, is GRAS under the conditions of its intended use.
Danisco discusses the identity and characteristic properties of L. acidophilus NCFM. Danisco describes L. acidophilus NCFM as a rod-shaped, non-motile and non-spore-forming lactic acid producing bacterium that occurs naturally in the human gut. The finished product is a white-to-cream powder. Danisco notes that L. acidophilus NCFM has been deposited in the ATCC as SD5221 and 700396, and in the German Collection of Microorganisms and Cell Cultures as 22091. Danisco notes that the strain was first isolated from human feces at North Carolina State University. Danisco states that the genome of L. acidophilus NCFM has been sequenced and no known antibiotic resistant genes were detected. Danisco also states that sequencing the 16S ribosomal RNA gene of L. acidophilus NCFM confirmed its identity as L. acidophilus. The genome sequence and corresponding annotation has been deposited in GenBank under accession number CP000033.
Danisco discusses the manufacturing process and provides microbial specifications for L. acidophilus NCFM. Danisco states that L. acidophilus NCFM is manufactured through a specific time and temperature controlled fermentation using food grade ingredients. Danisco describes the general preparation and characterization of the concentrated L. acidophilus NCFM starter culture from which the industrial fermentation is initiated. The starter culture is developed from seed lots that are independently verified for identity and stored at -80°C. The starter culture is then added to a sterilized fermentation broth and incubated to the fermentation end point at constant temperature. After the required incubation period, the pH is adjusted and the resulting bacteria are concentrated by centrifugation. Food-grade cryoprotectants are then added to the concentrated bacterial slurry and the mixture is subsequently freeze-dried, packaged, and stored in a cool, dry environment. Danisco states that the cultures are tested for stability on a regular basis to monitor shelf life over a 2-year storage period. Danisco provides microbial specifications for the L. acidophilus NCFM ingredient.
Danisco intends to use L. acidophilus NCFM as an ingredient in various foods at levels adjusted to provide 109 cfu/serving. To ensure a concentration of 109 cfu/serving throughout the shelf life of the food product, Danisco intends to add up to 5 x 1010 cfu/serving (depending on stability of the strain in the particular food product). Based on the assumption that the strain will be added to a limited number of foods and that consumers will likely obtain the intended amount of L. acidophilus NCFM in one serving per day, Danisco estimates a daily intake of L. acidophilus NCFM of 5 x 1010 cfu/day in the population aged 2 years and older.
Danisco discusses data from published studies that include genetic sequencing, a mouse study, and studies in human subjects using L. acidophilus NCFM, and concluded that no adverse effects were observed in the studies. Danisco also notes that L. acidophilus NCFM has been produced commercially since the 1970s, and is used in dairy products in the United States and globally with no reports of adverse effects to consumers. Based on these studies, the genomic data, and past use of the organism, Danisco concludes that use of L. acidophilus NCFM as an ingredient in food is GRAS, through scientific procedures, under the conditions of its intended use.
Standards of Identity
In the notice, Danisco states its intention to use L. acidophilus NCFM in several food categories, including foods for which standards of identity exist, located in Title 21 of the CFR. 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.
Potential Labeling Issues
In describing the clinical studies in support of the safe use of L. acidophilus NCFM, Danisco notes some results with potential health benefits. 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 relationship of an ingredient to a disease or health-related condition. If products that contain L. acidophilus NCFM bear any claims on the label or in labeling, such claims are the purview of ONLDS. The Office of Food Additive Safety 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 L. acidophilus NCFM on the label or in labeling.
Section 301 (ll) of the 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 Danisco’s notice that L. acidophilus NCFM is GRAS under the intended conditions of use, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing L. acidophilus NCFM. Accordingly, this response should not be construed to be a statement that foods that contain L. acidophilus NCFM, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Danisco, as well as other information available to FDA, the agency has no questions at this time regarding Danisco’s conclusion that L. acidophilus NCFM 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 L. acidophilus NCFM. As always, it is the continuing responsibility of Danisco 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 000357, 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.
Mitchell A. Cheeseman, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
1Reference amounts customarily consumed (21 CFR 101.12).