Agency Response Letter GRAS Notice No. GRN 000468
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CFSAN/Office of Food Additive Safety
December 23, 2013
Steven Hagens, Ph.D.
Nieuwe Kanaal 7P
6709 PA Wageningen
Re: GRAS Notice No. GRN 000468
Dear Dr. Hagens:
The Food and Drug Administration (FDA) is responding to the notice, dated April 2, 2013, that you submitted 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 9, 2013, filed it on April 30, 2013, and designated it as GRAS Notice No. GRN 000468.
The subject of the notice is a preparation containing the bacterial monophages FO1a and S16, specific to Salmonella serovars (Salmonella phage preparation). The notice informs FDA of the view of Micreos B.V. (Micreos) that Salmonella phage preparation is GRAS, through scientific procedures, for use as an antimicrobial to control Salmonella serovars in certain pork and poultry products at levels up to 108 plaque forming units per gram (PFU/g) of food.
Our use of “Salmonella phage preparation” 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, Labeling, and Dietary Supplements in the Center for Food Safety and Applied Nutrition.
Micreos describes Salmonella phage preparation as a clear, odorless liquid containing equal concentrations of phages FO1a and S16 in water. Phage FO1a was isolated from material obtained from a sewage plant in Zurich, Germany, and phage S16 was isolated from material obtained from a sewage plant in The Netherlands. According to Micreos, both phages are virulent (strictly lytic) and are specifically effective against Salmonella serovars. Micreos notes that phages consist of proteins and nucleic acids.
Micreos describes the method of manufacture for Salmonella phage preparation. The production strain for phages FO1a and S16 is a Salmonella bongori strain that has been deposited in culture repositories under the accession numbers NCTC 12419, DSM 13772, and ATCC 43975.(1) Phages FO1a and S16 are produced separately by fermentation using the S. bongori production strain. The phage-infected S. bongori cultures are fermented under controlled agitation and aeration. After fermentation, the cultures are centrifuged and filtered to remove cellular debris. The phages are purified and concentrated via ion exchange chromatography, then mixed and diluted with water to achieve a final concentration of 1011 PFU per milliliter (PFU/mL) of each phage in the commercial product. Micreos notes that the fermentation medium used during the manufacturing process contains only GRAS ingredients and processing aids. (2),(3)
Micreos provides specifications for potency (2x1011 PFU/mL), sterility, purity, total nitrogen, total organic carbon, and sulfur. Micreos also provides limits for heavy metals: arsenic (< 2 micrograms per liter (µg/L)), mercury (< 0.5 µg/L), and lead (< 8 µg/L). Salmonella phage preparation is stable for six months at 2–8 ºC.
Micreos estimates the dietary exposure to Salmonella phage preparation for the United States population based on per capita consumption data from the U.S. Department of Agriculture’s Economic Research Services. Based on the intended use in certain pork and poultry products, Micreos estimates that people will consume 2.8 x 1010 PFU per person per day.
Micreos discusses generally available, published, and unpublished information supporting the safety of Salmonella phage preparation. The genomes of both phages have been fully sequenced and are publicly available in the Genbank database. Micreos compares all phage FO1a and phage S16 open reading frames encoding proteins ≥ 29 amino acids against protein sequences found in the National Center for Biotechnology Information database and against amino acid sequences in the Allergen Online Database (University of Nebraska). These analyses did not reveal any similarities between phage FO1a or phage S16 genes or proteins and those known to be involved in pathogenicity or toxicity and those of known food allergens. Micreos discusses published information demonstrating that the structure of the phage FO1a genome eliminates the possibility for transduction of host DNA to other bacteria. Micreos states that unpublished analyses show that phage S16 does not transduce host DNA to other bacteria.
Micreos discusses generally available information about bacteriophages. Bacteriophages do not usually cross species or genus boundaries and thus, would not be expected to affect commensal bacteria in the gastrointestinal tract. Phages are the most abundant self-replicating units in the environment and are present in significant numbers in water, fermented foods such as sauerkraut and cheeses, and other foods including meats, poultry, and vegetables. Given their ubiquitous presence in foods, phages are routinely consumed at high levels and their prevalence in the human gastrointestinal tract is documented. Micreos further notes that phages are digested to common amino acids and nucleic acids found in foods.
Use in Products under USDA Jurisdiction
During its evaluation of GRN 000468, FDA consulted with the Risk and Innovations Management Staff (RIMS) of the Food Safety and Inspection Service (FSIS) of the United States Department of Agriculture (USDA). Under the Federal Meat Inspection Act, Poultry Products Inspection Act, and the Egg Products Inspection Act, FSIS is responsible for determining the efficacy and suitability of food ingredients in meat, poultry, and egg products as well as prescribing safe conditions of use. Suitability relates to the effectiveness of the ingredient in performing the intended purpose of use and the assurance that the conditions of use will not result in an adulterated product, or one that misleads consumers.
FSIS has determined that Micreos has provided sufficient data to support that Salmonella phage preparation is suitable for use as an antimicrobial and processing aid in the production of certain pork and poultry products as described below, to reduce Salmonella serovars. FSIS notes that Salmonella phage preparation would be applied at prechill and postchill locations on raw pork cuts and raw poultry carcasses and parts at a level up to 108 PFU/g of treated food. For the notified pork and poultry products treated with Salmonella phage preparation, FSIS states that there will be no requirement for labeling, so long as the conditions of intended use are satisfied.
FSIS requested that FDA advise Micreos to seek regulatory guidance from the RIMS of FSIS, about the use of Salmonella phage preparation in meat, poultry, and egg products. Micreos should direct such an inquiry to Dr. William K. Shaw Jr., Director, Risk and Innovations Management Staff, Office of Policy and Program Development, Food Safety and Inspection Service, via email at William.Shaw@fsis.usda.gov.
Section 301(ll) of the Federal Food, Drug and Cosmetics Act (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 Micreos’ notice that Salmonella phage preparation is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing phage preparation. Accordingly, this response should not be construed to be a statement that foods that contain phage preparation, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Micreos, as well as other information available to FDA, the agency has no questions at this time regarding Micreos’ conclusion that Salmonella phage preparation 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 phage preparation. As always, it is the continuing responsibility of Micreos 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 000468, 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
cc: William K. Shaw Jr., Ph.D.
Stop Code 3782, Patriots Plaza III
1400 Independence Ave. SW
Washington, DC 20250-3700
(1)Micreos cites published information showing that S. bongori strains do not cause infections in humans and do not produce enterotoxin.
(2)Micreos states that the only fermentation medium component with potential food allergenicity is a hydrolyzed soy peptone. Micreos states that the hydrolysis significantly reduces potential allergenicity. Micreos further states that the anion exchange chromatography conducted during purification of the phages further removes > 99% of all proteins, including medium components.
(3) FDA notes that soy is a major food allergen. The Food Allergen Labeling and Consumer Protection Act of 2004 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.