Agency Response Letter GRAS Notice No. GRN 000378

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CFSAN/Office of Food Additive Safety

March 26, 2012

Mark L. Itzkoff
Olsson Frank Weeda Terman Bode Matz PC
Attorneys At Law
Suite 400
1400 Sixteenth Street, N.W.
Washington, D.C. 20036

Re: GRAS Notice No. GRN 000378

Dear Mr. Itzkoff:

The Food and Drug Administration (FDA) is responding to the notice, dated April 13, 2011, that you submitted on behalf of PURAC 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 14, 2011, filed it on May 3, 2011, and designated it as GRAS Notice No. GRN 000378.

The subject of the notice is cultured dairy sources, sugars, wheat, malt, and fruit- and vegetable-based sources [1] fermented by Streptococcus thermophilus, Bacillus coagulans, Lactobacillus acidophilus, Lactobacillus paracasei subsp. paracasei, Lactobacillus plantarum, Lactobacillus sakei, Lactobacillus bulgaricus, and/or Proprionibacterium freudenreichii subsp. Shermanii, or mixtures of these microorganisms (hereinafter referred to as cultured substrates). The notice informs FDA of the view of PURAC that cultured substrates are GRAS, through scientific procedures, for use as antimicrobial agents in a variety of food categories typically at levels of 0.1 to 4.5%, including meat and poultry, but excepting infant formula and infant foods. The notice also states that use levels of cultured substrates will not result in exceeding the following concentrations of components of cultured substrates in the final products: 0.16% for sodium and calcium, 0.75% for potassium, 2.1% for lactate, 0.6% for acetate and propionate, 0.9% for protein, 0.25% for sugar and 0.1% for succinic acid.

Our use of "cultured substrates" 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 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. 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, PURAC includes a report by a panel of individuals (PURAC's GRAS panel) who evaluated the data and information that are the basis for PURAC's GRAS determination. PURAC considers its GRAS panel to be qualified by scientific training and experience to evaluate the safety of food ingredients. The data included information on the method of manufacturer and product specifications, analytical data, intended use levels, consumption estimates for all intended uses, and a comprehensive assessment of literature concerning the safety of cultured substrates and their components. Based on this review, PURAC's GRAS panel concluded that cultured substrates, meeting the presented food grade specifications and manufactured in a manner consistent with current good manufacturing practices (cGMP), are GRAS based on scientific procedures.

PURAC discusses the method of manufacture of cultured substrates. PURAC states that all processing aids used in the manufacture of cultured substrates are used in compliance with federal regulations. PURAC states that cultured substrates are manufactured in accordance with cGMP. PURAC also states that pasteurization, sterilization, and purification are conducted as needed to ensure that cultured substrates meet product specifications. PURAC states that the fermentation processes are carried out by cultures comprised of one of the microorganisms noted above, or combinations of these microorganisms. PURAC states that following fermentation, the liquid culture is neutralized and then purified to remove biomass, ions, and other impurities. PURAC states that the products may be spray dried and spray agglomerated to produce powdered products, or they may be mixed with water or other liquefied culture substrates and pH adjusted to produce solutions. PURAC states that the final product is a mixture of sodium, potassium and calcium salts of lactic acid, acetic acid, and propionic acid, as well as sugars (glucose, fructose, sucrose, lactose, and galactose), protein, and succinic acid. PURAC states that the exact composition will vary depending on starting materials (substrates and bacteria) and conditions of the fermentation process, which are tailored to meet the customer's needs.

PURAC provides specifications for cultured substrates, including those for sodium, potassium, calcium, lactate, acetate, and propionate ions, protein, sugars, succinic acid, moisture, pH, and lead. PURAC also provides microbial limits for cultured substrates.

PURAC calculates the estimated daily intake of cultured substrates [2] using four examples of cultured substrates products that are intended for use in specific food applications. For example, the cultured substrates product, PuraQ RS20 P, intended for use in cheese, contains calcium at levels of 11.0 to 14.0%, as calcium is the preferred cation for dairy products, but contains no sodium or potassium. PURAC estimated the 90th percentile all-user intakes for calcium, lactate, acetate and propionate for all proposed food uses of PuraQ RS20 P as 109, 359, 47, and 94 mg/person/day, respectively (1.7, 5.5, 0.7, and 1.4 mg/kg body weight/day, respectively).

PURAC reports on the safety of the cultured substrates and notes that all components of cultured substrates occur naturally in food, are approved for food use in the United States population, and/or are endogenous to the body. PURAC also reports on several published expert organizations/committee papers (Institute of Medicine, FAO/WHO Joint Expert Committee on Food Additives) to further support safety.

PURAC also discusses the nonpathogenic and nontoxigenic nature of the microorganisms that are used in the production of cultured substrates. PURAC states that these microorganisms do not produce antimicrobials during the manufacturing process for cultured substrates. PURAC also states that these microorganisms are commonly used as food ingredients, as well as in food processing applications.

Based on the data and information discussed above, PURAC concludes that the intended use of cultured substrates in food is safe.

Standards of Identity

In the notice, PURAC states its intention to use cultured substrates in foods, 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 Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) amends the Federal Food, Drug, and Cosmetic Act (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. Issues associated with labeling food are the responsibility of ONLDS.

Use in USDA Regulated Products

During its evaluation of GRN 000378, FDA consulted with the Risk and Innovations Management Division 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 determined that PURAC has provided sufficient data to support its conclusion that cultured substrates are suitable as an antimicrobial in meat and poultry products and has no objections to the use of cultured substrates at up to 4.5% of the product formula as an antimicrobial agent in meat and poultry products and ready to eat meat and poultry products that provide for the use of ingredients of this type. FSIS has suggested a product name of: "Cultured ______" where the blank is replaced by the common or usual name of the natural substrate used in fermentation, for example "Cultured whey."

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 PURAC's notice that cultured substrates are GRAS for the intended use, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing cultured substrates. Accordingly, this response should not be construed to be a statement that foods that contain cultured substrates, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).


Based on the information provided by PURAC, as well as other information available to FDA, the agency has no questions at this time regarding PURAC's conclusion that cultured substrates are 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 cultured substrates. As always, it is the continuing responsibility of PURAC 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 000378, 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

Dennis M. Keefe, Ph.D.
Office of Food Additive Safety
Center for Food Safety
and Applied Nutrition

cc: William K. Shaw, Jr.
Stop Code 3782, Patriots Plaza III, Cubicle 8-163A
1400 Independence Ave. SW
Washington, DC 20250-3700

[1] PURAC lists the substrates that it intends to culture for production of cultured substrates as follows: dairy sources (including milk, milk solids, whey, whey powder, whey permeate, lactose, yogurt), sugars (including those from corn, beet, palm, or sugar cane) and sugar sources (including honey, maple syrup, molasses, caramel), starches (including those from barley, corn, potato, rice, wheat, malt, and tapioca), fruit- and vegetable-based sources (including juices, pastes, and peels).

[2] In the notice, PURAC provides estimated exposures based on maximum usage of cultured substrates and does not consider replacement use. In an amendment dated September 19, 2011, PURAC notes that these original intake estimates are gross overestimates of the actual intakes and provides intake estimates for four examples of cultured substrate products that it states more accurately reflect the actual consumption of the major components of cultured substrate from the intended uses.

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