Agency Response Letter GRAS Notice No. GRN 000469
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CFSAN/Office of Food Additive Safety
June 7, 2013
Ray Matulka, Ph.D.
Director of Toxicology
801 North Orange Avenue, Suite 710
Orlando, FL 32801
Re: GRAS Notice No. GRN 000469
Dear Dr. Matulka:
The Food and Drug Administration (FDA) is responding to the notice, dated April 18, 2013, that you submitted on behalf of Solazyme Roquette Nutritionals, LLC (Solazyme) 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 19, 2013, filed it on May 15, 2013, and designated it as GRAS Notice No. GRN 000469.
The subject of the notice is Chlorella protothecoides strain S106 flour with 40-70% lipid (algal flour). The notice informs FDA of the view of Solazyme that algal flour is GRAS, through scientific procedures, for use as a partial replacement for cream, milk, eggs/egg yolks, and/or butter/shortening. Algal flour is intended for use in baked goods, beverages and beverage bases, breakfast cereals, cheese, non-dairy, egg products, fats and oils (including salad dressing and mayonnaise), frozen dairy products, puddings and custards, meal replacements, milk and milk products, snack foods, vegetable and seafood soups, and sweet sauces at levels ranging from 5 to 120 grams per kilogram (g/kg) of food.
Our use of “algal flour” 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 (ONLDS) in the Center for Food Safety and Applied Nutrition.
As part of its notice, Solazyme includes a report from a panel of individuals (Solazyme’s GRAS panel) that evaluated the data and information that are the basis for Solazyme’s GRAS determination. Solazyme considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Solazyme’s GRAS panel evaluated the identity and characteristic properties of C. protothecoides strain S106, as well as the method of manufacture, composition and specifications, estimates of dietary exposure, and published and unpublished data and information supporting the safety of algal flour. Based on this review, Solazyme’s GRAS panel concluded that algal flour produced in accordance with current good manufacturing practices and meeting established specifications is GRAS under the conditions of its intended use.
Solazyme discusses the identity and characteristic properties of C. protothecoides strain S106. Chlorella are nonmotile, unicellular, eukaryotic green microalgae that are widespread in fresh and salt water, soil, and air. Solazyme notes that C. protothecoides strain S106 was originally isolated from fresh water in The Netherlands and then deposited with the Culture Collection of Algae and Protozoa (CCAP) as a Chlorella vulgaris strain. The strain was later reclassified as C. protothecoides strain CCAP211/7C. The University of Texas’s UTEX Culture Collection of Algae obtained this strain from CCAP and designated it as strain S106.
Solazyme describes the method of manufacture of algal flour. Solazyme maintains frozen seed vials of C. protothecoides strain S106 in its culture bank and verifies the identity of the strain before fermentation. The fermentation medium is inoculated with the strain, and fermentation is conducted aseptically under controlled pH, temperature, agitation, and aeration rates. During fermentation, nutrients are added to the culture, and lipid production is induced under limiting inorganic nitrogen levels. After fermentation, the algal biomass is pasteurized to inactivate algal cells and separated from the fermentation medium by centrifugation. The algal biomass is then washed, concentrated, and milled. The pH is adjusted, and food grade antioxidants are added. The algal biomass is then homogenized, dried, and packaged. Solazyme states that a component of the fermentation medium contains wheat and that all ingredients used during the manufacturing process are suitable for use in food production.
Solazyme provides specifications for algal flour including appearance (golden yellow powder), fat (40-70%), oleic acid (at least 25% of the total fatty acids), fiber (10-50%), protein (2-15%), moisture (not more than 10%), and limits for microbial contaminants. The specifications also include limits for lead (<0.5 milligram (mg)/kg), arsenic (<0.2 mg/kg), mercury (<0.1 mg/kg), cadmium (<0.1 mg/kg), and chromium (<2 mg/kg). Solazyme provides batch analyses (three lots) demonstrating compliance with these specifications. Based on stability studies, Solazyme states that algal flour is stable for 12 months at -20°C in sealed foil pouches, and that the stability of the ingredient decreases at higher temperatures.
Solazyme estimates dietary exposure to algal flour, based on the United States Department of Agriculture’s 2003-2004 What We Eat in America Continuing Survey of Food Intakes by Individuals. Based on this survey, Solazyme estimates "eaters only" mean and 90th percentile intakes of 4.7 g per person per day (g/p/d) (78.3 mg/kg body weight (bw)/d) and 10.5 g/p/d (175 mg/kg bw/d), respectively.
Solazyme discusses the safety of C. protothecoides strain S106. Solazyme notes that all C. protothecoides strains held at ATCC are classified as Biosafety Level 1 organisms. The Centers for Disease Control considers that such organisms are not known to cause disease in healthy human adults. In addition, Solazyme discusses published information showing that C. protothecoides strain S106 does not produce algal toxins.
Solazyme discusses published and unpublished data and information supporting the safety of algal flour. In a published 90-day subchronic toxicity study, Hsd:Sprague Dawley rats, (n=10/sex/group) were fed diets of C. protothecoides S106 flour at up to approximately 4,800 mg/kg bw/d for males and 5,400 mg/kg bw/d for females; no adverse effects were observed. In a published 28-day study, Hsd:Sprague Dawley rats, (n=10/sex/group) were fed diets of C. protothecoides S106 flour at up to approximately 7,600 mg/kg bw/d for males and 8,100 mg/kg bw/d for females; no adverse effects were observed. The results of a published bacterial mutation study showed that algal flour (5000 microgram/plate) is neither genotoxic nor mutagenic. Additionally, a published study showed that algal flour did not induce a clastogenic response as evaluated by the bone marrow chromosomal aberration test in mice after a single oral dose (2000 mg/kg bw/d).
Solazyme analyzes the likelihood for food allergenicity of algal flour based on: (1) digestibility of the proteins contained within the algal strain, (2) information about C. protothecoides strain S106 proteins in the scientific literature, and (3) comparison of the amino acid sequences of proteins found in C. protothecoides strain S106 with sequences of known protein allergens. Solazyme states that proteins in C. protothecoides strain S106 are expected to be digested, absorbed, metabolized, and excreted through the same physiological processes as other plant materials common to the human diet. In its evaluation of the literature, Solazyme did not find any association of allergic response to any C. protothecoides strain. Solazyme conducted a BLAST query of the C. protothecoides strain S106 genome versus amino acid sequences of known allergens in SDAP. Based on its analyses of the results, Solazyme concludes that algal flour poses a low likelihood of food allergy.
Standards of Identity
In the notice, Solazyme states its intention to use algal flour 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.
Potential Requirement for a Color Additive Petition
In its notice, Solazyme describes algal flour as a golden yellow powder. As such, the use of algal flour in food products may constitute the use of a color additive under section 201(t)(1) of the Federal Food, Drug, and Cosmetic Act (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, ß-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, ß-carotene is used for both purposes. Importantly, if the use of algal flour 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, Solazyme states that the addition of its algal flour to the various food products occurs at sufficiently low levels, and that it will not impart significant color to the resulting food products. Furthermore, Solazyme states that the subject ingredient is not intended to function as a color additive and that the incorporation of algal flour with its golden yellow color falls outside of the definition of color additive (21 CFR 70.3(g)). Importantly, FDA’s response to GRN 000469 does not include any comment by FDA about Solazyme’s view of this issue. If, after receipt of this letter, Solazyme has any specific questions about this issue, we recommend that Solazyme contact the Division of Petition Review in the Office of Food Additive Safety (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. Algal flour obtained from cells grown on wheat-containing media may require labeling under FALCPA, because it may contain protein derived from wheat. Although issues associated with labeling food are the responsibility of the ONLDS, issues associated with FALCPA exemptions are the responsibility of the Food Allergen Coordinator in OFAS.
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 Solazyme’s notice that algal flour is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing algal flour. Accordingly, this response should not be construed to be a statement that foods that contain algal flour, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Solazyme, as well as other information available to FDA, the agency has no questions at this time regarding Solazyme’s conclusion that algal flour 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 algal flour. As always, it is the continuing responsibility of Solazyme 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 000469, 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