Mr. Steven M. Rapp
Vice President and General Counsel
Unilever North America
800 Sylvan Avenue – B1
Englewood Cliffs, New Jersey 07632
Re: Food Allergen Labeling Notification 008 – Ice Structuring Protein
Dear Mr. Rapp:
This letter is in response to a notification from Unilever North America (Unilever), received on January 7, 2013, and designated FALN 008. The notification was submitted pursuant to section 403(w)(7) of the Federal Food, Drug, and Cosmetics Act (the FD&C Act) (21 U.S.C. 343(w)(7)). Section 403(w)(7) of the FD&C Act provides that, “(A) A person need not file a petition under paragraph (6) to exempt a food ingredient described in section 201(qq)(2) from the allergen labeling requirements of [section 403(w)], if the person files with the Secretary a notification containing-- (i) scientific evidence (including the analytical method used) that demonstrates that the food ingredient (as derived by the method specified in the notification, where applicable) does not contain allergenic protein; or (ii) a determination by the Secretary that the ingredient does not cause an allergic response that poses a risk to human health under a premarket approval or notification program under section 409. (B) The food ingredient may be introduced or delivered for introduction into interstate commerce as a food ingredient that is not a major food allergen 90 days after the date of receipt of the notification by the Secretary, unless the Secretary determines within the 90-day period that the notification does not meet the requirements of [section 403(w)(7)], or there is insufficient scientific evidence to determine that the food ingredient does not contain allergenic protein or does not cause an allergenic response that poses a risk to human health.”
The Unilever notification informed the U.S. Food and Drug Administration (FDA or “we”) of Unilever’s conclusion that ice structuring protein (ISP) preparation from a bioengineered strain of Saccharomyces cerevisiae that contains a synthetic gene encoding ice structuring protein Type III HPLC12 from the species Macrozoaraces americanus (ocean pout) does not contain allergenic protein derived from fish.
Unilever described generally available information about ISPs. ISPs are naturally occurring proteins found in a wide variety of species that bind to and influence the growth and structure of ice crystals. There are at least 12 different types of ISPs that have been found in the serum of ocean pout and separated by high performance liquid chromatography (HPLC). The subject of this notice is one of these HPLC-purified ISPs - i.e., ISP type III HPLC 12. This protein is made up of 66 amino acids of known sequence, has a molecular weight of approximately 7 kDa, a pH stability range of 2-12, and is heat tolerant. It is a globular protein with short beta strands and hydrophobic patches, and it is normally not glycosylated. It is identified by the accession number P19614 in the Swiss Prot protein database.
Unilever noted that it would not be practicable to obtain sufficient quantities of ISP type III HPLC 12 for industrial use directly from ocean pout. In order to obtain large quantities of a protein with the same amino acid sequence as ISP type III HPLC 12, Unilever developed a bioengineered strain of Saccharomyces cerevisiae that contains a synthetic gene encoding ISP type III HPLC 12.
Unilever described the manufacture of ISP preparation, stating that it is produced using standard industrial-scale biotechnology processes and standard food ingredients. The protein is secreted from the yeast cells into the growth medium. The yeast cells are then separated from the medium by filtration, and the ISP is concentrated and purified by ultrafiltration. The final ISP preparation derived from this process is a mixture of ISP type III HPLC 12, glycosylated ISP, proteins and peptides from the yeast used to produce ISP, and sugars, acids, and salts that are commonly found in food. Unilever provided information about these components as well as specifications for ISP preparation.
To assess whether ISP type III HPLC 12 is an allergenic protein, Unilever discussed several published and unpublished studies. These studies include characterization of ISP, skin prick testing of fish allergic individuals, and assays of immunoglobulin E (IgE) binding using serum from these individuals.
Characterization of ISP to assess potential allergenicity was carried out by amino acid sequence analysis and by measuring resistance to pepsin digestion by immunoblotting. The conditions used for these characterizations were based on internationally recognized standards.
Unilever conducted skin prick testing on cod fish allergic individuals using preparations from eel, eel pout, and ocean pout to demonstrate that these individuals made IgE antibodies capable of binding to allergenic protein from ocean pout. Because specific allergy to ocean pout has not been previously documented in the medical literature, Unilever carried out these studies by recruiting individuals with known allergies to a more common fish species, cod fish. Unilever also conducted skin prick testing on these individuals using ISP and demonstrated that they did not have an IgE mediated skin response to ISP.
Unilever used serum from these individuals in direct and indirect radioallergosorbent test (RAST) assays and in basophil histamine release assays to determine if IgE from these individuals was able to bind ISP. Unilever concluded that IgE from these individuals did not bind ISP and would not trigger an allergic reaction in fish allergic individuals.
Based on the information provided by Unilever, as well as other information available to us, we have no questions at this time regarding FALN008.
We have carefully considered the potential environmental effects of this notification. We have determined that not making a determination under section 403(w)(7)(B) of the FD&C Act on this notification, resulting in no required labeling of this food ingredient as a major food allergen, will not have a significant impact on the human environment, and that an environmental impact statement is not required.
Dennis M. Keefe, Ph.D.
Office of Food Additive Safety
Center for Food Safety
and Applied Nutrition