Agency Response Letter - Objection; Lyophilized Probiotic Cultures FALN No. 006 (Docket No. 2006FL-0287)
9609 153rd Avenue, N.E.
Redmond, WA 98052
Dear Mr Blanch:
This letter is in response to the notification dated June 29, 2006, that Nutraceutix, Inc. (Nutraceutix) submitted in accordance with section 403(w)(7) of the Federal Food, Drug, and Cosmetic Act (the Act) requesting an exemption from the labeling requirements of subsection 403(w)(1). The U. S. Food and Drug Administration (FDA) received the notification on July 5, 2006 and designated it as FALN 006.
The subject of FALN 006 is Nutraceutix's "lyophilized probiotic cultures" (products) produced by fermentation in dairy whey and casein growth media and used as ingredients in dietary supplements to make powders, capsules, and tablets. The products may also be used in food applications (conventional foods). FALN 006 informs FDA of Nutraceutix's view that its products do not contain allergenic milk protein as demonstrated by scientific documentation provided in its notification.
As part of its notification, Nutraceutix includes information about the identity, composition, and method of manufacture of its products, as well as the analytical method and results for its products. Nutraceutix states that it manufactures its products containing as ingredients 26 bacteria (singly or mixed) which it identifies by genus and species. Nutraceutix claims that, based on the analytical data provided in FALN 006, its products do not contain allergenic milk protein.
This response does not evaluate or otherwise address whether these products meet other regulatory requirements for a dietary ingredient of a dietary supplement product, or whether any use of these products as an ingredient in conventional foods that are marketed in the United States is generally recognized as safe.
FDA objects to FALN 006. FALN 006 does not contain scientific evidence (including the analytical method used) that demonstrates that Nutraceutix's products (as derived by the method specified in the notification) do not contain allergenic milk protein, as required by section 403(w)(7). FALN 006 neither provides sufficient scientific evidence to determine that the products do not contain allergenic milk protein, nor does FALN 006 otherwise meet the requirements of section 403(w)(7).
Nutraceutix's claims that its products do not contain allergenic milk protein are based largely on data from an enzyme-linked immunosorbent assay (ELISA) kit. Nutraceutix contends that the results of these ELISA tests indicated no detectable milk protein at the limit of detection for the assay of 2.5 ppm. The results from the ELISA do not demonstrate that the products do not contain allergenic milk protein, for two separate reasons. First, this ELISA test kit has not been validated for this use. Nutraceutix states that the milk proteins in the culture media for its products are degraded as part of the products’ production process. However, there are no data presented in the notification to validate the performance of the test kit for detecting milk proteins that have been subjected to degradative treatment (e.g. heating, proteolysis, and hydrolysis) in a matrix that consists almost entirely of live microorganisms. Second, a negative test result from this ELISA test kit does not demonstrate the absence of milk protein or the lack of allergenicity from residual peptides (i.e. protein fragments of the original proteins formed as a result of the degradative treatment). In this case, a negative result demonstrates only the inability to detect specific epitopes, such as a string of amino acids recognized by antibodies in the test kit, from casein and whey milk proteins to a detectable limit of 2.5 ppm. There are no assurances from this ELISA test kit that these epitopes correlate with allergenic milk protein epitopes. Thus, this ELISA test kit is not an adequate analytical test to establish that the products do not contain allergenic milk protein.
In addition, the notification does not adequately define Nutraceutix's process control and provides no evidence of the ability of its process to deliver consistently a product that does not contain allergenic milk protein. Therefore, even if Nutraceutix had supplied data derived using an appropriate analytical method, there is no assurance that such test results would be representative of the products in commerce.
Given the limitations of the ELISA test kit described above, it is possible that the products contain some residual milk proteins that are allergenic. Reports in the scientific literature show that milk proteins degraded during processing (e.g. heating, proteolysis, and hydrolysis) are not uniformly rendered non-allergenic. In particular, there are reports in the literature that residual milk proteins from partially hydrolyzed and even extensively hydrolyzed whey-containing or casein-containing infant formula can bind specific immunoglobulin E (IgE) and trigger allergic reactions in milk allergic individuals (Caffarelli et al., 2002; Hoffman and Sampson, 1997; Niggemann et al., 1999). In addition, anaphylaxis to hydrolyzed whey-containing or casein-containing infant formula has been reported (Ellis et al., 1991; Saylor and Bahna, 1991).
Given these reports in the scientific literature, we would expect the Nutraceutix notification to contain evidence that demonstrates that its manufacturing process entirely eliminates allergenic milk proteins by either validating and verifying the manufacturing process or directly testing the products in a milk allergic population. The Nutraceutix notification contains no such evidence. First, the notification does not demonstrate that the manufacturing process would alter milk proteins such that they are no longer allergenic. The description of the manufacturing process contains little detail, and there is no evidence provided in the notification to support the conclusion that any of the various processing steps (such as enzymatic and bacterial proteolysis, pasteurization and sterilization) eliminate the allergenicity of residual milk proteins and peptides. Second, the notification does not present any direct clinical evidence from tests of these products in a clinically relevant milk allergic population that demonstrates that Nutraceutix's products do not elicit a response in allergic individuals. This kind of evidence, drawn from studies examining the effects of Nutraceutix's products in milk-allergic individuals and including in vitro methods (e.g. antigen-specific IgE serum screening, histamine release assays), or in vivo testing (e.g. skin testing, oral challenge studies) demonstrating the presence or absence of either IgE binding or clinical responsiveness, would provide information about the allergenicity of Nutraceutix's products (Germolec et al., 2003).
Thus, Nutraceutix's notification fails to address the question of allergenicity raised by the potential presence of residual milk proteins or peptides that may be present in its products. It is not possible in this case to demonstrate that no protein or peptide of any kind is present, given the presence of bacterial proteins. Nutraceutix did not demonstrate that the physical properties of any residual milk proteins or peptides in its products are such that they would not elicit an allergenic response, nor did Nutraceutix evaluate its products using tests predictive of consumer sensitivity or reactivity to the product.
Nutraceutix notifies FDA in FALN 006 of its view that its products which it refers to as "lyophilized probiotic cultures" do not contain allergenic milk protein. Based on its review, FDA has concluded that FALN 006 does not contain scientific evidence (including the analytical method used) that demonstrates that Nutraceutix's products (as derived by the method specified in the notification) do not contain allergenic milk protein, as required by section 403(w)(7). FALN 006 neither provides scientific evidence to determine that the products do not contain milk allergenic protein, nor does FALN 006 otherwise meet the requirements of section 403(w)(7). FDA therefore objects to FALN 006.
Michael M. Landa
Deputy Director for Regulatory Affairs
Center for Food Safety and Applied Nutrition
Caffarelli, C.; Plebani, A.; Poiesi, C.; Petroccione, T.; Spattini, A.; Cavagni, G. 2002. Determination of allergenicity to three cow’s milk hydrolysates and an amino acid-derived formula in children with cow’s milk allergy. Clin Exp Allergy 32:74-79.
Ellis, M. H.; Short, J. A.; Heiner, D. C. 1991. Anaphylaxis after ingestion of a recently introduced hydrolyzed whey protein formula. J Pediatr 118:74-77.
Germolec D.R.; Kimber I.; Goldman L.; Selgrade M. 2003. Key issues for the assessment of the allergenic potential of genetically modified foods: breakout group reports. Environ Health Perspect 111(8):1131-9.
Niggemann B.; Binder C.; Klettke U.; Wahn U. 1999. In vivo and in vitro studies on the residual allergenicity of partially hydrolysed infant formulae. Acta Paediatr 88(4):394-8.
Rosendal A. and Barkholt V. 2000. Detection of potentially allergenic material in 12 hydrolyzed milk formulas. J Dairy Sci 83(10):2200-10.
Saylor, J. D. and Bahna, S. L. 1991. Anaphylaxis to casein hydrolysate formula. J Pediatr 118:71-74.