Michael H. Auerbach, Ph.D.
Danisco USA, Inc.
440 Saw Mill River Road
Ardsley, NJ 10502-2605
Dear Dr. Auerbach,
This is in regard to the notification dated February 28, 2006, that Danisco USA, Inc. (Danisco) submitted in accordance with section 403(w)(7) of the Federal Food, Drug and Cosmetic Act (the Act). FDA received the notice on March 3, 2006, and designated it as FALN 005.
The subject of FALN 005 is Danisco's anhydrous lactitol and lactitol monohydrate (lactitol), which are manufactured and derived from cow's milk (milk). FALN 005 informs FDA of Danisco's view that, based on scientific evidence, lactitol does not contain allergenic protein from milk. Danisco's lactitol is intended for use as a specialty sweetener in multiple food applications.
As part of its notification, Danisco includes information about its products' method of manufacture, identity, and scientific data about the protein content of its lactitol products. Danisco argues, based on the analytical data provided in FALN 005, that its lactitol products do not contain allergenic protein.
FDA objects to FALN 005. FALN 005 does not contain scientific evidence (including the analytical method used) that demonstrates that lactitol (as derived by the method specified in the notification) does not contain allergenic protein as required by section 403(w)(7). FALN neither provides sufficient scientific evidence to determine that lactitol does not contain allergenic protein nor does FALN 005 otherwise meet the requirements of section 403(w)(7).
Danisco argues that its lactitol products do not contain allergenic protein based primarily on data from an enzyme-linked immunosorbent assay (ELISA) kit assay intended to detect milk proteins. This ELISA assay did not detect milk proteins at the detection limit specified by the kit manufacturer of 2.5 milligrams/kilogram (mg/kg) in two samples of each lactitol product. However, Danisco also reports analytical results from other methods, Lowry-Folin and Bradford assays, which measured concentrations of total protein ranging from 260 to 570 mg/kg in the same samples.
The results from the Lowry-Folin and Bradford assays indicate that its lactitol products contain protein, while the ELISA analysis reports no detectable milk protein at the limit of detection for the assay. Any protein present in the lactitol products would be expected to be milk protein derived from the lactose raw material, and the notification does not contend or demonstrate otherwise. The notification does not address this discrepancy or otherwise explain why the ELISA assay did not detect the proteins measured by the Lowry-Folin and Bradford methods. In addition, Danisco provides no information characterizing the proteins measured by the Lowry-Folin and Bradford methods, and no information indicating whether the proteins are intact or degraded. Additionally, Danisco does not furnish information about the allergenic potential of the proteins in humans. Even if the proteins present in lactitol were characterized and shown to be modified or partially degraded, that information may not be sufficient without additional data or information to conclude that such proteins are not allergenic.
Characterization of the proteins is important given evidence that certain allergenic proteins subjected to heat treatment or other processing conditions retain their ability to elicit allergenic reactions (Wall, 2003). Moreover, studies indicate that milk allergens retain their allergenicity after severe heat treatment (Lee, 1992; Taylor and Lehrer, 1997) and that milk peptides containing as few as twelve amino acids can bind to IgE from the serum of milk-sensitive individuals (Ball et al., 1994). In the absence of data characterizing the proteins remaining in the lactitol products it is not possible to determine whether the proteins can be considered non-allergenic.
With regard to the ELISA assay, Danisco provides limited information about this analysis, including information about the validation of the method. Danisco provides information from the kit manufacturer indicating that the kit is intended to be used for the quantitative analysis of milk residue in food products such as juices, wine, sauces or sorbets. However, Danisco does not provide information about validation to support the use of this kit for the analysis of allergenic milk protein in the lactitol products. In the absence of such validation data, it is not possible to make definitive conclusions from the data provided about the presence of allergenic protein in the lactitol products.
Additionally, Danisco reports analytical results from two samples of anhydrous lactitol and two samples of lactitol monohydrate. It is not clear whether the samples analyzed originated from a single batch of each product or from duplicate batches. Protein concentrations should be measured in a sufficient number of batches to accurately determine both average levels and standard deviations. Without this information, the variability in protein content of Danisco's lactitol per batch has not been adequately described.
Danisco notifies FDA in FALN 005 of its view that lactitol does not contain allergenic protein. In FDA's view, FALN 005 does not contain scientific evidence (including the analytical method used) that demonstrates that lactitol (as derived by the method specified in the notification) does not contain allergenic protein, as required by section 403(w)(7). FALN 005 neither provides scientific evidence to determine that lactitol does not contain allergenic protein, nor does FALN 005 otherwise meet the requirements of section 403(w)(7). FDA therefore objects to FALN 005.
Scott Gottlieb, M.D.
Deputy Commissioner for Policy
Ball G, Shelton MJ, Walsh BJ, Hill DJ, Hosking CS, Howden ME. (1994) A major continuous allergenic epitope of bovine β-lactoglobulin recognized by human IgE binding. Clin. Exp. Allergy. 24:758-764.
Lee Y-H. (1992) Food processing approaches to altering allergenic potential of milk-based formula. J. Pediatr. 121:S47.
Taylor SL and Lehrer SB. (1996) Principles and characteristics of food allergens. CRC Crit. Rev. Food Sci. Nutr. 36 (Suppl):S91.
Wall JM. (2003) Editorial: Thermal processing and allergenicity of foods. Allergy. 58:727-729