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FDA HAS NOT REJECTED A BIOTECH PRODUCT SOLELY FOR VARIATION

Executive Summary

FDA HAS NOT REJECTED A BIOTECH PRODUCT SOLELY FOR VARIATION from the natural form, Office of Biologics Research and Review Director Elaine Esber, M.D., noted at a Food and Drug Law Institute (FDLI) meeting in Washington, D.C. Dec. 9. Esber said that the agency has several concerns relating to alteration of molecular structure in bio-engineered products. However, she pointed out, "in reviewing the alterations in structure, we have not rejected any product solely because it varies from the natural product in the human body." A "major concern" of the agency as it reviews applications for the new biologicals, Esber explained, is heterogeneity of the amino terminal sequence. Synthesizing mammalian proteins in bacterium such as E. coli, Esber noted, creates certain problems in generating products that are identical to the native proteins found in humans. Many times the result is "a product that contains a heterogeneous mixture of proteins" with amino terminal variations, she said, making it "very difficult to evaluate." Another concern, Esber maintained, arises from chemical and physical alterations that can occur as a result of the use of detergents and protease inhibitors in the production process. These agents, she explained, "could denature or alter the structure of the molecule resulting in a product which may be recognized as foreign by the immune system of the patient." Also of concern to the agency, according to Esber, are alterations due to nonglycosylation or glycosylation, and protein folding and pairing of disulfide bonds. Correct pairing of the disulfide bonds of the protein, Esber said, is important in avoiding "the production of mixtures of products -- products that cannot be consistently manufactured, or products that may be recognized by the host as different from the natural molecule." Esber also noted that FDA has been informally extending a policy allowing for divided manufacturing among different companies. The policy was originally announced by the agency in 1983 as applying to hybridoma derived products, particularly in vitro diagnostics, but has been extended "to other cell derived products made by the new technologies where controls were available to monitor the product," Esber said. Esber noted that the agency is requiring that "certain conditions be met to assure the safety and effectiveness of the final product" under divided manufacturing. Among those conditions, she said, "is the expectation that the intermediary producer would request and receive an establishment end product license when the final product is licensed." Areas of concern to the agency during such an approval process would include "the facilities, the manufacturing processes, testing of the product, storage, shipping conditions," and labeling, Esber said.
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