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FINAL DOSE FORM MANUFACTURING PROCESS VARIATIONS

Executive Summary

FINAL DOSE FORM MANUFACTURING PROCESS VARIATIONS between different ANDA applicants using the same bulk drug supplier justify continued bioequivalence testing for each separate ANDA, FDA Bioequivalence Division Director Shrikant Dighe, PhD, noted in a July 15 letter to Mallinckrodt. Responding to Mallinckrodt's proposal to allow bioequivalence testing on bulk drugs to apply to subsequent ANDA's, without doing individual testing, Dighe wrote that "your proposal would involve reliance on your bioequivalence testing by not just one applicant but by many different ANDA applicants. And, under your proposal not only would a different formulation be possible from each applicant . . . but it is highly unlikely that the tablets you make would be made under the same conditions and on the identical equipment as those made by each of your customers." The FDA official continued: "It is also likely that each manufacturer might have to modify the formulation of the product to accommodate the manufacturing procedures, equipment and environment at their respective facilities. Thus in time, we could expect 'drift' from a once common formulation to potentially different formulations for each manufacturer." Mallinckrodt suggested the ANDA testing changes in an April 21 letter to FDA, in which it made reference to a drug master file for bioequivalence an dissolution studies. "Each specific drug product," Dighe replied, "must stand on its own, that is, each ANDA must contain information to show that the product is bioequivalent to the listed drug product." Dighe stressed the difference between a final "drug product" and a bulk "drug substance." "Assurance about quality or bioavailability, for example, made about the latter cannot automatically or consistently be extrapolated to the former," he said. Manufacturing variations, such as in the tableting process, required "certain testing on each separate and specific drug product," Dighe noted. "For example, even in those cases where the same ANDA holder (or applicant) changes its manufacturing site and seeks to perform comparative dissolution studies in lieu of in vivo studies to demonstrate bioequivalence for the products made at different sites, an in vivo test on the finished drug product may be required unless the formulation is virtually identical at both sites and the manufacturing process (including manufacturing procedure and equipment, among others) is identical."
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