Scientific Considerations in the Approval of Complex Generics

Abstract

A fundamental premise for generic approval is that the generic drug product contains the “same” active pharmaceutical ingredient as the brand name product. The vast majority of generics are traditional “small-molecule” drugs that have a simple chemical structure that is easily characterized. For those cases it is relatively straightforward to demonstrate the active ingredient is the “same” as the brand name. In complex drug substances, the active ingredient is not a traditional single-entity small molecule, but rather a distribution of molecular species. For those cases, there are scientific challenges toward demonstrating the “same” active ingredient. Over the past few years, FDA has approved generic versions of some complex active ingredients, including Lovenox (enoxaparin sodium) injection and Copaxone (glatiramer acetate) injection. Despite the fact these two active ingredients possess a significant level of molecular heterogeneity, an understanding of the origin of this heterogeneity, based upon source material and manufacturing process considerations, provides the basis for a simplified framework to demonstrate active ingredient sameness. This book chapter provides an overview of the common themes used to approve generics of these complex mixtures.