Regulatory considerations of pharmaceutical solid polymorphism in Abbreviated New Drug Applications (ANDAs).

A sponsor of an Abbreviated New Drug Application (ANDA) must have information to show that the proposed generic product and the innovator product are both pharmaceutically equivalent and bioequivalent, and therefore, therapeutically equivalent. Many pharmaceutical solids exist in several crystalline forms and thus exhibit polymorphism. Polymorphism may result in differences in the physico-chemical properties of the active ingredient and variations in these properties may render a generic drug product to be bioinequivalent to the innovator brand. For this reason, in ANDAs, careful attention is paid to the effect of polymorphism in the context of generic drug product equivalency. This review discusses the impact of polymorphism on drug product manufacturability, quality, and performance. Conclusions from this analysis demonstrate that pharmaceutical solid polymorphism has no relevance to the determination of drug substance "sameness" in ANDAs. Three decision trees for solid oral dosage forms or liquid suspensions are provided for evaluating when and how polymorphs of drug substances should be monitored and controlled in ANDA submissions. Case studies from ANDAs are provided which demonstrate the irrelevance of polymorphism to the determination of drug substance "sameness". These case studies also illustrate the conceptual framework from these decision trees and illustrate how their general principles are sufficient to assure both the quality and the therapeutic equivalence of marketed generic drug products.

Scientific considerations of pharmaceutical solid polymorphism in abbreviated new drug applications.

PURPOSE: This commentary is intended to provide a scientific perspective on pharmaceutical solid polymorphism in Abbreviated New Drug Applications (ANDAs). METHODS: This report proposes recommendations for monitoring and controlling drug substance polymorphs and describes scientific considerations of pharmaceutical solid polymorphism in the determination of drug substance sameness. RESULTS: It presents three decision trees for solid oral dosage forms or liquids containing undissolved drug substances to provide a process for evaluating when and how polymorphs of drug substances are monitored and controlled in ANDA submissions. CONCLUSIONS: It is scientifically concluded that differences in polymorphic composition of drug substances in generic drug products and reference-listed drugs are not directly relevant in the determination of drug substance sameness in ANDAs.