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

• Published in: Advanced drug delivery reviews Vol. 56; no. 3; pp. 397 - 414
• Main Authors: Raw, Andre S, Furness, M.Scott, Gill, Devinder S, Adams, Richard C, Holcombe, Frank O, Yu, Lawrence X
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 23.02.2004
• Subjects: Abbreviated New Drug Application (ANDA); Biological Availability; Carbamazepine - chemistry; Cefuroxime - analogs & derivatives; Cefuroxime - chemistry; Chemistry Techniques, Analytical; Crystallography; Decision Trees; Drug Approval - methods; Drug product; Drug Stability; Drug substance; Drugs, Generic - chemistry; Drugs, Generic - pharmacokinetics; Drugs, Generic - therapeutic use; Enalapril - chemistry; Humans; Molecular Conformation; Pharmaceutical solid; Phase Transition; Polymorph; Polymorphism; Prazosin - analogs & derivatives; Prazosin - chemistry; Quality Control; Ranitidine - chemistry; Solubility; Sulfonamides - chemistry; Technology, Pharmaceutical; Therapeutic Equivalency; United States; United States Food and Drug Administration; Warfarin - chemistry; Polymorph; Abbreviated New Drug Application (ANDA); Drug product; Pharmaceutical solid; Drug substance; Polymorphism
• ISSN: 0169-409X; 1872-8294
• DOI: 10.1016/j.addr.2003.10.011

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.