Abstract
Defining impurity profile is key element to ensure safe, efficacious and quality human drugs. Impurity profiling changed/transformed drastically over the years. Guidelines, specifications and requirements are evolving. Initially impurity profiling was based on simple methods later by degradation studies, then to understand drug strength and efficacy chiral impurities and stereo isomers were included followed by residual solvents, polymorphic forms, genotoxic impurity studies. Currently, elemental impurities are the latest addition. As per the GDUFA II guidelines to improve review efficiency and reduce review cycles, data requirements have changed. Based on recent guidance and review points, Impurity profiling has significant importance in ANDA filing and to ensure approval within 10 months (first cycle approval) which is an exiling aspect for industries to enter into the generic market quickly. Hence, Impurity profile is a key aspect scientifically, regulatory wise and commercially also. This is a review article on impurity profiling of Solid oral drug substances and products as per GDUFA II requirements the reference documents for the review are ICH guidance, relevant FDA GDUFA guidance and common industry practices.
Highlights
Impurity profiling was based on simple methods later by degradation studies, to understand drug strength and efficacy chiral impurities and stereo isomers were included followed by residual solvents, polymorphic forms, genotoxic impurity studies
As elemental impurities do not provide any therapeutic benefit to the patient, besides continuous exposure might be toxic, so their toxic levels in the drug product should be controlled within acceptable limits [46]
The residual solvents used in each stage of manufacturing process of Drug substance or excipient can either be analyzed and exhibited that they meet the ICH Q3C [48], USP requirements [49] or they can be analyzed in final stage, in either cases they should be analyzed with validated method or method specified in USP [49]
Summary
Impurity profiling is the basis for determining, assuring quality, safety and efficacy of the drug substance and drug product. It has gained more significance in GDUFA environment and in evolution of new guidance and review points [3]. Defining impurity profile of the drug substance (Active Pharmaceutical Ingredient) is the basis for impurity profiling of Drug product, it considers excipients and formulation process. Organic impurities can arise during the manufacturing process, drug substance-excipient interactions, and/or storage of the drug substance, drug product [1]. They can be identified or unidentified, volatile or nonvolatile. Chemical Name Code # MDD QT (%) QT (TDI) Regulatory QT Threshold (%)* Proposed AC (%)
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