Drug Substance and Drug Product Impurities, Now what?

Abstract

An unidentified peak in a drug substance or drug product chromatogram raises many questions. What is the impurity? What is the source of the impurity? How much impurity is there? Can the impurity level be reduced or eliminated? Is the impurity toxic? What do we do now? The answers to these questions are typically provided by scientists in chemistry, manufacturing and controls (CMC) and nonclinical toxicology with the single objective of assuring that unavoidable drug impurities induce no risk or an acceptable level of risk for the intended indication and the stage of development. To help address these issues, the International Council for Harmonisation (ICH) guidelines for impurities in drug substance (Q3A) and drug product (Q3B), and for genotoxic impurities (M7) have been adopted and implemented in the United States, Europe, and many other countries around the world. The guidelines address how impurities in drug substances and drug products should be reported, identified, and/or qualified. This Mini Review offers practical insights regarding drug substance and drug product impurities and next steps for the toxicologist when impurity levels exceed the ICH reporting, identification, and/or qualification thresholds. The information presented is largely derived from the following ICH Harmonised Tripartite Guidelines:Q3A(R2) Impurities in New Drug Substances (October 2006), Q3B(R2) Impurities in New Drug Products (June 2006), and M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk (June 2015) and/or the referenced literature. Insights regarding acceptible amounts of residual solvents and the calculation of permitted dialy exposures will be the subject of another review.