Genotoxic Impurities: From Structural Alerts to Qualification

Abstract

The presence of an in cerebro structural alert in a potential or actual impurity, most likely arising as a byproduct or carried-over reagent or starting material, in a drug substance or drug product is merely an indication that the compound may be a DNA-reactive genotoxin. The correlation between structural alerts for direct or indirect electrophilic characteristics and relevant biological activity is highly imperfect. For virtually all actual or potential impurities that are structurally alerting there is likely to be a variety of possibilities for clarifying their genotoxicity status based on published data, in silico assessments or de novo testing in bacterial reverse mutation assays. Even for compounds that test positive a number of options are available to enable a compound-specific qualification to be made involving the use of pre-existing toxicological data (particularly from lifetime rodent bioassays) and/or using information from appropriate additional studies. A review of representative compounds from several classes of structurally alerting substances (epoxides, hydrazines, aromatic amines, halides and aldehydes) provides examples of different types of qualification strategies Overall, it seems prudent to obtain maximum “leverage” from toxicological approaches, which are likely to be relatively low cost, before making any significant process-related changes to an active pharmaceutical ingredient (API) synthesis.