Risk Assessment of the Leachables’ Profile for Small-Molecule Pharmaceutical Drug Substances

Appropriate control of impurities from all sources is critically important during the development of a pharmaceutical product. One class of impurity that has gained considerable attention over the past few years is extractables and leachables. We report a model for assessment of the risk posed by leachable impurities for a small-molecule drug substance. The first step of this study consists of a high-level assessment of the risk posed by leachable impurities in the drug substance, by taking into account the drug product’s route of administration. In the case of parenteral route of administration, a more comprehensive process-specific second step risk assessment is typically warranted. This second step consists of risk assessment of polymer component(s) for the potential to release leachable impurities, risk scoring, and classification. For high-risk components, risk mitigation studies can be performed in step 3, such as leachable impurity removal via component pre-flush with the process solvent, extractables’ studies under harsher conditions, and toxicity assessments.