Control of Genotoxic Impurities in Active Pharmaceutical Ingredients: A Review and Perspective

Recent guidelines from drug regulatory authorities in Europe and the Untited States of America (USA) require the control of genotoxic and potentially genotoxic impurities at parts per million levels in drug substances. This review will discuss the background to the guidelines and the various strategies drug substance manufacturers have employed to comply with the very tight constraints. These strategies include (a) redesigning the drug substance synthesis to avoid introducing problematic impurities, (b) altering relevant process parameters to remove or reduce such impurities to insignificant levels, (c) deploying process understanding to prove that a particular genotoxic impurity either cannot be formed or will be efficiently removed, (d) conducting toxicity studies to demonstrate that a suspect impurity is not harmful at the low levels envisaged for it. Examples of each approach are given.