Setting Limits for Genotoxic Impurities in Drug Substances

Abstract

In December 2002, the Safety Working Party (SWP) of the European Committee for Proprietary Medicinal Products (CPMP) published a Position paper on the limits of genotoxic impurities. The European Union intended to supplement a gap in the International Conference on Harmonisation (ICH) guidelines on qualification of impurities, as it was deemed that impurities with genotoxic potential were a special case not specifically covered in terms of qualification by the Q3A and Q3B guidelines. In fact, the SWP's proposed approach follows a safety factor-based risk assessment process similar to that in ICH Guideline Q3C on limits for residual solvents, rather than a qualification process as described in ICH Q3A and B. The need to provide particular advice for the control of drug substance impurities that bear the risk of non-reversible toxicity (e.g. genotoxic impurities) is widely acknowledged. If such impurities can be shown to exert their genotoxicity via a mechanism with a threshold, then control of the impurity according to calculated permitted daily exposures (PDEs) should not pose major problems. However, in most cases, threshold mechanisms for such genotoxic impurities will not have been demonstrated. Employing conservative uncertainty factors to calculate PDEs in such cases may lead to limits that could be out of proportion to the impurity qualification limits (as per ICH quality guidelines), normally 1500 parts per million (≡ 1.5mg/1g substance), and orders of magnitude lower than exposures to genotoxins via other sources, such as diet and the environment. Alternative approaches based on the calculation of a lifetime cancer risk of 1/10 5 or 1/10 6 , which have been recommended for control of carcinogens in other circumstances, should be considered. This could lead to more realistic limits for genotoxic impurities, e.g. an intake of up to 1.5 μg/day for most genotoxic impurities without evidence of a threshold is considered to be toxicologically insignificant. Control of 'suspect' or 'known' potentially genotoxic impurities at such a level is important when one considers that many genotoxins present in drug substance at much higher concentrations would escape detection during standard genotoxicity testing of drug substance. Whilst a generic limit of 1.5 μg/day of an identified genotoxin may be suitable for chronic use drugs in a wide patient population, higher levels may be acceptable for shorter duration use, and in circumstances involving closely-defined patient populations, for example, where a case-specific assessment is appropriate.