Risk based qualification of non-mutagenic impurities.

The current approach to qualify NMIs (non-mutagenic impurities) exceeding the qualification threshold is to perform genotoxic, general toxicity and other specific studies in animals. Furthermore, these studies are rarely conducted on clean impurity samples. As a result, any toxicity identified in safety tests cannot be unambiguously attributed to the impurity alone, and hence the lack of impurity-specific safety data prevents results from being extrapolated to conditions such as increased impurity levels in the same drug product during shelf life. That is, animal safety tests would often need to be repeated in such cases. Moreover, NMIs are examined in animals at such a low level (despite being above the qualification threshold) that it is unlikely to detect a safety signal in these investigations, raising concerns about the design of these studies. Therefore, the current approach for qualification of impurities contradicts the 3Rs (Replacement, Reduction and Refinement) testing methodologies mandated by Directive 2010/63/EU on the protection of animals for scientific purposes, which applies to the regulatory testing of pharmaceutical compounds. We examine the integrated risk assessment approach for qualifying NMIs using non-animal methods while considering several variables that could influence the risk assessment process. We also discuss the benefits and present technological constraints in applying these alternate methodologies. The appropriately designed risk-based approach will eliminate unnecessary animal testing for qualification of impurities with low level of concern.