Risk Assessment of Potentially Genotoxic Impurities within the Framework of Quality by Design

A strategy for the risk assessment of potentially genotoxic impurities is described that utilizes Quality by Design in an effort to furnish greater process and analytical understanding, ultimately leading to a determination of impurity criticality. By identifying the risks and parameters that most influence those risks, an enhancement of both product and process control is attained that mitigates the potential impact of these impurities. This approach calls for the use of toxicological testing where necessary, chemical fate arguments when possible, multivariate analyses to develop design space, and use of spiking data to support specifications. Strong analytical support, especially with the development of low-level detection methods, is critical. We believe that this strategy not only aids in the development of a robust API process but also delivers on the identification and subsequent mitigation of risks to a class of impurities that are of high interest in the field.