International Workshop on Qualification and Control of Impurities *

Abstract

During the DIA International Workshop “Impurities and Degradation Products—Biological Qualification, Process Capability, and Analytical Control,” the EU Committee for Human Medicinal Products draft guideline on genotoxic impurities was presented. About half of the attendees expressed their support for the use of the threshold of toxicological concern concept as a pragmatic solution. The Food and Drug Administration guidance is under development. The process of qualification of impurities starts with identification. For genotoxic impurities, identification should start with an evaluation of the starting materials and the routes of synthesis to compile a list of impurities that can reasonably be expected to be present in the drug substance. Among this list, the search for alerting structures and classification of impurities as highly toxic can be facilitated by use of structure activity relationship databases. Relevant impurities that were identified as potentially genotoxic should be tested as isolated impurities because these impurities are usually present below the detection level of the genotoxicity assay when the drug substance is used in the assay. Knowledge of the impurity and its source is also the basis for a reduction of these compounds to the lowest possible level that can be achieved with reasonable effort. Trace analytical methods are usually required to monitor process optimization activities. Avoiding a hazardous impurity or a reduction of its levels may require a substantial effort and time in process chemistry or formulation development. The allowance of higher limits for short-term exposure is therefore seen as a pragmatic way to define reasonable effort, especially for batches used in the early clinical development. This remains an important issue that should be further addressed.