Strategic control of genotoxic impurity in innovative drug development

The assessment and control of genotoxic and potentially genotoxic impurities (GTIs) is a critical part of drug non-clinical safety evaluation, which is closely related to other toxicological studies, especially carcinogenicity and reproductive toxicity studies, and controlling genotoxic impurities in drugs to safety levels is the key to ensure the quality and safety of drugs.

Studies on genotoxic impurity research play an important role through thoroughly systematic research of the drugs, especially in the preclinical research phase, the research and results on genotoxic impurities will largely affect the progress of drug development, and is an important session for drugs entering clinical trials.

The requirements for assessment and control of genotoxic impurities are not addressed in sufficient detail in the existing guidelines; during drug synthesis, many impurities containing warning structures were actually generated, which have no toxicological data for reference; and the software based on the Quantitative Structure Activity Relationship have insufficient predicting capability, etc.

The Common Technical Documents for preclinical study lack the description and discussion of controlling genotoxic impurities for key materials, or the description and discussion of controlling genotoxic impurities is insufficient: the generation, removal and whereabouts of impurities are not written clearly and logically.

The risk assessment of generation and presence of genotoxic nitrosamine impurities was not conducted.

Based on the good overview of the synthetic reactions and routes of target compounds for preclinical research, reagents or reactants with genotoxic or carcinogenic or teratogenic risks will be replaced possibly, new synthetic routes will be designed and developed, and new purification techniques will be tried to avoid or reduce the generation of genotoxic impurities from the origin.

For genotoxic impurities unavoidable, appropriate quality controlling dot will be set to ensure that genotoxic impurities meet the specified limits.

Segmented control will be tried: decentralized control will be performed during process control (IPCs), in starting material control, in intermediate control, and in final product control; or spiking tests will be achieved for effective control of genotoxic impurities to reduce the challenge of analytical method development and validation and save production costs.