The presence of genotoxic impurities in drug substances and consequently in the final drug products represents a potential risk for users. These substances at low concentrations pose a risk of developing cancer, as they are reactive and can act directly on the genetic material of the individual. Concentrations of impurities in the active substance must be reduced to an acceptable level so that they do not represent a risk to human health. The field of impurities is regulated by the ICH, EMA and FDA guidelines.
As part of the master thesis, we found out that the implementation of the guideline represents important challenges for the pharmaceutical company. We reviewed EMA and FDA guidelines and the differences between them. We focused mainly on the new ICH M7 guideline, which has been used since 2016. The guideline complements the ICH Q3A and ICH Q3B guidelines and introduces a new approach to the evaluation of genotoxic impurities based on a combination of two complementary computational methods. According to ICH M7, genotoxic impurities are divided into five classes based on their mutagenic and carcinogenic potential.
The purpose of the task was to evaluate the DNA reactive impurities in silico in accordance with the new ICH M7 guideline and to demonstrate the guideline implementation on two model compounds.