Use of In Silico Methods for Regulatory Toxicological Assessment of Pharmaceutical Impurities.

The use of novel non-testing methodologies to support the toxicological assessment of drug impurities is having a growing impact in the regulatory framework for pharmaceutical development and marketed products. For DNA reactive (mutagenic) impurities specific recommendations for the use of in silico structure-based approaches (namely (Q)SAR methodologies) are provided in the ICH M7 guideline. In 2018 a draft reflection paper has been published by EMA addressing open issues in the qualification approach of non-genotoxic impurities (NGI) according to the ICH Q3A/Q3B guidelines, and proposing the use of alternative testing strategies, including TTC, (Q)SAR, read-across, and in vitro approaches, to gather impurity-specific safety information.In the present chapter we describe a workflow to perform the safety assessment of drug impurities based on non-testing in silico methodologies. The proposed approach consists of a stepwise decision scheme including three key phases: PHASE 1: assessment of bacterial mutagenicity and consequent classification of impurities according to ICH M7; PHASE 2: risk characterization of mutagenic impurities (Classes 1, 2 or 3); PHASE 3: qualification of non-mutagenic impurities (Classes 4 or 5). The proposed decision scheme offers the possibility to acquire impurity-specific data, also if testing is not feasible, and to decide on further in vitro testing, besides meeting 3R's principle.