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Management of pharmaceutical ICH M7 (Q)SAR predictions – The impact of model updates

Hasselgren C; Bercu J; Cayley A; Cross K; Glowienke S; Kruhlak NL; Muster W; Nicolette J; Reddy MV; Saiakhov R; Dobo KL;

Pharmaceutical applicants conduct (Q)SAR assessments on identified and theoretical impurities to predict their mutagenic potential. Two complementary models—one rule-based and one statistical-based—are used, followed by expert review. (Q)SAR models are continuously updated to improve predictions, with new versions typically released on a yearly basis. Numerous releases of (Q)SAR models will occur during the typical 6–7 years of drug development until new drug registration. Therefore, it is important to understand the impact of model updates on impurity mutagenicity predictions over time. Compounds representative of pharmaceutical impurities were analyzed with three rule- and three statistical-based models covering a 4–8 year period, with the individual time frame being dependent on when the individual models were initially made available. The largest changes in the combined outcome of two complementary models were from positive or equivocal to negative and from negative to equivocal. Importantly, the cumulative change of negative to positive predictions was small in all models (<5%) and was further reduced when complementary models were combined in a consensus fashion. We conclude that model updates of the type evaluated in this manuscript would not necessarily require re-running a (Q)SAR prediction unless there is a specific need. However, original (Q)SAR predictions should be evaluated when finalizing the commercial route of synthesis for marketing authorization.

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