Development of Fit-for-Purpose In Silico Models for the Assessment of Extractables and Leachables (P423)

The fitness for purpose given a specific use context determines the acceptability of in silico models. To support the assessment of extractables and leachables (E&L), several endpoints are evaluated including mutagenicity, and skin sensitization. Leachable reactivity with a protein/DNA based active pharmaceutical ingredient (API) may also be relevant. In silico models are applied to the assessment of E&L genotoxicity in line with the ICH M7 procedures. This work first describes the maturation of the mutagenicity knowledgebase by refinement of expert alert rules and previous work on aromatic amines (a representative class of E&L) is used as an example. The development of a protocol to implement genotoxicity in silico evaluations is also described. We then present the incorporation of knowledge derived from proprietary data into models which predict potency categories for skin sensitization and demonstrate high sensitivity and accuracy of the high potent class (82%) towards 925 non-training structures which were experimentally assessed. Finally, we discuss the use of in silico approaches to investigate the potential interaction of leachables with API biomolecules within a rapid and conservative framework. Using models that lay their foundation in electrophilicity (e.g., direct acting mutagenicity alerts, direct peptide reactivity and reaction domain profiling), a consensus approach was shown to be fit for purpose (sensitivity of 90% and negative predictivity of 88%), when benchmarked against 22 experimentally determined leachable-insulin glargine reactivity values. The models described herein can be used to support E&L assessments, such as described in ISO-10993 regarding medical devices and to address emerging regulatory questions.