P31-33 Classification based risk assessment in the safety evaluation of Extractables & Leachables

The toxicological assessment of extractables and leachables (E&Ls) is vital for ensuring pharmaceutical safety; however, no widely recognized harmonized guideline currently provides comprehensive coverage of this area. The ICH Q3E expert working group is putting forward guidelines on the best practices for the assessment of E&L. The guideline proposes a harmonized assessment of E&L which also includes an E&L control strategy based on science and risk-assessment principles. Characterizing the chemical landscape of E&Ls plays a crucial role in devising scientifically grounded safety assessment strategies. Here we present how structural clustering serves as a powerful tool in E&L safety assessment by facilitating the identification of representative compounds and supporting read-across approaches. Here, we consider how a classification-based approach can be utilized to reduce uncertainties in risk assessment that originates from incomplete structure identification. Previous studies have shown that E&L chemicals fall into several distinct structural classes defined by a core structural moiety. Differences between class members often include variations in structural attributes; for example, branching patterns, chain length, or cyclic versus acyclic variations. The high structural similarity of the class members supports the use of a class-level read-across approach. This strategy helps fill data gaps for the derivation of a permitted daily exposure (PDE) value that may be applied to the class members. To justify a class-based read-across approach, it is necessary to demonstrate sufficient biological, metabolic, and toxicological similarity among class members given the presence of structural differences. The derivation of a class-based exposure level, such as a PDE, can assist in the prioritization of chemicals for identification and analysis while also clearly defining the read-across methodology. We also postulate that the interaction of biotechnology products with leachables, could also be assessed based on the class of the leachable. As always, a comprehensive review of safety and product quality is needed in the event a class-based hazard is identified.