Application of clearance strategies for extractables and leachables and advances in process modeling

Abstract

Abstract: Single-use devices made from plastic materials and used in the manufacturing of pharmaceutical products were identified as sources of extractables and potentially process equipment-related leachables (PERLs), which may interfere with process performance and product quality. In this contribution, the sinks of PERLs in biopharmaceutical processes are explored and the underlying physical-chemical mechanisms are discussed. This includes an overview of studies on leachable clearance with ultrafiltration/diafiltration operations (UF/DF) and chromatographic steps, filter rinsing, and adsorption. Literature reveals that dilution and phase separation are the main drivers for reducing PERL exposure along a process. Integrating extractables release and established physical processes of dynamic dilution and phase separation allows to set up and populate mathematical models which can predict the fate of PERLs in batch and continuous bioprocessing. Integrating the fate of PERLs improves process understanding, supports process qualification studies, and, ultimately, strengthens the patient safety assessment. Key points: • It is possible to demonstrate that biopharmaceutical processes can significantly reduce PERLs. • Various process operation steps are identified as sinks for PERLs, and the fate of PERLs is predictable with simple mathematical models. • Using PERL exposure models improves process understanding and enhances the safety assessments for single-use devices used in bioprocessing.