Navigating PUPSIT implementation challenges for high-viscosity oligonucleotide drug products.

The implementation of the revised European Union (EU) EMA Annex 1 (effective August 2023) has introduced stricter requirements for the design and operation of sterile injectable manufacturing processes. Among these requirements, Pre-Use Post-Sterilization Integrity Testing (PUPSIT) has posed significant challenges for the pharmaceutical industry, necessitating strategic adaptations to ensure compliance. Oligonucleotide-based therapeutics have gained momentum as targeted therapies for unmet medical needs. However, due to their thermal sensitivity, these products often require aseptic processing, necessitating PUPSIT implementation. This case study highlights key challenges associated with PUPSIT for a high-concentration, high-viscosity antisense oligonucleotide (ASO) drug product and informs on critical considerations such as formulation impact, process design, and risk assessment. The findings provide insights into real-world challenges, industry best practices, and strategies to achieve successful PUPSIT implementation while maintaining regulatory compliance.