(184g) Viral Filtration Optimization for Challenging Non-Mab Exhibiting Rapid Flux Decay

The removal or inactivation of potential viral contaminants during the manufacture of therapeutic proteins is a critical component of the downstream purification process. Regulatory agencies typically recommend a minimum of two dedicated orthogonal viral clearance steps for biologically derived therapeutics. The diverse nature of viruses, such as variations in envelopment, necessitates the implementation of orthogonal viral clearance steps to decrease the likelihood of residual viral contaminants and increase product safety. Aside from a low pH viral inactivation, viral filtration (VF) uses a size-based membrane to achieve viral clearance. This poster presents a case study on VF optimization of a challenging, highly potent non-mAb protein that exhibited significant fouling at platform viral filtration conditions. The observed behavior necessitated substantial additional development beyond the standard VF platform fit, including a comprehensive evaluation of buffer composition, pH, conductivity, excipient concentration, and filter chemistry impact on flux, loading, yield, and filtrate product quality. Four different commercially available filters were screened at small-scale for loading prior to fouling. Dramatic differences in filter performance between Viresolve Pro (mixed cellulose ester), ViroSart CPV (polyethersulfone), Planova BioEx (polyvinylidene difluoride), Planova 20N and S20N (cuprammonium regenerated cellulose) were observed. The Planova 20N was selected as the filter of choice due to the achievement of higher loading prior to fouling and increased yield. The addition and identity of excipients as well as buffer pH and conductivity were critical factors in mitigating flux decay, while the buffer matrix had minimal impact. The optimized conditions resulted in a 50% improvement in VF filter loading compared to the starting platform settings and successfully mitigated adverse product quality impact during the VF step. These conditions enabled successful scale up of the VF step from bench to pilot and clinical scales. Most importantly, by confirming a VF screening methodology for a non-platform hazardous product, this work can be leveraged to streamline VF development on future challenging atypical molecules.