(682d) Towards a Next-Generation Harvest Strategy for Monoclonal Antibody Processes: Cost Considerations and New Technology Evaluation

Throughout the history of biologics processing, continuously increasing cell densities in the bioreactor and decreasing cell viabilities at harvest have posed a significant challenge to cell culture clarification operations. Separation technologies have evolved to meet this challenge, moving from normal flow filtration to microporous tangential flow filtration to centrifugation and depth filtration. Today, two strategies dominate harvest process: two-stage depth filtration for lower volume applications and centrifugation followed by secondary depth filtration for larger volume applications. However, continued difficulty in clarifying high cell titer cultures as well as a need for fully disposable, portable processes are driving improvement and innovation in clarification technologies.

Cost models have been developed to compare current cell culture clarification technologies for a monoclonal antibody (MAb) process. Among model parameters evaluated, the volumetric capacity of the primary depth filter in the two-stage depth filtration process was one of the key factors impacting the relative cost of these two technologies. Pretreatment methods such as acid precipitation and flocculation enhance the efficiency of the clarification process by increasing the average particle size in the cell culture broth. Use of a novel charged polymer for cell culture flocculation and a novel depth filter optimized for the larger particle size and increased solids content of the flocculated feed has achieved primary depth filter capacities in excess of 150 L/m². In many cases, no secondary clarification is required prior to sterilizing-grade filtration. This improved clarification technology has been demonstrated to work robustly for multiple cell culture streams of varying cell densities and viabilities, including high density cell cultures.

Analysis of these cell culture clarification technologies in the cost model indicates that a harvest strategy of cell culture pretreatment with the novel charged flocculating polymer followed by clarification with the optimized depth filter is cost advantageous to centrifugation followed by depth filtration at bioreactor volumes of up to 12,000 L. Detailed cost analyses for processes using these various cell culture harvest strategies will be presented. Performance data for the novel cell culture flocculant and optimized depth filter will be shown. Finally, the opportunities and challenges of a large volume, non-centrifuge MAb process will be outlined and discussed.