Biologics manufacturing still remains dominated by batch operations. As upstream titers continue to increase due to developments in higher producing cell lines, the downstream purification process must adapt to meet the demands of productivity and processing cadence as to avoid becoming the bottleneck in manufacturing operations. In this work, several next generation manufacturing technologies were evaluated and implemented at both benchtop and pilot scale for unit operations used in monoclonal antibody purification. Multi-column continuous capture chromatography was utilized in order to increase both specific productivity and resin capacity utilization by up to 2-3 fold and 30-40%, respectively. A variety of capture column scenarios were investigated in a DoE format to determine the optimal performance range depending on several different factors, including column size, operating flowrates and resin type. Model assisted design of multi-column capture was performed in order to allow the prediction of performance attributes based on process parameters and was validated by experimentation. Utilizing optimized process parameters from this modeling exercise, a 2-column continuous capture operation was carried out at pilot scale and showed good agreement to scale down models, achieving a productivity of 25 grams processed per liter of resin per hour and a 93% resin capacity utilization. The interconnection of two separate polishing operations was also carried out at benchtop and pilot scale, utilizing UV based criteria to allow for automated valve switching, effectively removing the need for in-process holding vessels. The streamlining of the polishing operation showed no sacrifice in yield or purity while decreasing processing and switchover time by up to 2 fold. The multi-column capture and integrated polishing operations were linked with an automated viral inactivation vessel to allow for automated pH control of intermediate pools, removing the necessity of in-process pool handling from the harvest step to viral filtration or concentration steps.

Scale up design and optimization for an intensified downstream process utilizing multi-column operations

255th National Meeting (2018)

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