High throughput screening (HTS) and miniaturization are well established strategies for streamlining downstream process development. During routine development, utilization of HTS technologies across the entire downstream process can enhance overall process understanding and better avoid process design gaps. During early phase development, HTS methods can facilitate development of multiple molecules in parallel as well as efficient, phase-appropriate work streams. The present work describes a strategy for integrated downstream development in a single 96-well filter plate experiment. The plate design allows for data collection on the colloidal, chemical, and thermal stability of a product over the full range of downstream solution conditions, including low pH viral inactivation. Additionally, in the same plate, batch binding studies are performed to investigate protein-adsorbent interactions over 5 types of chromatographic media. The plate-based method will screen protein A elution conditions, determine the static capacity, gradient elution strength, and selectivity for 2 cation exchange resins, and evaluate the selectivity of product and contaminants over a range of pH and conductivity for three different resins operated in flow-through mode. This approach enables an ultra-rapid development cycle wherein process development scientists determine molecule manufacturability and process operating ranges for an entire downstream process in a single plate-based experiment. When combined with miniaturized, automated robo-column chromatography to verify operating conditions, this work stream fits into a phase-appropriate development strategy that can dramatically reduce the time to clinic for Phase 1 products without sacrificing process understanding and robustness. Finally, the utilization of large HTS derived development data sets from multiple products to facilitate machine learning and <i>in silico</i> process development will be discussed.

Integration of downstream platform development into a single 96-well filter plate for ultra-rapid process definition

253rd National Meeting (2017)

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