Chemical stability often limits the allowable ambient hold times between unit operations during downstream processing of recombinant proteins. This is particularly true for harvested cell culture prior to the capture chromatography step and often results in over-sized columns designed to reduce processing time. This presentation will describe the design and qualification of a point-of-use and disposable heat exchanger for downstream processing of large molecules in a cGMP clinical trial plant. The goal of the heat exchanger is to warm material from 5°C to 20°C at point-of-use enabling operations to better manage ambient hold times. The system is fully automated to avoid manual intervention and facilitates a cost reduction strategy to minimize chromatography resin expenses. A 200-L Single-Use Mixer was selected from a first principles analysis because of its heat transfer capabilities, mixing efficiency, process automation integration, and disposable product contact layer. During design and qualification, the system was characterized to establish a control strategy for a wide range of processing conditions. Specifically, the system was modeled with Computational Fluid Dynamics to demonstrate efficient mixing and temperature spatial profiles in the vessel at varied processing conditions. The model established two results: the system is well mixed and the temperature profiles within the vessel mitigate product impact risk. Empirical testing was conducted for verification and determination of common cause variability. Overall, the system demonstrated consistent heat transfer across a variety of conditions expected at manufacturing scale. The system was implemented for use and qualification results demonstrated reliable temperature control. It has been successfully integrated into cGMP manufacturing for over one year and operates continually without manual intervention using plant-integrated process automation solutions for control and monitoring. The system has saved over $100,000 per campaign.

Implementation of a single-use mixer as a point-of-use and disposable heat exchanger in cGMP downstream processing

251st National Meeting (2016)

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