Manufacturing of biologics has evolved over the last ten years to improve culture productivity and overall facility throughput. One specific example is the advent of N-1 Perfusion. N-1 Perfusion allows the production culture to be inoculated at 8 to 10X the density of a traditional bioreactor resulting in either a shortened production bioreactor phase or the same duration with higher protein concentration at harvest. At Biogen, the N-1 is typically used to achieve high volumetric throughput. An added benefit is reducing the time spent in the production bioreactor which is currently the facility bottleneck. Biogen uses Tangential Flow Filtration (TFF) with hollow fiber filters for its N-1 perfusion operations operating at a higher working volume than traditionally used elsewhere in the industry. Maintaining a perfusion cell culture process at 3,000L working volume generates several challenges such as fouling of the hollow fiber filter membrane, physical cell damage due to operating conditions of the pump and skid design and overcoming oxygen mass transfer limitations while cells are being recirculated outside the bioreactor. All of these challenges were witnessed during our large scale perfusion system and influenced changes to the equipment and operating conditions. Additionally, our pilot scale down model was improved to more closely model the large scale. This work will discuss the pain points of the TFF N-1 perfusion at the 3,000L scale and improvements that were made to the process and equipment to mitigate some of these problems to create a sustainable perfusion platform for the future.

Challenges with TFF N-1 Perfusion in large scale manufacturing operations

2019 Spring National Meeting

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