Abstract
We designed small‐scale virus filtration models to investigate the impact of the extended process times and dynamic product streams present in continuous manufacturing. Our data show that the Planova 20N and BioEX virus filters are capable of effectively removing bacteriophage PP7 (>4 log) when run continuously for up to 4 days. Additionally, both Planova 20N and BioEX filters were able to successfully process a mock elution peak of increased protein, salt, and bacteriophage concentrations with only an increase in filtration pressure observed during the higher protein concentration peak. These experiments demonstrated that small‐scale viral clearance studies can be designed to model a continuous virus filtration step with specific process parameters.
Highlights
Biotechnology manufacturing has gradually evolved over the years from traditional batch mode operation to more continuous modes of operation with the implementation of continuous perfusion cell culture.[1,2] Recently, with technical advancements in continuous chromatography and an increased focus on single-use systems, focus has shifted to an integrated upstream and downstream continuous process
For a truly continuous manufacturing process, all upstream and downstream manufacturing steps are integrated with a continuous flow of product, which is in contrast to numerous hold tanks in traditional batch mode
While there has been recent published research on continuous chromatography and continuous viral inactivation, there has been little published data on the impact of continuous manufacturing on virus filtration. This study provides both novel ideas when considering small-scale design for mimicking continuous virus filtration conditions, including extended filtration process times and dynamic loading conditions, and experimental data to support the implementation into a continuous manufacturing setting
Summary
Biotechnology manufacturing has gradually evolved over the years from traditional batch mode operation to more continuous modes of operation with the implementation of continuous perfusion cell culture.[1,2] Recently, with technical advancements in continuous chromatography and an increased focus on single-use systems, focus has shifted to an integrated upstream and downstream continuous process. With technical advancements in continuous chromatography and an increased focus on single-use systems, focus has shifted to an integrated upstream and downstream continuous process. Due to technical constraints and lack of small-scale models, most theoretical continuous manufacturing designs focus on a hybrid continuous system with one or more dedicated virus removal/inactivation steps remaining in batch mode via traditional hold tanks (e.g., low pH inactivation) or as a dedicated offline step (e.g., virus filtration). To facilitate the design and implementation of a fully continuous downstream process, one must understand the differences and challenges between traditional batch mode purification and integrated continuous purification. It is necessary to understand how these differences can impact the performance of each unit operation and how to design small-scale studies of each continuous unit operation. Recent studies have focused mostly on implementation of continuous capture chromatography and continuous viral inactivation[3,4] with little research on the integration of virus filtration into continuous processes, aside from theoretical process design strategies.[5]
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