From development to implementation with a fully integrated downstream bioprocess
September 17-21, 2017
Boehringer Ingelheim and Pfizer have developed a unique continuous bioprocess consisting of a short duration perfusion upstream and fully integrated downstream. The process is designed to generate at least 1 kg of material from a 100 L bioreactor in approximate 2 weeks. The upstream strategy utilizes a non-steady state, short duration perfusion process to achieve volumetric productivities ranging from 0.5 to 4 g/L/day. This creates a unique challenge for the downstream process as the titer and impurity load change over the duration of the culture. To accommodate upstream, a fully integrated downstream process was created using a combination of traditional batch unit operations and continuous bioprocessing. The system design includes a pair of small proteins A columns operated consecutively, a continuous low pH inactivation chamber (cVI), an anion exchange chromatography column, a single pass tangential flow filter, a virus filter and batch UFDF. The key to the system is three distinct operation modes including continuous, periodic and batch phases. The resulting hybrid system provides flexible and robust downstream processing of the continuous perfusion bioreactor. We have successfully used this new downstream process at the predicted manufacturing scale to generate clinical quality drug substance for multiple monoclonal antibodies. With the success of the new integrated system, our team is shifting its focus to implementation on a clinical program. A key element of the ongoing work is to establish the control and robustness of novel elements of our process such as confirming that the critical pH has been achieved during cVI and demonstrating robust impurity removal for dynamic loading on an AEX polishing step. In this talk, we will explain our approach to integrated continuous downstream processing and our strategy for future implementation. Data from at-scale demonstration runs will show the robustness of the process over a wide range of loading conditions. This will include product quality data including HCP, DNA, charge variants and aggregate removal that is consistent with batch processes. Process data will show the control and robustness of the approach.
Jeff Salm, Rob Fahrner, Raquel Orozco, Min Zhang, Marcus Fiadeiro, Jill Kublbeck, Scott Godfrey, Bob Kottmeier, Dave Sullivan, Jon Coffman, and Samet Yildirim, "From development to implementation with a fully integrated downstream bioprocess" in "Integrated Continuous Biomanufacturing III", Suzanne Farid, University College London, United Kingdom Chetan Goudar, Amgen, USA Paula Alves, IBET, Portugal Veena Warikoo, Axcella Health, Inc., USA Eds, ECI Symposium Series, (2017). http://dc.engconfintl.org/biomanufact_iii/93
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