Novel, Linked Bioreactor System for Continuous Production of Biologics

Matthew Gagnon, Shashikant Nagre, Wenge Wang, Jon Coffman, Gregory W Hiller
Biotechnology and Bioengineering 2019 April 5
A novel, alternative intensified cell culture process comprised of a linked bioreactor system is presented. An N-1 perfusion bioreactor maintained cells in a highly proliferative state and provided a continuous inoculum source to a second bioreactor operating as a continuous-flow stirred-tank reactor (CSTR). An initial study evaluated multiple system steady-states by varying N-1 steady-state viable cell densities, N-1 to CSTR working volume ratios, and CSTR dilution rates. After identifying near optimum system steady-state parameters yielding a relatively high volumetric productivity while efficiently consuming media, a subsequent lab scale experiment demonstrated the start-up and long-term operation of the envisioned manufacturing process for 83 days. Additionally, to compensate for the cell-specific productivity loss over time due to cell line instability, the N-1 culture was also replaced with younger generation cells, without disturbing the steady-state of the system. Using the model cell line, the system demonstrated a 2-fold volumetric productivity increase over the commercial-ready, optimized fed-batch process. This article is protected by copyright. All rights reserved.

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