Novel, linked bioreactor system for continuous production of biologics. Issue 8 (23rd May 2019)

• Record Type: Journal Article
• Authors: Gagnon, Matthew; Nagre, Shashikant; Wang, Wenge; Coffman, Jon; Hiller, Gregory W.
• Is Part Of: Biotechnology and bioengineering. Volume 116:Issue 8(2019)
• Page Start: 1946
• Page End: 1958
• Publication Date: 2019-05-23
• Subjects: cell culture intensification -- CHO cells -- CSTR -- linked bioreactors -- perfusion; Biotechnology -- Periodicals; Bioengineering -- Periodicals; 660.6
• DOI: 10.1002/bit.26985
• Languages: English
• ISSNs: 0006-3592

Abstract

Abstract: 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 startup 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 two‐fold volumetric productivity increase over the commercial‐ready, optimized fed‐batch process. Abstract : 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).