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Biotechnol Bioeng. 2019 Apr 5. doi: 10.1002/bit.26985. [Epub ahead of print]

Novel, linked bioreactor system for continuous production of biologics.

Author information

1
Culture Process Development, Pfizer Inc, Andover, Massachusetts.
2
Upstream Process Development, Akston Biosciences, Beverly, Massachusetts.
3
Department of Process Science, Boehringer Ingelheim, Fremont, California.

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.

KEYWORDS:

CHO cells; CSTR; cell culture intensification; linked bioreactors; perfusion

PMID:
30950040
DOI:
10.1002/bit.26985

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