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Novel, linked bioreactor system for continuous production of biologics
Author(s) -
Gag Matthew,
Nagre Shashikant,
Wang Wenge,
Coffman Jon,
Hiller Gregory W.
Publication year - 2019
Publication title -
biotechnology and bioengineering
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.136
H-Index - 189
eISSN - 1097-0290
pISSN - 0006-3592
DOI - 10.1002/bit.26985
Subject(s) - bioreactor , continuous stirred tank reactor , steady state (chemistry) , continuous production , process engineering , dilution , scale up , volume (thermodynamics) , continuous flow , chemistry , environmental science , biochemical engineering , chemical engineering , engineering , thermodynamics , environmental engineering , physics , organic chemistry , classical mechanics
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.