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High cell density induces spontaneous bifurcations of dissolved oxygen controllers during CHO cell fermentations
Author(s) -
Chung John D.,
Chang Conway C.,
Groves James Ashley
Publication year - 2003
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.10763
Subject(s) - bioreactor , steady state (chemistry) , continuous stirred tank reactor , oxygen , chemistry , bifurcation , limiting oxygen concentration , bifurcation diagram , thermodynamics , physics , nonlinear system , organic chemistry , quantum mechanics
High cell density cultures of CHO cells growing in a bioreactor under dissolved oxygen control were found to undergo spontaneous bifurcations and a subsequent loss of stability some time into the fermentation. This loss of stability was manifested by sustained and amplified oscillations in the bioreactor dissolved oxygen concentration and in the oxygen gas flow rate to the reactor. To identify potential biological and operational causes for the phenomenon, linear stability analysis was applied in a neighborhood of the experimentally observed bifurcation point. The analysis revealed that two steady state process gains, K P1 and K P2 , regulated k l a and gas phase oxygen concentration inputs, respectively, and the magnitude of K P1 was found to determine system stability about the bifurcation point. The magnitude of K P1 , and hence the corresponding open‐loop steady state gain K OL1 , scaled linearly with the bioreactor cell density, increasing with increasing cell density. These results allowed the generation of a fermentation stability diagram, which partitioned K C ‐N operating space into stable and unstable regions separated by the loci of predicted critically stable controller constants, K C,critical , as a function of bioreactor cell density. This consistency of this operating diagram with experimentally observed changes in system stability was demonstrated. We conclude that time‐dependent increases in cell density are the cause of the observed instabilities and that cell density is the critical bifurcation parameter. The results of this study should be readily applicable to the design of a more robust controller. © 2003 Wiley Periodicals, Inc. Biotechnol Bioeng 84: 224–232, 2003.