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Combined metabolomics and proteomics reveals hypoxia as a cause of lower productivity on scale‐up to a 5000‐liter CHO bioprocess
Author(s) -
Gao Yuanwei,
Ray Somak,
Dai Shujia,
Ivanov Alexander R.,
AbuAbsi Nicholas R.,
Lewis Amanda M.,
Huang Zhuangrong,
Xing Zizhuo,
Borys Michael C.,
Li Zheng Jian,
Karger Barry L.
Publication year - 2016
Publication title -
biotechnology journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.144
H-Index - 84
eISSN - 1860-7314
pISSN - 1860-6768
DOI - 10.1002/biot.201600030
Subject(s) - bioprocess , bioreactor , biopharmaceutical , proteomics , chemistry , microbiology and biotechnology , metabolomics , productivity , reactive oxygen species , food science , pulp and paper industry , biology , biochemistry , botany , chromatography , engineering , paleontology , macroeconomics , economics , gene
Large‐scale bioprocessing is key to the successful manufacturing of a biopharmaceutical. However, cell viability and productivity are often lower in the scale‐up from laboratory to production. In this study, we analyzed CHO cells, which showed lower percent viabilities and productivity in a 5‐KL production scale bioreactor compared to a 20‐L bench‐top scale under seemingly identical process parameters. An increase in copper concentration in the media from 0.02 µM to 0.4 µM led to a doubling of percent viability in the production scale albeit still at a lower level than the bench‐top scale. Combined metabolomics and proteomics revealed the increased copper reduced the presence of reactive oxygen species (ROS) in the 5‐KL scale process. The reduction in oxidative stress was supported by the increased level of glutathione peroxidase in the lower copper level condition. The excess ROS was shown to be due to hypoxia (intermittent), as evidenced by the reduction in fibronectin with increased copper. The 20‐L scale showed much less hypoxia and thus less excess ROS generation, resulting in little to no impact to productivity with the increased copper in the media. The study illustrates the power of 'Omics in aiding in the understanding of biological processes in biopharmaceutical production.