Scale-up analysis for a CHO cell culture process in large-scale bioreactors

Authors

  • Zizhuo Xing,

    1. Process Sciences, Biologics Manufacturing and Process Development, Worldwide Medicines Group, Bristol-Myers Squibb Company, P.O. Box 4755, Syracuse, New York 13221-4755; telephone: 315-432-2131; fax: 315-432-2343
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  • Brian M. Kenty,

    1. Process Sciences, Biologics Manufacturing and Process Development, Worldwide Medicines Group, Bristol-Myers Squibb Company, P.O. Box 4755, Syracuse, New York 13221-4755; telephone: 315-432-2131; fax: 315-432-2343
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  • Zheng Jian Li,

    Corresponding author
    1. Process Sciences, Biologics Manufacturing and Process Development, Worldwide Medicines Group, Bristol-Myers Squibb Company, P.O. Box 4755, Syracuse, New York 13221-4755; telephone: 315-432-2131; fax: 315-432-2343
    • Process Sciences, Biologics Manufacturing and Process Development, Worldwide Medicines Group, Bristol-Myers Squibb Company, P.O. Box 4755, Syracuse, New York 13221-4755; telephone: 315-432-2131; fax: 315-432-2343
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  • Steven S. Lee

    1. Process Sciences, Biologics Manufacturing and Process Development, Worldwide Medicines Group, Bristol-Myers Squibb Company, P.O. Box 4755, Syracuse, New York 13221-4755; telephone: 315-432-2131; fax: 315-432-2343
    Current affiliation:
    1. A-Bio Pharma Pte Ltd, 41 Science Park Road, The Gemini, Singapore Science Park II, Singapore 117610.
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Abstract

Bioprocess scale-up is a fundamental component of process development in the biotechnology industry. When scaling up a mammalian cell culture process, it is important to consider factors such as mixing time, oxygen transfer, and carbon dioxide removal. In this study, cell-free mixing studies were performed in production scale 5,000-L bioreactors to evaluate scale-up issues. Using the current bioreactor configuration, the 5,000-L bioreactor had a lower oxygen transfer coefficient, longer mixing time, and lower carbon dioxide removal rate than that was observed in bench scale 5- and 20-L bioreactors. The oxygen transfer threshold analysis indicates that the current 5,000-L configuration can only support a maximum viable cell density of 7 × 106 cells mL−1. Moreover, experiments using a dual probe technique demonstrated that pH and dissolved oxygen gradients may exist in 5,000-L bioreactors using the current configuration. Empirical equations were developed to predict mixing time, oxygen transfer coefficient, and carbon dioxide removal rate under different mixing-related engineering parameters in the 5,000-L bioreactors. These equations indicate that increasing bottom air sparging rate is more efficient than increasing power input in improving oxygen transfer and carbon dioxide removal. Furthermore, as the liquid volume increases in a production bioreactor operated in fed-batch mode, bulk mixing becomes a challenge. The mixing studies suggest that the engineering parameters related to bulk mixing and carbon dioxide removal in the 5,000-L bioreactors may need optimizing to mitigate the risk of different performance upon process scale-up. Biotechnol. Bioeng. 2009;103: 733–746. © 2009 Wiley Periodicals, Inc.

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