期刊
JOURNAL OF BIOTECHNOLOGY
卷 135, 期 2, 页码 174-180出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jbiotec.2008.03.019
关键词
automated flow cytometry; bioreactor monitoring; mammalian cell culture; single-cell heterogeneity; Process Analytical Technology; PAT initiative
Detailed knowledge of mammalian cell culture proliferation kinetics is important to determine fed-batch strategies for industrial bioreactor operations. In particular, predicting the end of exponential proliferation in batch culture is a critical process parameter during culture scale-up. Using automated flow cytometry we show that an increase in the non-viable sub-population in CHO cell culture can predict the onset of stationary phase by approximately 40 h. This enables a completely automated culture scale-up process as well as a reliable and reproducible control of fed-batch additions during culture expansion. It is shown that the automated scale-up results in a significantly higher total cell count in the reactor than manual scale up initiated in stationary growth phase. During individual, subsequent culture expansions, a significant variation in the proliferation rate was observed despite control of bulk culture parameters. Thus, automated flow cytometry is critical to uncovering useful process parameters that enable new control strategies. Such improved process supervision derived from knowledge-based data analysis is central to the FDA's Process Analytical Technology (PAT) initiative and is expected to result in better and higher quality products. 2008 Elsevier B.V. All rights reserved.
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