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Biotechnol Bioeng. 2019 Jun 11. doi: 10.1002/bit.27087. [Epub ahead of print]

Metabolomic profiling of CHO fed-batch growth phases at 10, 100 and 1000 L.

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Laboratory Bioprocess Development, Technical Development Biologics MengeŇ°, Technical Research & Development, Novartis Pharma AG.
Department of Animal Science, Biotechnical faculty, University of Ljubljana, Ljubljana, Slovenia.
Laboratory of Bioinformatics, Faculty of computer science and informatics, University of Ljubljana, Ljubljana, Slovenia.


Established bioprocess monitoring is based on quick and reliable methods, including cell count and viability measurement, extracellular metabolite measurement and the measurement of physicochemical qualities of the cultivation medium. These methods are sufficient for monitoring of process performance, but rarely give insight into the actual physiological states of the cell culture. However, understanding of the latter is essential for optimization of bioprocess development. Our study employed LC-MS metabolomics as a tool for additional resolution of bioprocess monitoring and was designed at three bioreactors scales (10 L, 100 L, 1000 L) to gain insight into the basal metabolic states of the Chinese hamster ovary (CHO) cell culture during fed-batch. Metabolites characteristic of the four growth stages (early and late exponential phase, stationary phase, and the phase of decline) were identified by multivariate analysis. Enriched metabolic pathways were then established for each growth phase using the CHO metabolic network model. Biomass generation and nucleotide synthesis were enriched in early exponential phase, followed by increased protein production and imbalanced glutathione metabolism in late exponential phase. Glycolysis became downregulated in stationary phase and amino-acid metabolism increased. Phase of culture decline resulted in rise of oxidized glutathione and fatty acid concentrations. Intracellular metabolic profiles of the CHO fed-batch culture were also shown to be consistent with scale and thus demonstrate metabolomic profiling as an informative method to gain physiological insight into the cell culture states during bioprocess regardless of scale. This article is protected by copyright. All rights reserved.


CHO; Chinese hamster ovary; growth phase; metabolomic; profile; scale-up


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