Identifying inhibitory threshold values of repressing metabolites in CHO cell culture using multivariate analysis methods

Biotechnology Progress
Zizhuo XingSteven S Lee

Abstract

Elevation of lactate, ammonia, osmolality, and carbon dioxide to inhibitory levels was reported to have adverse effects on cell growth and protein productivity in mammalian cell culture. Multivariate analysis methods were used to investigate the roles of these repressing metabolites in a fed-batch CHO cell culture for antibody fusion protein B1 (B1) production. Principal Factor Analysis methodology was applied to manufacturing-scale data of 112 cell culture runs, which identified threshold values of four repressing metabolites as follows: (1) ammonium levels above 5.1 mM inhibit cell growth; (2) both lactate and osmolality levels above 58 mM and 382 mOsm/kg affect cell viability; and (3) carbon dioxide levels at or above 111 mmHg reduce protein quality. These threshold values were then verified by simulations using Monod-type equations and Canonical Correlation. These results suggest that adverse effects on cell growth, productivity, and product quality may be minimized under the ideal cell culture condition, in which the peak values of all four repressing metabolites are maintained below the threshold values. This strategy was evaluated in 45 cell culture runs in 50-L bioreactors. Eight out of 45 runs were operated under the i...Continue Reading

Citations

Mar 13, 2009·Biotechnology and Bioengineering·Zizhuo XingSteven S Lee
May 20, 2011·Biotechnology Progress·Yueming QianZheng Jian Li
Nov 15, 2013·Biotechnology Journal·Payel DattaRobert J Linhardt
Oct 15, 2013·Biotechnology Progress·Valerie Liu TsangThomas Ryll
Dec 17, 2009·Biotechnology Progress·Sarwat F KhattakZheng Jian Li
Apr 6, 2016·The AAPS Journal·Anurag S RathoreGaurav Pratap Singh Jadaun
Jul 23, 2015·Applied Microbiology and Biotechnology·Bassem Ben YahiaElmar Heinzle
Apr 8, 2015·Applied Microbiology and Biotechnology·David ReinhartRenate Kunert
Oct 23, 2016·Biotechnology Progress·Melissa M St AmandBabatunde A Ogunnaike
Dec 7, 2016·Biotechnology and Bioengineering·Zizhuo XingZheng Jian Li
Nov 11, 2009·Rapid Communications in Mass Spectrometry : RCM·William P K ChongYing Swan Ho
Oct 5, 2011·Biotechnology Advances·Jianwei Zhu

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