Bioprocess and Biosystems Engineering

, Volume 39, Issue 11, pp 1689–1702 | Cite as

Improving lactate metabolism in an intensified CHO culture process: productivity and product quality considerations

  • Sen XuEmail author
  • Linda Hoshan
  • Hao Chen
Original Paper


In this study, we discussed the development and optimization of an intensified CHO culture process, highlighting medium and control strategies to improve lactate metabolism. A few strategies, including supplementing glucose with other sugars (fructose, maltose, and galactose), controlling glucose level at <0.2 mM, and supplementing medium with copper sulfate, were found to be effective in reducing lactate accumulation. Among them, copper sulfate supplementation was found to be critical for process optimization when glucose was in excess. When copper sulfate was supplemented in the new process, two-fold increase in cell density (66.5 ± 8.4 × 106 cells/mL) and titer (11.9 ± 0.6 g/L) was achieved. Productivity and product quality attributes differences between batch, fed-batch, and concentrated fed-batch cultures were discussed. The importance of process and cell metabolism understanding when adapting the existing process to a new operational mode was demonstrated in the study.


Process intensification High cell density Alternating tangential flow Copper sulfate Product quality 



We would like to thank Mike Caruso, Alejandro Baloco, Debra Lutz, and D’Juan Gibson for bioreactor operations and media preparation, Elizabeth Wu for titer assay, Heera Khan, Mike Rauscher, and Sonja Battle for purification and quality assays. We would also like to thank John Bowers, Balrina Gupta, and David Roush for critical review of the manuscript.

Supplementary material

449_2016_1644_MOESM1_ESM.doc (104 kb)
Supplementary material 1 (DOC 104 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Process Development and Engineering, Biologics and VaccinesMerck & Co., Inc.KenilworthUSA

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