Neunstoecklin Benjamin, Villiger Thomas K, Lucas Eric, Stettler Matthieu, Broly Hervé, Morbidelli Massimo, Soos Miroslav
Department of Chemistry and Applied Biosciences, Institute for Chemical and Bioengineering, ETH Zurich, 8093, Zurich, Switzerland.
Merck Serono S.A., Biotech Process Sciences, Corsier-sur-Vevey, Switzerland.
Appl Microbiol Biotechnol. 2016 Apr;100(8):3489-98. doi: 10.1007/s00253-015-7193-x. Epub 2015 Dec 5.
Although several scaling bioreactor models of mammalian cell cultures are suggested and described in the literature, they mostly lack a significant validation at pilot or manufacturing scale. The aim of this study is to validate an oscillating hydrodynamic stress loop system developed earlier by our group for the evaluation of the maximum operating range for stirring, based on a maximum tolerable hydrodynamic stress. A 300-L pilot-scale bioreactor for cultivation of a Sp2/0 cell line was used for this purpose. Prior to cultivations, a stress-sensitive particulate system was applied to determine the stress values generated by stirring and sparging. Pilot-scale data, collected from 7- to 28-Pa maximum stress conditions, were compared with data from classical 3-L cultivations and cultivations from the oscillating stress loop system. Results for the growth behavior, analyzed metabolites, productivity, and product quality showed a dependency on the different environmental stress conditions but not on reactor size. Pilot-scale conditions were very similar to those generated in the oscillating stress loop model confirming its predictive capability, including conditions at the edge of failure.
尽管文献中提出并描述了几种哺乳动物细胞培养的放大生物反应器模型，但它们大多缺乏在中试或生产规模下的有效验证。本研究的目的是验证我们小组先前开发的一种振荡流体动力应力回路系统，该系统基于最大可耐受流体动力应力来评估搅拌的最大操作范围。为此，使用了一个用于培养Sp2/0细胞系的300升中试规模生物反应器。在培养之前，应用了一种应力敏感颗粒系统来确定搅拌和鼓泡产生的应力值。将从中试规模收集的、最大应力条件为7至28帕的数据与来自经典3升培养和振荡应力回路系统培养的数据进行了比较。生长行为、分析的代谢物、生产力和产品质量的结果表明，它们依赖于不同的环境应力条件，而不是反应器尺寸。中试规模条件与振荡应力回路模型中产生的条件非常相似，证实了其预测能力，包括在失效边缘的条件。
