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Equal mixing time enables scale-down and optimization of a CHO cell culture process using a shaken microbioreactor system

Wiegmann, V; Gardner, RA; Spencer, DIR; Baganz, F; (2021) Equal mixing time enables scale-down and optimization of a CHO cell culture process using a shaken microbioreactor system. Biotechnology Journal 10.1002/biot.202100360. (In press). Green open access

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Abstract

The advancement of microbioreactor technology in recent years has transformed early- and mid-stage process development. The monitoring and control capabilities of microbioreactors not only promote the quick accumulation of process knowledge but has also led to an increased scalability when compared to traditionally used systems such as shake flasks and microtitre plates. This study seeks to establish a framework for the micro-Matrix microbioreactor (Applikon-Biotechnology BV) as process development tool. Using the Dual Indicator System for Mixing Time, the system was initially characterized for mixing properties at varying operating conditions, which was found to yield mixing times between 0.9 and 41.8 s. A matched mixing time was proposed as scale-down criterion for an IgG4 producing GS-CHO fed-batch process between a 5 L stirred tank reactor (STR) and the micro-Matrix microbioreactor. Growth trends, maximum viable cell concentrations, final titre, and glycoprofiles were nearly identical at both scales. The scale-down model was then employed to optimize a bolus feeding regime using response surface methodology, which led to a 25.4% increase of the space-time yield and a 25% increase of the final titre. The optimized feeding strategy was validated at the small-scale and successfully scaled up to the 5 L STR. This work for the first time provides a framework of how the micro-Matrix microbioreactor can be implemented in a bioprocess development workflow and demonstrates scalability of growth and production kinetics as well as IgG4 glycosylation between the micro-Matrix and a benchtop-scale STR system. Graphical Abstract and Lay Summary: (Figure presented.) Microbioreactor technology has become an essential part of early- and mid-stage bioprocess development. This study provides a framework of how the shaken micro-Matrix system can be used for cell culture process development of a mammalian CHO cell line producing a monoclonal antibody. Following scale-down from a 5 L stirred tank bioreactor, the micro-Matrix was employed for the optimisation of a feeding strategy and the optimised protocol was successfully scaled up.

Type: Article
Title: Equal mixing time enables scale-down and optimization of a CHO cell culture process using a shaken microbioreactor system
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/biot.202100360
Publisher version: https://doi.org/10.1002/biot.202100360
Language: English
Additional information: © 2021 The Authors. Biotechnology Journal published by Wiley-VCH GmbH This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: CHO cell culture, design of experiment, high throughput, microbioreactor, mixing time characterization, scale down
UCL classification: UCL
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Biochemical Engineering
URI: https://discovery.ucl.ac.uk/id/eprint/10135205
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