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Model-based workflow for scale-up of process strategies developed in miniaturized bioreactor systems
Citation Link: https://doi.org/10.15480/882.3632
Publikationstyp
Journal Article
Publikationsdatum
2021-01-13
Sprache
English
Author
Arndt, Lukas
Möller, Johannes
TORE-URI
Enthalten in
Volume
37
Issue
3
Article Number
e3122
Citation
Biotechnology Progress 37 (3): e3122 (2021-05-01)
Publisher DOI
Scopus ID
Publisher
Wiley
Miniaturized bioreactor (MBR) systems are routinely used in the development of mammalian cell culture processes. However, scale-up of process strategies obtained in MBR- to larger scale is challenging due to mainly non-holistic scale-up approaches. In this study, a model-based workflow is introduced to quantify differences in the process dynamics between bioreactor scales and thus enable a more knowledge-driven scale-up. The workflow is applied to two case studies with antibody-producing Chinese hamster ovary cell lines. With the workflow, model parameter distributions are estimated first under consideration of experimental variability for different scales. Second, the obtained individual model parameter distributions are tested for statistical differences. In case of significant differences, model parametric distributions are transferred between the scales. In case study I, a fed-batch process in a microtiter plate (4 ml working volume) and lab-scale bioreactor (3750 ml working volume) was mathematically modeled and evaluated. No significant differences were identified for model parameter distributions reflecting process dynamics. Therefore, the microtiter plate can be applied as scale-down tool for the lab-scale bioreactor. In case study II, a fed-batch process in a 24-Deep-Well-Plate (2 ml working volume) and shake flask (40 ml working volume) with two feed media was investigated. Model parameter distributions showed significant differences. Thus, process strategies were mathematically transferred, and model predictions were simulated for a new shake flask culture setup and confirmed in validation experiments. Overall, the workflow enables a knowledge-driven evaluation of scale-up for a more efficient bioprocess design and optimization.
Schlagworte
mathematical process models
model-assisted scale-up
Monte Carlo uncertainty analysis
quality by design
DDC Class
570: Biowissenschaften, Biologie
600: Technik
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