|Title:||A scale-down approach to assess scale-up induced process variability in mammalian cell culture||Language:||English||Authors:||Brunner, Matthias||Qualification level:||Doctoral||Advisor:||Herwig, Christoph||Issue Date:||2017||Number of Pages:||80||Qualification level:||Doctoral||Abstract:||
A great share of biopharamceutical products is nowadays derived from mammalian cell cultivations. However, the scale-up of cell culture processes is a challenging task, often resulting in variable process performances across the scales. Due to the nature of bioreactor scale-up it is impossible to maintain all operational conditions equal between small-scale and large-scale cultivations. Variations in operational parameters can lead to a physiochemical variability with direct influence on cell specific physiological conditions, finally altering product quality and process performance. The goal of this thesis was to evaluate the impact of large-scale inhomogeneities, that arise during process scale-up, on cell physiology and process performance using a scale-down approach. Hereby physiological effects of large-scale inhomogeneities were uncovered through application and combination of a decoupled control strategy for process parameters (pH, pO2 and pCO2) with multivariate data analysis as well as metabolic flux analysis and the establishment of a two-compartment bioreactor system. Through this methodology novel process parameter interaction effects as well as intracellular metabolic regulations were revealed. Furthermore, the development and application of the two-compartment bioreactor system led to an improved understanding of the impact of temporary pH gradients on cell physiology and process performance. The gathered results demonstrate that the used scale-down approach in combination with appropriate investigative methods is capable of revealing novel effects that might occur during large-scale mammalian fermentation processes. The transferability of these obtained results back to the large-scale is however challenging due to the lack of knowledge of the actual large-scale conditions.
|Keywords:||Cell culture; scale-down; scale-up; monoclonal antibody; critical quality attributes (CQA)||URI:||https://resolver.obvsg.at/urn:nbn:at:at-ubtuw:1-129150
|Library ID:||AC14486652||Organisation:||E166 - Institut für Verfahrenstechnik, Umwelttechnik und Technische Biowissenschaften||Publication Type:||Thesis
|Appears in Collections:||Thesis|
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checked on Apr 29, 2021
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