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Linking high throughput cell culture, multivariate analysis and economics for more effective process integration

Antemie, AM; (2016) Linking high throughput cell culture, multivariate analysis and economics for more effective process integration. Doctoral thesis , UCL (University College London). Green open access

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Abstract

As the antibody sector has matured, it has seen significant increases in cell culture titres. However, it is hard to predict the consequences of titre increase on impurity levels and downstream processing (DSP) performance. Hence it is critical to have systematic methods to explore such interactions. This project explored the potential of high throughput cell culture linked to multivariate analysis, uncertainty analysis and bioprocess economics to characterise cell culture processes, not only in terms of growth and productivity but also host cell protein (HCP) levels, robustness and costs. A Quality by Design (QbD) approach to cell culture process development is presented. Using this QbD framework it was shown that there is scope for cell culture processes in which the ratio of mAb to HCP can be increased and the association of mAb titre to HCP reduced. It is therefore feasible to identify conditions whereby it is possible to increase antibody titre with little impact on HCP levels and hence subsequent DSP operations. (36.5 oC, 313 mOsm kg-1 media osmolality, 1 × 106 cells mL-1 seeding density, pH 6.8 and low cell generation number in this case). The impact of cell culture factors on protease activity (problematic HCP species) was assessed. Culture temperature was found to have a significant impact on protease activity, with a decrease in temperature resulting in lower protease activity. The relationship between HCP levels and protease activity was also examined and it was shown that an increase in total HCP levels at harvest did not result in a concomitant increase in protease activity. Multivariate data analysis based on regression was used to derive statistical cause-and-effect correlations able to link mAb titre and HCP levels to key cell culture factors. The resulting cell culture predictive correlations were then integrated into a whole bioprocess economics and optimisation framework. This allowed the identification of the most cost effective cell culture strategies as well as the impact of uncertainty in cell culture parameters on outputs (product output (kg) and HCP final (ng/mg)) and the likelihood of these falling out of specification. The work in this thesis highlights the benefits of a systematic approach to providing enhanced process understanding of the impact of cell culture strategies on downstream processes. This can be used to facilitate effective process integration and enable continuous improvements.

Type: Thesis (Doctoral)
Title: Linking high throughput cell culture, multivariate analysis and economics for more effective process integration
Event: University College London
Open access status: An open access version is available from UCL Discovery
Language: English
Keywords: antibody, HCP, ambr, protease, statistics, economics, QbD
UCL classification: UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
URI: http://discovery.ucl.ac.uk/id/eprint/1475468
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