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Title: Optimal design, operation and control of sequential multi-column chromatography for separation of biomolecules
Author: Ng, C. K. S.
ISNI:       0000 0004 5363 7398
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2014
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The increasingly stringent regulatory requirements on the quality and cost-effectiveness of biopharmaceuticals as well as the escalating upstream titre are placing considerable pressure on downstream bioprocessing. In particular, batch chromatography is fast becoming the process bottleneck due to its limited capacity and expensive operation. Recent developments in multi-column counter-current chromatography (MCC) for the separation of biomolecules have demonstrated the potential to overcome these limitations. However, the uptake of MCC processes by the biopharmaceutical industry is hindered by system complexity and the liable validation difficulties. This research provides a solution to the above challenges through the development of an integrated experimental and modelling design approach and a process analytical technology (PAT)-compliant controller. These tools were exemplified using protein A chromatography, because of its key role in purification and the associated adsorbent cost. Sequential multi-column chromatography (SMCC) was the MCC process of choice as it is universal to a wide range of chromatographic principles. The design approach was applied to both batch chromatography and SMCC for fair comparison of the two processes at their optimal performance. Significantly higher productivities (up to two-fold) were found for SMCC than for batch chromatography with varying improvements in each case. The integrated use of experimentation and modelling enabled sufficient process understanding to be gained quickly and efficiently, and thus providing a dramatic reduction in the time and costs to find the optimal design (up to an estimate of five-fold). The SMCC controller ensures robust and optimal process operation by controlling a set of characteristic points that were monitored within the system loop for various zones. Such a controller is simple to implement and offers quick actions (within 15 cycles for loading due to the multi-column effect and within 2 cycles for the other zones) against possible process disturbances and system uncertainties at system start-up.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available