The ultra scale-down technology (USD) is used in this body of work to mimic and study pharmaceutical manufacturing process steps with reduced material requirements. The production of a novel type of domain antibody in recombinant E. coli is used as a context in which the technology is studied. The main focus areas are fermentation, centrifugation, depth-filtration and membrane filtration. Process characterisation was achieved through the detailed study and establishment of sets of critical parameters, such as process material physical properties (e.g. viscosity, solids volume fraction, product quantity and quality) that affect the efficiency of each these process steps, and discoveries from this activity were fed back towards the development of more complete USD models. An understanding of the synergy between the fermentation process and subsequent primary recovery was discovered, which lead to the formulation of a series of trade-offs between product quantity and subsequent ease of recovery. The effect of the cell broth pre-treatment, such as exposure to hydrodynamic shear, homogenization or flocculation, on the efficiency of separation by centrifugation, and the impact on subsequent process steps was also studied. These were linked to theoretical models which allowed the evolution of a prediction for processability based on process material quality. Finally, a methodology was developed to discover the best processing conditions (in terms of flux and shear rate) during membrane microfiltration and a roadmap was developed to establish the rules for accurate scale-up. This work provides improvements and insights into how the USD technology can be used to increase the rate and quality of bioprocess discoveries during drug development. In all process steps studied, the USD technology has shown that a much wider range of conditions than would be possible at large scale can be investigated in a reduced amount of time, which allows a large window of operation to be used during scale-up decisions.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:634682 |
| Date | January 2014 |
| Creators | Chatel, A. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1458022/ |
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