Lamping, Sally Rhiannon; (2004) Design of a miniature bioreactor and its use in fermentation and cell culture. Doctoral thesis (D.Eng), UCL (University College London).

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Abstract

Major advances in molecular biology, genomics and analytical techniques have significantly increased the rate of discovery of new molecular entities. Automation and multi-well plate technology has played a vital role in these advances. The translation of discoveries to products demands parallel approaches which allow large numbers of process options to be rapidly explored. The engineering challenges in achieving this go well beyond those for discovery studies and provide the motivation for this work. In this thesis the fundamental engineering issues that impact fermentation and cell culture at micro-well scale are addressed. Results will be given based on experimental data obtained from a new miniature bioreactor and standard microwell plates. The miniature bioreactor is designed to have a working volume of 6 mL, with its major dimensions equal to those of a single well of a 24-well plate. Two prototypes are presented, one fabricated from Perspex to allow flow visualisation and the other is machined from stainless steel to allow steam sterilisation. Agitation in the miniature bioreactor is provided by a set of three micro-fabricated flat open turbine impellers positioned centrally in the vessel and driven from the top of the vessel by a micro-electric motor with a speed of up to 15,000 rpm. The bioreactor is equipped with fibre optic probes and sensors to measure key fermentation parameters including oxygen transfer rate, pH and cell growth. Experiments in the miniature bioreactor combined with computational fluid dynamics (CFD) show that the mass transfer conditions found in the miniature bioreactor can be controlled to give comparable conditions to those found at larger scale (15 L working volume). It is also shown that bacterial and mammalian cellgrowth in the miniature bioreactor are both feasible. Preliminary data are presented and compared with results from a laboratory scale bioreactor. The potential expansion of the miniature bioreactor into an automated parallel processing system is discussed. Translation of results to multi-well plate format has the potential to give a step increase in the speed of process development. The reduction of cost by automation of multi-well fermentation will allow process insight to be built up at an early stage of development in the life cycle of a potential drug candidate where the risk of clinical trial failure usually precludes any process study.

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