Al-Ramadhani, O; (2015) Design and characterisation of a parallel miniaturised bioreactor system for mammalian cell culture. Doctoral thesis , UCL (University College London).

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Abstract

Optimisation of a mammalian cell culture process requires the testing of many process parameters. High yielding processes can result in reduced batches, hence bringing the product to market quicker and increasing manufacturing capacity. To reduce the cost and duration of process optimisation a novel miniaturised stirred bioreactor system (MBR), the BioXplorer™, a prototype of a commercial MBR system initially developed for microbial fermentations is described here. The system enables the operation of 4-16, 500 mL, independently controlled bioreactors in parallel. Each bioreactor is a scale down model of a lab-scale stirred tank bioreactor (STR) and constructed from the same materials. Agitation of the bioreactor can be via a magnetically driven 4 blade marine impeller or a directly driven 3 blade marine impeller. Aeration can be achieved through a variety of sparger designs directly into the culture or via the headspace at a maximum flow rate of 200 mL/min. A detailed characterisation of the key engineering parameters has been conducted focusing on power input and the power to volume ratio (P/V), mixing time and the overall volumetric mass transfer coefficient (kLa). Successful scale comparison studies were conducted to 5L scale using constant P/V and mixing time, employing an industrially relevant GS-CHO cell line producing an IgG antibody. The growth kinetics and product titres compared favourably in both systems when conducting fed-batch operations. μ-max in the MBR was 0.024 h-1 and the maximum viable cell concentration was 10.4 x 106 cells/mL while in the 5L STR μ¬max was 0.029 h-1 and the maximum viable cell concentration was 9.8 x106 viable cells/mL. The product titres were also very similar in both the MBR (1.07 g/L) and the 5L STR (1.05 g/L). It has also been shown that the MBR can conduct continuous feeding using built-in peristaltic pumps, maintaining the glucose concentration in the culture at approximately 2.0 g/L after initiation of feeding. The MBR described here potentially provides a valuable and effective tool for process optimisation and is capable of performing complex feeding strategies.

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