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Title: The productivity limit of manufacturing blood cell therapy in scalable stirred bioreactors
Authors: Bayley, Rachel
Ahmed, Forhad
Glen, Katie E.
McCall, Mark J.S.
Stacey, Adrian J.
Thomas, Robert James
Keywords: Bioreactor
Blood
Cost
Culture
Erythrocyte
Manufacture
Productivity
Red cell
Issue Date: 2017
Publisher: Wiley / © The Authors
Citation: BAYLEY, R. ... et al, 2017. The productivity limit of manufacturing blood cell therapy in scalable stirred bioreactors. Journal of Tissue Engineering and Regenerative Medicine, DOI: 10.1002/term.2337
Abstract: Manufacture of red blood cells (RBCs) from progenitors has been proposed as a method to reduce reliance on donors. Such a process would need to be extremely efficient for economic viability given a relatively low value product and high 2E12 cell dose. Therefore, the aim of these studies was to define the productivity of an industry standard stirred-tank bioreactor and determine engineering limitations of commercial RBC production. Cord blood derived CD34+ cells were cultured under erythroid differentiation conditions in a stirred micro-bioreactor (ambr™). Enucleated cells of 80% purity could be created under optimal physical conditions: pH 7.5, 50% oxygen, without gas-sparging (which damaged cells) and with mechanical agitation (which directly increased enucleation). O2 consumption was low (~5x10(-8) µg/cell.hr) theoretically enabling erythroblast densities in excess of 5x10(8) /ml in commercial bioreactors and sub-10 L/unit production volumes. The bioreactor process achieved a 24% and 42% reduction in media volume and culture time respectively relative to unoptimized flask processing. However, media exchange limited productivity to 1 unit of erythroblasts per 500 L of media. Systematic replacement of media constituents, as well as screening for inhibitory levels of ammonia, lactate and key cytokines did not identify a reason for this limitation. We conclude that the properties of erythroblasts are such that the conventional constraints on cell manufacturing efficiency, such as mass transfer and metabolic demand, should not prevent high intensity production; furthermore this could be achieved in industry standard equipment. However, identification and removal of an inhibitory mediator is required to enable these economies to be realized.
Description: This is an open access article published by Wiley and distributed under the terms of the Creative Commons Attribution 4.0 Licence (CC BY 4.0), https://creativecommons.org/licenses/by/4.0/
Sponsor: This work was funded by the Wellcome Trust (102610) and EPSRC (EP/K00705X/1).
Version: Published
DOI: 10.1002/term.2337
URI: https://dspace.lboro.ac.uk/2134/23011
Publisher Link: http://dx.doi.org/10.1002/term.2337
ISSN: 1932-6254
Appears in Collections:Published Articles (Mechanical, Electrical and Manufacturing Engineering)

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