Fed-batch and perfusion culture processes: economic, environmental, and operational feasibility under uncertainty.
This article evaluates the current and future potential of batch and continuous cell culture technologies via a case study based on the commercial manufacture of monoclonal antibodies. The case study compares fed-batch culture to two perfusion technologies: spin-filter perfusion and an emerging perfusion technology utilizing alternating tangential flow (ATF) perfusion. The operational, economic, and environmental feasibility of whole bioprocesses based on these systems was evaluated using a prototype dynamic decision-support tool built at UCL encompassing process economics, discrete-event simulation and uncertainty analysis, and combined with a multi-attribute decision-making technique so as to enable a holistic assessment. The strategies were compared across a range of scales and titres so as to visualize how their ranking changes in different industry scenarios. The deterministic analysis indicated that the ATF perfusion strategy has the potential to offer cost of goods savings of 20% when compared to conventional fed-batch manufacturing processes when a fivefold increase in maximum viable cell densities was assumed. Savings were also seen when the ATF cell density dropped to a threefold increase over the fed-batch strategy for most combinations of titres and production scales. In contrast, the fed-batch strategy performed better in terms of environmental sustainability with a lower water and consumable usage profile. The impact of uncertainty and failure rates on the feasibility of the strategies was explored using Monte Carlo simulation. The risk analysis results demonstrated the enhanced robustness of the fed-batch process but also highlighted that the ATF process was still the most cost-effective option even under uncertainty. The multi-attribute decision-making analysis provided insight into the limited use of spin-filter perfusion strategies in industry. The resulting sensitivity spider plots enabled identification of the critical ratio of weightings of economic and operational benefits that affect the choice between ATF perfusion and fed-batch strategies.
Department of Biochemical Engineering, The Advanced Centre for Biochemical Engineering, University College London, Torrington Place, London WC1E 7JE, UK.
James
J
Pollock
Sa V
SV
Ho
Suzanne S
SS
Farid
D000911:Antibodies, Monoclonal / Q000378:metabolism; D061249:Batch Cell Culture Techniques / Q000191:economics / Q000295:instrumentation* / Q000379:methods*; D019149:Bioreactors; D001709:Biotechnology / Q000191:economics / Q000295:instrumentation* / Q000379:methods*; D002478:Cells, Cultured; D003198:Computer Simulation; D008954:Models, Biological; D009010:Monte Carlo Method; D010477:Perfusion; D013269:Stochastic Processes
D000911:Antibodies, Monoclonal