Fed‐batch and perfusion culture processes: Economic, environmental, and operational feasibility under uncertainty

Abstract

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.

Evaluating and Visualizing the Cost‐Effectiveness and Robustness of Biopharmaceutical Manufacturing Strategies

“…With the regulatory push for biopharmaceutical companies to embrace Quality by Design ( QbD ) to achieve greater process understanding, it will be benefi cial to link these decision -support tools to more predictive process models so as to ensure infeasible process options are screened out and to enable more accurate cost evaluations. Further features that deserve attention include devising environmental indices relevant to the bioprocessing industry to enable the technical, economic, risk, and environmental feasibility of these operations to be assessed simultaneously [3] . Ultimately each of these decision -support tools facilitates structured dialog between key stakeholders across different company divisions during both the building and analysis phases.…”

“…Newer perfusion reactor systems such as alternating tangential fl ow perfusion reactors aim to reach higher steady -state cell densities while having lower failure rates and faster turnaround times from failures. Further studies have illustrated how the introduction of these new technologies offers the potential for perfusion systems to become more economically competitive and robust when compared to fed -batch -based processes [3] .…”

Model-Based Design of Process Strategies for Cell Culture Bioprocesses: State of the Art and New Perspectives

“…Batch and fed-batch-operated processes are predominantly used in the industry, although perfusion processes have been proven for certain applications to be of higher advantage, for example, when fragile and highly glycosylated products are involved [19][20][21]. In principle, the reactor content is supplemented with nutrients during fed-batch cultivations.…”

Cell Culture Processes for Biopharmaceutical Manufacturing

“…A perspective on the pros and cons of the two modes of operation is presented 71 . Modelling frameworks have been developed to compare fed batch and perfusion process performance in terms of their economics and environmental impact while including different probabilities of failure of these processes 72,73 . Such analyses can help choose the right mode of operation during facility design.…”