Integrated continuous bioprocessing: Economic, operational, and environmental feasibility for clinical and commercial antibody manufacture

Abstract

This paper presents a systems approach to evaluating the potential of integrated continuous bioprocessing for monoclonal antibody (mAb) manufacture across a product's lifecycle from preclinical to commercial manufacture. The economic, operational, and environmental feasibility of alternative continuous manufacturing strategies were evaluated holistically using a prototype UCL decisional tool that integrated process economics, discrete-event simulation, environmental impact analysis, operational risk analysis, and multiattribute decision-making. The case study focused on comparing whole bioprocesses that used either batch, continuous or a hybrid combination of batch and continuous technologies for cell culture, capture chromatography, and polishing chromatography steps. The cost of goods per gram (COG/g), E-factor, and operational risk scores of each strategy were established across a matrix of scenarios with differing combinations of clinical development phase and company portfolio size. The tool outputs predict that the optimal strategy for early phase production and small/medium-sized companies is the integrated continuous strategy (alternating tangential flow filtration (ATF) perfusion, continuous capture, continuous polishing). However, the top ranking strategy changes for commercial production and companies with large portfolios to the hybrid strategy with fed-batch culture, continuous capture and batch polishing from a COG/g perspective. The multiattribute decision-making analysis highlighted that if the operational feasibility was considered more important than the economic benefits, the hybrid strategy would be preferred for all company scales. Further considerations outside the scope of this work include the process development costs required to adopt continuous processing. © 2017 The Authors Biotechnology Progress published by Wiley Periodicals, Inc. on behalf of American Institute of Chemical Engineers Biotechnol. Prog., 33:854-866, 2017.

Keywords: antibody manufacture; continuous chromatography; fed-batch; perfusion culture; process economics.

Figure 1

Downstream process scheduling for (a) the base case process sequence, (b) the continuous to batch process sequence, and (c) the continuous process sequence. Protein A, Protein A chromatography; VI, viral inactivation; AEX, anion exchange chromatography; VRF, viral retention filtration; UFDF, ultrafiltration/diafiltration.

Figure 2

Direct cost of goods category breakdown across the different manufacturing scales required for each development phase for the base case scenario shown as (a) direct cost per product per phase and (b) direct cost per gram. Categories: labor costs (gray dashed line), QCQA batch release costs (gray solid line), chromatographic resin costs (black solid line), fermentation media (black dotted line), and single‐use components and buffers (black dashed line).

Figure 3

Direct (black dashed line) and indirect (black line) cost of goods per gram across the different manufacturing scales required for each development phase for the base case scenario.

Figure 4

A comparison of the direct costs per gram for the base case batch strategy (B) and fully continuous strategy (C) on a category basis for material costs (black), labor costs (light gray), QCQA batch release costs (dark gray), and indirect costs (white), between the different manufacturing scales. The embedded table highlights the percentage cost contribution for the key direct cost categories.

Figure 5

Contour plots showing the impact of manufacturing scale and manufacturing strategies on the percentage difference in cost of goods per gram relative to the base case scenario for (a) the large‐sized company, (b) the medium‐sized company, and (c) the small‐sized company. (Pre‐Clinical, 1 × 0.5 kg; PoC, 1 × 4 kg; Phase III, 4 × 10 kg; Commercial, 20 × 10 kg).

Figure 6

Contour plots showing the impact of manufacturing scale and manufacturing strategies on (a) the most economically attractive manufacturing strategies for each scenario and (b) the resulting manufacturing cost per launch for all company sizes relative to the base case manufacturing strategy. (Pre‐Clinical, 1 × 0.5 kg; PoC, 1 × 4 kg; Phase III, 4 × 10 kg; Commercial, 20 × 10 kg).

Figure 7

A comparison of cost of goods per gram with a detailed breakdown of material costs on a category basis for (a) the base case, (b) FB‐CB, (c) ATF‐CB, (d) FB‐CC, (e) ATF‐CC scenario for a Phase III clinical batch in a medium‐sized company.

Figure 8

Sensitivity spider plots portraying the effect of the economic attribute combination ratio (R ₁) in the overall aggregate scores when the environmental combination rate is constant (0.1), for (a) the large‐sized company, (b) medium‐sized company, and (c) small‐sized company, for the base case (solid black line), FB‐CB (gray dashed line), ATF‐CB (gray dotted line), FB‐CC (black dashed line), and ATF‐CC (black dotted line). On the left‐hand side of each figure, when the economic attribute combination ratio is 0.1, the operational attribute combination ratio is 0.9 and operational benefits are considered more important in the overall aggregate score. On the right‐hand side of each figure, when the economic attribute combination ratio is 0.9, the operational attribute combination ratio is 0.1 and economic benefits are considered more important in the overall aggregate score.