Department of Biochemical Engineering, The Advanced Centre for Biochemical Engineering, University College London, Torrington Place, London WC1E 7JE, UK.
Biotechnol Bioeng. 2013 Jan;110(1):206-19. doi: 10.1002/bit.24608. Epub 2012 Aug 6.
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.
本文通过一项基于商业生产单克隆抗体的案例研究，评估了分批和连续细胞培养技术的当前和未来潜力。该案例研究比较了补料分批培养与两种灌注技术：旋转过滤灌注和新兴的利用切向流交替（ATF）灌注的灌注技术。使用 UCL 开发的原型动态决策支持工具，基于这些系统评估了整个生物工艺的操作、经济和环境可行性，该工具涵盖了工艺经济学、离散事件模拟和不确定性分析，并结合了多属性决策技术，以便能够进行全面评估。该策略在一系列规模和滴度上进行了比较，以便可视化其在不同行业情况下的排名变化。确定性分析表明，当假设最大可行细胞密度增加五倍时，与传统的补料分批制造工艺相比，ATF 灌注策略具有降低 20%产品成本的潜力。当 ATF 细胞密度相对于补料分批策略降低到三倍时，对于大多数滴度和生产规模组合，也可以看到节省。相比之下，补料分批策略在环境可持续性方面表现更好，用水量和消耗品用量较低。使用蒙特卡罗模拟探索了不确定性和故障率对策略可行性的影响。风险分析结果表明，补料分批过程的稳健性增强，但也强调即使存在不确定性，ATF 过程仍然是最具成本效益的选择。多属性决策分析提供了对工业中旋转过滤灌注策略有限使用的深入了解。生成的敏感性蜘蛛图使人们能够确定影响 ATF 灌注和补料分批策略之间选择的经济和运营效益权重的关键比率。
