Abstract:

Monoclonal antibody (mAb) is the most important biopharmaceuticals. With the continuous expansion of industrial-scale production and competition, the process rationality and economy have attracted more and more attention. In this paper, four scales of mAb manufacturing processes of 500, 2000, 5000 and 15000 L were established by using SuperPro Designer software, a bioprocess simulation software. Through the process analysis and cost evaluation, the economic 'hotspots' were determined and the optimization strategies were then proposed. The results showed that the scale effect on the production cost was obvious. With the increase of production scale, the cost would be significantly reduced, and the economic hotspots were transferred from equipment-dependent costs to raw materials and consumables, including serum-free medium and Protein A affinity resin. The key for upstream optimization was to increase the titer of mAb expression during cell culture. But when the titer was higher than 5 g/L, the effect of titer increasing on the cost was weakened and the cost was then mainly controlled by downstream process. The downstream optimization should focus on Protein A affinity resins, including capacity,price and the reuse cycles. The optimization of overall process would be the stagger mode with three main bioreactors corresponding one downstream line, for which the production scale and equipment cost were two key factors. The results demonstrated that with the aid of reasonable process simulation and economic evaluation, some hotspots of manufacture process could be identified and the appropriate optimization strategies would be proposed to improve the process efficiency and reduce the production cost.

Key words: monoclonal antibody, process simulation, economic evaluation, hotspots analysis, process optimization

摘要：

单克隆抗体（简称单抗）是最重要的生物技术药物，随着产业规模的持续扩大和同行竞争的不断加剧，制备流程的合理性和过程经济性越来越受到重视。本文采用生物过程模拟软件SuperPro Designer分别建立了500、2000、5000和15000 L四个培养规模的单抗制备流程，通过过程分析和成本核算，确定经济热点并提出相应的优化策略。结果表明，单抗制备的规模效应明显，随着规模扩大，生产成本显著降低，经济热点从设备相关成本转移到原材料和消耗品，主要包括无血清培养基和蛋白A亲和层析介质。上游优化的关键是提高细胞的单抗表达量，当表达量达到5 g/L以上时，对成本影响减弱，转为下游过程控制；下游优化的重点在于蛋白A亲和层析介质，包括载量、价格和循环使用次数；整体优化可利用交错模式，采用三个主生物反应器配置一条下游生产线，其中生产规模和设备成本是关键。研究表明，通过合理的过程模拟和经济评价，可以充分了解单抗制备过程的关键热点，提出合适的优化策略，提高生产效率，降低制备成本。

关键词: 单克隆抗体, 过程模拟, 经济评价, 热点分析, 过程优化