高通量灌流培养模型在生物工艺开发中的应用研究

近年来,连续型细胞培养由于其高单位体积产量、稳定的产品质量属性以及潜在的成本节约效应正成为生物大分子制药生产的工艺焦点。相比传统的流加培养模式,灌流培养因培养的连续性、操作的复杂性,致使其反应器规模培养需消耗大量培养基,产生更高人力成本,不能满足当今加速化高效化的工艺开发需求。为获得稳健的灌流培养工艺并控制较低成本,高通量灌流培养模型被用于批量化的小规模灌流培养,进行灌流培养前期的克隆筛选、培养基筛选及工艺参数优化等工作,为后期大规模培养提供实用性数据支持,同时也被用于预测大规模培养的细胞表型和产品质量属性。重点介绍了当前高通量系统包括摇瓶/摇管系统、多平行自动化系统以及微流控体系用作灌流培养的特征、具体应用及比较,同时论述当前高通量灌流培养系统在生物工艺领域发展所面临的机遇及挑战,并展望其应用前景。

Research on Applications of High-Throughput Perfusion Models in Bioprocessing Development

Recently, continuous cell culture is becoming the process focus in the pharmaceutical industry due to its high volumetric productivity, stable product quality attributes, and cost- effectiveness. Compared to the traditional fed-batch culture, benchtop-scale perfusion culture requires quantities of media and labor costs due to its longer culture duration and operation complexity, thus failing to satisfy the current requirement of accelerated and efficient process development. To obtain a robust perfusion process with reduced costs, high-throughput perfusion models are utilized for batches of small-scale perfusion culture in the early-stage process development including clone screening, media selection and process parameter optimization, providing practical process data for late-stage large-scale bioprocessing. Furthermore, they are also applied to predict the phenotype and product quality attributes in large-scale culture. This article will focus on the characteristics, applications and comparisons of current high-throughput systems including shake flasks and spin tubes, parallelized automated ambr systems and microfluidic systems, and discuss the opportunities and challenges faced with high-throughput perfusion models in the bioprocessing development, then look forward to the future prospects.