Rameez Shahid, Mostafa Sigma S, Miller Christopher, Shukla Abhinav A
Process Development and Manufacturing, KBI Biopharma Inc., 2 Triangle Dr, Research Triangle Park, NC, 27709.
Biotechnol Prog. 2014 May-Jun;30(3):718-27. doi: 10.1002/btpr.1874. Epub 2014 Feb 5.
Decreasing the timeframe for cell culture process development has been a key goal toward accelerating biopharmaceutical development. Advanced Microscale Bioreactors (ambr™) is an automated micro-bioreactor system with miniature single-use bioreactors with a 10-15 mL working volume controlled by an automated workstation. This system was compared to conventional bioreactor systems in terms of its performance for the production of a monoclonal antibody in a recombinant Chinese Hamster Ovary cell line. The miniaturized bioreactor system was found to produce cell culture profiles that matched across scales to 3 L, 15 L, and 200 L stirred tank bioreactors. The processes used in this article involve complex feed formulations, perturbations, and strict process control within the design space, which are in-line with processes used for commercial scale manufacturing of biopharmaceuticals. Changes to important process parameters in ambr™ resulted in predictable cell growth, viability and titer changes, which were in good agreement to data from the conventional larger scale bioreactors. ambr™ was found to successfully reproduce variations in temperature, dissolved oxygen (DO), and pH conditions similar to the larger bioreactor systems. Additionally, the miniature bioreactors were found to react well to perturbations in pH and DO through adjustments to the Proportional and Integral control loop. The data presented here demonstrates the utility of the ambr™ system as a high throughput system for cell culture process development.
缩短细胞培养工艺开发的时间框架一直是加速生物制药开发的关键目标。先进的微型生物反应器（ambr™）是一种自动化微型生物反应器系统，配备有工作体积为10 - 15 mL的一次性微型生物反应器，并由一个自动化工作站控制。该系统在重组中国仓鼠卵巢细胞系中生产单克隆抗体的性能方面与传统生物反应器系统进行了比较。结果发现，这种小型化生物反应器系统所产生的细胞培养曲线在不同规模下与3 L、15 L和200 L搅拌罐生物反应器相匹配。本文所使用的工艺涉及复杂的补料配方、扰动以及设计空间内严格的工艺控制，这些都与生物制药商业化规模生产所使用的工艺一致。ambr™中重要工艺参数的变化导致了可预测的细胞生长、活力和滴度变化，这与传统大规模生物反应器的数据高度吻合。研究发现，ambr™能够成功再现与大型生物反应器系统类似的温度、溶解氧（DO）和pH条件变化。此外，通过对比例积分控制回路进行调整，发现微型生物反应器对pH和DO的扰动反应良好。此处呈现的数据证明了ambr™系统作为细胞培养工艺开发高通量系统的实用性。
