Janakiraman Vijay, Kwiatkowski Chris, Kshirsagar Rashmi, Ryll Thomas, Huang Yao-Ming
Cell Culture Development, Biogen, Inc., Research Triangle Park, NC, 27709.
Cell Culture Development, Biogen, Inc., Cambridge, MA, 02142.
Biotechnol Prog. 2015 Nov-Dec;31(6):1623-32. doi: 10.1002/btpr.2162. Epub 2015 Sep 28.
High-throughput systems and processes have typically been targeted for process development and optimization in the bioprocessing industry. For process characterization, bench scale bioreactors have been the system of choice. Due to the need for performing different process conditions for multiple process parameters, the process characterization studies typically span several months and are considered time and resource intensive. In this study, we have shown the application of a high-throughput mini-bioreactor system viz. the Advanced Microscale Bioreactor (ambr15(TM) ), to perform process characterization in less than a month and develop an input control strategy. As a pre-requisite to process characterization, a scale-down model was first developed in the ambr system (15 mL) using statistical multivariate analysis techniques that showed comparability with both manufacturing scale (15,000 L) and bench scale (5 L). Volumetric sparge rates were matched between ambr and manufacturing scale, and the ambr process matched the pCO2 profiles as well as several other process and product quality parameters. The scale-down model was used to perform the process characterization DoE study and product quality results were generated. Upon comparison with DoE data from the bench scale bioreactors, similar effects of process parameters on process yield and product quality were identified between the two systems. We used the ambr data for setting action limits for the critical controlled parameters (CCPs), which were comparable to those from bench scale bioreactor data. In other words, the current work shows that the ambr15(TM) system is capable of replacing the bench scale bioreactor system for routine process development and process characterization.
高通量系统和工艺通常是生物加工行业工艺开发和优化的目标。对于工艺表征，实验室规模的生物反应器一直是首选系统。由于需要针对多个工艺参数执行不同的工艺条件，工艺表征研究通常跨越数月，且被认为耗时耗力。在本研究中，我们展示了一种高通量微型生物反应器系统，即先进微尺度生物反应器（ambr15™）的应用，该系统能够在不到一个月的时间内完成工艺表征并制定输入控制策略。作为工艺表征的先决条件，首先在ambr系统（15毫升）中使用统计多变量分析技术开发了一个缩小模型，该模型与生产规模（15000升）和实验室规模（5升）均具有可比性。ambr和生产规模之间的体积曝气速率相匹配，ambr工艺的pCO2曲线以及其他几个工艺和产品质量参数也相匹配。利用该缩小模型进行了工艺表征实验设计研究并得出了产品质量结果。与实验室规模生物反应器的实验设计数据相比，两个系统中工艺参数对工艺产量和产品质量的影响相似。我们利用ambr数据为关键控制参数（CCP）设定作用限度，这些限度与实验室规模生物反应器数据得出的限度相当。换句话说，当前的工作表明ambr15™系统能够替代实验室规模的生物反应器系统用于常规工艺开发和工艺表征。
