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首页> 外文期刊>Biotechnology Progress >Quick generation of Raman spectroscopy based in-process glucose control to influence biopharmaceutical protein product quality during mammalian cell culture
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Quick generation of Raman spectroscopy based in-process glucose control to influence biopharmaceutical protein product quality during mammalian cell culture

机译：基于哺乳动物细胞培养过程中的基于过程中的拉曼光谱法的快速生成影响生物制药蛋白质产品

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Mitigating risks to biotherapeutic protein production processes and products has driven the development of targeted process analytical technology (PAT); however implementing PAT during development without significantly increasing program timelines can be difficult. The development of a monoclonal antibody expressed in a Chinese hamster ovary (CHO) cell line via fed-batch processing presented an opportunity to demonstrate capabilities of altering percent glycated protein product. Glycation is caused by pseudo-first order, non-enzymatic reaction of a reducing sugar with an amino group. Glucose is the highest concentration reducing sugar in the chemically defined media (CDM), thus a strategy controlling glucose in the production bioreactor was developed utilizing Raman spectroscopy for feedback control. Raman regions for glucose were determined by spiking studies in water and CDM. Calibration spectra were collected during 8 bench scale batches designed to capture a wide glucose concentration space. Finally, a PLS model capable of translating Raman spectra to glucose concentration was built using the calibration spectra and spiking study regions. Bolus feeding in mammalian cell culture results in wide glucose concentration ranges. Here we describe the development of process automation enabling glucose setpoint control. Glucose-free nutrient feed was fed daily, however glucose stock solution was fed as needed according to online Raman measurements. Two feedback control conditions were executed where glucose was controlled at constant low concentration or decreased stepwise throughout. Glycation was reduced from approximate to 9% to 4% using a low target concentration but was not reduced in the stepwise condition as compared to the historical bolus glucose feeding regimen. (c) 2015 American Institute of Chemical Engineers Biotechnol. Prog., 32:224-234, 2016
机译：减轻生物治疗蛋白质生产过程和产品的风险驱动了有针对性过程分析技术的发展（PAT）;然而，在开发期间实施PAT，而不会显着增加计划时间表可能是困难的。通过FED分批处理在中国仓鼠卵巢（CHO）细胞系中表达的单克隆抗体的发展提出了一种能够证明改变糖化蛋白质产物百分比的能力的机会。糖化是由伪级的伪阶，与氨基的还原糖的非酶促反应引起。葡萄糖是化学定义介质（CDM）中的最高浓度的还原糖，因此利用拉曼光谱进行反馈控制，开发了生产生物反应器中的葡萄糖的策略。通过在水和CDM中的尖峰研究确定葡萄糖区域。在旨在捕获宽葡萄糖浓度空间的8个长凳批量期间收集校准光谱。最后，使用校准光谱和尖峰研究区域建立了能够将拉曼光谱转化为血糖浓度的PLS模型。哺乳动物细胞培养的推注导致宽葡萄糖浓度范围。在这里，我们描述了实现葡萄糖设定值控制的过程自动化的开发。每天喂食无葡萄糖营养饲料，但根据在线拉曼测量，根据需要喂养葡萄糖储备溶液。执行两种反馈控制条件，其中葡萄糖以恒定的低浓度控制或逐步降低。与历史推注葡萄糖喂养方案相比，使用低靶浓度从近似达到9％至4％的糖化降低到9％至4％。 （c）2015美国化学工程研究所生物科技。 Prog。，32：224-234,2016

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