Soft‐sensors application for automated feeding control in high‐throughput mammalian cell cultures

谷氨酰胺 中国仓鼠卵巢细胞 补料分批培养 生物反应器 生物技术 计算机科学 吞吐量 软传感器 工艺工程 生化工程 生物 细胞培养 生物化学 工程类 无线 过程(计算) 发酵 操作系统 电信 植物 遗传学 氨基酸
作者
I. Martínez-Monge,Constanza Martínez,Marianne Decker,Isuru A. Udugama,Igor Marin de Mas,Krist V. Gernaey,Lars K. Nielsen
出处
期刊:Biotechnology and Bioengineering [Wiley]
卷期号:119 (4): 1077-1090 被引量:2
标识
DOI:10.1002/bit.28032
摘要

The ever-increasing demand for biopharmaceuticals has created the need for improving the overall productivity of culture processes. One such operational concept that is considered is fed-batch operations as opposed to batch operations. However, optimal fed-batch operations require complete knowledge of the cell culture to optimize the culture conditions and the nutrients feeding. For example, when using high-throughput small-scale bioreactors to test multiple clones that do not behave the same, depletion or overfeeding of some key components can occur if the feeding strategy is not individually optimized. Over the recent years, various solutions for real-time measuring of the main cell culture metabolites have been proposed. Still, the complexity in the implementation of these techniques has limited their use. Soft-sensors present an opportunity to overcome these limitations by indirectly estimating these variables in real-time. This manuscript details the development of a new soft-sensor-based fed-batch strategy to maintain substrate concentration (glucose and glutamine) at optimal levels in small-scale multiparallel Chinese Hamster Ovary Cells cultures. Two alternatives to the standard feeding strategy were tested: an OUR soft-sensor-based strategy for glucose and glutamine (Strategy 1) and a dual OUR for glutamine and CO2 /alkali addition for glucose soft-sensor strategy (Strategy 2). The results demonstrated the applicability of the OUR soft-sensor-based strategy to optimize glucose and glutamine feedings, which yielded a 21% increase in final viable cell density (VCD) and a 31% in erythropoietin titer compared with the reference one. However, CO2 /alkali addition soft-sensor suffered from insufficient data to relate alkali addition with glucose consumption. As a result, the culture was overfed with glucose resulting in a 4% increase on final VCD, but a 9% decrease in final titer compared with the Reference Strategy.
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