Manufacturing of cell therapy products requires sufficient understanding of the cell culture variables and associated mechanisms for adequate control and risk analysis. The aim of this study was to apply an unstructured ordinary differential equation-based model for prediction of T-cell bioprocess outcomes as a function of process input parameters. A series of models were developed to represent the growth of T-cells as a function of time, culture volumes, cell densities, and glucose concentration using data from the Ambr®15 stirred bioreactor system. The models were sufficiently representative of the process to predict the glucose and volume provision required to maintain cell growth rate and quantitatively defined the relationship between glucose concentration, cell growth rate, and glucose utilization rate. The models demonstrated that although glucose is a limiting factor in batch supplied medium, a delivery rate of glucose at significantly less than the maximal specific consumption rate (0.05 mg 1 × 10⁶ cell h⁻¹) will adequately sustain cell growth due to a lower glucose Monod constant determining glucose consumption rate relative to the glucose Monod constant determining cell growth rate. The resultant volume and exchange requirements were used as inputs to an operational BioSolve cost model to suggest a cost-effective T-cell manufacturing process with minimum cost of goods per million cells produced and optimal volumetric productivity in a manufacturing settings. These findings highlight the potential of a simple unstructured model of T-cell growth in a stirred tank system to provide a framework for control and optimization of bioprocesses for manufacture.

中文翻译：

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应用简单的非结构化动力学和商品成本模型来支持 T 细胞疗法制造

细胞治疗产品的制造需要充分了解细胞培养变量和相关机制，以进行充分的控制和风险分析。本研究的目的是应用基于非结构化常微分方程的模型来预测 T 细胞生物过程结果作为过程输入参数的函数。使用来自 Ambr®15 搅拌生物反应器系统的数据，开发了一系列模型来表示 T 细胞的生长随时间、培养体积、细胞密度和葡萄糖浓度的变化。这些模型充分代表了预测维持细胞生长速率所需的葡萄糖和体积供应的过程，并定量地定义了葡萄糖浓度、细胞生长速率和葡萄糖利用率之间的关系。⁶ 细胞h ^-1 )由于相对于葡萄糖Monod常数确定细胞生长速率较低的葡萄糖Monod常数确定葡萄糖消耗速率将充分维持细胞生长。由此产生的体积和交换要求被用作运营 BioSolve 成本模型的输入，以建议一种具有成本效益的 T 细胞制造工艺，每百万细胞生产的商品成本最低，并且在制造环境中具有最佳的体积生产率。这些发现突出了搅拌罐系统中 T 细胞生长的简单非结构化模型的潜力，为制造生物过程的控制和优化提供了框架。