Cellular metabolism plays a role in the observed variability of a drug substance's Critical Quality Attributes (CQAs) made by biomanufacturing processes. Therefore, here we describe a new approach for monitoring biomanufacturing processes that measures a set of metabolic reaction rates (named Critical Metabolic Parameters (CMP) in addition to the macroscopic process conditions currently being used as Critical Process Parameters (CPP) for biomanufacturing. Constraint‐based systems biology models like Flux Balance Analysis (FBA) are used to estimate metabolic reaction rates, and metabolic rates are used as inputs for multivariate Batch Evolution Models (BEM). Metabolic activity was reproducible among batches and could be monitored to detect a deliberately induced macroscopic process shift (i.e., temperature change). The CMP approach has the potential to enable “golden batches” in biomanufacturing processes to be defined from the internal metabolic activity and to aid in detecting process changes that may impact the quality of the product. Overall, the data suggested that monitoring of metabolic activity has promise for biomanufacturing process control.

中文翻译：

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根据内部代谢活动定义生物制造过程中的黄金批次，以检测可能影响产品质量的工艺变化


细胞代谢在生物制造工艺观察到的原料药关键质量属性 （CQA） 的可变性中起着一定的作用。因此，我们在这里描述了一种监测生物制造过程的新方法，该方法除了测量目前用作生物制造关键过程参数 （CPP） 的宏观过程条件外，还测量一组代谢反应速率（称为关键代谢参数 （CMP））。基于约束的系统生物学模型，如通量平衡分析 （FBA），用于估计代谢反应速率，代谢速率用作多变量批量进化模型 （BEM） 的输入。代谢活性在批次之间是可重复的，并且可以监测以检测故意诱导的宏观过程偏移（即温度变化）。CMP 方法有可能使生物制造过程中的“黄金批次”能够从内部代谢活动中定义，并有助于检测可能影响产品质量的工艺变化。总体而言，数据表明，代谢活性监测有望实现生物制造过程控制。