Ultrafiltration and diafiltration (UF/DF) unit operations are widely used for the manufacture of therapeutic antibodies to control drug substance protein concentration, pH, and excipient properties. During UF/DF, molecular interactions and volume exclusion effects often lead to substantial differences in pH and excipient concentrations between the diafiltration buffer and final UF/DF pool. These differences complicate the design process beyond simply specifying a buffer with the desired drug substance pH and excipient conditions. This article describes a UF/DF process model which dynamically and accurately simulates UF/DF retentate pool pH and excipient conditions throughout the UF/DF process. This multiscale model accounts for microscopic descriptions of ion‐protein charge interactions using the Poisson–Boltzmann equation as well as macroscopic descriptions of volume exclusion and mass transfer. Model predictions of the final UF/DF pool properties were experimentally verified through comparisons to design of experiment (DoE) data from four monoclonal antibody (mAb) processes, each with differing formulations and UF/DF operating conditions. Additionally, model simulations of the retentate pool properties throughout the UF/DF process were verified for two mAb processes through comparisons to experimental data collected at intermediate process points. Model results were qualified, using statistical equivalence tests, against the outputs from large‐scale GMP runs which confirmed that the model accurately captures large‐scale process performance. Finally, the model was applied toward the simulation of process scenarios beyond those examined experimentally. These in‐silico experiments demonstrate the model's capability as a tool for augmented process design and it is potential to reduce the extent of UF/DF laboratory experiments.

中文翻译：

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治疗性抗体超滤和渗滤过程中 pH 值和赋形剂浓度的机械模型

超滤和渗滤 (UF/DF) 单元操作广泛用于生产治疗性抗体，以控制药物蛋白质浓度、pH 值和赋形剂特性。在 UF/DF 过程中，分子相互作用和体积排斥效应通常会导致渗滤缓冲液和最终 UF/DF 池之间的 pH 值和赋形剂浓度存在显着差异。除了简单地指定具有所需原料药 pH 值和赋形剂条件的缓冲液之外，这些差异使设计过程变得复杂。本文介绍了一种 UF/DF 工艺模型，该模型可动态准确地模拟整个 UF/DF 工艺中的 UF/DF 渗余液池 pH 值和赋形剂条件。该多尺度模型解释了使用泊松-玻尔兹曼方程对离子-蛋白质电荷相互作用的微观描述以及体积排阻和传质的宏观描述。通过与四种单克隆抗体 (mAb) 工艺的实验设计 (DoE) 数据进行比较，实验验证了最终 UF/DF 池特性的模型预测，每种工艺具有不同的配方和 UF/DF 操作条件。此外，通过与在中间过程点收集的实验数据进行比较，验证了两个 mAb 过程的整个 UF/DF 过程中渗余物池特性的模型模拟。模型结果合格，采用统计等效检验，与大规模 GMP 运行的输出相比，这证实该模型准确地捕获了大规模过程性能。最后，该模型应用于模拟超出实验检查范围的过程场景。这些计算机内实验证明了该模型作为增强工艺设计工具的能力，并且有可能减少 UF/DF 实验室实验的范围。