Cation exchange chromatography (CEX) is an essential part of most monoclonal antibody (mAb) purification platforms. Process characterization and root cause investigation of chromatographic unit operations are performed using scale down models (SDM). SDM chromatography columns typically have the identical bed height as the respective manufacturing‐scale, but a significantly reduced inner diameter. While SDMs enable process development demanding less material and time, their comparability to manufacturing‐scale can be affected by variability in feed composition, mobile phase and resin properties, or dispersion effects depending on the chromatography system at hand. Mechanistic models can help to close gaps between scales and reduce experimental efforts compared to experimental SDM applications. In this study, a multicomponent steric mass‐action (SMA) adsorption model was applied to the scale‐up of a CEX polishing step. Based on chromatograms and elution pool data ranging from laboratory‐ to manufacturing‐scale, the proposed modeling workflow enabled early identification of differences between scales, for example, system dispersion effects or ionic capacity variability. A multistage model qualification approach was introduced to measure the model quality and to understand the model's limitations across scales. The experimental SDM and the in silico model were qualified against large‐scale data using the identical state of the art equivalence testing procedure. The mechanistic chromatography model avoided limitations of the SDM by capturing effects of bed height, loading density, feed composition, and mobile phase properties. The results demonstrate the applicability of mechanistic chromatography models as a possible alternative to conventional SDM approaches.

中文翻译：

---

机械阳离子交换色谱模型的跨尺度质量评估

阳离子交换色谱 (CEX) 是大多数单克隆抗体 (mAb) 纯化平台的重要组成部分。使用按比例缩小模型 (SDM) 执行色谱单元操作的过程表征和根本原因调查。SDM 色谱柱通常具有与相应制造规模相同的床高度，但内径显着减小。虽然 SDM 可以实现需要更少材料和时间的工艺开发，但它们与制造规模的可比性可能会受到进料组成、流动相和树脂性质的可变性或取决于手头色谱系统的分散效应的影响。与实验性 SDM 应用相比，机械模型有助于缩小尺度之间的差距并减少实验工作量。在这项研究中，将多组分空间质量作用 (SMA) 吸附模型应用于 CEX 抛光步骤的放大。基于从实验室到制造规模的色谱图和洗脱池数据，所提出的建模工作流程能够及早识别规模之间的差异，例如系统分散效应或离子容量变异性。引入了多阶段模型鉴定方法来衡量模型质量并了解模型在不同尺度上的局限性。实验 SDM 和计算机模型使用相同的最先进的等效测试程序对大规模数据进行了验证。机械色谱模型通过捕捉床高、装载密度、进料组成和流动相特性的影响，避免了 SDM 的限制。