DSP Development, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Karlsruhe Institute of Technology (KIT), Institute of Engineering in Life Sciences, Section IV: Biomolecular Separation Engineering, Karlsruhe, Germany.
DSP Development, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany.
J Chromatogr A. 2022 Oct 11;1681:463421. doi: 10.1016/j.chroma.2022.463421. Epub 2022 Aug 13.
A fundamental process understanding of an entire downstream process is essential for achieving and maintaining the high-quality standards demanded for biopharmaceutical drugs. A holistic process model based on mechanistic insights could support process development by identifying dependencies between process parameters and critical quality attributes across unit operations to design a holistic control strategy. In this study, state-of-the-art mechanistic models were calibrated and validated as digital representations of a biopharmaceutical manufacturing process. The polishing ion exchange chromatography steps (Q Sepharose FF, Poros 50 HS) were described by a transport-dispersive model combined with a colloidal particle adsorption model. The elution behavior of four size variants was analyzed and included in the model. Titration curves of pH adjustments were simulated using a mean-field approach considering interactions between the protein of interest and other ions in solution. By including adjustment steps the important process control inputs ionic strength, dilution, and pH were integrated. The final process model was capable to predict online and offline data at manufacturing scale. Process variations at manufacturing scale of 94 runs were adequately reproduced by the model. Furthermore, the process robustness against a 20% input variation of concentration, size variant and ion composition, volume, and pH could be confirmed with the model. The presented model demonstrates the potential of the integrated approach for predicting manufacturing process performance across scales and operating units.
对于实现和维持生物制药所需的高质量标准，对整个下游工艺的基本过程理解是必不可少的。基于机械洞察力的整体过程模型可以通过识别单元操作之间的过程参数和关键质量属性之间的依赖性，为设计整体控制策略提供支持，从而支持工艺开发。在这项研究中，最先进的机械模型被校准和验证为生物制药制造过程的数字表示。抛光离子交换色谱步骤（Q Sepharose FF、Poros 50 HS）通过与胶体颗粒吸附模型相结合的传质分散模型进行描述。分析了四个尺寸变体的洗脱行为，并将其纳入模型中。使用考虑溶液中目标蛋白与其他离子之间相互作用的平均场方法模拟 pH 调整的滴定曲线。通过包括调整步骤，将重要的过程控制输入离子强度、稀释和 pH 整合在一起。最终的过程模型能够预测制造规模的在线和离线数据。该模型能够很好地再现制造规模 94 次运行的过程变化。此外，该模型还可以确认该过程对浓度、尺寸变体和离子组成、体积和 pH 的 20%输入变化的稳健性。所提出的模型展示了跨规模和操作单元预测制造工艺性能的集成方法的潜力。
