优化和表征多模式色谱过程的高通量硅学工作流程。

IF 2.5 3区 生物学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Biotechnology Progress Pub Date : 2024-06-10 DOI:10.1002/btpr.3483
Scott H Altern, Jessica Y Lyall, John P Welsh, Sean Burgess, Vijesh Kumar, Chris Williams, Abraham M Lenhoff, Steven M Cramer
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引用次数: 0

摘要

虽然高通量(HT)实验和机理建模在色谱工艺开发中应用已久,但如何在开发工作流程中协同使用这些技术仍不明确。在这项工作中,我们构建了一个基于高通量实验和机理建模的工艺开发工作流程。HT 与建模方法的整合提高了工作流程的效率和速度。这种高通量硅学(HT-IS)工作流程被用于开发用于去除 mAb 聚集体的 Capto MMC 研磨步骤。首先在一系列流动相条件下生成了高通量批量等温线数据,并采用了一套分析方法。对多组分系统的扩展立体质量作用(SMA)等温线参数进行了回归。使用 CADET 建模软件,将扩展 SMA 等温线与一般色谱速率模型相结合,进行了模型验证。在此,我们预测了八次 RoboColumn 运行在离子强度、pH 值和负载密度范围内的阶跃洗脱曲线。通过最小化基于关键工艺指标的复杂目标函数,生成了优化工艺。使用两种成分不同的原料对实验室规模的工艺进行了评估。结果证实,这两种工艺都能获得较高的单体产量(>85%),并能去除 ∼ 50 % $$ \sim 50\% $$ 的聚合物种。然后进行了柱模拟,以确定对各种工艺输入的敏感性。发现洗脱缓冲液 pH 值是最关键的工艺参数,其次是树脂离子容量。总之,这项研究证明了 HT-IS 工作流程在快速工艺开发和表征方面的实用性。
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High-throughput in silico workflow for optimization and characterization of multimodal chromatographic processes.

While high-throughput (HT) experimentation and mechanistic modeling have long been employed in chromatographic process development, it remains unclear how these techniques should be used in concert within development workflows. In this work, a process development workflow based on HT experiments and mechanistic modeling was constructed. The integration of HT and modeling approaches offers improved workflow efficiency and speed. This high-throughput in silico (HT-IS) workflow was employed to develop a Capto MMC polishing step for mAb aggregate removal. High-throughput batch isotherm data was first generated over a range of mobile phase conditions and a suite of analytics were employed. Parameters for the extended steric mass action (SMA) isotherm were regressed for the multicomponent system. Model validation was performed using the extended SMA isotherm in concert with the general rate model of chromatography using the CADET modeling software. Here, step elution profiles were predicted for eight RoboColumn runs across a range of ionic strength, pH, and load density. Optimized processes were generated through minimization of a complex objective function based on key process metrics. Processes were evaluated at lab-scale using two feedstocks, differing in composition. The results confirmed that both processes obtained high monomer yield (>85%) and removed 50 % $$ \sim 50\% $$ of aggregate species. Column simulations were then carried out to determine sensitivity to a wide range of process inputs. Elution buffer pH was found to be the most critical process parameter, followed by resin ionic capacity. Overall, this study demonstrated the utility of the HT-IS workflow for rapid process development and characterization.

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来源期刊
Biotechnology Progress
Biotechnology Progress 工程技术-生物工程与应用微生物
CiteScore
6.50
自引率
3.40%
发文量
83
审稿时长
4 months
期刊介绍: Biotechnology Progress , an official, bimonthly publication of the American Institute of Chemical Engineers and its technological community, the Society for Biological Engineering, features peer-reviewed research articles, reviews, and descriptions of emerging techniques for the development and design of new processes, products, and devices for the biotechnology, biopharmaceutical and bioprocess industries. Widespread interest includes application of biological and engineering principles in fields such as applied cellular physiology and metabolic engineering, biocatalysis and bioreactor design, bioseparations and downstream processing, cell culture and tissue engineering, biosensors and process control, bioinformatics and systems biology, biomaterials and artificial organs, stem cell biology and genetics, and plant biology and food science. Manuscripts concerning the design of related processes, products, or devices are also encouraged. Four types of manuscripts are printed in the Journal: Research Papers, Topical or Review Papers, Letters to the Editor, and R & D Notes.
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