下游生物制造中杂质沉淀的可扩展性建模。

IF 2.5 3区 生物学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Biotechnology Progress Pub Date : 2024-03-27 DOI:10.1002/btpr.3454
Jing Guo, Steven J. Traylor, Mohamed Agoub, Weixin Jin, Helen Hua, R. Bertrum Diemer, Xuankuo Xu, Sanchayita Ghose, Zheng Jian Li, Abraham M. Lenhoff
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引用次数: 0

摘要

在单克隆抗体(mAb)纯化工艺的病毒灭活、中和及深度过滤步骤中进行沉淀,可以量化并显著减少杂质。然而,由于缺乏具有代表性的缩小模型来描述杂质去除情况,这一单元操作的商业化实施受到了限制。这项工作的目的是比较一种单克隆抗体产品从台式生产到中试生产的不同规模的等电点杂质沉淀行为。研究了搅拌和容器几何形状等规模参数,并通过浊度和流动成像显微镜确定了沉淀量和粒度分布 (PSD)。对数据的定性分析表明,在没有更详细模拟的情况下,保持一致的能量耗散率(EDR)可用于近似调整容器几何形状和搅拌器速度。不过,为了采用更严格的方法,我们通过计算流体动力学(CFD)对搅拌进行了模拟,并将这些结果与种群平衡模型一起用于模拟沉淀物粒度分布的轨迹。CFD 结果是在两室混合模型的框架内进行分析的,该模型由高能量和低能量搅拌区域组成,两者之间存在物质交换。对每个区域内的颗粒形成、生长和破碎的速率项进行了定义,并考虑了对湍流的依赖性。这种分叉模型成功地捕捉到了不同尺度颗粒大小随时间的变化。这种方法增强了对杂质沉淀机理的理解,并为工艺缩放的模型辅助预测提供了更多工具。
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Modeling scalability of impurity precipitation in downstream biomanufacturing

Precipitation during the viral inactivation, neutralization and depth filtration step of a monoclonal antibody (mAb) purification process can provide quantifiable and potentially significant impurity reduction. However, robust commercial implementation of this unit operation is limited due to the lack of a representative scale-down model to characterize the removal of impurities. The objective of this work is to compare isoelectric impurity precipitation behavior for a monoclonal antibody product across scales, from benchtop to pilot manufacturing. Scaling parameters such as agitation and vessel geometry were investigated, with the precipitate amount and particle size distribution (PSD) characterized via turbidity and flow imaging microscopy. Qualitative analysis of the data shows that maintaining a consistent energy dissipation rate (EDR) could be used for approximate scaling of vessel geometry and agitator speeds in the absence of more detailed simulation. For a more rigorous approach, however, agitation was simulated via computational fluid dynamics (CFD) and these results were applied alongside a population balance model to simulate the trajectory of the size distribution of precipitate. CFD results were analyzed within a framework of a two-compartment mixing model comprising regions of high- and low-energy agitation, with material exchange between the two. Rate terms accounting for particle formation, growth and breakage within each region were defined, accounting for dependence on turbulence. This bifurcated model was successful in capturing the variability in particle sizes over time across scales. Such an approach enhances the mechanistic understanding of impurity precipitation and provides additional tools for model-assisted prediction for process scaling.

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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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