Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, Zürich 8093, Switzerland.
YMC ChromaCon, Technoparkstrasse 1, Zürich 8005, Switzerland.
J Chromatogr A. 2020 May 24;1619:460943. doi: 10.1016/j.chroma.2020.460943. Epub 2020 Feb 4.
Increasing molecular diversity and market competition requires biopharmaceutical manufacturers to intensify their processes. In this respect, frontal chromatography on cation exchange resins has shown its potential to effectively remove aggregates. However, yield losses during the wash step need to be accepted in order to ensure robust product quality. In this work, we present a novel counter-current frontal chromatography process called Flow2, which uses inline dilution during an interconnected wash phase to allow high monomer recovery without contaminating the product pool with impurities. Its model-based design spaces under purity and yield constraints are compared with those corresponding to traditional batch processes in terms of size and process attributes yield and productivity. The Flow2 process shows the largest extent of feasible operating points independent of feed conditions. Thereby, it allows the implementation of higher ionic strength wash, thus widening the range of operating conditions resulting in yields above 95% compared to batch processes. Productivities of batch and counter-current processes are the same at short regeneration times and equal residence time. However, long regeneration times, while influencing the size of the Flow2 design space, are not detrimental for its productivity resulting in twice as high values as obtained for the batch process. Furthermore, process robustness is evaluated by the ability of the process to maintain the required product quality when subjected to process parameter perturbations. It is found that the Flow2 process is able to retain a larger design space associated also with higher yields showing its ability to improve process attributes without sacrificing robustness at the same time.
为了提高分子多样性和市场竞争力，生物制药制造商需要加强其生产工艺。在这方面，阳离子交换树脂的前沿色谱技术已显示出有效去除聚集物的潜力。然而，为了确保产品质量的稳健性，需要接受在洗涤步骤中的收率损失。在这项工作中，我们提出了一种称为 Flow2 的新型逆流前沿色谱工艺，该工艺在相互连接的洗涤相中使用在线稀释，从而在不将杂质污染产品池的情况下实现高单体回收率。根据纯度和收率的约束条件，其基于模型的设计空间与传统批处理工艺的设计空间在大小和工艺属性（收率和生产力）方面进行了比较。Flow2 工艺在不依赖进料条件的情况下，表现出最大程度的可行操作点。因此，它允许采用更高的离子强度洗涤，从而拓宽了收率高于 95%的操作条件范围，与批处理工艺相比。在短再生时间和相等的停留时间下，批处理和逆流工艺的生产力相同。然而，长的再生时间虽然会影响 Flow2 设计空间的大小，但对其生产力没有不利影响，其生产力值是批处理工艺的两倍。此外，还通过评估工艺在受到工艺参数扰动时保持所需产品质量的能力来评估工艺稳健性。结果发现，Flow2 工艺能够保留更大的设计空间，同时也具有更高的收率，表明其在不牺牲稳健性的情况下提高工艺属性的能力。
