Design space and robustness analysis of batch and counter-current frontal chromatography processes for the removal of antibody aggregates
•Novel two-column counter-current frontal chromatography process is presented: Flow2.•Model-based design spaces are established for counter-current and batch processes.•Design spaces reveal higher operational flexibility of the counter-current process.•Perturbation studies reveal increased robustnes...
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Published in | Journal of Chromatography A Vol. 1619; p. 460943 |
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Format | Journal Article |
Language | English |
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Elsevier B.V
24.05.2020
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Abstract | •Novel two-column counter-current frontal chromatography process is presented: Flow2.•Model-based design spaces are established for counter-current and batch processes.•Design spaces reveal higher operational flexibility of the counter-current process.•Perturbation studies reveal increased robustness of the counter-current process.
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. |
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AbstractList | •Novel two-column counter-current frontal chromatography process is presented: Flow2.•Model-based design spaces are established for counter-current and batch processes.•Design spaces reveal higher operational flexibility of the counter-current process.•Perturbation studies reveal increased robustness of the counter-current process.
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. 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. |
ArticleNumber | 460943 |
Author | Müller-Späth, Thomas Morbidelli, Massimo Vogg, Sebastian |
Author_xml | – sequence: 1 givenname: Sebastian orcidid: 0000-0002-6890-6744 surname: Vogg fullname: Vogg, Sebastian organization: Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, Zürich 8093, Switzerland – sequence: 2 givenname: Thomas surname: Müller-Späth fullname: Müller-Späth, Thomas organization: YMC ChromaCon, Technoparkstrasse 1, Zürich 8005, Switzerland – sequence: 3 givenname: Massimo orcidid: 0000-0002-0112-414X surname: Morbidelli fullname: Morbidelli, Massimo email: massimo.morbidelli@polimi.it organization: Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, Zürich 8093, Switzerland |
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Keywords | Design space Frontal chromatography Continuous chromatography Aggregate Counter-current chromatography Antibody |
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Snippet | •Novel two-column counter-current frontal chromatography process is presented: Flow2.•Model-based design spaces are established for counter-current and batch... Increasing molecular diversity and market competition requires biopharmaceutical manufacturers to intensify their processes. In this respect, frontal... |
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SubjectTerms | Aggregate Antibody Continuous chromatography Counter-current chromatography Design space Frontal chromatography |
Title | Design space and robustness analysis of batch and counter-current frontal chromatography processes for the removal of antibody aggregates |
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