Multi-attribute PAT for UF/DF of Proteins—Monitoring Concentration, particle sizes, and Buffer Exchange
Ultrafiltration/diafiltration (UF/DF) plays an important role in the manufacturing of biopharmaceuticals. Monitoring critical process parameters and quality attributes by process analytical technology (PAT) during those steps can facilitate process development and assure consistent quality in produc...
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| Veröffentlicht in: | Analytical and bioanalytical chemistry 2020-04, Vol.412 (9), p.2123-2136 |
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| creator | Rolinger, Laura Rüdt, Matthias Diehm, Juliane Chow-Hubbertz, Jessica Heitmann, Martin Schleper, Stefan Hubbuch, Jürgen |
| description | Ultrafiltration/diafiltration (UF/DF) plays an important role in the manufacturing of biopharmaceuticals. Monitoring critical process parameters and quality attributes by process analytical technology (PAT) during those steps can facilitate process development and assure consistent quality in production processes. In this study, a lab-scale cross-flow filtration (CFF) device was equipped with a variable pathlength (VP) ultraviolet and visible (UV/Vis) spectrometer, a light scattering photometer, and a liquid density sensor (microLDS). Based on the measured signals, the protein concentration, buffer exchange, apparent molecular weight, and hydrodynamic radius were monitored. The setup was tested in three case studies. First, lysozyme was used in an UF/DF run to show the comparability of on-line and off-line measurements. The corresponding correlation coefficients exceeded 0.97. Next, urea-induced changes in protein size of glucose oxidase (GOx) were monitored during two DF steps. Here, correlation coefficients were ≥ 0.92 for static light scattering (SLS) and dynamic light scattering (DLS). The correlation coefficient for the protein concentration was 0.82, possibly due to time-dependent protein precipitation. Finally, a case study was conducted with a monoclonal antibody (mAb) to show the full potential of this setup. Again, off-line and on-line measurements were in good agreement with all correlation coefficients exceeding 0.92. The protein concentration could be monitored in-line in a large range from 3 to 120 g L
− 1
. A buffer-dependent increase in apparent molecular weight of the mAb was observed during DF, providing interesting supplemental information for process development and stability assessment. In summary, the developed setup provides a powerful testing system for evaluating different UF/DF processes and may be a good starting point to develop process control strategies.
Graphical Abstract
Piping and instrumentation diagram of the experimental setup and data generated by the different sensors. A VP UV/Vis spectrometer (FlowVPE, yellow) measures the protein concentration. From the data of the light scattering photometer (Zetasizer, green) in the on-line measurement loop, the apparant molecular weight and z-average are calculated. The density sensor (microLDS) measures density and viscosity of the fluid in the on-line loop |
| doi_str_mv | 10.1007/s00216-019-02318-8 |
| format | Article |
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− 1
. A buffer-dependent increase in apparent molecular weight of the mAb was observed during DF, providing interesting supplemental information for process development and stability assessment. In summary, the developed setup provides a powerful testing system for evaluating different UF/DF processes and may be a good starting point to develop process control strategies.
Graphical Abstract
Piping and instrumentation diagram of the experimental setup and data generated by the different sensors. A VP UV/Vis spectrometer (FlowVPE, yellow) measures the protein concentration. From the data of the light scattering photometer (Zetasizer, green) in the on-line measurement loop, the apparant molecular weight and z-average are calculated. The density sensor (microLDS) measures density and viscosity of the fluid in the on-line loop</description><identifier>ISSN: 1618-2642</identifier><identifier>EISSN: 1618-2650</identifier><identifier>DOI: 10.1007/s00216-019-02318-8</identifier><identifier>PMID: 32072210</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Advances in Process Analytics and Control Technology ; Analytical Chemistry ; Animals ; Antibodies, Monoclonal - analysis ; Biochemistry ; Biological products ; Buffers ; Case studies ; Characterization and Evaluation of Materials ; Chemistry ; Chemistry and Materials Science ; Correlation analysis ; Correlation coefficient ; Correlation coefficients ; Cross flow ; Dynamic Light Scattering ; Equipment Design ; Exchanging ; Food Science ; Glucose oxidase ; Glucose Oxidase - analysis ; Humans ; Information processing ; Laboratory Medicine ; Light scattering ; Lysozyme ; Mathematical analysis ; Molecular weight ; Monitoring ; Monitoring/Environmental Analysis ; Monoclonal antibodies ; Muramidase - analysis ; Oxidases ; Particle Size ; Pharmaceutical industry ; Photometers ; Photon correlation spectroscopy ; Process control ; Process controls ; Process parameters ; Proteins ; Proteins - analysis ; Quality assurance ; Quality management ; Research Paper ; Scattering ; Sensors ; Spectrophotometry, Ultraviolet ; Stability analysis ; Technology assessment ; Technology, Pharmaceutical - instrumentation ; Time dependence ; Ultrafiltration ; Ultrafiltration - instrumentation ; Ultraviolet radiation ; Urea</subject><ispartof>Analytical and bioanalytical chemistry, 2020-04, Vol.412 (9), p.2123-2136</ispartof><rights>Springer-Verlag GmbH Germany, part of Springer Nature 2020</rights><rights>COPYRIGHT 2020 Springer</rights><rights>Analytical and Bioanalytical Chemistry is a copyright of Springer, (2020). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c479t-9e5542c8326372480a6ba3c7252e440e0019eacb127907bfcda527f5fdd428e03</citedby><cites>FETCH-LOGICAL-c479t-9e5542c8326372480a6ba3c7252e440e0019eacb127907bfcda527f5fdd428e03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00216-019-02318-8$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00216-019-02318-8$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32072210$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rolinger, Laura</creatorcontrib><creatorcontrib>Rüdt, Matthias</creatorcontrib><creatorcontrib>Diehm, Juliane</creatorcontrib><creatorcontrib>Chow-Hubbertz, Jessica</creatorcontrib><creatorcontrib>Heitmann, Martin</creatorcontrib><creatorcontrib>Schleper, Stefan</creatorcontrib><creatorcontrib>Hubbuch, Jürgen</creatorcontrib><title>Multi-attribute PAT for UF/DF of Proteins—Monitoring Concentration, particle sizes, and Buffer Exchange</title><title>Analytical and bioanalytical chemistry</title><addtitle>Anal Bioanal Chem</addtitle><addtitle>Anal Bioanal Chem</addtitle><description>Ultrafiltration/diafiltration (UF/DF) plays an important role in the manufacturing of biopharmaceuticals. Monitoring critical process parameters and quality attributes by process analytical technology (PAT) during those steps can facilitate process development and assure consistent quality in production processes. In this study, a lab-scale cross-flow filtration (CFF) device was equipped with a variable pathlength (VP) ultraviolet and visible (UV/Vis) spectrometer, a light scattering photometer, and a liquid density sensor (microLDS). Based on the measured signals, the protein concentration, buffer exchange, apparent molecular weight, and hydrodynamic radius were monitored. The setup was tested in three case studies. First, lysozyme was used in an UF/DF run to show the comparability of on-line and off-line measurements. The corresponding correlation coefficients exceeded 0.97. Next, urea-induced changes in protein size of glucose oxidase (GOx) were monitored during two DF steps. Here, correlation coefficients were ≥ 0.92 for static light scattering (SLS) and dynamic light scattering (DLS). The correlation coefficient for the protein concentration was 0.82, possibly due to time-dependent protein precipitation. Finally, a case study was conducted with a monoclonal antibody (mAb) to show the full potential of this setup. Again, off-line and on-line measurements were in good agreement with all correlation coefficients exceeding 0.92. The protein concentration could be monitored in-line in a large range from 3 to 120 g L
− 1
. A buffer-dependent increase in apparent molecular weight of the mAb was observed during DF, providing interesting supplemental information for process development and stability assessment. In summary, the developed setup provides a powerful testing system for evaluating different UF/DF processes and may be a good starting point to develop process control strategies.
Graphical Abstract
Piping and instrumentation diagram of the experimental setup and data generated by the different sensors. A VP UV/Vis spectrometer (FlowVPE, yellow) measures the protein concentration. From the data of the light scattering photometer (Zetasizer, green) in the on-line measurement loop, the apparant molecular weight and z-average are calculated. The density sensor (microLDS) measures density and viscosity of the fluid in the on-line loop</description><subject>Advances in Process Analytics and Control Technology</subject><subject>Analytical Chemistry</subject><subject>Animals</subject><subject>Antibodies, Monoclonal - analysis</subject><subject>Biochemistry</subject><subject>Biological products</subject><subject>Buffers</subject><subject>Case studies</subject><subject>Characterization and Evaluation of Materials</subject><subject>Chemistry</subject><subject>Chemistry and Materials Science</subject><subject>Correlation analysis</subject><subject>Correlation coefficient</subject><subject>Correlation coefficients</subject><subject>Cross flow</subject><subject>Dynamic Light Scattering</subject><subject>Equipment Design</subject><subject>Exchanging</subject><subject>Food Science</subject><subject>Glucose oxidase</subject><subject>Glucose Oxidase - analysis</subject><subject>Humans</subject><subject>Information processing</subject><subject>Laboratory Medicine</subject><subject>Light scattering</subject><subject>Lysozyme</subject><subject>Mathematical analysis</subject><subject>Molecular weight</subject><subject>Monitoring</subject><subject>Monitoring/Environmental Analysis</subject><subject>Monoclonal antibodies</subject><subject>Muramidase - 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analysis</topic><topic>Biochemistry</topic><topic>Biological products</topic><topic>Buffers</topic><topic>Case studies</topic><topic>Characterization and Evaluation of Materials</topic><topic>Chemistry</topic><topic>Chemistry and Materials Science</topic><topic>Correlation analysis</topic><topic>Correlation coefficient</topic><topic>Correlation coefficients</topic><topic>Cross flow</topic><topic>Dynamic Light Scattering</topic><topic>Equipment Design</topic><topic>Exchanging</topic><topic>Food Science</topic><topic>Glucose oxidase</topic><topic>Glucose Oxidase - analysis</topic><topic>Humans</topic><topic>Information processing</topic><topic>Laboratory Medicine</topic><topic>Light scattering</topic><topic>Lysozyme</topic><topic>Mathematical analysis</topic><topic>Molecular weight</topic><topic>Monitoring</topic><topic>Monitoring/Environmental Analysis</topic><topic>Monoclonal antibodies</topic><topic>Muramidase - analysis</topic><topic>Oxidases</topic><topic>Particle Size</topic><topic>Pharmaceutical industry</topic><topic>Photometers</topic><topic>Photon correlation spectroscopy</topic><topic>Process control</topic><topic>Process controls</topic><topic>Process parameters</topic><topic>Proteins</topic><topic>Proteins - 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Academic</collection><jtitle>Analytical and bioanalytical chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rolinger, Laura</au><au>Rüdt, Matthias</au><au>Diehm, Juliane</au><au>Chow-Hubbertz, Jessica</au><au>Heitmann, Martin</au><au>Schleper, Stefan</au><au>Hubbuch, Jürgen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Multi-attribute PAT for UF/DF of Proteins—Monitoring Concentration, particle sizes, and Buffer Exchange</atitle><jtitle>Analytical and bioanalytical chemistry</jtitle><stitle>Anal Bioanal Chem</stitle><addtitle>Anal Bioanal Chem</addtitle><date>2020-04-01</date><risdate>2020</risdate><volume>412</volume><issue>9</issue><spage>2123</spage><epage>2136</epage><pages>2123-2136</pages><issn>1618-2642</issn><eissn>1618-2650</eissn><abstract>Ultrafiltration/diafiltration (UF/DF) plays an important role in the manufacturing of biopharmaceuticals. Monitoring critical process parameters and quality attributes by process analytical technology (PAT) during those steps can facilitate process development and assure consistent quality in production processes. In this study, a lab-scale cross-flow filtration (CFF) device was equipped with a variable pathlength (VP) ultraviolet and visible (UV/Vis) spectrometer, a light scattering photometer, and a liquid density sensor (microLDS). Based on the measured signals, the protein concentration, buffer exchange, apparent molecular weight, and hydrodynamic radius were monitored. The setup was tested in three case studies. First, lysozyme was used in an UF/DF run to show the comparability of on-line and off-line measurements. The corresponding correlation coefficients exceeded 0.97. Next, urea-induced changes in protein size of glucose oxidase (GOx) were monitored during two DF steps. Here, correlation coefficients were ≥ 0.92 for static light scattering (SLS) and dynamic light scattering (DLS). The correlation coefficient for the protein concentration was 0.82, possibly due to time-dependent protein precipitation. Finally, a case study was conducted with a monoclonal antibody (mAb) to show the full potential of this setup. Again, off-line and on-line measurements were in good agreement with all correlation coefficients exceeding 0.92. The protein concentration could be monitored in-line in a large range from 3 to 120 g L
− 1
. A buffer-dependent increase in apparent molecular weight of the mAb was observed during DF, providing interesting supplemental information for process development and stability assessment. In summary, the developed setup provides a powerful testing system for evaluating different UF/DF processes and may be a good starting point to develop process control strategies.
Graphical Abstract
Piping and instrumentation diagram of the experimental setup and data generated by the different sensors. A VP UV/Vis spectrometer (FlowVPE, yellow) measures the protein concentration. From the data of the light scattering photometer (Zetasizer, green) in the on-line measurement loop, the apparant molecular weight and z-average are calculated. The density sensor (microLDS) measures density and viscosity of the fluid in the on-line loop</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>32072210</pmid><doi>10.1007/s00216-019-02318-8</doi><tpages>14</tpages></addata></record> |
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| ispartof | Analytical and bioanalytical chemistry, 2020-04, Vol.412 (9), p.2123-2136 |
| issn | 1618-2642 1618-2650 |
| language | eng |
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| source | MEDLINE; Springer Nature - Complete Springer Journals |
| subjects | Advances in Process Analytics and Control Technology Analytical Chemistry Animals Antibodies, Monoclonal - analysis Biochemistry Biological products Buffers Case studies Characterization and Evaluation of Materials Chemistry Chemistry and Materials Science Correlation analysis Correlation coefficient Correlation coefficients Cross flow Dynamic Light Scattering Equipment Design Exchanging Food Science Glucose oxidase Glucose Oxidase - analysis Humans Information processing Laboratory Medicine Light scattering Lysozyme Mathematical analysis Molecular weight Monitoring Monitoring/Environmental Analysis Monoclonal antibodies Muramidase - analysis Oxidases Particle Size Pharmaceutical industry Photometers Photon correlation spectroscopy Process control Process controls Process parameters Proteins Proteins - analysis Quality assurance Quality management Research Paper Scattering Sensors Spectrophotometry, Ultraviolet Stability analysis Technology assessment Technology, Pharmaceutical - instrumentation Time dependence Ultrafiltration Ultrafiltration - instrumentation Ultraviolet radiation Urea |
| title | Multi-attribute PAT for UF/DF of Proteins—Monitoring Concentration, particle sizes, and Buffer Exchange |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-28T10%3A03%3A00IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Multi-attribute%20PAT%20for%20UF/DF%20of%20Proteins%E2%80%94Monitoring%20Concentration,%20particle%20sizes,%20and%20Buffer%20Exchange&rft.jtitle=Analytical%20and%20bioanalytical%20chemistry&rft.au=Rolinger,%20Laura&rft.date=2020-04-01&rft.volume=412&rft.issue=9&rft.spage=2123&rft.epage=2136&rft.pages=2123-2136&rft.issn=1618-2642&rft.eissn=1618-2650&rft_id=info:doi/10.1007/s00216-019-02318-8&rft_dat=%3Cgale_proqu%3EA617572024%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2377012602&rft_id=info:pmid/32072210&rft_galeid=A617572024&rfr_iscdi=true |