Parallel experimental design and multivariate analysis provides efficient screening of cell culture media supplements to improve biosimilar product quality
ABSTRACT Rational and high‐throughput optimization of mammalian cell culture media has a great potential to modulate recombinant protein product quality. We present a process design method based on parallel design‐of‐experiment (DoE) of CHO fed‐batch cultures in 96‐deepwell plates to modulate monocl...
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| Veröffentlicht in: | Biotechnology and bioengineering 2017-07, Vol.114 (7), p.1448-1458 |
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| creator | Brühlmann, David Sokolov, Michael Butté, Alessandro Sauer, Markus Hemberger, Jürgen Souquet, Jonathan Broly, Hervé Jordan, Martin |
| description | ABSTRACT
Rational and high‐throughput optimization of mammalian cell culture media has a great potential to modulate recombinant protein product quality. We present a process design method based on parallel design‐of‐experiment (DoE) of CHO fed‐batch cultures in 96‐deepwell plates to modulate monoclonal antibody (mAb) glycosylation using medium supplements. To reduce the risk of losing valuable information in an intricate joint screening, 17 compounds were separated into five different groups, considering their mode of biological action. The concentration ranges of the medium supplements were defined according to information encountered in the literature and in‐house experience. The screening experiments produced wide glycosylation pattern ranges. Multivariate analysis including principal component analysis and decision trees was used to select the best performing glycosylation modulators. Subsequent D‐optimal quadratic design with four factors (three promising compounds and temperature shift) in shake tubes confirmed the outcome of the selection process and provided a solid basis for sequential process development at a larger scale. The glycosylation profile with respect to the specifications for biosimilarity was greatly improved in shake tube experiments: 75% of the conditions were equally close or closer to the specifications for biosimilarity than the best 25% in 96‐deepwell plates. Biotechnol. Bioeng. 2017;114: 1448–1458. © 2017 Wiley Periodicals, Inc.
A novel rational experimental design method combining high‐throughput CHO cell‐culture testing and multivariate data analysis was developed to identify compounds modulating the quality of a monoclonal antibody. The effect of 17 medium supplements was assessed in 5 parallel 96‐deepwell plate experiments. A multivariate methodology combining principal component analysis, correlation‐based quantification of biosimilarity, and decision trees identified the best performing glycosylation modulators, which were confirmed in shake tubes. A substantial improvement towards the targeted glycosylation profile resulted in two experimental rounds. |
| doi_str_mv | 10.1002/bit.26269 |
| format | Article |
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Rational and high‐throughput optimization of mammalian cell culture media has a great potential to modulate recombinant protein product quality. We present a process design method based on parallel design‐of‐experiment (DoE) of CHO fed‐batch cultures in 96‐deepwell plates to modulate monoclonal antibody (mAb) glycosylation using medium supplements. To reduce the risk of losing valuable information in an intricate joint screening, 17 compounds were separated into five different groups, considering their mode of biological action. The concentration ranges of the medium supplements were defined according to information encountered in the literature and in‐house experience. The screening experiments produced wide glycosylation pattern ranges. Multivariate analysis including principal component analysis and decision trees was used to select the best performing glycosylation modulators. Subsequent D‐optimal quadratic design with four factors (three promising compounds and temperature shift) in shake tubes confirmed the outcome of the selection process and provided a solid basis for sequential process development at a larger scale. The glycosylation profile with respect to the specifications for biosimilarity was greatly improved in shake tube experiments: 75% of the conditions were equally close or closer to the specifications for biosimilarity than the best 25% in 96‐deepwell plates. Biotechnol. Bioeng. 2017;114: 1448–1458. © 2017 Wiley Periodicals, Inc.
A novel rational experimental design method combining high‐throughput CHO cell‐culture testing and multivariate data analysis was developed to identify compounds modulating the quality of a monoclonal antibody. The effect of 17 medium supplements was assessed in 5 parallel 96‐deepwell plate experiments. A multivariate methodology combining principal component analysis, correlation‐based quantification of biosimilarity, and decision trees identified the best performing glycosylation modulators, which were confirmed in shake tubes. A substantial improvement towards the targeted glycosylation profile resulted in two experimental rounds.</description><identifier>ISSN: 0006-3592</identifier><identifier>EISSN: 1097-0290</identifier><identifier>DOI: 10.1002/bit.26269</identifier><identifier>PMID: 28197999</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Animals ; Antibodies, Monoclonal ; antibody glycosylation ; Batch Cell Culture Techniques - methods ; Batch Cell Culture Techniques - standards ; Batch culture ; Bioengineering ; Biosimilar Pharmaceuticals - metabolism ; Biosimilar Pharmaceuticals - standards ; Cell culture ; CHO cell culture ; CHO Cells ; Cricetulus ; Culture media ; Culture Media - chemistry ; Culture Media - metabolism ; Culture Media - standards ; Decision analysis ; Decision trees ; Design factors ; Design of experiments ; Dietary supplements ; DoE ; Experimental design ; Glycosylation ; High-Throughput Screening Assays - methods ; High-Throughput Screening Assays - standards ; high‐throughput ; Modulators ; Monoclonal antibodies ; Multivariate Analysis ; Optimization ; Pattern analysis ; Plates ; Principal Component Analysis ; Principal components analysis ; Protein Engineering - methods ; Protein Engineering - standards ; Quality Control ; Recombinant Proteins - biosynthesis ; Recombinant Proteins - standards ; Risk reduction ; Screening ; sequential process development ; Specifications ; Temperature effects ; Tissue Array Analysis - methods ; Tubes</subject><ispartof>Biotechnology and bioengineering, 2017-07, Vol.114 (7), p.1448-1458</ispartof><rights>2017 Wiley Periodicals, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3909-d4f6e2b7686bdbec2f4e3e21ce7f4be5449e657f656f195381da0fc1d79a91d23</citedby><cites>FETCH-LOGICAL-c3909-d4f6e2b7686bdbec2f4e3e21ce7f4be5449e657f656f195381da0fc1d79a91d23</cites><orcidid>0000-0001-8033-6812</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fbit.26269$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fbit.26269$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28197999$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Brühlmann, David</creatorcontrib><creatorcontrib>Sokolov, Michael</creatorcontrib><creatorcontrib>Butté, Alessandro</creatorcontrib><creatorcontrib>Sauer, Markus</creatorcontrib><creatorcontrib>Hemberger, Jürgen</creatorcontrib><creatorcontrib>Souquet, Jonathan</creatorcontrib><creatorcontrib>Broly, Hervé</creatorcontrib><creatorcontrib>Jordan, Martin</creatorcontrib><title>Parallel experimental design and multivariate analysis provides efficient screening of cell culture media supplements to improve biosimilar product quality</title><title>Biotechnology and bioengineering</title><addtitle>Biotechnol Bioeng</addtitle><description>ABSTRACT
Rational and high‐throughput optimization of mammalian cell culture media has a great potential to modulate recombinant protein product quality. We present a process design method based on parallel design‐of‐experiment (DoE) of CHO fed‐batch cultures in 96‐deepwell plates to modulate monoclonal antibody (mAb) glycosylation using medium supplements. To reduce the risk of losing valuable information in an intricate joint screening, 17 compounds were separated into five different groups, considering their mode of biological action. The concentration ranges of the medium supplements were defined according to information encountered in the literature and in‐house experience. The screening experiments produced wide glycosylation pattern ranges. Multivariate analysis including principal component analysis and decision trees was used to select the best performing glycosylation modulators. Subsequent D‐optimal quadratic design with four factors (three promising compounds and temperature shift) in shake tubes confirmed the outcome of the selection process and provided a solid basis for sequential process development at a larger scale. The glycosylation profile with respect to the specifications for biosimilarity was greatly improved in shake tube experiments: 75% of the conditions were equally close or closer to the specifications for biosimilarity than the best 25% in 96‐deepwell plates. Biotechnol. Bioeng. 2017;114: 1448–1458. © 2017 Wiley Periodicals, Inc.
A novel rational experimental design method combining high‐throughput CHO cell‐culture testing and multivariate data analysis was developed to identify compounds modulating the quality of a monoclonal antibody. The effect of 17 medium supplements was assessed in 5 parallel 96‐deepwell plate experiments. A multivariate methodology combining principal component analysis, correlation‐based quantification of biosimilarity, and decision trees identified the best performing glycosylation modulators, which were confirmed in shake tubes. A substantial improvement towards the targeted glycosylation profile resulted in two experimental rounds.</description><subject>Animals</subject><subject>Antibodies, Monoclonal</subject><subject>antibody glycosylation</subject><subject>Batch Cell Culture Techniques - methods</subject><subject>Batch Cell Culture Techniques - standards</subject><subject>Batch culture</subject><subject>Bioengineering</subject><subject>Biosimilar Pharmaceuticals - metabolism</subject><subject>Biosimilar Pharmaceuticals - standards</subject><subject>Cell culture</subject><subject>CHO cell culture</subject><subject>CHO Cells</subject><subject>Cricetulus</subject><subject>Culture media</subject><subject>Culture Media - chemistry</subject><subject>Culture Media - metabolism</subject><subject>Culture Media - standards</subject><subject>Decision analysis</subject><subject>Decision trees</subject><subject>Design factors</subject><subject>Design of experiments</subject><subject>Dietary supplements</subject><subject>DoE</subject><subject>Experimental design</subject><subject>Glycosylation</subject><subject>High-Throughput Screening Assays - methods</subject><subject>High-Throughput Screening Assays - standards</subject><subject>high‐throughput</subject><subject>Modulators</subject><subject>Monoclonal antibodies</subject><subject>Multivariate Analysis</subject><subject>Optimization</subject><subject>Pattern analysis</subject><subject>Plates</subject><subject>Principal Component Analysis</subject><subject>Principal components analysis</subject><subject>Protein Engineering - methods</subject><subject>Protein Engineering - standards</subject><subject>Quality Control</subject><subject>Recombinant Proteins - biosynthesis</subject><subject>Recombinant Proteins - standards</subject><subject>Risk reduction</subject><subject>Screening</subject><subject>sequential process development</subject><subject>Specifications</subject><subject>Temperature effects</subject><subject>Tissue Array Analysis - methods</subject><subject>Tubes</subject><issn>0006-3592</issn><issn>1097-0290</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc1O3TAQRq2qCC6URV-gstQNXQRsJ3HiZYtaQEJqF3QdOfYYDXJ-sGPKfZa-LA4XWFTqyrJ15oz8fYR85OyUMybOelxOhRRSvSMbzlRTMKHYe7JhjMmirJU4IIcx3uVr00q5Tw5Ey1WjlNqQv7900N6Dp_A4Q8ABxkV7aiHi7Uj1aOmQ_IIPOqBeID9ov40Y6RymB8wUBefQYJ6i0QSAEcdbOjlqwHtq8mgKQAewqGlM8-xhXRDpMlEcVgfQHqeIA3odVqlNZqH3SXtcth_IntM-wvHLeUR-__h-c35ZXP-8uDr_el2YUjFV2MpJEH0jW9nbHoxwFZQguIHGVT3UVaVA1o2TtXRc1WXLrWbOcNsorbgV5RE52Xnz_vsEcekGjOsH9AhTih1vs1pVVcky-vkf9G5KIYeSKcUErxgrV-GXHWXCFGMA1805WR22HWfd2liXG-ueG8vspxdj6nNOb-RrRRk42wF_0MP2_6bu29XNTvkEVZekiA</recordid><startdate>201707</startdate><enddate>201707</enddate><creator>Brühlmann, David</creator><creator>Sokolov, Michael</creator><creator>Butté, Alessandro</creator><creator>Sauer, Markus</creator><creator>Hemberger, Jürgen</creator><creator>Souquet, Jonathan</creator><creator>Broly, Hervé</creator><creator>Jordan, Martin</creator><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QF</scope><scope>7QO</scope><scope>7QQ</scope><scope>7SC</scope><scope>7SE</scope><scope>7SP</scope><scope>7SR</scope><scope>7T7</scope><scope>7TA</scope><scope>7TB</scope><scope>7U5</scope><scope>8BQ</scope><scope>8FD</scope><scope>C1K</scope><scope>F28</scope><scope>FR3</scope><scope>H8D</scope><scope>H8G</scope><scope>JG9</scope><scope>JQ2</scope><scope>KR7</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>P64</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-8033-6812</orcidid></search><sort><creationdate>201707</creationdate><title>Parallel experimental design and multivariate analysis provides efficient screening of cell culture media supplements to improve biosimilar product quality</title><author>Brühlmann, David ; Sokolov, Michael ; Butté, Alessandro ; Sauer, Markus ; Hemberger, Jürgen ; Souquet, Jonathan ; Broly, Hervé ; Jordan, Martin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3909-d4f6e2b7686bdbec2f4e3e21ce7f4be5449e657f656f195381da0fc1d79a91d23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Antibodies, Monoclonal</topic><topic>antibody glycosylation</topic><topic>Batch Cell Culture Techniques - methods</topic><topic>Batch Cell Culture Techniques - standards</topic><topic>Batch culture</topic><topic>Bioengineering</topic><topic>Biosimilar Pharmaceuticals - metabolism</topic><topic>Biosimilar Pharmaceuticals - standards</topic><topic>Cell culture</topic><topic>CHO cell culture</topic><topic>CHO Cells</topic><topic>Cricetulus</topic><topic>Culture media</topic><topic>Culture Media - chemistry</topic><topic>Culture Media - metabolism</topic><topic>Culture Media - standards</topic><topic>Decision analysis</topic><topic>Decision trees</topic><topic>Design factors</topic><topic>Design of experiments</topic><topic>Dietary supplements</topic><topic>DoE</topic><topic>Experimental design</topic><topic>Glycosylation</topic><topic>High-Throughput Screening Assays - methods</topic><topic>High-Throughput Screening Assays - standards</topic><topic>high‐throughput</topic><topic>Modulators</topic><topic>Monoclonal antibodies</topic><topic>Multivariate Analysis</topic><topic>Optimization</topic><topic>Pattern analysis</topic><topic>Plates</topic><topic>Principal Component Analysis</topic><topic>Principal components analysis</topic><topic>Protein Engineering - 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Academic</collection><jtitle>Biotechnology and bioengineering</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Brühlmann, David</au><au>Sokolov, Michael</au><au>Butté, Alessandro</au><au>Sauer, Markus</au><au>Hemberger, Jürgen</au><au>Souquet, Jonathan</au><au>Broly, Hervé</au><au>Jordan, Martin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Parallel experimental design and multivariate analysis provides efficient screening of cell culture media supplements to improve biosimilar product quality</atitle><jtitle>Biotechnology and bioengineering</jtitle><addtitle>Biotechnol Bioeng</addtitle><date>2017-07</date><risdate>2017</risdate><volume>114</volume><issue>7</issue><spage>1448</spage><epage>1458</epage><pages>1448-1458</pages><issn>0006-3592</issn><eissn>1097-0290</eissn><abstract>ABSTRACT
Rational and high‐throughput optimization of mammalian cell culture media has a great potential to modulate recombinant protein product quality. We present a process design method based on parallel design‐of‐experiment (DoE) of CHO fed‐batch cultures in 96‐deepwell plates to modulate monoclonal antibody (mAb) glycosylation using medium supplements. To reduce the risk of losing valuable information in an intricate joint screening, 17 compounds were separated into five different groups, considering their mode of biological action. The concentration ranges of the medium supplements were defined according to information encountered in the literature and in‐house experience. The screening experiments produced wide glycosylation pattern ranges. Multivariate analysis including principal component analysis and decision trees was used to select the best performing glycosylation modulators. Subsequent D‐optimal quadratic design with four factors (three promising compounds and temperature shift) in shake tubes confirmed the outcome of the selection process and provided a solid basis for sequential process development at a larger scale. The glycosylation profile with respect to the specifications for biosimilarity was greatly improved in shake tube experiments: 75% of the conditions were equally close or closer to the specifications for biosimilarity than the best 25% in 96‐deepwell plates. Biotechnol. Bioeng. 2017;114: 1448–1458. © 2017 Wiley Periodicals, Inc.
A novel rational experimental design method combining high‐throughput CHO cell‐culture testing and multivariate data analysis was developed to identify compounds modulating the quality of a monoclonal antibody. The effect of 17 medium supplements was assessed in 5 parallel 96‐deepwell plate experiments. A multivariate methodology combining principal component analysis, correlation‐based quantification of biosimilarity, and decision trees identified the best performing glycosylation modulators, which were confirmed in shake tubes. A substantial improvement towards the targeted glycosylation profile resulted in two experimental rounds.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>28197999</pmid><doi>10.1002/bit.26269</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-8033-6812</orcidid></addata></record> |
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| subjects | Animals Antibodies, Monoclonal antibody glycosylation Batch Cell Culture Techniques - methods Batch Cell Culture Techniques - standards Batch culture Bioengineering Biosimilar Pharmaceuticals - metabolism Biosimilar Pharmaceuticals - standards Cell culture CHO cell culture CHO Cells Cricetulus Culture media Culture Media - chemistry Culture Media - metabolism Culture Media - standards Decision analysis Decision trees Design factors Design of experiments Dietary supplements DoE Experimental design Glycosylation High-Throughput Screening Assays - methods High-Throughput Screening Assays - standards high‐throughput Modulators Monoclonal antibodies Multivariate Analysis Optimization Pattern analysis Plates Principal Component Analysis Principal components analysis Protein Engineering - methods Protein Engineering - standards Quality Control Recombinant Proteins - biosynthesis Recombinant Proteins - standards Risk reduction Screening sequential process development Specifications Temperature effects Tissue Array Analysis - methods Tubes |
| title | Parallel experimental design and multivariate analysis provides efficient screening of cell culture media supplements to improve biosimilar product quality |
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