Characterization of Opalescence in low Volume Monoclonal Antibody Solutions Enabled by Microscale Nephelometry
Monoclonal antibody (mAb)-based drugs are often prone to unfavorable solution behaviors including high viscosity, opalescence, phase separation, and aggregation at the high concentrations needed to enable patient-centric subcutaneous dosage forms. Given that these can have a detrimental impact on ma...
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| Veröffentlicht in: | Journal of pharmaceutical sciences 2021-09, Vol.110 (9), p.3176-3182 |
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| creator | Kingsbury, Jonathan S. Lantz, Michaela M. Saini, Amandeep Wang, Michael Z. Gokarn, Yatin R. |
| description | Monoclonal antibody (mAb)-based drugs are often prone to unfavorable solution behaviors including high viscosity, opalescence, phase separation, and aggregation at the high concentrations needed to enable patient-centric subcutaneous dosage forms. Given that these can have a detrimental impact on manufacturability, stability, and delivery, approaches to identifying, monitoring, and controlling these behaviors during drug development are critical. Opalescence presents a significant challenge due to its relationship to liquid-liquid phase separation. Quantitative characterization of opalescence via turbidimetry is often restrictive due to large volume requirements (>2 mL) and alternative microscale approaches based on light transmittance (Eckhardt et al., J Pharm Sci Technol. 1994, 48: 64–70) may pose challenging with respect to accuracy. To address the need for accurate and quantitative microscale opalescence measurements, we have evaluated the use of a ‘de-tuned’ static light scattering detector which requires |
| doi_str_mv | 10.1016/j.xphs.2021.05.005 |
| format | Article |
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Given that these can have a detrimental impact on manufacturability, stability, and delivery, approaches to identifying, monitoring, and controlling these behaviors during drug development are critical. Opalescence presents a significant challenge due to its relationship to liquid-liquid phase separation. Quantitative characterization of opalescence via turbidimetry is often restrictive due to large volume requirements (>2 mL) and alternative microscale approaches based on light transmittance (Eckhardt et al., J Pharm Sci Technol. 1994, 48: 64–70) may pose challenging with respect to accuracy. To address the need for accurate and quantitative microscale opalescence measurements, we have evaluated the use of a ‘de-tuned’ static light scattering detector which requires <10 μL sample per measurement. We show that tuning of the laser power to a range far below that of traditional light scattering measurements results in a stable detector response that can be accurately calibrated to the nephelometric turbidity unit (NTU) scale using appropriate standards. The calibrated detector signal yields NTU values for mAbs and other protein solutions that are comparable to a commercial turbidimeter. We used this microscale approach to characterize the opalescence of 48 commercial mAb drug products and found that the majority have opalescence below 15 NTU. However, in products with mAb concentrations greater than 75 mg/mL, a broad range of opalescence was observed, in a few cases greater than 20 NTU. These measurements as well as nephelometric characterization of several IgG1 and IgG4 mAbs across a broad pH range highlight subclass-specific tendencies toward opalescence in high concentration solutions.</description><identifier>ISSN: 0022-3549</identifier><identifier>EISSN: 1520-6017</identifier><identifier>DOI: 10.1016/j.xphs.2021.05.005</identifier><identifier>PMID: 34004217</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Antibodies, Monoclonal - analysis ; Biopharmaceutical characterization ; High concentration ; Immunoglobulin G ; Iridescence ; Monoclonal antibody ; Nephelometry ; Nephelometry and Turbidimetry ; Solutions ; Viscosity</subject><ispartof>Journal of pharmaceutical sciences, 2021-09, Vol.110 (9), p.3176-3182</ispartof><rights>2021 American Pharmacists Association</rights><rights>Copyright © 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c422t-e7b8dd4cea66da468ceca0518542afd2cb6a61cf701499b87c38c00c7a3e64843</citedby><cites>FETCH-LOGICAL-c422t-e7b8dd4cea66da468ceca0518542afd2cb6a61cf701499b87c38c00c7a3e64843</cites><orcidid>0000-0001-8216-5439</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34004217$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kingsbury, Jonathan S.</creatorcontrib><creatorcontrib>Lantz, Michaela M.</creatorcontrib><creatorcontrib>Saini, Amandeep</creatorcontrib><creatorcontrib>Wang, Michael Z.</creatorcontrib><creatorcontrib>Gokarn, Yatin R.</creatorcontrib><title>Characterization of Opalescence in low Volume Monoclonal Antibody Solutions Enabled by Microscale Nephelometry</title><title>Journal of pharmaceutical sciences</title><addtitle>J Pharm Sci</addtitle><description>Monoclonal antibody (mAb)-based drugs are often prone to unfavorable solution behaviors including high viscosity, opalescence, phase separation, and aggregation at the high concentrations needed to enable patient-centric subcutaneous dosage forms. Given that these can have a detrimental impact on manufacturability, stability, and delivery, approaches to identifying, monitoring, and controlling these behaviors during drug development are critical. Opalescence presents a significant challenge due to its relationship to liquid-liquid phase separation. Quantitative characterization of opalescence via turbidimetry is often restrictive due to large volume requirements (>2 mL) and alternative microscale approaches based on light transmittance (Eckhardt et al., J Pharm Sci Technol. 1994, 48: 64–70) may pose challenging with respect to accuracy. To address the need for accurate and quantitative microscale opalescence measurements, we have evaluated the use of a ‘de-tuned’ static light scattering detector which requires <10 μL sample per measurement. We show that tuning of the laser power to a range far below that of traditional light scattering measurements results in a stable detector response that can be accurately calibrated to the nephelometric turbidity unit (NTU) scale using appropriate standards. The calibrated detector signal yields NTU values for mAbs and other protein solutions that are comparable to a commercial turbidimeter. We used this microscale approach to characterize the opalescence of 48 commercial mAb drug products and found that the majority have opalescence below 15 NTU. However, in products with mAb concentrations greater than 75 mg/mL, a broad range of opalescence was observed, in a few cases greater than 20 NTU. These measurements as well as nephelometric characterization of several IgG1 and IgG4 mAbs across a broad pH range highlight subclass-specific tendencies toward opalescence in high concentration solutions.</description><subject>Antibodies, Monoclonal - analysis</subject><subject>Biopharmaceutical characterization</subject><subject>High concentration</subject><subject>Immunoglobulin G</subject><subject>Iridescence</subject><subject>Monoclonal antibody</subject><subject>Nephelometry</subject><subject>Nephelometry and Turbidimetry</subject><subject>Solutions</subject><subject>Viscosity</subject><issn>0022-3549</issn><issn>1520-6017</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE9v1DAQxS0EokvhC3BAPnJJGDu2k5W4VKtCkVp64M_VcpyJ1ivHDnYWWD59HW3hiOYwh3nvad6PkNcMagZMvTvUv-d9rjlwVoOsAeQTsmGSQ6WAtU_JBoDzqpFie0Fe5HwAAAVSPicXjQAQnLUbEnZ7k4xdMLk_ZnEx0DjS-9l4zBaDReoC9fEX_R79cUJ6F0O0Pgbj6VVYXB-HE_1STqsz0-tgeo8D7U_0ztkUsy059DPOe_RxwiWdXpJno_EZXz3uS_Ltw_XX3U11e__x0-7qtrKC86XCtu-GQVg0Sg1GqM6iNSBZJwU348Btr4xidmyBie2271rbdBbAtqZBJTrRXJK359w5xR9HzIueXCnkvQkYj1lzybstlFFFys_S9eGccNRzcpNJJ81Ar5z1Qa-c9cpZg9SFczG9ecw_9hMO_yx_wRbB-7MAS8ufDpPO1q1AB5fQLnqI7n_5D5IekPk</recordid><startdate>202109</startdate><enddate>202109</enddate><creator>Kingsbury, Jonathan S.</creator><creator>Lantz, Michaela M.</creator><creator>Saini, Amandeep</creator><creator>Wang, Michael Z.</creator><creator>Gokarn, Yatin R.</creator><general>Elsevier 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>7X8</scope><orcidid>https://orcid.org/0000-0001-8216-5439</orcidid></search><sort><creationdate>202109</creationdate><title>Characterization of Opalescence in low Volume Monoclonal Antibody Solutions Enabled by Microscale Nephelometry</title><author>Kingsbury, Jonathan S. ; Lantz, Michaela M. ; Saini, Amandeep ; Wang, Michael Z. ; Gokarn, Yatin R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c422t-e7b8dd4cea66da468ceca0518542afd2cb6a61cf701499b87c38c00c7a3e64843</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Antibodies, Monoclonal - analysis</topic><topic>Biopharmaceutical characterization</topic><topic>High concentration</topic><topic>Immunoglobulin G</topic><topic>Iridescence</topic><topic>Monoclonal antibody</topic><topic>Nephelometry</topic><topic>Nephelometry and Turbidimetry</topic><topic>Solutions</topic><topic>Viscosity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kingsbury, Jonathan S.</creatorcontrib><creatorcontrib>Lantz, Michaela M.</creatorcontrib><creatorcontrib>Saini, Amandeep</creatorcontrib><creatorcontrib>Wang, Michael Z.</creatorcontrib><creatorcontrib>Gokarn, Yatin R.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of pharmaceutical sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kingsbury, Jonathan S.</au><au>Lantz, Michaela M.</au><au>Saini, Amandeep</au><au>Wang, Michael Z.</au><au>Gokarn, Yatin R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Characterization of Opalescence in low Volume Monoclonal Antibody Solutions Enabled by Microscale Nephelometry</atitle><jtitle>Journal of pharmaceutical sciences</jtitle><addtitle>J Pharm Sci</addtitle><date>2021-09</date><risdate>2021</risdate><volume>110</volume><issue>9</issue><spage>3176</spage><epage>3182</epage><pages>3176-3182</pages><issn>0022-3549</issn><eissn>1520-6017</eissn><abstract>Monoclonal antibody (mAb)-based drugs are often prone to unfavorable solution behaviors including high viscosity, opalescence, phase separation, and aggregation at the high concentrations needed to enable patient-centric subcutaneous dosage forms. Given that these can have a detrimental impact on manufacturability, stability, and delivery, approaches to identifying, monitoring, and controlling these behaviors during drug development are critical. Opalescence presents a significant challenge due to its relationship to liquid-liquid phase separation. Quantitative characterization of opalescence via turbidimetry is often restrictive due to large volume requirements (>2 mL) and alternative microscale approaches based on light transmittance (Eckhardt et al., J Pharm Sci Technol. 1994, 48: 64–70) may pose challenging with respect to accuracy. To address the need for accurate and quantitative microscale opalescence measurements, we have evaluated the use of a ‘de-tuned’ static light scattering detector which requires <10 μL sample per measurement. We show that tuning of the laser power to a range far below that of traditional light scattering measurements results in a stable detector response that can be accurately calibrated to the nephelometric turbidity unit (NTU) scale using appropriate standards. The calibrated detector signal yields NTU values for mAbs and other protein solutions that are comparable to a commercial turbidimeter. We used this microscale approach to characterize the opalescence of 48 commercial mAb drug products and found that the majority have opalescence below 15 NTU. However, in products with mAb concentrations greater than 75 mg/mL, a broad range of opalescence was observed, in a few cases greater than 20 NTU. These measurements as well as nephelometric characterization of several IgG1 and IgG4 mAbs across a broad pH range highlight subclass-specific tendencies toward opalescence in high concentration solutions.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>34004217</pmid><doi>10.1016/j.xphs.2021.05.005</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0001-8216-5439</orcidid></addata></record> |
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| subjects | Antibodies, Monoclonal - analysis Biopharmaceutical characterization High concentration Immunoglobulin G Iridescence Monoclonal antibody Nephelometry Nephelometry and Turbidimetry Solutions Viscosity |
| title | Characterization of Opalescence in low Volume Monoclonal Antibody Solutions Enabled by Microscale Nephelometry |
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