Comparative analysis of marketed factor VIII products: recombinant products are not alike vis‐a‐vis soluble protein aggregates and subvisible particles
Essentials Aggregation is a critical quality attribute of protein therapeutics influencing immunogenicity. Aggregates and subvisible particles in 9 recombinant factor VIII (rFVIII) products were analyzed. Major differences in aggregate and particle concentrations were detected after reconstitution....
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| Veröffentlicht in: | Journal of thrombosis and haemostasis 2018-06, Vol.16 (6), p.1176-1181 |
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| container_title | Journal of thrombosis and haemostasis |
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| creator | Anzengruber, J. Lubich, C. Prenninger, T. Gringeri, A. Scheiflinger, F. Reipert, B. M. Malisauskas, M. |
| description | Essentials
Aggregation is a critical quality attribute of protein therapeutics influencing immunogenicity.
Aggregates and subvisible particles in 9 recombinant factor VIII (rFVIII) products were analyzed.
Major differences in aggregate and particle concentrations were detected after reconstitution.
rFVIII product quality determined aggregation propensity under use‐relevant stress.
Summary
Background
Recombinant protein technologies have facilitated the development of novel factor VIII (FVIII) therapeutics with improved production efficiency, potency and half‐live, and a low risk of viral transmission. The increasing number of recombinant FVIII (rFVIII) products and information on their efficacy, safety and cost allow patients and healthcare professionals to adjust treatment to individual needs. Nonetheless, 20–32% of previously untreated patients with severe hemophilia A develop inhibitory antibodies to rFVIII following treatment. The root cause of the immunogenicity of rFVIII products is not well understood. Data for human interferon and human insulin products suggest that critical quality parameters such as soluble protein aggregates (SPAs) and subvisible particles (SVPs) influence the immunogenicity of protein therapeutics. Therefore, we analyzed SPA and SVP concentrations in commercially available rFVIII products and determined how these parameters change upon exposure of rFVIII products to relevant stress conditions.
Objectives
Compare critical quality parameters such as SPA and SVP concentrations in rFVIII products under intended use and use‐relevant stress conditions.
Methods
Nine rFVIII products (≥ 3 lots each) were analyzed by high‐performance liquid chromatography‐size exclusion chromatography (HPLC‐SEC) and flow cytometry‐based particle analysis.
Results/conclusions
SPAs and SVPs were present at different concentrations in all freshly reconstituted rFVIII products: SPA concentrations ranged from 0.2% to 11.6%; SVPs were 0.7 × 106 to 114.0 × 106 / 1000 IU. Under use‐relevant stress conditions (agitation and shear stress) the products formed additional SPAs and SVPs to different degrees. The collected data indicate that product quality determines its propensity to form SVPs and SPAs, and highlights differences between marketed rFVIII products. |
| doi_str_mv | 10.1111/jth.14125 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2027070376</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2047986353</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3885-dd81831b648330402ae4e88461f69ca83a6da21a32a2fd6dec2c194547eee9533</originalsourceid><addsrcrecordid>eNp1kc9u1DAQhy1ERUvhwAsgS1zgsK3_JI7DrVpRulWlXgrXaGJPFm-TeLGdor3xCL3zdjwJ3t22B6Rasjwaff40mh8h7zg74fmcrtKPE15wUb4gR7yUelZpqV4-1rWUh-R1jCvGeF0K9oocilqpUhTiiPyZ-2ENAZK7Qwoj9JvoIvUdHSDcYkJLOzDJB_p9sVjQdfB2Mil-pgGNH1o3wpieuhQC0tEnCr27RXrn4t_f95Bvrmj0_dT2uIUTupHCchlwCQnzt9HSOLWZcjsCQnKmx_iGHHTQR3z78B6Tb-dfbuYXs6vrr4v52dXMSK3LmbWaa8lbVWgpWcEEYIFaF4p3qjagJSgLgoMUIDqrLBpheF2URYWIdSnlMfm49-bZfk4YUzO4aLDvYUQ_xUYwUbGKyUpl9MN_6MpPIa9tSxVVrZXcCT_tKRN8jAG7Zh1cXuim4azZJtbkxJpdYpl9_2Cc2gHtE_kYUQZO98Av1-PmeVNzeXOxV_4DFRykKQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2047986353</pqid></control><display><type>article</type><title>Comparative analysis of marketed factor VIII products: recombinant products are not alike vis‐a‐vis soluble protein aggregates and subvisible particles</title><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>Anzengruber, J. ; Lubich, C. ; Prenninger, T. ; Gringeri, A. ; Scheiflinger, F. ; Reipert, B. M. ; Malisauskas, M.</creator><creatorcontrib>Anzengruber, J. ; Lubich, C. ; Prenninger, T. ; Gringeri, A. ; Scheiflinger, F. ; Reipert, B. M. ; Malisauskas, M.</creatorcontrib><description>Essentials
Aggregation is a critical quality attribute of protein therapeutics influencing immunogenicity.
Aggregates and subvisible particles in 9 recombinant factor VIII (rFVIII) products were analyzed.
Major differences in aggregate and particle concentrations were detected after reconstitution.
rFVIII product quality determined aggregation propensity under use‐relevant stress.
Summary
Background
Recombinant protein technologies have facilitated the development of novel factor VIII (FVIII) therapeutics with improved production efficiency, potency and half‐live, and a low risk of viral transmission. The increasing number of recombinant FVIII (rFVIII) products and information on their efficacy, safety and cost allow patients and healthcare professionals to adjust treatment to individual needs. Nonetheless, 20–32% of previously untreated patients with severe hemophilia A develop inhibitory antibodies to rFVIII following treatment. The root cause of the immunogenicity of rFVIII products is not well understood. Data for human interferon and human insulin products suggest that critical quality parameters such as soluble protein aggregates (SPAs) and subvisible particles (SVPs) influence the immunogenicity of protein therapeutics. Therefore, we analyzed SPA and SVP concentrations in commercially available rFVIII products and determined how these parameters change upon exposure of rFVIII products to relevant stress conditions.
Objectives
Compare critical quality parameters such as SPA and SVP concentrations in rFVIII products under intended use and use‐relevant stress conditions.
Methods
Nine rFVIII products (≥ 3 lots each) were analyzed by high‐performance liquid chromatography‐size exclusion chromatography (HPLC‐SEC) and flow cytometry‐based particle analysis.
Results/conclusions
SPAs and SVPs were present at different concentrations in all freshly reconstituted rFVIII products: SPA concentrations ranged from 0.2% to 11.6%; SVPs were 0.7 × 106 to 114.0 × 106 / 1000 IU. Under use‐relevant stress conditions (agitation and shear stress) the products formed additional SPAs and SVPs to different degrees. The collected data indicate that product quality determines its propensity to form SVPs and SPAs, and highlights differences between marketed rFVIII products.</description><identifier>ISSN: 1538-7933</identifier><identifier>ISSN: 1538-7836</identifier><identifier>EISSN: 1538-7836</identifier><identifier>DOI: 10.1111/jth.14125</identifier><identifier>PMID: 29665242</identifier><language>eng</language><publisher>England: Elsevier Limited</publisher><subject>Chromatography ; Coagulation factors ; Comparative analysis ; factor VIII ; Factor VIII deficiency ; Flow cytometry ; Hemophilia ; hemophilia A ; High-performance liquid chromatography ; Immunogenicity ; Insulin ; Interferon ; Patients ; protein aggregates ; protein stability ; Proteins ; recombinant proteins ; Spas</subject><ispartof>Journal of thrombosis and haemostasis, 2018-06, Vol.16 (6), p.1176-1181</ispartof><rights>2018 The Authors. published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.</rights><rights>2018 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.</rights><rights>Copyright © 2018 International Society on Thrombosis and Haemostasis</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3885-dd81831b648330402ae4e88461f69ca83a6da21a32a2fd6dec2c194547eee9533</citedby><cites>FETCH-LOGICAL-c3885-dd81831b648330402ae4e88461f69ca83a6da21a32a2fd6dec2c194547eee9533</cites></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/29665242$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Anzengruber, J.</creatorcontrib><creatorcontrib>Lubich, C.</creatorcontrib><creatorcontrib>Prenninger, T.</creatorcontrib><creatorcontrib>Gringeri, A.</creatorcontrib><creatorcontrib>Scheiflinger, F.</creatorcontrib><creatorcontrib>Reipert, B. M.</creatorcontrib><creatorcontrib>Malisauskas, M.</creatorcontrib><title>Comparative analysis of marketed factor VIII products: recombinant products are not alike vis‐a‐vis soluble protein aggregates and subvisible particles</title><title>Journal of thrombosis and haemostasis</title><addtitle>J Thromb Haemost</addtitle><description>Essentials
Aggregation is a critical quality attribute of protein therapeutics influencing immunogenicity.
Aggregates and subvisible particles in 9 recombinant factor VIII (rFVIII) products were analyzed.
Major differences in aggregate and particle concentrations were detected after reconstitution.
rFVIII product quality determined aggregation propensity under use‐relevant stress.
Summary
Background
Recombinant protein technologies have facilitated the development of novel factor VIII (FVIII) therapeutics with improved production efficiency, potency and half‐live, and a low risk of viral transmission. The increasing number of recombinant FVIII (rFVIII) products and information on their efficacy, safety and cost allow patients and healthcare professionals to adjust treatment to individual needs. Nonetheless, 20–32% of previously untreated patients with severe hemophilia A develop inhibitory antibodies to rFVIII following treatment. The root cause of the immunogenicity of rFVIII products is not well understood. Data for human interferon and human insulin products suggest that critical quality parameters such as soluble protein aggregates (SPAs) and subvisible particles (SVPs) influence the immunogenicity of protein therapeutics. Therefore, we analyzed SPA and SVP concentrations in commercially available rFVIII products and determined how these parameters change upon exposure of rFVIII products to relevant stress conditions.
Objectives
Compare critical quality parameters such as SPA and SVP concentrations in rFVIII products under intended use and use‐relevant stress conditions.
Methods
Nine rFVIII products (≥ 3 lots each) were analyzed by high‐performance liquid chromatography‐size exclusion chromatography (HPLC‐SEC) and flow cytometry‐based particle analysis.
Results/conclusions
SPAs and SVPs were present at different concentrations in all freshly reconstituted rFVIII products: SPA concentrations ranged from 0.2% to 11.6%; SVPs were 0.7 × 106 to 114.0 × 106 / 1000 IU. Under use‐relevant stress conditions (agitation and shear stress) the products formed additional SPAs and SVPs to different degrees. The collected data indicate that product quality determines its propensity to form SVPs and SPAs, and highlights differences between marketed rFVIII products.</description><subject>Chromatography</subject><subject>Coagulation factors</subject><subject>Comparative analysis</subject><subject>factor VIII</subject><subject>Factor VIII deficiency</subject><subject>Flow cytometry</subject><subject>Hemophilia</subject><subject>hemophilia A</subject><subject>High-performance liquid chromatography</subject><subject>Immunogenicity</subject><subject>Insulin</subject><subject>Interferon</subject><subject>Patients</subject><subject>protein aggregates</subject><subject>protein stability</subject><subject>Proteins</subject><subject>recombinant proteins</subject><subject>Spas</subject><issn>1538-7933</issn><issn>1538-7836</issn><issn>1538-7836</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><recordid>eNp1kc9u1DAQhy1ERUvhwAsgS1zgsK3_JI7DrVpRulWlXgrXaGJPFm-TeLGdor3xCL3zdjwJ3t22B6Rasjwaff40mh8h7zg74fmcrtKPE15wUb4gR7yUelZpqV4-1rWUh-R1jCvGeF0K9oocilqpUhTiiPyZ-2ENAZK7Qwoj9JvoIvUdHSDcYkJLOzDJB_p9sVjQdfB2Mil-pgGNH1o3wpieuhQC0tEnCr27RXrn4t_f95Bvrmj0_dT2uIUTupHCchlwCQnzt9HSOLWZcjsCQnKmx_iGHHTQR3z78B6Tb-dfbuYXs6vrr4v52dXMSK3LmbWaa8lbVWgpWcEEYIFaF4p3qjagJSgLgoMUIDqrLBpheF2URYWIdSnlMfm49-bZfk4YUzO4aLDvYUQ_xUYwUbGKyUpl9MN_6MpPIa9tSxVVrZXcCT_tKRN8jAG7Zh1cXuim4azZJtbkxJpdYpl9_2Cc2gHtE_kYUQZO98Av1-PmeVNzeXOxV_4DFRykKQ</recordid><startdate>201806</startdate><enddate>201806</enddate><creator>Anzengruber, J.</creator><creator>Lubich, C.</creator><creator>Prenninger, T.</creator><creator>Gringeri, A.</creator><creator>Scheiflinger, F.</creator><creator>Reipert, B. M.</creator><creator>Malisauskas, M.</creator><general>Elsevier Limited</general><scope>24P</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope></search><sort><creationdate>201806</creationdate><title>Comparative analysis of marketed factor VIII products: recombinant products are not alike vis‐a‐vis soluble protein aggregates and subvisible particles</title><author>Anzengruber, J. ; Lubich, C. ; Prenninger, T. ; Gringeri, A. ; Scheiflinger, F. ; Reipert, B. M. ; Malisauskas, M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3885-dd81831b648330402ae4e88461f69ca83a6da21a32a2fd6dec2c194547eee9533</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Chromatography</topic><topic>Coagulation factors</topic><topic>Comparative analysis</topic><topic>factor VIII</topic><topic>Factor VIII deficiency</topic><topic>Flow cytometry</topic><topic>Hemophilia</topic><topic>hemophilia A</topic><topic>High-performance liquid chromatography</topic><topic>Immunogenicity</topic><topic>Insulin</topic><topic>Interferon</topic><topic>Patients</topic><topic>protein aggregates</topic><topic>protein stability</topic><topic>Proteins</topic><topic>recombinant proteins</topic><topic>Spas</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Anzengruber, J.</creatorcontrib><creatorcontrib>Lubich, C.</creatorcontrib><creatorcontrib>Prenninger, T.</creatorcontrib><creatorcontrib>Gringeri, A.</creatorcontrib><creatorcontrib>Scheiflinger, F.</creatorcontrib><creatorcontrib>Reipert, B. M.</creatorcontrib><creatorcontrib>Malisauskas, M.</creatorcontrib><collection>Wiley-Blackwell Open Access Titles</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of thrombosis and haemostasis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Anzengruber, J.</au><au>Lubich, C.</au><au>Prenninger, T.</au><au>Gringeri, A.</au><au>Scheiflinger, F.</au><au>Reipert, B. M.</au><au>Malisauskas, M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Comparative analysis of marketed factor VIII products: recombinant products are not alike vis‐a‐vis soluble protein aggregates and subvisible particles</atitle><jtitle>Journal of thrombosis and haemostasis</jtitle><addtitle>J Thromb Haemost</addtitle><date>2018-06</date><risdate>2018</risdate><volume>16</volume><issue>6</issue><spage>1176</spage><epage>1181</epage><pages>1176-1181</pages><issn>1538-7933</issn><issn>1538-7836</issn><eissn>1538-7836</eissn><abstract>Essentials
Aggregation is a critical quality attribute of protein therapeutics influencing immunogenicity.
Aggregates and subvisible particles in 9 recombinant factor VIII (rFVIII) products were analyzed.
Major differences in aggregate and particle concentrations were detected after reconstitution.
rFVIII product quality determined aggregation propensity under use‐relevant stress.
Summary
Background
Recombinant protein technologies have facilitated the development of novel factor VIII (FVIII) therapeutics with improved production efficiency, potency and half‐live, and a low risk of viral transmission. The increasing number of recombinant FVIII (rFVIII) products and information on their efficacy, safety and cost allow patients and healthcare professionals to adjust treatment to individual needs. Nonetheless, 20–32% of previously untreated patients with severe hemophilia A develop inhibitory antibodies to rFVIII following treatment. The root cause of the immunogenicity of rFVIII products is not well understood. Data for human interferon and human insulin products suggest that critical quality parameters such as soluble protein aggregates (SPAs) and subvisible particles (SVPs) influence the immunogenicity of protein therapeutics. Therefore, we analyzed SPA and SVP concentrations in commercially available rFVIII products and determined how these parameters change upon exposure of rFVIII products to relevant stress conditions.
Objectives
Compare critical quality parameters such as SPA and SVP concentrations in rFVIII products under intended use and use‐relevant stress conditions.
Methods
Nine rFVIII products (≥ 3 lots each) were analyzed by high‐performance liquid chromatography‐size exclusion chromatography (HPLC‐SEC) and flow cytometry‐based particle analysis.
Results/conclusions
SPAs and SVPs were present at different concentrations in all freshly reconstituted rFVIII products: SPA concentrations ranged from 0.2% to 11.6%; SVPs were 0.7 × 106 to 114.0 × 106 / 1000 IU. Under use‐relevant stress conditions (agitation and shear stress) the products formed additional SPAs and SVPs to different degrees. The collected data indicate that product quality determines its propensity to form SVPs and SPAs, and highlights differences between marketed rFVIII products.</abstract><cop>England</cop><pub>Elsevier Limited</pub><pmid>29665242</pmid><doi>10.1111/jth.14125</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of thrombosis and haemostasis, 2018-06, Vol.16 (6), p.1176-1181 |
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| source | Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Chromatography Coagulation factors Comparative analysis factor VIII Factor VIII deficiency Flow cytometry Hemophilia hemophilia A High-performance liquid chromatography Immunogenicity Insulin Interferon Patients protein aggregates protein stability Proteins recombinant proteins Spas |
| title | Comparative analysis of marketed factor VIII products: recombinant products are not alike vis‐a‐vis soluble protein aggregates and subvisible particles |
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