Comparative analysis of marketed factor VIII products: recombinant products are not alike vis‐a‐vis soluble protein aggregates and subvisible particles

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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Bibliographic Details
Published in:Journal of thrombosis and haemostasis Vol. 16; no. 6; pp. 1176 - 1181
Main Authors: Anzengruber, J., Lubich, C., Prenninger, T., Gringeri, A., Scheiflinger, F., Reipert, B. M., Malisauskas, M.
Format: Journal Article
Language:English
Published: England Elsevier Limited 01-06-2018
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
recombinant proteins
hemophilia A
protein aggregates
factor VIII
protein stability
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Summary: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.
Bibliography:ObjectType-Article-2
SourceType-Scholarly Journals-1
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content type line 23
ISSN:1538-7933
1538-7836
1538-7836
DOI:10.1111/jth.14125