A solvent/detergent-treated and 15-nm filtered factor VIII: a new safety standard for plasma-derived coagulation factor concentrates

• Published in: Vox sanguinis 2007-05, Vol.92 (4), p.327-337
• Main Authors: Chtourou, S., Porte, P., Nogré, M., Bihoreau, N., Cheesman, E., Samor, B., Sauger, A., Raut, S., Mazurier, C.
• Format: Article
• Language: English
• Subjects: Blood Component Removal - methods; Blood Component Removal - standards; Calcium - metabolism; coagulation factor VIII; Detergents; Factor VIII - chemistry; Factor VIII - isolation & purification; Factor VIII - metabolism; Factor Xa - metabolism; Filtration - methods; Filtration - standards; FVIII-vWF complex; Humans; In Vitro Techniques; Micropore Filters; nanofiltration; Nanotechnology; Phospholipids - metabolism; Plasma - virology; Prions - blood; Prions - isolation & purification; Protein Binding; Protein Structure, Quaternary; Safety; Solvents; Thrombin; transmissible spongiform encephalopathy; viral safety; Viruses - isolation & purification; von Willebrand Factor - chemistry; von Willebrand Factor - isolation & purification; von Willebrand Factor - metabolism; vWF multimers
• ISSN: 0042-9007; 1423-0410
• DOI: 10.1111/j.1423-0410.2007.00892.x

Background  Since the early 1990s the Committee for Proprietary Medicinal Products has set the mandatory requirement that all manufacturing processes for blood products include two virus removal/inactivation steps that are complementary in their action. Objectives  The objective was to develop a manufacturing process for factor VIII (FVIII) including two complementary steps of viral inactivation/elimination. Methods  A 35–15 nm nanofiltration step was added to a former FVIII manufacturing process that included solvent/detergent (S/D) treatment to generate a new FVIII concentrate called Factane®. The impact of nanofiltration on the structural and functional characteristics of FVIII, as well as virus/transmissible spongiform encephalopathy reduction factors were assessed. Results  Using an innovative approach, FVIII was successfully nanofiltered at 35–15 nm, while the biological properties of the active substance were unmodified. FVIII coagulant and antigen content for Factane® and previous S/D‐treated FVIII (FVIII‐LFB, commercialized as Facteur VIII‐LFB®) were comparable. The FVIII one‐stage chromogenic and coagulant/antigen ratios confirmed that nanofiltered FVIII was not activated. After nanofiltration, the copurified von Willebrand factor (vWF) was reduced but vWF/FVIII binding properties were unaffected. Phospholipid binding and thrombin proteolysis studies displayed no differences between Factane® and FVIII‐LFB. The rate of factor Xa generation was slightly lower for Factane® when compared to FVIII‐LFB. Viral validation studies with different viruses showed no detectable virus in the filtrate. Conclusions  Nanofiltration of FVIII at 15 nm is feasible despite the large molecular weight of FVIII and vWF. Nanofiltration has been proven to be highly effective at removing infectious agents while preserving the structural and functional integrity of FVIII.