On “Composition, Quality Control, and Labeling of Plasma-Derived Products for the Treatment of von Willebrand Disease” (Semin Thromb Hemost 2006;32: 529-536)

It is with great interest that we read the recent publication by Mazurier[1] regarding the composition, quality control, and labeling of plasma-derived products for the treatment of von Willebrand disease (vWD). We agree that an optimal selection of the product to use in this complicated clinical setting must, among other requirements, be based on the level of safety in eliminating potential blood-born pathogens, and that such information should be made available for all products with the potential to be used in a vWD indication. Mazurier has compared characteristics of the only two products developed for this very special indication, namely Wilfactine^® (Laboratoire français du Fractionnement et des Biotechnologies [LFB]; Les Ulis, France) and Wilate^® (Octapharma Pharmazeutika Produktionsges. Vienna, Austria; also indicated for hemophilia A), with several other concentrates currently used to treat vWD patients.

Table [1] in Mazurier's publication displays all the relevant details for the 12 different von Willebrand factor (vWF)/factor VIII (FVIII) concentrates discussed in the article. The concentrates vary significantly in terms of both the number and nature of specific viral safety steps incorporated into the manufacturing processes. It is evident that some of these concentrates do not comply with the recommendations of the Committee for Proprietary Medicinal Products (CPMP,[2] a working committee of the European Agency for the Evaluation of Medicinal Products) implying that two distinct and effective steps for the enveloped viruses and at least one for the nonenveloped viruses should be incorporated into the manufacturing process, and that the viral safety margin is likely to be higher for those products with two or more relevant steps included in the production process than those relying solely on a single viral inactivation step.[3] Unfortunately, Mazurier's table does not contain the correct details for Wilate in terms of the viral inactivation/elimination steps used for the routine manufacturing of this product. Because it is of utmost importance that both the treating physicians and vWD patients in need of vWF/FVIII concentrate treatment are properly informed about the viral safety of all these products, we see the need to comment on this missing information.

Table 1 Pathogen Inactivation/Elimination by the Wilate® Manufacturing Process Pathogen* HIV HBV HCV WNV HAV B19 vCJD Model Used* HIV-1 PRV SBV SBV HAV PPV HAS 263 K Step Logarithmic Reduction Factor [log10] Sequential precipitations 1.8 Ion exchange chromatography 1.9 3.3 Sequential chromatography purifications 2.4 S/D treatment ≥ 7.5 ≥ 8.5 ≥ 8.6 ≥ 8.6 PermaHeat treatment ≥ 5.8 4.9 ≥ 5.5 ≥ 5.5 ≥ 5.7 4.1 Total ≥ 13.3 ≥ 13.4 ≥ 14.1 ≥ 14.1 ≥ 7.6 7.4 4.2 HIV, human immunodeficiency virus; HBV, hepatitis B virus; HCV, hepatitis C virus; WNV, West-Nile virus; HAV, hepatitis A virus; B19, human parvovirus B19; vCJD, variant Creutzfeldt-Jakob disease; PRV, pseudorabies virus; SBV, sindbis virus; PPV, porcine parvovirus; HAS, hamster-adapted scrapie.

Wilate is manufactured utilizing two distinct viral inactivation steps with different modes of action.[2] The optimized solvent/detergent (S/D) treatment and prolonged terminal dry-heat (named PermaHeat) treatment of the lyophilized product at a specified residual moisture (RM) provide, as recommended, two very effective and robust viral inactivation procedures for enveloped viruses, and one step for nonenveloped viruses. These steps are aggressive enough to inactivate viruses efficiently, yet gentle enough to maintain the structural integrity and function of the vWF and FVIII molecules. The S/D step is performed under continuous agitation at + 25.5 ± 2.5°C for 4-4.5 hours in the presence of 0.3% (w/w) tri(n-butyl)phosphate (TnBP) and 1% (w/w) Octoxynol-9 (also referred to as Triton X-100). The subsequent ion exchange chromatography not only removes the S/D reagents and impurities, but also viruses such as HAV and B19. The closed final containers of Wilate are heated at + 100 ± 0.5°C for 120 ± 1.5 minutes at a RM of 0.7-1.6%, which are controlled by near infrared spectrophotometry (NIR) in every vial both before and after PermaHeat treatment. The results of our virus validation studies, as well as prion investigations, are shown in Table [1]. Combined with a full nucleic amplification test (NAT) screening for HIV, HBV, HCV, HAV (all negative), and B19 viruses (cut-off value: ≤ 4 log₁₀ IU/mL), the Wilate manufacturing process leads to a vWF/FVIII concentrate with a very convincing pathogen safety profile, which is reassuring to all the individuals using this product on a daily basis for prophylaxis and treatment of both vWD and hemophilia A hemorrhages.

REFERENCES

• 1 Mazurier C. Composition, quality control, and labeling of plasma-derived products for the treatment of von Willebrand disease.  Semin Thromb Hemost. 2006;  32 529-536
• 2 Committee for Proprietary Medicinal Products (CPMP) .Note for guidance on plasma-derived medicinal products. CPMP/BWP/269/95 rev.3 January 25, 2001
• 3 Stadler M, Gruber G, Kannicht C et al.. Characterisation of a novel high-purity, double virus inactivated von Willebrand factor and factor VIII concentrate (Wilate^® .  Biologicals. 2006;  34 281-288