Characterisation of the Novel, High Purity, Double Virus Inactivated Von Willebrand Factor and Factor VIII Concentrate Wilate®.

Abstract

Purpose: This study summarizes the characteristics and virus safety profile of Wilate®, a new human plasma-derived, high purity, double virus inactivated VWF/FVIII concentrate. The manufacturing process comprises two chromatographic steps, ensuring high purity and preserving the integrity and functionality of the VWF/FVIII complex. The optimised solvent/detergent treatment (S/D) and terminal dry-heat treatment (PermaHeat) of the lyophilised product provide two effective and robust virus inactivation steps for enveloped (EV) and one step for non-enveloped viruses (NEV). Methods: Functional and structural properties of the VWF/FVIII concentrate were studied utilising state-of-the-art assays. The reduction factors for a panel of model viruses were determined in down-scale experiments valid for the respective manufacturing steps. Summary of results: The integrity of the VWF/FVIII concentrate was confirmed by all tests. The ratio between VWF:RCo and FVIII:C was close to that in plasma of blood donors. The VWF multimeric profile demonstrated >10 bands in all batches and the triplet structure was very well preserved. A high specific activity, on average 122 IU FVIII:C/mg total protein, was measured in 15 batches recently produced. SE–HPLC revealed a one-peak-product, representing the VWF/FVIII-complex. All viruses tested were rapidly inactivated by at least 4 log10. The PermaHeat treatment of the lyophilised product at +100°C for 2 hours, at a specified residual moisture of 0.7–1.6%, was efficient for the inactivation of both EV and NEV. Conclusion: Wilate® is a high purity, double virus inactivated concentrate containing functional VWF and FVIII in a ratio close to plasma of healthy subjects. The product has an excellent viral safety profile. The safe and effective treatment of patients with von Willebrand disease and haemophilia A was demonstrated in multiple clinical trials.

Effect of manufacturing process parameters on virus inactivation by dry heat treatment at 80 °C in factor VIII

“…These findings confirm the robustness of this virus inactivation step and allow manufacturing control limits to be set for the full‐scale manufacturing process. Severe dry heat treatments has been successfully incorporated into a number of coagulation factor concentrates [18] using 72 h at 80 °C [19–21] or 0·5–2 h at 100 °C [22–24]. These sets of conditions are essentially comparable in their capacity to inactivate viruses [25].…”

Treatment of von Willebrand Disease

“…A wide range of VWF concentrates are currently available worldwide (summarized in ►Table 5). [36][37][38][39][40][41][42][43][44][45] There are several expert and national guidelines or recommendations for VWD treatment (►Table 6). 2,12,[46][47][48][49] There are additional differential global features worth noting.…”

Monitoring Therapy during Treatment of von Willebrand Disease

“…A wide range of VWF concentrates are currently available worldwide (summarized in ►Table 4). 12,18,[33][34][35][36][37][38][39][40][41][42][43][44][45][46] There are also several expert and national guidelines or recommendations for VWD treatment. 2,12,43-46 There are additional important points show a two-to fivefold increase from baseline and their VWF (usually measured using VWF:RCo) and FVIII:C levels are above 50 U/dL at 1 hour.…”