Measures Taken for Effective Virus Reduction of Plasma-Derived Coagulation Factor Concentrates.

The application of the complementary approaches (i) selection and testing of starting material, (ii) testing the product intermediate at appropriate steps of the production and (iii) assessing the capacity of the production process to reduce a wide range of viruses as well as prions, the causative agent for vCJD, results in plasma-derived coagulation factor concentrates with a remote risk of pathogen transmission. Selecting donors only from low-risk geographic areas considerably reduces the risk of a donation entering the plasma pool for fractionation which harbors either viruses (currently) unknown in the donor population or prions. Use of a sensitive assay to detect virus genome sequences results in the interdiction of contaminants in donations during window periods. Single window period donations with a total virus load of up to 9.9 log₁₀ HAV RNA IU, 6.0 log₁₀ HBV DNA IU, 11.9 log₁₀ HCV RNA IU, 10.9 log₁₀ HIV RNA IU and 16.9 log₁₀ B19V DNA IU are identified and destroyed, and will not enter the plasma pool for fractionation. Plasma pools for fractionation likewise are released for further processing only if non-reactive for serological virus markers and for sequences of virus genome. Thus, potential errors made by not discarding, but pooling window period donations can be precluded, as even one window period donation with a high virus titre would be detected in the plasma pool for fractionation, and the entire plasma pool would be destroyed. A wide range of enveloped and non-enveloped viruses are effectively inactivated by pasteurization (heat treatment at 60°C for 10 hours in stabilized aqueous solution). Additionally, the manufacturing process of plasma-derived coagulation factor concentrates, as the VWF/FVIII product Haemate^® P / Humate-P^®, contains process steps reliably contributing to the reduction of viruses. As demonstrated in virus validation studies, pasteurization inactivates not only the known blood-borne viruses but also potential “emerging viruses”.

Furthermore, scaled-down spiking studies demonstrate that the manufacturing process reliably removes deliberately added prions, derived from scrapie-infected hamster brains, by 6.4 log₁₀ for a microsomal preparation and by 7.9 log₁₀ for a purified, non membrane-associated PrP^Sc preparation. By these measures in the aggregate - selection of donors, testing of individual donations, retesting of plasma pools, implementation of effective pathogen reduction steps in manufacturing - a high margin of safety with regard to viruses and prions can be achieved for plasma-derived coagulation factor concentrates as Haemate^® P / Humate-P^®. As pasteurization very effectively inactivates a wide range of enveloped and non-enveloped viruses and further manufacturing steps contribute to virus reduction, indirect evidence is provided that the manufacturing procedure will inactivate/remove also other novel or unpredictable virus contamination.