Objective:
To assure plasma-derived clotting factor concentrates are pathogen safe, virus inactivation and removal methods are applied to the manufacturing process. The effectiveness of currently used methods and procedures was demonstrated.
Methods:
The virus reduction capacity of the manufacturing process for a specific product was quantitated for selected steps of the manufacturing process. A prerequisite of such virus validation studies is a valid downscaling of the manufacturing process to a laboratory scale. After spiking product intermediates with a panel of viruses the same as or similar to known and emerging pathogens, the manufacturing steps were performed according to the defined procedures and the reduction factors for the different viruses measured. Prion reduction was also studied, employing both a microsomal preparation (membrane-associated prions) and purified prion protein. Methods in the manufacturing process solely for the purpose of pathogen reduction, such as pasteurization, solvent-detergent treatment, dry heat treatment of the final container, and virus (nano) filtration, as well as manufacturing steps for purification and concentration of the desired protein(s) such as partitioning by precipitation or chromatography, were studied. The residual risk of transmitting pathogens was assessed based on the results of these studies and the potential virus load in the plasma pool used to produce these products.
Summary:
For a pasteurized FVIII/vWF concentrate, the overall log reduction factors were ≥10.2 for HIV, ≥11.7 for BVDV, 10.2 for PRV, 7.8 for HAV, and 6.0 for CPV, as well as 6.4 and 7.9 for the 2 prion preparations, respectively. For a FVIII/vWF concentrate using solvent- detergent and dry heat, values were ≥12.5 for HIV, ≥13.1 for BVDV, ≥11.4 for PRV, ≥12.2 for HAV, and 6.7 for parvoviruses, as well as 4.0 and 4.9 for the 2 prion preparations. For a FIX concentrate using affinity chromatography and virus filtration, values were ≥10.2 for HIV, ≥12.6 for BVDV, ≥12.8 for WNV, ≥16.1 for PRV, ≥6.7 for HAV, and ≥14.8 for parvoviruses. For a FXIII concentrate using adsorption, chromatography, heat treatment, and virus filtration, values were ≥10.2 for HIV, ≥12.6 for BVDV, ≥12.8 for WNV, ≥16.1 for PRV, ≥6.7 for HAV, and ≥14.8 for parvoviruses, as well as 9.6 and 9.7 for the 2 prion preparations.
Conclusions:
Pathogen safety is based on the overall pathogen reduction factor considerably exceeding the amount of pathogen potentially entering the manufacturing pool. Validation studies verify that safety is attained for currently manufactured plasma-derived clotting factor concentrates.