ABSTRACT
BACKGROUND: Viral safety is of paramount importance for human plasma-derived therapeutic proteins. Recent reports of blood-associated transmission and continuous regional outbreaks of dengue fever have prompted a validation of clearance of dengue virus in the manufacture processes of the plasma-derived products. STUDY DESIGN AND METHODS: A high titer of cultured dengue virus serotype 2 was spiked into process samples before individual steps of albumin and immunoglobulin manufacture processes, including cold ethanol precipitation, cation-exchange chromatography, pasteurization, solvent/detergent treatment, and virus filtration. Clearance of dengue virus was quantified with TCID(50) assays in the culture of Vero E6 cells and, when appropriate, real-time polymerase chain reaction (RT-PCR) assays. RESULTS: The individual process steps were all effective in the inactivation and/or removal of dengue virus, and the data obtained clearly demonstrate that the risk of dengue virus transmission was reduced cumulatively by at least 10.12 and at least 14.24 log in the albumin and immunoglobulin manufacture processes, respectively. CONCLUSION: The dedicated viral inactivation and/or removal approaches currently implemented in the manufacture of plasma-derived products provide a good safety margin with regard to the transmission of dengue virus.
