Virus inactivation during the freeze-drying processes as used for the manufacture of plasma-derived medicinal products

Abstract

Background: Freeze-drying is a technology widely used during the production of plasma-derived medicinal products. Several studies have shown that freeze-drying can also result in virus inactivation and particularly of hepatitis A virus (HAV). To date, however, the variables critical for virus inactivation during freeze-drying have not been investigated systematically.

Study design and methods: Five different lyophilization processes covering the range used for different plasma-derived medicinal products (Factor [F]VII, FVIII, F IX, FVIII inhibitor bypassing activity, and fibrin sealer protein [FSP]) were investigated for their potential to inactivate HAV as well as bovine viral diarrhea virus (BVDV) and pseudorabies virus (PRV).

Results: Our investigation demonstrates that freeze-drying results in significant inactivation of HAV, with reduction factors between 2.5 and 5.9 log [TCID(50)]. Also, BVDV and PRV were inactivated, although to a lesser extent. While the specific details of the freeze-drying processes investigated only had a minor influence on virus inactivation, the different compositions of product intermediates had a rather pronounced impact.

Conclusion: Lyophilization contributes to the safety of plasma derivatives, in particular with the inactivation of HAV. The extent of HAV inactivation is strongly influenced by the respective product matrix rather than the design of the lyophilization cycle, which will require a case-to-case assessment for each product intermediate.