INACTIVATION OF HEPATITIS-A VIRUS BY PASTEURIZATION AND ELIMINATION OF PICORNAVIRUSES DURING MANUFACTURE OF FACTOR-VIII CONCENTRATE

Hepatitis A virus (HAV) infections have been reported among hemophiliacs who received factor VIII concentrates which had been purified by ion-exchange chromatography and treated by the solvent detergent (SD) method. Since the virus inactivation procedure of our manufacturing process is heat treatment of the stabilized, aqueous protein solution at 60 degrees C for 10 h (pasteurization), we investigated whether this method inactivated picornaviruses such as HAV and poliovirus type I, which we routinely use as a test virus for non-enveloped viruses. HAV was substantially inactivated by pasteurization but the stabilizers used in the manufacturing process of the commercial products considerably delayed HAV inactivation. Residual infectious HAV was found even after 10 h heat treatment of the stabilized preparation. Thus HAV is more stable in the presence of stabilizers than poliovirus type 1. Furthermore, we studied stage by stage the elimination of poliovirus type 1 by the manufacturing procedure of these pasteurized factor VIII concentrates. Three other stages of the manufacturing process apart from pasteurization eliminated poliovirus by approximately three orders of magnitude each. Taking into account this efficient elimination of the picornavirus poliovirus and the substantial inactivation of HAV by pasteurization, we conclude that a high margin of safety exists for pasteurized factor VIII concentrates regarding HAV. This conclusion is supported by the fact that no HAV infection has been reported in hemophilia patients treated with pasteurized factor VIII concentrates. Furthermore, in a retrospective study, none of 95 patients subjected to a long-term treatment with pasteurized factor VIII concentrates had developed anti-HAV seroconversion as a result of this treatment.