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 hemophilia cs who received factor VIII concentrates which had been purified by io n-exchange chromatography and treated by the solvent detergent (SD) me thod. Since the virus inactivation procedure of our manufacturing proc ess is heat treatment of the stabilized, aqueous protein solution at 6 0 degrees C for 10 h (pasteurization), we investigated whether this me thod inactivated picornaviruses such as HAV and poliovirus type I, whi ch 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 d elayed HAV inactivation. Residual infectious HAV was found even after 10 h heat treatment of the stabilized preparation. Thus HAV is more st able in the presence of stabilizers than poliovirus type 1. Furthermor e, we studied stage by stage the elimination of poliovirus type 1 by t he manufacturing procedure of these pasteurized factor VIII concentrat es. Three other stages of the manufacturing process apart from pasteur ization eliminated poliovirus by approximately three orders of magnitu de each. Taking into account this efficient elimination of the picorna virus poliovirus and the substantial inactivation of HAV by pasteuriza tion, we conclude that a high margin of safety exists for pasteurized factor VIII concentrates regarding HAV. This conclusion is supported b y the fact that no HAV infection has been reported in hemophilia patie nts treated with pasteurized factor VIII concentrates. Furthermore, in a retrospective study, none of 95 patients subjected to a long-term t reatment with pasteurized factor VIII concentrates had developed anti- HAV seroconversion as a result of this treatment.