Laboratory and preclinical evaluation of the virus safety of coagulation factor concentrates

Studies of virus sterilization of coagulation factor concentrates using marker viruses, AIDS, hepatitis B (HBV) and non-A, non-B hepatitis (NANBHV) viruses indicate the following: Strategies adopted to stabilize coagulation factors to heat denaturation, including addition of high concentrations of solutes or lyophilization, stabilize virus. At 60 degrees C, heating in the liquid state provides more rapid virus kill than heating in the lyophilized state with 2% residual moisture. To achieve the same virucidal potency as achieved on heating albumin at 60 degrees C for 10 hours, stabilized coagulation factor concentrates would require a substantial increase in the dose of heat. The rate of inactivation by either thermal or solvent/detergent methods slows with time. Improved virus kill is attained more easily by increasing the temperature than by extending the duration of exposure. Viruses vary widely in their sensitivity to thermal denaturation or solvent/detergent action. Because studies on the rate of inactivation of HBV and NANBHV are not feasible, assessment of their sensitivity is at best approximate. Sensitivity to thermal inactivation appears to follow the order HTLV-III greater than VSV, EMC greater than NANBHV?, Sindbis much greater than HBV. Sensitivity to organic solvent/detergent mixtures appears to follow the order HTLV-III greater than Sindbis, Sendai, HBV?, NANBHV? greater than VSV much much greater than EMC. Protein enveloped forms of NANBHV must occur rarely or not at all. Use of marker viruses to compare virucidal potency of methods that inactivate by different mechanisms may lead to erroneous conclusions; however, marker virus data probably provide useful comparisons of related sterilization methods or of a single method applied to different protein mixtures. If virus sterilization processes are to be validated in a manner which enables a meaningful comparison between laboratory and clinical results, higher titers of virus will be required.