Efficacy of viral clearance methods used in the manufacture of activated prothrombin complex concentrates: focus on AUTOPLEX® T

Abstract

Various methods are described for the elimination of infectious viruses from activated prothrombin complex concentrates (aPCCs) and for the analysis of the final products (AUTOPLEX T and FEIBA VH). Viruses of concern in human plasma-derived products are enveloped (hepatitis B and C, cytomegalovirus, Epstein-Barr virus, and human immunodeficiency virus [HIV]) and nonenveloped (hepatitis A and parvovirus B19). Donated blood used for AUTOPLEX T is screened for antihepatitis C, HBsAg, anti-HIV types 1 and 2, and p24 antigen. Plasma pools utilized for raw materials are also tested by PCR for HIV and hepatitis C virus. Partial virus inactivation and partitioning are achieved by purification of the aPCC. Further reduction of virus infectivity is accomplished by lyophilization and dry-heat treatment. Each step undergoes virus elimination validation studies in which a relevant sample is 'spiked' with the appropriate virus or model virus. The total reduction in virus from raw material to final product can then be calculated. For AUTOPLEX T the cumulative log10 reduction factors for several viruses vary from 4.2 to 14.3. This ensures an exceptionally high margin of safety. Definitive evidence for product safety was obtained by clinical observation of treated patients. The viral inactivation process of AUTOPLEX T involves a four-tier viral safety program, including Cohn alcohol fractionation and dry-heat treatment, in place of the two-stage vapour-heating process for FEIBA.

- Plasma Immunoglobulins

“…280 The reaction of factor IXa is greatly enhanced in the presence of heparin and results in the formation of a complex with a molecular mass of approximately 90 kDa. 289,290 In addition, the problems with the thrombogenicity of PCCs 291,292 led to the development of highly purified plasma-derived factor IX products. 279,281 The reaction of factor IXa with antithrombin is slower than that observed for factor Xa or thrombin.…”

Evidence for the Use of Activated Prothrombin Complex Concentrates (aPCCs) in the Treatment of Patients with Haemophilia and Inhibitors

“…Both FEIBA TM and Autoplex ® T undergo viral inactivation procedures during manufacture [13]. The starting material for Autoplex ® T undergoes an augmented Cohn alcohol fractionation and then the final product is dry heat treated for 6 days at 57°C.…”