"The U.S. Food and Drug Administration today notified Ranbaxy Laboratories, Ltd., that it is prohibited from manufacturing and distributing active pharmaceutical ingredients (APIs) from its facility in Toansa, India, for FDA-regulated drug product"...
Hemophilia A is a hereditary bleeding disorder characterized by deficient coagulant activity of the specific plasma protein clotting factor, factor VIII. In afflicted individuals, hemorrhages may occur spontaneously or after only minor trauma. Surgery on such individuals is not feasible without first correcting the clotting abnormality. The administration of Koate (antihemophilic factor) -DVI provides an increase in plasma levels of factor VIII and can temporarily correct the coagulation defect in these patients.
After infusion of Antihemophilic Factor (Human), there is usually an instantaneous rise in the coagulant level followed by an initial rapid decrease in activity, and then a subsequent much slower rate of decrease in activity.2-4 The early rapid phase may represent the time of equilibration with the extravascular compartment, and the second or slow phase of the survival curve presumably is the result of degradation and reflects the true biologic half-life of the infused Antihemophilic Factor (Human).3 The removal and inactivation of spiked relevant and model enveloped and non-enveloped viruses during the manufacturing process for Koate (antihemophilic factor) -DVI have been validated in laboratory studies at Talecris Biotherapeutics, Inc. Studies performed with the model enveloped viruses indicated that the greatest reduction was achieved by TNBP/polysorbate 80 treatment and 80°C heat. For this reason, VSV (Vesicular Stomatitis Virus, model for RNA enveloped viruses) and HIV-1 (Human Immunodeficiency Virus Type 1) were studied only at these two steps of the manufacturing process. The efficacy of the dry heat treatment was studied using all of the viruses, including BVDV (Bovine Viral Diarrheal Virus, model for hepatitis C virus) and Reo (Reovirus Type 3, model for viruses resistant to physical and chemical agents, such as hepatitis A), and the effect of moisture content on the inactivation of HAV (Hepatitis A Virus), PPV (Porcine Parvovirus, model for parvovirus B19), and PRV (Pseudorabies Virus, model for large enveloped DNA viruses) was investigated.
Table 1. Summary of In Vitro Log10 Viral Reduction
|Enveloped Model Viruses||Non-enveloped Model Viruses|
|Model for||HIV-1/2||HCV||Large enveloped DNA viruses||RNA enveloped viruses||HAV and viruses resistant to chemical and physical agents||HAV||B19|
|Global Reduction Factor||≥ 9.4||≥ 10.3||≥ 9.3||≥ 10.9||9.4||≥ 4.5||3.7|
Similar studies have shown that a terminal 80°C heat incubation for 72 hours inactivates non-lipid enveloped viruses such as hepatitis A and canine parvovirus in vitro, as well as lipid enveloped viruses such as hepatitis C.5, 6, 7
Koate (antihemophilic factor) -DVI is purified by a gel permeation chromatography step serving the dual purpose of reducing the amount of TNBP and polysorbate 80 as well as increasing the purity of the factor VIII.
A two-stage clinical study using Koate (antihemophilic factor) -DVI was performed in individuals with hemophilia A who had been previously treated with other plasma-derived AHF concentrates. In Stage 1 of the pharmacokinetic study with 19 individuals, statistical comparisons demonstrated that Koate (antihemophilic factor) -DVI is bioequivalent to the unheated product, Koate (antihemophilic factor) w-HP. The incremental in vivo recovery ten minutes after infusion of Koate (antihemophilic factor) -DVI was 1.90% IU/kg (Koate (antihemophilic factor) -HP 1.82% IU/kg). Mean biologic half-life of Koate (antihemophilic factor) -DVI was 16.12 hours (Koate (antihemophilic factor) -HP 16.13 hours). In Stage II of the study, participants received Koate (antihemophilic factor) -DVI treatments for six months on home therapy with a median of 54 days (range 24–93). No evidence of inhibitor formation was observed, either in the clinical study or in the preclinical investigations.2
2. Data on file.
3. Aronson DL: Factor VIII (antihemophilic globulin). Semin Thromb Hemostas 6(1):12–27, 1979.
4. Britton M, Harrison J, Abildgaard CF: Early treatment of hemophilic hemarthroses with minimal dose of new factor VIII concentrate. J Pediatr 85(2):245–7, 1974.
5. Winkelman L., Feldman PA, Evan DR: Severe heat treatment of lyophilised coagulation factors in Virus Inactivation in Plasma Products. Curr Stud Hematol Blood Transfus. Morgenthaler J-J (ed.), Basel, Karger, 1989, No. 56, pp. 55-69.
6. Skidmore SJ, Pasi KJ, Mawson SJ, et al: Serological evidence that dry heating of clotting factor concentrates prevents transmission of non-A, non-B hepatitis. J. Med Virol. 30(1):50-2, 1990.
7. Hart HF, Hart WG, Crossley J, et al: Effect of terminal (dry) heat treatment on non-enveloped viruses in coagulation factor concentrates. Vox Sang 67(4): 345-50, 1994.
Last reviewed on RxList: 2/20/2009
This monograph has been modified to include the generic and brand name in many instances.
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