"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"...
Antihemophilic Factor (Human) is a constituent of normal plasma and is required for clotting. The administration of Alphanate (antihemophilic factor) ® temporarily increases the plasma level of this clotting factor, thus minimizing the hazard of hemorrhage.2-3 Following the administration of Alphanate (antihemophilic factor) ® during clinical trials, the mean in vivo half-life of Factor VIII observed in 12 adult subjects with severe hemophilia A was 17.9 ± 9.6 hours. In this same study, the In vivo recovery was 96.7 ± 14.5% at 10 minutes postinfusion.4 Recovery at 10 minutes postinfusion was also determined as 2.4 ± 0.4 IU FVIII rise/dL plasma per IU FVIII infused/kg body weight.4
The solvent detergent treatment process has been shown by Horowitz, et al., to provide a high level of virus kill without compromising protein structure and function.5 The susceptibility of human pathogenic viruses such as the human immunodeficiency viruses, hepatitis viruses, as well as marker viruses such as sindbis virus and vesicular stomatitis virus (VSV), to inactivation by organic solvent detergent treatment has been discussed in the literature.6
In vitro inactivation studies to evaluate the solvent detergent treatment step used in the manufacture of Alphanate (antihemophilic factor) ® employed an assay with a sensitivity of 2 logs of virus for the marker viruses, vesicular stomatitis virus (VSV) and sindbis virus. The studies demonstrated a log kill of ≥ 4.1 for VSV and ≥ 4.7 for sindbis virus. Greater than or equal to 11.1 logs of HIV-1 and greater than or equal to 6.1 logs of HIV-2 were inactivated by the solvent detergent treatment step. The number of viral particles inactivated by the process represents the maximum amount of virus added initially to the sample, thus the results of the study indicate that all the added HIV virus was killed.4
In another study, the dry heat cycle of 80 °C for 72 hours of the Alphanate (antihemophilic factor) ® manufacturing process was shown to inactivate greater than or equal to 5.8 logs of hepatitis A virus (HAV).
In a different study, the following steps in the manufacturing process of Alphanate (antihemophilic factor) ® were evaluated for virus reduction/removal capability: precipitation with 3.5% polyethylene glycol (PEG), solvent detergent treatment with 0.3% tri-n-butyl phosphate and 1.0% polysorbate 80, heparin-actigel-ALD chromatography, lyophilization of Factor VIM and heat treatment at 80 °C for 72 hours. The following viruses were used in these studies: bovine herpes (BHV), bovine viral diarrhea virus (BVD), human poliovirus Sabin type 2 (POL), canine parvovirus (CPV) and human immunodeficiency virus, type 1 (HIV-1).
Table 1 summarizes the reduction factors for each virus evaluated for each viral inactivation/removal step validated in the manufacturing process of Alphanate (antihemophilic factor) ®.4
However, no treatment method has yet been shown capable of totally eliminating all potential infective virus in preparations of coagulation factor concentrates.
|Virus Reduction (log10)||Processing Step|
|3.5% PEG Precipitation||Solvent Detergent treatment||Column chromatography||Lyophilization of Factor VIII||Dry heat Cycle (80 °C, 72h)||Total Log Removal|
|BHV||< 1.0||≥ 8.0||7.6||1.3||2.1||≥ 19.0|
|BVD||< 1.0||≥ 4.5||< 1.0||< 1.0||≥ 4.9||≥ 9.4|
|POL||3.3||_||< 1.0||3.4||≥ 2.5||≥ 9.2|
|CPV||1.2||-||< 1.0||< 1.0||4.1||5.3|
|VSV||-||≥ 4.1||-||-||-||≥ 4.1|
|Sindbis||-||≥ 4.7||-||-||-||≥ 4.7|
|HIV-1||< 1.0||≥ 11.1||≥ 2.0||-||-||≥ 13.1|
|HIV-2||-||≥ 6.1||-||-||-||≥ 6.1|
|HAV||-||2.1||> 5.8||≥ 7.9|
1. Fujimura, Y., Titani, K., Holland, L.Z., Roberts, J.R., Kostel, P., Ruggeri, Z.M., Zimmerman, T.S. A Heparin-Binding Domain of Human Von Willebrand Factor: Characterization and Localization to a Tryptic Fragment Extending from Amino Acid Residue Val-449 to Lys-728. I Biol Chem 1987, 262(4): 1 734-1 739.
2. Hershgold, E.J. Properties of Factor VIII (Antihaemophilic Factor). In: Spaet, T.H., ed. Progress in Hemostasis and Thrombosis, Grune and Stratton Publisher, 1974, 2:99-139.
3. Ashenhurst, J.B., Langehenning, P.L., Seeier, R.A. Early Treatment of Bleeding Episodes with 10 U/Kgof Factor VIII. Blood 1977, 50:181.
4. Data on file at Grifols Biologicals Inc.
5. Edwards, C.A., Piet, M.P.J., Chin, S., Horowitz, B. Tri(n-Butyl) Phosphate/Detergent Treatment of Licensed Therapeutic and Experimental Blood Derivatives. Vox Sang 1987, 52:53-59.
6. Horowitz, B. Investigations into the Application of Tri(n-Butyl) Phosphate/Detergent Mixture to Blood Derivatives. In: Morgenthaler, J-J. ed. Viral Inactivation in Plasma Products, Karger, 1989, 56:83-96.
Last reviewed on RxList: 11/14/2008
This monograph has been modified to include the generic and brand name in many instances.
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