"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"...
PROPLEX T, Factor IX Complex, Heat Treated is a combination of vitamin K-dependent clotting factors found in normal plasma. The administration of PROPLEX T, Factor IX Complex, Heat Treated provides an increase in plasma levels of Factor VII and Factor IX and can temporarily correct the coagulation defect of patients with deficiencies in these factors. Plasma levels of Factors II and X will also be increased.
The half-life of Factor VII in non-treated Factor IX Complex, administered to Factor VII deficient patients, has been found to range from 3 to 6 hours.1,2
The half-life of Factor IX in non-treated Factor IX Complex, administered to Factor IX deficient patients, has been found to range from 24 to 32 hours.3,4
PROPLEX T, Factor IX Complex, Heat Treated is manufactured by the modified Cohn-Oncley cold ethanol fractionation process which includes a series of cold-ethanol precipitation, centrifugation and/or filtration of human plasma. PROPLEX T, Factor IX Complex, Heat Treated solution is then lyophilized and heat treated at 60 ± 1.0°C for 144-153 hours. This process accomplishes both purification of PROPLEX T, Factor IX Complex, Heat Treated and reduction of viruses.
The PROPLEX T, Factor IX Complex, Heat Treated manufacturing process provides a significant viral reduction in in vitro studies.10 These viral reduction studies, summarized in Table 1, demonstrate viral clearance during the PROPLEX T, Factor IX Complex, Heat Treated manufacturing process using bovine diarrhea virus (BVD) as a model for lipid enveloped RNAviruses such as hepatitis C virus (HVC); human immunodeficiency virus, type 1 (HIV-1), a relevant blood borne pathogen; and a herpes virus, pseudorabies virus (PRV) as a model for lipid enveloped DNAviruses. Studies were also performed with two non-lipid enveloped viruses: hepatitis A(HAV) virus, a relevant non-lipid enveloped RNAvirus; and porcine parvovirus (PPV), as a model for non-lipid enveloped DNAviruses. These studies indicate that specific steps in the manufacture of PROPLEX T, Factor IX Complex, Heat Treated are capable of eliminating/ inactivating a wide range of relevant and model viruses exhibiting diverse physicochemical properties.
Table 1 : In Vitro Virus Clearance During the Fractionation
Process of PROPLEX T (factor ix complex)
|Process Step Evaluated||Viral Reduction Factor (log10)|
|Cohn-Oncley Cold Ethanol Fractionation Process||4.6||1.2||8.2||1.9||1.4|
The effectiveness of the heating step in reducing viral infectivity was assessed by in vitro viral inactivation studies using, as markers, viruses not commonly found in plasma and the results are listed in Table 2 for PROPLEX T, Factor IX Complex, Heat Treated. The model viruses used were sindbis virus (SIN), a lipid enveloped RNA virus; vesicular stomatitis virus (VSV), an enveloped RNAvirus and pseudo rabies virus (PRV), a lipid enveloped DNAvirus. When known quantities of these viruses were added to the product, the heat treatment employed inactivated the following quantities of virus (Table 2):
Table 2 : In Vitro Virus Clearance During the Lyophilization
and Heat Treatment of PROPLEX T (factor ix complex)
|Process Step Evaluated||Viral Reduction Factor (log10)|
|Lyophilization and Heat Treatment Cycle||10.5||1.4||5.6|
In addition, it has been shown that cytomegalo virus does not survive the manufacturing process. As these data indicate, all viruses are not equally affected by the heat treatment. Work by Colombo, et al with first-exposure hemophiliacs who received heat treated Antihemophilic Factor (Human) showed that while some reduction of hepatitis infectivity may have been achieved by heat treatment, a substantial portion of the patients who had not previously received blood products developed signs and/or symptoms of hepatitis.5 (See WARNINGS).
It has been reported that HIV is heat labile and that it is inactivated by treatment with 19-20% alcohol.6,7,8 Lengthy exposure to 20% ethanol occurs in the Cohn cold ethanol fractionation procedure from which this product is derived. In a retrospective study conducted with patients receiving AUTOPLEX, Anti-Inhibitor Coagulant Complex which is also derived from the Cohn process, none of the patients who received AUTOPLEX, Anti-Inhibitor Coagulant Complex exclusively seroconverted for HIV antibodies, while 56% of those patients who received other treatment modalities seroconverted during the three year study.9 Heat treatment has also been shown to be an effective means of inactivating HIV.10. In a study comparing heat treated HEMOFIL T, Antihemophilic Factor (Human), to untreated Antihemophilic Factor (Human) products, none of the patients receiving the heat treated product developed antibodies to HIV, while 17% of the patients receiving untreated products did seroconvert by the end of the study.11
1. White GC, Lundblad RL, Kingdon HS: Prothrombin complex concentrates: Preparation, properties and clinical uses. Curr Top Hematol 2:203-244, 1979
2. Marder VJ, Shulman NR: Clinical aspects of congenital Factor VII deficiency. Am J Med 37:182-192, 1964
3. Mollison PL: The transfusion of platelets, leucocytes and plasma components (Ch 3) in Blood Transfusion in Clinical Medicine, Sixth Ed. Oxford, Blackwell Scientific Publications, 1979, pp 103-113
4. Zauber NP, Levin J: Factor IX levels in patients with hemophilia B (Christmas disease) following transfusion with concentrates of Factor IX or fresh frozen plasma (FFP). Medicine 56:213-224, 1977
5. Colombo M, Carnelli V, Gazengel C, et al: Transmission of non-A, non-B hepatitis by heat-treated Factor VIII concentrate. Lancet 2:1-4, 1985
6. Update: Acquired immune deficiency syndrome (AIDS) in persons with hemophilia. Morbidity and Mortality Weekly Report 33:589-591, October 26, 1984
7. Spire B, Barre-Sinoussi F, Montagnier L, et al: Inactivation of lymphadenopathy associated virus by chemical disinfectants. Lancet 2:899-901, 1984
8. Piszkiewicz D, Kingdon H, Apfelzweig R, et al: Inactivation of HTLV-III/LAV during plasma fractionation. Lancet 2:1188-1189, 1985
9. Gazengel C, Larrieu MJ: Lack of seroconversion for LAV/HTLV-III in patients exclusively given unheated activated prothrombin complex prepared with ethanol step. Lancet 2:1189, 1985
10. Petricciani J, McDougal JS, Evatt BL: Case for concluding that heat-treated, licensed anti-haemophilic factor is free from HTLV-III. Lancet 2:890-891, 1985
11. Rouzioux C, Chamaret S, Montagnier L, et al: Absence of antibodies to AIDS virus in haemophiliacs treated with heat-treated Factor VIII concentrate. Lancet 1:271-272, 1985
Last reviewed on RxList: 3/5/2009
This monograph has been modified to include the generic and brand name in many instances.
Additional Proplex-T Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.