Antihemophilic Factor (Human) - Koate-DVI; -Factor VIII:von Willebrand’s factor; Factor VIII:C
Status: approved; marketed
Organizations involved:
Talecris Biotherapeutics Inc. – Manuf.; R&D; Tech.; USA mark.
Instituto Grifols, S.A. – Parent
NPS Pharmaceuticals Inc – Former
Bayer Corp. – Former
Bayer Schering Pharma AG – Intl. mark.; Parent
New York Blood Center, Inc. – Tech.
Cross ref: See the Factor VIII Products entry (#715). See also other Factor VIII:vWF entries, e.g., Humate-P (#726) and Alphanate (#725).
Description: Antihemophilic Factor (Human) or Koate-DVI is a lyophilized (freeze-dried) formulation of a natural noncovalently bound complex of Antihemophilic Factor (Human) or Factor VIII with von Willebrand’s factor (vWF), i.e., Factor VIII:vWF, manufactured from pooled Plasma with manufacturing including ion-exchange and gel chromatography and two viral inactivation steps (double viral inactivation; DVI) using both the solvent detergent (tri-n-butyl phosphate and polysorbate 80) process and a dry heat (pasteurization) treatment (80˚C) of the lyophilized powder in final container vials. The Factor VIII:wWF complex is the major form in which Factor VIII exists in vivo, with the von Willebrand’s factor acting to stabilize Factor VIII against degradation and proteolysis.
Koate-DVI is intended for use in treatment of classical hemophilia (hemophilia A). Although containing vWF, the product is not approved for treatment of von Willebrand’s disease indications: (as is a similar product, Humate-P, from CSL Bioplasma). As indicated by supplemental approvals, heat treatments for viral inactivation have changed over the years, including dry heat and/or wet heating in solution.
Koate is 300 to 1,000 times purified for Factor VIII compared to Plasma. When reconstituted, Koate contains about 50- to 150-times as much Factor VIII as an equal volume of fresh Plasma. The average specific activity of Koate-DVI, prior to addition of Albumin (Human) as a stabilizer, is about 50 IU/mg protein. The specific activity, after addition of Albumin (Human) as a stabilizer, is in the range of 9-22 IU/mg protein.
Koate-DVI is available in 250, 500 and 1,000 IU size vials, with each vial labeled with its Antihemophilic Factor (Factor VIII) activity content in international units (IU), for intravenous infusion. Koate-DVI is tested for Antihemophilic Factor activity using the aPTT coagulation assay. Inactive proteins in Koate-DVI are primarily Albumin (Human) and a trace of fibronectin. Other plasma proteins are below detection limits. The final reconstituted product contains not more than (NMT) 5 units heparin/ml, NMT 1,500 ppm polyethylene glycol (PEG), NMT 0.05 M glycine, NMT 25 ppm polysorbate 80 (Tween 80), NMT 5 ppm tri-n-butyl phosphate (TNBP), NMT 3 nM calcium chloride, NMT 1 ppm aluminum, NMT 0.06 M histidine, and NMT 10 mg/ml Albumin (Human). The product has a six-month shelf-life at room temperature (up to 25˚C/77˚F)
Since 1989, over two billion units (IU) of Koate have been administered, with no documented cases of associated hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), or HIV infection.
Nomenclature: Factor VIII:vWF/Talecris [BIO]; Koate-DVI [TR (Ko¯ate’ is the registered trademark, with the dash symbol for long vowel pronunciation over the ‘a’; pronounced as ‘ko 8’; DVI = ‘double viral inactivated’)]; Antihemophilic Factor (Human) [FDA]; Antihemophilic Factor [USAN]; Antihemophilic Factor, Human [USAN former]; Antihemophilic Factor USP [USP]; 9001-27-8 [CAS RN]; Ko¯ate HP [TR former, prior to launch of DVI; HP = ‘heat pasteurized’]; Koate-HS [TR former; HS = ‘heated in solution’)]; Factor VIII:von Wille-brand’s factor complex [SY]; Koate-DVI [SY]; AHF SY]; Factor VIII:vWF [SY]; Factor VIII:C
Companies.: Koate-DVI was developed and previously manufactured by Bayer Corp., now Bayer Schering Corp. (formerly Miles Labs.; before that Cutter Labs.), FDA CBER est. no. 0008, at facilities in Clayton, NC. Koate-DVI was previously marketed in the U.S. by Bayer Corp., and internationally by Bayer AG. In April 2005, Talecris Biotherapeutics Inc., a subsidiary of NPS Pharmaceuticals Inc., acquired the blood/plasma products business of Bayer AG, now Bayer Schering Pharma AG, including manufacturing and U.S marketing, with Bayer Schering Pharma AG retaining international marketing.
In Feb. 2011, Grifols S.A./Instituto Grifols acquired Talecris Biotherapeutics.
Manufacture: Koate-DVI is purified from the cold insoluble fraction (cryoprecipitate) from pooled Fresh-Frozen Plasma by modification and refinements of the methods first described by Hershgold, Pool, and Pappenhagen (see, “The Potent Antihemophilic Globulin Concentrate Derived from a Cold Insoluble Fraction of Human Plasma: Characterization and Further Data on Preparation and Clinical Trial,” J. Lab. Clin. Med., vol. 67, no. 1, p. 23-32, 1966). Part of the plasma fractionation may be performed by another licensed manufacturer.
The Koate-DVI production process includes multiple steps that remove extraneous non-Factor VIII:vWF proteins, including acid precipitation, adsorption with aluminum hydroxide, and polyethylene glycol (PEG) precipitation. In addition, the product is gel-filtered to achieve an approximate 100-fold purification of from the starting cryoprecipitate. Since Antihemophilic Factor (Factor VIII:vWF) is a reactive protein, prone to protease degradation, Albumin (Human) USP is added as a stabilizer to the formulation before freeze-drying.
As originally approved, the product was apparently virus inactivated by wet heating in solution. Subsequently, approvals were obtained for dry heat and solvent detergent inactivation. The current overall manufacturing process has been shown to result in the following log titer reductions in virus-spiked samples: ≥ 9.4 log reduction in HIV-1, ≥ 10.3 log for bovine viral diarrheal virus (BVDV), ≥ 9.5 log for parvovirus B19, ≥ 10.9 log for vesicular stomatitis virus (VSV), ≥ 9.0 for reovirus, ≥ 3.4 log for hepatitis A virus (HAV), and ≥ 3.7 log for porcine parvovirus (PPV). The greatest reduction in virus load is achieved by the two specific inactivation steps, with at least a 4 log reduction obtained per step for each of the model viruses. The average reduction of PPV by 80˚C heat is calculated to be 3.72 ± 0.34 log. While studying the effectiveness and reproducibility of 80˚C heating of freeze-dried Koate-DVI vials, Bayer found that the moisture content in the vial is an important factor for viral reduction. Bayer controls the humidity inside the vial within a narrow range to maximize virus inactivation of the 80˚C dry heating step.
FDA class: Biologic PLA
CBER class: Blood And Blood Derivatives
Approvals: Date = 19740124; Antihemophilic Factor from Cutter/Miles; Indication = hemophilia A
Date = 19840117; PLA supplement (no. 83-341); addition of an unspecified viral inactivation step during manufacture
Date = 19840229; PLA supplement (no. 83-481); unspecified heat treatment process-related approval
Date = 19860416; supplemental PLA (no. 85-397); heat treatment process-related approval (60˚C, 10 hr.), unspecified whether dry or wet
Date = 19890302; PLA supplement 88-460; addition of solvent detergent viral inactivation as a second viral inactivation process (Double Viral Inactivation or DVI)
Date = 19990520; supplemental PLA; Indication = addition or modification of a viral inactivation step in the manufacturing process (perhaps increase in dry heating to current 80˚C)
Date = 20030423; BLA supplement; Indication = approval of new sterile Clayton, NC, filling facility
Indications: [full text of the "Indications and Usage” section of product insert/labeling]:
Koate-DVI is indicated for the treatment of classical hemophilia (hemophilia A) in which there is a demonstrated deficiency of activity of the plasma clotting factor, Factor VIII. Koate-DVI provides a means of temporarily replacing the missing clotting factor in order to control or prevent bleeding episodes, or in order to perform emergency and elective surgery on individuals with hemophilia. Koate-DVI contains naturally occurring von Willebrand’s factor, which is co-purified as part of the manufacturing process. Koate-DVI has not been investigated for efficacy in the treatment of von Wille-brand’s disease, and hence is not approved for such usage.
Tech. transfer: Solvent detergent viral inactivation technology was developed by and nonexclusively licensed from the New York Blood Center, e.g., see U.S. patent 4,820,805. See the entry for Pooled Plasma, Solvent Detergent Treated (SD Plasma; #799) for further information about solvent detergent viral inactivation, used primarily for inactivation of enveloped viruses (e.g., HIV, hepatitis B and C viruses).
Market: The 2007 Average Wholesale Price (AWP) is $0.92/IU (unchanged from 2004) (Red Book, 2007).
Medicare reimbursement for inpatient and home care is set at $0.90/IU, and at $0.51/IU for outpatient care. Estimated Acquisition Costs (for hospitals, treatment centers) is $0.66/IU [data from NHF].
In its April 2005 price list, FFF Enterprises, a major biologics distributor, reported $0.57/IUfor all vial sizes ($0.82/IU in March 2004).
Companies involvement:
Full monograph
724 Factor VIII:vWF/Talecris
Nomenclature:
Factor VIII:vWF/Talecris [BIO]
Ko¯ate-DVI [TR ['Ko¯ate', the registered trademark, is Koate with a dash symbol for long vowel pronunciation over the 'a' (pronounced as '8'); DVI = 'double viral inactivated']]
Ko¯ate HP [TR [former, prior to launch of double viral inactivated product]]
Ko¯ate-HS [TR (former; HS = heat-treated in solution)]
Antihemophilic Factor (Human) [FDA]
Antihemophilic Factor [USAN]
Antihemophilic Factor, Human [USAN (former)]
Antihemophilic Factor USP [USP]
9001-27-8 [CAS RN]
AHF [SY]
Factor VIII:von Willebrand's factor complex [SY]
Factor VIII:vWF complex [SY]
Koate-DVI [SY]
FDA Class: Biologic PLA
Year of approval (FDA) = 1974
Date of 1st FDA approval = 19740124
(in format YYYYMMDD)
Index Terms:
antihemophilic factors
biopharmaceutical products
blood products
human materials used<!-- humansource -->
Albumin (Human)
aluminum
aluminum hydroxide
calcium chloride
fibronectin
heat treatment (pasteurization)
heparin
histidine
octoxynol (Triton X-100)
Plasma (Human)
polyethylene glycol (PEG)
polysorbate 80 (Tween 80)
tri-n-butyl phosphate (TNBP)
viral inactivation, solvent detergent
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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