Antihemophilic Factor (Recombinant) - Recombinate; Factor VIII, recombinant
Status - approved; marketed (but superceded by Advate, its follow-on)
Organizations involved:
Baxter Hyland Immuno – Manuf.; Tech.; World mark.;
Genetics Institute, Inc. – R&D; Tech.; Former
Wyeth – Manuf; Tech.
Bayer Corp. – Tech.; Patent Dispute
Genentech, Inc. – Tech.; Patent dispute
Columbia University – Tech.; Patent dispute
Scripps Research Institute – Patent dispute
Cross ref.: See the Factor VIII Products entry (#715) in the Blood Products, Human section. See also the entry above for Antihemophilic Factor Concentrate (Recombinant) (For Further Manufacturing Use) from Genetics Institute/Wyeth, from which Recombinate is manufactured. See also Bioclate (#152) from CSL Behring, which is the same product as Recombinate simply repackaged by Baxter for marketing by CSL Behring.
Description: Recombinate is a lyophilized (freeze-dried) formulation of recombinant Factor VIII glycoprotein expressed by a Chinese Ovary Hamster (CHO) cell line with purification including immunoaffinity chromatography of recombinant Factor VIII:von Willebrand’s Factor complex using matrix-bound monoclonal antibody. Recombinate was the first marketed recombinant Factor VIII product. Recombinate is manufactured by Baxter Hyland Immuno from Antihemophilic Factor Concentrate (Recombinant) (For Further Manufacturing Use) or purified recombinant Factor VIII:von Willebrand’s factor complex (Factor VIII:vWF; Factor VIII:C) manufactured by Genetics Institute, Inc., Wyeth (See entry above). The recombinant Factor VIII in Recombinate has the same primary sequence (2,332 amino acids) and biological effects as Antihemophilic Factor (Human) or Factor VIII purified from blood plasma, and structurally has a combination of heterogenous heavy and light chains similar to native human Factor VIII.
Product identical to Recombinate is provided by Baxter Hyland Immuno to CSL Behring LLC for marketing under the trade name Bioclate. See the Bioclate entry.
During manufacture by Genetics Institute, now Wyeth, recombinant Factor VIII and von Willebrand’s factor (vWF) are co-expressed by transformed CHO cells, with the vWF non-covalently binding to Factor VIII to form Factor VIII:vWF complex or Factor VIII:C (much the same as the native human form of this complex), with vWF stabilizing Factor VIII during processing and storage. The vWF is removed by Baxter using an immunoaffinity chromatography column with matrix-bound murine (mouse) monoclonal antibody. The final formulation is stabilized with Albumin (Human).
Recombinate is packaged in single-dose bottles with nominal potencies of 250, 500 and 1,000 IU per bottle, along with 10 mL of Sterile Water for Injection, USP, a double-ended needle, and an 18-guage needle. Prior to administration, the powder is reconstituted (diluted) with Sterile Water for Injection, USP, for intravenous administration. Each bottle is labeled with the Factor VIII activity of its contents expressed in International Units (IU) , referenced to the World Health Organization (WHO) standard for Factor VIII:C Concentrate. Each reconstituted bottle contains less than or equal to: 12.5 mg/ml Albumin (Human); 0.100 IU/ml von Willebrand factor (vWF) or 2 ng vWF/IU Factor VIII (not enough recombinant von Willebrand factor to have any clinically relevant effect in patients with von Willebrand’s disease or other clotting disorders); 1.5 mg/ml polyethylene glycol (PEG; 3,350 Da); 120-180 mEg/L sodium; 55 nM histidine; 1.5 µg/Factor VIII International Unit (IU) polysorbate 80 (Tween 80); and 0.20 mg/mL calcium. The product contains no preservatives.
Recombinate contains trace amounts of murine (mouse) protein (maximum of 0.1 ng/IU) from immunoaffinity chromatography; hamster protein (maximum of 1 ng CHO protein/IU rAHF) from host cells, and bovine protein (maximum of 1 ng bovine serum albumin or BSA/IU rAHF) from use of bovine albumin in culture media. The product can be stored at 2-8˚C (refrigerated) or room temperature (not to exceed 30˚C or 86˚F). The expiration date is printed on each bottle.
Nomenclature: Factor VIII, rDNA, Mab purif./Baxter [BIO]; Recombinate [TR]; Antihemophilic Factor (Recombinant) [FDA]; Antihemophilic Factor [USAN]; octocog alfa [INN]; Antihemophilic Factor, Human [former USAN]; Factor VIII (rDNA) [BAN]; Antihemophilic Factor USP [USP]; Blood-coagulation factor VIII, complex [CAS]; 9001-27-8 [CAS RN]; Factor VIII, recombinant [SY]; Factor VIII:von Willebrand’s factor complex [SY for an intermediate]; Factor VIII:C [SY for an intermediate]; NDC 0944-2938-01, NDC 0944-2938-02, NDC 0944-2938-03 [NDC]
Companies.: Genetics Institute, Inc. CBER/FDA est. no. 1163, now Wyeth, CBER/FDA est. no. 0003, manufactures recombinant Factor VIII:C (Factor VIII:vWF) concentrate at its Andover, MA, establishment for further manufacturing by Baxter. This Antihemophilic Factor Concentrate (Recombinant)(For Further Manufacturing Use) is manufactured for Baxter by Wyeth under a shared manufacturing agreement. Wyeth is the sole supplier, and Baxter is the sole customer for the concentrate. See the entry above for the bulk Factor VIII:vWF concentrate.
Baxter Hyland Immuno (Glendale, CA), CBER/FDA est. no. 0140, manufactures, formulates, packages and markets Recombinate in the U.S. and worldwide. Baxter also formulates the same product and repackages it for marketing by CSL Behring under the trade name Bioclate.
Baxter has received approval and now also manufactures its own recombinant Factor VIII (for Recombinate and Bioclate) (and may have stopped or lessened its dependency on Genetics Inst./Wyeth for manufacture of bulk intermediate product). In Oct.1998, new Baxter facilities (Suite A) in Thousand Oaks, CA, were approved by FDA for manufacture of Recombinate (and Bioclate). In late 2000, Baxter received U.S. and European Union approvals for manufacture in Suites B and C, with product from these facilities dedicated for export to Europe. Baxter had been producing Recombinate in Suite A facilities for both the U.S. and European markets. The newer facilities allowed Suite A production to be dedicated to supplying the U.S. market. Each suite houses a 2,500-liter (660 gallon) stainless steel tank fermentor with capacity for manufacture of 275 million IU of Recombinate/Bioclate annually. The new facilities are expected to help alleviate a shortage of supplies of Recombinate. In Jan. 2002, Baxter reported that its facility in Thousand Oaks, CA, had shipped more than one billion units of Recombinate in 2001, and that the facility had manufactured a total of 4.5 billion units of Recombinate.
With recombinant Factor VIII demand nearly doubling annually worldwide since 1995, Baxter is constructing additional manufacturing facilities, including a fourth production suite at its Thousand Oaks facility, with approval expected by late 2004. Baxter is also constructing a multi-purpose recombinant protein manufacturing facility in Neuchatel, Switzerland. By 2006, Baxter will have total capacity for over two billion units of recombinant Factor VIII annually, with four suites at its facility in Neuchatel and four at Thousand Oaks. The Neuchatel site currently manufactures clinical supplies of Advate, Baxter’s “next-generation” recombinant Factor VIII therapy (see related entry ).
Manufacture: See the above entry for Antihemophilic Factor Concentrate (Recombinant)(For Further Manufacturing Use) from Wyeth for information about manufacture of bulk recombinant Factor VIII:von Willebrand’s factor (Factor VIII:vWF; Factor VIII:C); and the entry below for Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method (Advate). The concentrate manufactured by Wyeth is shipped to Baxter’s Glendale, CA, facility frozen at -80 degrees C (±10˚C). Once Baxter receives a shipment of concentrate from Wyeth and it is released (confirmed that it meets acceptance criteria), the bulk concentrate in frozen containers (containing 1-6 lots of concentrate) is thawed, pooled, further purified, and formulated with pasteurized Albumin (Human) as a stabilizer in an aqueous elution buffer solution (50 nM TRIS, 0.1% Tween-80, 5 nM CaCl2, 400 mM NaCl) with no preservatives added.
Purification includes immunoaffinity chromatography involving immobilization and subsequent release (elution) of Factor VIII using matrix-bound F8.1 Factor VIII murine monoclonal antibody specific for the 90 Da heavy chain of factor VIII. The same F8.1 monoclonal antibody used in this process is also used by Baxter for purification of its immunoaffinity chromatography-purified, blood plasma-derived Factor VIII (Hemofil) and for plasma- and sucrose-free recombinant Factor VIII (Advate). The antibodies apparently are produced in a plasma and albumin-free culture by Baxter in Hayward, CA, from the GI-F8/1.5.6 (ATCC HB 11552) cell line developed by Genetics Institute/Wyeth, and purified using Protein A affinity chromatography. The same monoclonal antibodies are used for purification of Factor VIII for Recombinate and plasma-derived Hemophil. See related entries. Recombinate has specific activity >4,000 IU/mg prior to stabilization with Albumin (Human). The final bulk has a potency range of 220-1,240 IU per final container. The final bulk product is sterile filtered, filled into vials and lyophilized (freeze-dried).
Final container testing includes immunoblotting, potency, total protein, specific activity, sterility, pyrogenicity, general safety, moisture, solubility, pH, Albumin (Human) content, identity (Factor VIII), sodium, histidine, polyethylene glycol, calcium, and absence of von Willebrand Factor antigen.
FDA class: Biologic PLA
CBER class: Blood And Blood Derivatives
Approvals: Date = 19921210; PLA 90-0381, ELA 91-0125
Date = 19981000; supplemental approval; Indication = new Baxter facility in Thousand Oaks, CA
Date = 20001005; supplemental approval; Indication = new Thousand Oaks, CA, production suite (suite B) approved for manufacture of Recombinate
Date = 20030808; BLA supplement; Indication = change in source for Sterile Water for Injection, with Baxter making the product itself
Indications: [full text of "INDICATIONS AND USAGE” section of product insert/labeling]:
The use of Antihemophilic Factor (Recombinant), Recombinate is indicated in hemophilia A (classical hemophilia) for the prevention and control of hemorrhagic episodes. Recombinate is also indicated in the perioperative management of patients with hemophilia A (classical hemophilia).
Recombinate can be of significant therapeutic value in patients with acquired AHF inhibitors not exceeding 10 Bethesda Units per mL. In clinical studies with Recombinate, patients with inhibitors who were entered into the previously treated patient trial and those previously untreated children who have developed inhibitor activity on study, showed clinical hemostatic response when the titer of inhibitor was less than 10 Bethesda Units per mL. However, in such uses, the dosage of Recombinate should be controlled by frequent laboratory determinations of circulating AHF levels.
Recombinate is not indicated in von Willebrand’s disease.
Status: Recombinate (and Bioclate) is apparently exempt from CBER FDA lot release requirements.
Recombinate is marketed in Europe and most other territories worldwide. It has not received EU centralized approval, with European approvals country-by-country.
Tech. transfer: This product was originally developed by Genetics Institute (GI), now Wyeth. Baxter licensed exclusive marketing and manufacturing rights from GI/Wyeth. Note, Wyeth also manufactures and markets a different, second generation recombinant Factor VIII product, ReFacto. See the Factor VIII Products entry in the Blood Products, Human section and other recombinant Factor VIII entries for further discussion of Factor VIII patents and technology transfer.
Genetics Institute (GI; now Wyeth) was a licensee of Columbia University’s patents concerning cotransformation, a broadly-useful genetic engineering method allowing selection and isolation of transformed cells. Baxter paid GI/Wyeth’s royalties to Columbia as part of its licensing deal with GI/Wyeth. The original patents and license expired in 2000, but Columbia received another patent in 2002 and was again seeking royalties, which Wyeth and other companies challenged in court. Recently, the University decided not to continue to press infringement suits and seek royalties, but the patent office is reexaming the relevant patent, and the university could against pursue infringement and royalties at a later date. See the “Tech. transfer” section of the Recombinant DNA Products entry (#100) for further information.
Immunoaffinity purification of Factor VIII from Factor VIII:vWF complex is described in U.S. patent reissue 32,011 (Re. 32,011), Zimmerman and Fulcher, assigned to The Scripps Reseach Institute (Scripps). This patent specifically claimed purification of Factor VIII from plasma-derived Factor VIII:vWF complex using matrix-bound monoclonal antibody, particularly the 2.2.9 monoclonal antibody, specific for the vWF portion of the complex, with uncomplexed Factor VIII later eluted from the complex bound to the chromatography column. This patent specifically claimed purification of plasma-derived Factor VIII, not recombinant Factor VIII. Companies manufacturing recombinant Factor VIII products did not take a license. A Genentech contractor in the U.K. had used this patented process to manufacture immunoaffinity-purified plasma-derived Factor VIII:C, which Genentech used in its effort to clone the Factor VIII:C gene.
The issue of Scripp’s patent was resolved after a decade-long (1984-1994) legal dispute, Scripps vs. Genentech, in which Scripps claimed its patent applied to Genentech’s cloning of Factor VIII, which involved using recombinant Factor VIII purified from recombinant Factor VIII:vWF. Scripps eventually lost, due to the patent only specifically claiming natural, not recombinant, Factor VIII purification. At issue, among other things, was whether Genentech’s Factor VIII:C prepared by a recombinant methods infringed Scripps’ product-by-process claims directed to Factor VIII:C purified from human plasma using a chromatographic adsorption technique. In the decision of Scripps Clinic & Research Foundation v. Genentech, Inc., 18 USPQ 2nd 1001 (Fed. Cir. 1991), a three-judge panel of the Federal Circuit held that the “product-by-process” claims at issue were properly interpreted as product claims. See the Factor VIII Products entry in the Blood Products, Human entry for further information.
Baxter AG (now Bayer Schering Pharma) has received Factor VIII-related U.S. patents including 6,475,725 and 6,936,441, “Recombinant cell clones having increased stability and methods of making and using the same,” Nov. 5, 2002. This includes claims concerning stable recombinant cell clones stable in serum- and protein-free medium for at least 40 generations, including CHO cell culture in serum- and protein-free media with added purified, ultrafiltered soybean peptide.
Baxter AG has also received U.S. 6,307,032, “Highly purified factor VIII complex,” Oct. 23, 2001. This concerns methods for manufacture and highly purified Factor VIII :vWF complex having a specific activity of at least 70, preferably 100 to 300 U factor VIII:C/mg using immunoaffinity chromatography with anti-vWF antibodies.
Medical: As with other Factor VIII products, the dosage regimen for each patient must be determined on an individual basis. Recombinate is appropriate for use in adults and children of all ages, including the newborn. In general, the expected in vivo peak increase in Factor VIII activity (expressed as IU/dl of plasma or percent of normal) can be estimated by multiplying the dose administered per kg (IU/kg) by two. In patients with inhibitor (Factor VIII-neutralizing antibodies) at levels less than 10 Bethesda Units per mL, administration of additional Recombinate may neutralize the inhibitor.
Despite manufacture using multiple animal-sourced products, well over 5 billion units of Recombinate have administered since the first clinical study in 1987, and there have been no confirmed cases of disease transmission associated with its use. The remote possibility exists that patients treated with this product may develop hypersensitivity to its trace nonhuman mammalian proteins. Baxter also manufactures and markets recombinant Factor VIII (Advate) without addition of any animal or human sourced products.
Market: Total 2006 worldwide sales were about $530 million, with Wyeth reportedly have $357.6 million in sales and Baxter having ~$173 million.
The 2007 Average Wholesale Price (AWP) is $1.41/IU ($1.40/IU in 2004) irrespective of size (Red Book, 2007). This is unchanged since at least 2005.
Medicare reimbursement is set at $1.29/IU for inpatient and home care, and $1.01/IU for outpatient care. Estimated Acquisition Costs (for hospitals, treatment centers) is $.77-$.91/IU [from NHF].
In its March 22, 2006 price list, FFF Enterprises, a major biologics distributor, reported its price as $1.05/IU (the same in 2004).
Companies involvement:
Full monograph
147 Factor VIII, rDNA/Baxter
Nomenclature:
Factor VIII, rDNA, Mab purif./Baxter [BIO]
Recombinate [TR]
Antihemophilic Factor (Recombinant) [FDA]
octocog alfa [INN]
Antihemophilic Factor [USAN]
Antihemophilic Factor, Human [former USAN]
Factor VIII (rDNA) [BAN]
Antihemophilic Factor USP [USP]
Blood-coagulation factor VIII, complex [CAS]
9001-27-8 [CAS RN]
AHF [SY]
Factor VIII, recombinant [SY]
Factor VIII:C [SY for an intermediate]
Factor VIII:von Willebrand's Factor complex [SY for an intermediate]
NDC 0944-2938-01, 0944-2938-02 and 0944-2938-03 [NDC]
molecular weight (kDa) = 226
FDA Class: Biologic PLA
Year of approval (FDA) = 1992
Date of 1st FDA approval = 19921210
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2019, based on 6,475,725 and extension of 6,936,441 |
U.S. Patent Expiration Year: | 2019 |
U.S. Biosimilars Data Exclusivity Expiration: | 2004 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 1999 |
U.S. Biosimilars Launchability Year: | 2019 |
U.S. Biobetters Launchability Year: | 2019 |
Biosimilars/biobetters-related EU Patents: | 2017, based on EP 0906340 process patent; Note, no EP equivalents of 6475725 or 6,936,441; No centralized EU approval, no biosimilar approvals possible |
EU Patent Expiration Year: | 2017 |
EU Biosimilars Data Exclusivity Expiration: | |
EU Biosimilars Orphan Exclusivity Expiration: | |
EU Biosimilars Launchability Year: | 2017 |
EU Biobetters Launchability Year: | 2017 |
Index Terms:
antihemophilic factors
biopharmaceutical products
blood products
bovine materials used<!-- bovinesource -->
exempt from CBER lot release requirements
hamster source materials
human materials used<!-- humansource -->
murine (mouse) materials used
recombinant DNA
rodent source materials
albumin, bovine
ATCC HB 10494
bovine serum albumin (BSA)
Chinese hamster ovary (CHO) cells
gentamicin (gentamycin)
mammalian cell culture
murine feeder cells
rodent cells <!-- rodentcells -->
2,3,5,6-tetrafluorophenyl-4,5-bis-S-(1-ethoxyehtyl)-thioacetoamidopentoate)
Albumin (Human)
calcium chloride
exempt from CBER lot release requirements
Factor VIII monoclonal antibodies
hamster proteins
histidine
immunoaffinity chromatography
lyophilized (freeze-dried)
monoclonal antibody hP67.6
monoclonal antibody, carcinoembryonic antigen (CEA)
murine monoclonal antibody, CD3
murine monoclonal antibody, Factor VIII
murine proteins
polyethylene glycol (PEG)
polysorbate 80 (Tween 80)
protective antigen (PA)
sodium chloride
Sterile Water for Injection
tris (tromethamine)
von Willebrand's factor (vWF)
WHO Intl. Standard Factor VIII:C Concentrate
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
exempt from CBER lot release requirements
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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