Antihemophilic Factor Concentrate (Recombinant) (For Further Manufacturing Use) - Factor VIII:von Willebrand’s factor complex, recombinant concentrate; rAFH-C; Factor VIII:C, rDNA
Status – FDA-approved as intermediate; not marketed
Organizations involved:
Wyeth – Manuf.; R&D; Tech.; Parent
Genetics Institute, Inc. – R&D; Tech.; Former
Baxter Hyland Immuno – Manuf.
Bayer Corp. – Tech.
Genentech, Inc. – Tech.; Patent dispute
Columbia University – Tech.; Patent dispute
Cross ref.: See the Factor VIII Products entry in the Blood Products, Human section, and the entry for Recombinate (#147) which is manufactured from this intermediate concentrate.
Description: Antihemophilic Factor Concentrate (Recombinant)(For Further Manufacturing Use) or rAFH-C is a nonsterile bulk aqueous concentrate of recombinant Factor VIII:von Willebrand’s factor complex (Factor VIII:vWF or Factor VIII:C) manufactured by Genetics Institute, now Wyeth, using transformed Chinese hamster ovary (CHO) cells, and sold exclusively to Baxter Hyland Immuno for further manufacture of recombinant Factor VIII sold by Baxter under the trade name Recombinate (and also packaged by Baxter as Bioclate for marketing by Aventis Behring, now CSL Behring). Note, Wyeth also manufactures its own, second generation, recombinant Factor VIII product (Refacto).
Excipients used in formulation of this intermediate complex are sucrose, calcium chloride, L-histidine, polysorbate 80 (Tween 80), and sodium chloride. The product labeling (i.e., cover sheet apparently used for shipment to Baxter) describes the product as “non-sterile drug substance in elution buffer” composed of an aqueous solution of 50 mM tris (tromethamine), 0.1% Tween 80 (polysorbate 80), 5 mM calcium chloride (CaCl2), and 400 mM sodium chloride (NaCl), with no preservatives (and no albumin as a stabilizer), to be shipped and stored at -80˚C. The dating period for this product is 24 months from the date of manufacture when stored at -80 +/- 10˚C. The date of manufacture is the date of elution from the final chromatography column.
During manufacture by Wyeth, recombinant Factor VIII and von Willebrand 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. This complex is much the same as the native human circulating Factor VIII:vWF (Factor VIII:C) complex, with vWF stabilizing the Factor VIII molecule (in the case of this product, during processing and storage). Later, in processing by Baxter, Factor VIII is purified and vWF removed (eluted) by immunoaffinity column chromatography using matrix-bound murine (mouse) monoclonal antibodies with affinity for the 90 Da heavy chain of Factor VIII. The final product (Recombinate/Bioclate) is stabilized with Albumin (Human), with this and other aspects of formulation performed by Baxter.
Nomenclature: Factor VIII:vWF, rDNA conc. [BIO]; Antihemophilic Factor Concentrate (Recombinant)(For Further Manufacturing Use) [FDA]; Recombinant human Factor VIII concentrate (for further manufacturing use) [FDA former]; Antihemophilic Factor Concentrate (Recombinant)(For Further Manufacturing Use) (non-sterile drug substance in elution buffer) [FDA full text from labeling]; rAFH-C [SY]; Factor VIII:von Willebrand’s factor (Factor VIII:vWF) complex, recombinant [SY]; Factor VIII:C, rDNA [SY]; Factor VIII, recombinant concentrate [SY]; Factor VIII:vWF [SY]; FVIII:vWF, rDNA [SY]; NDC 58394-030-00 [NDC]
Companies.: Genetics Institute, Inc., formerly CBER/FDA est. no. 1163, now Wyeth, CBER/FDA est. no. 0003, developed and manufactures recombinant human Factor VIII:vWF concentrate (for further manufacture of the active ingredient in Recombinate and Bioclate), at its Andover, MA establishment. The product is manufactured exclusively for further manufacturing by Baxter.
In Oct. 1998, Baxter received approval for its own facility in Thousand Oaks, CA, for manufacture of Factor VIII, decreasing (or eliminating) dependency on Wyeth and increasing supplies of Recombinate (and Bioclate).
Manufacture: Recombinant human Factor VIII and human von Willebrand’s factor (vWF) are both expressed in a transformed recombinant Chinese Ovary Hamster (CHO) cell line. The CHO cells are cultured by a batch-fed process [unlike Factor VIII:vWF for Advate which is manufactured by a continuous (chemostat) perfusion process]. Coexpression of vWF into the culture medium helps to stabilize the recombinant Factor VIII during processing, with the two molecules forming a complex (Factor VIII:vWF or Factor VIII:C) mimicking the complex formed in vivo by association of the two native molecules (with vWF stabilizing Factor VIII). The Factor VIII:vWF is purified from the culture medium using ion exchange and size exclusion chromatography. The purification process has been validated to reduce potential contaminants including host cell proteins, media constituents, and host cell DNA using scaled-down chromatography columns. The concentrate has a dating period (shelf life) of two years, with the date of manufacture being the date of elution from the final chromatography column.
Acceptance criteria for the Factor VIII:vWF include: Factor VIII:C from 1,000-6,000 IU/mL; ratio of Factor VIII:C/Factor VIII:antigen, 0.70-1.70; pH of 6.7 ±0.5; protein, not less than (NLT) 0.25 mg/mL; UV spectrometry, max. wavelength 275 ±5 nm; SDS-PAGE analyses with and without prior digestion with thrombin; partial amino acid sequencing; reverse phase HPLC following thrombin digestion; CHO protein, not more than (NMT) 1 µg/1,000 IU Factor VIII:C; CHO DNA, NMT 1.5 µg/IU Factor VIII:C; ethylene glycol, NMT 3 µg/mL; aluminum, NMT 10 ng/IU factor VIII:C; absence of mycoplasma; bioburden, NMT 10 CFU/ml; and endotoxin, NMT 2 EU/100 IU Factor VIII:C.
FDA class: Biologic PLA
CBER class: Blood And Blood Derivatives
Approvals: Date = 19921210; first approval; PLA 90-0380, ELA 90-0379
Indications: = [from Summary Basis of Approval (SBA)]:
“to manufacture and ship for sale to Baxter Healthcare Corporation, Antihemophilic Factor Concentrate for further manufacture into Antihemophilic Factor (Recombinant) under a shared manufacturing agreement”
Status: Approval included exemption from CBER/FDA lot release provisions (Title 21, CFR 610.2).
Tech. transfer: This recombinant Factor VIII:C (Factor VIII:vWF) was originally developed by Genetics Institute (now Wyeth). Baxter licensed exclusive marketing and manufacturing rights for the final product, Factor VIII (Recombinate). See the Recombinate entry for discussion of Factor VIII patents and technology transfer.
Companies involvement:
Full monograph
146 Factor VIII:vWF, rDNA conc.
Nomenclature:
Factor VIII:vWF, rDNA conc. [BIO]
Antihemophilic Factor Concentrate (Recombinant)(For Further Manufacturing Use) [FDA]
Recombinant human Factor VIII concentrate (for further manufacturing use) [FDA former]
Antihemophilic Factor Concentrate (Recombinant)(For Further Manufacturing Use) (non-sterile drug substance in elution buffer) [FDA full text from label]
AHF [SY]
Factor VIII, recombinant concentrate [SY]
Factor VIII:C, rDNA [SY]
Factor VIII:von Willebrand's Factor complex [SY]
Factor VIII:von Willebrand's Factor complex, recombinant [SY for intermediate]
Factor VIII:vWF complex [SY for intermediate]
FVIII:vWF, rDNA [SY]
rAFH-C [SY]
B02BD02 [ATC [EMEA pharmacotherapeutic group]]
NDC 58394-030-00 [NDC]
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; Note, it is unclear whether biosmilar version of intermediates/APIs having received their own BLAs can receive biosimilar approval; See the Recombinate entry |
U.S. Patent Expiration Year: | |
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; Never approved in the EU ; See the Recombinate entry |
EU Patent Expiration Year: | 2017 |
EU Biosimilars Data Exclusivity Expiration: | |
EU Biosimilars Orphan Exclusivity Expiration: | |
EU Biosimilars Launchability Year: | |
EU Biobetters Launchability Year: | 2017 |
Index Terms:
antihemophilic factors
biopharmaceutical products
blood products
exempt from CBER lot release requirements
hamster source materials
human materials used<!-- humansource -->
intermediate/precursor products
recombinant DNA
rodent source materials
Chinese hamster ovary (CHO) cells
mammalian cell culture
rodent cells <!-- rodentcells -->
calcium chloride
histidine
Plasma (Human)
polysorbate 80 (Tween 80)
sodium chloride
sucrose
tris (tromethamine)
von Willebrand's factor (vWF)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
exempt from CBER lot release requirements
North American coral snake
North American coral snake
EU200 Currently Approved in EU
UM999 Not Available/Not Marketed in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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