Fibrin Sealant (Human)], Vapor Heated, Solvent Detergent Treated - Artiss; Fibrin Sealant, VH S/D 4; Fibrin Sealant, Vapor Heated Solvent/Detergent 4x Inactivated; Sealer Protein Concentrate (Human) plus Thrombin (Human)
Status: BLA granted in 3/2008
Organizations involved:
Baxter Hyland Immuno – Manuf.; R&D; Tech.; USA mark.
Baxter Healthcare Corp. – Parent
Cross ref: See the entry below for Tisseel, another fibrin sealant from Baxter. See the entries for Fibrin Sealant Products (#735) and Thrombin, conc.(#807), used in the manufacture of Artiss.
Description: Fibrin Sealant, Two-Component Fibrin Sealant, Vapor Heated or Artiss is a kit containing lyophilized or frozen fibrinogen and thrombin, both fractionated and purified from pooled human plasma and subjected to vapor heating and solvent-detergent (S/D) treatment for viral inactivation. The kit has two main reactive components–Sealer Protein (fibrinogen) and Thrombin Solution. When combined in a dual-chamber mixing applicator immediately before application, these components form fibrin, essentially mimicking natural clot formation by the mixing of activated fibrinogen and thrombin at bleeding sites.
Artiss differs from Tisseel and other fibrin sealants, including that it contains a lower concentration of thrombin. Artiss is only approved for gluing on skin grafts, while other fibrin sealants are generally used for maintaining homestasis (stopping bleeding). The lower thrombin concentration allows surgeons more time to position skin grafts over burns before the graft begins to adhere to the skin. Artiss also contains aprotinin, a synthetic protein that delays the break down of blood clots.
Artiss is the first and only slow-setting fibrin sealant indicated for use in adhering skin grafts in adult and pediatric burn patients. This allows for the delayed setting and controlled manipulation of skin grafts for ~60 seconds, relative to rapid-setting fibrin sealants, which set in five to 10 seconds. Skin grafts can be fixed without the use of staples or sutures, which may help reduce post-operative complications and patient anxiety about pain during staple removal.
ARTISS is presented either as a kit containing the two lyophilized biological components with their respective diluents (aprotinin solution for the Sealer Protein and calcium chloride solution for Thrombin), or as two components frozen in pre-filled syringes (Sealer Protein Solution and Thrombin Solution). Both the freeze-dried and frozen forms are supplied as 2 mL, 4 mL or 10 mL (total volume) pack sizes. Excipients in the Sealer Protein Solution include human albumin, tri-sodium citrate, histidine, niacinamide, polysorbate 80 and water for injection. The Thrombin Solution also contains human albumin, sodium chloride and water for injection. Artiss is presented either as a kit containing the two lyophilized biological components with their respective diluents (aprotinin solution for the Sealer Protein and calcium chloride solution for Thrombin), or as two components frozen in pre-filled syringes (Sealer Protein Solution and Thrombin Solution). Both the freeze-dried and frozen forms are supplied as 2 mL, 4 mL or 10 mL (total volume) pack sizes. Excipients in the Sealer Protein Solution include human albumin, tri-sodium citrate, histidine, niacinamide, polysorbate 80 and water for injection. The Thrombin Solution also contains human albumin, sodium chloride and water for injection. Sealer Protein and the Thrombin are stable for 4 hours after reconstitution when stored at up to room temperature (2-25˚C).
Sealer Protein (Human) is a sterile, non-pyrogenic, vapor-heated and solvent/detergent treated preparation made from pooled human plasma. To obtain Sealer Protein (Human), cryoprecipitate derived from Plasma is washed, dissolved in buffer solution, solvent/detergent treated, vapor heat treated, sterile filtered and either freeze-dried in vials or frozen in pre-filled syringes. Sealer Protein (Human) is provided either as a freeze-dried powder [Sealer Protein Concentrate (Human)] for reconstitution with Fibrinolysis Inhibitor Solution (Synthetic) or as a frozen liquid solution pre-filled into one side of a dual-chambered syringe. The active agent in Sealer Protein (Human) is fibrinogen. Fibrinolysis Inhibitor, Aprotinin (Synthetic) is included in the Sealer Protein (Human) component to delay fibrinolysis. Aprotinin (Synthetic) is manufactured by solid phase synthesis from materials completely of nonhuman/non-animal origin. Both Sealer Protein (Human) and Thrombin (Human) are made from pooled human plasma collected at U.S. licensed collection centers.
Thrombin (Human) is a sterile, non-pyrogenic, vapor-heated and solvent/detergent treated preparation made from pooled human plasma. Thrombin is prepared from plasma through a series of separation and filtration steps, followed by incubation of the solution with calcium chloride to activate prothrombin to thrombin. The solution subsequently undergoes ultra/diafiltration, vapor heat treatment, solvent-detergent treatment, sterile filtration and is either freeze-drying in vials or frozen in pre-filled syringes. Thrombin (Human) is provided either as a freeze-dried powder for reconstitution with Calcium Chloride Solution or as a frozen liquid solution pre-filled into one side of a dual-chambered syringe.
The dating period for Sealer Protein /Aprotinin and for the Thrombin in the frozen presentation is 24 months from the date of manufacture when stored at or below -20˚C. Product in unopened pouches, thawed at room temperature, may be stored for up to 7 days at 15-25˚C. Following quick thawing, product must be used within 12 hours after warming to 33-37˚C. The dating period for Sealer Protein Concentrate and for the Thrombin in the lyophilized (kit) presentation is 24 months from the date of manufacture when stored at 2-25˚C. Following reconstitution the product must be used within 4 hours. The dating period for the Calcium Chloride for the kit is 36 months from the date of manufacture when stored at room temperature. The dating period for the Aprotinin Solution for the kit is 24 months from the date of manufacture when stored at or below 25˚C. The date of manufacture is defined as the date of final sterile filtration of the formulated drug product. The expiration date for the packaged product, whether in the kit or frozen presentation, is dependent on the shortest expiration date of any component.
Artiss is packaged either as a kit containing the two lyophilized biological components with their respective diluents (aprotinin solution for the Sealer Protein and calcium chloride solution for Thrombin); or as two components frozen in pre-filled syringes (Sealer Protein Solution and Thrombin Solution). ARTISS Kit (Freeze-Dried) is supplied as 2 mL, 4 mL and 10 mL (total volume) pack sizes with and without the DUPLOJECT (2-compartment spray/injector) system. ARTISS Pre-filled Syringe (Frozen) is supplied as 2 mL, 4 mL and 10 mL (total volume) pack sizes with the DUO injector/spray set. Both the freeze-dried and frozen forms are supplied as 2 mL, 4 mL or 10 mL (total volume) pack sizes. Excipients in the Sealer Protein Solution include Albumin (human), trisodium citrate, histidine, niacinamide, polysorbate 80 (Tween 80) and water for injection. The Thrombin Solution also contains human Albumin (human), sodium chloride and water for injection. Artiss Kit (Freeze-Dried) requires reconstitution prior to use. Both types of kits are stored froze. Artiss Pre-filled Syringe (Frozen) requires thawing prior to use.
The reconstituted solution or pre-filled syringe contains: the Sealer Protein Solution, containing 96-125 mg/mL total protein; 67 – 106 mg/mL fibrinogen; and 250-3750 KIU/mL Fibrinolysis Inhibitor (Synthetic), as a preservative. The Thrombin Solution contains 2.5 – 6.5 IU/mL Thrombin (Human); and 36-44 µmol/mL calcium chloride. Note, the concentration of the thrombin component is much lower in Artiss than in Tisseel.
The approximate areas requiring skin graft fixation ad the required package sizes of ARTISS are: 100 cm2, 2 mL; 200 cm2, 4 mL; and 500 cm2, 10 mL.
Artiss was developed in parallel to Tisseel Fibrin Sealant. See related entry.
Nomenclature: Fibrin Sealant/Artiss [BIO]; Artiss [TR]; Fibrin Sealant VH S/D 4 (Human) [USAN]; Fibrin Sealant (Human)], Vapor Heated, Solvent Detergent Treated [FDA]; Fibrin Sealant, VH S/D 4 [SY]; Fibrin Sealant, Vapor Heated Solvent/Detergent 4x Inactivated [SY]
Manufacture: The manufacturing process includes steps designed to further reduce the risk of viral transmission - vapor heating and solvent/detergent treatment processes. These are included in the manufacturing of Sealer Protein Concentrate and Thrombin. Validation studies were conducted using samples drawn from manufacturing intermediates for each of the two human plasma derived components. These samples were spiked with stock virus suspensions of known titers followed by further processing under conditions equivalent to those in the respective manufacturing steps. The virus reduction factors (as log10) of independent manufacturing steps for Sealer Protein were:
a) HIV-1: S/D treatment, >5.3 log; vapor heat treatment, >5.5; overall, >10.8
b) hepatitis A virus: S/D treatment, N.A.; vapor heat treatment, >5.6; overall, >5.6
c) bovine viral diarrhea virus (a model for hepatitis C virus): S/D treatment, >5.7 log; vapor heat treatment, >5.7; overall, >11.4
d) pesudorabies virus (a model for enveloped DNA viruses): S/D treatment, >5.9 log; vapor heat treatment, >6.7; overall, >12.6
e) mouse minute virus (a model for human parvovirus B19): S/D treatment, N.A.; vapor heat treatment, 1.2; overall, 1.2.
For the Thrombin component, virus reduction factors associated with processing steps were:
a) Thrombin precursor mass capture S/D treatment: HIV, N.A.; hepatitis A virus, N.A.; bovine diarrhea virus, 1.8; porcine parvovirus, N.A.; and mouse minute virus, 1.2
b) vapor heat treatment: HIV, >5.5.; hepatitis A virus, >4.9.; bovine diarrhea virus, >5.3; porcine parvovirus, >6.7; and mouse minute virus, 1.0.
c) solvent-detergen treatment: HIV, >5.3.; hepatitis A virus, N.A.; bovine diarrhea virus, >5.5; porcine parvovirus, >6.4; and mouse minute virus, N.A.
d ) ion exchange chromatography: HIV, N.A.; hepatitis A virus, N.A.; bovine diarrhea virus, N.A; porcine parvovirus, N.A.; and mouse minute virus, 3.6.
The overall virus reductions for the Thrombin component are: HIV-1, >10.8; hepatitis A virus, >4.9; bovine diarrhea virus, >12.6; porcine parvovirus, >13.1; and mouse minute virus, 4.6.
Companies.: Artiss was developed and is manufactured and marketed by Baxter Hyland Immuno, Baxter Corp., CBER/FDA est. no. 0140.
FDA class: Biologic BLA
Approval: Date = 20080319; BLA (BL 125266/0)
Indications: [full text of the "Indications and USAGE" section of the product insert/labeling]:
ARTISS is indicated to adhere autologous skin grafts to surgically prepared wound beds resulting from burns in
adult and pediatric populations. ARTISS is not indicated for hemostasis.
Status: Artiss was launched in the U.S. on March 25, 2008.
Tech. transfer: The U.S. product insert cites U.S. 4,640,834; 5,962,405; 5,714,370 and 6,579,537, in addition to others (unspecified) including patents pending. U.S. 4,640,834, "Method of inactivating reproducible filterable pathogens in blood products as well as a method of producing blood products," assigned to Immuno AG, now Baxter, concerns vapor heat viral inactivation. 5,962,405, "Storage-stable fibrinogen preparations," assigned to Immuno AG, now Baxter, concerns methods for improving the solubility of lyophilized fibrinogen preparations, e.g., using calcium chloride. 5,714,370, "Thrombin and method of producing the same," assigned to Immuno AG, now Baxter, activation of prothrombin (to thrombin) with heat treatment for the inactivation of infectious agents. 6,579,537, "Method for producing fibronectin and fibrinogen compositions using a polyalkylene glycol and glycine or beta-alanine," assigned to Baxter, concerning methods for manufacture of fibrinogen, particularly precipitation.
Trials: During its Phase III multicenter clinical trial, Artiss was evaluated for its ability to attach skin grafts on two wound sites for 138 patients. At one test site, the skin graft was fixed with Artiss; at the other test site, the graft was fixed with surgical staples. The results showed that Artiss was, within a statistical error, as good as staples to attain complete wound closure. Results were reported in the Journal of Burn Care and Research; March/April 2008.
Regeneron is looking to expand the label for Arcalyst, which upon U.S. approval was being evaluated in a Phase II trial for gout flares. In Feb. 2008, Regeneron initiated a double-blind, placebo controlled Phase II study of IL-Trap for the prevention of gout flares induced by the initiation of allopurinol (uric acid-lowering drug therapy used to control the disease). The study enrolled 80 patients and the primary endpoint is the number of flares during the 16 week period after the initiation of allopurinol therapy. IL-1 Trap has shown a statistically significant reduction in patient pain scores in a single-blind, placebo run-in-controlled study of 10 patients with chronic active gout..
Medical: Using the supplied or other dual-compartment, mixing-type spray injector, the two active components are mixed and applied in a thin coat to the wound area.
Market: Upon it U.S. launch, Arcalyst was priced at $250,000 per patient or $5,000 per vial per week, with " modest sales of $10 million expected in 2008."
Companies involvement:
Full monograph
736.5 Fibrin Sealant/Artiss
Nomenclature:
Fibrin Sealant/Artiss [BIO]
Artiss [TR]
Fibrin Sealant (Human)], Vapor Heated, Solvent Detergent Treated [FDA]
Fibrin Sealant VH S/D 4 (Human] [USAN]
Fibrin Sealant, Vapor Heated Solvent/Detergent 4x Inactivated [SY]
Fibrin Sealant, VH S/D 4 [SY]
FDA Class: Biologics BLA
Year of approval (FDA) = 2008
Date of 1st FDA approval = 20080319
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
blood products
fibrin
human materials used<!-- humansource -->
nonoxynol 101 (Triton N101)
Albumin (Human)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
calcium chloride
fibrinogen
fibrinolysin
heat treatment (pasteurization)
histidine
neutropenia
Plasma (Human)
polysorbate 80 (Tween 80)
SDS-polyacrylamide gels
sodium chloride
sodium citrate
thrombin, human
trisodium citrate
viral inactivation, solvent detergent
Water for Injection
EU000 Not yet/Never filed with EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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