Fibrin Sealant (Human) - Evicel; CROSSEAL; Quixil; Biological Active Component (BAC), a concentrate of human clottable protein (mainly fibrinogen and fibronectin), and Thrombin (Human)
Status: new version, Evicel, marketed in U.S. and EU
Organizations involved:
Omrix Biopharmaceuticals Ltd. – Manuf.; R&D; Tech.; Former
Ethicon, Inc. – World mark.
Johnson & Johnson (J&J) – Parent
Talecris Biotherapeutics Inc. – Manuf. other
Instituto Grifols, S.A. - Parent
Octapharma AG – Tech.
Israel (State of Israel) – Patent dispute
Baxter Hyland Immuno – Former
American National Red Cross (ARC) – Former
New York Blood Center, Inc. – Tech.
MDA Blood Bank, Sheba Hospital – Manuf. other
Cross ref.: See the entries above for Fibrin Sealant Products (#735) and the other fibrin sealants. See the entries for Thrombin Products (#929) and Thrombin/Omrix (#809) regarding a component of this product.
Description: Evicel, originally/formerly CROSSEAL, is a fibrin sealant kit involving the combination of two human Plasma-derived liquids, Biological Active Component (BAC), a concentrate of human plasma-derived clot-table protein (mainly fibrinogen and fibronectin), and plasma-derived Thrombin (Human), in a special mixing and syringe/applicator for spraying or dripping the mixed components. Each of the two components undergoes two separate virus inactivation/removal steps during manufacturing. BAC is treated with solvent--detergent viral inactivation and pasteurization (heat treatment). Thrombin is treated with solvent-detergent viral inactivation and nanofiltration. The solvent detergent process primarily inactivates enveloped viruses without affecting the biological activity of the plasma proteins. Pasteurization inactivates both enveloped and non-enveloped viruses. Nanofiltration, using a membrane with an average pore size of 28 nm, removes both enveloped and non-enveloped viruses. Tranexamic acid, a specific plasmin (protease) inhibitor, was added as stabilizer to BAC used in Crosseal to prevent proteolytic breakdown of the proteins. Tranexamic acid has been used for over 20 years as an oral and intravenous antifi-brin-olytic drug. Evicel is Crosseal reformulated without tranexamic acid.
Evicel, a new, second-generation version of Crosseel received FDA approval in May 2007 and European Union approval in Oct. 2008. Evicel differs from first-generation fibrin Crosseal, in that Evicel does not contain tranaxemic acid as a stabilizer, and therefore does have the neurosurgical contraindication required of Crosseal (surgical procedures involving direct contact with cerebrospinal fluid and/or dura mater); and Evicel received approval for new, broader indications:.
Thrombin is a highly specific protease that transforms the fibrinogen contained in BAC into fibrin, resulting formation of a fibrin clot. The two components are mixed in the MixJect applicator, a special two-component mixing syringe, for application to bleeding tissue. As with other fibrin sealant products, when the components are combined, a fibrin clot in formed, which cross-links directly with exposed tissue collagen, anchoring the clot to the wound.
Evicel/Crosseal is the only commercially available liquid fibrin sealant in the U.S. that does not contain any non-human, animal-derived components. Derived from human plasma, Crosseal carries no risk of immunogenic reaction due to animal proteins, unlike fibrin sealants containing bovine-sourced materials, e.g., Tisseel and Hemaseel. Each batch of Biological Active Component 2 (formerly BAC, now called BAC2 to indicate its reformulation; containing fibrinogen) is manufactured from pooled Plasma from up to 3,600 donations, and each batch of Thrombin originates from up to 1,800 donations, with each kit originating from up to 5,400 individual Plasma donations. Both of the components and the fibrin clot they form are fully biocompatible and biodegradable.
Evicel (and formerly Crosseal) is supplied as a single use kit consisting of one vial each of frozen sterile solutions of Biological Active Component 2 (BAC2) and Thrombin, and a sterile single-use spray application device and an air tube with a 0.2 µm bacteriological filter, which is used to supply air to the device to aerosolize (spray) Crosseal, which may also be dripped onto tissues. The kit is supplied as 1 ml, 2 ml or 5 ml dosages. The two liquid components are supplied frozen in 1, 2 and 5 mL vials. The Thrombin solution contains Thrombin 1,000 IU/mL (800-1200 IU/mL thrombin, 5.6-6.2 mg/ml calcium chloride). Thrombin potency is expressed in International Units (IU) by comparison to the World Health Organization (WHO) standard. BAC2 is a sterile solution, pH 6.7-7.2, consisting mainly of a concentrate of human fibrinogen (a protein from human blood that forms a clot when combined with thrombin. BAC2 contains human fibrinogen (55-85 mg/ml) formulated with excipients: arginine hydrochloride, glycine, sodium chloride, sodium citrate, calcium chloride, and Water for injection (WFI). The BAC (first-generation product) was a sterile solution, pH 6.9-7.3, containing 40-60 mg/mL of clottable human proteins, primarily fibrinogen (and fibronectin), along with other ingre-dients: tranexamic acid, arginine hydrochloride, glycine, sodium chloride, sodium citrate, calcium chloride, and Water for injection. The Thrombin (a highly specific protease that transforms the fibrinogen contained in BAC2 into fibrin) is a sterile solution, pH 6.8-7.2, containing highly purified human thrombin and calcium chloride for activation of clotting of the final combined product. The Thrombin solution contains thrombin (800-1200 IU/ml) and excipients: calcium chloride, Albumin (Human), mannitol, sodium acetate, and Water for injection (WFI).
Vials of Thrombin and BAC are stored frozen at -18°C or colder. Once thawed, unopened vials can be stored at 2-8˚C (refrigerated) for up to 30 days. This stability of its components in the liquid state allows Crosseal to be available for immediate use when required. Both components of Crosseal have been shown to be stable for up to 24 hours at room temperature. The spray device package should be stored separately at room temperature. The dating period for Evicel and Quixil is 24 months from the date of manufacture when stored frozen below -18˚C, with an allowance for storage at 2-8˚C for up to 30 days within the dating period. The date of manufacture for each component is the date of sterile filtration for each formulated bulk.
Nomenclature: Fibrin sealant/OMRIX [BIO]; Evicel [TR]; Crosseal [TR]; Quixil [TR ex-U.S.]; Fibrin Sealant (Human) [FDA for kit]; Thrombin (Human) [FDA for a component]; Fibrinogen [FDA for a component]; fibronectin [SY for a component]; Biological Active Component (BAC) [SY; for a component of Crosseal];; Biological Active Component 2 (BAC2) [SY; for a component of Evicel]
Biological.: Studies in animals have demonstrated that Evicel is as effective as Crosseal in achieving hemostasis on hepatic wounds in rabbits and in a partial nephrectomy model in rats. A further study on clot stability in rabbits indicated that the duration of the Evicel clot in vivo is comparable to that of Crosseal.
Companies.: Crosseal was developed and is manufactured by OMRIX Biopharmaceuticals Ltd., CBER/FDA est. no. 1603, with its manufacturing facility located within MDA Blood Bank, Sheba Hospital (Ramat Gan, Israel). With the acquisition of OMRIX by Johnson & Johnson, Evicel is not marketed worldwide by its Ethicon subsidiary.
OMRIX had previously marketed the product itself in Israel under the trade name Quixil.
In Feb. 2003, American Red Cross Plasma Services, American National Red Cross (ARC), concluded an agreement with Omrix for exclusive North American/U.S. marketing and distribution rights for Crosseal.
In June 2003, Johnson & Johnson Wound Management, a division of ETHICON, INC., a subsidiary of Johnson & Johnson Co. (J&J), concluded an agreement with Omrix for exclusive European marketing and distribution rights for Quixil. In Oct. 2004, Johnson & Johnson Wound Management received exclusive North American marketing and distrbution rights for Crosseal (taking over from ARC).
In Oct. 2006, Omrix concluded an agreement with Talecris Biotherapeutics, Inc. (“Talecris”) for supply of Cryoprecipitate (cryo), a plasma fraction containing coagulation proteins, for further manufacture of BAC2 for Evicel. Prior to this, OMRIX purchased source plasma and through fractionation manufactured cryo itself. By purchasing cryo in lieu of plasma, OMRIX reduces its dependence on the availability of plasma and secures the supply of its raw material.
Omrix is building a new production facility in Israel. Expected to be complete in 2009, the additional production capacity will allow the company to meet its supply demands for the foreseeable future after 2009.
Ethicon has been marketing Quixil/Evicel in the EU and several other European countries since 2003, marketing it as an adjunct to hemostasis for general surgical use. Also, Ethicon has been marketing Crosseal/Evicel as an adjunct to hemostasis in liver surgery in the U.S. since 2004. OMRIX has been marketing Quixil in Israel since 1998 for similar indications: and through distributors in Mexico since 2000 as an adjunct to hemostasis for general surgical use.
In Nov. 2008, Johnson & Johnson (J&J) fully acquired OMRIX.
In Feb. 2011, Grifols S.A./Instituto Grifols acquired Talecris Biotherapeutics.
Manufacture: Cryoprecipitate, the starting material for BAC, and cryo-poor (cryoprecipitate-removed) plasma, the starting material for the production of Thrombin are both manufactured from pooled human plasma obtained from U.S. licensed plasma collection centers. Besides the screening of each plasma unit for viral contamination required for all plasma-derived products, the plasma is tested in mini-pools by OMRIX using Nucleic Acid Testing (NAT), i.e., polymerase chain reaction (PCR), and must be negative for hepatitis A, B and C viruses (HAV; HBV, HCV) and HIV-1. Only NAT for HCV is approved, while the other tests are considered experimental. NAT for parvovirus B19 is performed and the level of contamination is n/ot permitted to exceed 10,000 copies/ml (to restrict the viral load of parvovirus B19 in the starting plasma pool).
For BAC2 (Evicel) and BAC (1st generation Crosseal), cryoprecipitate is treated with aluminum hydroxide gel to adsorb the Vitamin K dependent clotting factors and then incubated with a solvent detergent (SD) mixture consisting of 1% tri-n-butyl phosphate (TNBP; solvent) and 1% Triton X-100 for (Tween 100; detergent) for 4 hours at 30˚C for inactivation of enveloped viruses (first virus inactivation step). The SD reagents are removed by castor oil extraction and reverse phase chromatography (C-18 column). Sucrose (1.8 g/g column filtrate) and glycine (0.11 g/g) are added as stabilizers (against heat of pasteurization), and the mixture is warmed to 37 °C under stirring and pH is adjusted to 6.8-7.4. The solution is then pasteurized by heating to 60 ± 0.5 °C for 10 hours. After pasteurization, the stabilizers used for heat treatment are removed by diafiltration and the product is concentrated by ultrafiltration. For BAC, tranexamic acid was added as a stabilizer prior to sterile filtration. For BAC2 (current Evicel), an affinity chromatography (ligand unspecified) step is used to remove plasminogen from the product, after which it is concentrated,_formulated and sterile filtered. The filtered solution is filled aseptically in 1 ml, 2 ml or 5 ml aliquots, frozen at ≤ -60 °C and stored at -30±5°C until distribution.
For Thrombin, cryo-poor plasma is applied to an anion exchange column for binding of prothrombin and activation into thrombin. The resultant thrombin does not bind to the column and is eluted with calcium chloride. Thrombin subjected to SD treatment (1%TNBP, plus 1% Triton X-100) for 6 hours at 26 ± 1°C. The SD reagents are removed by cation exchange chromatography. Mannitol (as a 15% solution), and Albumin (Human) are added to the product as stabilizers to a final concentration of 2% (w/w) and 0.2% (w/w), respectively. The stabilized solution is passed through a nanofiltration module (second viral clearance step). The filtrate is formulated with calcium chloride to 40 mM and the concentration of albumin is adjusted to 0.6%. Thrombin bulk solution is sterile filtered and aseptically filled in 1 ml, 2 ml or 5 ml aliquots, frozen at ≤- 60°C and then stored at -30±5° C.
For BAC2, the log10 reduction in viral titers after the SD process is HIV-1, >4.42; bovine viral diarrheal virus (BVDV), >4.39; pseudorabies (PRV), >3.96; encephalo-myocarditis virus (EMCV), not applicable (NA); hepatitis A virus (HAV), NA; and canine parvovirus (CPV), 0.0. Pasteurization reduces HIV-1, >4.39; BVDV, >5.46; PRV, NA; EMCV, 3.69; HAV, 2.66; and CPV, 1.33. The global reduction factors are HIV-1, >8.81; BVDV, >9.85; PRV, ≥3.96; EMCV, 3.69; HAV, 2.66; and CPV, 1.33.
For Thrombin the SD process provides reductions of HIV-1, >5.82; sindbis virus (SB), >5.31; BVDV, >4.74; PRV, >4.25; EMCV, NA; HAV, NA; and CPV, 0.0. Nanofiltration provides reductions of HIV-1, >4.36; SBV, >5.32; BVDV, NA; PRV, >5.47; EMCV, 6.37; HAV, 6.95; and CPV, 5.85. The global reduction factor is HIV-1, >10.18; SBV, >10.63; BVDV, >4.74; PRV, >9.72; EMCV, 6.37; HAV, 6.95; and CPV, 5.85.
Note, Quixel is still manufactured and marketed in the European Union, several other European countries, Mexico, Brazil and Israel (as an adjunct to hemostasis for general surgical use). Presumably, Evicell will replace Quixel in these territories after it receives approval for general surgery use.
FDA class: Biologic BLA
CBER class: Blood And Blood Derivatives
Approvals: Date = 20030321; BLA (125010/0)
Date = 20050523; BLA supplement.
Date = 20060610; BLA supplement; Indication = approval of Evicel (Crosseal formulated without a stabilizer)
Date = 20070509; BLA supplement; Indication = approval of Evicel Fibrin Sealant, i.e., approval for use as an adjunct to hemostasis in patients undergoing liver or vascular surgery when control of bleeding by standard surgical techniques is ineffective or impractical
Date = 20070706; BLA supplement; Indication = use of cryoprecipitate from Talecris for manufacture of Evicel
Date = 20080102; BLA supplement; Indication = use in general surgery
Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling, from FDA Web site, 8/26/2008]:
EVICEL Fibrin Sealant (Human) is indicated as an adjunct to hemostasis for use in patients undergoing surgery, when control of bleeding by standard surgical techniques is ineffective or impractical.
Status: FDA original approval of Crosseal was granted on Feb. 21, 2003. The approval letter did not specify any post-approval testing requirements.
On July 10, 2006, Evicel, a next-generation version of Crosseel, received FDA approval. Crosseal/Evicel, is indicated as an adjunct to hemostasis in patients undergoing liver surgery. Crosseal/Evicel is not indicated for the treatment of massive and brisk arterial bleeding, or for general surgical use.
In July 2006, OMRIX reported that it had submitted a Prior Approval Supplement (PAS) to the FDA with the results of a prospective, randomized, multi-center, Phase III controlled study comparing the hemostatic efficacy of Evicel to standard-of-care in peripheral vascular surgery in 150 patients. OMRIX submitted this PAS to expand the indication of Evicel to include vascular surgery.
Quixil was approved in the European Union in 1999 “as supportive treatment to improve haemostasis and to reduce operative and post-operative bleeding and oozing during the following procedures: liver surgery such as liver resection and reduced-size liver transplantation; and orthopaedic surgery such as total hip replacement and total knee replacement.” These indications: are broader than those FDA-approved.
On Nov. 6, 2006, Omrix filed a BLA for FDA approval of its topical human thrombin as a stand-alone product with a general hemostasis. See the Thrombin/Omrix entry (#809). In its BLA, the FDA allowed Omrix to cross reference the Chemistry, Manufacturing and Controls (CMC) and preclinical sections of its Evicel file.
In Nov. 2006, Omrix filed a BLA supplement for Evicel for general hemostasis use in surgery. FDA approval of for general hemostasis requires the completion of at least three pivotal clinical studies, including liver and peripheral vascular surgery. Evicel will likely be the first fibrin sealant in the U.S. with a general hemostasis indication in surgery, with approval expected in early 2008.
In May 2007, FDA approved Evicel. As explained by FDA, Crosseal "became Evicel in May 2007 when FDA expanded the indication to include use during vascular surgery."
In Jan. 2008, Evicel received supplemental approval from FDA for use in general surgery.
On May 23, 2005, the U.K. granted Quixil approval for use in supportive treatment during surgery for improvement of hemostasis, where standard surgical techniques are insufficient. The indications: for use are no longer limited to the procedures in which trials have been performed. It was previously only indicated for liver surgery and orthopedic surgery in large joint replacement. Quixil remains contraindicated in neurosurgery where contact with cerebrospinal fluid and dura mater could occur. The approval followed the publication of “Fibrin Sealant Guidelines” by U.K. authorities in Jan. 2005. Quixil was the first fibrin sealant to meet these new guidelines.
On Oct. 16, 2008, the European Union (EU) granted approval to Evicel, "As a supportive treatment in surgery where standard surgical techniques are insufficient for improvement of hemostasis. Evicel is also indicated as suture support for hemostasis in vascular surgery."
Tech. transfer: Solvent detergent viral inactivation was developed by and nonexclusively licensed from the New York Blood Center. For example, 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).
In Dec. 2009, the State of Israel filed a NIS 500 million ($1.32 million) lawsuit in the Tel Aviv District Court against Omrix Biopharmaceuticals Ltd. (Johnson & Johnson) and entrepreneur Robert Taub, charging that Prof. Uriel Martinowitz is the real inventor of Omrix's patent portfolio, since when Prof. Martinowitz developed the inventions he worked in the Israili Defense Force (IDF) and subsequently in Sheba Hospital which is state-owned. However, since the relevant Israel patent application has been abandoned, the
defendants argued that the Israel Court has no jurisdiction, and that the case should have been filed in the US. Apparently, J&J prevailed (with no news reported that the State won its case). In a public statement at the time, Omrix noted, "The patent authorities in Europe and the US (as well as in other countries) ruled more than a decade ago that the concepts that the government attributes to Martinovich are not new and cannot be invented, but are included in prior patents....Martinovich himself confirmed this ruling by the patent authorities, in his signed statement, in which he declared that he made no contribution to the patents...he patents cover only Omrix's unique production process of the biological sealant, which was invented and developed solely by Octopharma Ltd., and not by Martinovich.""
Trials: At the time of its FDA approval, over 7,000 patients had been treated with Crosseal since non-US marketing was initiated in 1997, with no spontaneous reports of seroconversion (infection).
The Prior Approval Supplement (PAS) filed with FDA to support expansion of Evicel indications: to include vascular surgery contained the results of a prospective, randomized multi-center Phase III controlled study comparing the hemostatic efficacy of Evicel to standard-of-care in peripheral vascular surgery in 150 patients.
A 150-patient study of Evicel in kidney surgery is currently underway.
The sBLA for general hemostasis included the results of a prospective, randomized, multi-center Phase III controlled study comparing the hemostatic efficacy of Evicel to standard-of-care in retroperitoneal or intra-abdominal surgery in 135 patients. This clinical trial is the third pivotal study performed with EVICEL and meets FDA requirements necessary for a general hemostasis indication.
Medical: Standard surgical techniques for hemorrhagic control, including suture, ligature and cautery, should be attempted prior to using Crosseal. For application, BAC and Thrombin are thawed and aspirated into the application device through the MixJect vial transfer mechanism and applied topically either by dripping or by spraying in short bursts (0.1 - 0.2 ml) to produce a thin, even layer. Crosseal forms a thin transparent elastic layer, through which the wound area can be examined. If the hemostatic effect is not complete, a second layer is applied. The amount of Crosseal required depends upon the area of tissue to be treated and the method of application. Presuming a layer of 1 mm thickness is produced by spraying Crosseal, the 1.0 mL kit can cover 20 cm2 surface area, 2.0 mL can cover 40 cm2, and 5.0 mL can cover 100 cm2.
Crosseal/Quixil has several competitive advantages over other liquid fibrin sealants on the market. It is readily available for spraying and dripping, because it can be prepared from thawed product in approximately one minute in the operating room; it results in a clot that OMRIX believes “has better adherence to tissue and greater elasticity;” it avoids the possibility of an adverse reaction associated with bovine proteinsm because it does not contain animal-derived components; and it can be refrigerated in a liquid form, thereby avoiding waste of unused product, for up to 30 days after thawing.
Market: The 2007 Average Wholesale Price (AWP) is not available (not in 2007 or 2005 Red Book). The 2004 AWPs were $750.00/5 mL kit with catheter; $140.000/1 mL vial; $280.00/2 mL vial; and $700.00/5mL vial.
With its specific indication restricted to liver surgery, U.S. sales of Crosseal had been relative-ly small. At the time of U.S. approval, OMRIX reported that only over 7,000 patients internationally had received Crosseal since its marketing started in 1997.
For 2006 and 2007, OMRIX reported $13.4 million and $19.3 million, respectively, in total revenues from direct commercial sales and sales to Ethicon and other distributors of Evicel, Quixil and Evithrom, including revenues recognized from upfront fees and milestone payments. Thus, Evicel revenue for OMRIX was less definitely less than $19 million in 2007. For calendar year 2005, OMRIX reported $7.0 million in revenues from direct commercial sales and sales to Ethicon and its other distributors of Crosseal/Quixil, including revenues recognized from upfront fees and milestone payments.
With the July 2007 approval for broader indications: (but still not yet general surgery), Ethicon, Inc., will actively promote Evicel to surgeons for procedures where a vascular anastomosis or reconstruction is performed. In addition to liver surgeons, Evicel will be marketed to peripheral vascular surgeons, cardiac surgeons (specifically for vascular components), plastic surgeons performing microvascular anastomoses, transplant surgeons (when blood vessels are connected), and trauma surgeons performing vascular repair.
Omrix “believes that the vascular surgery market is approximately twice the size of the market previously addressed with Evicel’s indication in liver surgery.”
R&D: OMRIX is developing Crosseal II/Quixil II, a second generation fibrin sealant, for expanded indications: in hemostasis; thrombin (stand-alone and flowable) for specific surgical applications; and a BHD, comprised of BAC II and thrombin embedded in a biodegradable device for the management and rapid control of bleeding, including severe or brisk bleeding, and for use on active bleeding sites in trauma and surgical patients.
Companies involvement:
Full monograph
736 Fibrin Sealant/Omrix
Nomenclature:
BAC2 [SY for a component of 2nd generation Evicel]
Fibrin sealant/OMRIX [BIO]
CROSSEAL [TR]
Evicel [TR]
Fibrin Sealant (Human) [FDA]
Fibrinogen [FDA for a component]
Thrombin (Human) [FDA for a component]
BAC [SY for a component]
Biological Active Component [SY]
fibrin sealant kit [SY]
fibronectin [SY for a component]
MixJect applicator [SY for a component of 1st generation Crosseal]
Quixil [TR outside U.S.]
FDA Class: Biologic BLA
Year of approval (FDA) = 2003
Date of 1st FDA approval = 20030321
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
blood products
fibrin
human materials used<!-- humansource -->
adw, hepatitis B virus subtype
Albumin (Human)
arginine
calcium chloride
castor oil
fibrinogen
fibronectin
glycine
heat treatment (pasteurization)
mannitol
Namalva cells
Plasma (Human)
sodium acetate
sodium chloride
sodium citrate
Sterile Water for Injection
tranexamic acid
viral (nano)filtration
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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