Status: recently approved in U.S.; marketed in Europe

Organizations involved:

Thermogenesis Corp. – Manuf.; R&D; Tech.; USA mark.

Misc. companies – Europe mark.

Cross ref.: See the entries for Fibrin Sealants (#735) and the Factor VIII, cryoprecipitate (#716).

Description: The CryoSeal FS System is a automated cryogenic separation device (free-standing machine) and companion sterile blood processing disposables used to prepare fibrin sealants, i.e., cryoprecipitate rich in fibrinogen (and Factor VIII other clotting factors) and thrombin, from platelet-depleted plasma in about an hour from a unit of blood taken from a single patient for autologous transfusion (back into the donor). The CryoSeal FS System simultaneously produces fibrin sealant components (fibrinogen-rich cryoprecipitate and thrombin) from a single unit of autologous or single donor plasma in about one hour. In addition to fibrinogen and thrombin, CryoSeal Fibrin Sealant also contains concentrated amounts of critical clotting factors, including Factor VIII, Factor XIII, von Willebrand’s Factor and fibronectin.

CryoSeal Fibrin Sealant produces four sterile sets of two syringes filled with equal amounts of cryoprecipitate and thrombin. Total volume of sealant produced is 6-16mL. The cryoprecipitate provided by the CryoSeal FS device is comparable to conventionally (non-automated) manufactured autologous cryoprecipitate (see the Factor VIII, cryoprecipitate entry, #716). The cryoprecipitate can be stored at -18ºC or colder for up to an entire year. Once thawed, cryoprecipitate maintains effectiveness for up to 6 hours (at 34-37ºC).

The CryoSeal FS system consists of two major components, a cryogenic or freezing device and a sterile plastic device which together can prepare both components of fibrin sealant from a single unit of plasma. The cryogenic device uses a heat transfer plate to control plasma freezing and thawing. This results in a separation of cryoprecipitate from the plasma. Active thrombin is harvested from a reaction chamber of the Thrombin Activation Device (TAD). Active thrombin and cryoprecipitate are collected in three pairs (16 mL each) of sterile over-wrapped syringes and stored frozen at -80ºC until just prior to use.

To prepare fibrin sealant for use, both the cryoprecipitate and thrombin fractions are thawed. Mixing of the fibrinogen- and thrombin-rich fractions in the supplied applicator results in formation of clotted fibrin, providing an adhesive gel useful for sealing and adhering bleeding tissues during surgery.

The cryoprecipitate prepared by CryoSeal FS onsite from blood from a single patient contains a mixture of patient Plasma-derived proteins, unlike Tiseeal (see related entry) which uses purified proteins manufactured in large scale. CryoSeal FS is the first commercial fibrin sealant produced solely from human plasma proteins, compared to other commercially available surgical sealants which may contain bovine substances such as aprotinin, collagen, thrombin, or albumin, which increase the risk to patient of viral or prion infection and/or allergic responses. Traditional blood bank preparations of Cryo (cryoprecipitate) comparably contain high concentrations of antihemophilic factor (Factor VIII) and fibrinogen, but require several days, numerous pieces of laboratory equipment, and more staff handling to prepare. The efficiency or yield of the CryoSeal FS production process is poor, but the procedure itself is simple and quick; and the small volume of plasma required allows use in the preoperative autologous setting. CryoSeal FS components are prepared in a closed system, typically away from autologous plasma, which eliminates the infection risks associated with pooled plasma products. CryoSeal FS is 100% human and contains no bovine or animal components and no synthetics.

The Fibrin Sealant Warming Tray part of the system warms Fibrin Sealant syringe sets and then maintains the CryoSeal Fibrin Sealant at approximately 35ºC until surgical use. The warming tray can hold up to three syringe sets at one time. Features such as one-touch activation, automated 10-minute cycle, and LED display of cycle status make the Fibrin Sealant Warming Tray convenient for use in the operating room, and eliminate the use of using water baths and warm towels, which may cool down.

Nomenclature: Fibrin Sealant/Thermogenesis [BIO]; CryoSeal Fibrin Sealant System [TR]; CryoSeal FS System [SY]; CSS [SY]; ryoprecipitate plus thrombin, autologous [SY]

Companies.: Thermogenesis developed, manufactures and markets CryoSeal FS in the U.S.

Affinity Supplies, LLC markets CryoSeal FS in Ireland. BitMedical GmbH markets CryoSeal FS in Switzerland. Asahi Kasei Medical Co., Ltd. markets CryoSeal FS in Japan. Investigacion Bio-tecnologica (IBT SL) markets CryoSeal FS in Spain and Portugal. Interlux Joint-Stock Company, Ltd. markets CryoSeal FS in Lithuania and Latvia. Vivacom s.r.o. markets CryoSeal FS in the Czech Republic and Slovakia, Amed Therapeutics Ltd. markets CryoSeal FS Greece.

Manufacture: CryoSeal FS involves a cryogenic device (CS-1 ) featuring a temperature-controlled rocker plate and a clear, plastic, single-use plasma-processing container (CP-3) that rests on the rocker plate. The CP-3 plasma processing disposable is comprised of a cryoprecipate chamber, Thrombin Processing Device (TPD) and four pairs of overwrapped syringe sets. The CryoSeal FS System consists of the CS-1 instrument, disposables and accessories.

Upon initiation of Cryo processing, the device automatically transfers the donor plasma from a transfer pack to the processing container by a peristaltic pump in a closed system of tubing. The device then lowers the temperature and sets the plate in motion to rapidly freeze the plasma to -27°C. The rocker plate temperature is then raised to 2°C to thaw the plasma while rocking the plate in a manner that causes the insoluble clotting and adhesive proteins (Cryo) to agglomerate and migrate to the tip of the processing container for removal by an attached syringe. The residual Cryo-poor plasma is then automatically transferred back to the transfer pack to yield a Cryo volume of ~10.0 mL. During component harvesting, each syringe set (one thrombin syringe and one cryoprecipitate syringe) is sterile filled in equal volumes. Individual syringe sets may be stored frozen for up to six months at -18°C or colder until use. These prepared syringe sets are transferred to surgery for use as needed. The surgeon then chooses the appropriate application tip for use in the surgical procedure.

CryoSeal FS provides higher concentrations and yields of factor VIII and fibrinogen than conventional/classic cryoprecipiate preparations. This process is highly automated and takes ~1 h to complete the freeze–thaw cycles, markedly less than traditional blood bank methods. The Cryo prepared by CryoSeal FS is available for either immediate clinical use or freezing and long-term storage.

FDA class: Medical Device; PMA

Approvals: Date = 20070726; PMA (BP060001/0)

indications: [full text of the "Indications” section of product insert/labeling];

The CryoSeal FS System is intended for the preparation of fibrin sealant from a unit of autologous plasma in a closed, sterile fluid path. The autologous fibrin sealant is indicated for use as an adjunct to hemostasis on the incised liver surface in patients undergoing liver resection when control of bleeding by standard surgical techniques is ineffective or impractical.

Status: In March 2001, CryoSeal FS System received the CE-Mark approval in the European Union.

Thermogenesis filed a Pre-market approval (PMA) application with FDA for approval of CryoSeal FS as an adjunct to hemostasis in liver resection surgeries. In May 2007, Thermogenesis received an approvable letter from FDA confirming the device is approvable, but requesting further information, including submission of final labeling, operator manual, and related documents. Thermogenesis anticipated completely responding to FDA by July 1. The PMA was granted on July 27, 2007.

indications: [Full text of the "Indications:" section of product insert/labeling]:

The Cryoseal FS system is intended for the preparation of fibrin sealant from a single unit of autologous human plasma only in a closed, sterile fluid path. The autologous fibrin sealant is indicated for use as an adjunct to hemostasis on the incised liver surface in patients undergoing liver resection when control of bleeding by standard surgical techniques is ineffective or impractical.

Tech. transfer: Thermogenesis has received a number of U.S. and other patents covering aspects of CryoSeal FS. U.S. 5,520,885; 5,750,658 15; and 5,939,023, each titled “Fibrinogen processing apparatus, method and container,” claim apparatus for cryogenic extraction of fibrinogen from human blood. Other U.S. patents include 5,557,943, “Rapid cooling through a thin flexible membrane;” 5,939,023, “Fibrinogen processing apparatus method and container;” 6,077,447, “Fibrinogen apparatus, method and container;” 6,274,090, “Apparatus and method of preparation of stable, long term thrombin from plasma and thrombin formed thereby;” 6,472,162, “Method for preparing thrombin for use in a biological glue;” 7,182,107, “Biological adhesive loading station and method;” and 7,056,722, “Apparatus and method of preparation of stable, long term thrombin from plasma and thrombin formed thereby.”

Trials: In Aug. 2001, an IDE was filed with the FDA requesting approval to initiate Phase III trials with CryoSeal FS as an adjunct to hemostasis for cancer patients undergoing liver resection surgery against a control, Instat, a collagen absorbable hemostat. In June 2005, enrollment of the 150 patients at multiple U.S. teaching hospitals was completed. In Oct. 2005, Thermogenesis reported that the trial met its primary endpoint of equivalency, i.e., that results obtained using the CryoSeal FS System were “non-inferior” to results achieved with Instat. The data showed statistical significance for “non-inferiority”, and patients treated with CryoSeal FS actually showed “superiority”, demonstrating statistically significant quicker time to hemostasis (cessation of bleeding) versus the control group (p ≤ 0.001). Median time to hemostasis in 100 CryoSeal FS recipients was (+/-S.D) was. 3.43 +/-3.41 minutes, compared to 8.65 +/-10.18 minutes for Instat., with 92% of CryoSeal FS patients achieving hemostasis in < 10 minutes, compared to 60.40% for Instat. There were no unanticipated adverse device effects (UADEs) reported by the physicians to either the study or control materials.

Medical: Thermogenesis reports, “Because of the volume of fibrin sealant made available with the CryoSeal FS System, physicians both in Japan and Europe have reported finding CryoSeal FS System well suited for large bleeding surgical applications such as cardiac, ear, nose and throat (ENT), orthopaedic, neurological, and gastrointestinal (GI) surgeries.”

Market: Depending on its price and perceptions of its cost-benefits, the CryoSeal FS System, with its convenient automation, may find a ready market in the U.S.