The safety of fibrin sealants

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Abstract

Fibrin sealants are prepared from fibrinogen, thrombin and sometimes also factor XIII that have been purified from human plasma. Bovine aprotinin is also included in some preparations. Each of these components has the potential to carry blood-borne pathogens, albeit at a very low frequency. In order to minimize the risk of viral transmission from commercial fibrin sealants, plasma donations undergo a series of procedures that contribute to avoiding, inactivating and eliminating potential contaminants.

The procedures for selection and screening of plasma donors, and the testing of donated plasma, incorporates highly sensitive molecular techniques (e.g. PCR testing) and contributes significantly to reducing the theoretical possibility of viral transmission. The starting material for bovine aprotinin is also carefully selected, and the manufacturing process rigorously assessed, to minimize the putative risk of transmission of bovine spongiform encephalopathies.

The manufacturing process for commercial fibrin sealants comprises a range of procedures, including heat treatment (e.g. pasteurization, dry or vapor heating), filtration, solvent/detergent treatment, precipitation, pH treatment and chromatography. Some steps are an inherent part of the purification process and others (e.g. pasteurization, nanofiltration) are deliberately introduced to inactivate/eliminate potential pathogens.

Current manufacturing processes provide a very high degree of safety for fibrin sealants. In 20 years of worldwide use, there have been no known cases of hepatitis or HIV transmission associated with the use of commercial fibrin sealants.

Introduction

Human plasma proteins achieve a high margin of viral safety and are associated with a very low risk of viral transmission. The safety of commercial plasma-derived products is ensured by four complementary approaches: (1) careful selection of blood or plasma donors and donations; (2) extensive testing of the donation for markers of disease; (3) the rigorous removal of infectious human pathogenic viruses by a range of protein purification methods; and (4) the use of efficient virus-inactivation methods during the manufacturing process. The methods used to avoid, inactivate and eliminate potential contaminants are critical to the production and preparation of all blood products and warrant careful consideration.

Fibrin sealants consist of four highly purified active components. Three of the four components — fibrinogen, thrombin and factor XIII — are derived from human plasma. The fourth, aprotinin, is derived from bovine lung. The purification and fractionation of these components, regardless of the source, is a multistep procedure.

Noncommercial fibrin sealants are associated with a higher risk of viral transmission than commercial fibrin sealants. Blood samples and plasma donations collected in the hospital blood-bank setting come from a relatively small donor pool and may be used for autologous donation, homologous donation or directed donation. All donations are carefully screened to reduce the risk of viral transmission. Autologous and homologous samples are associated with a lower level of viral markers than the overall population. Samples given as directed donations (i.e. from the patient’s family, friends and colleagues) are reported to have a similar level of viral markers as the overall population. Blood donated at a blood bank undergoes less rigorous testing for viral markers than plasma used in commercial fibrin sealants. Moreover, noncommercial fibrin sealants do not undergo the same virus inactivation and elimination procedures that are used in commercial production. These two factors result in a higher risk of viral transmission being associated with blood-bank derived fibrin sealants.

The aim of this paper is to highlight the methods used in the production of commercial fibrin sealants that avoid, inactivate and eliminate potential contamination, and show how these methods contribute to the safety of the final product.

Section snippets

Plasma donor selection and screening

Firstly, plasma donors are carefully selected and blood donations are screened for viral contamination. This selection and screening procedure excludes people from donation if they have certain high-risk factors such as a history of (or likely exposure to) relevant diseases (HIV, hepatitis) and certain behavioral risk factors (e.g. IV drug abuse or high-risk sexual behavior) and contributes significantly to the reduction of viral transmission. The screening of donated blood for infectivity is

Bovine material

All therapeutics originating from bovine sources carry a potential risk of viral and bovine spongiform encephalopathy (BSE) contamination. To assure the safety of final products, tissue of bovine origin is rigorously tested [6], [7]. The purification process used in the production of purified bovine aprotinin has been validated in an attempt to ensure effective elimination/inactivation of potential viral and BSE contaminants [6], [7].

Additionally, bovine lung tissue is only taken from animals

Viral inactivation and elimination

Plasma derivatives and bovine lung tissue undergo a variety of procedures during processing, which involve viral inactivation and elimination [14], [15] (Table 1). The aim of this multistep process is to reduce the potential risk of viral transmission for blood products. This section of the review gives a brief description of the types of viral inactivation and elimination processes used in the commercial manufacture of plasma-derived medicines.

Plasma fractionation is reported to reduce the

Nucleic acid amplification tests (NAT) and polymerase chain reaction (PCR)

PCR is now widely accepted and used as a sensitive molecular biology technique to amplify known DNA and/or RNA sequences in biological fluid and tissue samples for subsequent detection and quantification. In recent years there has been considerable progress in the amplification technology and its use to detect blood-borne viruses in manufactured blood products has the potential to reduce the risk of viral transmission and ensure the safety of the final product.

PCR is a very sensitive nucleic

Viral reduction steps used in the production of fibrin sealants

Plasma samples are collected from nationally licensed blood transfusion and apheresis centers. These samples are used in the production of fibrin sealant components i.e. fibrinogen, factor XIII and thrombin. Plasma donors are carefully selected and the donated units are screened in accordance with current legal requirements [29], [30].

Once screened, only plasma from healthy donors, that is negative for Hepatitis B surface antigen and antibodies against HIV-1/2 and HCV, is used to produce

Summary

The careful selection of blood or plasma donors and bovine materials, along with the rigorous viral elimination and inactivation steps involved in fibrin sealant production have made it possible to produce fibrin sealants with exceptional safety records. In 20 years of worldwide use, no commercial fibrin sealant product has been reported to be responsible for an incidence of hepatitis or HIV transmission. With the continued development and incorporation of screening techniques, the risk of

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