Hepatitis: Burnouf T

Farrugia A, Evers T, Falcou PF, Burnouf T, Amorim L, Thomas S. · Blood and Tissues Unit, Office of Devices, Blood and Tissues, Therapeutic Goods Administration, Woden, ACT 2606, Australia. · Biologicals. · Pubmed #19289290 No free full text.

Abstract: Procurement and processing of human plasma for fractionation of therapeutic proteins or biological medicines used in clinical practice is a multi-billion dollar international trade. Together the private sector and public sector (non-profit) provide large amounts of safe and effective therapeutic plasma proteins needed worldwide. The principal therapeutic proteins produced by the dichotomous industry include gamma globulins or immunoglobulins (including pathogen-specific hyperimmune globulins, such as hepatitis B immune globulins) albumin, factor VIII and Factor IX concentrates. Viral inactivation, principally by solvent detergent and other processes, has proven highly effective in preventing transmission of enveloped viruses, viz. HBV, HIV, and HCV.

Burnouf T. · Human Plasma Product Services, Lille, France. · Transfus Med Rev. · Pubmed #17397761 No free full text.

Abstract: Protein products fractionated from human plasma are an essential class of therapeutics used, often as the only available option, in the prevention, management, and treatment of life-threatening conditions resulting from trauma, congenital deficiencies, immunologic disorders, or infections. Modern plasma product production technology remains largely based on the ethanol fractionation process, but much has evolved in the last few years to improve product purity, to enhance the recovery of immunoglobulin G, and to isolate new plasma proteins, such as alpha1-protease inhibitor, von Willebrand factor, and protein C. Because of the human origin of the starting material and the pooling of 10,000 to 50,000 donations required for industrial processing, the major risk associated to plasma products is the transmission of blood-borne infectious agents. A complete set of measures--and, most particularly, the use of dedicated viral inactivation and removal treatments--has been implemented throughout the production chain of fractionated plasma products over the last 20 years to ensure optimal safety, in particular, and not exclusively, against HIV, hepatitis B virus, and hepatitis C virus. In this review, we summarize the practices of the modern plasma fractionation industry from the collection of the raw plasma material to the industrial manufacture of fractionated products. We describe the quality requirements of plasma for fractionation and the various treatments applied for the inactivation and removal of blood-borne infectious agents and provide examples of methods used for the purification of the various classes of plasma protein therapies. We also highlight aspects of the good manufacturing practices and the regulatory environment that govern the whole chain of production. In a regulated and professional environment, fractionated plasma products manufactured by modern processes are certainly among the lowest-risk therapeutic biological products in use today.

Burnouf T, Radosevich M. · Human Plasma Product Service, Lille, France. · Haemophilia. · Pubmed #12558776 No free full text.

Abstract: This review presents the current status on the use and benefits of viral removal filtration systems--known as nanofiltration--in the manufacture of plasma-derived coagulation factor concentrates and other biopharmaceutical products from human blood origin. Nanofiltration of plasma products has been implemented at a production scale in the early 1990s to improve margin of viral safety, as a complement to the viral reduction treatments, such as solvent-detergent and heat treatments, already applied for the inactivation of human immunodeficiency virus, hepatitis B and hepatitis C virus. The main reason for the introduction of nanofiltration was the need to improve product safety against non-enveloped viruses and to provide a possible safeguard against new infectious agents potentially entering the human plasma pool. Nanofiltration has gained quick acceptance as it is a relatively simple manufacturing step that consists in filtering protein solution through membranes of a very small pore size (typically 15-40 nm) under conditions that retain viruses by a mechanism largely based on size exclusion. Recent large-scale experience throughout the world has now established that nanofiltration is a robust and reliable viral reduction technique that can be applied to essentially all plasma products. Many of the licensed plasma products are currently nanofiltered. The technology has major advantages as it is flexible and it may combine efficient and largely predictable removal of more than 4 to 6 logs of a wide range of viruses, with an absence of denaturing effect on plasma proteins. Compared with other viral reduction means, nanofiltration may be the only method to date permitting efficient removal of enveloped and non-enveloped viruses under conditions where 90-95% of protein activity is recovered. New data indicate that nanofiltration may also remove prions, opening new perspectives in the development and interest of this technique. Nanofiltration is increasingly becoming a routine step in the manufacture of biopharmaceutical products.

Goubran HA, Burnouf T, Radosevich M. · Clinical Haematology Unit, Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt. · Haemophilia. · Pubmed #11122382 No free full text.

Abstract: Since HIV first burst onto the scene of transfusion medicine, the quest for viral inactivation processes for plasma and plasma products has not ceased. Sophisticated methods for improving viral safety are currently used in the industrial world. However, in developing countries, with no facilities for treating plasma, nonviral-inactivated fresh frozen plasma [FFP] continues to be used extensively, and as screening may not be optimal (or may even be absent), FFP still contributes to the spread of HIV and other infectious viruses. The feasibility of heat-treating FFP at the liquid state, in its collection bag, was explored by testing diverse conditions of temperature and duration, in the presence of biologically compatible stabilisers. Quality of the heat-treated plasma was evaluated by haematological, biochemical and animal assays. The efficiency of the method to inactivate viruses was validated using HIV and model viruses. The selected heating conditions are 50 degrees C for 3 h. The optimized combination of stabilizers is composed of 30 mM trisodium citrate, 10 g L-1 L-lysine, 12 mM calcium gluconate and 150 g L-1 sorbitol. Plasma coagulability is appropriately preserved as shown by the KCT ratio (1.4). Recovery of biological activity of most coagulation factors is higher than 70% (including fibrinogen & von Willebrand factor). Electrophoretic and immunoblotting studies did not evidence protein aggregation and/or degradation. Viral validation studies of this procedure have shown complete inactivation of HIV (> 6.6 log) in less than 1 h of treatment. A viral reduction of at least 4 log for various model viruses, including those of hepatitis A and C viruses, suggests a potential contribution of the method to diminish the risk from various blood-borne viruses. The selected formulation appears to preserve plasma protein integrity and properties. The procedure does not require sophisticated equipment but it is mandatory to monitor it carefully to ensure quality and reproducibility. If properly controlled and standardized, this approach offers an opportunity to reduce the risk of transmission of HIV and other viruses, particularly in poor countries with a high incidence of HIV.

Burnouf T, Goubran HA, Radosevich M, El-Ekiaby M. · Human Protein Process Sciences, Research and Development, 18, rue Saint-Jacques, 59000 Lille, France. · Transfus Clin Biol. · Pubmed #18538608 No free full text.

Abstract: Non-virally inactivated plasma, cryoprecipitate and cryoprecipitate-poor plasma, prepared by blood establishments, are still used in many countries in the world, in both the developing world and industrialized countries, for the treatment of various hematological disorders. In the absence of viral inactivation treatment, these fractions may be involved, in spite of increasingly sensitive viral detection methods, into the transmission of plasma-borne viruses, most critically HIV and Hepatitis B (HBV) or C (HCV). We have adapted the well-established industrial solvent-detergent (SD) viral inactivation treatment to allow its application in a small scale using a single-use plastic bag system. The procedure can be used by blood establishments, without the need to build an industrial-scale manufacturing facility. Results show a good recovery of the functional activity of plasma proteins, including coagulation factors (such as factor VIII and coagulable fibrinogen) and/or protease inhibitors (such as alpha 2-antiplasmin). Viral validation studies revealed reduction factors greater than 4.17, greater than 4.73 and greater than 4.72 for HIV, BVDV and PRV, respectively, within a few minutes of treatment. A single-use SD treatment and SD-elimination system is currently under development to allow standardized use of the procedure by blood establishments or national or regional service centers.

Burnouf T, Radosevich M, El-Ekiaby M, Satoh S, Sato T, Amin SN, Savidge GF, Goubran HA. · Human Plasma Product Services, Lille, France. · Vox Sang. · Pubmed #12609017 No free full text.

Abstract: BACKGROUND AND OBJECTIVES: Major technical developments have been made in recent years to improve the quality and safety of human plasma for transfusion and fractionation. The present study was performed to assess, for the first time, the feasibility of applying a nanofiltration process, using 75-nm and 35-nm mean pore size membranes (Planova) 75N and Planova 35N), to human plasma. MATERIALS AND METHODS: Ten apheresis plasma units were obtained from 10 plasma donors. Within 4 h of collection, plasma was subjected to leucoreduction and filtration (using 75-nm and 35-nm mean pore size membranes) at 35 degrees C, at less than 1 bar pressure. Aliquots of plasma were taken at all steps of the filtration procedure and numerous plasma quality parameters were measured. In addition, six hepatitis C virus (HCV)-positive plasma donations were experimentally subjected to the same filtration sequence and subsequently assessed by RNA polymerase chain reaction (PCR) and branched-chain DNA-quantification assays. RESULTS: Leucoreduced plasma can be reproducibly nanofiltered onto a sequence of 75-nm and 35-nm membranes, at a flow rate of 450 ml/h and a temperature of 35 +/- 0.5 degrees C. Some protein dilution, or loss, was found during filtration, but the plasma filtered through membranes with a mean pore size of 75 nm and 35 nm met in vitro specifications for use in transfusion or fractionation. There were no signs of activation of the coagulation system. HCV-positive plasma donations became negative, as judged by PCR and branched-chain DNA assay results, after filtration through the 35-nm membrane. CONCLUSIONS: It is possible to apply a 75 + 35-nm filtration process to leucoreduced human plasma. This technology may have important future benefits in improving the quality and safety of plasma, by removing blood cell debris and infectious agents.