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Notes: The demonstration of iatrogenic transmission of Creuzfeldt–Jakob disease (CJD) through therapeutic interventions led to substantial concerns in communities requiring blood products in the 1980s and 1990s. These concerns led some regulatory authorities to adopt a very precautionary approach and require recall of plasma products, including factor concentrates, which included donors at risk of CJD. The FDA's approach on recall contributed to a substantial lack of plasma products on the world market in the mid- to late 1990s. Growing epidemiological evidence of non-transmission of CJD to humans through blood, as well as demonstration of the plasma fractionation system's ability to eliminate CJD-type agents, led the FDA to rescind its measures for product recall in 1998.Although no evidence exists that the variant strain of CJD (vCJD) will behave any differently to the classic strain (cCJD) of the disease during fractionation, indications that higher levels of the strain may be present in the blood in vCJD, as well as the uncertainty regarding the epidemiology of the disease, has led to a new round of precautionary measures aimed at minimizing vCJD risk. Currently, the traditional approach to product safety through appropriate donor selection, screening using laboratory tests and systematic pathogen elimination is not completely possible for addressing the risk of vCJD. The only definite risk factor for vCJD is residence in a country where meat products from cattle with bovine spongiform encephalopathy (BSE) have been consumed; currently this is predominantly the United Kingdom but the appearance of BSE in other European countries has stimulated non-European regulatory authorities to defer blood donors from most of Europe. There is currently no screening test available for vCJD. Plasma fractionation techniques fortuitously appear to eliminate substantial amounts of vCJD like agents but only one pathogen eliminating technique, nanofiltration, has been proposed for specifically eliminating vCJD-like agents.Despite the current uncertainty, it is possible to be cautiously optimistic regarding the safety of factor concentrates from the risk of vCJD. An accumulating body of evidence suggests that it is unlikely that the plasma pool from countries with moderate BSE epidemics will contain sufficient levels of vCJD agent to lead to an infective final product. Nevertheless, the development of a blood screening test and more dedicated elimination methods are high priorities for the blood industry as it faces this new threat. The community of blood product users, including people with haemophilia, need to be in a position to make an informed choice regarding the risk of this new agent. Such a choice needs to take into account the alternatives to plasma product therapy such as recombinant concentrates and the risks to product supply ensuing from an excessive reliance on one form of product.

Notes: The past decade has seen a consolidation of the safety measures built into the manufacture of coagulation factor concentrates for people with haemophilia. The scientific developments of the 1980s have been fully reflected in the manufacturing principles and the regulatory control of concentrate production, so that the safety of concentrate therapy now exceeds the safety of normal blood transfusion. A clear understanding of the epidemiology of the transfusion-transmitted viruses allows the selection of donors with a satisfactory safety profile. Source material for plasma-derived concentrates is now screened with sensitive tests that detect viral infection in donors at a very early phase in the viral life cycle. This decreases the potential viral load to levels that are easily eliminated by well-accredited viral inactivation procedures. These measures have ensured a high level of assurance regarding the safety of products from the traditional transfusion-transmitted infections. However, testing for some transfusion-transmitted viruses does not yet form part of mainstream blood screening; alternative strategies based upon the particular needs of pooled plasma product recipients may be more feasible. Whereas the risk of emerging pathogens has to be kept constantly under review, four such viruses identified over the 1990s have proven to be of little relevance to plasma product recipients and the need for measures specifically directed against them is debatable. The risk of variant Creuzfeldt–Jakob Disease (vCJD) is a special case of an emerging infection that is insufficiently well characterized to allow a conclusive assessment of its role in the safety of concentrates; however, data regarding the capacity of concentrate manufacturing methods to clear the putative agent are encouraging. The relative uncertainty surrounding vCJD has caused the influential regulatory authorities of North America to take a precautionary approach regarding the selection of blood donors. This is having an effect on the supply of factor VIII concentrates and has possibly affected the rate at which developed countries have switched to recombinant products. The safety of recombinant products continues to be supported through patient monitoring, and the new generation of plasma protein-free products will further enhance the role of these products as the treatment of choice with people with haemophilia. However, their cost-effectiveness relative to the current generation of plasma-derived products makes it unlikely that they will be accessible by developing countries. The dependence of most of the world's population of people with haemophilia on a safe and sufficient blood supply will therefore continue into the foreseeable future, and with it the need to maintain constant vigilance on blood safety matters.

Notes: Haemophilia care and treatment products have greatly improved over the past 2 decades. Transitions in treatment produced by these changes were accompanied by the emergence of unexpected risks and new complications. In order to provide the best comprehensive care to patients with haemophilia, healthcare providers periodically need to re-evaluate and adjust their management and therapeutic products to prevent or minimize the effects produced by the emerging issues. For example, reducing the effects of infectious agents remains the highest priority for the haemophilia community because of the high level of morbidity and mortality that has resulted from earlier therapeutic agents. In many countries, the goal has been to achieve absolute zero risk for infectious agents. In some instances, the screening procedures to achieve these goals reduced the availability of plasma needed for manufactured derivatives and produced another emerging risk, shortages of clotting factor preparations. Similarly, better diagnostic methods identified other potential agents that were not inactivated by current technology. Likewise, immune tolerance regimens and the prophylactic management of haemophilia introduced different therapeutic delivery systems with their own risks. The drugs used to manage diseases such as human immunodeficiency virus (HIV), which were transmitted by products manufactured before mid-1980, create their own set of risks for this community.Topical emerging risks of treatment, including variant Creutzfeldt–Jakob disease, an assessment of its risks and impact, the complications of using indwelling catheters, and the role of protease inhibitors used to treat HIV may have on bleeding complications of haemophilia are discussed.

Notes: Summary.  The provision of concentrates of the deficient coagulation factors is an essential component of the provision of comprehensive haemophilia care. Their safety, quality and efficacy need to be assured independently of the measures dictated by the market and the individual manufacturers. Over the past 20 years, this assurance has become the role of regulatory authorities, which in the developed world have generated a framework that assesses haemophilia products as medicines in the highest category of risk relative to other therapeutic agents. Systems of official regulation mandating standards and other measures are now coupled with voluntary standards adopted by industry bodies as additional features of a comprehensive nexus of arrangements contributing to product quality and risk minimization. Currently, the regulation of products for haemophilia in less developed economies relies on reference to decisions in the first-world authorities. This may not always result in optimal outcomes as most of the haemophilia care in the developing world is through local plasma and cryoprecipitate, which are not subject to the oversight of mainstream regulators. Furthermore, the emergence of companies based outside the developed world and seeking to supply the emerging economies of the developing world with haemophilia concentrates has necessitated new strategies for regulation that are independent of the established frameworks. Overall, the principles used by mainstream agencies may be applied in all environments seeking to assure the quality of haemophilia care. Applied properly, they can contribute to maintaining the delivery of a form of therapy that is nowadays amongst the safest in therapeutic practice. A rigid interpretation can seriously impede access to treatment, and therefore the development of independent expertise and appropriate strategies in assuring product safety and quality in the developing world is essential if patient safety and access to products can be assured.

Notes: Summary.  Plasma may be procured for use as a therapeutic product or as a raw material for manufacture of other products, and may be collected as a by-product of whole blood, or as a plasma donation from aphaeresis. When collected for fractionation, the quality and safety of the plasma are intimately linked to the quality and safety of the manufactured plasma derivatives. High quality plasma can be obtained either from whole blood or from plasmapheresis; quality can, however, be adversely affected by poor storage conditions after collection. Quality standards for plasma for fractionation are necessarily different than for plasma for transfusion and, with modern fractionation methods, certain quality aspects become less relevant. Similarly, the relevance of certain recent technological advances, such as nucleic acid testing (NAT), for maximizing the safety of plasma for fractionation are questionable, although their introduction through the linkage of recovered plasma to whole blood collection can improve the safety of fresh blood components. Viruses that are not screened for at blood banks may also be excluded from the plasma pool they are more clinically relevant when multiple products made from a pool may infect a large number of recipients, in contrast to components given to one or a small number of patients.

Notes: In preliminary studies on the stability of recombinant factor VIII (rFVIII) concentrates post reconstitution, a rise in potency to 200% of labelled values was observed in concentrates stored at 22 °C over 24 h. This was observed in potency estimates by the one-stage clotting, but not the two-stage clotting or chromogenic assays, and was not observed for intermediate-purity product derived from plasma (IPVIII). Use of human serum albumin (HSA), rather than the usual bovine material (BSA), to dilute product for the stability study abolished the rise in potency. Incorporating purified von Willebrand Factor (VWF) in the diluent buffer abolished the rise observed in BSA. A similar rise was observed upon incubating rFVIII in the presence of 10−4 u of thrombin per mL in HSA buffer. Potency estimates using the HSA in the dilution buffer resulted in severe underpotency in relation to the label claim when using the two-stage clotting and the chromogenic assays, but not the one-stage clotting assay. Predilution in severe haemophilic plasma restored potency levels to those claimed. We conclude that (i) commercial preparations of BSA may be unsuitable for inclusion in buffers for rFVIII studies; (ii) FVIII in rFVIII concentrates is exquisitely sensitive to activation by thrombin, presumably as a result of the lack of VWF; (iii) accurate potency estimation in the two-stage assay systems requires VWF in the assay system.

Notes: Summary.  During the past two decades, the improvement of therapeutic agents for the management of haemophilia has created the opportunity for individuals with haemophilia to live normal lives. However, in some instances, the progress made has been accompanied by emergence of unexpected risks and other new complications. A number of viruses have either emerged, or become greater risks to people with haemophilia. In addition, the drive of many countries towards self-suffiency in blood products may in fact be endangering people with haemophilia by restricting blood donation to a pool of donors with high infection risk, discouraging commercial interests from developing safer products, and discouraging use of ‘foreign’ products even where that may be the safer option. Gene therapy for haemophilia, although an encouraging new treatment, has brought with it a number of adverse events, including risk of virus infection and development of carcinomas. The risk of inhibitors is still the most important problem for people with haemophilia, and a recent report showed that the type of factor concentrate does not impact significantly on this risk. Despite the advent of new and promising treatments for haemophilia, heathcare providers must be alert to new risks posed by them.

Notes: Summary.  While many developed countries are moving to recombinant coagulation factors as their preferred modality for delivering haemophilia care, the cost of these products currently impedes their access by developing countries. A number of options are available to these countries for the provision of plasma-derived therapeutic products. The decreasing market for plasma-derived coagulation factors in the developed world is leading to the generation of a surplus of these products and an ability to offer them outside their traditional markets if prices are affordable. Current indications are that the commercial fractionation industry of the developed world has an excess capacity in both available plasma and fractionation plants. It would seem that accessing this capacity might have attractions for the developing world. Countries wedded to achieving self-sufficiency in haemophilia products may elect to develop a strategy for fractionating domestically sourced plasma. This may be achieved by the generation of a capacity to fractionate within the country or by contracting the fractionation to an external agency overseas. However, reliance on domestic plasma should not be allowed to impede access to sufficient and safe coagulation products. Irrespective of the route chosen, products need to attain satisfactory compliance to standards for safety, quality and efficacy. This is best done through alignment of the products with the requirements of credible regulatory agencies. While the approval of the mainstream regulators of the developed world affords considerable assurance regarding product quality, the increasing efforts made by fractionation agencies in the developing world to attain best practice is commendable and augurs well for the enhancement of haemophilia care in these countries.

Notes: Summary.  The survival and well-being of people with haemophilia depends on the supply of safe therapeutic products. Safety and supply are entirely intertwined principles; in the absence of adequate amounts of coagulation products, safety measures may be compromised in order to enhance supply, leading to risks which may result in morbidity and mortality. As haemophilia therapy has emerged through the development of blood transfusion and plasma fractionation, the safety of the blood supply in general has had a strong effect on haemophilia care. Despite the gradual detachment of haemophilia care from blood transfusion through the use of recombinant products, the majority of the world's population with haemophilia in the developing world will be reliant on blood products for the foreseeable future. It is, therefore, important to continue efforts for a safe and sufficient blood supply worldwide. As such a blood supply develops, possibly in tandem with an independent plasma fractionation industry, the level of haemophilia care should improve with the gradual introduction of concentrates for the ultimate goal of covering all aspects of care. Constant vigilance for the threat of blood-borne pathogens should be linked to considerations of how these products are to be manufactured. This should be governed entirely by considerations of safety and pharmaceutical competence. Of equal importance is a governmental capacity to oversee the entry and maintenance of these products on the market. While it is not possible for all countries to have a regulatory authority of the same status as that of the developed countries, it is perfectly feasible to develop a set of basic principles which allow an assessment of basic product safety, quality and efficacy to be made.

Notes: The ovaries of 501 female eastern Atlantic bluefin tuna (Thunnus thynnus Linnaeus, 1758) captured in the Mediterranean Sea from May to September between 1998 and 2004 were analysed histologically. Body size at median sexual maturity (L50) was 103.6 cm fork length (FL), while 100% maturity was reached above 135 cm FL. The age analysis, based on the count of the translucent zones of the first spiniform ray of the first dorsal fin, showed that most of the specimens with FL = L50 were 3 years old while 100% maturity was reached between 4 to 5 years. The reported evidence indicates that for the eastern Atlantic bluefin tuna stock, the size and age of first sexual maturity of females was lower than in the western Atlantic stock.