Examples of approaches used for the manufacture of human plasma products are provided in recent WHO guidelines [109], and a CPMP note for guidance provides recommendation on production of immunsera [19]. validated for the manufacture of some human IgG products, appear to provide the best potential for viral inactivation of antivenoms. As many manufacturers of antivenoms located in developing countries lack the resources to conduct formal viral validation studies, it is hoped that this review will help in the scientific understanding of the viral safety factors of antivenoms, in the controlled implementation of the manufacturing steps with expected impact on viral safety, and in the overall reinforcement of good manufacturing practices of these essential therapeutic products. 1.?Introduction Antivenoms are important biopharmaceutical products made from the plasma of immunized horses or sheep. They are used in human medicine to treat the potentially severe pathophysiological complications resulting from the bites and stings from various animals, such as snakes, scorpions, spiders, cnidarians, lepidopterans or fishes, as well as from intoxications with plants [1], [2]. Envenomings are a serious health problem world-wide and are most particularly dreadful in rural areas of the developing world [3], where shortage of antivenom Flavopiridol (Alvocidib) products [4] and lack of sufficient medical facilities explain numerous fatalities [5], [6]. Snake bites represent the major cause of envenoming. Case fatality associated with some snake bites reach 50% or more but can be reduced to less than 5% through antivenom therapy, the only available current treatment [5], [7], [8], [9]. Global mortality from snake bites may range from 50,000 to 100,000 per year, but these figures are likely underestimated [5], [10]. Viperid snake bite envenoming induces local effects, such as swelling, pain, necrosis, hemorrhage and blistering, often accompanied by secondary contamination [9]. Systemic viperid envenoming is usually characterized by a complex pathophysiological profile including coagulopathy, hemorrhage, hypovolaemia, shock and acute Flavopiridol (Alvocidib) renal failure [9], [11]. Progressive paralysis may be caused by elapid snake venom neurotoxins, and by some viperid venoms displaying neurotoxic effects. Some elapid venoms also induce local necrosis and rhabdomyolysis [9]. Snake bite survivors may have major chronic physical and neurological disability. Scorpion stings are the second major cause of human fatalities from envenoming (probably amounting to several hundreds per year). Scorpion venoms contain toxins which target sodium, potassium, calcium and chloride channels, causing direct effects and release of neutrotransmitters such as acetylcholine and catecholamines, inducing intense local pain Rabbit Polyclonal to PAR1 (Cleaved-Ser42) and potentially fatal neurotoxic and hemodynamic disturbances [12]. The role of antivenom in the treatment of scorpion stings and other arachnids remains controversial but several reports support their manufacture and use, particularly in severe cases [13], [14]. Fatalities have also occurred from envenoming by jellyfish, and venomous fishes. Long-term anecdotal experience supports the beneficial effect of stonefish antivenoms [2], but those may need to be given very early to fight a rapid onset of cardiotoxicity. Stings by cnidarians, lepidoptera, centipedes and coneshells and bites by spiders, ticks and one genus of octopus, probably account for about 100 deaths per year [5]. Finally, envenomings by massive attacks of Africanised bees cause some 30 deaths each year in the Americas [5]. Antivenoms are most often made by fractionation of plasma of horses (less frequently sheep) that have been immunized with crude venoms [1]. Pooled hyperimmune plasma is usually processed to purify the horse immunoglobulin G (IgG) fraction that may be subjected to enzymatic treatment to obtain F(ab)2 and Fab antibody fragments, and caprylate or ammonium sulphate precipitation to improve their purity [1]. To some extent, some manufacturing steps have features similar to those used to prepare human plasma-derived IgG. Although there is no known transmission of Flavopiridol (Alvocidib) any infectious agent through.