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How Antivenom Is Made During A Global Shortage - Big Business - Business InsiderAntivenom manufacturing -
Side effects may be severe. Versions are available for spider bites , snake bites , fish stings , and scorpion stings. Antivenom was first developed in the late 19th century and came into common use in the s. Antivenom is used to treat certain venomous bites and stings. In the US, approved antivenom, including for pit viper rattlesnake , copperhead and water moccasin snakebite, is based on a purified product made in sheep known as CroFab.
coral snake antivenom is no longer manufactured, and remaining stocks of in-date antivenom for coral snakebite expired in fall , leaving the U. without a coral snake antivenom.
Efforts are being made to obtain approval for a coral snake antivenom produced in Mexico which would work against U. coral snakebite, but such approval remains speculative. As an alternative when conventional antivenom is not available, hospitals sometimes use an intravenous version of the antiparalytic drug neostigmine to delay the effects of neurotoxic envenomation through snakebite.
A monovalent antivenom is specific for one toxin or species, while a polyvalent one is effective against multiple toxins or species. The majority of antivenoms including all snake antivenoms are administered intravenously; however, stonefish and redback spider antivenoms are given intramuscularly.
The intramuscular route has been questioned in some situations as not uniformly effective. Antivenoms bind to and neutralize the venom, halting further damage, but do not reverse damage already done.
Thus, they should be given as soon as possible after the venom has been injected, but are of some benefit as long as venom is present in the body. Since the advent of antivenoms, some bites which were previously invariably fatal have become only rarely fatal provided that the antivenom is given soon enough.
Antivenoms are purified from animal serum by several processes and may contain other serum proteins that can act as immunogens. Some individuals may react to the antivenom with an immediate hypersensitivity reaction anaphylaxis or a delayed hypersensitivity serum sickness reaction, and antivenom should, therefore, be used with caution.
Although rare, severe hypersensitivity reactions including anaphylaxis to antivenom are possible. Although it is a popular myth that a person allergic to horses "cannot" be given antivenom, the side effects are manageable, and antivenom should be given rapidly as the side effects can be managed.
Most antivenoms are prepared by freeze drying synonym, cryodesiccation, lyophilization. The process involves freezing the antisera, followed by application of high vacuum. This causes frozen water to sublimate. Sera is reduced to powder with no water content. In such an environment, microorganisms and enzymes cannot degrade the antivenom, and it can be stored for up to 5 years [at normal temperatures].
Antivenoms act by binding to and neutralizing venoms. The principle of antivenom is based on that of vaccines , developed by Edward Jenner ; however, instead of inducing immunity in the person directly, it is induced in a host animal and the hyperimmunized serum is transfused into the person.
They are not immediately inactivated by heat, however, so a minor gap in the cold chain is not disastrous. The use of serum from immunized animals as a treatment for disease was pioneered in by Emil von Behring and Shibasaburo Kitasato , who first demonstrated that the infectious diseases diphtheria and tetanus could be prevented or cured using transfusions from an immune animal to a susceptible one.
Natural immunity of snakes to their own venom was observed at least as long ago as , by Felice Fontana in his work Ricerche Fisiche sopra il Veleno della Vipera Physical Research on the Venom of the Viper.
However, the snake-catcher was unsure whether this was actually effective and therefore continued to treat his snakes with care. Nicholson, along with other Britons, began to consider that venom might provide its own cure.
Although Scottish surgeon Patrick Russell had noted in the late 18th century that snakes were not affected by their own venom, [27] it was not until the late 19th century that Joseph Fayrer, Lawrence Waddell , and others began to consider venom-based remedies again.
However, they and other naturalists working in India did not have the funding to fully develop their theories. In Sir Thomas Fraser , Professor of Medicine at the University of Edinburgh, picked up Fayrer and Waddell's research to produce a serum to act against cobra venom.
His "antivenene" was effective in the laboratory, but failed to make an impact as the public were focused on contemporary Pasteurian discoveries. In , Vital Brazil , working at the Instituto Butantan in São Paulo , Brazil , developed the first monovalent and polyvalent antivenoms for Central and South American Crotalus and Bothrops genera, [29] as well as for certain species of venomous spiders , scorpions , and frogs.
In Mexico in , Daniel Vergara Lope developed an antivenom against scorpion venom, by immunizing dogs. CSL has developed antivenoms for the redback spider, funnel-web spiders and all deadly Australian snakes. Mulford company began producing "Nearctic Crotalidae antivenin" [32] in , via a consortium called the Antivenin Institute of America.
Over time, a variety of improvements have been made in the specificity, potency, and purity of antivenom products, including " salting out " with ammonium sulphate or caprylic acid , [34] enzymatic reduction of antibodies with papain or with pepsin , affinity purification , and a variety of other measures.
There is an overall shortage of antivenom to treat snakebites. Because of this shortage, clinical researchers are considering whether lower doses may be as effective as higher doses in severe neurotoxic snake envenoming. Antivenom undergoes successive price markups after manufacturing, by licencees, wholesalers and hospitals.
Availability, from region to region, also varies. Internationally, antivenoms must conform to the standards of pharmacopoeia and the World Health Organization WHO. The name "antivenin" comes from the French word venin , meaning venom , which in turn was derived from Latin venenum , meaning poison.
Historically, the term antivenin was predominant around the world, its first published use being in Contents move to sidebar hide. Article Talk. Read Edit View history. Tools Tools. What links here Related changes Upload file Special pages Permanent link Page information Cite this page Get shortened URL Download QR code Wikidata item.
Download as PDF Printable version. Medical treatment for venomous bites and stings. For the comics character, see Anti-Venom.
Milking a snake for the production of antivenom. Stuart MC, Kouimtzi M, Hill SR eds. WHO Model Formulary World Health Organization. ISBN Medical Toxicology.
Archived from the original on British Medical Association. Tropical Medicine and Infectious Disease. doi : PMC PMID Wired — via www. The Economist. ISSN Retrieved Handbook of Pharmaceutical Biotechnology. World Health Organization model list of essential medicines: 21st list Geneva: World Health Organization.
License: CC BY-NC-SA 3. Florida Poison Information Center - Tampa. May Retrieved October 31, Toxnet: Toxicology Data Network. September 15, org , July 31, Australian Prescriber.
viridis , N. haje , N. nigricollis , and N. In the case, where no cross-reactivity is present, antibodies are needed for all toxins from all venoms. Consequently, we can calculate the total antibodies in mol needed for neutralizing all venoms n Tox.
This is described by the following equation Eq. Finally, COGM FDP was calculated as described above. Here, M Ab required was calculated using n Tox and M Ab Eq 6. We also wanted to understand the impact of the small molar mass of alternative antibody formats, such as Fragment antigen binding Fab; 50 kDa and single-chain variable fragments scFvs, 25 kDa , as well as alternative protein scaffolds, e.
To understand the impact that different molar masses can have on the COGM FDP of a potentially expensive antivenom, we investigated this in the context of a recombinant FAV-Afrique biosimilar antivenom. Understanding the dynamics of the manufacturing costs for next-generation antivenoms is pivotal toward developing effective, but also cost-competitive therapies for snakebite victims.
Therefore, in the following, we present key variables to consider when assessing potential manufacturing costs for recombinant antivenoms using a bottom-up approach and conclude that they indeed represent a promising solution for next-generation snakebite envenoming therapy.
Many different strategies exist for the manufacture of recombinant antibodies. These utilize different downstream processes such as chromatography and caprylic acid precipitation and have different cost structures Figure 2A.
Based on available data from the scientific literature, and assuming an annual production volume of kg of antibodies, the most costly manufacturing strategy for recombinant antibodies is continuous perfusion followed by chromatography, which is estimated to have a COGM API of USD 89 per gram of antibody.
Conversely, the most inexpensive strategy may involve a combination of the hybrid upstream process and caprylic acid purification USD 33 per gram of antibody. This suggests that, from a cost perspective, the latter approach might be the most applicable for manufacture of recombinant antivenoms, for which cost is a major concern, as snakebite envenoming is most prevalent in rural impoverished areas of the tropics Harrison et al.
Our calculations also demonstrate the impact of formulation on the COGM FDP Figure 2B. Therefore, formulation costs are critical to take into consideration when manufacturing costs are low. Figure 2. Cost of manufacture for recombinant antivenoms in relation to manufacturing process and treatment dose.
A Cost impact of different manufacturing strategies in relation to how many grams of antibodies are required for a full antivenom treatment of a snakebite envenoming case. The three upstream processes included are the fed-batch process, the hybrid process, and the continuous perfusion process.
Each upstream process was combined with either chromatographic or caprylic acid purification steps to calculate the respective Cost of Goods Manufactured of the Active Pharmaceutical Ingredient COGM API per treatment.
The white numbers in the cells correspond to the exact COGM API corresponding to that particular cell. B The impact of formulation on the final drug product FDP cost for very cheap, cheap, and expensive COGM API.
The molar mass and amount of a given venom to be neutralized for a given snakebite case are also important cost-affecting factors Figure 3. An amount of venom comprising toxins with lower molar masses will require more mols of antibodies for neutralization compared to the same amount of venom comprising toxins with higher molar masses.
This is further amplified by the absolute amounts of venom being injected by a given snake. Consequently, bites from snakes that produce large volumes of venom comprising toxins with low average molar mass require the most antibodies and are, therefore, the most costly to neutralize.
In contrast, bites from snakes that produce small volumes of venom comprising toxins with high average molar mass require the least antibodies and are the least costly to neutralize. Figure 3. How the molecular weight and amount of venom to be neutralized affect the Cost of Goods Manufactured of the Active Pharmaceutical Ingredient COGM API for recombinant antivenoms.
The heat map includes three variables, namely the amount of venom to be neutralized in grams, the average molecular mass of the venom toxins in kDa, and the COGM API in USD. Based on our previous calculations, we quantified the cost of four different putative monovalent recombinant antivenoms Figure 4.
These calculations were based on the assumption that the recombinant antibodies are manufactured via the hybrid process followed by caprylic acid precipitation. The calculations were conducted for three different toxin-to-antibody ratios i. Furthermore, to understand the above-mentioned cost dynamics of average venom toxin molar mass and venom amount, we included four snakes with different types of venoms and venom yields.
The first snake M. nigrocinctus has a venom comprising toxins with a comparatively small average molar mass 13 kDa and can only produce a very small volume of venom 0. atrox presents a venom comprising toxins with a large average molar mass 63 kDa , but still at a relatively small volume 0.
adamanteus has a venom with a comparatively lower molar mass 23 kDa , but can produce 0. australis venom has an average molar mass for its venom toxins of 40 kDa and can produce up to 0. It is notable that for both M. nigrocinctus and B. atrox , antibody efficacy and percentage of maximum venom yield injected had no major impact on the COGM FDP of the respective monovalent antivenom Figure 4 , as the cost of formulation and packaging is the main cost driver.
This was not the case when calculating the costs for the two other monovalent antivenoms against C. adamanteus and P. Whilst the percentage of volume injected had a significant impact on the COGM FDP for both antivenoms, the efficacy of the antibodies reflected by the toxin-to-antibody ratio had the largest effect on the cost.
For instance, a monovalent recombinant antivenom of C. adamanteus that contained highly efficacious antibodies i.
Figure 4. Cost of monovalent recombinant antivenoms against four representative species of venomous snakes. The calculations are for Cost of Goods Manufactured for the Final Drug Product for a full treatment of a given snakebite COGM FDP and, thus, include formulation and packaging costs.
Whilst monovalent antivenoms fulfill an important role in certain regions of the world such as Australia , polyvalent antivenoms that are effective against a wide range of different venoms are key to solving the global crisis of snakebite envenoming Gutiérrez et al.
Polyvalent antivenoms eliminate the need for medical practioners to identify the species of venomous snake that bit the patient and, thus, removes the issue of diagnostic uncertainty for the medical practioner Gutiérrez et al.
The drawback to polyvalent recombinant antivenoms is the complexity of developing them, since it requires that more monoclonal antibodies are included in the formulation of the antivenom, and likely also that the individual antibodies are broadly neutralizing, for the antivenom to be efficacious against many different venoms.
To estimate the costs of polyvalent recombinant antivenoms, we explored both a simple antivenom that could neutralize the four most medically relevant snakes in India i. naja , B.
caeruleus , D. russelii , and E. carinatus and a more complex antivenom 10 different venoms from Dendroaspis spp. We calculated the costs for very efficacious, efficacious, and less efficacious antibodies, reflected by the toxin-to-antibody ratios , , and , respectively.
Notably, cross-reactivity appears to influence antivenom cost less than antibody efficacy, particularly in the polyvalent recombinant antivenom for the four Indian snakes.
However, it appears that the impact of cross-reactivity is significantly higher when assessing more complex and expensive antivenoms, such as the polyvalent recombinant antivenom for sub-Saharan Africa. Additionally, cross-reactivity would simplify the manufacturing process, since less antibodies would need to be produced and quality control would be easier.
Consequently, cross-reactivity is likely to have further indirect impact on the COGM FDP than just in the context of the neutralizing capacity of the recombinant antivenom. However, this is not taken into account here due to its rather speculative nature. Nevertheless, the COGM FDP for both polyvalent recombinant antivenoms compare favorably with prices of existing antivenoms.
Current Indian polyvalent antivenom costs approximately USD 6. This equates to an antivenom price of USD per treatment, which is comparable to both recombinant solutions containing very effective antibodies and toxin-to-antibody , with cost estimates of USD per treatment.
However, it is of note that this is not taking profit margins into account for the recombinant antivenoms, as well as indirect costs affected by efficacy and safety of treatments are not accounted for here. Similarly, the COGM FDP for a recombinant antivenom appears to compare favorably to the price of the former high-quality polyvalent antivenom for sub-Saharan Africa, FAV-Afrique.
Although no longer in production, FAV-Afrique used to be priced between USD per vial, and treatments typically required 2—8 vials, resulting in the treatment price ranging from USD Trop, ; Brown, ; Harrison et al.
This price is comparable to both recombinant antivenoms containing very effective antibodies and toxin-to-antibody , with cost estimates of USD per treatment. Together, these calculations indicate that polyvalent recombinant antivenoms, even with very broad species coverage, might not only match, but also significantly lower the cost of treatment, whilst likely also providing safer and more efficacious therapy, provided that the antibodies included in the antivenoms are of high therapeutic quality and efficacy.
Figure 5. Cost estimates for two polyvalent recombinant antivenoms. A Putative Cost of Goods Manufactured for the Final Drug Product COGM FDP for a recombinant antivenom that can neutralize the venoms of the four most medically relevant snakes in India i.
B Cost estimates for a recombinant antivenom that can neutralize 10 different species of snakes in sub-Saharan Africa i.
gabonica, E. leuconogaster, E. ocellatus, Dendroaspis polylepis, D. jamesoni, D. viridis, N. haje, N. All of the calculations are conducted for three different toxin-to-antibody ratios , , and The costs are calculated for the final drug product, which includes formulation costs.
The price per treatment for two animal plasma-derived polyvalent antivenoms for both India VINS polyvalent and sub-Saharan Africa FAV-Afrique — out of production are also provided for comparison please note that these are sales prices, which also reflect financial parameters other than COGM alone, such as sales, distribution, indirect costs, and profit margin.
IgG antibodies have many advantages, such as a long serum half-life, extensive clinical validation, and established manufacturing strategies. Yet, other smaller formats, including Fabs, scFvs, DARPins, nanobodies, and Avimers, have their own set of advantages Jenkins et al.
Indeed, these formats have more binding sites per mass unit due to their smaller molar mass, which could have a favorable influence on cost dynamics, as the amount of antitoxin required for neutralizing a given venom may be less in terms of gram.
Consequently, this could lower the final product cost assuming equimolarity for antivenoms products. We found a major difference in COGM FDP between all scaffolds and a linear relationship between size of the scaffold and the cost of the final drug product.
This demonstrates that even in rare cases where IgGs might not be financially viable, alternative antitoxin scaffolds could be used instead to achieve economic viability. There are, however, other variables to consider when calculating the costs of a recombinant antivenom using alternative antitoxin scaffolds, such as their short half-life likely requiring administration of larger amounts of the antivenom and different volumes of distribution Jenkins et al.
Many alternative antitoxin scaffolds can be produced via microbial expression, rather than mammalian cell cultivation, which may have the potential to be even more cost-competitive at large production volumes. However, given the lack of manufacturing cost data for microbial expression, we decided not to overspeculate in this regard and use the same COGM API for all antitoxin formats Jenkins et al.
The actual costs for alternative antitoxin scaffolds may, thus, be even more attractive than presented here. Figure 6. The influence of molar mass of the antitoxin on the cost of recombinant antivenoms for different antibody formats and alternative antitoxin scaffolds. The bubbles indicate the percentage of cost increase from one format to the next and the text in the columns indicate the cost of the final drug product.
Whilst the safety and efficacy of any therapeutic should stand at the forefront of all development considerations, it is also key that the product can be manufactured cost-competitively. Indeed, cost of manufacture is of high importance when catering to predominantly low income markets, such as those heavily affected by snakebite envenoming Harrison et al.
Consequently, we aimed to provide cost estimates for potential recombinant antivenoms to demonstrate that such products are likely to be manufacturable at a cost-competitive level to conventional antivenoms.
It is, however, of note that all of our estimates rely on the industry data available to us and the assumptions provided in the methods, such as an expected annual production volume of kg of antibodies.
It should also be noted that the calculations are technical and based on theoretical modeling, which might limit the applicability of the findings to the field.
Therefore, the numbers provided here should not be seen as a definitive conclusion to the cost of manufacture for recombinant antivenoms, but rather as a rough guideline toward understanding the cost dynamics at play.
Core challenges in improving the accessibility and efficacy of antivenom remain to be resolved in the management of snakebite envenoming. New therapeutics often come with exciting treatment prospects for patients. However, it is pivotal to ensure that any new therapy is commercially viable to manufacture and distribute to the market.
This is particularly important for antivenoms, which are predominantly required in impoverished regions around the globe. Therefore, in this article, we present the first ever bottom-up cost estimates for recombinant antivenoms.
Whilst the numbers should not be taken as definitive conclusions and rather as estimates based on available industry data, the cost dynamics presented here should aid future research and development decisions and strategy.
Together, our data indicates that innovative envenoming therapies based on monoclonal antibodies could be manufacturable at a comparable or lower cost to current antivenoms.
Indeed, we found that monovalent recombinant antivenoms could be manufactured for USD per treatment and more complex polyvalent recombinant antivenoms could be manufactured for USD per treatment. These numbers are slightly higher when compared to previous estimates USD per treatment , yet those calculations were based on a less differentiated top-down approach Laustsen et al.
Nevertheless, the COGM FDP of recombinant antivenoms falls within a similar spectrum as the prices of currently employed antivenoms USD per treatment. Finally, manufacturing costs may be even lower for recombinant antivenoms based on alternative antitoxin scaffolds, such as DARPins and nanobodies, which may warrant further research efforts in experimenting with these proteins as putative antitoxins.
Given the likelihood of recombinant antivenoms being cost-competitive, alongside their potential therapeutic benefits over conventional antivenoms, further investigation and development of such novel snakebite therapeutics seems warranted. The raw data and calculations supporting the conclusions of this article are available upon request to the authors.
TJ and AL conceived this study. TJ conducted the analyses and prepared the figures, Both authors drafted and finalized the manuscript.
This study was funded by the Villum Foundation grant no. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Snakebite envenoming.
Antivenoms from hyperimmune animal Antivenom manufacturing are the only specific pharmaceuticals against manufacthring. The Antivenom manufacturing of downstream Preventing diabetes through community outreach strategies is of Antivdnom interest, not only in Antivenom manufacturing of purity Ahtivenom, but also from yield-to-cost perspective and rational use of plasma of animal origin. We report on development of an efficient refinement strategy for F ab' 2 -based antivenom preparation. Process design was driven by the imperative to keep the active principle constantly in solution as a precautionary measure to preserve stability of its conformation precipitation of active principle or its adsorption to chromatographic stationary phase has been completely avoided. Final polishing was accomplished by a combination of diafiltration and flow-through chromatography.
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