Artemisinin, extracted from Sweet wormwood extract, also known as Artemisia annua plant, or “quinghao”, was used in ancient Chinese therapy to treat various illnesses, including fevers typical of malaria. As the precursor to artemisinin-based combination therapies (ACTs), Artemisinin is regarded the most effective drugs against the deadliest malaria parasite at present.
In the 1970s, Chinese scientists rediscovered it and identified its active ingredient, artemisinin, and artemisinin is now extracted from sweet wormwood grown commercially in China, Southeast Asia and Africa. Artemisinin is the key chemical compound used to prepare several active pharmaceutical ingredients (APIs), including artemether, artesunate and dihydroartemisinin, that exhibit antimalarial properties and that are used to manufacture artemisinin-based combination therapies (ACTs), which are the WHO-recommended treatment for uncomplicated malaria caused by the parasite Plasmodium falciparum.
Global demand for artemisinin has increased since 2005, when the World Health Organization identified ACTs as the most effective malaria treatment available. With an estimated 219 million malaria infections and 660,000 deaths – mainly children under five – annually, the disease is one of the world’s biggest killers.
The problems with natural artemisinin from sweet wormwood plant
As far as the natural artemisinin is concerned, the quality, supply and cost have been unpredictable and inconsistent. Artemisinin, the key ingredient in the WHO-recommended first-line malaria treatment artemisinin-combination therapy (ACT), has only been available by extraction from the sweet wormwood tree, native to Asia. However, climatic factors have meant it has suffered from uneven supply over the years. The uncertainty of natural artemisinin’s availability has led to bulk buying and speculation in the market, leading to the price of the raw product varying widely - from US$400 per kg to $1,000 per kg - over the years. Variable harvests and a production cycle lasting at least 14 months have created a volatile market where prices and availability fluctuate wildly. ‘Not everyone could get the drugs they needed,’ says Ponni Subbiah, a drug-development programme leader at PATH, a global health organisation based in the US.
Recent biosynthetic developments now enable artemisinin to be obtained by synthetic or semi-synthetic means. The availability of non-plant-derivedartemisinin offers the potential for important advances in the treatment of malaria since it means that seasonal production of artemisinin no longer limits the production of ACTs.
The WHO Prequalification of Medicines Programme (PQP) is pleased to announce the acceptability of the first source of non-plant-derived-artemisinin, manufactured by Sanofi, for use in the manufacture of active pharmaceutical ingredients or finished pharmaceutical products submitted to WHO for prequalification, or that have already been WHO prequalified.
The introduction of Semi-synthetic artemisinin by Sanofi
The "semi-synthetic" artemisinin is chemically modified to an active drug, such as artesunate, and combined in ACT with another antimalarial drug to lessen the chance that the malaria parasite will develop resistance to artemisinin. Sanofi plans to produce 35 tons of artemisinin in 2013 and, on average, 50 to 60 tons a year by 2014, which will translate to between 80 and 150 million ACT treatments. Following regulatory approval expected later this year, semisynthetic artemisinin will be ready for rapid integration into the supply chain for antimalarial therapies, according to the company.
Sanofi expects to make about 35 tonnes of artemisinin this year in 2013 and 50–60 tones next year, which will meet about one-third of the global need. It will initially cost $350-400 (£230 –260) per kilogram, roughly the same as the botanical source.
Benefits of the using semi-synthetic artemisinin drug:
The production of semisynthetic artemisinin will help secure part of the world's supply and maintain the cost of this raw material at acceptable levels for public health authorities around the world and ultimately benefit patients. This is a pivotal milestone in the fight against malaria."
The production of semi-synthetic artemisinin will help secure part of the world’s supply and maintain the cost of this raw material at acceptable levels for public health authorities around the world and ultimately benefit patients… Having multiple sources of high-quality artemisinin will strengthen the artemisinin supply chain, contribute to a more stable price, and ultimately ensure greater availability of treatment to people suffering from malaria.
The availability of the semi-synthetic version is expected to make artemisinin more readily available, while also driving down the cost of artemisinin-based antimalarial drugs.
Problems with Semi-synthetic artemisinin:
But as with all pharmaceutical products, quality must be assured. The challenge presented by non-plant-derived artemisinin is to ensure that such material is comparable to plant-derived-artemisinin, rather than to assess the acceptability of non-plant-derived-artemisinin as an API per se. Recognizing the importance of this substance to achieving public health treatment goals, PQP therefore developed a procedure for assessing it, and for its introduction by manufacturers participating in WHO medicines prequalification.
The comparison of manufacturing process for natural artemisinin and synthetic artemisinin
Agricultural method for natural artemisinin:
1. Cultivation. Seed of Sweet wormwood or Artemisia annua plant is grew and cultivated, and
2.extraction. Plant in powder form is then extracted in the extracting tank by physical and chemical process.
The lead time from seed to ACT (artemisinin-based combination therapies) takes 15 months
Semi-synthetic method for synthetic artemisinin
Fermentation technology is applied here by translating Artemisinic Acid into Dihydro-artemisinic Acid by photo-Chemistry, and then artemisinin. The general lead time from lab to ACT is about 3 months.
From the above, we may find that the lead time for synthetic artemisinin is shortened by 12months, maybe in the long term, the time can be even less. While the natural plant takes more than a year to grow in the field, and long time is inevitable.
Although the difference in mass production, the method for making artemisinin derivatives is the same, artemisinin is the raw material, and then come with artemether, artesunate, artenimol, arteether, Dihydroartemisinin, etc.
The relationship between natural artemisinin and semi-synthetic artemisinin
Plant-based production will continue to play an important role in the ACT manufacturing process in the future. Nonetheless, it is clear that there is a need for additional sources of artemisinin. It is anticipated that synthetic alternatives, fermentation and high yield A. annua will all be needed to secure supply and reduce the cost of artemisinin.
Not a replacement
The project goal of semi-synthetic Artemisinin is to create a complementary source of non-seasonal, high-quality, and affordable artemisinin to supplement the current plant-derived supply; Ensure semi-synthetic artemisinin is available to all qualified derivative manufacturers, and contribute to stabilizing the price of ACTs to benefit patients and payers.
It would be important for the supply of the natural version of artemisinin to continue alongside the semi-synthetic production.
“We hope that the message will not be that it will replace the natural product, because this would act as a disincentive to the farmers, who could stop producing their crops. It should be complementary, with a growing share of the market,” he added. “Hopefully, we will see the price of ss artemisnin matching the lowest price available for the natural product.”
Both WHO’s Fake and MSF’s de Smet say there is no need for concern over differences in efficacy or safety, as drugs manufactured with both versions of artemisinin contained the same active chemical ingredient.
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