Operation Jupiter rains on fake antimalarials

But replicating 'Operation Jupiter', which employed a battery of forensic tests ranging from mass spectrometry to palynology (pollen analysis) to track down a source of fake artesunate in southern China, would require technical capacity and resources as well as collaborative efforts that at present are sorely lacking in the countries most affected by counterfeiting.

In the developed countries where fake pharmaceuticals are still at a relatively low ebb, counterfeiting can infiltrate a wide range of drugs, but in particular lifestyle products such as the erectile dysfunction treatments Viagra (sildenafil citrate, Pfizer) and Cialis (tadalafil, Eli Lilly).

The focus of the operation co-ordinated by the World Heath Organization's (WHO) Western Pacific Regional Office, the International Criminal Police Organisation (INTERPOL) and the Wellcome Trust-University of Oxford South-east Asian Tropical Medicine Research Programme, in close co-operation with the Chinese authorities, was a generic medicine for a tropical disease that threatens some 40 per cent of the world's population and still claims over a million lives a year.

Originally developed in China, artesunate is a crucial component of the artemisinin combination therapy (ACT) that has raised hopes of controlling the spread of malaria in the developing world.

The drug is widely used in South East (SE) Asia and, increasingly, Africa for the treatment of Plasmodium falciparum malaria, with millions of tablets produced each year by at least 16 manufacturers of artemisin and its derivatives in SE and East Asia.

Antimalarials may be essential but they are also especially susceptible to counterfeiting.

According to an account of the Operation Jupiter programme published in the open-access journal PLoS Medicine , ad hoc surveys since 2000 in Myanmar (Burma), the Thai- Myanmar border, Laos, Cambodia and Vietnam, suggest that 33 to 55 per cent of bought artesunate is counterfeit, containing either none of the claimed active ingredient or sub-therapeutic quantities of artesunate.

This can have a devastating - albeit very difficult to quantify - effect on malaria morbidity and mortality.

Not only does the absence of artesunate in counterfeit versions cause avoidable death, undermine confidence in the drug and drain the revenues of legitimate manufacturers, it also presents additional clinical risks through the range of potentially dangerous substitute actives found in the fake tablets - for example, chrloramphenicol and metamizole, which may lead to inexplicable syndromes such as bone marrow failure.

Moreover, the presence of sub-therapeutic quantities of artesunate, artemisin and sulphonamides in counterfeit artesunate - included as a means of avoiding routine screening tests - could greatly exacerbate the emergence and spread of drug-resistant malaria parasites.

With little action taken against these widening problems in comparison with their public health impact, a confidential meeting at the WHO Regional Office for the Western Pacific in May 2005 brought together WHO officials, physicians, pharmacists and scientists working in the Greater Mekong Sub-Region of South East Asia (i.e., Cambodia, Laos, Myanmar, Thailand, Vietnam and China's Yunnan Province) with INTERPOL to discuss how more effective steps could be taken.

Operation Jupiter set out to investigate where counterfeit artesunate was being manufactured and to develop an intelligence document that could be presented to affected governments.

Laboratory analysis focused on 391 samples of genuine and counterfeit artesunate collected in Vietnam, Cambodia, Laos and Myanmar, as well as on the Thai/Myanmar border, between 1999 and 2006 by the Wellcome Trust-Oxford SE Asian Tropical Medicine Research Programme.

Samples were subjected to high-performance liquid chromatography (HPLC), organic mass spectrometry, gas-chromatographic 'head space' analysis of the gases surrounding tablets in blister packs, palynology and detailed inspection of packaging.

What these analyses highlighted in particular was the considerable diversity in counterfeit artesunate emanating from and distributed in South East Asia.

For example, a total of 16 different types of fake hologram were identified on packaging, ranging from crude stickers to highly sophisticated copies.

In terms of the samples' chemical composition, all of the specimens thought to be counterfeit (195 out of 391, or 49.9 per cent) on the basis of their packaging turned out to contain either no or small quantities (up to 12mg per tablet, as opposed to 50mg per genuine tablet) of artesunate.

Of the 321 samples labelled as manufactured by one major and heavily targeted Asian producer, Guilin Pharmaceutical from China's Guangxi autonomous region, 195 or 61% were found to be counterfeit.

The researchers also detected a wide variety a substitute active ingredients in the counterfeit artesunate, including paracetamol, several different erythromycin antibiotics, banned compounds such as metamizole, the carcinogen safrole, and raw material for the production of methylenedioxymethamphetamine (ecstacy).

Evidence from chemical, mineralogical, biological and packaging analysis - including the use of forensic palynology to study spore and pollen contamination in the fake tablets - suggested that at least some of the counterfeits were manufactured in southeast China.

This was presented by INTERPOL to the Chinese Ministry of Public Security, which launched a criminal investigation resulting in the arrest of a native of Yunnan Province alleged to have bought 240,000 blister packs of counterfeit artesumate - enough to 'treat' almost a quarter of a million adults - from a native of Guangdong Province (also arrested).

While the MPS was able to seize 24,000 of these packs, a total of 160,000 blister packs of fake artesunate were alleged to have been sold to a non-Chinese national on the Yunnan-Myanmar border and a further 56,000 packs at another border crossing near Ruili.

During the same period, Guilin Pharmaceutical exported some 272,000 blister packs of artesunate to Myanmar and Thailand.

Therefore, the researchers comment in PLos Medicine, " of the visible trade in 512,000 blister packs of artesunate, 47 per cent was in fake artesunate, consistent with previous estimates of the proportion of fake artesunate in mainland SE Asian shops ".

Those arrested in the move against artesunate counterfeiters are now awaiting trial.

Despite this successful outcome, the Operation Jupiter team cautions that investment in forensic analysis and building sustainable links between concerned organisations is essential if this collaborative approach is to be applied more widely.

While forensic evidence would allow overstretched police forces to concentrate on objective leads, there are " very few laboratories (only one in Asia/Pacific) with the appropriate reference collections and ability to analyse pollen assemblages in tablets ", the investigators note, adding that " the work is very labour-intensive and specialised and therefore expensive ".

Similarly, there are " very few (less than ten) public laboratories or research groups with the adequate tools and human resources to perform detailed forensic chemistry of fakes, and the equipment required is expensive ".

" We were fortunate in that diverse international and national bodies were able to provide their time and skill to try to solve a single important problem ," the authors conclude.