Poor quality vital anti-malarials in Africa - an urgent neglected public health priority
- Paul N Newton1, 2, 3, 4Email author,
- Michael D Green5,
- Dallas C Mildenhall6,
- Aline Plançon7,
- Henry Nettey5,
- Leonard Nyadong8,
- Dana M Hostetler8,
- Isabel Swamidoss5,
- Glenn A Harris8,
- Kristen Powell8,
- Ans E Timmermans9,
- Abdinasir A Amin10,
- Stephen K Opuni11,
- Serge Barbereau12,
- Claude Faurant13,
- Ray CW Soong6,
- Kevin Faure6,
- Jonarthan Thevanayagam2,
- Peter Fernandes2,
- Harparkash Kaur3,
- Brian Angus2,
- Kasia Stepniewska2, 14,
- Philippe J Guerin2, 4 and
- Facundo M Fernández8
© Newton et al; licensee BioMed Central Ltd. 2011
Received: 22 July 2011
Accepted: 13 December 2011
Published: 13 December 2011
Plasmodium falciparum malaria remains a major public health problem. A vital component of malaria control rests on the availability of good quality artemisinin-derivative based combination therapy (ACT) at the correct dose. However, there are increasing reports of poor quality anti-malarials in Africa.
Seven collections of artemisinin derivative monotherapies, ACT and halofantrine anti-malarials of suspicious quality were collected in 2002/10 in eleven African countries and in Asia en route to Africa. Packaging, chemical composition (high performance liquid chromatography, direct ionization mass spectrometry, X-ray diffractometry, stable isotope analysis) and botanical investigations were performed.
Counterfeit artesunate containing chloroquine, counterfeit dihydroartemisinin (DHA) containing paracetamol (acetaminophen), counterfeit DHA-piperaquine containing sildenafil, counterfeit artemether-lumefantrine containing pyrimethamine, counterfeit halofantrine containing artemisinin, and substandard/counterfeit or degraded artesunate and artesunate+amodiaquine in eight countries are described. Pollen analysis was consistent with manufacture of counterfeits in eastern Asia. These data do not allow estimation of the frequency of poor quality anti-malarials in Africa.
Criminals are producing diverse harmful anti-malarial counterfeits with important public health consequences. The presence of artesunate monotherapy, substandard and/or degraded and counterfeit medicines containing sub-therapeutic amounts of unexpected anti-malarials will engender drug resistance. With the threatening spread of artemisinin resistance to Africa, much greater investment is required to ensure the quality of ACTs and removal of artemisinin monotherapies. The International Health Regulations may need to be invoked to counter these serious public health problems.
Plasmodium falciparum malaria remains a major public health problem in much of the world, despite decades of interventions . The tragedy remains that many more malaria patients would survive if they had timely access to good quality, affordable and efficacious medicines. With the implementation of pivotal artemisinin-based combination therapy (ACT) throughout malarious Africa and attempts to make it accessible and affordable, hope of controlling malaria has been rekindled [2, 3]. Of 42 African countries with P. falciparum malaria, ACT is now national policy in 40 (95%).
A diverse range of important problems reduce ACT effectiveness, including inaccessibility, poor prescribing, poor adherence and poor medicine quality. There are two main categories of poor quality medicine. Counterfeit (or falsified, spurious) medicines (i.e. 'deliberately and fraudulently mislabelled with respect to identity and/or source;[5, 6]) and substandard medicines (i.e. 'genuine medicines produced by manufacturers authorized....which do not meet quality specifications set for them by national standards';[6–8]). Substandard medicines frequently, and counterfeits occasionally, contain sub-therapeutic amounts of active pharmaceutical ingredients (API) and/or may show suboptimal release of API (dissolution), exposing parasites to sub-lethal concentrations of API(s) [8–10]. However, the percentage API in genuine medicines may also be reduced after manufacture if they are degraded by extremes of temperature and humidity .
Substandard and counterfeit anti-malarials were major problems in pre-ACT Africa. Those medicines with subtherapeutic amounts of API are likely to have contributed to the spread of resistance to previous generations of anti-malarials, such as sulphadoxine-pyrimethamine (SP) and chloroquine [10, 12, 13](Additional file 1). With evidence that SP and chloroquine-resistant P. falciparum entered Africa from SE Asia [14, 15], the recent descriptions of artesunate resistance there  suggests that, in addition to major local repercussions, it is very likely to spread to Africa.
Analyses of packaging, chemistry and botany were performed blindly. The results have been reported using the MEDQUARG guidelines where possible . Samples were stored at +4°C for between 1 month and 6 years before analysis. Counterfeit, substandard and degraded were defined based on the above definitions, with packaging analysis, in comparison to authentic samples, as the crucial evidence for the distinction between counterfeit and substandard/degraded. This was performed without any intellectual property considerations. When data did not allow such classification but the sample contained API% outside reference ranges, such medicines are referred to as 'poor quality'.
The physical appearance and text on packaging were examined and compared with known genuine samples when available . Nineteen companies were asked for genuine samples of their products and 6 (32%) responded. DigitalColorMeter (v3.4.1, Apple Inc.) was used to measure the percentage of red (R), green (G) and blue (B) pixels at predefined points on the packaging.
Sample API was quantified using a modified high performance liquid chromatography (HPLC) method with photo diode array detection . Samples were also screened by two direct ionization mass spectrometry (MS) methods: Direct Analysis in Real Time (DART) and Desorption Electrospray Ionization (DESI) in both conventional and reactive modes [28, 29]. Select samples were also analysed by X-ray diffractometry (XRD; X'Pert Pro, Philips, Almelo) and isotope ratio MS to determine the mineral composition . GlaxoSmithKline plc (GSK) performed analysis of 'halofantrine' samples using Fourier Transform Infra Red spectroscopy (FTIR), verified when necessary by HPLC with electrospray ionization and mass spectrometry detection (Eckers & Wolffe pers. comm.)(Additional file 2).
A sample was defined as one dosage unit-such as a blister or blisters in one packet (if present) or one bottle. The %API range, relative to the stated dosage, allowed on HPLC analysis was 90-110%. An important issue, barely addressed, is that in work such as this, the available sample size of dosage units (such as one blister) is considerably less than that required in testing described in pharmacopoeias [e.g. ]. Testing for uniformity commonly requires that if one tablet in a sample contains < 75% or > 125% of API relative to the stated dosage, the sample fails the assay . Tablets within this range may represent a Type II error of accepting a sample when it is poor quality. Ignoring the variability in chemical assays, assuming that tablet API% in an "acceptable" population is normally distributed with standard deviation of < 5% (to ensure that all tablets are within 75-125% range) there are, at most, chances of 1.3/1,000, 2.3/1,000 and 0.5/1,000 of finding a tablet with 75%-85%, 75%-90% and 75%-90% API, respectively. Therefore, for tablets with API > 75%, taking a pragmatic approach that a sample fails if more than 1 dosage unit falls outside the 90-110% range, carries a relatively small chance of rejecting a compliant sample or Type I error.
Tablet samples were analysed for pollen/spores , which could be indicative of either the place of manufacture, the source of the individual ingredients or both, and be influenced by wind dispersal, seasonality and transplantation beyond their known natural range.
Summary of case reports of poor anti-malarial medicine quality in Africa.
'Artesunate' 50 mg tablets
'Mekophar Chemical Pharmaceutical Joint-Stock Company'
Marketed by: 'Neros Pharmaceuticals Ltd., Lagos Nigeria'
Contains chloroquine. No artesunate detected. Pollen grains of bulrush (Typha angustifolia). Pollen and chemistry suggests two different types
Collected because of suspicion of their low cost (1500 FCFA ~$3/pack of 12 tablets). Packet and leaflet colours and holograms differed and the counterfeit packets were heavier.
'Artesunate' 100 mg tablets
'Marinate'. No manufacturers details on the packaging. Only 'GUJ/DRUGS/1407'
79 and 88% artesunate/tablet, but analysed 19 months after expiry
Probably labeled as made in Gujerat, India. Genuine packaging not available
'Artesunate' 100 mg tablets
Astrinate on one face of leaflet and Arinate on reverse
Stated to be 'Manufactured for AT17 RUE POISSONNIERS 75018 PARIS'
88.5, 70.9 mg artesunate/tablet
No agent/company in Rue Poissonniers. 'Arinate' is the trade name of artesunate monotherapy from Dafra Pharma, Belgium.
'Artesunate' 50 mg tablets
Stated to be manufactured by
'ADAMS PHARAMCEUTICAL (ANHUI) CO., LTD. ANHUI, CHINA
Division of Sunflower Int'l Group'
artesunate 39.0, 43.0, 47.0, 47.0 mg/tablet
Unable to obtain sample of genuine packaging
'Dihydroartemisinin' 60 mg tablets
'Jiaxing Nanhu Pharmaceutical Co. Ltd. Jiaxing City, under license of Beijing Holley-Cotec Pharmaceuticals (PR China)' with stated trade name 'Cotecxin'
No dihydroartemisinin detected. Chenopodiaceae pollen consistent with a source in SE China or in adjacent areas of SE and south Asia but not with Africa
The counterfeit tablet diameter and blister foil are larger and markedly lighter orange, respectively
250 mg tablets
Sierra Leone, Nigeria, Cameroon, DRC, Tanzania, Liberia, China
'SmithKline Beecham Laboratoires Pharmacetiques'
One contained correct % halofantrine-fraudulent extension of expiry date. Artemisinin, acetaminophen, dipyrone, pyrimethamine wrong APIs. Fagopyrum (buckwheat) and Sesamum (sesame) pollen in counterfeits. Consistent (but does not prove) with seasonally arid source in southern China. Betula (birch) pollen grain and a Stenochlaena fern spore in other counterfeits suggesting E/SE Asia, inconsistent with India/Africa
12 counterfeit Halfan tablets were classified as Types A, B, C, D, & E. Type A contained artemisinin while B, C, D & E contained acetaminophen or no API detected
Syrup 30 ml bottle
'SmithKline Beecham Laboratoire Pharmaceutiques Esplanade Charles de Gaulle 92731 NANTERRE Cedex,'
No API detected
Came with a spoon, leaflet and packet, suggesting considerable investment in deception.
40/320 mg tablets
'Zheijiang Holley Nanhu Pharmaceutical Group Ltd Under license of HolleyPharm' with stated trade name 'Duo-Cotecxin'
Sildenafil (Viagra; median (range) 10.4 (6.1-18.4) mg/tablet) detected in the matrix of the counterfeit tablets. Cibotium fern, widespread in SE and south Asia in both counterfeits and comparator genuine samples, suggesting that both manufactured in same region
Packaging with language errors with English and French (Franglais)
20/120 mg tablets
'Beijing Novartis Pharma Ltd, Beijing, China'
No artemether or lumefantrine detected. Contain pyrimethamine (6.2-25 mg/tablet) and unidentified yellow pigment in counterfeits. Pollen in counterfeit samples consistent with manufacture in E/SE Asia but not in Africa or India
8 tablets/blister for counterfeits rather than 6 for genuine. Errors in German language spelling
20/120 mg tablets
'Beijing Novartis Pharma Ltd, Beijing, China'
No artemether or lumefantrine detected. Contained pyrimethamine and sulphadiazine
6 tablets/blister for counterfeits
Artesunate & amodiaquine co-blistered. 100/300 mg tablet
'Pharmanova Limited, Accra, Ghana. Manufactured by: Atlantic Pharmaceuticals Limited Accra, Ghana'
Artesunate 92.0, 103 mg/tablet and amodiaquine 237, 240 mg/tablet
Unable to obtain sample of genuine packaging
Six blisters of 'Mekophar' artesunate tablets were collected in 2007 in Bamenda, Cameroon. All contained chloroquine but no artesunate was detected by HPLC or MS. XRD and botanical analysis suggested that CAM S5/07 had a different source from the other counterfeits. Bulrush (Typha angustifolia) pollen was found in this specimen only, suggesting use of contaminated water or a source near swampland in East Asia or Africa.
In ad hoc sampling in West Africa in 2008 (by JT & PF) of 13 artesunate monotherapies, one (Gh 08/15) had 2/4 tablets outside reference API% range. The authors were unable to obtain genuine samples of this product and it may be substandard, degraded or counterfeit. An additional six (46%) samples had one tablet with artesunate content < 90%, relative to the stated dose.
Dihydroartemisinin (DHA) monotherapy
Of the three DHA samples collected during ad hoc sampling in West Africa, although relatively few tablets could be analysed, all had one tablet outside reference %API range. No differences were detected in the packaging of Gh 08/07 in comparison to samples from the authentic manufacturer. A sample of DHA collected in Nigeria was counterfeit  and was found to contain paracetamol (acetaminophen) by MS.
A sample of counterfeit halofantrine syrup, collected (by SB) in Kivu, DRC, in 2006 had no API detected. Nor did it contain sulphamethazine as previously reported from another counterfeit halofantrine syrup . This came with a spoon, leaflet and packet, suggesting considerable investment in deception.
Eight blisters of co-formulated dihydroartemisinin-piperaquine (Duo-Cotecxin) due to be shipped to Africa from China were provided by Holley-Cotec Pharmaceuticals, China in 2007. DHA and piperaquine were detected in the four genuine samples but not in the four counterfeit samples. Sildenafil (Viagra; median (range) 10.4 (6.1-18.4) mg/tablet) was detected in the matrix of the counterfeit tablets, not in the coating. Botanical analysis of both genuine and counterfeit samples revealed spores of the fern Cibotium, widespread in SE and south Asia, suggesting that both genuine and counterfeit manufacturers were in the same region.
The Food and Drug Board, Government of Ghana provided in 2009, via INTERPOL, two packets of 'Coartem' stated to be co-formulated artemether-lumefantrine (eight tablets/blister) and stated to be manufactured by 'Beijing Novartis Pharma Ltd'. Samples of genuine private sector Coartem with eight tablets/blister were not available and therefore a sample bought in Kenya was used as a comparator (Ken 06/01). Both Ghanaian samples contained no detectable artemether or lumefantrine but did contain pyrimethamine (6.2-25 mg/tablet). All tablets analysed were yellow, which in the case of genuine Coartem results from the presence of lumefantrine. An insoluble (in weak acid) yellow pigment was detected in both counterfeit samples but no amodiaquine, another yellow anti-malarial, was detected by HPLC or MS. The yellow pigment was adsorbed on a nylon filter membrane and eluted with alkaline methanol and had maximum absorbance at 425 nm but could not be identified by MS. The genuine Coartem samples contained Dacrydium pierrei pollen, a tree growing in southernmost China and in the mountains of northern SE Asia. Pollen in the counterfeit samples were consistent with manufacture in E/SE Asia but not in Africa or India.
Suspect Coartem from Cameroon were provided via Novartis and INTERPOL in 2010. These consisted of blisters of six tablets, labelled as made in 2008, containing no artemether-lumefantrine, but containing pyrimethamine and sulphadiazine. This suggests that the criminals producing them differed from the counterfeiters operating in Ghana or that they changed their packaging in response to changes made by Novartis.
Of one co-blistered artesunate+amodiaquine collected in Ghana, 1/2 pairs of tablets (only 3 pairs per blister) analysed contained less than the reference range for artesunate and amodiaquine and may be counterfeit, substandard or degraded.
This wide diversity of different counterfeit and substandard anti-malarials from eight sub-Saharan African countries are cause of great concern. However, this study has important limitations, especially since it involved ad hoc collection and estimates of the frequency of poor quality anti-malarials cannot be deduced from these data. Tablet dissolution was not measured. The sampling method will bias towards finding counterfeit, rather than substandard, anti-malarials. It provides early warning, worrying for public health, as would a case series of new rapidly fatal epidemic influenza strains. However, that counterfeit formulations of ACT have been found at all is extremely alarming and will increase treatment failure, death and morbidity, yield covert unprotected monotherapy, increase the frequency of anti-malarial drug resistance and produce unexpected and clinically confusing adverse events. That 32% of artesunate and all DHA and DHA-piperaquine in the West Africa and DRC collections had one analysed tablet outside %API reference range is difficult to interpret. Analysis with larger numbers of tablets/sample is needed to understand the clinical implications.
There has been a dramatic rise in reports of poor quality non-artemisinin and artemisinin containing anti-malarials in Africa, suggesting an important worsening situation and/or an emerging interest (Figure 2)[34–36]. There are no data available that allow accurate estimation of the prevalence of poor quality anti-malarials in Africa, but enough information is available to know that it is a serious problem. Public health bodies should not wait for large-scale evidence based on random surveys to decide on interventions, as these data will take years to acquire. Unless action is taken quickly, poor ACT quality and profligate use of monotherapy (whether genuine or poor quality) will contribute to the failure of ACT. Although, the correlation between artemisinin resistance and poor drug quality has not been proven, modeling strongly suggests that underdosing is an important factor in the spread of P. falciparum drug resistance . Poor quality anti-malarials, usually substandards, resulting in blood concentrations between those that kill resistant and sensitive parasites and those that kill only sensitive parasites will select for drug resistance. Counterfeits may also aid and abet this process by increasing the risk of hyperparasitaemia and recrudescence and the co-circulation of substandard and counterfeit medicines may be especially prone to engender drug resistance especially where patients 'shop' around when treatments fail.
The initial misclassification of a counterfeit artemether-lumefantrine as genuine emphasizes the importance of analysing both packaging and the pharmaceutical chemical composition and the importance of access to samples of the authenticated packaging, which was found to be difficult with only 32% companies responding. In addition, we may have classified counterfeit samples, containing correct %API, as genuine because we were unable to compare all samples with genuine packaging.
The discovery of unexpected APIs in counterfeit anti-malarials have important public health implications . Unexpected pyrimethamine, especially if taken repeatedly, could give rise to clinically-confusing adverse effects, such as bone marrow suppression, rash and insomnia . Depending on the background level of P. falciparum antifolate resistance [39, 40], they may-at least initially-alleviate some malaria symptoms but are extremely unlikely to be curative. Pyrimethamine, in combination with sulphadoxine, is still used in sub-Saharan Africa, especially for Intermittent Preventive Treatment in pregnancy (IPTp) . The presence of pyrimethamine as hidden monotherapy in counterfeits will engender the further spread of P. falciparum dihydrofolate reductase mutations in Africa, increasing therapeutic failure and reducing the useful life of SP for IPTp. Covert consumption of anti-malarials will also confuse our understanding of changes through time of the frequency of clinical failure and molecular markers of chloroquine and SP resistance [39–41]. The median concentration of sildenafil, a wrong API in DHA-piperaquine, was 10.4 mg/tablet, whilst the smallest dose/tablet of Viagra is 25 mg, suggesting that covert administration may cause unexpected penile erection and, as it is not usually taken by the acutely ill, unknown complications. The consequences could be severe especially as this drug is contraindicated in those with hypotension and myocardial ischaemia. In addition, patients may be exposed to dangerous drug interactions between covert consumption and other medicines patients may take, such as sildenafil with anti-HIV medication and chloroquine and pyrimethamine with anti-epileptics . Pollen analyses of the counterfeit anti-malarials were consistent with an origin in eastern Asia, but do not prove this. In 2001 Guangzhou police arrested Nigerian and Chinese men for production of counterfeit halofantrine . No evidence was found, from pollen analysis, of counterfeit pharmaceutical production in Africa. However, production facilities for counterfeit anti-malarial packaging have been seized in Nigeria .
What should be done [6, 8, 10, 12, 44]? Multiple parallel strategies are urgently needed to improve the quality of medicines people take and to ensure that they are available and taken at the recommended doses. The enormous investment in the development, evaluation and deployment of anti-malarials is wasted if the medicines that patients actually take are, due to criminality or carelessness, sub-therapeutic. Objective data on the epidemiology of poor quality anti-malarials are needed to allow quantification and mapping of the problem , the relative public health importance of counterfeit and substandard 'products', determine intervention prioritization and, through following changes through time, evaluate their effectiveness. Second, WHO estimated that 30% of countries have either 'no drug regulation or a capacity that hardly functions' [45, 46] and presumably many of these are economically-poor and malarious. MRAs are keystones for crucial interventions to improve medicine quality and without them most interventions are doomed. There are only three countries with WHO pre-qualified Quality Control medicine analysis laboratories in the whole of malarious Africa . Investment in African MRAs and quality-assured medicine quality laboratories would facilitate countries ability to regulate medicines. There is a danger of poor quality medicines use in clinical trials, likely to bias results and therefore mandatory testing of such medicines should be carried out, preferably at one of the WHO-prequalified laboratories. Third, increasing the reach of affordable good quality ACT will reduce mortality [2, 3] and undercut the counterfeiters, by reducing their profit margins. Stockouts of ACT may encourage poor quality anti-malarial distribution. Fourth, artemisinin monotherapies are still very widely available in large quantities [37, 48], despite appeals to restrict their use, and their removal where patients have access to ACT is a key intervention. Fifth, much more attention needs to be paid to substandard medicines, with inspection and facilitation of good quality production. Sixth, increased cooperation between MRAs, police, customs, malaria control programmes, pharmaceutical companies and international organizations is vital in countering the trade in counterfeit medicines. Seventh, new portable and rapid techniques, based on Raman and Near-Infrared spectroscopy, have been used in the screening of medicine quality and assisted in recent seizure of imported counterfeit ACT in Nigeria . Although which technique is the most accurate and appropriate remains unclear, they could potentially empower drug inspectors in the screening of pharmacy stock for poor quality medicines. Eighth, we are woefully ignorant as to how best to tackle poor medicine quality in different situations and there has been a damaging lack of public health, civil society and political will to tackle the problem, which those combating the fake Chinchona bark and quinine scandals in the 17th-19th centuries would have found puzzling . Importantly, African heads of state and President Chirac issued the Cotonou Appeal for more action against counterfeit medicines in Africa .
With artemisinin resistance in Asia, authorities there have a duty to contain resistant parasites so that they do not spread to Africa. African countries may wish to lobby for more political will in Asia for containment and for financial and human capacity support of African MRAs. The International Health Regulations (IHR) may be a method of facilitating change. In the IHR "disease" means an "illness or medical condition, irrespective of origin or source, that presents or could present significant harm to humans". Poor quality medicines and inappropriate monotherapies-being man-made public health hazards-fall within this definition and the IHR could be invoked to try to stop the spread of poor quality medicines. In addition, a treaty, drafted under the auspices of the WHO, to bring international agreement on interventions to reduce the frequency of both substandard and counterfeit medicines would allow coordinated action . Action is needed immediately or the hopes of controlling malaria in Africa may, again, be dashed.
The description of a wide diversity of different counterfeit and substandard anti-malarials from eight sub-Saharan African countries are cause of great concern. Criminals are producing diverse harmful anti-malarial counterfeits with important public health consequences. The presence of artesunate monotherapy, substandard and/or degraded and counterfeit medicines containing sub-therapeutic amounts of unexpected anti-malarials will engender drug resistance. With the threatening spread of artemisinin resistance to Africa, much greater investment is required to ensure the quality of ACT and removal of artemisinin monotherapies. Support for MRAs is likely to be a key intervention. The International Health Regulations may need to be invoked to counter these poor quality medicines.
Acknowledgements and funding
We are extremely grateful to the many people who have assisted with the collection of samples without which this would not have been possible. We thank Professor TT Hien, Mekophar Chemical Pharmaceutical Joint-Stock Company, Guilin Pharmaceutical Co. Ltd., Denk Pharma GmbH & Co, Zheijiang Holley Nanhu Pharmaceutical Group Co. Ltd., Bliss GVS Pharma Ltd, Novartis Pharma AG, GlaxoSmithKline plc, Neil Carter, Christine Eckers, Ulrike Fillinger, Jeremy Farrar, Roger Bate, Nicholas J White, Jean-Claude Wolff, the International Rescue Committee (IRC), the ACT Consortium and anonymous collectors for their help and advice. We are very grateful to Patricia Tabernero for checking Additional File 1.
The method development work of FMF was funded by an NSF CAREER grant. LN was partially supported by a USP graduate fellowship. PNN is supported by the Wellcome Trust of Great Britain. Forensic analysis was conducted through the support of the Wellcome Trust and the ACT Consortium, funded by the Bill & Melinda Gates Foundation to the London School of Hygiene and Tropical Medicine. The funding bodies had no role in the design and conduct of the study and had no role in the decision to publish.
The opinions and assertions contained herein are the private views of AET and are not to be construed as official or as reflecting the views of the U.S. Department of the Army or the Department of Defense.
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