JAC Advance Access originally published online on June 5, 2007
Journal of Antimicrobial Chemotherapy 2007 60(2):214-236; doi:10.1093/jac/dkm109
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Counterfeit or substandard antimicrobial drugs: a review of the scientific evidence
1 Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece 2 Department of Medicine, Tufts University School of Medicine, Boston, MA, USA
* Correspondence address. Alfa Institute of Biomedical Sciences (AIBS), 9 Neapoleos Street, 151 23 Marousi, Athens, Greece. Tel: +30-694-611-0000; Fax: +30-210-683-9605; E-mail: m.falagas{at}aibs.gr
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Abstract |
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Top
Abstract
IntroductionThere is growing universal concern regarding counterfeit medications. In particular, counterfeit antimicrobial drugs are a threat to public health with many devastating consequences for patients; increased mortality and morbidity and emergence of drug resistance. In addition, physicians treating these patients lose their confidence in the medications used and report high levels of bacterial resistance. The problem with fake and suboptimal medications got worse with the advent of the World Wide Web; a significant proportion of medications that are sold through Internet pharmacies is counterfeit. Various initiatives of the WHO (the International Medical Products Anti-Counterfeiting Taskforce) are hopefully going to tackle this very important public health issue. In this article, we review the available evidence in peer-reviewed articles and World Wide Web information resources regarding the issue of counterfeit antimicrobials.
Keywords: low-quality antimicrobials , quality testing , fake antimicrobial agents
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Introduction |
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Drug quality is currently receiving renewed international attention.1 Over the past decade, there has been an increase in public awareness of the existence of counterfeit and substandard drugs,2–5 which have been increasingly reported in developing countries where drug regulations are ineffective.6–14 Although practically all types of pharmaceutical products have been shown to be involved, the existing data suggest that anti-infectious agents, particularly antibiotics and antiparasitic agents, are the most counterfeited products in developing countries.1,15,16
To implement effective countermeasures against counterfeit and substandard drugs, there is a need for more data to define the extent of the problem. The issue of poor quality drugs has been discussed more in the mass media including newspapers than in the biomedical literature. Many reports that this topic are however anecdotal, which makes quantitative assessment difficult.10,17 Few studies have been reported that systematically examine drug quality,7–12 and have investigated poor quality drugs in terms of correct amount of active ingredient present. More specifically, although drugs that treat serious diseases such as malaria, tuberculosis, AIDS or other infections are more often the object of counterfeits,18,19 there have been scarce reports that systematically review data of low-quality antimicrobials. Therefore, we performed a review of the available scientific evidence on counterfeit and/or substandard antimicrobial drugs. More specifically, we set out to explore the causes and prevalence of this problem and summarize the categories of antimicrobials that have been reported to be counterfeit or substandard. We then discuss the characteristics of these low-quality antimicrobials, their consequences to patients and in our society and finally what interventions have been put into place to cope with this menace.
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Literature review |
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Two reviewers (T. K. and I. K.) independently performed the literature search, study selection and data extraction. The following terms were used in searches of the PubMed database (1966–2006): ‘counterfeit drugs’, ‘substandard drugs’, ‘fake drugs’, ‘substandard antimicrobial agents’, ‘fake antimicrobial agents’, ‘counterfeit antimicrobial agents’, ‘substandard antibiotics’, ‘fake antibiotics’ and ‘counterfeit antibiotics’. Magazine and newspaper articles were searched for with Google and we screened articles related to the initially identified publications to expand our data sources.
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Definitions |
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The subject of overall drug quality has been addressed in several WHO publications.20–22 Substandard drugs are genuine products that have not passed the quality testing protocols previously set for each product.23 The testing protocols and specifications are published in official pharmacopoeias such as the United States Pharmacopoeia (USP), the European Pharmacopoeia and the WHO International Pharmacopoeia. In addition, many countries have published their own pharmacopoeias. More specifically, substandard drugs have incorrect quantity of active ingredient, which could be secondary to excessive decomposition of active ingredient as a result of high temperature and humidity, and poor quality assurance during the manufacture of pharmaceutical products in less-developed countries.
One special class of substandard drugs is the class of counterfeit drugs. Several countries have their own definitions as to what constitutes a counterfeit drug and there is no consensus. This poses a problem in that what may be considered a counterfeit product in one country will not necessarily be so in another country. The WHO has defined counterfeit drugs as those that are deliberately and fraudulently mislabelled with respect to identity and/or source.24 Counterfeit products include drugs with the correct ingredients or with the wrong ingredients, without active ingredients, with insufficient active ingredient or with fake packaging.25 According to a WHO report, analysis of the content of a drug preparation cannot therefore determine whether or not the sample is counterfeit, because the inclusion of inappropriate quantities of active ingredient during manufacture cannot be identified as deliberate.15
Using the above definitions, the variations in active ingredient and weight above or below the recognized limits found in different studies in the current report point to problems in good manufacturing practice, deliberate counterfeiting or poor retail management. Although it is very important to make a clear distinction between the various terms for poor quality medications such as ‘counterfeit’, ‘fake’ or ‘substandard’ drugs in the majority of reports reviewed herein, it was not clarified whether the substandard drug was counterfeit or simply the result of a defect in the manufacturing process.7,12 Thus, although these two terms are indicative of different problems that must be addressed using different strategies, we use the term ‘counterfeit/substandard’ drug, whenever the cause of the poor quality medication is not clear.
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Causes of poor quality drugs |
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The poor quality of drugs has been linked to counterfeiting of medicines,26 chemical instability especially in tropical climates,27 and poor quality control during manufacture.28 Many factors contribute to the increased prevalence of substandard and counterfeit medications. Much of the counterfeit drug trade is probably linked to organized crime, corruption, the narcotics trade, the business interests of unscrupulous politicians and unregulated pharmaceutical companies.29,30 According to the WHO guidelines, factors that influence the prevalence of counterfeit drugs in any particular country include weak or absent drug regulatory authority, absence of a legal mandate for licensing of manufacture/import of drugs, lack of regulation by exporters and within free trade zones, proliferation of small pharmaceutical industries, complex transactions involving many intermediaries, high demand for curative and preventive drugs and vaccines exceeding supply, high prices and inefficient cooperation among stakeholders.1 The WHO Essential Drug Program has failed in most countries31 because of personal financial interests at local, national and foreign levels or a black market. Studies indicate that a country's capacity to restrict dangerous drugs depends heavily on its wealth.9 It is surprising that almost a third of WHO member countries have poor means of controlling counterfeit medications.30 In these circumstances, the market for counterfeit and substandard drugs becomes a lucrative one. In addition, lack of good manufacturing practices (GMP) is common in local pharmaceutical industries in most developing countries because of many hurdles such as frequent power cuts and shortage of water.9 In addition to the existence of substandard drugs, assurance of the stability of pharmaceuticals marketed in developing countries (most of which have tropical climates) is a challenging issue as poor storage conditions, high temperature and high humidity conditions generally enhance chemical degradation and may alter the biopharmaceutical properties of the drugs,32,33 as it has been shown for antibiotics such as tetracyclines.34 Finally, medicine sellers often exhibit lack of concern about expiration dates and storage conditions, especially in poor settings and in the absence of national control, and this can increase the spread of substandard antimicrobials.35,36 Manufacture of generic versions of patented drugs for humanitarian reasons may also be abused in developing countries.37
In contrast, in developed countries such as the USA, other factors contribute to the spread of counterfeit medicines. For example, it is well known that underinsured or uninsured individuals and some states and local governments are turning to the Internet and foreign pharmacies, particularly what they believe to be safe, reputable Canadian pharmacies, to find less costly medications. However, Internet pharmacies, even licensed ones in Canada, are increasingly buying from foreign sources themselves to meet American demand38 and thus import of counterfeit and substandard medications may be enhanced. Finally, certain antimicrobials such as artemisin derivatives are not only confined to Asia and Africa but also to other countries of the industrialized world as they have a natural plant origin and tourists commonly buy them in the tropics as a standby treatment and they are also readily available on the Internet.39
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Prevalence of counterfeit and substandard antimicrobials |
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The magnitude of the drug-counterfeiting problem is considerable and is difficult to gauge as any true estimate of prevalence is difficult. The WHO estimates that up to 10% of the world's pharmaceutical trade—25% in developing countries—consists of fakes,18,40 whereas up to 25% of all drugs consumed in poor countries are thought to be counterfeit or substandard, according to the figures from the US Food and Drug Administration (FDA).41 Many studies have tried to provide estimates of prevalence of counterfeit/substandard antimicrobials [Table S1, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)].
A search of the medical literature yields a limited number of primary published research reports concerning counterfeit drugs and much of the information is only found in the grey literature and newspapers. Few published studies describing the prevalence of counterfeit anti-infectives provided sufficient methodological details to interpret the results6,7,11,12,14,36,42–59 and to control for potential bias or other factors such as instability of some medicines,42 whereas only in very few studies, there was random sampling with adequate description of methods.7 In the current review, we analyse the major studies that have been published regarding counterfeit/substandard antimicrobials (Tables 1 and 2) and also describe the separate categories of these antimicrobials, which include antibiotics, antiviral and antiparasitic agents and vaccines.
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Categories of poor quality antimicrobials |
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There have been reports of substandard/counterfeit drugs in almost all categories of antimicrobials including antibiotics and drugs used to treat tuberculosis, malaria and HIV/AIDS. In the developing world, antibiotics and antiparasitic agents, the drugs that are most needed there, are the counterfeiters' favourites. Other pharmacotherapeutic groups were represented in almost equal frequencies.60 There are 8–10 times more reports for counterfeit antibiotics and 2–3 times more reports for antiparasitic drugs in comparison with other counterfeit drugs.60
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Antibacterial agents |
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A wide range of antibacterial agents have been found to be substandard or fake (Tables 1 and 2). Although no part of the world is exempted, southeast Asia and Africa seem to be particularly plagued by counterfeited antibacterial agents. Especially ‘old’ antibiotics, such as penicillin, tetracycline, trimethoprim–sulfamethoxazole and chloramphenicol, are among the favoured counterfeited antimicrobials.6
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Antituberculosis (anti-TB) drugs |
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A substantial number of anti-TB drugs from several countries, particularly fixed-dose combinations, were found to be substandard [Table S2, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)]. In contrast, some other studies have shown good quality of anti-TB drugs.61–63
In contrast to other medications, anti-TB drugs are stable under storage conditions, so substandard levels are usually not caused by instability.61,64 Specific, robust and simple colorimetric methods such as thin-layer chromatography (TLC) can be used for the detection of substandard TB medications, especially in many Third World countries with relatively modest laboratory facilities63 where resources such as HPLC are not available or routine use is impractical.65 These substandard anti-TB medications can lead to emergence of drug resistance. Patients receiving a lower therapeutic dose than would be required for their treatment due to a substandard anti-TB drug could lead to drug resistance and treatment failure, despite 100% adherence to the treatment regimen by patients.65,66
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Antiviral agents |
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Counterfeit antiviral agents such as oseltamivir and interferon and antiretroviral agents have been reported [Table S3, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)]. Most of these reports, however, are anecdotal. More specifically, the recent report of substandard/counterfeit antiretroviral agents either alone or in combinations is very alarming [Table S3, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)]. On the other hand, in one study, drug content among generic antiretroviral preparations containing the non-nucleoside reverse transcriptase inhibitor nevirapine has been studied, and no substandard preparations were identified.51 Importantly, the recent discovery of counterfeit antiretrovirals raises the prospect of a disastrous setback in the treatment of AIDS in areas such as sub-Saharan Africa, unless vigorous action is taken now.
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Antiparasitic agents |
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Antimalarials
The quality of antimalarial drugs is especially crucial, given the widespread nature of the disease and its importance to global public health.67 As more than 40% of the world's population is at risk of malaria, antimalarial drugs have become a favourite target of counterfeiters. In the last years, many articles reported examples of counterfeit and substandard antimalarial medicines in developing countries (Tables 3 and 4). In a WHO survey of seven African countries, 20% to 90% of antimalarial drugs failed quality testing.68 Many studies have reported that a considerable proportion of antimalarial drugs obtained from east African countries is of poor quality7,12,17,69 and that even counterfeits of new antimalarial drugs, such as artesunate and mefloquine, are circulating in southeast Asia.14,70,71 Counterfeit artemisinins are a significant problem in southeast Asia14,55,72 and are expected to become a serious problem in Africa where artemisinin combination therapy is being implemented.39 The problem of antimalarial drug resistance as a result of counterfeit drugs has been addressed in recent reports.73 Considering the importance of antimalarial treatment in the tropical developing countries, where malaria is endemic and is the first cause of death for children, the presence of counterfeit and substandard drugs on the pharmaceutical market is a risk to the life of millions of people.
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Other antiparasitic drugs
Except for antimalarial drugs, there are reports for substandard anthelmintics and other antiparasitic agents such as pentavalent antimonials [Table S4, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)], which contribute to poor compliance, therapeutic failure and the appearance of resistance in parasites.74
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Other antimicrobial agents |
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Substandard/counterfeit antifungal agents such as griseofulvin and nystatin have been reported in Sierra Leone75 and Ukraine,76 respectively. In addition, there have been reports about substandard antiseptics such as betadine.77 Finally, substandard/counterfeit vaccines have been reported [Table S4, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)] and according to a study, only 3 of 10 vaccine-producing countries in the Asia-Pacific region were assessed to have internationally acceptable standards for vaccine production and quality control and effective regulatory mechanisms.78
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Characteristics of substandard/counterfeit drugs |
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Counterfeit drug products come in many variations. Some do not contain any of the active (pharmaceutical) ingredients (AI) or include the ingredient in harmful amounts. Other preparations come from an unacceptable source or are differently formulated, may contain unacceptably high levels of impurities or impurities such as mould or packaging that falsifies the product's true expiration date, whereas others contain a completely different active ingredient.
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Inappropriate packaging |
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Fake pharmaceuticals often have the same appearance as the brand name and generic drugs they mimic. They are generally indistinguishable in their outward packaging, and pill colour, shape, size and markings; they even have electronic bar codes, which pharmacists scan to verify drug authenticity.79 In developing countries, many of the purchased drugs without packaging were counterfeit.53 Examples of antimicrobials with false packaging and labelling include antibiotics such as penicillin,48 chloramphenicol,6 tetracyclines,6,36,54,57,80 co-trimoxazole,58 quinolones36 and aminoglycosides75,81 and antimalarials such as chloroquine,53 mefloquine,59 quinine82 and artesunate.14,44,61,70
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Reduced stability and bioavailability |
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Several studies that have reported on the stability of essential drugs under real storage conditions in the tropics27,33,83,84 in warehouses and in some wholesale pharmacies may not be satisfactory for ensuring the integrity of drug products.85–87 Antibiotics in particular, e.g. ampicillin,88 may degrade during transportation or storage at temperatures above 25°C and high humidity.33 Other drugs, however, may be stable under such conditions83 and there are studies that have shown that high storage temperatures do not affect adversely the content of many antibiotics including penicillins and tetracyclines12,83 and this may suggest that the most likely cause of low quality is to be found during manufacturing.48
Moreover, interactions may occur when products are stored at high temperature and humidity, consequently reducing the dissolution rate.85 Although many substandard antimicrobials may contain the appropriate amount of active ingredient, they can have suboptimal activity and this may be due to reduced bioavailability. Examples include tetracyclines,34 co-trimoxazole,32 metronidazole,32 pyrimethamine,50,89,90 chloroquine91 and mefloquine.59
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Reduced concentration of active ingredient |
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Low concentration of active ingredient in antimicrobials may be the result of poor manufacturing or could be the effect of poor transport and storage conditions and often it is not possible to distinguish between these two causes (Tables 2 and 4). Decomposition was the cause of poor quality in a number of samples,7,88 but as it has been shown that many antibiotics may be stable even under tropical conditions,83 overall poor manufacturing appeared to be the prevalent cause of low quality.7,48 However, the effect of storage conditions on drug quality has not been assessed in all studies.42 Finally, reduced concentration of active ingredient could also be the result of dilution of drugs with other substances such as contaminated water29,79 or sugar.92
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Altered chemical content |
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Additionally, counterfeit drugs may be characterized by altered odour because they contain diluted active ingredients, or in many cases harmful additives. Sometimes, the counterfeit drugs are chemically identical to the real product, making them counterfeit generics; however, most fakes contain inactive or harmful ingredients. The capsules or tablets may contain, for example, a wrong antibiotic such as erythromycin,39 or they may contain only worthless flour, starch or powder.29,39,93,94 Notorious recent real examples include neomycin eye drops and meningococcal vaccine made of