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Substandard medicines in resource-poor settings: a problem that can no longer be ignoredTropical Medicine and International Health volume 13 no 8 pp 1062–1072 august 2008 Substandard medicines in resource-poor settings: a problemthat can no longer be ignored J.-M. Caudron1,2, N. Ford1, M. Henkens1, C. Mace´1, R. Kiddle-Monroe1 and J. Pinel1,2 1 Me´decins Sans Frontie`res, Geneva, Switzerland2 AEDES Foundation, Brussels, Belgium The circulation of substandard medicines in the developing world is a serious clinical and public healthconcern. Problems include under or over concentration of ingredients, contamination, poor qualityingredients, poor stability and inadequate packaging. There are multiple causes. Drugs manufactured forexport are not regulated to the same standard as those for domestic use, while regulatory agencies in theless-developed world are poorly equipped to assess and address the problem. A number of recentinitiatives have been established to address the problem, most notably the WHO pre-qualificationprogramme. However, much more action is required. Donors should encourage their partners to includemore explicit quality requirements in their tender mechanisms, while purchasers should insist thatproducers and distributors supply drugs that comply with international quality standards. Governmentsin rich countries should not tolerate the export of substandard pharmaceutical products to poor countries,while developing country governments should improve their ability to detect substandard medicines.
keywords substandard medicines, quality assurance, drug export, contamination, quality standards et al. 2001). However, the problem is very poorly addressed compared to other problems related to quality In October 2004 a doctor working for Me´decins Sans drug supply such as counterfeit (fake) medicines and Frontie`res (MSF) in Darfur reported that a local donation inappropriate drug donations (Box 1). This article high- of Ringer’s lactate infusions was contaminated with a lights some of the key concerns derived from MSF’s work fungal growth. Subsequent investigations revealed that to assure the quality of medicines for medical relief weaknesses in the bottling and quality control procedure programmes in less-developed countries, supported by a during manufacture led to the contamination. The product literature review. Articles were retrieved from a PubMed then passed through three intermediates, including one UN search for the phrase ‘substandard medicines’ (1988- agency, before being offered to relief agencies in Darfur, present) and further refined with bibliographic search of only one of which reported the problem. The World Health Organization (WHO) and the supplier jointly issued arecall of the contaminated batches. Six months after the One standard for the rich, another for the poor recall, however, less than 15% (2200 of 15 000 bottles) ofthe contaminated product had been located.
In the industrialized world drug regulatory authorities have This example illustrates the problem of substandard developed strict standards and controls to ensure drugs are medicines that is commonly confronted by health staff in effective and safe. However, in the less-developed world, developing countries. Substandard medicines can have lack of human and financial resources within the health serious clinical and public health consequences: contami- sector as a whole limits the capacity of drug regulatory nation can cause fatal toxicity (O’Brien et al. 1998); lack of agencies, resulting in a suboptimally regulated environment active ingredient can lead to ineffective treatment and in which substandard drug production can persist without prolonged illness or death (Aldhous 2005); while under dosing of active ingredient carries the additional risk of Circulation of substandard drugs is further encouraged promoting drug resistance (Laserson et al. 2001; Taylor by the fact that drugs manufactured for export are often Tropical Medicine and International Health volume 13 no 8 pp 1062–1072 august 2008 J.-M. Caudron et al. Substandard medicines in poor countries transit through their countries’ (WHO 1999a). This was Box 1 counterfeit and substandard drugs: distinct followed by a European Commission directive in 2003 stipulating that ‘all medicinal products for human use, Counterfeit ⁄ fake drugs: Multiple definitions have been including medicinal products intended for export, are to proposed for counterfeit drugs, with the common point be manufactured in accordance with the principles and that they are the result of deliberate criminal activity, guidelines of good manufacturing practices’ (European ‘deliberately and fraudulently mislabelled with respect to identity and ⁄ or source’ (WHO 2006e).
However, the reality today is that the quality of drugs for Counterfeiting can apply to both branded and generic export from developed to developing countries is still products and may include products with the correct determined through a much less rigorous evaluation than ingredients or with the wrong ingredients, without for the domestic market (European Commission Human- active ingredients, with insufficient active ingredients or itarian Aid Department 2006). Efficacy and safety are often with fake packaging (WHO 2003). The United States not evaluated at all. Drugs destined for international aid Food and Drug Administration states that, ‘counterfeit and development programmes are also often exempted drugs are, by definition, outside of the regulatory from regulatory control (Andriollo et al. 1997). The regime’ (Carpenter 2004), while WHO considers expectation is that the recipient country will evaluate the counterfeiting as a serious criminal offence that puts quality of the imported drug. While this may be an human lives at risk and should be combated and acceptable expectation between rich countries, placing this burden of responsibility on countries that do not have theresources to do it is impractical, even exploitative.
Substandard drugs: According to the WHO,‘Substandard drugs are genuine drug products which do not meet quality specifications set for them.’ Similarly,The United States Pharmacopoeia defines a substandard Poor compliance with GMP standards can lead to sub- product as a ‘legally branded or generic product, but standard production. This may be accidental (such as one that does not meet international standards for human error) or the result of insufficient resources quality, purity, strength or packaging’ (Smine 2002).
(expertise, appropriate manufacturing infrastructure, or Simply put, they are as medicines that do not conform human and financial resources). Other deliberate causes are to the pharmacopoeial standards set for them (Behrens often ignored or underestimated. Quality audits of manu- facturing sites done by MSF pharmacists (180 sites visitedover the last 4 years) have found that manufacturers thatregularly pass the most stringent inspections adjust theirstandards to that of the recipient country. In our obser- not regulated to the same standard as those manufactured vations, parallel productions can exist in the same ‘GMP- for domestic use. An analysis done by the European Union compliant’ facilities: a high standard of production for the and the French Ministry of Cooperation (Andriollo et al.
strictly regulated markets and for exacting clients such as 1997) revealed many problems in the export legislation UN organizations and international aid agencies; an from European countries to developing countries, includ- intermediate standard of production for middle-income ing imprecise controls regarding good manufacturing countries; and a much lower standard for poorly regulated practices for exported products, lack of quality control of products that have not been marketed in Europe, anddiscordant information between drugs to be exported and Quality is not demanded by drug purchasers drugs for European use (Andriollo et al. 1997).
A World Health Assembly Resolution in 1988 Developing country governments often purchase drugs requested WHO to ‘initiate programmes for the preven- without adequate reference to quality standards. While tion and detection of the export, import, and smuggling these are available through WHO publications and via the of… substandard pharmaceutical preparations’ (WHO Internet (US Pharmacopeia 2008), local authorities in a 1988). More than a decade later the World Health number of countries have expressed to us their difficulty in Assembly urged member states to ‘establish and enforce accessing these documents and translating this information regulations that ensure good uniform standards of quality into clauses for tenders and contracts. Non-governmental assurance for all pharmaceutical materials and products organizations working in developing countries also issue manufactured in, imported to, exported from, or in drug tenders without applying minimum quality assurance Tropical Medicine and International Health volume 13 no 8 pp 1062–1072 august 2008 J.-M. Caudron et al. Substandard medicines in poor countries procedures (European Commission Humanitarian Aid instances where this is in fact the result of a poor manufacture of the intravenous fluid resulting in contam-ination with pyrogens.
Drug Regulatory Authorities have recently expressed Capacity for technical evaluation is limited frustration at not being able to dedicate more resources to The World Health Organisation (WHO) estimates that post-marketing surveillance (WHO 2006a), all too aware only one in six countries has fully functional drug that weak pharmacovigilance limits the detection of regulatory systems (WHO 2004a). Even relatively simple substandard drugs, preventing corrective action and sup- chromatographic or pharmacopeial methods for quality verification (O’Brien et al. 1998) are not routinely avail-able (Newton et al. 2006) or used effectively (Risha et al.
Diminishing number of quality manufacturers for key 2006). Increasingly, drug registration is a pre-requisite for purchase in resource-limited countries, but authorizationto register a medicine is often granted on the basis of a Pharmaceutical production is profit-driven, and essential simple review of documents. Quality is impossible to medicines are for the most part old molecules that are no assure in the absence of proper controls that at minimum longer patent-protected, and therefore generate less profit.
would include verification of information submitted for For example, penicillins are considered as essential drugs evaluation through site inspections, review of batch doc- by the WHO (2007a), form part of the United Nations umentation, and random analysis of drugs supplied Interagency Emergency Health kit (WHO 2006b), and are (European Commission Humanitarian Aid Department still used in significant quantities in developing countries.
2006). Regional co-operation to improve technical capac- However, penicillin production has been progressively ity has been proposed for over 20 years (Jayasena 1985) abandoned in the developed world in favour of more recent and sophisticated antibiotics such as cephalosporins, qui-nolones, and macrolides. MSF and the UNICEF recentlyassessed 11 production sites for injectable penicillins. Of these, only two were found to be WHO GMP compliant.
In the developed world, pharmacovigilance – the detection The other nine sources are routinely found on the market and prevention of adverse effects and other drug-related problems – is an essential component of any health system,ensuring that problems are quickly detected and resolved.
However, the setting up of a functioning pharmacovigi-lance system, which allows for the rapid communication of In general, medical staff have little idea of the risk that problems and recall of harmful drugs is a costly and substandard products can pose to patients, and there is complicated process that has to compete with many other significant underreporting (Moride et al. 1997). Poor pressing health system priorities in resource-limited set- reporting in turn reinforces a limited understanding of the problem. Up to half of medicines tested in prevalence Where pharmacovigilance systems are weak or non- surveys were substandard (Table 1), but these surveys are existent, a higher degree of responsibility is placed on rare, often limited to a few drug classes and test for a narrow medical staff to guard against adverse effects. Such set of problems (usually concentration of active ingredient).
informal surveillance is further compromised by the acutelack of health staff in most developing countries, where Common problems associated with substandard medicines are often prescribed by necessity to patients by health auxiliaries who only receive a very short and basictraining that does not emphasize the detection of drug side- Common problems associated with substandard medicines effects. Patients for their part often have to travel long include under or over concentration, contamination, poor distances to receive medication and can rarely afford the quality ingredients, poor stability and packaging problems.
time or financial cost of remaining under supervision.
Table 2 provides a summary of these problems together Moreover, many toxic side effects are difficult to detect by clinical observation. For example, the rise in tempera- A study in Nigeria (Taylor et al. 2001) found that almost ture often observed after post-surgery administration of half of randomly sampled antibiotic and antiparasitic drugs intravenous fluids is usually interpreted to reflect a general did not comply with set pharmacopoeial limits. Over and degradation of the patient’s condition, but we have noted under concentration were equally frequent, and drugs Tropical Medicine and International Health volume 13 no 8 pp 1062–1072 august 2008 J.-M. Caudron et al. Substandard medicines in poor countries Table 1 Summary of major prevalence surveys for substandard drugs chloramphenicol,rifampicin, co-trimoxazoleand ranitidine (n = 212) chloramphenicol.
rifampicin. Diazepam,salbutamol (n = 288) concentration ofactive ingredient;over concentrationof non-activeingredient;disintegration Tropical Medicine and International Health volume 13 no 8 pp 1062–1072 august 2008 J.-M. Caudron et al. Substandard medicines in poor countries active ingredient;no active ingredient(20%);contamination ReMeD, Re´seau Me´dicaments et Developpment.
labelled as originating from developed countries (Belgium, noted by WHO which has published guidelines for the Holland, Switzerland and the UK) had similarly imprecise purchase of rifampicin-containing products (WHO 1999b; contents as those labelled as originating from less-devel- Newton et al. 2006). Nevertheless, MSF has been con- fronted with several sources of rifampicin (both single Contamination is a recurrent problem, and can have ingredient and fixed-dose combination tablets) that are fatal consequences, particularly with intravenous products.
registered, marketed and used in many African and Asian In MSF’s experience, microbial contamination of injections countries but have no proof of efficacy.
and infusions is often the result of poor sterilization Non-active ingredients (excipients) can pose as much as management, obsolete equipment, inappropriate produc- a threat as active ingredients, perhaps more so given that tion environment or too short sterilization cycles (to cut manufacturers are generally not required to provide any costs). It can also be the result of poor quality packaging information at all on excipients. One of the most frequently cited cases of substandard drugs – the death of Contamination of active pharmaceutical ingredient (API) 88 children in Haiti after ingestion of paracetamol liquid – with residues of solvents used in the synthesis or other was the consequence of a poor quality excipient. It is not toxic impurities is another frequent and important concern.
clear whether this was the result of counterfeiting or not The quality of the API is one of the major determinants of quality for all pharmaceuticals. However, it is also here Product stability is another parameter that has a direct that compromise can lead to the greatest cost saving as influence on the quality and efficacy of the medicine.
APIs can represent over 80% of the price of finished Pharmaceutical degradation is generally accelerated by heath and humidity and WHO recommends stability An example is rifampicin, a key agent in the first line testing in tropical conditions (WHO 2006c), but this not treatment against tuberculosis. Production of the API is always done (Omer 1990; Arya 1995). Artesunate, an complex and can lead to forms of the molecule which are essential antimalarial drug, is extremely sensitive to heat not equally soluble and therefore of variable bioavailabil- and humidity. Stable formulations of Artesunate are ity. This can have dramatic consequences in terms of public difficult to produce (the quality of the packaging material is health, since poorly effective drugs can lead to the critical) (Fawaz & Millet 2006) while co-formulations of development of drug resistance. This problem has been Artesunate with other antimalarials are even more Tropical Medicine and International Health volume 13 no 8 pp 1062–1072 august 2008 J.-M. Caudron et al. Substandard medicines in poor countries Table 2 Different categories of substandard medicines contamination of Nelfinavir API andformulations Variable solubility and bioavailability of Diethylene glycol used instead of propylene glycol in a cough syrup killed more than30 children in India Tropical Medicine and International Health volume 13 no 8 pp 1062–1072 august 2008 J.-M. Caudron et al. Substandard medicines in poor countries shape, poor quality plastic or roughtransportation (resulting in higher and quicker peak inblood and toxicity) DRA, drug regulatory authority; ReMeD, Re´seau Me´dicaments et Developpement.
challenging as these latter molecules can increase the medicines were genuine products, yet this study has been instability of Artesunate. MSF has found it difficult to cited elsewhere by WHO as evidence of counterfeiting obtain consistent stability data from producers, although this is crucial information for guaranteeing the efficacy of Because substandard drugs are frequently portrayed as a the product and avoid the emergence of resistance. When consequence of counterfeiting, it is hardly surprising that stability studies are performed they often do not adhere to the majority of international attention and action is WHO guidelines, especially for the testing in zone IV directed at the latter. This is partly because counterfeit drugs undermine the markets of pharmaceutical companieswho put significant energy into tackling the problem. As aresult, WHO is promoting a global approach to combat the problem of counterfeit medical products through reporting Substandard medicines represent a far larger risk to public procedures and enhanced access to information (WHO health than counterfeit medicines. However, with some 1999c), and has launched a taskforce (International exceptions (Shakoor et al. 1997; Taylor et al. 2001; Medical Products Anti-Counterfeiting Taskforce) against Behrens et al. 2002; Kelesidis et al. 2007; Newton et al.
counterfeit drugs (WHO 2006d). The Pan American 2008) substandard and counterfeit drugs are regularly Health Organisation works collaboratively with the United conflated and confused (Verduin-Muttiganzi & Verduin- States against counterfeits (US Pharmacopeia 2008) and Muttiganzi 1998; Laserson et al. 2001; Po 2001; Figueras the International Conference of Drug Regulatory Author- et al. 2002; Wertheimer et al. 2003; Rassool 2004; Amin ities, promoted by WHO, has incorporated the problem of et al. 2005; Videau 2006; Atemnkeng et al. 2007).
drug counterfeiting in the agendas of its meetings since The problem of counterfeit medicines is serious, and indeed has been described as ‘epidemic’ in the case of In contrast, there is little commercial incentive to invest artesunate in South-East Asia (Newton et al. 2008).
in reducing the proliferation of substandard medicines, and Determining whether a medicine is counterfeit is prob- this remains a poorly quantified and ill addressed problem.
lematic (Behrens et al. 2002), yet the few published reports When actions are taken, resources are often focused on ad that did differentiate between the two problems have found hoc quality controls while what is in fact needed is a strong that the majority of poor quality drugs were genuine, but quality assurance framework to ensure that the products substandard drugs, and not the result of counterfeiting produced are of an acceptable quality in the first place (Wondemagegnehu 1999; Syhakhang et al. 2004; (WHO 2003a). Quality control is part of quality assurance Atemnkeng et al. 2007). One WHO study (Syhakhang and investing in quality control only makes sense if a et al. 2004) found that almost all (18 ⁄ 19) poor quality strong quality assurance system is in place.
Tropical Medicine and International Health volume 13 no 8 pp 1062–1072 august 2008 J.-M. Caudron et al. Substandard medicines in poor countries The purchase of medicines in developed and developing Box 2 Outline of MSF’s qualification system countries must be based on a technical evaluation andapproval of the manufacturing site and the product itself.
One important step in this direction is the establishment of compliance: Sites approved in the previous 2 years by the WHO pre-qualification programme (mednet3.who.
internationally recognized inspectors* are approved de int ⁄ prequal ⁄ ) that has had a major impact on the quality facto by MSF. Other sites of potential interest are of medicines across the developing world, providing a benchmark of quality for resource-limited countries in anotherwise chaotic environment.
Product evaluation: Once WHO GMP compliance is The pre-qualification programme mobilizes a high level established, MSF pharmacists undertake product of technical expertise for the evaluation of manufacturing evaluation using classic quality indicators organizing in sites (GMP inspections) and assessment of product dos- the following categories: country of origin ⁄ countries of siers. The Global Fund and other major donors refer to the registration of the product; stability studies; finished list of WHO pre-qualification products and encourage product specifications; active pharmaceutical countries to purchase them preferentially. In 2005 four ingredients; packaging ⁄ labelling ⁄ patient information; African countries refused to register a US Food and Drugs GMP status of the manufacturing site; and proof of Administration antiretroviral combination therapy because therapeutic equivalence when required.
the drug had not been pre-qualified by the WHO pre-qualification project (Donnelly 2005). To support the pre- Decision process: On the basis of this information qualification project, WHO has also invested significant products are then approved or rejected for use in MSF resources to build capacity in developing countries through programmes. This decision is communicated to the GMP training for local inspectors and pharmacovigilance workshops in the context of HIV ⁄ AIDS programmes.
Until recently the pre-qualification project only covered No quality source identified: There are sometimes cases medicines for HIV ⁄ AIDS, TB, and malaria. Drugs for where the technical information provided by the reproductive health and avian influenza have recently been producers is not sufficient to validate the product.
added. However, insufficient resources mean that even MSF’s primary mandate is to provide emergency within this narrow scope it is limited in the speed of the medical assistance and the drug quality assessment review and quantity of drugs it is able to process.
cannot be detrimental to the ability to respond to Nevertheless, the WHO pre-qualification programme has emergency needs. A balanced risk-benefit assessment is given a clear signal to producers, distributors, regulators, done by the Medical Directors and, if the product is to and health providers that essential quality standards can be accepted, a temporary exceptional authorization to and should be applied, and that the proliferation of supply is granted. The result of the evaluation is substandard products is not an inevitability.
available for the National Drug Regulatory Authorities Two other initiatives have recently been launched by WHO. The Model Drug Registration Package (WHO2007b) aims to improve understanding of drug regulatory *Member inspectorates of the Pharmaceutical Inspec- requirements and facilitate collaboration and technical tion Co-operation Scheme, the International Conference exchange between drug regulatory authorities in developed on Harmonization or the WHO Pre-qualification pro- and developing countries, while the Model Quality Assur- ance System (MQAS) (WHO 2006e) provides guidelinesfor procurement agencies on quality assurance and stim-ulates exchange and collaboration between drug regulatoryagencies in developed and developing countries. Unfortu-nately, in our experience very few procurement agencies 2003 to ensure that the drugs purchased by its procurement comply with the MQAS, while few purchasers have the centres are in line with WHO standards. MSF’s qualifica- capacity to assess the compliance of their procurement tion system draws on existing international procedures, standards and specifications (WHO 1997, 1999d, 2004c, In order to fill the current gap between what these new 2006f, 2007b, Maponga & Ondari 2003) to assess specific initiatives can currently deliver and the immediate need to product dossiers and manufacturing sites (Box 2). This support medical programmes with a broad range of drug qualification process is only undertaken for drugs not requirements, MSF developed a qualification system in already validated by stringent regulatory agencies or the Tropical Medicine and International Health volume 13 no 8 pp 1062–1072 august 2008 J.-M. Caudron et al. Substandard medicines in poor countries WHO pre-qualification project. The work is done by MSF Developing country governments can make important pharmacists with the assistance of external experts for improvements with minor investments, particularly by particular areas that require specialized assistance such as making more use of technical resources that are already bioequivalence studies or GMP audits.
available from WHO and other organizations. This wouldbe further enhanced through regional collaboration.
The reality today is that health care providers in resource- poor settings are finding it increasingly difficult to find Significant resources have been devoted to tackle counter- sustainable and affordable sources of essential quality drugs.
feit medicines, but very little specific attention has been Confronted with situations where no quality assured prod- given to the far more serious and widespread problem of uct is available, they must make the impossible calculation substandard medicines. This is partly a consequence of the of weighing the risk of not treating against that of using a poor differentiation made between these two distinct drug whose quality and safety is unknown. This unaccept- problems. However, reducing the problem of substandard able situation will continue and in all likelihood worsen medicines to a consequence of counterfeiting skews unless those responsible assume their responsibilities.
resources towards legal action alone, complicating efforts Acknowledging the problem would be a good place to start.
to define targeted strategies to specifically address theproblem of the substandard medicines. The focus of attention should rather be on the detection and removal ofpoor quality medicines, whether they are counterfeit or We thank Emmanuel Baron, Marine Buisonniere, Rowan not, while at the same time assisting legitimate manufac- Gillies, Andy Gray, Karim Laouabdia, Jean-Denis Mallet, turers to improve the quality of their pharmaceutical Carmen Perez-Casas, Raffaella Ravinetto, Tido von Schoen- Angerer and Ellen ‘t Hoen for their valuable contributions to The limited resources available for the development of earlier drafts of this article, and all pharmacists working efficient pharmacovigilance systems in developing coun- with MSF who have contributed to our understanding of the tries compound the problem. Because the consequences of problem. We also gratefully acknowledge the assistance of substandard medicines, both on individuals and on public Jean-Luc Malie`re in undertaking the literature review.
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Medication Administration Policy We are happy to assist students who need medication at school. For safety reasons, we ask for the utmost compliance and cooperation regarding very specific provincial/CNABC requirements. Most medications, even those scheduled for three times per day, can usually be given outside of school hours. If your child requires “Emergency Medications” (i.e.