Global scenario of counterfeit antimalarials: A potential threat
Taruna Arora, Supriya Sharma
ICMR–National Institute of Malaria Research, New Delhi, India
Date of Submission 07-Oct-2018
Date of Web Publication 30-Nov-2020
Dr. Taruna Arora
ICMR–National Institute of Malaria Research, Sector 8, Dwarka, New Delhi–110 077
Malaria, a parasitic infectious disease causes approximately >1 million deaths annually worldwide. Treatment with effective antimalarials is one of the major strategies to combat malaria-related mortalities. However, there is a continuous threat of counterfeit antimalarials in the community. Counterfeit antimalarial drugs not only result in an economic loss but also decrease the efficacy of treatment resulting in the loss of faith in the health system and increases the the chances of drug resistance in the parasites. Counterfeit drugs hamper the intellectual property-based innovation paradigms as well. Awareness about these counterfeit drugs not only helps in avoiding drug resistance but may also enhance the drug therapeutic value. This review discusses the prevalence of counterfeit drugs in different geographic areas across the globe, the methods deployed for its detection and possible anticounterfeiting strategies. Literature search was conducted through PubMed, Google and International Pharmaceutical Abstracts using the terms 'counterfeit antimalarials', 'substandard', 'falsified', and 'drug resistance'. Free searches in other search engines included the terms 'antimalarial counterfeit drugs' and 'drug resistance'. Analysis of the literature survey indicated that majority of such studies were conducted in Southeast Asia and Africa region. The prevalence of substandard antimalarials was reported as high as 88.4% in Africa region and 53 % in Southeast Asia region. There is a need to follow a multifaceted approach to prevent the entry of falsified drugs with pre- and post-marketing surveillance. The samples need to be examined by regulatory bodies and strict legislation should be envisaged in order to maintain the quality of medicines.
Keywords: Antimalarial drugs; counterfeit; drug resistance; falsified; substandard
Arora T, Sharma S. Global scenario of counterfeit antimalarials: A potential threat. J Vector Borne Dis 2019;56:288-94
Arora T, Sharma S. Global scenario of counterfeit antimalarials: A potential threat. J Vector Borne Dis [serial online] 2019 [cited 2021 Jan 18];56:288-94. Available from: https://www.jvbd.org/text.asp?2019/56/4/288/302030
Malaria is a life-threatening disease and is widespread in the tropical and subtropical regions mainly around the equator. India has seen success in recent years in terms of significant decline in malaria cases and deaths. Amid many possible reasons for mortality related to malaria are counterfeit antimalarials which are a menace to the community. A counterfeit drug is a fake medicine which may contain inappropriate ingredients or product with correct ingredients but without active ingredients or with incorrect packing[1]. Different categories of counterfeit drugs like antibiotics, hormones, analgesics, steroids, and antihistamines are reported to circulate in the market.
The problem of a counterfeit drug is widespread, affecting both developing as well as developed nations. India is the fifth and main player for the distribution of counterfeited drug manufacture and exporter. Counterfeit antimalarials are a major health problem worldwide and >50% of the drugs are reported to be substandard or falsified. The World Health Organization reports that approximately 35% of the fake drugs are sold by India alone which accounts for a business of 40 billions[2]. However, recently India released a press statement saying that US is attacking on low-cost generic drugs and India strongly and outrightly rejects allegation on fake drug circulation.
Counterfeit drugs involve risk to the patients because they may contain inactive/wrong or harmful ingredients. These drugs increase morbidity and mortality, drug resistance, an adverse effect due to incorrect ingredients and failure to achieve therapeutic efficacy during the treatment[3]. The marketing of counterfeit drugs is a sensitive issue and needs serious attention. This review is an attempt to describe the spread of counterfeit antimalarial drugs across the world along with the methods applicable for its detection and the possible anticounterfeiting strategies. The literature search indicates that very few studies have been conducted in India on such drugs; and therefore, such studies are the need of the hour. It can help the nation to fight against the threat of counterfeit drugs.
Key databases like PubMed, Google and International Pharmaceutical Abstracts were used for conducting literature search for the year 2000–2018, using the terms 'counterfeit antimalarials', 'substandard', 'falsified', and 'drug resistance'. Free searches including the terms 'antimalarial counterfeit drugs' and 'drug resistance' were also carried out in other search engines. The terms used for classifying counterfeits are explained in [Table 1]. Records identified were assessed and scrutinised to include articles related to substandard antimalarials and their detection. In our literature survey, we found 35 such studies, of which 29 were conducted in Africa region and six studies were carried out in the southeast Asia (SEA) region [Table 2]. The prevalence of substandard antimalarials was reported as high as 53% in SEA and 88.4% in the Africa region.
Table 1: Terms used for classifying counterfeits
Table 2: Summary showing major prevalence studies on substandard antimalarials
Methods for the detection of counterfeit/substandard antimalarials
Methods used for the detection of counterfeit drugs include sophisticated techniques such as high-performance liquid chromatography (HPLC), mass spectrometry, infrared spectroscopy, and X-ray powder diffraction[4],[5],[6]. Assays such as dissolution and colorimetry coupled with visual inspection could be deployed to detect minor cases of drug counterfeiting[7]. [Figure 1] provides a succinct listing of methods that can be utilized to detect drug counterfeiting. A combination of visual inspection of packaging and labeling, disintegration assay, colorimetric assay, and thin-layer chromatography (TLC) can be helpful for detecting counterfeits in the field settings. The label description of a drug is regulated by a national-level legislation. Hence, information about the labeling requirement is also helpful for detecting counterfeits. A typical label includes information such as the name of the product, active ingredients, dosages form, date of expiry, lot number and storage precautions. However, the counterfeit drug packaging includes missing or wrong information such as lack of an "Rx only" symbol, no information in English language, lot number in foreign language. It may contain compromised signs such as broken seal, repaired, damaged and or opened, reformed otherwise[8].
Figure 1: Listing of methods which can be utilized to detect drug counterfeiting.
A disintegration test gives an estimate of drug solubility. Disintegration test is typically performed in distilled water at 37 °C for 30 min, however, for enteric-coated drugs either diluted hydrochloric acid or phosphate buffer at pH 6.8 can be used. A minimum number of six tablets from the same lot are required to pass the test. After the complete disappearance of drug tablet except the coating, the disintegration is thought to be achieved.
Colorimetric test relies on the change of color due to chemical reaction with an analytical reagent which is typically performed with the active pharmaceutical ingredient in solution. Such as chloroquine (CQ) gives a brown colour with Fast Red TR dye while the yellow colour represents the presence of artesunate (AS). However, the colorimetric test requires an experienced field worker, as the colour formation reaction depends on the spectral properties of source light, object and visual discriminatory power of observer[7].
The TLC provides an operational simplicity in field settings and is used to estimate the presence of active pharmaceutical ingredients semiquantitatively. It usually involves silica gel or cellulose as the stationary phase[9]. On the stationary phase, the test samples are kept with a reference standard which allows migration of the drug because of the capillary action of the solvent (mobile phase). The movement of the drug in the stationary phase indicates the presence of an active pharmaceutical ingredient. Quantitative estimation of active pharmaceutical ingredients is achieved by HPLC. The method for determining active pharmaceutical ingredients using HPLC is generally adopted from pharmacopoeia or the scientific literature. A calibration curve is normally plotted by running the various concentrations of a reference drug. The area under the curve of an analyte is plotted in the calibration to find out the concentration of active pharmaceutical ingredient in the sample[10]. However, further research is needed to develop newer methods that should be rapid, robust and of low operational cost.
Reports on counterfeit antimalarials
Counterfeited antimalarials are a major health problem in Africa. In African countries, more than 50% of the pharmaceutical is adulterated with counterfeit drugs[11]. Counterfeit AS was detected with CQ adulteration, substandard dihydro-artemisinin with sildenafil and artemether-lumefantrine (AL) containing pyrimethamine, in eight countries of Africa[4]. Substandard antimalarials such as CQ (50%), sulphadoxine-pyrimethamine (SP) (13%), quinine (QN) (12%), amodiaquine (8%), AS (12%), AL (5%) have been observed in Burkina Faso[5]. Quantitative assessment of antimalarials such as CQ, QN, and antifolates were failed to meet the pharmacopeial specifications in 38, 74, and 12% of the collected samples, respectively in Cameroon[12] In post-marketing surveillance of antimalarial medicines used in Malawi, 88.4% (99/112) of the samples were found to be of substandard quality[10].
In Ghana, only 3 (17.6%) AS samples met with the European Pharmacopoeia content requirements, while 14 (82.4%) were found to be of substandard quality[13]. Surveys indicate that up to 55.2% SP suspensions and 61.1% of the substandard AQ tablets were found to be counterfeit in Kenya[14]. Atemnkeng et al[15] reported that the AS injection has lower drug content and dry powder suspension had no active ingredient in the districts of Kenya and the Democratic Republic of the Congo. A study carried out in southeast Nigeria related to the quality of antimalarials found that 37% of the antimalarials did not meet United States Pharmacopoeia (USP) specifications; either they contain a less active pharmaceutical ingredient or suboptimal concentration of active pharmaceutical ingredient[7]. Distribution of substandard antimalarial has also been reported from Senegal where 44% of the samples were counterfeit, 35% CQ tablets and 55% SP did not contain the active ingredient and did not meet the requirement as specified in USP[16]. Also, a post-marketing survey in Sudan reported 27% CQ and 100% of QN injections failed when tested with various analytical methods specified in pharmacopoeia specifications[17]. There was an enhanced production of substandard antimalarials circulating in the Sudanese market.
In Tanzania, nationwide surveys on the quality of antimalarials found that 12.2% of samples were counterfeit[6]. Different formulations of SP were noted to have low bioavailability. In a study of 11 brands of SP in Tanzania, differential results were observed depending on the type of test used, e.g. hardness, disintegration, friability, etc[18].
Analyses of the counterfeit drugs manufactured in SEA revealed that several antimalarial drugs such as artemether, AS, CQ, mefloquine, QN, SP, and tetracycline are found to be fake because of correct ingredients yet with deficient dose, or packaging, or wrong ingredients[3]. A survey by Dondorp et al[9] indicates that 53% of 118 tablets of AS and 9% of 44 tablets of MQ are counterfeit because of less active ingredient[9].
In a survey, conducted in seven countries of sub Saharan Africa, 497 (35%) drug samples failed in chemical analysis whereas 423 (46%) of 919 samples failed in packaging analysis, hence, multifaceted approach is needed to control the production of substandard antimalarials[19]. However, it has been documented that 8 (35%) of 23 fake AS samples contained the wrong active ingredients (erythromycins and paracetamol) as analyzed by liquid chromatography coupled to mass spectrometry[19]. Similarly, 27% antimalarial samples were found as a counterfeit drug in Cambodia when analyzed by TLC and disintegration test[1]. Also, in Afghanistan, 26% of the samples were found to be of poor quality, and it did not meet the requirement of USP.
Bate et al[20] reported that 12% of samples from Delhi and 5% of samples from Chennai (antimalarial, antimyco-bacterial, antibiotic) failed either in TLC or in disintegration test by using field-deployable techniques. Another Indian study on counterfeit drugs revealed that significant number of AS samples were below (71–89.2%) the normal manufacturing range (90–110% stated content) when analyzed using Liquid Chromatography–Mass Spectrometry[21]. Ioset and Kaur[22] developed a novel colour reaction-based assay technique to check the drug quality at a small scale. Hence, there is a need to establish empowered national authorities to take necessary action against counterfeit drugs[23].
Conclusively, majority of the studies related to counterfeit antimalarials have been conducted in Africa and the SEA region. These studies reported the testing of various antimalarial agents such as CQ, AL, artemisinin derivatives, AS+SP, PQ, AS+MQ, etc. The studies indicate that there is an urgent need to protect artemisinin and its derivatives from drug resistance as it has already been reported for most antimalarials[24]. Some countries have also reported artemisinin resistance in the recent years[25].
Provoking factors for counterfeiting antimalarial drugs
Antimalarial drugs require a robust supply chain which is often absent in developing countries. The imbalance between demand-supply ratio is a conductive factor for the entry of counterfeits in the drug supply chain. Drug manufacturing companies in developing countries have a resource constraint environment, such as lack of capital investment or basic infrastructure which further leads to a drug with low quality.
The weakness in the regulatory system such as inadequate testing facilities makes the detection of counterfeits difficult. The manufacturing process could have errors like non-adherence to standard good manufacturing practices, which makes it almost difficult to quantify or rectify the error in drug formulation. Other sources of counterfeited drugs are the sectors which are not effectively regulated by the national regulatory authorities such as internet pharmacies and illegal cross-border drug traders.
Strict laws for counterfeit drugs
Counterfeit drug manufacturing can be controlled by regulatory authorities to prevent the circulation of counterfeit drugs in the supply chain. There is an urgent need to establish and strengthen the drug quality by regulatory authorities to estimate the prevalence of substandard antimalarial medicines. Regulatory authorities must undertake serious anticounterfeiting efforts to reduce its supply in the market. Health professionals should remain vigilant about counterfeit drugs distributed in the market. This situation is worsened in some countries those don't develop medical policy, legislation, and enforcement strategies to control the substandard manufacturing of medicines. The penalty for counterfeit drug manufacturing in India is guided by the State licensing authorities by Drug and Cosmetic Act 1940, which includes imprisonment not <10 yr and a fine, not less than ` one million. However, the quantum of punishment has been debated by experts as an inefficient deterrent given the profit involved in counterfeiting drugs. Different regulatory bodies at the international and national levels are listed in [Table 3]. These regulatory agencies play a pivotal role in registration, manufacturing, distribution, price control, intellectual property protection and activities like efficacy, safety, quality, rules and regulation guidelines for drug development, licensing, registration and labeling of pharmaceutical products. They also work on import, production, storage, and supply of drugs. In India, Drug Controller General India (DCGI) is responsible for monitoring such activities.
Table 3: Different regulatory bodies for counterfeit drugs
What should be done to prevent counterfeit drugs?
Drug quality testing in the field settings: Such as the taste, colour, and odour of the suspected formulation should match with the genuine product. Research is needed to develop the assays which can be efficiently performed in a field setting [Figure 2].
Figure 2: Diagrammatic representation of anticounterfeiting strategies.
Monitoring of drugs through the supply chain: Regulatory agencies should check the drugs from the supply chain that reach the consumer.
Technology-based innovations: Labeling the drugs using new generation bar codes such as holographic, radio frequency identification devices (RFIDs), etc.
Laws regulation, awareness, and vigilance: Central drug regulatory authorities need to be set up in every state. Counterfeit drug offences should be investigated by an independent investigation agency. The penalty for imprisonment should be increased for the counterfeit drug manufacturers.
International collaborations: Organizations like International Medical Products Anti-Counterfeiting Taskforce (IMPACT) is promoted by the World Health Organization as regulator to reduce the trade of counterfeit drugs in the international markets. Members of this task force are from non-government organizations, manufacturers, wholesalers, health care professionals, and national drug regulatory authorities. This organization is set up just to fight against this issue.
Antimalarials counterfeiting has turned out as a huge profitable business model across the world primarily managed by big sophisticated operators with potential of escaping detection by the drug-regulatory bodies. Hence, there is need to strengthen pharmaceutical management systems such as post-marketing surveillance in India to ensure that the antimalarials are safe and of high quality. Increased collaboration between stakeholders, manufacturers, government, regulatory authorities along with the judiciary system as well as the national and international database would be the demotivating key factors against persistently available counterfeit/falsified antimalarials in the community. Reports of drug resistance against the widely used antimalarial drugs like artemisinin and its derivatives demand better techniques of identifying such spurious drugs. Hence, it is very important to prospectively monitor the adequate dosage of antimalarial drugs to prevent further drug resistance against AS and its combination therapies.
Ethical statement: Not applicable.
Conflict of interest: None.
The author TA is grateful to the Indian Council of Medical Research (ICMR), New Delhi for the Postdoctoral fellowship. Authors are grateful to the Director ICMR–National Institute of Malaria Research (NIMR), New Delhi for providing research support facilities.
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[Figure 1], [Figure 2]
Arora T
Sharma S
Antimalarial drugs; counterfeit; drug resistance; falsified; substandard