A cross-sectional investigation of the quality of selected medicines in Cambodia in 2010

Spurious/falsely labeled/falsified/counterfeit (SFFC) medicines are deliberately and fraudulently mislabeled with respect to identity or source [1, 2]. Falsifying is greatest in those regions where regulatory and legal oversight is weakest. Although precise, detailed data on SFFC medicines are difficult to obtain, estimates range from less than 1% of sales in developed countries to over 10% in developing countries, depending on the geographic area [3]. Several reports have documented adverse health consequences from consumption of SFFC medicines. More than 200 children died in a hospital in Bangladesh through ingesting SFFC paracetamol, which contained diethylene glycol, in 1990–93 [4]. In 1998, 30 infants died from SFFC paracetamol in India [5]. In Southeast Asia in 2001, 38% of 104 anti-malaria drugs were found to be SFFC [6]. In Cambodia in 1999, at least 30 people died through SFFC artesunate containing sulfadoxine-pyrimethamine, which is an older, less effective anti-malarial [5]. In 2005, a man aged 23 years treated with SFFC artesunate died in eastern Burma (Myanmar) [7]. In 1999, two people died through taking fake anti-diabetic medicines containing illegal quantities of glibenclamide in China; in 2008, four people died in Singapore after taking an SFFC phosphodiesterase type 5 inhibitor containing glibenclamide [8, 9]. In addition to SFFC products, substandard and degraded medicines are classified as poor-quality medicines [10]. Substandard medicines are genuine medicines produced by legitimate manufacturers that do not meet the quality specifications declared by the producer [11]. Degraded products may result from exposure of good-quality medicines to light, heat, and humidity; however, it can be difficult to distinguish degraded medicines from those that left the factory as substandard [12]. Substandard and degraded medicines reduce the effectiveness of therapy.

In Cambodia, the Ministry of Health (MoH) reported in 2001 that 13% of medicines were SFFC, with 21% being substandard and 50% unregistered [13]; in the same country, 35 medicines were found to be SFFC among 142 products in 2004 [14]. Furthermore, in our previous study in Cambodia in 2006–09, we identified 19 SFFC products among life-saving essential medicines [15, 16]. Evidence suggests that lack of awareness and inappropriate management in the supply chain could facilitate the distribution of SFFC medicines in the country [17].

To oppose the threat of SFFC medicines and prevent their spread, the Department of Drugs and Food (DDF) of the MoH has been conducting surveillance on the quality of medicines since 2006. In 2010, we selected some newer-generation medicines, including antibiotics, to assess falsifying trends in the context of this developing country. At the same time, we sought to identify the influential factors in falsifying practices and develop a cost-effective surveillance system to ensure the quality of medicines.

The results of this survey indicate a number of problems in the manufacturing and distribution conditions, quality, and packaging of medicines in Cambodia. Among 111 drug outlets we visited, including wholesalers, only one pharmacy in Phnom Penh and all 14 wholesalers had air conditioning in their storage areas. Despite temperature rises above 40°C in the dry season in Cambodia, the other drug outlets did not have any temperature-control measures [22]. Storing medicines at high temperature and humidity could result in deterioration of quality and might facilitate the distribution of degraded medicines in the market [23–25]. In Cambodia, good pharmacy practice, distribution practice, and storage practice have not been implemented. Hence, the deterioration in quality may be due to storage or distribution. To prevent the distribution of degraded products, storage conditions at drug outlets need to be better controlled. To this end, good pharmacy practice will be introduced in Cambodia by the end of 2013.

Following quality evaluation of the collected samples, we found that some products had problems in their outer packaging, such as different colors and/or layout for the same product, spelling errors, and a lack of identification codes. These discrepancies may have resulted from insufficient awareness of the risks and countermeasures adopted by legitimate manufacturers against SFFC or substandard medicines. Such shortcomings could make it more difficult to distinguish SFFC medicines, and dealing with this problem should help prevent the entry of such products into the market. Additionally, the circulation of unregistered medicines and unauthorized distribution of publicly donated ones could affect the emergence of SFFC medicines in the supply chain. The SFFC medicine we detected in this survey—cefixime tablets bearing a false lot number—did not have Cambodian registration, bore spelling errors on the label, and was obtained at a pharmacy. Nevertheless, we found the sample to be acceptable in quantity, content uniformity, and dissolution tests according to USP 30. Cefixime, an oral third-generation cephalosporin, has excellent therapeutic action against infections caused by bacteria and is relatively high in price. Counterfeiters thus have an incentive in producing such antibiotics [26]. This is possibly the first report of SFFC cefixime in Cambodia. The findings of this survey indicate that not only are earlier-generation, commonly used essential medicines targeted by counterfeiters, newer-generation medicines are similarly falsified because of a better profit margin. Sildenafil, a newer-generation medicine, is a medicine that is more likely to be counterfeited in developed countries [27]. The present study shows that sildenafil had low distribution, and no counterfeit product was found. This finding suggests that the target medicine for counterfeiting may vary depending on the country.

In the pharmaceutical quality evaluation of the 325 samples we identified, 103 (31.7%) were unacceptable in one or more of the quantity, content uniformity, and dissolution tests. Most of those were enteric-coated omeprazole capsules, which especially showed an unacceptably high failure ratio in the dissolution test. Unacceptable samples in the dissolution test for omeprazole may have resulted from poor enteric coating, which could cause degradation of the omeprazole by gastric acid and lead to ineffectiveness after oral administration. Variables related to formulation or manufacturing processes of medicines can significantly affect dissolution and the expected medical effects. Consequently, some pharmaceutical manufacturers, mainly from overseas, may not have attained the necessary technical level to produce enteric preparations. To maintain the quality of medicines, exporting countries should not allow substandard medicines to be exported to other developing countries. Furthermore, each manufacturer selects its specifications among existing pharmacopoeias and in-house specifications; thus, for some medicines, the conditions in dissolution testing are different between USP and BP standards. Indeed, it would be desirable for the MoH to define uniform requirements for dissolution testing. In early 2011, the MoH began implementing the dissolution test for registration; there was, however, no focus on this issue before 2011. Thus, samples collected in 2010 may have been particularly subject to problems with the dissolution test. Since dissolution testing has been added as a mandatory requirement for registering medicines in Cambodia, the situation may improve in the near future. Furthermore, the lack of information in package inserts and non-compliance with linguistic requirements of the ACTD could hinder the safe, proper use of medicines. Having adequate information on the packaging and inserts could minimize the misuse of medicines and reduce therapeutic failure [28, 29]. For package inserts, three languages—French, English, and Khmer—are officially accepted in Cambodia. To encourage the proper use of medicines, some key words have been translated into Khmer by the MoH for products lacking Khmer instructions. Essentially, the contents of all package inserts need to be translated into Khmer from French or English. Furthermore, ACTD was implemented in Cambodia only at the end of 2010. Before 2008, there was no checking and verification of all registered products by design and brand name. Therefore, the MoH has carried out such checking and verification only since 2008. However, products registered before 2008 can be distributed and sold as usual until their licenses expires; it is not until the papers relating to such products are submitted for license renewal that the ACTD requirements come into effect. ACTD was fully implemented in early 2011.

Printing technology has improved and become widely available to the point where SFFC medicines are able to show very close similarity to original products [21, 30]. Even medical practitioners may fail to spot SFFC medicines in their practices. Stopping SFFC medicines from entering the market is one way of preventing consumers being subjected to the health hazards associated with such medicines.

Toward creating a healthy, secure system for pharmaceutical distribution, it is likewise imperative to stop SFFC medicines from entering the market. Improved regulation of illegal medicines, revision and compliance of existing rules for pharmaceuticals, and introducing a pharmaceutical traceability system could help ensure the circulation of genuine medicines.

The collected samples in this study may not have been representative of conditions throughout Cambodia because of the limited area of sample collection, insufficient sample size in the stratified random sampling in Phnom Penh, and convenient sampling of some samples from selected drug outlets. Additionally, we did not receive responses relating to the authenticity investigation from 26 manufacturers; therefore, we were unable to confirm 95 samples as having been genuine or SFFC. Because of the insufficient number of samples, we could not verify the status of 43 medicines in our quality evaluation. These limitations make it difficult to assess the actual extent of SFFC and substandard medicines in the entire Cambodian supply chain.

In conclusion, the results of this survey indicate that medicine falsifying is not limited to essential medicines in Cambodia: newer-generation medicines are also targeted. Concerted efforts by manufacturers—both domestic and overseas—along with those by wholesalers, retailers, and regulatory authorities are necessary to ensure the quality of medicines.