Quality of anti-malarials in the public sector in Brazil and Guyana
For the purpose of performing quality control, AMI countries collected anti-malarial medicines between 2005 and 2010. The results have been reported in [
12], which also contains detailed information on the medicines collected and the sampling methodology, as well as failures percentages by country and type of medicine. Most of the medicines collected in Brazil (301/313 between 2006 and 2008) and Guyana (220/289 between 2007 and 2010) were sampled in the public sector. Although the report provides information on the results obtained with screening tests in the field, in Brazil and Guyana –following protocol– failed samples and a subset of passing samples were reanalyzed for certain tests at the Official Medicine Control Laboratory (OMCL). In the majority of the cases, there was concordance between the field tests and those repeated at the OMCL (see table four in [
12]). Artemisinin derivatives comprised four of the anti-malarials collected in Brazil and 92 of those collected in Guyana. In the case of Suriname, 20 anti-malarials were collected in 2007; 15 were artemisinin-containing medicines. Because samples in Suriname were collected in the informal sector, results will be discussed in the following section.
In Brazil and Guyana, medicines were visually inspected and assessed for disintegration, identity, content, and impurities (the three latter through thin layer chromatography (TLC)). These are tests that require minimal equipment and can be performed in the field. The percentage of anti-malarials that failed quality control tests in Brazil and Guyana were 6.4 and 7.3%, respectively, of which disintegration and TLC failures accounted for 4.5% in each country. However, no failures were reported in disintegration or TLC for artemisinin derivatives. The only type of failure found in artemisinin-containing medicines in both countries was that some samples were beyond their expiry date. For all anti-malarial medicines tested in Brazil (313), six (1.9%) were expired, among the latter only one artesunate. In the case of Guyana, from 289 samples, 8 (2.8%) were expired, and among the latter three artemether and three FDC of artemether and lumefantrine. Based on the results discussed in this section, the quality of anti-malarials in the public sector in Brazil and Guyana apparently was not a major risk factor for lesser artemisinin efficacy.
Quality of anti-malarials in the private and informal sector in Guyana and Suriname
For information on the medicines collected (Active Pharmaceutical Ingredient-API, and sector) and the sampling methodology utilized in the Guyana and Suriname study see [
11]. The samples were analyzed at laboratories operating in compliance with internationally recognized standards (Peru OMCL: ISO:EIC 17025:2005 accreditation and WHO prequalification, and USP: ISO:EIC 17025:2005 accreditation). All collected medicines were analysed through the comprehensive battery of validated methodologies detailed in [
11], not the field tests utilized in the studies described in the section above. This allowed for better accuracy in the measurement of content and impurities and also for the assessment of additional quality attributes such as dissolution and uniformity of content. As discussed below, these sectors are the ones more readily available to the migratory mining population, which constituted the majority of malaria patients assessed during the efficacy studies that showed higher parasitaemia after three days of treatment with an artemisinin derivative.
Guyana
Malaria medicines were sampled in the private and informal sectors in 2009. From these, 42% (32/77) were collected in the private sector and 58% (45/77) in the informal sector. In total, 46 samples (60%) were collected in the three high malaria incidence regions, while 31 samples (40%) were from three non-endemic 'source’ regions; the latter being regions with urban centres where people purchase medicine before travelling to the more remote endemic areas. Therefore, medicines from both sectors and types of regions were more or less equally represented in this study. Most of the samples (64%; 40/77) contained artemisinin derivatives, of which 7.5% (3/40) were monotherapy (artesunate).
The artemisinin-containing medicines collected included a monotherapy (Artesunate) and fixed-dose combinations (Artecom: dihydroartemisinin, piperaquine, trimethoprim, primaquine; Artemos-40: dihydroartemisinin, piperaquine, trimethoprim; Co-Ariante: artesunate, sulphamethoxypyrazine, pyrimethamine; Artemos-Plus: artemether, lumefantrine) containing artemisinin derivatives. Except for Artemos-Plus, none of the other artemisinin-containing medicines collected were included in the anti-malarial treatment policy of the country, and Artecom®, prevalent among all anti-malarials collected (26/77), is not even registered in Guyana. A fixed-dose combination of dihydroartemisinin, piperaquine and trimethoprim was also a prevalent medicine found and collected (34%; 26/77).
From all the medicines sampled in the private and informal market, 58% (45/77) failed quality control testing, which is a significantly higher percentage than the 7.3% discussed above for the public sector. Two factors contributed, in part, to this larger number: (a) All Artecom samples (26) failed visual inspection because of incomplete information on the primaquine tablet content in the insert, and (b) Failures in Uniformity of Dosage Units, some impurities and dissolution are not assessed with the field screening tests utilized in [
12]. However, even if from the total of 45 failures, that could have been detected with the a field screening test (TLC), the percentage failing would be 17% (13/77), still significantly higher than the 4.5% (13/289) reported for medicines collected mostly in the public sector [
12]. Thus, one may conclude that the anti-malarials commercialized in the private and the informal sectors represent a much higher risk for the population than those provided free of charge at public sector facilities.
More important in the context of potential onset of resistance to artemisinin, is that 67% (33/45) of the failures identified in the private and informal sector were in artemisinin-containing medicines. Some of those failures, such as content and dissolution, could result in diminished levels of active pharmaceutical ingredients in the blood stream. All the samples collected from four out of five different artemisinin-containing medicines failed. Although no further investigation was done on the artemisinin-containing medicines that failed, based on the deviations from the declared content or their claimed source, none of them could be considered, prima facie, counterfeits. These results show an additional threat that malaria patients face in endemic mining areas, where private and informal facilities are prevalent and public sector facilities may be difficult to access.
For all anti-malarials, the risk of purchasing poor quality medicines existed both in the private sector (34%; 11/32) and the informal sector (16%; 7/45), and were equally prevalent in endemic regions (24%; 11/46) and non-endemic source regions (23%; 7/31). In endemic regions, almost twice as many samples (seven) failed in the informal sector than in the private sector (four), and in non-endemic source regions, all failures (seven) were identified in the private sector. Thus, based on these findings there is a clear risk of purchasing poor quality malaria medicines in the private or informal sector, both in endemic areas as well as non-endemic regions.
Suriname
The results reported in [
12] in the informal sector showed no failures, though this data should be taken cautiously. Of the 15 anti-malarials containing an artemisinin derivative, 12 had dihydroartemisinin, one as a monotherapy and 11 as the fixed-dose combinations dihydroartemisinin, piperaquine and trimethoprim; for those, only disintegration was assessed because the field test for TLC was not available at the time. In addition, the paucity of samples in Suriname (20 in 2007) precludes making any generalization for this country based on that sole report.
In Suriname, medicines were collected during 2009 only in facilities from the informal sector [
11], mostly along rivers that constitute the supply-line in mining areas; some samples were collected also in the capital, Paramaribo City. The prevalence of Artecom® in this sector was also very high, constituting 86% (49/57) of all sampled medicines, and those were analysed at USP.
Of note is that three of the eight lots of Artecom® sampled in Suriname had the same lot number as those sampled in Guyana. The existence of the same lots in the two countries would suggest that there is commerce of medicine across borders and/or that supplier(s) of this unregistered medicine work across borders. All Artecom® samples failed visual inspection because they lacked information on the content of the co-packaged primaquine tablet, though the co-packaged fixed-dose combination tablets passed analytical testing.
Based on these assessments, quality does not seem to be a risk factor for the most prevalent medicine collected. However, as discussed below, the risk posed by this extensively utilized non-registered medicine is related to irrational use and lack of adherence to treatment guidelines.