Quality of Essential Medicines from Different Sources in Enugu and Anambra, Nigeria.

This study investigated the quality of 13 essential medicines in the states of Enugu and Anambra, Nigeria. A total of 260 samples were purchased from licensed pharmaceutical manufacturers and wholesalers and from vendors in pharmaceutical markets with unclear licensing status. Samples were analyzed for identity, content, and dissolution according to the United States Pharmacopeia (USP) 42 monographs. Forty-five samples of this study could be examined for authenticity with the Mobile Authentication Service scheme of the Nigerian National Agency for Food and Drug Administration and Control. Out of all samples, 25.4% did not comply with the USP 42 specifications. Strikingly, 21 out of 22 dexamethasone tablet samples (95%) were out of specification (OOS). Nine out of 19 glibenclamide samples (47%) failed dissolution testing, and 7 out of 17 cotrimoxazole samples (41%) failed assay testing. Medicines against noncommunicable diseases showed a slightly higher percentage of OOS samples than anti-infectives (21.2% versus 17.6%). The rates of OOS samples were similar in medicines stated to be produced in Nigeria, India, and China but were very different between individual manufacturers from each of these countries of origin. Therefore, prequalification of products, manufacturers, and suppliers are very important for quality assurance in medicine procurement. Unexpectedly, the total proportions of OOS samples were similar from licensed vendors (25.2%) and from markets (25.5%). Four samples (1.5%), all collected in markets, were clearly falsified and did not contain the declared active pharmaceutical ingredients. The proportion of falsified medicines was found to be lower than frequently reported in the media for Nigeria.

An open-source smartphone app for the quantitative evaluation of thin-layer chromatographic analyses in medicine quality screening.

Substandard and falsified medicines present a serious threat to public health. Simple, low-cost screening tools are important in the identification of such products in low- and middle-income countries. In the present study, a smartphone-based imaging software was developed for the quantification of thin-layer chromatographic (TLC) analyses. A performance evaluation of this tool in the TLC analysis of 14 active pharmaceutical ingredients according to the procedures of the Global Pharma Health Fund (GPHF) Minilab was carried out, following international guidelines and assessing accuracy, repeatability, intermediate precision, specificity, linearity, range and robustness of the method. Relative standard deviations of 2.79% and 4.46% between individual measurements were observed in the assessments of repeatability and intermediate precision, respectively. Small deliberate variations of the conditions hardly affected the results. A locally producible wooden box was designed which ensures TLC photography under standardized conditions and shielding from ambient light. Photography and image analysis were carried out with a low-cost Android-based smartphone. The app allows to share TLC photos and quantification results using messaging apps, e-mail, cable or Bluetooth connections, or to upload them to a cloud. The app is available free of charge as General Public License (GPL) open-source software, and interested individuals or organizations are welcome to use and/or to further improve this software.

Surveillance for substandard and falsified medicines by local faith-based organizations in 13 low- and middle-income countries using the GPHF Minilab.

This study evaluates the use of the Global Pharma Health Fund (GPHF) Minilab for medicine quality screening by 16 faith-based drug supply organizations located in 13 low- and middle-income countries. The study period included the year before the COVID-19 pandemic (2019) and the first year of the pandemic (2020). In total 1,919 medicine samples were screened using the GPHF Minilab, and samples showing serious quality deficiencies were subjected to compendial analysis in fully equipped laboratories. Thirty-four (1.8%) of the samples were found not to contain the declared active pharmaceutical ingredient (API), or less than 50% of the declared API, or undeclared APIs, and probably represented falsified products. Fifty-four (2.8%) of the samples were reported as substandard, although the true number of substandard medicines may have been higher due to the limited sensitivity of the GPHF Minilab. The number of probably falsified products increased during the COVID-19 pandemic, especially due to falsified preparations of chloroquine; chloroquine had been incorrectly advocated as treatment for COVID-19. The reports from this project resulted in four international WHO Medical Product Alerts and several national alerts. Within this project, the costs for GPHF Minilab analysis resulted as 25.85 € per sample. Medicine quality screening with the GPHF Minilab is a cost-effective way to contribute to the global surveillance for substandard and falsified medical products.

Out of the boxes, out of the silos: The need of interdisciplinary collaboration to reduce poor-quality medical products in the supply chain.

In this paper, we argue that understanding and addressing the problem of poor-quality medical products requires a more interdisciplinary approach than has been evident to date. While prospective studies based on rigorous standardized methodologies are the gold standard for measuring the prevalence of poor-quality medical products and understanding their distribution nationally and internationally, they should be complemented by social science research to unpack the complex set of social, economic, and governance factors that underlie these patterns. In the following sections, we discuss specific examples of prospective quality surveys and of social science studies, highlighting the value of cross-sector partnerships in driving high-quality, policy-relevant research in this area.

Identification of Substandard and Falsified Medicines: Influence of Different Tolerance Limits and Use of Authenticity Inquiries.

Substandard and falsified medicines have severe public health and socioeconomic effects, especially in low- and middle-income countries. The WHO has emphasized the need for reliable estimates of the prevalence of such medicines to efficiently respond to this problem. In the present study, we used 601 medicine samples collected in Cameroon, the DR Congo, and Malawi to assess the rates of substandard and falsified medicines based on different criteria. Based on the specifications of the U.S. Pharmacopoeia for the amount of the active pharmaceutical ingredients, the rate of out-of-specification medicines was 9.3%. By contrast, this rate ranged from 3.3% up to 35.0% if the tolerance limits of other pharmacopoeias or recently published medicine quality studies were used. This shows an urgent need for harmonization. Principal methods to assess the rate of falsified medicines are packaging analysis, chemical analysis, and authenticity inquiries. In the present study, we carried out an authenticity inquiry for the aforementioned medicine samples, contacting 126 manufacturers and 42 distributors. Response rates were higher for samples stated to be manufactured in Asia (52.4%) or Europe (53.8%) than for samples manufactured in Africa (27.4%; P < 0.001). One sample had been identified as falsified by packaging analysis by the local researchers and two additional ones by chemical analysis. Notably, seven additional falsified samples were identified by the authenticity inquiries. The total rate of falsified medicines resulted as 1.7%. Considerations are discussed for assessing the rates of "substandard" and "falsified" medicines in future medicine quality studies.

Quality of oxytocin and misoprostol in health facilities of Rwanda.

Sustainable Development Goal 3.1 calls for a reduction of the maternal mortality ratio to less than 70 per 100,000 live births by 2030. The most important cause of maternal mortality is post-partum haemorrhage (PPH). Oxytocin injections and misoprostol tablets are medicines of first choice for the management of PPH in low- and middle-income countries (LMICs). Unfortunately, both substances are chemically unstable, and previous studies have revealed serious quality problems of these medicines in LMICs. The present study is the first report on their quality in Rwanda. From 40 randomly selected health facilities (hospitals, health centers, retail pharmacies and private clinics) in different parts of Rwanda, as well as from six wholesalers and government stores, oxytocin injections and misoprostol tablets were collected. Oxytocin storage temperatures in the health facilities were monitored for six months using temperature data loggers, and found to correctly follow the storage requirements stated by the manufacturers (2-8°C, or room temperature) with few minor deviations. Oxytocin injections (57 samples, representing seven batches of four brands) were tested for their oxytocin content and pH value according to the United States Pharmacopeia. Twenty-four samples from three European manufacturers passed all tests. However, all nine samples of one batch of a Chinese manufacturer showed an excessive content of oxytocin (range 117.2-121.5% of the declared amount). Another batch of the same manufacturer showed extreme variations of the concentration of the preservative benzyl alcohol. Misoprostol tablets (25 samples, representing ten batches of six brands) were tested for content and dissolution according to the International Pharmacopoeia. Fifteen samples passed, but all 10 samples of two brands from India failed with extreme deviations, containing only 42.5-48.7% of the stated amount of misoprostol. In conclusion, oxytocin quality in Rwanda was better than reported from other African countries. However, two extremely substandard brands of misoprostol tablets were found. The Rwandan authorities reacted quickly and efficiently, and recalled these substandard medicines from the market. For oxytocin and misoprostol, with their well-known problems of quality and stability, procurement should possibly be restricted to medicines which are WHO-prequalified or which have been manufactured in countries with stringent regulatory authorities.

Quality assurance in anti-tuberculosis drug procurement by the Stop TB Partnership-Global Drug Facility: Procedures, costs, time requirements, and comparison of assay and dissolution results by manufacturers and by external analysis.

BACKGROUND: Quality-assured medicines are a principal means of achieving health-related Sustainable Development Goals. An example of quality assurance/quality control (QA/QC) procedures in drug procurement is provided by the operation of the Global Drug Facility (GDF) of the Stop TB Partnership, the largest provider of tuberculosis (TB) medicines to the public sector worldwide. METHODS: Procedures and results of GDF's quality assurance/quality control (QA/QC) over the five-year period 2013-2017 were analysed retrospectively. 13,999 batches of 51 different medicines had been procured and reviewed within this period. 1,388 of these batches had been analysed in the laboratories of GDF's external quality control agent (QCA). Assay and dissolution results determined by the manufacturers and by the external QCA were compared using Bland-Altman analysis. RESULTS: All investigated batches of medicines were in specifications at the time of shipment. The costs for QA/QC were 0.8% of purchase costs. The median time required for chemical analysis was 10 working days. Comparison of the medicine quality analysis results showed for the poorly water-soluble compound rifampicin a bias of 4.4%, with the manufacturers reporting higher values than the external QCA, most likely due to different methods employed for the analysis. Overall 95% limits of agreement (LOAs) were -6.7 to +8.0% for assay, and -10.1 to +11.8% for dissolution. In case of kanamycin injections, 95% LOAs for assay reached -14.5 to +13.2%, largely attributable to samples from one manufacturer who had used a microbiological assay while the external QCA had used an HPLC assay. CONCLUSIONS: GDF's procedures represent a useful benchmark when evaluating QA/QC procedures of other medicine procurement operations. Inter-laboratory comparison using Bland-Altman plots allows to investigate bias and variability in medicine quality control and should be considered as a routine procedure by drug procurement agencies, to identify priorities for further improvements.

Stability of misoprostol tablets collected in Malawi and Rwanda: Importance of intact primary packaging.

Misoprostol is listed in the WHO essential medicines list and can be used for induction of labour, for prevention and treatment of post-partum haemorrhage, and for abortions. The compound is unstable, and substandard misoprostol preparations have been detected in low- and middle-income countries. We now investigated the stability of misoprostol tablets according to the international guidelines for stability testing of pharmaceutical products. Three brands (four batches) of misoprostol tablets were collected in Malawi and Rwanda: the originator product, a WHO-prequalified product, and a generic product without WHO prequalification. A further batch of the originator product was collected in Germany. To investigate the effect of damage to the primary packaging, additional blister strips of one sample were intentionally damaged with a needle and investigated in parallel. Samples were placed in stability chambers for six months at 40°C/75% relative humidity (RH) and at 25°C/60% RH. After 0, 1, 2, 3 and 6 months, misoprostol content was determined according to the International Pharmacopeia. At 40°C/75% RH, all samples showed a decline of misoprostol content, but four of the batches still remained within the pharmacopeial specifications, while one of the two batches of the generic product without WHO-prequalification showed a final content of 86.2% which is out of specifications. Damage to the primary packaging greatly decreased stability, resulting in a final content of only 48.2% of the declared misoprostol amount. At 25°C/60% RH all samples remained in specifications for six months, even the sample with the damaged blister. Dissolution of misoprostol remained in specifications of the pharmacopoeia for six months for all batches, except for the sample with damaged blisters stored at 40°C/75% RH. This study confirms that the stability of misoprostol tablets must be ensured by intact, good-quality primary packaging. Careful supplier qualification is required in the procurement process.

Stability of Oxytocin Preparations in Malawi and Rwanda: Stabilizing Effect of Chlorobutanol.

Oxytocin is used for the prevention and treatment of postpartum hemorrhage, the leading cause of maternal mortality in low- and middle-income countries. Because of the high instability of oxytocin, most products are labeled for storage at 2-8°C. Some other products are on the market which are labeled for non-refrigerated storage, but independent evaluations of their stability hardly exist. In the present study, seven brands (nine batches) of oxytocin were purchased from wholesalers and medical stores in Malawi and Rwanda and investigated by accelerated stability testing according to the ICH/WHO guidelines. Two oxytocin brands approved by a stringent regulatory authority (SRA) or by the WHO Prequalification of Medicines program and purchased in Europe were used as comparison. All investigated brands which were either produced in countries with SRAs, or were WHO-prequalified products, were labeled for storage at 2-8°C, and all of them passed stability testing with very good results. Even exposure to 25°C or 30°C for several months hardly affected their oxytocin content. However, two other investigated brands were labeled for non-refrigerated storage, and both of them had been produced in countries without SRAs. These two preparations showed not higher but lower stability than the brands labeled for storage at 2-8°C, and, for both of them, noncompliance with pharmacopoeial specifications was found after accelerated stability testing. At 40°C, and in forced degradation studies at 80°C, chlorobutanol showed a remarkable stabilizing effect on oxytocin, which may deserve further investigation. The results of the present study support the policy "Buy Quality Oxytocin, Keep It Cool."

Prices, availability and affordability of medicines in Rwanda.

BACKGROUND: Access to affordable and good quality medicines is a key to meeting Sustainable Development Goal No. 3 by the year 2030. Prices, availability and affordability of essential medicines have been studied in many developing countries, but no such information has been published about Rwanda yet. This study aimed at providing data on prices, availability and affordability of medicines in different health facilities of Rwanda. METHODS: A survey was carried out on availability, prices and affordability of 18 medicines in Kigali City and five districts of Rwanda. 44 health facilities were surveyed, including public and faith-based hospitals, public and faith-based health centers and private pharmacies. The standardized methodology developed by WHO and Health Action International (HAI) was used to collect and analyze the data. FINDINGS: Prices for generic medicines in public and faith-based health facilities were remarkably low, with median price ratios (MPRs) of 1.0 in comparison to the international procurement prices published by Management Sciences for Health. In private pharmacies, prices were twice as high (MPR = 1.99 for generics). Availability of medicines fell short of the of 80% target set by WHO, but was better than reported from many other developing countries. Availability of medicines was highest in the private sector (71.3%) and slightly lower in the faith-based (62.8%) and public (59.6%) sectors. The government procurement agency was found to work efficiently, achieving prices 30% below the international procurement price given in the International Medical Product Price Guide. Affordability of medicines was better in the public and faith-based sectors than in the private sector. CONCLUSION: In Rwanda, medicines are affordable but poorly available in both the public and the faith-based sectors. Further improvements of the availability of medicines in the public and the faith-based health facilities represent the most important key to increase accessibility and affordability of medicines in Rwanda.

Identification of Falsified Chloroquine Tablets in Africa at the Time of the COVID-19 Pandemic.

Reports that chloroquine and hydroxychloroquine may be effective against COVID-19 have received worldwide attention, increasing the risk of the introduction of falsified versions of these medicines. Five different types of falsified chloroquine tablets were discovered between March 31, 2020 and April 4, 2020, in Cameroon and the Democratic Republic of Congo by locally conducted thin layer chromatographic analysis. Subsequent investigation by liquid chromatography and mass spectrometry in Germany proved the absence of detectable amounts of chloroquine and the presence of undeclared active pharmaceutical ingredients, that is, paracetamol and metronidazole, in four of the samples. The fifth sample contained chloroquine, but only 22% of the declared amount. Such products represent a serious risk to patients. Their occurrence exemplifies that once medicines or vaccines against COVID-19 may be developed, falsified products will enter the market immediately, especially in low- and middle-income countries (LMICs). Timely preparations for the detection of such products are required, including the establishment of appropriate screening technologies in LMICs.

Substandard and Falsified Antibiotics and Medicines against Noncommunicable Diseases in Western Cameroon and Northeastern Democratic Republic of Congo.

Falsified and substandard medicines may undermine the progress toward the Sustainable Development Goals. The present study investigated the quality of 13 essential medicines in Cameroon and the Democratic Republic of Congo (DR Congo). Five hundred six medicine samples were collected from the government and faith-based health facilities, private pharmacies, and informal vendors (total 60 facilities). Collected samples were analyzed according to the U.S. Pharmacopeia (USP) for identity, content, and dissolution of their active pharmaceutical ingredients (APIs) and for uniformity of dosage units. Three samples (0.6%) were identified as falsified. Overall, 8.5% of the samples failed USP specifications for the content of the API and 11.7% failed dissolution testing. Medicines from informal vendors showed a higher out-of-specification rate (28.2%) than other types of drug outlets (12.3%; P < 0.0001). All three falsified medicines had been sold by informal vendors. The failure rate of medicines stated to be produced in Europe (5.1%) was lower than that for medicines from Asia (17.7%; P = 0.0049) and Africa (22.2%; P = 0.0042). Medicines against noncommunicable diseases showed a higher failure rate than antibiotics (25.3% versus 12.1%; P = 0.0004). Four hundred fifty-one of the samples were analyzed in Cameroon and the DR Congo with the Global Pharma Health Fund Minilab (thin-layer chromatography and disintegration testing). The three falsified medicines were readily detected in Minilab analysis. However, substandard samples were detected with low sensitivity. A well-enforced ban of medicine sales by informal vendors and increased attention to supplier qualification in the procurement process may reduce the prevalence of substandard and falsified medicines.

Quality, availability and storage conditions of oxytocin and misoprostol in Malawi.

BACKGROUND: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality in low- and middle-income countries (LMICs). Oxytocin and misoprostol are used for the prevention and treatment of PPH. However, both medicines are chemically unstable and sensitive to environmental conditions. Previous studies reported a high prevalence of substandard oxytocin and misoprostol preparations in LMICs. METHODS: In randomly selected health facilities of four districts of Malawi, the availability of oxytocin and misoprostol was determined, and the knowledge of health workers on storage requirements and use of oxytocics was assessed. Temperature loggers were used to record the storage temperature of oxytocics. Samples of oxytocin injections and misoprostol tablets were collected from the health facilities and from wholesalers. Oxytocin samples were analysed for identity, assay (= quantity of oxytocin) and for pH value according to United States Pharmacopeia 40. Misoprostol samples were analysed for identity, assay, dissolution and related substances according to the International Pharmacopeia 2017. RESULTS: All visited hospitals and health centers had oxytocin available. At non-refrigerated storage sites, the recorded mean kinetic temperature exceeded the oxytocic's storage temperature stated on the labels in 42% of the sites. At refrigerated storage sites, the required temperature of 2-8 °C was exceeded in 33% of the sites. Out of 65 oxytocin samples, 7 (11%) showed moderate deviations from specification, containing 82.2-86.8% of the declared amount of oxytocin. Out of 30 misoprostol samples, 5 (17%) showed extreme deviations, containing only 12.7-30.2% of the declared amount. The extremely substandard misoprostol was reported to the national authorities and to WHO, leading to an immediate recall of the respective brand in Malawi. The UK-based distributor of this brand closed its business shortly thereafter. CONCLUSION: Availability of oxytocin was excellent in Malawi, and its quality was better than reported in previous studies in other LMICs. However, storage conditions at the health facilities often did not meet the requirements. Extremely substandard misoprostol tablets were found, representing a serious risk to maternal health. This shows the need for continued efforts for quality assurance in medicine procurement and registration, as well as for post-marketing surveillance.

Availability, prices and affordability of selected antibiotics and medicines against non-communicable diseases in western Cameroon and northeast DR Congo.

Access to safe, effective and affordable medicines of good quality is included into the Sustainable Development Goals of the United Nations. Furthermore, WHO has developed a Global Action Plan with the aim to raise access to essential medicines against non-communicable diseases (NCDs) to 80%, and to improve their affordability. In order to contribute to the monitoring of progress towards these goals, the present study investigated the availability and affordability of seven antibiotics and six medicines against non-communicable diseases in the northeast of the Democratic Republic of Congo and the west of the Republic of Cameroon. Data on availability and prices of these medicines were collected in 60 different sites (34 in the DR Congo, 26 in Cameroon), including government health facilities, church health facilities, private pharmacies and informal vendors, as part of a study on medicine quality. The data were analyzed using a standardized procedure developed by WHO and Health Action International (HAI). Average availability of the investigated antibiotics ranged from 62% to 98% in the different types of facilities in both countries, including the informal vendors. Average availability for medicines against NCDs in the different types of facilities showed a higher variation in both countries, ranging from 11% up to 87%. The average availability of medicines against NCDs in government health facilities was only 33% in Cameroon, and as low as 11% in the DR Congo. In contrast, availability of medicines against NCDs in church health facilities in Cameroon was 70%, not far from the 80% availability goal set by WHO. Medicine prices were clearly higher in Cameroon than in the DR Congo, with median price ratios to an international reference price of 5.69 and 2.17, respectively (p < 0.001). In relation to the daily minimum wages in both countries, treatment courses with five of the seven investigated antibiotics could be considered as affordable, while in each country only one out of the five investigated medicines against NCDs could be considered as affordable. Especially generic medicines provided by government and church health facilities showed reasonable affordability in most cases, while originator medicines offered by private pharmacies were clearly unaffordable to a major part of the population. Despite some encouraging findings on the availability of antibiotics in both countries, the availability and affordability of medicines against NCDs urgently requires further improvements.

Quality of medicines in southern Togo: Investigation of antibiotics and of medicines for non-communicable diseases from pharmacies and informal vendors.

Substandard and falsified medicines represent a serious threat for public health and patient safety. Especially in low and middle-income countries, the prevalence of substandard and falsified medicines is reportedly high. However, reliable information on the prevalence of poor-quality medicines is scarce. In this study, 12 essential medicines, including antibiotics, antidiabetics, cardiac drugs and antiasthmatic drugs, were collected from six informal vendors and six licensed pharmacies in the southern part of Togo (regions Maritime and Plateaux). A mystery shopper approach was used in both types of outlets. In total, 64 samples were collected from licensed pharmacies and 30 from informal vendors. Both availability of medicines and prices of medicines were higher in licensed pharmacies than in informal vendors. 92 medicine samples were analyzed by visual examination, followed by chemical analysis for the content and for the dissolution of the active pharmaceutical ingredients according to the respective monographs of the United States Pharmacopoeia. 7 samples (8%) did not comply with the pharmacopoeial specifications, and one sample (1%) showed even extreme deviations. None of the samples was obviously falsified. However, one sample of amoxicillin capsules contained only 47% of the declared content of the active pharmaceutical ingredient, indicating that it may represent amoxicillin capsules 250 mg, rather than 500mg as declared on the label. Medicines stated to originate from Asia (i.e. mainly from India and China) showed a significantly higher proportion (24%) of non-compliant samples than those from Africa and Europe (4%, p = 0.007). High failure rates were observed in medicines both from informal vendors (13%) and from licensed pharmacies (5%), but the difference between both groups was not statistically significant (p = 0.152). The observed high prevalence of substandard medicines requires action from regulatory authorities and health care providers. Testing of selected samples for related substances indicated that inappropriate transport and storage conditions may have been an important cause for substandard quality.

Surveillance for falsified and substandard medicines in Africa and Asia by local organizations using the low-cost GPHF Minilab.

BACKGROUND: Substandard and falsified medical products present a serious threat to public health, especially in low- and middle-income countries. Their identification using pharmacopeial analysis is expensive and requires sophisticated equipment and highly trained personnel. Simple, low-cost technologies are required in addition to full pharmacopeial analysis in order to accomplish widespread routine surveillance for poor-quality medicines in low- and middle-income countries. METHODS: Ten faith-based drug supply organizations in seven countries of Africa and Asia were each equipped with a Minilab of the Global Pharma Health Fund (GPHF, Frankfurt, Germany), suitable for the analysis of about 85 different essential medicines by thin-layer chromatography. Each organization was asked to collect approximately 100 medicine samples from private local medicine outlets, especially from the informal sector. The medicine samples were tested locally according to the Minilab protocols. Medicines which failed Minilab testing were subjected to confirmatory analysis in a WHO-prequalified medicine quality control laboratory in Kenya. RESULTS: Out of 869 medicine samples, 21 were confirmed to be substandard or falsified medical products. Twelve did not contain the stated active pharmaceutical ingredient (API), six contained insufficient amounts of the API, and three showed insufficient dissolution of the API. The highest proportion of substandard and falsified medicines was found in Cameroon (7.1%), followed by the Democratic Republic of Congo (2.7%) and Nigeria (1.1%). Antimalarial medicines were most frequently found to be substandard or falsified (9.5% of all antimalarials). Thin-layer chromatography according to the Minilab protocols was found to be specific and reproducible in the identification of medicines which did not contain the stated API. Since only samples which failed Minilab testing were subjected to confirmatory testing using pharmacopeial methods, this study did not assess the sensitivity of the Minilab methodology in the detection of substandard medicines, and may underestimate the prevalence of poor-quality medicines. CONCLUSIONS: Surveillance for poor-quality medicines can be carried out by local organizations in low- and middle-income countries using a simple, low-cost technology. Such surveillance can identify an important subgroup of the circulating substandard and falsified medical products and can help to prevent them from causing harm in patients. A collaboration of the national drug regulatory authorities with faith-based organizations and other NGOs may therefore represent a promising strategy towards the Sustainable Development Goal of "ensuring access to quality medicines".

Availability and affordability of antimalarial and antibiotic medicines in Malawi.

BACKGROUND: Availability and affordability of medicines are key determinants of universal health coverage, yet achieving them presents a major challenge especially in low-income countries. We here present an analysis of availability and prices of antimalarial and antibiotic medicines in public, faith-based and private health facilities in Malawi. Medicines are provided free of charge in the public health care system of Malawi. In contrast, facilities of the Christian Health Association of Malawi (CHAM) usually charge their patients for medicines, as do private for-profit facilities. METHODS: As part of a study on medicine quality, samples of six antimalarial and six antibiotic medicines were collected in 31 health facilities in four districts of southern Malawi. These included 15 public facilities (i.e. health centres, district hospitals and central hospitals), eight CHAM and eight private facilities. Random selection was used in choosing the included health facilities. The availability of medicines was recorded, including the number of units which could be collected of each medicine, as well as the prices of medicines which were charged in CHAM and private facilities. These data were analyzed using the standard methodology developed by the World Health Organization (WHO) and Health Action International (HAI). RESULTS: Availability of the antimalarials artemether/lumefantrine and sulfadoxine/pyrimethamine, which are provided with financial support from international donors, was high in public and CHAM facilities (93% and 100%, respectively). However, availability of antibiotics was much lower (e.g. 40% availability of amoxicillin tablets/capsules in public health centres). Medicine prices were lower than reported from many other countries. The median price ratio (MPR) to a wholesale international procurement price was 2.8 in CHAM facilities and even lower in the private sector (MPR 2.3). Nevertheless, for 10 of the 12 investigated medicines the cost for one course of treatment exceeded the daily wage of a low-paid government worker in Malawi and therefore had to be considered as unaffordable for a major part of the population. CONCLUSIONS: Continued efforts are required to improve the availability of essential medicines in Malawi. The free provision of medicines in the public health care system remains important in order to achieve universal health coverage, due to the low income in this country.

Low Prevalence of Substandard and Falsified Antimalarial and Antibiotic Medicines in Public and Faith-Based Health Facilities of Southern Malawi.

AbstractSubstandard and falsified antimalarial and antibiotic medicines represent a serious problem for public health, especially in low- and middle-income countries. However, information on the prevalence of poor-quality medicines is limited. In the present study, samples of six antimalarial and six antibiotic medicines were collected from 31 health facilities and drug outlets in southern Malawi. Random sampling was used in the selection of health facilities. For sample collection, an overt approach was used in licensed facilities, and a mystery shopper approach in nonlicensed outlets. One hundred and fifty-five samples were analyzed by visual and physical examination and by rapid prescreening tests, that is, disintegration testing and thin-layer chromatography using the GPHF-Minilab. Fifty-six of the samples were analyzed according to pharmacopeial monographs in a World Health Organization-prequalified quality control laboratory. Seven out-of-specification medicines were identified. One sample was classified as falsified, lacking the declared active ingredients, and containing other active ingredients instead. Three samples were classified as substandard with extreme deviations from the pharmacopeial standards, and three further samples as substandard with nonextreme deviations. Of the substandard medicines, three failed in dissolution testing, two in the assay for the content of the active pharmaceutical ingredient, and one failed in both dissolution testing and assay. Six of the seven out-of-specification medicines were from private facilities. Only one out-of-specification medicine was found within the samples from public and faith-based health facilities. Although the observed presence of substandard and falsified medicines in Malawi requires action, their low prevalence in public and faith-based health facilities is encouraging.

Use of thin-layer chromatography to detect counterfeit sulfadoxine/pyrimethamine tablets with the wrong active ingredient in Malawi.

BACKGROUND: Substandard and falsified anti-malarial medicines pose a serious threat to public health, especially in low-income countries. Appropriate technologies for drug quality analysis in resource-limited settings are important for the surveillance of the formal and informal drug market. The feasibility of thin-layer chromatography (TLC) with different solvent systems was tested using the GPHF Minilab in a study of the quality of sulfadoxine/pyrimethamine tablets in Malawi. METHODS: Twenty eight samples of sulfadoxine/pyrimethamine tablets were collected from randomly selected health facilities of four districts of southern Malawi. A mystery shopper approach was used when collecting samples from illegal street vendors, and an overt approach for the other facilities. Samples were subjected to visual inspection, disintegration testing and TLC analysis. 10 samples were further investigated according to the methods of the US Pharmacopeia using high performance liquid chromatography (HPLC). RESULTS: One sample was found to be falsified, containing a mixture of paracetamol tablets and co-trimoxazole tablets. These had been repackaged into paper strip packs labelled as a brand of sulfadoxine/pyrimethamine. TLC with different solvent systems readily proved that these tablets did not comply with their declaration, and provided strong evidence for the active pharmaceutical ingredients which were actually contained. Full pharmacopeial analysis by HPLC confirmed the results suggested by TLC for this sample, and showed two further samples to be of substandard quality. CONCLUSIONS: Due to the absence of the declared anti-malarial ingredients and due to the presence of other pharmaceutical ingredients, the identified falsified medicine represents a serious health risk for the population. Thin-layer chromatography (TLC) using different solvent systems proved to be a powerful method for the identification of this type of counterfeiting, presenting a simple and affordable technology for use in resource-limited settings.

Diversity of ABBA Prenyltransferases in Marine Streptomyces sp. CNQ-509: Promiscuous Enzymes for the Biosynthesis of Mixed Terpenoid Compounds.

Terpenoids are arguably the largest and most diverse family of natural products, featuring prominently in e.g. signalling, self-defence, UV-protection and electron transfer. Prenyltransferases are essential players in terpenoid and hybrid isoprenoid biosynthesis that install isoprene units on target molecules and thereby often modulate their bioactivity. In our search for new prenyltransferase biocatalysts we focused on the marine-derived Streptomyces sp. CNQ-509, a particularly rich source of meroterpenoid chemistry. Sequencing and analysis of the genome of Streptomyces sp. CNQ-509 revealed seven putative phenol/phenazine-specific ABBA prenyltransferases, and one putative indole-specific ABBA prenyltransferase. To elucidate the substrate specificity of the ABBA prenyltransferases and to learn about their role in secondary metabolism, CnqP1 -CnqP8 were produced in Escherichia coli and incubated with various aromatic and isoprenoid substrates. Five of the eight prenyltransferases displayed enzymatic activity. The efficient conversion of dihydroxynaphthalene derivatives by CnqP3 (encoded by AA958_24325) and the co-location of AA958_24325 with genes characteristic for the biosynthesis of THN (tetrahydroxynaphthalene)-derived natural products indicates that the enzyme is involved in the formation of debromomarinone or other naphthoquinone-derived meroterpenoids. Moreover, CnqP3 showed high flexibility towards a range of aromatic and isoprenoid substrates and thus represents an interesting new tool for biocatalytic applications.