Assessment of the effectiveness of the CD3+ tool to detect counterfeit and substandard anti-malarials.

BACKGROUND: The US FDA recently developed CD3+, a counterfeit detection tool that is based on sample illumination at specific wavelengths of light and visual comparison of suspect sample and packaging materials to an authentic sample. To test performance of the CD3+ in field conditions, a study was conducted in Ghana which compared the CD3+ side-by-side with two existing medicine quality screening technologies-TruScan™ Portable Raman spectrometer and GPHF Minilab(®). METHODS: A total of 84 anti-malarial test samples comprising artemether-lumefantrine tablets and artesunate-amodiaquine tablets were used. The technologies were evaluated for sensitivity in determining counterfeit/substandard (The term counterfeit or falsified is used in this article to refer to medicines that carry a false representation of identity or source or both. The term substandard is used to refer to medicines that do not meet the quality specifications given in the accepted pharmacopeia.) medicines, specificity in determining authentic products, and reliability of the results. Authentic samples obtained from manufacturers were used as reference standards. HPLC analysis data was used as the "gold standard" for decisions regarding a sample being authentic or substandard/counterfeit. RESULTS: CD3+ had a sensitivity of 1.00 in detecting counterfeit/substandard products compared to Minilab (0.79) and TruScan (0.79). CD3+ had a lower specificity (0.53) in determining authentic products compared to the specificities reached by Minilab (0.99) and TruScan (1.00). High sensitivity in this context means that the technology is effective in identifying substandard/counterfeit products whereas the low specificity means that the technique can sometimes mischaracterize good products as substandard/counterfeit. Examination of dosage units only (and not packaging) using CD3+ yielded improved specificity 0.64. When only assessment of sample identification was done, the TruScan provided sensitivity (1.00) and specificity (0.99); and the Minilab provided sensitivity (1.00) and specificity (1.00). All three technologies demonstrated 100 % reliability when used to analyse the same set of samples over 3 days by a single analyst and also when used to determine the same set of samples by three different analysts. Eight of the field samples were confirmed to be counterfeits with no active pharmaceutical ingredient content. All three technologies identified these samples as counterfeits. CONCLUSIONS: The study revealed the relative effectiveness of the technologies as quality control tools. Using a combination of CD3+, with either the Minilab or TruScan, to screen for medicine quality will allow for complete examination of both the dosage units and the packaging to decide whether it is authentic or counterfeit.

Were medicine quality and pharmaceutical management contributing factors in diminishing artemisinin efficacy in Guyana and Suriname?

BACKGROUND: Recent studies in Guyana and Suriname unveiled diminished efficacy of artemisinin derivatives based on day-3 parasitaemia. The migrant characteristics of the population at risk and the potential development of resistance pose a serious health threat in the region. Assessment of factors that may have contributed to this situation is warranted, and analysis of the data generated in those countries on quality and pharmaceutical managements of anti-malarials may contribute to a better understanding of this occurrence. METHODS: Data on malaria medicine quality and pharmaceutical management, generated in the context of the Amazon Malaria Initiative (AMI), was reviewed and discussed. RESULTS: Numerous substandard artemisinin-containing malaria medicines were identified in both countries, particularly in Guyana, where a larger number and variety of anti-malarials were sampled. Poor quality was more frequent in the private and informal sector than in the public sector, posing a greater threat to the populations at risk, which are mostly located in hard to reach areas with scarce public facilities. Stock-outs identified in the public sector in Guyana could enhance the need to access those alternative sectors, exacerbating the risk of utilizing poor quality medicines. The availability of monotherapies and other non-recommended therapies for Plasmodium falciparum malaria, could also have contributed to the diminished efficacy. The type of quality deficiencies identified -reduced content of active pharmaceutical ingredient (API) and/or poor dissolution- and the irrational use of non-recommended treatments could result in non-sustained or lower levels of API in blood, favouring survival of more resistant mutants by exposing parasites to sub-lethal doses of the active ingredient. CONCLUSIONS: The quality of malaria medicines and the availability and use of non-recommended treatments could have played a role in the diminished efficacy of artemisinin derivatives described in Guyana and Suriname. However, also other factors need to be considered and a more comprehensive and extensive assessment on quality and pharmaceutical management is necessary to establish a tighter cause-effect correlation. Nevertheless, relevant authorities in these and neighbouring countries should take into consideration the reviewed data to properly address the problem when implementing corrective actions.

The quality of antimalarial medicines in western Cambodia: a case study along the Thai-Cambodian border.

The prevalence, availability, and use of antimalarial medicines (AMLs) were studied in six Cambodian provinces along the Thai-Cambodian border. The study was divided into two parts: the first looked at the quality of AMLs available in Pursat, Pailin, Battambang, Bantey Meanchey, Oddar Meanchey, and Preah Vihear and the second obtained information about the availability and use of AMLs. A randomized sampling methodology was used to select locations and collect samples, which were screened using Global Pharma Health Fund (GPHF) Minilabs. A subset of samples was sent to quality control laboratories for confirmatory testing. For the second part of the study, face-to-face interviews were conducted using standardized surveys with members of randomly selected households and staff of health facilities in the villages with highest malaria incidence to find out where they acquired their AMLs and which were most frequently used. The results showed an overall failure rate of 12.3% (n = 46 of 374 total AML samples). The causes of medication sample failure were low active pharmaceutical ingredient (API) content, failed dissolution properties, and unacceptably high levels of impurities. A total of 86.2% of survey respondents (n = 1,648 of 1,912) reported a member of their household having malaria in the previous year. The most commonly used medicines were paracetamol (67.1% of respondents), Malarine (A+M co-blistered, 28.6%), artesunate + mefloquine co-blistered (public sector product, 17.3%), quinine (16.7%), and artesunate monotherapy (11.9%). Health staff typically prescribed co-blistered artesunate plus mefloquine in the public sector (67.8%), the artesunate plus mefloquine "social marketing" product from Population Services International (PSI), Malarine (50.3%) in the private sector, artemether (49.7%), chloroquine (39%) and paracetamol (72.9%) to reduce fever.

The quality of antimalarial medicines in eastern Thailand: a case study along the Thai-Cambodian border.

This study examined the prevalence, availability, and use of antimalarial medicines (AMLs) along the Thai-Cambodian border. The study was divided into two parts: the first looked at the quality of AMLs available in six Thai provinces and the second obtained information about the availability and use of AMLs. A randomized sampling methodology was used to select locations and collect samples, which were screened using Global Pharma Health Fund (GPHF) Minilabs. A subset of samples was sent to quality control laboratories for verification testing. For the second part of the study, face-to-face interviews were conducted with members of randomly selected households and the staff of health facilities in villages with the highest malaria incidence to find out where they acquired their AMLs and which were used most frequently. The results of quality testing showed an overall failure rate of 1% (7 of 709 samples) for active pharmaceutical ingredients (API); however, the API failure rate varied from 0.0% to 2.2% by location and the overall failure rates of samples by province varied from 0.0% to 3.4%. A total of 97.9% (n = 272) of respondents had taken AMLS. The most commonly used medicines were primaquine (30% of respondents), chloroquine (15.8%), artesunate+mefloquine (12%), and quinine (10%). Most respondents (97.9%) had received medications from public hospitals or malaria clinics.

A call to action: securing an uninterrupted supply of Africa's medical products and technologies post COVID-19.

The COVID-19 pandemic unveiled the vulnerability of many African healthcare systems, amplifying inadequacies and constraints in the supply chain for medical products and technologies on the continent. Disruptions in the global supply chain due to the pandemic resulted in the continent's population of over one billion people grappling with shortages in the supply of essential medicines. The shortages and their consequences set back achievement of Sustainable Development Goals and progress towards universal health coverage. A virtual meeting of global experts in medical products and supply chain identified as urgent the need for Africa to build capacity for a self-reliant public health system. Discussants challenged the governments of African countries to turn the continent from its current import driven economy to a continent of indigenous research and development, local production, and an exporter of its medical products and innovations.

Quality of anti-malarials collected in the private and informal sectors in Guyana and Suriname.

BACKGROUND: Despite a significant reduction in the number of malaria cases in Guyana and Suriname, this disease remains a major problem in the interior of both countries, especially in areas with gold mining and logging operations, where malaria is endemic. National malaria control programmes in these countries provide treatment to patients with medicines that are procured and distributed through regulated processes in the public sector. However, availability to medicines in licensed facilities (private sector) and unlicensed facilities (informal sector) is common, posing the risk of access to and use of non-recommended treatments and/or poor quality products. METHODS: To assess the quality of circulating anti-malarial medicines, samples were purchased in the private and informal sectors of Guyana and Suriname in 2009. The sampling sites were selected based on epidemiological data and/or distance from health facilities. Samples were analysed for identity, content, dissolution or disintegration, impurities, and uniformity of dosage units or weight variation according to manufacturer, pharmacopeial, or other validated method. RESULTS: Quality issues were observed in 45 of 77 (58%) anti-malarial medicines sampled in Guyana of which 30 failed visual & physical inspection and 18 failed quality control tests. The proportion of monotherapy and ACT medicines failing quality control tests was 43% (13/30) and 11% (5/47) respectively. A higher proportion of medicines sampled from the private sector 34% (11/32) failed quality control tests versus 16% (7/45) in the informal sector. In Suriname, 58 medicines were sampled, of which 50 (86%) were Artecom®, the fixed-dose combination of piperaquine-dihydroartemisinin-trimethoprim co-blistered with a primaquine phosphate tablet. All Artecom samples were found to lack a label claim for primaquine, thus failing visual and physical inspection. CONCLUSIONS: The findings of the studies in both countries point to significant problems with the quality of anti-malarial medicines available in private and informal sector facilities as well as the availability of therapy not compliant with national treatment guidelines. They also stress the need to strengthen regulatory control efforts on the availability of anti-malarial medicines in these sectors and in endemic areas.

Implementation of basic quality control tests for malaria medicines in Amazon Basin countries: results for the 2005-2010 period.

BACKGROUND: Ensuring the quality of malaria medicines is crucial in working toward malaria control and eventual elimination. Unlike other validated tests that can assess all critical quality attributes, which is the standard for determining the quality of medicines, basic tests are significantly less expensive, faster, and require less skilled labour; yet, these tests provide reproducible data and information on several critical quality attributes, such as identity, purity, content, and disintegration. Visual and physical inspection also provides valuable information about the manufacturing and the labelling of medicines, and in many cases this inspection is sufficient to detect counterfeit medicines. The Promoting the Quality of Medicines (PQM) programme has provided technical assistance to Amazon Malaria Initiative (AMI) countries to implement the use of basic tests as a key screening mechanism to assess the quality of malaria medicines available to patients in decentralized regions. METHODS: Trained personnel from the National Malaria Control Programmes (NMCPs), often in collaboration with country's Official Medicine Control Laboratory (OMCL), developed country- specific protocols that encompassed sampling methods, sample analysis, and data reporting. Sampling sites were selected based on malaria burden, accessibility, and geographical location. Convenience sampling was performed and countries were recommended to store the sampled medicines under conditions that did not compromise their quality. Basic analytical tests, such as disintegration and thin layer chromatography (TLC), were performed utilizing a portable mini-laboratory. RESULTS: Results were originally presented at regional meetings in a non-standardized format that lacked relevant medicines information. However, since 2008 information has been submitted utilizing a template specifically developed by PQM for that purpose. From 2005 to 2010, the quality of 1,663 malaria medicines from seven AMI countries was evaluated, mostly collected from the public sector, 1,445/1,663 (86.9%). Results indicate that 193/1,663 (11.6%) were found not to meet quality specifications. Most failures were reported during visual and physical inspection, 142/1663 (8.5%), and most of these were due to expired medicines, 118/142 (83.1%). Samples failing TLC accounted for 27/1,663 (1.6%) and those failing disintegration accounted for 24/1,663 (1.4%). Medicines quality failures decreased significantly during the last two years. CONCLUSIONS: Basic tests revealed that the quality of medicines in the public sector improved over the years, since the implementation of this type of quality monitoring programme in 2005. However, the lack of consistent confirmatory tests in the quality control (QC) laboratory, utilizing methods that can also evaluate additional quality attributes, could still mask quality issues. In the future, AMI countries should improve coordination with their health authorities and their QC lab consistently, to provide a more complete picture of malaria medicines quality and support the implementation of corrective actions. Facilities in the private and informal sectors also should be included when these sectors constitute an important source of medicines used by malaria patients.

Implementation of a rapid and automated high performance liquid chromatography method development strategy for pharmaceutical drug candidates.

A comprehensive, fully automated strategy is demonstrated for HPLC-UV chromatographic method development using ChromSword optimization software. The strategy involves: (1) the automated screening of various column and mobile phase combinations, (2) rational selection of the best starting conditions; and (3) subsequent automated method development to generate optimized separation methods. Pharmaceutical compounds were applied to solve problematic drug impurity separations. ChromSword software automates the screening, optimization, and documentation steps thus reducing the method development time. The strategy was compared to a manual method development approach showing the automated method strategy affords better selectivity in a shorter time.

"Orthogonal" separations for reversed-phase liquid chromatography.

A general procedure is proposed for the rapid development of a reversed-phase liquid chromatographic (RP-LC) separation that is "orthogonal" to a pre-existing ("primary") method for the RP-LC separation of a given sample. The procedure involves a change of the mobile-phase organic solvent (B-solvent), the replacement of the primary column by one of very different selectivity, and (only if necessary) a change in mobile phase pH or the use of a third column. Following the selection of the "orthogonal" B-solvent, column and mobile phase pH, further optimization of peak spacing and resolution can be achieved by varying separation temperature and either isocratic %B or gradient time. The relative "orthogonality" of the primary and "orthogonal" RP-LC methods is then evaluated from plots of retention for one method versus the other. The present procedure was used to develop "orthogonal" methods for nine routine RP-LC methods from six pharmaceutical analysis laboratories. The relative success of this approach can be judged from the results reported here.

Monitoring the quality of medicines: results from Africa, Asia, and South America.

Monitoring the quality of medicines plays a crucial role in an integrated medicines quality assurance system. In a publicly available medicines quality database (MQDB), the U.S. Pharmacopeial Convention (USP) reports results of data collected from medicines quality monitoring (MQM) activities spanning the period of 2003-2013 in 17 countries of Africa, Asia, and South America. The MQDB contains information on 15,063 samples collected and tested using Minilab® screening methods and/or pharmacopeial methods. Approximately 71% of the samples reported came from Asia, 23% from Africa, and 6% from South America. The samples collected and tested include mainly antibiotic, antimalarial, and antituberculosis medicines. A total of 848 samples, representing 5.6% of total samples, failed the quality test. The failure proportion per region was 11.5%, 10.4%, and 2.9% for South America, Africa, and Asia, respectively. Eighty-one counterfeit medicines were reported, 86.4% of which were found in Asia and 13.6% in Africa. Additional analysis of the data shows the distribution of poor-quality medicines per region and by therapeutic indication as well as possible trends of counterfeit medicines.

Assessment of the performance of a handheld Raman device for potential use as a screening tool in evaluating medicines quality.

The TruScan(®) handheld Raman device is used for testing finished pharmaceutical products in the field to detect counterfeit and substandard medicines. Present work reports on the device's ability to discriminate between a specific product and similar products from different manufacturers, unrelated medicines, and medicines with different strengths. This investigation evaluated its ability to differentiate between similar drug products of similar or different strengths, focusing on the specificity and precision of the testing. First, several units of the same medicine's dosage form were compared; then comparisons were made between unrelated products, similar products, and products with different strengths. The six pharmaceutical products used in testing were from commonly used analgesic, antimalarial, and antidiarrheal medicines. The results showed that the performance of the TruScan(®) device depends on the nature and the strength of the dosage form tested; while the device could be suitable for authentication of some finished pharmaceutical products and, hence, could be used to detect some counterfeit medicines, it could not be used to detect substandard medicines. Careful consideration should be given when using the device as a screening tool for counterfeit medicines.

Improved protocol and data analysis for accelerated shelf-life estimation of solid dosage forms.

PURPOSE: To propose and test a new accelerated aging protocol for solid-state, small molecule pharmaceuticals which provides faster predictions for drug substance and drug product shelf-life. MATERIALS AND METHODS: The concept of an isoconversion paradigm, where times in different temperature and humidity-controlled stability chambers are set to provide a critical degradant level, is introduced for solid-state pharmaceuticals. Reliable estimates for temperature and relative humidity effects are handled using a humidity-corrected Arrhenius equation, where temperature and relative humidity are assumed to be orthogonal. Imprecision is incorporated into a Monte-Carlo simulation to propagate the variations inherent in the experiment. In early development phases, greater imprecision in predictions is tolerated to allow faster screening with reduced sampling. Early development data are then used to design appropriate test conditions for more reliable later stability estimations. RESULTS: Examples are reported showing that predicted shelf-life values for lower temperatures and different relative humidities are consistent with the measured shelf-life values at those conditions. CONCLUSIONS: The new protocols and analyses provide accurate and precise shelf-life estimations in a reduced time from current state of the art.

Implementation of basic quality control tests for malaria medicines in Amazon Basin countries: results for the 2005–2010 period

Background: Ensuring the quality of malaria medicines is crucial in working toward malaria control and eventual elimination. Unlike other validated tests that can assess all critical quality attributes, which is the standard for determining the quality of medicines, basic tests are significantly less expensive, faster, and require less skilledlabour; yet, these tests provide reproducible data and information on several critical quality attributes, such asidentity, purity, content, and disintegration. Visual and physical inspection also provides valuable information aboutthe manufacturing and the labelling of medicines, and in many cases this inspection is sufficient to detectcounterfeit medicines. The Promoting the Quality of Medicines (PQM) programme has provided technical assistanceto Amazon Malaria Initiative (AMI) countries to implement the use of basic tests as a key screening mechanism toassess the quality of malaria medicines available to patients in decentralized regions.Methods: Trained personnel from the National Malaria Control Programmes (NMCPs), often in collaboration with countrys Official Medicine Control Laboratory (OMCL), developed country- specific protocols that encompassed sampling methods, sample analysis, and data reporting. Sampling sites were selected based on malaria burden,accessibility, and geographical location. Convenience sampling was performed and countries were recommendedto store the sampled medicines under conditions that did not compromise their quality. Basic analytical tests, suchas disintegration and thin layer chromatography (TLC), were performed utilizing a portable mini-laboratory...(AU)