Pharmacopeial quality of artemether-lumefantrine anti-malarial agents in Uganda.

BACKGROUND: Substandard anti-malarial agents pose a significant challenge to effective malaria control and elimination efforts especially in sub-Saharan Africa. The quality of anti-malarials in most low-and-middle income countries (LMICs) is affected by several factors including inadequate regulation and limited resources. In this study, the pharmacopeial quality of artemether-lumefantrine (AL) in low and high malaria transmission settings in Uganda was assessed. METHODS: This was a cross-sectional study conducted among randomly selected private drug outlets. The AL anti-malarials available in drug outlets were purchased using overt method. The samples were screened for quality using visual inspection, weight uniformity, content assay and dissolution tests. The assay test was done using liquid chromatography-mass spectrometry (LC-MS). The samples were considered substandard if the active pharmaceutical ingredient (API) content was outside 90-110% range of the label claim. Dissolution test was conducted following United States Pharmacopoeia (USP) method. Data was analysed using descriptive statistics and presented as means with standard deviations, frequencies, and proportions. Correlation between medicine quality and independent variables was determined using Fisher's exact test of independence at 95% level of significance. RESULTS: A total of 74 AL anti-malarial samples were purchased from high (49/74; 66.2%) and low (25/74; 33.8%) malaria transmission settings. The most common batch of AL was LONART, 32.4% (24/74), with 33.8% (25/74) being 'Green leaf'. Overall prevalence of substandard quality artemether-lumefantrine was 18.9% (14/74; 95% CI: 11.4-29.7). Substandard quality AL was significantly associated with setting (p = 0.002). A total of 10 samples (13.5%) failed artemether content assay test while, 4 samples (5.4%, 4/74) failed the lumefantrine assay test. One sample from a high malaria transmission setting failed both artemether and lumefantrine assay content test. Of the samples that failed artemether assay test, 90% had low (< 90%) artemether content. All the samples passed visual inspection and dissolution tests. CONCLUSION: Artemether-lumefantrine agents, the recommended first-line treatment for uncomplicated malaria with APIs outside the recommended pharmacopeial content assay limit is common especially in high malaria transmission settings. There is need for continuous surveillance and monitoring of the quality of artemisinin-based anti-malarials across the country by the drug regulatory agency.

Green Analytical Methods of Antimalarial Artemether-Lumefantrine Analysis for Falsification Detection Using a Low-Cost Handled NIR Spectrometer with DD-SIMCA and Drug Quantification by HPLC.

Two green analytical approaches have been developed for the analysis of antimalarial fixed dose tablets of artemether and lumefantrine for quality control. The first approach consisted of investigating the qualitative performance of a low-cost handheld near-infrared spectrometer in combination with the principal component analysis as an exploratory tool to identify trends, similarities, and differences between pharmaceutical samples, before applying the data driven soft independent modeling of class analogy (DD-SIMCA) as a one-class classifier for proper drug falsification detection with 100% of both sensitivity and specificity in the studied cases. Despite its limited spectral range and low resolution, the handheld device allowed detecting falsified drugs with no active pharmaceutical ingredient and identifying specifically a pharmaceutical tablet brand name. The second approach was the quantitative analysis based on the green and fast RP-HPLC technique using ethanol as a green organic solvent and acetic acid as a green pH modifier. The optimal separation was achieved in 7 min using a mobile phase composed of ethanol 96% and 10 mM of acetic acid pH 3.35 (63:37, v/v). The developed method was validated according to the total error approach based on an accuracy profile, was applied to the analysis of tablets, and allowed confirming falsified drugs detected by spectroscopy.

Development of a dissolution method for lumefantrine and artemether in immediate release fixed dose artemether/lumefantrine tablets.

BACKGROUND: Dissolution of artemether (ART) and lumefantrine (LUM) active pharmaceutical ingredients (APIs) in fixed dose combination (FDC) ART/LUM tablets is one of the critical quality attributes. Thus, the verification of the release profile of ART and LUM from FDC ART/LUM tablets using a robust and discriminatory dissolution method is crucial. Therefore, the aim of this study was to develop and validate an appropriate dissolution method for quality control of FDC ART/LUM tablets. METHODS: The dissolution medium was selected based on saturation solubility data and sink conditions. The effect of agitation speed, pH and surfactant concentration on the release of ART and LUM was evaluated by employing a two-level factorial experiment. The resulting final method was validated for linearity, precision, robustness and API stability. In addition, the discriminatory power of the method was evaluated using expired and unexpired FDC ART/LUM products. RESULTS: A suitable dissolution profile of FDC ART/LUM tablets was obtained in 900 ml HCl (0.025 N, pH 1.6) with 1%Myrj 52 using paddle method at 100 rpm and 37 °C. ART and LUM were analysed using a HPLC method with UV detection at wavelengths of 210 and 335 nm, respectively. The results from the stability study showed that ART and LUM were sufficiently stable in HCl (0.025 N, pH 1.6) with 1%Myrj 52 at 37 °C. The method was linear (r2 = 0.999) over the concentration range of 6.25-100 µg/ml. The results for precision were within the acceptance limit (%RSD < 2). The percent relative standard deviation (< 2%) and statistically non-significant (p > 0.05) difference in release of ART and LUM observed between deliberately changed dissolution method settings (pH = 1.6 ± 0.2 or agitation speed = 100 ± 2) and optimized dissolution conditions revealed the robustness of the dissolution method. The method was capable to discriminate among different FDC ART/LUM products with different quality. CONCLUSIONS: The developed dissolution method is robust and discriminatory. It can be used in the quality evaluation of FDC ART/LUM tablets.

Usefulness of combined screening methods for rapid detection of falsified and/or substandard medicines in the absence of a confirmatory method.

BACKGROUND: The influx of substandard and falsified medicines is a global public health challenge and its rapid detection is a key solution to the menace. This study used three screening methods and one confirmatory method for the quality assessment of 25 batches of artemether/lumefantrine dosage forms from the Ghanaian market to test that combined screening methods only can rapidly detect substandard and/or falsified medicines in areas where confirmatory methods may not be available. METHODS: The quality of artemether/lumefantrine tablet products obtained from pharmacies and licensed chemical seller shops within the Accra metropolis in Ghana were analysed using three screening methods (GPHF Minilab, Colorimetry and Counterfeit Drug Indicator) and one confirmatory method (high-performance liquid chromatography). RESULTS: The results showed that 18/25 batches of the artemether/lumefantrine samples passed using the combined screening and confirmatory methods and 5/25 batches of the artemether/lumefantrine samples failed using the combined screening and confirmatory methods. However, 1/25 batch of the artemether/lumefantrine samples failed using the combined screening methods but passed using the confirmatory method. Also, 1/25 batch of the artemether/lumefantrine samples passed using the combined screening methods but failed using the confirmatory method. This notwithstanding, the combined screening methods and the confirmatory method provided equivalent quality assessment profiles for 23/25 (92%) batches of the artemether/lumefantrine tablet products. Out of the 6 samples that failed the confirmatory test, 1/6, 2/6, and 3/6 failed on the high (> 110%), low (< 90%), and no active ingredient (0%), respectively. The sensitivity of Minilab, colorimetric, CoDI, and the combined screening methods at 95% confidence level were 0.5 ± 0.57, 0.83 ± 0.33, 0.75 ± 0.49, and 0.83 ± 0.33, respectively. Also, the specificity of Minilab, colorimetric, CoDI, and the combined screening methods at 95% confidence level were 1.00, 0.95 ± 0.10, 1.00, and 0.95 ± 0.10, respectively. CONCLUSION: The combined screening methods may be used for rapid detection of falsified and/or substandard medicines without using a confirmatory method. However, additional research on the best combinations of screening devices/methods to rapidly detect the quality of medicines is recommended.

Quality of fixed dose artemether/lumefantrine products in Jimma Zone, Ethiopia.

BACKGROUND: Malaria caused by Plasmodium vivax and Plasmodium falciparum is among the major public health problems in most endemic areas of the world. Artemisinin-based combination therapy (ACT) has been recommended as a first-line treatment for uncomplicated Plasmodium falciparum malaria almost in all endemic regions. Since ineffectively regulated medicines in resource limited settings could favour infiltration of poor quality anti-malarial medicines into pharmaceutical supply chain and jeopardize a positive treatment outcome, regular monitoring of the quality of anti-malarial medicines is critical. Thus, the aim of this study was to assess the quality of fixed dose combination (FDC) artemether (ART)/lumefantrine (LUM) tablets available in Jimma zone, Ethiopia. METHODS: This study was conducted in Jimma zone, Ethiopia. A total of 74 samples of FDC ART/LUM (20 mg ART/120 mg LUM) tablets were collected from 27 public facilities. All samples were subjected to visual inspection and the relevant information was recorded. The samples were transported to Jimma University Laboratory of Drug Quality (JuLaDQ) and stored at ambient temperature (20 °C to 25 °C) until analysis. The Pharmacopoeial conform/non-conform methods and the risk-based Derringer's desirability function approach were employed to assess the pharmaceutical quality of the investigated products. RESULTS: The visual inspection results revealed that there were no signs of falsified in the investigated products. Identification test results of samples indicated that all samples contained the stated active pharmaceutical ingredients (APIs). The results of uniformity of mass indicated that all samples complied with International Pharmacopoeial specification limits. The assay results, expressed as percent label claim (%lc) of ART (89.8 to 108.8%, mean ± SD = 99.1 ± 3.9%) and LUM (90.0 to 111.9%, mean ± SD = 98.2 ± 3.8%) revealed that, all samples complied with International Pharmacopoeia acceptance specification limits (i.e. 90-110%lc), except one generic product (IPCA Laboratories Ltd., India) which contains excessive LUM (111.9 ± 1.7%lc). The risk priority number (RPN) results revealed that assay (RPN = 392) is relatively the most critical quality attribute followed by identity (RPN = 280) and mass uniformity (40). Quality evaluation based on psycho-physical Harrington's scale revealed that more than 96% of samples were within the acceptable ranges (D ≥ 0.7-1.0). CONCLUSIONS: Both Pharmacopoeial and risk-based desirability function approaches to quality evaluation applied to the investigated products revealed that above 96% FDC ART/LUM tablets circulating in public settings of Jimma zone are of good quality.

Quantitative determination of the antimalarials artemether and lumefantrine in biological samples: A review.

Malaria is a worldwide health issue, with 216 million cases reported in 2016. Due to the widespread resistance of Plasmodium falciparum to conventional drugs, the first line treatment recommended by World Health Organization for uncomplicated malaria is artemisinin-based combined therapy (ACT), which combines two drugs with different mechanisms of action. The association of artemether and lumefantrine is the most common ACT used in the clinical practice. However, there have been reports of clinical artemisinin and derivatives partial resistance, which is defined as delayed parasite clearance. In this context, the monitoring of drug concentration in biological matrices is essential to evaluate treatment response, the need of dose adjustment and the occurrence of dose dependent adverse effects. Furthermore, it is also important for pharmacokinetic studies and in the development of generic and similar drugs. Determination of antimalarial drugs in biological matrices requires a sample pre-treatment, which involves drug extraction from the matrix and analyte concentration. The most used techniques are protein precipitation (PP), liquid-liquid extraction (LLE) and solid phase extraction (SPE). Subsequently, a liquid chromatography step is usually applied to separate interferences that could be extracted along with the analyte. Finally, the analytes are detected employing techniques that must be selective and sensitive, since the analyte might be present in trace levels. The most used approach for detection is tandem mass spectrometry (MS-MS), but ultraviolet (UV) is also employed in several studies. In this article, a review of the scientific peer-review literature dealing with validated quantitative analysis of artemether and/or lumefantrine in biological matrices, from 2000 to 2018, is presented.

The Quality of Medicines Used in Children and Supplied by Private Pharmaceutical Wholesalers in Kinshasa, Democratic Republic of Congo: A Prospective Survey.

Poor-quality medicines are a threat to public health in many low- and middle-income countries, and prospective surveys are needed to inform corrective actions. Therefore, we conducted a cross-sectional survey on a sample of products used for children and available in the private market in Kinshasa, Democratic Republic Congo: amoxicillin (AX) and artemether/lumefantrine (AL), powders for suspension, and paracetamol (PC) tablets 500 mg. Overall, 417 products were covertly purchased from 61 wholesalers. To obtain a representative sample, the products were weighted on their market shares and a subset of 239 samples was randomly extracted to undergo in-depth visual inspection locally, and they were chemically assessed at two accredited laboratories in Belgium. Samples were defined of "poor-quality" if they failed to comply with at least one specification of the International Pharmacopoeia (for AL) or United States Pharmacopoeia 37 (for AX and PC). Results are reported according to the Medicine Quality Assessment Reporting Guideline. The visual inspection detected nonconformities in the aspects of antimalarial powders for suspension, and poor-quality labels across all medicine types. According to chemical analysis, 27.2% samples were of poor quality and 59.5% of AL samples were underdosed in artemether. Poor quality was more frequent for locally manufactured antimalarials (83.3%, P = 0.021; 86.4%, P = 0.022) and PC (4.8%, P = 0.000). The poor quality of the surveyed products may decrease the treatment's efficacy and favor the development of resistances to antimalarials. It is hoped that these findings may guide the corrective actions of the Democratic Republic of Congo Regulatory Authority, which was the main partner in the research.