A pharmaceutical monitoring system to assess the quality of antituberculosis drug products used in Mauritania
Amor R. Cáceres-Pérez ,Mohamed B. El Kory, Javier Suárez-González, Mabel Soriano, M. Magdalena Echezarreta, Ana Santoveña-Estévez, José B. Fariña
Abstract
The quality of drug products may be affected from manufacture to dispensing, particularly at high temperature and humidity as in Mauritania. This country is not included in the World Health Organization reports on poor quality products due to the lack of a qualified laboratory and monitoring system. Ensuring the quality of medicine is even more relevant in the case of diseases such as Tuberculosis, due to its high prevalence, complex treatment and continuous bacterial resistance. The aim was to develop a monitoring system to assess the quality of antituberculosis drugs products, by the substandard detection based on European and United States Pharmacopeial recommendations regarding quality control. In addition to studying the influence of accelerated storage conditions (40 ± 2°C/75 ± 5% relative humidity) on their qualities and comparing the dissolution profiles to contrast the quality. 18 antituberculosis drug products were taken from Europe and Mauritania, and quality was studied through visual inspection and according to the compliance of the mass uniformity, uniformity of dosage units, dissolution, disintegration and friability pharmacopeial tests. Furthermore, a dissolution profile comparison was carried out to examine quality. A stability study was conducted to assess the influence of climatic conditions on the content and the dissolved amount of the active pharmaceutical ingredients, which were determined by an ultra-performance liquid chromatography system.
Introduction
Market globalisation and the increased complexity of the drug products supply chain has led to the inclusion of poor-quality medical products within the pharmaceutical market. This global issue is even serious in low and middle income countries (LMIC) because of the lack of resources to detect substandard drug products [1, 2]. These types of medical products include substandard, falsified and unregistered drug products. Substandard drug products, also referred to as out of specification, are authorized drug products that fail to meet either their quality standards or their specifications, or both. Falsified drug products whose composition, identity or manufacturing origin are misrepresented deliberately. Unregistered drug products are not authorised to be commercialized or approval is under evaluation [3].
Material and methods
The following materials were used: Levofloxacin (≥97.3%, Mylan Laboratories Limited®, Spain), Pyrazinamide (≥99.0%, Sigma-aldrich®, China), Rifampicin (≥97.0%, Sigma-aldrich®, China), Isoniazid (≥100.2%, Acofarma®, Spain), Ethambutol (≥99.0%, Sigma-aldrich®, USA), Hydrazine monohydrate (≥ 98%, Sigma-aldrich®, Germany), hydrochloric acid solution 1M (Fluka®, Germany), formic acid (Fluka®, Switzerland), sodium chloride (Sigma-aldrich®, Denmark), di-potassium hydrogen phosphate (Merck®, Germany), potassium dihydrogen phosphate (Supelco®, Germany), di-sodium hydrogen phosphate anhydrous (Panreac®, USA), acetonitrile (Sigma-aldrich®, Germany), triethylamine (Sigma-aldrich®, Belgium) and benzaldehyde (Sigma-aldrich®, Belgium). Purified water was obtained from a water purification system (Puranity TU 12, VWR, Radnor, PA). APIs were analysed before being used and compared with technical sheet provided by the manufacture.
To proceed with the analysis of the APIs of the selected drug products, an Acquity Ultra Performance Liquid Chromatography (UPLC)® H-Class System (Waters, Milford, MA, USA) was used. The data acquisition software was Astra 6.0.1. (Chromatographic Manager, Waters Corporation).
Results
Sampling
Table 3 shows the 18 collected drug products as well as their sampling sites, manufacturer countries and the codification employed to identify them for quality control and stability studies. All drug products were commercialized in blister.Previously, the methods to detect and quantify rifampicin, isoniazid, pyrazinamide and hydrazine were successfully validated, being linear, precises and accurate as can be found in previously published studies [19, 20].
Discussion
ANOVA was done, confirming the method linearity for a significant level of 0.05 (α = 0.05), obtaining the following equation for levofloxacin: Area (μV*sec-1) = 160117 + 175080*C (μg/ml); r2 = 0.981. Coefficient variation (CV) of this method was 4.3%. It was precise (0.7%) and accurate (101.3%) because these values met with the limit values established, lower than 1% and between 97–103% for being precise and accurate, respectively. Its LOD and LOQ were 0.6 and 1.8 μg/ml respectively.
Conclusion
All European and 3 Mauritanian formulations of the 18 drug products studied, complied with the pharmacopeial test after collection, meaning that 9 drugs of the 13 Mauritanian samples were categorized as substandard and 1 could not be determined. The 3 remaining formulations met specifications. Mauritanian substandard drugs failed friability test for every UT, CU test for 4 FDC drugs due to the high AVs obtained or dissolution test because the content of rifampicin was not released. Furthermore, hydrazine was not detected in any sample even during the stability tests.
Acknowledgments
Authors wish to recognize Kane Elhadj Malick, from the Programme National de Lutte contre la Tuberculose et la Lèpre, and the Ministry of Health of Islamic Republic of Mauritania for their contribution. The research group would like to thank to Laboratorios Cinfa for the selfless donation of levofloxacin.
Citation: Cáceres-Pérez AR, El Kory MB, Suárez-González J, Soriano M, Echezarreta MM, Santoveña-Estévez A, et al. (2023) A pharmaceutical monitoring system to assess the quality of antituberculosis drug products used in Mauritania. PLoS ONE 18(3): e0282023. https://doi.org/10.1371/journal.pone.0282023
Editor: Francesca Baratta, University of Turin, ITALY
Received: June 7, 2022; Accepted: February 7, 2023; Published: March 16, 2023
Copyright: © 2023 Cáceres-Pérez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper.
Funding: This work was funded by Cooperation Programme Interreg V-A MAC 2014-2020, ISACAM (MAC2/1.1a/219). In addition, Amor R Cáceres Pérez (Grant number: TESIS2020010045) was beneficiary of the pre-doctoral training programme for research personnel in the Canary Islands of the Consejería de Economía, Conocimiento y Empleo, 85% co-financed by the European Social Fund (ESF) and Canarian Research Agency, within the framework of the ESF Operational Programme for the Canary Islands 2014-2020.The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no Competing interests exist.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0282023#abstract0
