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The Silent Development of Counterfeit Medications in Developing Countries – A Systematic Review of Detection Technologies
Abstract
Drug counterfeiting detection is very important for the safety of patients around the world. Counterfeit pharmaceutical products can be referred to the production and distribution of mislabeled medications in which the identity, authenticity, and/or effectiveness is altered. Drugs are often counterfeited to reduce manufacture costs, while still marketing it at as an authentic product. Increased incidence of drug counterfeiting is most noticeable in developing countries, which may not have the resources to supply counterfeit detection devices at a large scale. It is important to consider the direct problems that it may cause and to propose options for controlling and reducing the prevalence of counterfeit medications. Certain counterfeit detection devices have been successfully used for qualitative and quantitative assessment to differentiate counterfeit medications from the reference product. Different technologies are needed to identify the chemical properties of a questioned drug product, which can then be used to determine its authenticity. This review examines the implications of counterfeit medications and the current technological approaches that are able to detect counterfeited pharmaceuticals.
... The result showed good discrimination between unadulterated pain reliever herbal and adulterated samples and can be applied to distinguish whether there was adulteration in sample mixture [9]. Still, FTIR spectroscopy needs multiple spectra for each drug reference and cannot distinguish a low dose amount of sample in the vast matrix [10]. Proton Nuclear Magnetic Resonance ( 1 H -NMR) emerges as a promising technique to accurately analyse illicit herbal medicine by providing abundant structural information about compounds [11]. 1 H -NMR has been widely used as an elucidation structure technique for qualitatively analysing the new compound product. ...
... Proton Nuclear Magnetic Resonance ( 1 H -NMR) emerges as a promising technique to accurately analyse illicit herbal medicine by providing abundant structural information about compounds [11]. 1 H -NMR has been widely used as an elucidation structure technique for qualitatively analysing the new compound product. Unlike other analytical methods, 1 H -NMR offers some advantages as sophisticated analysis technique such as the capability to gain more reproducibility, quick analysis, and can create a library of data collected [10]. Recent studies showed that 1 H -NMR could detect and identify sibutramine and phenolphthalein in dietary herbal supplements. ...
... All samples for NMR Analysis were conditioned according to previous studies [10] with a slight change. 25 mg powder from each mixture and pure pain reliever herbal was analytically weighed and located into a 2.0 mL microtube. ...
... Main reasons for the prevalence of counterfeit products throughout the world are (a) high demand for less expensive drugs, (b) low availability of medical products, (c) social tolerance for counterfeit products, (d) globalization and consumer access to the internet (e-commerce), (e) complex and fragile supply chains, (f) limited technical capacity to monitor products throughout the supply chain, (g) complex import-export mechanisms, (h) the use of free and special economic and trade zones, (i) lack of law enforcement, (g) weak national regulatory policies on the manufacturing and marketing of medications, and (k) lack of adequate financial and political commitments [3][4][5]11,[14][15][16][17][18][19]. For these reasons the penetration of counterfeit products is generally higher in developing countries with West Africa and South America being reported as the areas mostly affected [11,20,21]. ...
... This indicates that the problem in developed countries may have been underestimated. However, high-income countries have a strict regulatory framework, technological means, and financial resources to detect and limit the distribution of fake drugs and pharmaceuticals [15]. ...
... In the United Kingdom almost 32 % of those who have bought one or more counterfeit medicines have suffered a health issue as a result [28]. Considering that in Africa almost 60 % of the medications are substandard one can imagine the magnitude of the consequences [15,29]. In China it was reported in a newspaper that almost 192,000 of its citizens died as a result of counterfeit medications [30], while WHO estimates 72,430 and 116,000 additional deaths occur annually from the use of counterfeit drugs for pneumonia and malaria, respectively [20]. ...
Counterfeit, fake, adulterated or falsified drugs and pharmaceuticals, could be branded or generic drugs, excipients and active substances (in drugs and vaccines), medical supplies and devices, etc, intended to pass as the original. Counterfeits are always inferior in terms of quality, safety and efficacy compared to the original pharmaceuticals, and subsequently, they pose an unpredictable risk to public health and lead to loss of confidence in medicines, healthcare providers, and health systems. In the decades before the outbreak of the COVID-19 pandemic, a constant trend of increased trafficking was reported. However, the pandemic created a combination of public health emergency, economic distress, and misinformation-driven panic that made problematic the access and supply of high quality essential medicines and health products, and pushed consumers and vendors even more towards counterfeit pharmaceuticals. This contribution aims to review the trends in counterfeit drugs and pharmaceuticals trafficking, the health impact of their use, as well as, measures and actions implemented to restrict their proliferation, before and during COVID-19 pandemic; the relative recommendations, the expressed perspectives and the existing limitations are thoroughly discussed.
... The growth of publications on SF medicines was influenced by the milestone initiatives by international organizations to fight falsified medicines [5]. The overall growth of publications seen in the last decade was also attributed to the sale of fake medicines through online pharmacies [27,28] and the trafficking of falsified medicines across borders in countries with regulatory policies in this regard [29,30]. Researchers from the UK claimed that 25 % of surveyed general practitioners reported they had cared for individuals who had experienced adverse effects from medications ordered online [28]. ...
... Websites and social media are new powerful instruments to sell fake medicines and generate profit [57]. A large number of publications on counterfeit Viagra and other sexual stimulants were dedicated to the development of detection technologies [29]. It has been suggested to use blockchain technology as well as strengthening regulatory bodies and policies to fight the internet pharmaceutical trade [58]. ...
... The use of detection technology such as chromatography and spectrophotometry constituted another research topic in the retrieved documents. Such technologies are in use to detect falsified medications, especially in developing countries [29]. ...
Objective
Substandard and falsified (SF) medical products are a global public health threat. The presence and spread of SF drugs negatively affect (1) patients’ safety and health outcomes, (2) national economy, (3) public trust in the healthcare system, and (4) the international fight against serious health challenges such as malaria and antimicrobial resistance. The objective of the current study was to investigate and provide a snapshot analysis of the evolution and developmental patterns of global research publications on SF products.
Methods
A bibliometric approach was adopted using terms such as fake, falsified, counterfeit, substandard, and others. No language restriction was made. The study period was from 1900 up to 2020. The search strategy was validated and implemented using Scopus database.
Results
The search strategy retrieved 978 documents authored by 2861 researchers from 100 different countries and published in 421 different journals. The retrieved documents received 11,237 citations (11.5 citations per document) with an H-index of 53. The 978 documents retrieved from Scopus were published from 1961 to 2020, giving an average of 16.6 publications per year. The present study indicated that research on SF medical products: (a) has experienced a steep growth from 2001 to 2012 followed by a steady-state growth; (b) was disseminated in a wide range of journals, mainly in the fields of the pharmaceutical industry, analytical chemistry, public health, infectious diseases, and internal medicine; (c) was published by scholars with diverse and distant geographical backgrounds; (d) was mainly produced in the United States, United Kingdom, and Germany; (d) has fragmented research networks and a limited number of researchers per network; (e) has limited cross-country collaboration except for that between the US and the UK in one hand and countries in the Mekong region in the other hand; (f) emphasized on medications related to malaria and sexual stimulants; and (g) received relatively inadequate funding.
Conclusions
Research on SF medical products is important and should remain a priority to ensure good quality of medications. Research activity in the field needs to be encouraged in world regions such as Africa and the Middle East where drug regulations are unsatisfactory and cross-border trade of illegal medications is common.
... Counterfeit food and pharmaceuticals are a global threat with dire consequences to the health of millions worldwide [1]. The already existing measures such as barcodes, QR codes, and serial numbers on the packaging do not alleviate the problem as they can be easily reproduced by counterfeiters. ...
... From Fig. 4 (b), the Gaussian fit of the Hamming Distance produces a of 0.49 and of 0.063 for this particular set of 16 PUFs. Since the Hamming distance is influenced by the similarities and differences between the keys, the and of the Gaussian fit can be used to find out the degrees of freedom of the PUF system by Equation (1). Using the degrees of freedom, the actual encoding capacity for this set of PUFs can be determined by Equation (2) ...
On-dose authentication (ODA) enhances security by incorporating customized molecular or micro-tags into each pill, preventing counterfeit products in genuine packages. ODA's security relies on tag non-replication and non-reverse engineering. Combining ODA with graphical Physical Unclonable Functions (PUF) promises maximum security. PUF uses intrinsic micro or nanoscale randomness as a unique ‘fingerprint’. However, current graphical PUFs have limitations like specific illumination requirements and the use of toxic materials, restricting their use in pharmaceuticals.
In this study, we propose a novel approach called on-dose PUF. This method involves embedding microspheres randomly within micro biocompatible hydrogel particles. We showcase two distinct types of such on-dose PUFs. The first type utilizes randomly distributed superparamagnetic colloids (SPC) of identical diameters, while the second type utilizes vortexed sunflower oil drops of various diameters. The diameter and coordinates of the microspheres serve as input for generating cryptographic keys. A universal circle identification and binning program is used for extracting this information. One advantage of this approach is that it enables imaging using white light illumination and low-magnification microscopy, as color and signal intensity information are not crucial. This method enables patients to verify their medication by using their mobile phones from home.
To assess the performance of the proposed on-dose PUF, we conducted canonical investigations on the single-diameter system. This system can only generate one layer of cryptographic keys, making it potentially more vulnerable than the multiple-diameter system. However, the single-diameter system successfully passed NIST Statistical tests and exhibited sufficient randomness, ideal bit uniformity, Hamming distance, and device uniqueness. Furthermore, we found that the encoding capacity of the single-diameter system was 9.2×1018, providing ample labeling potential.
... In this review we discuss how current developments in mass spectrometry, e.g., the access to new samples and previously Table 1. Modern analytical methods used in medicinal drug inspection (based on [2,13,[18][19][20]). Mass spectrometry has achieved a leading role in characterization of falsified medicines, due to the specificity and sensitivity provided by current MS instruments, but its applications in forensic science include not only analysis of drugs, but also warfare agents [21], gun-shot residues [22,23], ink differentiation [24], and other forensically relevant samples [1]. ...
... The requirements of separation methods include volatility and thermal stability for GC, and solubility and solution stability for LC. There are several reports discussing the preferences for a particular separation method in forensic cases, with LCMS with soft ionization methods gaining influence, due to the growing demand for analysis of biomolecules [19,20,27]. ...
This review presents numerous studies in which mass spectrometry has been used to assist forensic investigation. Due to its unique capabilities, mainly high-resolution mass data and structural information, high sensitivity, and cooperation with separation techniques, this method provides access to many tools streamlining and accelerating sample analysis. Low analyte consumption, advanced derivatization procedures and availability of isotopically labeled standards offer opportunities to study materials previously not considered viable evidence, opening new avenues in forensic investigations.
... Te high-performance liquid chromatography (HPLC) is a versatile tool for the quantifcation of pharmaceuticals while maintaining high levels of specifcity and sensitivity [16,17]. However, it has the problems of requiring higher level training, requiring a high-power source to operate, and it is expensive [21]. Liquid chromatography-mass spectrometry (LC-MS) is a combination of the ability to separate molecules through liquid chromatography and then identify the compound through mass spectrometry [18,19]. ...
Metformin (MET) is an oral antidiabetic drug widely used as the primary treatment for type 2 diabetes mellitus (T2DM). While various spectrophotometric assays exist for determining MET in pharmaceutical formulations, they often have limited throughput for quality control purposes. This study describes the validation of a 96-microwell plate spectrophotometer method using charge-transfer complexes (CTCs) with chloranilic acid (CLA) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) for the quality control and detected of MET. This reaction was carried out in 96-microwell plates, and the absorbance of the colored complexes of CLA and DDQ were measured at 530 nm and 460 nm, respectively, using an absorbance microplate reader. This study aims to identify and quantify the use of a 96-microwell plate spectrophotometer analytical technique for assessing complicated formulations. The method was successfully used for the quantification of MET in the tablet dosage form. The results showed good correlation coefficients (0.996 and 0.997) with CLA and DDQ, respectively. The present method showed high precision with RSD % not exceeding 2.17%. The accuracy of the method was obtained by recovery percentage, with percentage values less than ±5%. The Analytical Greenness Metric (AGREE) was used to evaluate greenness of the assays. The result show that the microwell assay method is greenness and suitable for handling large samples on a daily used with high throughput analysis. The use of the 96-microwell-plate method is superior to the existing method in terms of simplicity of the procedure, the low economic cost, and its consumption of low amounts of reagents and organic ethanol solvent, making it an environmentally friendly method. Therefore, these advantages make them suitable and rapid alternatives method to current methods for routine metformin analysis in quality control laboratories.
... In regard to the identi cation, legitimacy, and/or effectiveness of the product, counterfeit pharmaceutical products can be de ned as the manufacture and distribution of dishonestly labeled drugs. The widespread use of fake drugs has had life-threatening effects on populations, including an increased risk of chronic illness, inadequate treatment results, severe drug responses, and fatality (Bolla et al., 2020). ...
Introduction
The U.S. healthcare sector is characterized by a diverse mix of public and private funding and provision, resulting in a lack of a singular governing philosophy. Both the public and private sectors are known for providing high-quality medical services. However, since 1980, healthcare spending in the U.S. has substantially increased. The immense size and financial resources of the healthcare sector make it a prominent target for fraudulent activities.
Aim
This study investigated the impact of collaborative efforts between managed care organizations (MCOs) and oversight agencies on the detection and reduction of healthcare fraud within the Illinois Medicaid program.
Method
This study examines how collaboration between MCOs and oversight agencies impacts healthcare fraud in Illinois Medicaid. A FOIA request for complaint data was sent to the Illinois Department of Healthcare and Family Services. The Illinois Medicaid Office of the Inspector General oversees program integrity and maintains e database to prevent the enrollment of excluded providers.
Results
As of September 20, 2023, 2,741 providers were sanctioned, including 857 physicians, 679 waiver service providers, 159 pharmacies, and 157 Medicare providers. Over the period from September 2022 to August 2023, 1,059 fraud referrals were recorded, with internal data mining contributing the most (448) and County Care being the top-referring MCO (260 cases). The collaborative efforts between MCOs and the Medicaid – Office of Inspector General led to the identification of 13,441,726 in fiscal year 2021.
Conclusion/Recommendation
The findings emphasize the significance of data sharing and transparency in the fight against fraud. The imposition of sanctions on errant healthcare providers has emerged as a key deterrent against fraudulent activities. To combat fraud and information gaps, a comprehensive strategy is needed. This includes empowering patients, improving communication, using advanced analytics, and enforcing regulations. User-friendly digital platforms provide reliable information, enabling informed decisions and reducing disparities. Strengthened collaboration and advanced analytics are crucial for early fraud detection, preserving healthcare integrity, and preventing financial losses.
... Frost et al. (19) reported that poor quality antibiotics in less regulated markets are attributed to poor manufacturing practices of the pharmaceutical companies. Use of counterfeit products compromises public health (33) and contributes to AMR and drug resistant infections (34). Weak postmarket surveillance due to financial constraints and insufficient laboratory capacity has resulted in difficulty in assessing the quality of drugs on the market. ...
Introduction
To effectively regulate and reduce antibiotic use, in the livestock sector, a thorough understanding of the flow of veterinary antibiotics will help to identify key nodes in the chain for targeted interventions. The aim of this study was to understand the flow of antibiotics from import to end-user, and identify relevant governance mechanisms.
Methods
A mixed methods approach was used to collect data in three Kenyan counties (Nairobi, Kiambu, and Kajiado). Focus group discussions (n = 23), individual interviews (n = 148), and key informant interviews (n = 10) were conducted.
Results
The key actors identified include primary wholesalers, secondary wholesalers, retailers, animal health service providers (AHSPs), and farmers. Kenya imports 100% of its veterinary antibiotics: primary wholesalers legally import antibiotics as finished pharmaceutical products (90%) or active pharmaceutical ingredients (10%) after approval by the Veterinary Medicines Directorate. Secondary wholesalers play a major role in the distribution of antibiotics (60% of antibiotics) from importers to farmers, AHSPs, and retailers. Some of the illegal sources of antibiotics include unlicenced/unauthorized middlemen and online platforms that sell directly to retailers, AHSPs, and farmers.
Discussion
Despite the presence of various laws and regulations governing the antibiotic value chain, implementation has been a challenge due to financial and human resource constraints. This contributes to over-the-counter sale of antibiotics without prescription, unlicensed businesses selling antibiotics, illegal importation, and presence of poor-quality drugs. There is a need to review the applicability of existing policies and address policy gaps (e.g., product containing antibiotic combinations, and use of human critically important antibiotics) to ensure the prudent sale and use of antibiotics, pharmacovigilance, antimicrobial use surveillance, and developing a business model that aligns with antibiotic stewardship. Additional interventions include awareness raising and capacity building of the different stakeholders along the antibiotic distribution chain to reduce antibiotic mis- and overuse.
... This specialized chromatographic technique utilizes a gaseous mobile phase, involving the separation of a sample into its constituents through gas chromatography, followed by the analysis of each component using mass spectrometry. A significant advantage of GC-MS lies in its ability to effectively identify volatile impurities but it is expensive [23]. Moreover, the major fatty acids found in these oils are oleic acid, linoleic acid, palmitic acid, myristic acid, and lauric acid, which constitute more than 90% of the total fatty acid content, making date seed oil a rich source of diverse fatty acids with potential health benefits [16,24]. ...
Since ancient times, date fruit has been used as a staple food because of its high nutritional value and caloric content. With the development of food science and the application of modern instrumentation, we now know that date seeds contain large amounts of dietary fiber, phenols, polyphenols, amino acids, fatty acids, and many vitamins and minerals. Due to the presence of these functional food ingredients, date seeds are used in various applications, including foods such as bread, hot beverages, cosmetics such as hair and skin products, and as feed for culturing aquatic animals. Date seeds have been used in clinical applications, making use of their antioxidant, anti-inflammatory, anti-cancer, anti-diabetic, and antimicrobial properties. There is now growing awareness of the value of date seeds, which were considered a waste product. In this review, we focused on explaining the major biochemical constituents of date seeds and developing these constituents for various applications. We also highlight the expected developments in date seed use for the future.
... Infidelity with its consequences results among other factors due to lack of sexual satisfaction and many shy away from medical attention. On the other hand, many deaths have been recorded due to over use (in most cases without prescription) of these libido enhancing agents [8][9][10]. More so, resveratrol (3,5,4′ -trihydroxy-trans-stilbene), belongs to the polyphenol stilbenoids group. ...
... Drugs are frequently imitated to lower production costs while still being sold as genuine medicines. Developing nations lack the capacity to supply and implement counterfeit detection technologies on a wide scale to prevent drug counterfeiting [1]. To reduce the risk of illegal and counterfeit drugs entering the market, the digital traceability of pharmaceutical drugs has proven to be an incredibly effective process. ...
Pharmaceutical drug serialization is typically a regulatory requirement adopted by major nations to combat pharmaceutical drug counterfeiting. Since the 19th century, drug fraud has been a serious issue for the healthcare sector. Periodically, regulatory and healthcare organizations struggle to reduce the risk of negative effects brought on by fake drugs. Drugs are frequently imitated to lower production costs while still being sold as genuine medicines. Developing nations lack the capacity to supply and implement counterfeit detection technologies on a wide scale to prevent drug counterfeiting [1]. To reduce the risk of illegal and counterfeit drugs entering the market, the digital traceability of pharmaceutical drugs has proven to be an incredibly effective process. Currently, every drug packet in developed nations like the United States and Europe must have a unique identifier with a 2D barcode. On the other hand, it is difficult to implement digital traceability of pharmaceutical drugs in developing nations due to a lack of technical infrastructure, lax regulations, geopolitical unrest, poverty, low literacy, and political will. Generally, Economic depression in developing nations prevents them from allocating cash for research and development that would enhance their healthcare systems. The recent COVID-19 pandemic also contributed significantly to the collapse of their whole healthcare system. Global supply chain limits and resource scarcity have an influence on developing nations, causing inflation and unemployment.
... Another drug successfully studied using UV-Vis spectrometry has been carried out on Tylenol. UV-Vis spectrophotometry could separate peaks of Tylenol and its ingredients, and the concentration of Tylenol could be determined accurately [32]. ...
Spectroscopic method in the UV-Vis region is considered the most molecular spectrometric method for content determination of a single component. However, a lot of pharmaceutical dosage forms comprise two or more components which lead to peak overlapping. Moreover, in the chemical stability test, active pharmaceutical ingredient (API) was also found along with the degradation products, impurities, and adulterant compounds. UV-Vis spectroscopy is one of the methods of choice for the determination or quantification of a single component in pharmaceutical preparations. The pharmaceutical products typically contain two or more APIs having chromophoric agents capable of absorbing UV-Vis beams and the absorbance values are summative from the absorption of each UV-Vis active compound according to the additive nature of Lambert-Beer law. The main problem for the simultaneous determination of API along with impurities and the degradation products in pharmaceutical preparations is the presence of overlapping peaks of UV-Vis spectra. The chemometrics-assisted spectroscopy is one of the analytical efforts to solve these problems. This review highlighted the application of chemometrics in combination with UV-Vis spectroscopy for the assay of API, impurities, adulteration issues and degradation products present in pharmaceutical dosage forms.
... 2.1.7. Pharmaceuticals/Counterfeits (with a focus on differentiation of legitimate versus counterfeit products, or for monitoring quality control for legitimate pharmaceutics) 2019 analytical method for the analysis of active ingredients in pharmaceutical products and illegal drugs, based on benchtop NMR spectroscopy [998]; HPLC method on RP-C18 core-shell particulate and monolithic columns for simultaneous analysis of avanafil, sildenafil, apomorphine, trazodone, yohimbine, tramadol and dapoxetine in pharmaceutical dosage forms, counterfeit products and human plasma [999]; 2020 low-wavenumber Raman spectral database of pharmaceutical excipients for qualitative and quantitative analysis, counterfeit detection and pharmaceutical process control [1000]; review of the implications of counterfeit medications and the current technological approaches that are used to detect counterfeited pharmaceuticals [1001]; 2021 HPLC-UV and UPLC-MS/MS methods for the simultaneous analysis of sildenafil, vardenafil, and tadalafil and their counterfeits dapoxetine, paroxetine, citalopram, tramadol, and yohimbine in 50 commercial products including honey sachets, instant coffee and pharmaceutical products [1002]; Time-Domain Nuclear Magnetic Resonance (TD-NMR) method to detect adulterated pharmaceutical materials [1003]; electrochemical sensor for determination of acetaminophen in pharmaceutical formulations [1004]; electrochemical sensor for determination of pharmaceutical compounds [1005]; paper spray ionization (PSI) coupled to fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) for determining the chemical profiling of 92 samples of counterfeit medicines and ecstasy tablets [1006]; qualitative and quantitative analyses of pharmaceutical and dietary supplements seized from the black market between January 2016 and December 2019 using GC-MS and LC-HRMS [1007]; development and validation of a UHPLC-UV method to quantify sildenafil and tadalafil in the presence of six degradation products in the pharmaceutical analysis of genuine and seized medicines [1008]; NMR method for verifying drug compliance, drug identity, purity and quality [1009]; ion beam analysis (IBA) procedure to characterize authentic Viagra (R) tablets and sildenafil-based illegal products [1010]; ATR-FTIR and DSC for the quick detection of counterfeit medicines through the polymer analysis of blister packaging materials [1011]; discrimination of counterfeit erectile dysfunction medicines using an Ultra-Compact Raman Scattering Spectrometer for the analysis of tadalafil (Cialis), vardenafil (Levitra), and sildenafil (Viagra) tablets purchased on the internet [1012]; 2022 analytical strategy which enables the structural identification, comprehensive characterization and quantification of monoclonal antibodies in potentially counterfeit samples [1013]. ...
... [8] A worrisome hazard of counterfeit drugs is being consumed unnoticed, [3] and the magnitude of the global problem relies on estimates and predictions and is being under-reported, particularly in developing countries. [15][16][17] To the best of our knowledge, very few studies if any, have been undertaken to explore the perceived influence of the COVID-19 lockdown on the circulation of counterfeit drugs and medical supplies through the electronic market. The outcome and recommendations of this study would help reduce crimes of counterfeit pharmaceutical and medical products through the electronic market. ...
Objectives
Drugs and medical supplies counterfeiting is one of the worldwide major problems that pose a significant threat to both global public health and the economy. Nowadays, one of the major unprecedented challenges of the COVID-19 pandemic is the disastrous repercussions on the economy worldwide. The latter brought forth a noticeable rise in pharmaceutical and medical counterfeit products. Drug counterfeiting has thrived parallel to the expansion of electronic networks and the Internet during the COVID-19 pandemic. The objective of the current study is to explore the perceived influence of the COVID-19 lockdown on the circulation of counterfeit drugs and medical supplies through the electronic market in Jordan.
Methods
A cross-sectional survey study was conducted in Jordan. The questionnaire was self-administered to the public as they are the probable counterfeit medicine victims and as drug counterfeiting is a nationwide problem. To capture participants’ views, a total of 460 respondents were recruited and a simple random sampling strategy was used to collect data. The inclusion criteria were consumers aged 18 years old and above, who use the Internet when purchasing drugs and medical supplies, and are willing to participate in the study.
Key findings
The study indicated an increase in using electronic websites when purchasing medicines during the COVID-19 lockdown. Additionally, there was a significant correlation the between COVID-19 lockdown and the circulation of counterfeit drugs and medical supplies through the electronic market in Jordan.
Conclusions
The study indicated that the COVID-19 lockdown had influenced counterfeit drugs and medical supplies circulation through the electronic market in Jordan.
... The problem of authenticity detection of drug tablets is directly related to the life and health of patients. Counterfeit drugs not only worsen the patient's condition but can even cause death in extreme cases [50,51]. Figure 5 shows the detection of the counterfeit drugs using the Raman Hyperspectral method [52]. ...
The quality and safety of medicinal products are related to patients’ lives and health. Therefore, quality inspection takes a key role in the pharmaceutical industry. Most of the previous solutions are based on machine vision, however, their performance is limited by the RGB sensor. The pharmaceutical visual inspection robot combined with hyperspectral imaging technology is becoming a new trend in the high-end medical quality inspection process since the hyperspectral data can provide spectral information with spatial knowledge. Yet, there is no comprehensive review about hyperspectral imaging-based medicinal products inspection. This paper focuses on the pivotal pharmaceutical applications, including counterfeit drugs detection, active component analysis of tables, and quality testing of herbal medicines and other medical materials. We discuss the technology and hardware of Raman spectroscopy and hyperspectral imaging, firstly. Furthermore, we review these technologies in pharmaceutical scenarios. Finally, the development tendency and prospect of hyperspectral imaging technology-based robots in the field of pharmaceutical quality inspection is summarized.
... Worldwide, an estimated 10% of medicines on the market are falsified [1][2][3][4][5][6][7][8]. In developing countries, the percentage of falsified and substandard drugs is higher, at about 10-30% [3,[9][10][11][12][13][14][15][16]. Particularly at risk of counterfeiting are those drugs that are expensive or promise high sales. ...
Falsified medicines are a major issue and a threat around the world. Various approaches are currently being investigated to mitigate the threat. In this study, a concept is tested that encodes binary digits (bits) on the surface of Fused Deposition Modelling (FDM) 3D printed geometries. All that is needed is a computer, a FDM 3D printer and a paper scanner for detection. For the experiments, eleven different formulations were tested, covering the most used polymers for 3D printing in pharma: Ethylene-vinyl acetate (EVA), polyvinyl alcohol (PVA), polylactic acid (PLA), Hypromellose (HPMC), ethyl cellulose (EC), basic butylated-methacrylate-copolymer (EPO), and ammonio-methacrylate-copolymer type A (ERL). In addition, the scanning process and printing process were evaluated. It was possible to print up to 32 bits per side on oblong shaped tablets corresponding to the dimensions of market preparations of oblong tablets and capsules. Not all polymers or polymer blends were suitable for this method. Only PVA, PLA, EC, EC+HPMC, and EPO allowed the detection of bits with the scanner. EVA and ERL had too much surface roughness, too low viscosity, and cooled down too slowly preventing the detection of bits. It was observed that the addition of a colorant or active pharmaceutical ingredient (API) could facilitate the detection process. Thus, the process could be transferred for 3D printed pharmaceuticals, but further improvement is necessary to increase robustness and allow use for more materials.
... Counterfeiters manufacture counterfeit medicines to trick and confuse medical professionals, patients and consumers by imitating authentic medical products. Due to similar packaging, users are often unable to detect the difference between genuine and fake medicine [9]. ...
The detection of counterfeit pharmaceuticals is always a major challenge, but the early detection of counterfeit medicine in a country will reduce the fatal risk among consumers. Technically, fast laboratory testing is vital to develop an effective surveillance and monitoring system of counterfeit medicines. This study proposed the combination of Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) and Differential Scanning Calorimetry (DSC) for the quick detection of counterfeit medicines, through the polymer analysis of blister packaging materials. A sample set containing three sets of original and counterfeit medicine was analyzed using ATR-FTIR and DSC, while the spectra from ATR-FTIR were employed as a fingerprint for the polymer characterization. Intending to analyze the polymeric material of each sample, DSC was set at a heating rate of 10 °C min−l and within a temperature range of 0–400 °C, with nitrogen as a purge gas at a flow rate of 20 mL min−1. The ATR-FTIR spectra revealed the chemical characteristics of the plastic packaging of fake and original medicines. Further analysis of the counterfeit medicine’s packaging with DSC exhibited a distinct difference from the original due to the composition of polymers in the packaging material used. Overall, this study confirmed that the rapid analysis of polymeric materials through ATR-FTIR and comparing DSC thermograms of the plastic in their packaging effectively distinguished counterfeit drug products.
After emergency incidents, the issue of emergency supplies counterfeiting persists. Relying solely on government intervention often falls short of preventing fraud related to emergency supplies counterfeiting. Hence, this paper explores a new anti‐counterfeiting approach for emergency supplies, led by the government with legitimate manufacturers' support, and establishes a differential game model based on consumer demand, legitimate manufacturers reputation, and anti‐counterfeiting efforts. Upon exploring the anti‐counterfeiting efforts and benefits for two participants, and systems in three scenarios, we find that system benefits, legitimate manufacturer reputation, and respective gains for both participants are the highest in the collaboration scenario. However, compared with a no‐cost‐sharing scenario, the cost‐sharing scenario achieves a Pareto improvement in both social welfare and legitimate manufacturer benefits, with the government choosing to share a portion of the anti‐counterfeiting cost for legitimate manufacturers only under certain conditions.
Drug counterfeits have been an international issue for almost two decades, and the latest statistics show that fake medications will continue to penetrate legitimate pharmaceutical supply chains (PSCs). Therefore, identifying the issues faced by PSCs is essential to combat the counterfeit drug problem, which will require the implementation of technologies in various phases of the PSC to gain better visibility. In this regard, a literature review was conducted to fulfill the following objectives: (i) review the application of traceability technologies in various PSC phases to detect counterfeits; (ii) analyze the various barriers affecting the establishment of a safe PSC and the critical success factors used to overcome those barriers; and (iii) develop a conceptual framework and guidelines to demonstrate the influence of traceability technologies and success factors on overcoming the various barriers in different phases of the PSC. The major finding of this review was that traceability technologies and the critical success factors have a significant influence on overcoming the barriers to establishing a safe PSC.
Distribution of substandard and falsified (SF) medicines is on the rise, and its impact on public health, particularly in low-resource countries, is becoming increasingly significant. Portable, nondestructive screening devices can support regulatory authorities in their defense against the spread of SF medicines. Vibrational spectroscopy is an ideal candidate due to its sampling ease and speed. In this work, five portable, among which four are considered low-cost, spectroscopic devices based on near-infrared (NIR), Raman, and mid-infrared (MIR) were evaluated to quantify active pharmaceutical ingredients (APIs) and formulation accuracy within simulated authentic, falsified, and substandard medicines. Binary sample mixtures containing a typical API in antimalarial, antiretroviral, or anti-tuberculosis medicines were assessed. In both univariate and multivariate analyses, the API quantification performance of the digital light processing (DLP) NIR spectrometer and a handheld Raman device consistently matched or exceeded that of the other NIR spectrometers and a scientific grade MIR spectrometer. In the formulation accuracy tests, data from all devices, other than the silicon photodiode array NIR spectrometer, were able to create regression models with less than 6% error. From this exploratory study, we conclude that certain portable NIR devices hold significant promise as cost-effective screening tools for falsified and potentially substandard medicines, and they warrant further investigation and development.
Counterfeit and substandard medicines are recognized as one of serious threats to public health. The product quality of antibacterial medicine will compromise patients’ recovery and increase the chance of antibacterial resistance. The review aims to provide a summary of low quality levofloxacin issues and the risk factors as well as suggesting the aspects of product quality that need to be regulated strictly. Quality of the active ingredient, levofloxacin, has an important role to contribute to successful therapy. The poor quality of raw material, directly and indirectly, causes treatment failure as the presence of insufficient dose, mislabeled content, and poor dissolution characteristics can lead to lower bioavailability. Identifying and reporting these factors can potentially help in improving the quality of drug marketed in various developing countries and may also reduce the incidences of treatment failure. Dissolution test is used for testing the dissolution profiles and the rate of drug release from solid formulation such as oral formulations, thus providing information regarding the in vivo performance of a formulation and its bioequivalence. On the other hand, quality-testing procedures are used for comparing the quality of products.
The World Health Organization suggests that approximately 10% of medicines worldwide are either falsified or substandard with higher figures in low and middle income countries. Such poor quality medicines can seriously harm patients and pose a threat to the economy worldwide. This study investigates attenuated total reflectance-fourier transform infrared (ATR-FTIR) spectroscopy as a simple and rapid method for determination of drug content in tablet dosage forms. Paracetamol was used as the model pharmaceutical ingredient. Spectra of standard mixtures of paracetamol with different excipients formed the basis for multivariate PLS based quantitative analysis of simulated tablet content using different selected infrared absorbance bands. Calibration methods using ATR-FTIR were compared with the ATR-FTIR and conventional ultraviolet spectroscopic analyses of real tablet samples and showed that the paracetamol/microcrystalline cellulose mixtures gave optimum results for all spectral bands tested. The quantitative data for band 1524–1493cm⁻¹ was linear (R² ˃ 0.98; LOQ ≥ 10%w/w tablet). Global examples of paracetamol tablets were tested using this protocol and 12% of the tablet samples examined was identified as substandard. Each sample analysis was completed in just a few minutes. ATR-FTIR can therefore be used in the rapid screening of tablet formulations. The simplicity of the proposed method makes it appropriate for use in low and middle income countries where analytical facilities are not available.
Importance
Substandard and falsified medicines burden health systems by diverting resources to ineffective or harmful therapies, causing medical complications and prolonging illnesses. However, the prevalence and economic impact of poor-quality medicines is unclear.
Objective
To conduct a systematic review and meta-analysis to assess the prevalence and estimated economic burden of substandard and falsified essential medicines in low- and middle-income countries.
Data Sources
Five databases (PubMed, EconLit, Global Health, Embase, and Scopus) were searched from inception until November 3, 2017.
Study Selection
Publications were assessed to determine whether they examined medicine quality and the prevalence and/or economic burden of substandard and falsified medicines in low- and middle-income countries. Studies with a sample size of 50 or more were included in the meta-analysis.
Data Extraction and Synthesis
The study is registered in PROSPERO and reported via the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Study quality was assessed using an adapted Medicine Quality Assessment Reporting Guidelines scoring metric. Multiple reviewers conducted the data extraction and quality assessment independently.
Main Outcomes and Measures
Prevalence and/or estimated economic impact of substandard and falsified medicines.
Results
Two hundred sixty-five studies that estimated the prevalence of poor-quality essential medicines in low- and middle-income countries were identified. Among 96 studies that tested 50 samples or more (67 839 total drug samples), overall prevalence of poor-quality medicines was 13.6% (95% CI, 11.0%-16.3%), with regional prevalence of 18.7% in Africa (95% CI, 12.9%-24.5%) and 13.7% in Asia (95% CI, 8.2%-19.1%). Of studies included in the meta-analysis, 19.1% (95% CI, 15.0%-23.3%) of antimalarials and 12.4% (95% CI, 7.1%-17.7%) of antibiotics were substandard or falsified. Eight approximations of the economic impact, focused primarily on market size, with poor or undisclosed methods in estimation were identified, ranging from 200 billion.
Conclusions and Relevance
Poor-quality essential medicines are a substantial and understudied problem. Methodological standards for prevalence and rigorous economic studies estimating the burden beyond market size are needed to accurately assess the scope of the issue and inform efforts to address it. Global collaborative efforts are needed to improve supply-chain management, surveillance, and regulatory capacity in low- and middle-income countries to reduce the threat of poor-quality medicines.
Trial Registration
PROSPERO Identifier: CRD42017080266
Nowadays, nuclear magnetic resonance (NMR) spectroscopy is one of the most essential research tools in material science and engineering. It received a considerable interest in membrane technology that offers structural information [1], blend miscibility [2], blend phase morphology [3], and purity of polymers [4]. It provides details about the stability and degradation of the polymers such as degree of acetylation, degree of amination, and degree of sulfonation [5–8]. It is also used to predict the pore size distributions of the polymer matrix [9]. The main objective of this book chapter is to increase our knowledge of using NMR spectroscopy on membrane technology. In addition, the chemical nature and the surface features of polymeric membranes and their proton conductivity properties were correlated.
The fight against medicine counterfeiting is a current focus of the pharmaceutical world. Reliable analytical tools are needed to pursue the counterfeiters. Handheld devices present the advantage of providing quick results, with analyses possibly performed on the field. A large number of solid-dosage form medicines have been analyzed with a handheld Raman spectrometer. 33 out of 39 product families could be successfully analysed. The methods were validated with 100% of correct identification. Each product was additionally tested by the methods of the other products and successfully rejected. A second validation was performed using counterfeits, placebos, and generics. All the counterfeits were rejected, with p values close to zero. Some generics presented a similar formulation to the brand products and were then identified as such. One placebo was positively identified, showing that low dosage products are difficult to analyze with Raman. Robustness tests were carried out, showing, for instance, that the operator has no influence on the results and that the analyses might be performed through transparent packaging. The discovery mode was also investigated, which proposes the chemical composition of the samples. The results demonstrated that the Raman handheld device is a reliable tool for the field analysis of counterfeits.
Chromatography is an important biophysical technique that enables the separation, identification, and purification of the components of a mixture for qualitative and quantitative analysis. Proteins can be purified based on characteristics such as size and shape, total charge, hydrophobic groups present on the surface, and binding capacity with the stationary phase. Four separation techniques based on molecular characteristics and interaction type use mechanisms of ion exchange, surface adsorption, partition, and size exclusion. Other chromatography techniques are based on the stationary bed, including column, thin layer, and paper chromatography. Column chromatography is one of the most common methods of protein purification.
Potential infiltration of counterfeit drug products - containing the wrong or no active pharmaceutical ingredient (API) - into the bona fide drug supply poses a significant threat to consumers worldwide. Raman spectroscopy offers a rapid, non-destructive avenue to screen a high throughput of samples. Traditional qualitative Raman identification is typically done with spectral correlation methods that compare the spectrum of a reference sample to an unknown. This is often effective for pure materials but is quite challenging when dealing with drug products that contain different formulations of active and inactive ingredients. Typically, reliable identification of drug products using common spectral correlation algorithms can only be made if the specific product under study is present in the library of reference spectra, thereby limiting the scope of products that can be screened. In this paper, we introduce the concept of the Raman barcode for identification of drug products by comparing the known peaks in the API reference spectrum to the peaks present in the finished drug product under study. This method requires the transformation of the Raman spectra of both API and finished drug products into a barcode representation by assigning zero intensity to every spectral frequency except the frequencies that correspond to Raman peaks. By comparing the percentage of nonzero overlap between the expected API barcode and finished drug product barcode, the identity of API present can be confirmed. In this study, 18 approved finished drug products and nine simulated counterfeits were successfully identified with 100% accuracy utilizing this method.
A mini-laboratory to help low-income countries detect counterfeit and substandard quality medicines has been developed by the German Pharma Health Fund (GPHF), a charity organisation established by research-based pharmaceutical companies in Germany. The GPHF-Minilab provides a reliable, simple and inexpensive method for rapid drug quality verification of antituberculosis, antimalarial and antiretroviral drugs as well as major antibiotics and some other essential medicines in particular for childhood diseases. The kit is of special interest to vertical disease programmes, hospitals and other healthcare providers, which are constantly at risk of having their supply chain infiltrated by pharmaceuticals of spurious quality.
The objective of the current study was to develop a validated, specific and stability-indicating reverse phase HPLC method for the quantitative determination of Dronedarone and its related substances. The determination was done for active pharmaceutical ingredient and its pharmaceutical dosage forms in the presence of degradation products, and its process-related impurities. The drug was subjected to stress conditions of hydrolysis (acid and base), oxidation, photolysis and thermal degradation per International Conference on Harmonization (ICH) prescribed stress conditions to show the stability-indicating power of the method. Significant degradation was observed during acid, oxidative and photo stress studies. In the developed HPLC method, the resolution between Dronedarone and its process-related impurities was found to be greater than 2.0. Regression analysis shows an r value (correlation coefficient) of greater than 0.999 for Dronedarone and it’s all the five impurities. The chromatographic separation was achieved on a C8 stationary phase. The method employed a linear gradient elution and the detection wavelength was set at 288 nm. The stress samples were assayed against a qualified reference standard and the mass balance was found to be close to 99.6%. The developed HPLC method was validated with respect to linearity, accuracy, precision and robustness.
Counterfeit medicines are a global public health risk. We assess counterfeit reports involving the legitimate supply chain using 2009-2011 data from the Pharmaceutical Security Institute Counterfeit Incident System (PSI CIS) database that uses both open and nonpublic data sources. Of the 1,510 identified CIS reports involving counterfeits, 27.6% reported China as the source country of the incident/detection. Further, 51.3% were reported as counterfeit but the specific counterfeit subcategory was not known or verifiable. The most prevalent therapeutic category was anti-infectives (21.1%) with most reports originating from health-related government agencies. Geographically, Asian and Latin American regions and, economically, middle-income markets were most represented. A total of 127 (64.8%) of a total of 196 countries had no legitimate supply chain CIS counterfeit reports. Improvements in surveillance, including detection of security breaches, data collection, analysis, and dissemination are urgently needed to address public health needs to combat the global counterfeit medicines trade.
© The American Society of Tropical Medicine and Hygiene.
Background/Aims
Most current knowledge regarding amiodarone toxicity derives from clinical trials. This study was performed to investigate the incidence and risk factors of overall adverse effects of amiodarone in real-world practice using a large sample size.
Methods
Between January 1, 2000 and March 10, 2012, a total of 930 consecutive patients who had been treated with amiodarone for arrhythmia were reviewed retrospectively. An amiodarone-associated adverse event was considered in cases of discontinuation or drug dose reduction due to an unexpected clinical response.
Results
The mean daily dose of amiodarone was 227 ± 126 mg, and the mean duration was 490 ± 812 days. During the mean follow-up duration of 982 ± 1,137 days, a total of 154 patients (16.6%) experienced adverse effects related to amiodarone, the most common being bradycardia or conduction disturbance (9.5%). Major organ toxicities in the thyroid (2.5%), liver (2.2%), eyes (0.6%), and lungs (0.3%) were rare. All patients recovered fully without complications after amiodarone discontinuation or dose reduction. The only independent predictor of adverse effects was the duration of amiodarone treatment (odds ratio, 1.21; 95% confidence interval, 1.03 to 1.41; p = 0.016, per year).
Conclusions
Low-dose amiodarone is well tolerated in a real-world clinical population. Further studies with a prospective design are needed to confirm this finding.
Counterfeit and illegal pharmaceutical products are an increasing worldwide problem and constitute a major challenge for analytical laboratories to detect and characterize them. Spectroscopic techniques such as infrared spectroscopy and Raman spectroscopy have always been the first methods of choice to detect counterfeits and illegal preparations, but due to the evolution in the seized products and the necessity of risk assessment, chromatographic methods are becoming more important in this domain. This review intends to give a general overview of the techniques described in literature to characterize counterfeit and illegal pharmaceutical preparations, focusing on the role of chromatographic techniques with different detection tools.
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. It is associated with significant morbidity and mortality. At the societal level, AF carries an enormous cost. Strategies aimed at reducing AF morbidity and mortality and containing the associated fiscal burden are of paramount importance. This review will discuss AF treatment strategies and economics, focusing on the impact of dronedarone, a novel antiarrhythmic agent. © 2012 Khaykin and Shamiss, publisher and licensee Dove Medical Press Ltd.
Counterfeit drugs are inherently dangerous and a growing problem; counterfeiters are becoming increasingly sophisticated. Growth of the counterfeit medication market is attributable in part to phosphodiesterase type 5 inhibitor (PDE5i) medications for erectile dysfunction (ED). Millions of counterfeit PDE5is are seized yearly and account for the bulk of all counterfeit pharmaceutical product seizures. It has been estimated that up to 2.5 million men in Europe are exposed to illicit sildenafil, suggesting that there may be as many illegal as legal users of sildenafil. Analysis of the contents of counterfeit PDE5is shows inconsistent doses of active pharmaceutical ingredients (from 0% to > 200% of labelled dose), contaminants (including talcum powder, commercial paint and printer ink) and alternative ingredients that are potentially hazardous. In one analysis, only 10.1% of samples were within 10% of the labelled tablet strength. Estimates place the proportion of counterfeit medications sold over the Internet from 44% to 90%. Of men who purchase prescription-only medication for ED without a prescription, 67% do so using the Internet. Counterfeit PDE5is pose direct and indirect risks to health, including circumvention of the healthcare system. More than 30% of men reported no healthcare interaction when purchasing ED medications. Because > 65% actually had ED, these men missed an opportunity for evaluation of comorbidities (e.g. diabetes and hypertension). Globally, increased obstacles for counterfeiters are necessary to combat pharmaceutical counterfeiting, including fines and penalties. The worldwide nature of the counterfeit problem requires proper coordination between countries to ensure adequate enforcement. Locally, physicians who treat ED need to inform patients of the dangers of ordering PDE5is via the Internet.
Liquid chromatography-mass spectrometry (LC-MS) is now a routine technique with the development of electrospray ionisation (ESI) providing a simple and robust interface. It can be applied to a wide range of biological molecules and the use of tandem MS and stable isotope internal standards allows highly sensitive and accurate assays to be developed although some method optimisation is required to minimise ion suppression effects. Fast scanning speeds allow a high degree of multiplexing and many compounds can be measured in a single analytical run. With the development of more affordable and reliable instruments, LC-MS is starting to play an important role in several areas of clinical biochemistry and compete with conventional liquid chromatography and other techniques such as immunoassay.
A method for rapidly screening pharmaceuticals by thin-layer chromatography has been designed for use in areas with limited resources and by operators with limited training. An apparatus for performing the analysis in a plastic bag under equilibrium conditions was designed. Results can be reproduced by different operators and in different locations. The analysis can be performed without electricity or in a remote area, away from a laboratory. It is especially suited for field use in developing countries. The method is low cost, maintenance-free, fast, and reliable; it also uses limited volumes of solvents. The analyses can be performed without weighing if reference materials can be supplied in tablet form, provided the drug content is listed and only one unit is required for each analysis. All procedures were developed for the analysis of drugs from a partial list of essential drugs established by the World Health Organization. Three drugs were selected and prepared in the form of reference tablets. Comparisons with the analyses of the drugs in standard dosage forms were made by using reference tablets and primary USP standards. Comparable results were obtained, proving that the screening process can be conducted by using reference tablets and without weighing either the sample or the reference. The method has been successfully demonstrated and used in Swaziland, by high school teachers in the United States, and by personnel from the Ministry of Health in Saudi Arabia. Personnel can be trained in a short time to perform screening analysis of drugs.
The production of substandard and fake drugs is a vast and underreported problem, particularly affecting poorer countries. Cockburn and colleagues argue that the pharmaceutical industry and governments must both take action.
Levofloxacin is a third-generation fluoroquinolone antimicrobials drug that inhibits bacterial DNA replication. Driven by huge profit, one kind of particular counterfeit, e.g., repackaged expired tablets, becomes very common especially in developing countries. The feasibility of identifying expired levofloxacin tablets by combining NIR spectroscopy with chemometrics was investigated. Five kinds of levofloxacin samples from different manufacturers were collected for experiment. Two types of expired mode were considered and a simple model-independent algorithm was used for feature selection. Principal component analysis (PCA) was used for exploratory analysis and simple discriminant analysis. Taking seventy samples as the target class, a final one-class model based on Data Driven Soft Independent Modeling by Class Analogy with abbreviation DD-SIMCA was constructed, which achieved 97% sensitivity and 100% specificity on the independent set composed of 34 unexpired and 128 expired tablets. These results confirm that the combination of NIR spectroscopy, feature selection and class-modeling is feasible for identifying the expired levofloxacin tablets. Such a method can be extended to the analysis of similar drugs.
Falsified medicines represent a serious threat to public health. Among the different measures to effectively combat this scourge, analytical methods play a key role in their detection and removal from the market before they reach patients. The present study evaluates for the first time the potential of a benchtop low-field (LF) Nuclear Magnetic Resonance (NMR) spectrometer for uncovering drug falsification by focusing on the analysis of fifteen erectile dysfunction and nine antimalarial medicines, the most commonly reported falsified medicines in developed and developing countries respectively. After a simple and rapid sample preparation and ≈ 5 min of spectrum recording, LF ¹H NMR allows to conclude on the quality of the medicine: presence or absence of the expected active pharmaceutical ingredient (API), presence of unexpected API, absence of any API. Some 2D experiments are also described but although conclusive they are hampered by the duration of the experiments. The LF ¹H NMR assay, based on the internal standard method, is validated by the determination of its accuracy, repeatability, limits of detection (LOD) and quantification (LOQ), and by comparison of the data obtained on some medicines after 45 min of spectrum recording to those measured with high-field ¹H NMR. Because of its saving capabilities (cost, space, user experience), LF ¹H NMR spectroscopy might become a routine screening tool in laboratories in charge of detecting falsified medicines.
Background:
Oxytocin is the drug of choice for preventing and treating postpartum haemorrhage, an important cause of maternal death. Oxytocin is widely available in low and middle-income countries (LMIC) but there are concerns about its quality.
Objective:
To identify, critically appraise and synthesise the findings of studies on the quality of oxytocin available in LMIC.
Search strategy:
We searched seven electronic databases, without language restriction.
Selection criteria:
Studies reporting results of tests to assess quality of oxytocin samples from LMIC.
Data collection and analysis:
Study selection, data extraction and quality assessment were performed in duplicate. Results are presented descriptively.
Main results:
The search identified 2611 unique citations; eight studies, assessing 559 samples from 15 different countries were included. Most samples were collected from facility level settings (n = 509) and from the private sector (n = 321). The median prevalence of oxytocin samples that failed quality tests was 45.6% (range 0-80%), mostly due to insufficient amounts of active pharmacological ingredient. Over one-third of the samples (n = 204) had low (<90%) oxytocin content indicating substandard medicine; two samples had no active ingredient, suggesting possible counterfeit drugs. The proportion of low fails was higher in samples collected in Africa than in Asia or Latin America (57.5% versus 22.3% versus 0%, respectively, P < 0.0001), in private than in public sectors (34.0% versus 25.3%, P = 0.032) and in facilities than in central distributors (37.9% versus 22.0%, P = 0.030).
Conclusion:
There is a high prevalence of poor-quality oxytocin samples in LMIC countries, mainly due to inadequate amounts of active ingredient.
Tweetable abstract:
Systematic review points to problems with quality of oxytocin samples from low- and middle-income countries.
Two simple, accurate, and precise chromatographic methods have been developed and validated for the determination of dronedarone (DRO) HCl and amiodarone (AMI) HCl either alone or in binary mixtures due to the possibility of using AMI as a counterfeit of DRO because of its lower price. First, an RP-HPLC method is described for the simultaneous determination of DRO and AMI. Chromatographic separation was achieved on a BDS Hypersil C18 column (150 × 4.6 mm, 5 μm). Isocratic elution based on potassium dihydrogen phosphate buffer with 0.1% triethylamine pH 6-methanol (10 + 90, v/v) at a flow rate of 2 mL/min with UV detection at 254 nm was performed. The second method is RP ultra-HPLC in which the chromatographic separation was achieved on an Acclaim(TM) RSLC 120 C18 column (100 × 2.1 mm, 2.2 μm) using isocratic elution with potassium dihydrogen phosphate buffer with 0.1% triethylamine pH 6-methanol (5 + 95, v/v) at a flow rate of 1 mL/min with UV detection at 254 nm. Linearity, accuracy, and precision of the two methods were found to be acceptable over the concentration ranges of 5-80 μg/mL for both DRO and AMI. The results were statistically compared using one-way analysis of variance. The optimized methods were validated and proved to be specific, robust, precise, and accurate for the QC of the drugs in their pharmaceutical preparations.
In the last decade, counterfeit pharmaceutical products have become a widespread issue for public health. Raman spectroscopy which is easy, non-destructive and information-rich is particularly suitable as screening method for fast characterization of chemicals and pharmaceuticals. Combined with chemometric techniques, it provides a powerful tool for the analysis and determination of counterfeit medicines. Here, for the first time, a systematic study of the benefits and limitations of Raman spectroscopy for the analysis of pharmaceutical samples on a large set of model tablets, varying with respect to chemical and physical properties, was performed. To discriminate between the different mixtures, a combination of dispersive Raman spectroscopy performing in backscattering mode and principal component analysis was used. The discrimination between samples with different coatings, a varying amount of active pharmaceutical ingredients and a diversity of excipients were possible. However, it was not possible to distinguish between variations of the press power, mixing quality and granulation. As a showcase, the change in Raman signals of commercial acetylsalicylic acid effervescent tablets due to five different storage conditions was monitored. It was possible to detect early small chemical changes caused by inappropriate storage conditions. These results demonstrate that Raman spectroscopy combined with multivariate data analysis provides a powerful methodology for the fast and easy characterization of genuine and counterfeit medicines.
Copyright © 2015 Elsevier B.V. All rights reserved.
Objectives: To review the global implications associated with the use of substandard and or counterfeit drugs in developing and may be developed countries. The focus of this review is particularly on antiretroviral (ARVs), antimalarials and other drugs.
Methods: Review of various literatures through Pub-Med, Medline, Google and Internet search to retrieve and download published materials was done by the author of this review paper.
Results: When patients receive a counterfeit medicines, they are subjected to multiple risks. They often suffer more than just an inconvenience; as they become victims of fraud medicines and are all put at risk of adverse effects from unprescribed medicines or substandard ingredients.
Additionally, patients may lose confidence in health care professionals including their physician and pharmacist, and potentially modern medicine or the pharmaceutical industry in general. Counterfeit or substandard (poor quality) drugs pose threats to society; not only to the individual in terms of the health side effects experienced, but also to the public in terms of trade relations, economic implications, and the effects on global pandemics. It is vital for suppliers, providers, and patients to be aware of current trends in counterfeiting in order to best prepare for encounters with suspicious products. Furthermore, this is an issue that needs to be continually dealt with on national and international policy levels. Developing countries should try their level best to establish good laboratories for monitoring and checking quality of all pharmaceuticals manufactured locally and those imported or donated to these countries. The Ministries of Health and all stakeholders
involved in this issue must ensure that all drugs meet the set or established international standards and national standards. Failure to do so will be to misuse the hard earned forex that is normally borrowed from banks for the procurement and distribution of drugs to its people. Indeed sub-standard medications do more harm than good to people's health and it is unethical to give such drugs to people. Of course, in any market, some corruption and fraud always exist, but there are few commercial markets where fraud can have such drastic impact on global health and welfare. It is essential, therefore, that a multi-faceted approach be used to control this problem which affects the international community and
continuously threatens the health of millions of people especially in developing countries.
Conclusion: Developing countries should try their best at all costs establish good laboratories for monitoring or checking for quality control for all pharmaceuticals locally manufactured and those imported (entering) or donated to countries to make sure that they meet the set or established international or national standards. Short of that countries will be wasting a lot of money using forex which has been borrowed in a form a loans procuring and distributing to its people sub-standard medications which will do more harm than good to its indigenous people and this is unethical per se to give people drugs not meeting required set international standards. East African Journal of Public Health Vol. 5 (3) 2008: pp.205-210
Regular quality control and post-marketing surveillance of pharmaceuticals has been a critical challenge for countries of the developing world ever since. Counterfeit and substandard medicines are widely distributed and the real extent of their prevalence still remains unknown. Compendial protocols and methods utilizing high-performance liquid chromatography (HPLC) which are described in the major pharmacopoeias are widely applied for the quality control of a compound. They often require expensive solvents, delicate reagents and/or sophisticated apparatus, and may not be applicable and affordable for laboratories with limited capabilities. Simple but robust HPLC methods for the determination of five commonly used antimalarial agents, i.e. amodiaquine, mefloquine, proguanil, artemether and lumefantrine, were developed and their suitability for routine use in resource-restraint environments is discussed. They solely require readily available chemicals and solvents and exhibit a high grade of ruggedness.
Reports of low quality pharmaceuticals have been on the rise in the last decade with the greatest prevalence of substandard medicines in developing countries, where lapses in manufacturing quality control or breaches in the supply chain allow substandard medicines to reach the marketplace. Here, we describe inexpensive test cards for fast field screening of drug tablets containing beta lactam antibiotics or combinations of the four first-line TB drugs. The devices detect the active pharmaceutical ingredients (APIs) ampicillin, amoxicillin, rifampicin, isoniazid, ethambutol, and pyrazinamide, and also screen for substitute pharmaceuticals such as acetaminophen and chloroquine that may be found in counterfeit pharmaceuticals. The tests can detect binders and fillers like chalk, talc, and starch not revealed by traditional chromatographic methods. These paper devices contain twelve lanes, separated by hydrophobic barriers, with different reagents deposited in the lanes. The user rubs some of the solid pharmaceutical across the lanes and dips the edge of the paper into water. As water climbs up the lanes by capillary action, it triggers a library of different chemical tests and a timer to indicate when the tests are completed. The reactions in each lane generate colors to form a "color bar code" which can be analyzed visually by a trained user. While quantification of the APIs is poor compared to conventional analytical methods, the sensitivity and selectivity for the analytes is high enough to pick out suspicious formulations containing no API or a substitute API, as well as formulations containing APIs that have been "cut" with inactive ingredients.
It has been shown that NMR spectroscopy is an effective analytical method to rapidly screen creams and ointments for counterfeit corticosteroids. Extraction and NMR procedures have been developed. Ten over the counter creams and ointments sold in health care shops were screened and two creams were found to contain counterfeited corticosteroids.
A new unapproved analogue of sildenafil was detected in capsules of a herbal dietary supplement promoted as a libido enhancing product. Using LC-DAD-MS, MS-MS, HRMS, IR and NMR the analogue was shown to be a derivative of the PDE-5 inhibitor aildenafil with a nitrosamine moiety. A hydrolysis experiment showed that the new analogue was a prodrug of aildenafil and was therefore named nitroso-prodenafil. A capsule contained 108 mg of nitroso-prodenafil which is equivalent to 84 mg of aildenafil and 5.1 mg of nitrogen monoxide (NO). Although it is unknown how much NO can be usefully generated there is 3-fold more NO present than in a 10 mg isorbide nitrate tablet. Both PDE-5 inhibitors and nitrosamines cause vasodilatation by increasing levels of NO. To their coincidental use is warned against because it may cause a fatal drop in blood pressure. In addition, nitrosamines are known carcinogens. This is the first time a PDE-5 inhibitor and a potential NO donor were identified in one molecule. The findings indicate the dangerous level of advancement in medicinal chemistry by producers of unapproved drugs.
A liquid chromatography-electrospray ionisation-mass spectrometry (LC-ESI-MS) method was developed to screen for the presence of synthetic phosphodiesterase type 5 (PDE-5) inhibitors including sildenafil, tadalafil and vardenafil. The method was applied to the analysis of dietary supplements and bulk herbal materials. Bulk powders or composites of tablets, capsules or liquids were prepared and an extraction of PDE-5 inhibitors was performed using a mixture of acetonitrile and water with sonication. Identification of sildenafil, vardenafil or tadalafil was accomplished using a single quadrupole mass spectrometer coupled to a liquid chromatograph with an electrospray interface. Positive ion detection in the full scan mode was used while in-source collision induced dissociation (CID) provided several structurally significant fragment ions to aid in the mass spectral identification. Approximately half of the 40 botanical products analyzed were found to contain undeclared synthetic PDE-5 inhibitors. For products found to contain one of these three compounds by LC-MS, HPLC with UV detection was used for quantitation.
Pharmaceutical counterfeiting is becoming a serious problem both in developed and developing countries. This paper considers the extent of the problem and provides several examples of drugs which have been counterfeited. Additionally, the effects of counterfeit products on consumers, health care providers, drug manufacturers and governments are discussed. Several of the currently used methods of detection are described and these include near-infrared spectroscopy, Raman spectroscopy, isotopic characterization, tensiography, chromatographic and mass spectrometric approaches. Finally, anti-counterfeiting measures such as the use of holograms, tracers and taggants and electronic tracking are summarized.
A high-performance liquid chromatography-diode array detection (HPLC-DAD) method and a liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method were developed to screen for the presence of synthetic phosphodiesterase-5 (PDE-5) inhibitors and their analogues, namely sildenafil, vardenafil, tadalafil, homosildenafil, acetildenafil and hydroxyhomosildenafil. The methods were applied to pre-market samples submitted to the Health Sciences Authority of Singapore (HSA) for testing. One sample was in the form of capsules while six other samples were pre-mixed bulk powder samples for dietary supplements to be repackaged or formulated into the final dosage forms (usually capsules). Identification of PDE-5 inhibitors and their analogues was achieved by comparing individual peak retention times, UV spectra and mass spectra with those of reference standards. The seven samples were found to contain at least one of the following compounds: sildenafil, vardenafil, hydroxyhomosildenafil, homosildenafil and acetildenafil. The five compounds were simultaneously determined by LC-ESI-MS/MS in multiple reactions monitoring (MRM) scan mode. The method has been validated for accuracy, precision, linearity and sensitivity.
Pharmaceutical counterfeiting is becoming a serious problem in the world, especially in developing countries including China. Herein an isocratic reversed-phase high performance liquid chromatography (RP-HPLC) method was developed for screening counterfeit medicines and adulterated dietary supplement products. The developed method could be employed to separate and determine simultaneously six anti-diabetic drugs (glipizide, gliclazide, glibenclamide, glimepiride, gliquidone, repaglinide) on an isocratic solvent system using an Alltima C18 column (5 microm, 150 mmx4.6 mm) with an isocratic mobile phase of methanol-phosphate buffer (pH 3.0; 0.01 mol/L) (70:30, v/v), at a flow rate of 1.0 mL/min and at a wavelength of 230 nm. The proposed method was successfully applied to the analysis of medicinal and dietary supplement samples purchased from the local market in China.
Buprenorphine, commonly known by the trademark Temgesic, is one of the most popular drugs of abuse among the opioid-addicted young individuals in Iran. Temgesic, Bungesic, etc. are the most popular and important illicit opioid drugs in Tehran's illicit drugs black market, and are now among the most widely abused by opioid addicts. Because of this, counterfeiting of this drug has increased in Tehran. In this study, the qualitative analysis of counterfeit buprenorphine by gas chromatography-mass spectrometry (GC-MS) and high performance liquid chromatography (HPLC) demonstrates the presence of diacetylmorphine, acetylcodeine and pheniramine, as well as the absence of buprenorphine. In conclusion, due to the absence of quality control and difficulties in differentiating counterfeit buprenorphine from genuine products, the use of counterfeit buprenorphine leads the opioid abusers to health risks.
The Tanzania Food and Drugs Authority piloted the use of Minilab kits, a thin-layer-chromatographic based drug quality testing technique, in a two-tier quality assurance program. The program is intended to improve testing capacity with timely screening of the quality of medicines as they enter the market. After 1 week training of inspectors on Minilab screening techniques, they were stationed at key Ports-of-Entry (POE) to screen the quality of imported medicines. In addition, three non-Ports-of-Entry centres were established to screen samples collected during Post-Marketing-Surveillance. Standard operating procedures (SOPs) were developed to structure and standardize the implementation process. Over 1200 samples were tested using the Minilab outside the central quality control laboratory (QCL), almost doubling the previous testing capacity. The program contributed to increased regulatory reach and visibility of the Authority throughout the country, serving as a deterrent against entry of substandard medicines into market. The use of Minilab for quality screening was inexpensive and provided a high sample throughput. However, it suffers from the limitation that it can reliably detect only grossly substandard or wrong drug samples and therefore, it should not be used as an independent testing resource but in conjunction with a full-service quality control laboratory capable of auditing reported substandard results.
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