Dissertations / Theses on the topic 'Substandard and counterfeit drugs'

Världsmarknaden för läkemedlen beräknades år 2011 till 900 miljarder US$ enligt IMS-health. Marknaden för illegala läkemedel uppskattas vara värd mellan 75-200 miljarder dollar. I Sverige uppskattas den illegala läkemedelsmarknaden till motsvarande ≤0,5 %. Straffet för insmuggling av läkemedel till Sverige är böter eller max 2 års fängelse. Tullverket räknar med att man endast hittar 10 % av det som smugglas in. I andra länder kan straffet variera mellan böter (ekonomisk brottslighet i Afrika) till dödsstraff i Kina. I Utvecklingsländerna uppskattas 10-30 % av alla läkemedel som säljs vara förfalskade, jmf 1 % I-länderna. l. Förekomsten av förfalskade läkemedel har många allvarliga konsekvenser på människor som exempelvis, utebliven effekt, toxiska reaktioner, förgiftningar, som kan i värsta fall leda till döden. Ett annat alvarligt problem är resistensutveckling, ökad spridning av smittsamammasjukdomar som exempel, tuberkulos och/ eller HIV/AIDS. Syftet med detta examensarbete är att besvara frågan: Vilka problem ger den ökande förekomsten av förfalskade läkemedel i samhället. Undersökningen fokuserar på livstidsläkemedel, dvs ett läkemedel en person måste ta resten av sitt liv för behandling av sin kroniska sjukdom. För att komma till rätta med de problem, som förfalskade läkemedel, skapar krävs ett mer utvecklat samarbete mellan olika läkemedelsmyndigheter, läkemedelsföretag, internationella polisorganisationer, tull m.fl. Arbetet med att utveckla förpackningar som är svåra att förfalska bör intensifieras. Straffsatser bör kanske ses över. Det är viktigt att öka medvetandet bland allmänheten om risker med att köpa läkemedel utanför apotek (t ex via nätet).

The prevalence of counterfeit and substandard medicines has been growing rapidly over the past decade, and fast, non-destructive techniques for their detection are urgently needed to counter this trend. In this thesis, both energy-dispersive X-ray diffraction (EDXRD) and pixelated diffraction (“PixD”) combined with chemometric methods were assessed for their effectiveness in detecting poor-quality medicines within their packaging. Firstly, a series of caffeine, paracetamol and cellulose mixtures of known concentrations were pressed into tablets. EDXRD spectra of each tablet were collected both with and without packaging. Principal component analysis (PCA) and partial least-squares regression (PLSR) were used to study the data and construct calibration models for quantitative analysis. The concentration prediction errors for the packaged data were found to be very similar to those obtained in the unpackaged case, and were also on a par with reported values in the literature using higher-resolution angular-dispersive X-ray diffraction (ADXRD). Following this, soft independent modelling by class analogy (SIMCA) classification was used to compare EDXRD spectra from a test set of over-the-counter (OTC) medicines containing various combinations of active pharmaceutical ingredients (APIs) against PCA models constructed using spectra collected for paracetamol and ibuprofen samples. The test samples were selected to emulate different levels of difficulty in authenticating medicines correctly, ranging from completely different APIs (easy) to those with a small quantity of additional API (difficult). This classification study found that the sensitivity and specificity were optimal at data acquisition times on the order of 75~150s, and regardless of whether layers of blister and card packaging surrounded the tablet in question. This experiment was repeated on a novel, compact system incorporating a pixellated detector, which was found to reduce the required data acquisition times for optimal classification by a factor of five.

Thesis (Ph.D.)--Boston University<br>Counterfeit and substandard medicines are a grave public health concern that comprises a $75B black market and claims over 100,000 lives every year. The World Health Organization estimates that 10-50% of medicines in countries around the world are adulterated, and their presence imposes serious financial and economic burdens while also contributing to the rise of drug-resistant pathogens. Although a plethora of technologies are available for field-based quality screening, none reliably quantify active pharmaceutical ingredient (API) content or kinetic release from a dissolving tablet. The United States Pharmacopeia, a global leader in medicines standards for over 150 years, indicates that these quality measures are vitally important yet remain outside of the reach ofexisting screening tools. The current field standard relies on thin layer chromatography to only provide qualitative results that make it difficult to discern between tablets that contain 80% and 100% API. Meanwhile, international standards set the threshold for substandard medicines at 90%. This clear lack of appropriately quantitative and field- ready analytical tools poses a serious problem for national and international policymakers who are plagued with wildly variable information that prevents focused and deliberate action against the spread ofthese medications. This work presents an alternative analytical technique that can specifically and accurately quantify drug API content and kinetic release. PharmaChk provides an orthogonal approach to existing technologies using a portable, inexpensive, and easy-to-use platform. We demonstrate that aptamers can provide a simple and effective way to target a wide range of APis, while maintaining high quantitative precision and accuracy. A microfluidic, flow-through system is employed to obtain valuable drug quality information using a single step procedure. Through our research, we demonstrate the development of the PharmaChk platform from the proof-of-concept stage to beta prototyping and field-testing. By providing a portable, robust, and quantitative approach to medicines testing, PharmaChk can enable the collection of important drug quality information throughout pharmaceutical supply chains and ultimately save the lives of millions that are not afforded safe and essential medicines.

The objective of this study was to evaluate the status of the counterfeit pharmaceuticals in Jordan. Four types of pharmaceuticals Lipitor (Atorvastatin-calcium), Concor (bisoprolol fumarate), Co-Diovan (Valsartan, hydrochlorothiazide) and Plavix (clopidogrel) were subjected to physical and chemical analysis. 173 samples of these four medicines were collected from the three most populated cities in the country, namely Amman, the capital of Jordan, Zarqa and Irbid. A sample of confiscated counterfeited medicines was obtained from the health authorities and tested utilising the HPLC and dissolution testing, in order to validate the reliability of the testing procedures. Samples were then tested using High Performance Liquid Chromatography (HPLC) and dissolution tests in order to assess the quality of these samples. Results of both chemical and physical analyses revealed that all samples were found to fall within the specification limits of United States Pharmacopoeia (USP) and no evidence was found of any counterfeit drug products in the samples examined. Since this study found no indication of a drug counterfeiting problem in Jordan, the researcher has concluded that there seemed to be two contributing factors to this result: first, the very effective legislative campaigns conducted by the health authorities’ in Jordan against counterfeit trade through new public health and pharmacy law which has been launched in 2008. Second, the rigorous tough enforcement measures conducted by health and law enforcement agencies in the country.

North Korea began its involvement in illicit activities in the 1970s, but it took the United States until the new millennium to develop a series of major law enforcement approaches to counter these activities. North Korea's illicit activities are purportedly the funding input for the development of its nuclear weapons program, which constitutes the output. The main illicit activities to be discussed include drug production and trafficking, the counterfeiting of U.S. currency, cigarettes and pharmaceuticals, missile sales and human trafficking. The United States has aggressively addressed the nuclear threat that North Korea poses, but has been slow to address the inputs that fund the outputs. This thesis seeks to answer the question of why it took the United States over three decades to address the illicit activities of North Korea that purportedly fund its nuclear program.<br>US Air Force (USAF) author.

Malaria is still an epidemic in many parts of the world-about 220 million people are still infected with malaria worldwide and about 700 thousand people die from this disease per year. Most of the drugs used to treat malaria work well if they are used as required and they contain the right amounts of the active ingredient; however, it is estimated that more than 10% of drugs traded worldwide are counterfeits including 38% to 53% of antimalarial tablets produced in China and India. Due to the lack of data covering the extent of counterfeit antimalarial drugs in Ghana, the purpose of this quantitative study was to determine the percentage of counterfeit antimalarial drugs sold in Ghana by assessing the amounts of the 2 most common antimalarial drugs, artemether (ATMT) and lumefantrine (LMFT) in drugs sold in Ghana retail outlets. These drugs were purchased from retail outlets in Ghana and analyses at the Mayo Clinic Pharmacology core lab (Rochester, MN). The quality of the drugs were characterized by comparing the actual amount of ATMT & LMFT in each tablet to the expected amount. Using explanatory theory along with dose response-response occupancy theory, the researcher addressed quantitative solutions to questions related to the percentage and distribution of counterfeit ATMT and LMFT tablets. The results revealed that overall 20% of the drugs are counterfeit; this is not dependent on the location or kind of outlet but rather depends on whether the tablets were imported or locally manufactured and whether the tablets had a pedigree scratch panel. This study provides a better understanding of how much antimalarial medication is counterfeit in Ghana, which will aid interventions to minimize the adverse effects of counterfeit antimalarial medication in Ghana

PONTIFÍCIA UNIVERSIDADE CATÓLICA DO RIO DE JANEIRO<br>O objetivo desta dissertação é investigar os aspectos regulatórios e de controle de qualidade de medicamentos para minimizar o grave problema da falsificação desses produtos na Guatemala. A motivação para reforçar o Sistema Nacional da Qualidade da Guatemala identificando as vulnerabilidades do sistema regulatório aplicável ao controle de medicamentos levou o Ministério da Economia da Guatemala a buscar cooperação internacional. O Programa de Pós-Graduação em Metrologia, Qualidade e Inovação da Pontifícia Universidade Católica de Rio de Janeiro (PUC-Rio) ofereceu então a infraestrutura necessária para o desenvolvimento da pesquisa. A metodologia inclui revisão bibliográfica e um estudo de caso para avaliar os métodos analíticos a fim de determinar e quantificar o conteúdo de camptotecina e seus derivados (irinotecana e topotecana), utilizados em medicamentos no tratamento de câncer. Dentre os resultados encontrados, destacam-se o diagnóstico de aspectos regulatórios na Guatemala e a avaliação crítica dos métodos analíticos aplicáveis às substâncias anticancerígenas mencionadas. As principais conclusões do trabalho sinalizam para as vulnerabilidades do marco regulatório que favorecem a falsificação de medicamentos. Além disso, métodos analíticos validados exercem papel preponderante na caracterização da falsificação destes medicamentos. A eletroforese capilar e a espectrofluorimetria mostraram-se mais eficazes que outros métodos de referência usados na identificação da falsificação das substâncias anticancerígenas estudadas. Ainda que muitos artigos científicos estudados indiquem parâmetros de mérito diversos, poucos fazem menção à incerteza associada à medição do sinal analítico dos analitos de interesse.<br>The objective of this dissertation is to study regulatory and quality control aspects to tackle medicines’ counterfeiting in Guatemala. The motivation to reinforce Guatemala’s National Quality System by identifying vulnerabilities in the country’s pharmaceutical regulatory system has led the Guatemalan Finance Ministry to seek cooperation. The Postgraduate Programme in Metrology for Quality and Innovation of the Catholic University of Rio de Janeiro (PUC-Rio) offered the infrastructure within the context of quality control assessment to carry out this investigation. The methodology includes a literature survey to investigate the main themes of this work, and a case study to assess analytical methods to identify and quantify the content of camptothecin and its derivatives (irinotecan and topotecan) used in cancer treatment. A comparison between the Brazilian and Guatemalan regulatory framework was made. A critical evaluation of the analytical methods applied to the above mentioned substances was made. Conclusions have shown that vulnerabilities in the regulatory framework favor the manufacturing, trade and indiscriminate use of counterfeit drugs. Furthermore, analytical methods play an important role in its characterization. Capillary electrophoresis and espectrofluorimetric proved to be more efficient than other methods for determining counterfeit or substandard drugs of the substances studied. Most scientific studies indicate a wide range of validation parameters, but only one of them mentioned the uncertainty associated with the analytical signal of the analites of interest.<br>El objetivo de esta disertación es investigar los aspectos regulatorios y de control de calidad de medicamentos para minimizar el grave problema de la falsificación de estos productos en Guatemala. La motivación de este trabajo reside en el interés en reforzar el Sistema Nacional de la Calidad de Guatemala, mediante la identificación de las vulnerabilidades del sistema regulatorio aplicable al control de medicamentos, lo que llevó al Ministerio de Economía de Guatemala a buscar cooperación internacional para este propósito. El Programa de Pos-Graduación en Metrología, Calidad e Innovación de la Universidad Católica de Río de Janeiro (PUC-Rio) ofreció la infraestructura necesaria para el desarrollo de la investigación. La metodología incluye una revisión bibliográfica y un estudio de caso para evaluar los métodos analíticos utilizados para determinar y cuantificar la camptotecina y sus derivados (irinotecan e topotecan), en medicamentos utilizados para el tratamiento de cáncer. Entre los resultados encontrados, se destacan el diagnóstico de aspectos regulatorios en Guatemala y la evaluación crítica de los métodos analíticos aplicables a las substancias anticancerígenas mencionadas. Las principales conclusiones del trabajo señalan las vulnerabilidades del marco regulatorio, que favorecen la falsificación de medicamentos. Asimismo, destaca la importancia de los métodos analíticos validados para la caracterización de medicamentos falsificados o deficientes. La electroforesis capilar y la espectrofluorimetría se mostraron más eficaces que otros métodos de referencia, para la identificación de falsificaciones de las substancias anticancerígenas estudiadas. A pesar de que muchos artículos científicos estudiados indicaron parámetros de mérito diversos, pocos hacen mención a la incertidumbre asociada a la medición de la señal analítica de los analitos de interés.

The production and distribution of counterfeit drugs is a critical health problem that plagues nations worldwide. The presence of counterfeit antimalarials has become especially worrying, as these drugs are most often needed by those living in nations whose resources to verify the medicine supply are lacking. Rapid analysis methods used for screening large quantities of poor quality antimalarials are critical in the battle to protect those in less developed regions of the world. Simple, cost effective analysis methods that can be used in the field must be developed so those whose governments cannot afford to maintain medicine regulatory agencies can still have faith in their medicinal supply. A very powerful screening method, Direct Analysis in Real Time Mass Spectrometry (DART-MS) has been used to investigate thousands of poor quality medicines. This method, however, is known to fragment molecules more readily than commonly used, 'softer' ionization methods, such as electrospray ionization. Excess fragmentation in 'harder' ionization sources is due to deposition of additional internal energy to the ionized molecules. This internal energy deposition can be measured, so the analyst can be knowledgeable as to what to expect when examining unknowns using this recently developed ionization source. Quantitation of the active pharmaceutical ingredient (API) in pharmaceuticals is crucial to the determination of what class a poor quality medicine fits into. Because poor quality drugs can be of different types, it is important to accurately classify them, in hopes of improving the supply of medicines available to those in less developed regions of the world. High performance liquid chromatography (HPLC) is most commonly used to quantify the active pharmaceutical ingredient in poor quality medicines, however, this method is time consuming, preventing its use in high throughput settings. During the course of my research, hundreds of poor quality pharmaceuticals were analyzed using DART-MS. The active pharmaceutical ingredient was detected during the rapid screening for many of these drugs, however, a more in depth analysis would often reveal less than the expected quantity of active ingredient. A rapid non-chromatographic quantitation method was developed using a mass spectrometer as the detector. This method allows for both quantitative and qualitative information regarding a specific sample to be obtained simultaneously, saving the analyst time and resources. Utilizing this non- chromatographic mass spectrometric method, degradation products have been identified, thus increasing our ability to classify drugs into their respective divisions.

This Thesis examines the benefits and usefulness of a National Drug Policy (NDP) for the developing of the Health Care System in Kuwait. The NDP is one of the most important structures of the Health System which can lead to improved health services by establishing guidelines, proposals and directives to organize, structure and regulate health legislation; it is of help to ensure the availability of quality, safety and efficacy in using medicines and it can reduce the irrational use of medicines. The NDP is a frame work between the government, schools and universities, media, health professionals, pharmaceutical industries and companies and public. It is cooperation between the public and private sectors to achieve the goal of access to good quality medicines for all. However there are many key factors which need to be examined before the National Drug Policy is introduced and these are considered the baseline for establishing a good policy, and includes; selection of essential drugs, affordability of drugs, drug financing, supply management, drug regulation, rational use of drugs, drugs registration, purchasing of drugs, health research and human resource development. During this research study from 2012 – 2015 several visits to the public and private health areas, were undertaken. At this time there were discussions with 121 health professionals and data was collected and this indicated that in Kuwait there are no such policies. This is despite the availability of financial means, specialized human resources and the existence of the ministerial decisions and regulations governing the health sector in both public and private, whether hospitals, health centers, pharmacies and health departments. In addition it is suggested that the process of a good NDP should be built around 3 main components which includes: 1.Development, 2. Implementation and 3. Monitoring and Evaluation. Therefore the establishing of a NDP without implementation and monitoring is not enough and does not achieve the desired results. The aim of this Thesis is to establish a NDP in the State of Kuwait. This policy is necessary for the State of Kuwait to ensure development an improvement of the Health Care System and ensure better health for population.

Submitted by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2016-09-22T19:12:48Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Willian Ricardo da Rosa de Almeida.pdf: 1728935 bytes, checksum: add5d55f493e0f08fd42042f07a7a9b7 (MD5)<br>Approved for entry into archive by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2016-09-22T19:15:44Z (GMT) No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Willian Ricardo da Rosa de Almeida.pdf: 1728935 bytes, checksum: add5d55f493e0f08fd42042f07a7a9b7 (MD5)<br>Made available in DSpace on 2016-09-22T19:15:44Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Willian Ricardo da Rosa de Almeida.pdf: 1728935 bytes, checksum: add5d55f493e0f08fd42042f07a7a9b7 (MD5) Previous issue date: 2016<br>A sildenafila é um fármaco utilizado como tratamento de primeira escolha para a disfunção erétil, sendo disponível comercialmente na forma farmacêutica de comprimidos. Atualmente, a sildenafila está entre os medicamentos mais vendidos no mercado mundial. Por esta razão, também está entre os medicamentos que mais são contrabandeados e/ou falsificados. O desenvolvimento de métodos analíticos para avaliar a qualidade de produtos farmacêuticos bem como aqueles voltados para análise de amostras forenses são de extrema importância e constituem-se como ferramentas para a disponibilização de medicamentos com qualidade garantida. Desta forma, o presente trabalho teve por objetivo desenvolver e validar um método analítico indicativo de estabilidade por UFLC para a quantificação de sildenafila em comprimidos, bem como avaliar a cinética de degradação fotolítica e a segurança biológica dos fotoprodutos de degradação obtidos. Ainda, amostras suspeitas de falsificação de comprimidos de sildenafila (cedidas pela Superintendência Regional da Polícia Federal do Rio Grande do Sul) foram avaliadas em relação aos critérios de qualidade estabelecidos em compêndios internacionais através dos testes de: (a) resistência mecânica, (b) desintegração, (c) dissolução, (d) teor, (e) perfil químico por espectrometria no infravermelho médio e (f) perfil físico (diâmetro, peso e altura). Os resultados foram avaliados utilizando ferramentas de controle estatístico de processo e análise multivariada. No desenvolvimento do método por UFLC, as seguintes condições foram estabelecidas: fase móvel acetonitrila:trietilamina pH 4,0 (60:40, v:v), fluxo 0,7 ml min-1, coluna C18 (100mm x 4,6mm x 5μm), temperatura 50°C e detecção em 290 nm. O método foi validado segundo a normativa do ICH e mostrou-se específico, linear, preciso, exato e robusto. A segurança biológica foi determinada pelos ensaios de: (a) de Azul de Tripan, (b) Teste de Micronúcleos e (c) Ensaio Cometa. O fármaco e seus produtos de fotodegradação apresentaram citotoxicidade, no entanto não foram observados mutagenicidade e genotoxicidade. Na avaliação dos comprimidos suspeitos de falsificação não foram encontrados desvios de qualidade e a análise multivariada (por Análise Hierárquica de Agrupamentos) se mostrou adequada para classificação das amostras quanto ao perfil físico.<br>Sildenafil is the first choice pharmaceutical product for erectile dysfunction treatment and commercially available in tablets dosage form. Nowadays, Sildenafil is among the largest selling pharmaceutical products in the worldwide marketing. For this reason, is also among the most falsified and/or smuggled in the world. The development of analytical techniques that aim to evaluate pharmaceutical products’ quality, as well as those that aim forensic samples, are extremely valuable, once they are resources for quality guaranteed pharmaceutical products availability. Thus, our present study aimed to develop and validate a stability-indicative analytical method by UFLC, in order to quantify Sildenafil in tablets. Photolytic degradation’s kinetics and biological safety of Sildenafil’s photoproducts were evaluated. Additionally, Sildenafil tablets that were suspect of falsification (conceded by Regional Superintendence of Federal Police), were evaluated according to quality criteria previously established by international compendiums, being them: (a) mechanical resistance, (b) disintegration, (c) dissolution, (d) assay, (e) chemical profile by infrared spectroscopy, and (f) physical profile. The results were evaluated by control-process statistical and multivariate analysis. The following conditions were established for UFLC method: acetonitrile:triethylamine (60:40, v:v) as mobile phase, flux at 0.7mL.min-1, C18 column (100mm x 4,6mm x 5μm), 50°C, pH 4.0 and 290 nm. Proposed method was validated following ICH’s guidance, and showed specificity, linearity, precision, accuracy, and robustness. Biological safety was determined by the following assays: (a) Trypan Blue, (b) Micronucleus, and (c) Comet assay. The intact molecule, as well as its photoproducts showed cytotoxicity even no mutagenicity or genotoxicity was detected. Finally, tablets (suspected of falsification) had no quality deviation and multivariate analysis (Hierarchical Component Analysis) applied in physical profile showed adequate for sample’s classification.

Falsified and substandard drugs are classified as a global problem and continue to increase as manufacturing becomes globalized and the complexity of distribution systems expands. The falsified and substandard drugs come with major health risks and socioeconomic consequences. The pharmaceutical supply chain is handled by several parties, making it harder to detect when falsified and substandard drugs end up in distribution. Since the rise of the cryptocurrency bitcoin, blockchain technology has been recognized for its transparency and security. Previous research describes blockchain as a decentralized database structure that preserves a chronological chain of blocks where each block contains a registered valid network activity verified by consensus of the participants in the network. The purpose of this study is to create a broader understanding of how blockchain can improve the transparency and traceability of the pharmaceutical supply chain in order to reduce the incidence of falsified and substandard drugs. The study is based on a qualitative method in the form of five semi-structured interviews with representatives from the pharmaceutical industry and two blockchain companies. In the study's discussion section, the literature study is set against the collected empirical material. Two tables also illustrate how the pharmaceutical industry is working with traceability and what effects blockchain can provide a supply chain. Finally, the study notes that regulations on the pharmaceutical industry primarily control which database structure is implemented on the supply chain. It is also stated that blockchain has characteristics that can improve transparency and traceability of a supply chain, but the technology is to some extent limited mainly by its large need for capacity

Thesis (Ph.D)--Chemistry and Biochemistry, Georgia Institute of Technology, 2010.<br>Committee Chair: Fernández, Facundo; Committee Member: Bottomley, Lawrence; Committee Member: Mizaikoff, Boris; Committee Member: Orlando, Thomas; Committee Member: Prausnitz, Mark. Part of the SMARTech Electronic Thesis and Dissertation Collection.

Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2016<br>Fake, fraudulent, poor quality, falsified and unregulated drugs are also commonly known as “counterfeit medicines”, which are now endemic in the global drug supply chain and represent perhaps the greater challenge for patient security, public health and global health safety. These medicines exist everywhere, from unregulated to traditional healthcare sectors, including the internet. Counterfeit medicines are growing in both geographic and therapeutic scope, leading to antimicrobial resistance, profiting organized criminal groups, and representing great threat to patient lives. (1,2) To better understand the background of this threat, a review of the literature was made considering the definition of Counterfeit Medicines, the importance of the problem in developed countries and the loopholes related to the legitimate distribution chain and the Internet. The point of view of the problem on the main victims, patients and consumers, but also on the pharmaceutical industries and on national economies has been considered. Lastly, the recent regulatory measures created to address this situation, and the partnership’s and international operation’s results were investigated to have a better perspective of this danger. The aim of this master thesis is to determine the evolution of the falsified and substandard medicines problem in Portugal in the last six years by a retrospective review of drug quality alerts and pharmaceutical industry recalls detected in medicines between 2010 and 2015. This data was collected directly from the Portuguese Regulatory Agency website. The gathered information includes the drug active principle ingredient, category and formulation, entity and date in which the alert was originated, number of medicines in each quality alert, pharmaceutical company, type of defect and action taken. Studying this data brought to the essay the next noteworthy results. There were 253 incidents involving substandard medicines and 242 involving possible falsifications. The two more recurrent defects found in defective pharmaceuticals were contamination (26%) and stability failure (20%). Formulations for parenteral use were the most frequently affected with 54% of the total drugs mentioned. In conclusion, the reporting of substandard medicines in Portugal is on the rise. There was an increase from incidents in 2010 to 2015 in over 46%. Parenteral formulations have been presented as the most reported. Due to the lack of information related to their toxicity the clinical significance of the problem is unknown, however, contaminated parenteral formulations represent a larger probability of injury to the patient. Healthcare providers and general public should know how to assess the quality of medicines and be better informed about the real counterfeit situation of medicines. For a better understanding of this problem, further studies are suggested with access to full disclosure data. It has been found that it is uncertain whether the increasing number of reports is related to the growth of the number of substandard and falsified medicines or if these results mean an improvement of the detection procedures. Additional studies could address future challenges such as the problem of regulation in a globalized world, the implications of organized crime in the problem developments, reasons for the rise of drug theft and trends for the next top falsified categories.<br>Medicamentos falsos, de contrafação, de má-qualidade, falsificados ou medicamentos não regulamentados são também conhecidos como "medicamentos contrafeitos". Estes produtos representam um dos maiores desafios atuais no âmbito da segurança do doente, da saúde pública e da própria segurança da saúde global pelo risco que representam quando inseridos na cadeia de abastecimento. Estes medicamentos são transversais a todas as áreas, desde sectores não regulamentados até aos sectores de saúde tradicionais, passando pela a Internet. Esta ameaça tem aumentado tanto em âmbito geográfico como terapêutico, levando a resistências antimicrobianas e beneficiando grupos de crime organizado representando assim uma grande ameaça para a vida de todos os cidadãos. (1,2) Para entender melhor o complexo contexto dos medicamentos contrafeitos, foi feita uma revisão da literatura, analisando as definições de Contrafação de Medicamentos, a importância do problema em países desenvolvidos e as lacunas relacionadas com a cadeia de distribuição legítima e da Internet. Foi abordado o problema do ponto de vista das principais vítimas, os doentes e os consumidores, mas também foi considerado o problema na perspectiva da indústria farmacêutica e da economia nacional. Por último, foram revistas as medidas regulatórias criadas para lidar com esta situação e os resultados das parcerias nacionais e operações internacionais de forma a contextualizar globalmente esta ameaça. O objetivo desta tese de mestrado é determinar a evolução do problema de medicamentos falsificados e medicamentos de baixa qualidade em Portugal nos últimos seis anos através de uma revisão retrospectiva de alertas de qualidade de medicamentos e produtos farmacêuticos e recolhas voluntárias da indústria, entre 2010 e 2015. Estes dados foram colhidos diretamente no site do INFARMED, I.P.. Foi recolhida informação dos alertas sobre o nome comercial e farmacológico do medicamento, classe terapêutica e formulação, entidade e a data em que o alerta foi originado, número de medicamentos em cada alerta de qualidade, empresa farmacêutica, tipo de defeito e as medidas tomadas. Depois de analisados e tratados os dados deram origem aos seguintes resultados. Houve 253 incidentes envolvendo medicamentos de qualidade deficiente e 242 envolvendo possíveis falsificações. Dentro dos produtos com parâmetros de qualidade comprometidos, os dois defeitos mais recorrentes foram contaminação (26%) e falhas nos parâmetros de estabilidade (20%). As formulações para uso parentérico foram as mais afetadas, correspondendo a 54% do número total dos incidentes avaliados. Em conclusão, a comunicação de alertas de qualidade de medicamentos em Portugal está a aumentar. Houve um aumento da frequência total de incidentes de 2010 para 2015 em mais de 46%. As formulações parentéricas têm sido apresentadas como as mais relatadas. Devido à falta de informação global relacionada com a toxicidade destes produtos, o significado clínico do problema é desconhecido, no entanto, o facto de existir uma grande expressão de formulações parentéricas contaminadas indica um maior risco de lesão ao doente. Os profissionais de saúde e o público em geral devem ser informados sobre a situação real da contrafação de medicamentos e saber como avaliar a qualidade dos medicamentos. Para uma melhor compreensão deste problema são sugeridos estudos adicionais com acesso a dados completos (incluindo critérios de farmacovigilância). Não é possível inferir por este estudo que o número crescente de relatórios está diretamente relacionado com o crescimento do número de medicamentos falsificados ou de baixa qualidade, ou se estes resultados mostram uma melhoria dos procedimentos de atuação e detecção. Estudos adicionais poderiam clarificar estas hipóteses e abordar os desafios futuros, como o problema da regulação num mundo globalizado, as implicações do crime organizado nos desenvolvimentos dos medicamentos contrafeitos, razões para o aumento do roubo de drogas e tendências para as próximas principais categorias de falsificados.

The World Health Organization estimates that about 10-30% of pharmaceuticals in the world are either substandard or counterfeit. The number is even higher in the developing countries. From a public health perspective, a key contributor to the development and proliferation drug resistant strains of infections, including tuberculosis (TB), malaria and other infections that are leading killers in resource limited settings is poor quality medicines. Most of the main causes are profit driven corruption in many pharmaceutical companies, the poor manufacture and quality control, and/or the inappropriate storage conditions. Poor quality drugs lead to loss of life, create morbidity, strain the financial structure of the health system and lead to long-term drug resistance that affects us all. The current technology for screening poor quality drugs can be divided into 2 categories: the high end, precise and high cost technologies (such as High Performance Liquid Chromatography) and lower cost and qualitative technologies (such as Thin-Layered Chromatography). The high-end methods can give a precise measurement of active pharmaceutical ingredient (API) concentration and the presence of impurities in the tablets, but require trained personnel, advanced machine and lab set up, not suitable for field testing where most of poor quality pharmaceuticals have been found. The lower cost techniques require little training and simple equipment to operate at a relatively inexpensive price, but only gives qualitative results. In addition, most of current methods do not look at the dissolution profile of the tablets simultaneously with the concentration of API. Therefore, we propose to develop an assay that can quantify the concentrations of multiple APIs simultaneously and measure dissolution rates. In order to address current gaps in knowledge, my research proposal has three main parts in the assay development: 1) Development of an fluorescent/luminescent assay for detection of counterfeit/substandard antimalarial using small-molecules-based methods and field testing in Ghana; 2) Development of a fluorescent assay for detection of water-soluble pharmaceuticals using SELEX; and 3) Design a detection platform using microfluidic chips for real time quantification of multiple active pharmaceutical ingredients. For proof-of-concept, an antimalarial drug (artesunate and amodiaquine) and antibacterial antibiotics (sulfamethoxazole and trimethoprim) are selected to demonstrate the probe development and test the chip performance. Overall, the assay will be rapid, robust, portable, inexpensive, multiplexed, quantitative, specific, and sensitive. At a big picture level, emphasizing drug quality and creating robust mechanisms of drug testing will improve health outcomes and enhance treatment efficacy in resource limited settings.

Substandard and counterfeit medicines are major obstacles to the treatment of infectious diseases. Substandard medicines vary from standard drugs in terms of dose, bioavailability, or the presence of impurities. Current methods to identify substandard and counterfeit antimicrobial drugs are either resource intensive or have poor specificity. This dissertation examined two issues related to poor quality antimicrobial medicines: 1) Methods to detect and prevent the consumption of substandard drugs. 2) The relationship between substandard medicines and the evolution of rifampicin resistance. This dissertation advanced two technologies that may aid in the detection of substandard medicines: aptamers and biosensors. Oligonucleotide aptamers may be adapted for drug detection by coupling binding events to changes in fluorescence, luminescence or colorimetric signals. A computational model was developed to discover experimental factors that increase the probability of selecting a high affinity aptamer. Among them are: micromolar drug target concentration, high affinity substrate to partition aptamers, and high aptamer library affinity distribution. Random losses of aptamers due to experimental noise greatly decreased the probability of selecting an aptamer. Experimental parameters to optimize the process of aptamer discovery for small molecules are discussed. Bacterial biosensors are an alternative strategy for the detection of active pharmaceutical ingredients. Here, luciferase-expressing Escherichia coli were used to create profiles of drug interactions for anti-mycobacterial drugs. Drug interactions were tested by the Loewe additivity model. A novel method to differentiate rifamycin drugs from the drug degradation product rifampicin quinone was developed by analyzing each drug’s unique interactions. While subinhibitory drug doses are known to select for antimicrobial resistance in vitro, the role of substandard anti-mycobacterial medicines in the development of rifampicin resistance remains poorly understood. The role of the drug degradation product rifampicin quinone on rifamycin resistance was assessed through in vitro studies of bacteria. Wild type Escherichia coli and Mycobacterium smegmatis cultured in the presence of rifampicin quinone acquired high levels of resistance to rifamycin drugs. Resistance was associated with genetic mutations in the rifampicin resistance cluster of the rpoB gene. The studies presented here demonstrate that substandard medicines can contribute towards rifamycin resistance, and offer methodologies to identify substandard medicines.<br>2020-10-24T00:00:00Z

Although the prevalence of substandard and counterfeit pharmaceutical products is a global problem, it is more critical in resource-constrained countries. The national medicines regulatory authorities (MNRA) in these countries have limited resources to cater for regular quality surveillance programmes aimed at ensuring that medicines in circulation are of acceptable quality. Among the reasons explained to hinder the implementation of these strategies is that compendial monographs are too complicated and require expensive infrastructures in terms of environment, equipment and consumables. In this study it was therefore aimed at developing simple, precise, and robust HPLC and HPTLC methods utilizing inexpensive, readily available chemicals (methanol and simple buffers) that can determine the APIs, other API than declared one, and which are capable of impurity profiling. As an outcome of this study, three isocratic and robust HPLC and two HPTLC methods for sulfadoxine, sulfalene, pyrimethamine, primaquine, artesunate, as well as amodiaquine have been developed and validated. All HPLC methods are operated using an isocratic elution mode which means they can be implemented even with a single pump HPLC system and standard C18 columns. The densitometric sulfadoxine/sulfalene and pyrimethamine method utilizes standard TLC plates as well as inexpensive, readily available and safe chemicals (toluene, methanol, and ethyl acetate), while that for artesunate and amodiaquine requires HPTLC plates as well as triethylamine and acetonitrile due to challenges associated with the analysis of amodiaquine and poorly the detectable artesunate. These HPTLC methods can be implemented as alternative to those requiring HPLC equipment e.g. in countries that already have acquired densitometer equipment. It is understood that HPTLC methods are less sensitive, precise and accurate when compared to HPLC methods, but this hindrance can easily be addressed by sending representative samples to third party quality control laboratories where the analytical results are verified using compendial HPLC methods on a regular basis. It is therefore anticipated that the implementation of these methods will not only address the problem of limited resources required for medicines quality control but also increase the number of monitored targeted antimalarial products as well as the number of resource- constrained countries participating in quality monitoring campaigns. Moreover, the experiences and skills acquired within this work will be applied to other API groups, e. g. antibiotics, afterwards<br>Trotz der weltweiten Verbreitung gefälschter Arzneimittel und solcher, die nicht die deklarierte Menge an Wirkstoff enthalten, sind vor allem Entwicklungs- und Schwellenländer von dieser Problematik betroffen. Die Arzneimittelüberwachungs- bzw. Zulassungsbehörden dieser Länder verfügen nur über eingeschränkte Möglichkeiten, die Arzneimittelqualität regelmäßig zu überwachen und somit sicherzustellen, dass die im Markt befindlichen Medikamente eine gute Qualität aufweisen. Einer der Gründe hierfür ist unter anderem, dass die in Arzneibüchern beschriebenen Methoden oftmals sehr komplex sind und eine umfassende Laborausstattung, spezielle Geräte oder teure Chemikalien benötigen. In dieser Arbeit wurden einfache, genaue und robuste flüssigchromatographische Methoden entwickelt, die lediglich günstige, überall verfügbare Chemikalien (z. B. Methanol oder einfache Puffersalze) benötigen und mit denen der Gehalt des deklarierten Arzneistoffes, Arzneistoffverwechslungen sowie das Verunreinigungsprofil bestimmt werden kann. Es konnten drei isokratische, robuste flüssigchromatographische sowie zwei dünnschichtchromatographische Methoden zur Bestimmung von Sulfadoxin, Sulfalen, Pyrimethamin, Primaquin, Artesunat sowie Amodiaquin entwickelt und validiert werden. Alle flüssigchromatographischen Methoden arbeiten isokratisch, folglich können sie auch mit sehr einfachen HPLC-Geräten mit beispielsweise nur einem Pumpenkopf genutzt werden. Zudem werden nur einfache, kommerziell erhältliche C18-Säulen benötigt. Die densitometrischen Methoden für Sulfadoxin/Sulfalen sowie Pyrimethamin benötigen standardisierte Dünnschichtchromatographie-Platten sowie günstige, überall verfügbare und wenig toxische Chemikalien wie beispielsweise Toluol, Methanol oder Ethylacetat. Für die Methode zur Bestimmung von Artesunat und Amodiaquin werden Hochleistungsdünnschichtchromatographie-Platten und Triethylamin sowie Acetonitril benötigt. Dieser Umstand ist der Tatsache geschuldet, dass Amodiaquin und Artesunat sich anderweitig nur ungenügend trennen ließen. Die dünnschichtchromatographischen Protokolle können als Alternative zur HPLC eingesetzt werden, beispielsweise überall dort, wo bereits die entsprechenden Gerätschaften vorhanden sind. Natürlich weisen dünnschichtchromatographische Methoden im Vergleich zur Flüssigchromatographie eine geringere Sensitivität, Präzision und Richtigkeit auf, dies kann jedoch dadurch umgangen werden, die entsprechenden Methoden nur zum Screening zu verwenden und die zu analysierenden Proben anderweitig, z. B. in externen Laboratorien, detailliert zu untersuchen. Dort können beispielsweise Methoden aus gängigen Arzneibüchern verwendet werden. Durch die Implementierung der neu entwickelten Methoden kann zum einen das Problem schlecht verfügbarer Chemikalien umgangen werden und gleichzeitig die Anzahl an untersuchten Arzneimitteln erhöht werden. Dies ist ein wichtiger Beitrag zur Qualitätskontrolle in Ländern mit eingeschränkten Infrastrukturen

Background: In many countries, a significant proportion of medicines traded and consumed are of poor or variable quality. Meanwhile, failures in appropriately framing and responding to the problem have led to a proliferation of public health and governance challenges. Objective: To examine the issues exacerbating the trade and consumption of medicines of poor or variable quality, as well as present locally relevant strategies. Methods: Analytic triangulation was applied to the synthesis of publicly available documents. Results: Where economic and regulatory environments are less structured, supply chain security strategies that fixate on ‘counterfeits’ often fail in limiting the prevalence of poor quality medicines. In addition to a multivariate drug quality classification chart, three quality frameworks are presented for examining appropriate policy strategies in mediating drug quality. Conclusion: These tools can assist stakeholders in determining more locally relevant and context-specific strategies, while interrogating the proposition for greater transparency vis-à-vis drug quality.

Herewith are presented the results of an investigation the statistical power of USP compendial release tests and recommended alternatives. &lt;br&gt;The U.S. drug supply chain, formerly protected by a closed distribution network, is now threatened by the legal and illegal importation of drug products. Whereas quality can never be inspected into final products, compendial release standards may represent the only valid assessment that products of dubious origin would receive. Reliable tests for content uniformity and dissolution are required to protect the safety of the supply chain. A study was designed to test the hypothesis that existing compendial tests for content uniformity and dissolution would protect the supply chain against substandard and counterfeit drugs if basic field tests failed. &lt;br&gt;Compendial tests for content uniformity and dissolution were evaluated for statistical power using simulation studies. The results revealed that the revised content uniformity test, based on tolerance analysis, was subject to an unacceptable level of consumers' risk. The Bergum method proved to be an excellent secondary standard for product assessment and is recommended as an alternative to the USP method. Simulations with the USP dissolution test revealed significant weaknesses and inconsistencies in the test structure. Theoretical models and power assessments confirmed that the coverage specification of the dissolution test was an unacceptably high 50% coverage with 50% confidence. &lt;br&gt;A Bayesian D-optimal design program was used to investigate alternative methods to improve the coverage capability of the USP dissolution test. The result of this program was the identification of two alternatives to the existing USP procedure. The first alternative is based on the addition of attribute coverage tests to stages 2 and 3 of the USP test, whereas the second alternative is based on the concept of tolerance analysis. &lt;br&gt;Validation studies confirmed that both alternatives significantly improved the statistical power of the USP dissolution test without increasing the sample size or modifying the current three-stage procedure. The attribute test is non-parametric and behaves similarly to the existing USP with improved coverage, whereas the continuous alternative is more sensitive and is consistent with the recent revisions to the content uniformity test.<br>Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences<br>Pharmaceutics<br>PhD<br>Dissertation

Orientação : João Martins<br>A panóplia de medicamentos e produtos de saúde existentes no mercado é enorme, existindo uma escolha alargada para os consumidores. Contudo, por vezes os preços são elevados; o medicamento que o consumidor quer não é legal no país onde se encontra; o consumidor, por vergonha, não se desloca a locais licenciados para comprar o medicamento que quer ou, o país ainda não tem acesso a um determinado medicamento inovador. E por estas razões o consumidor pode obter medicamentos falsificados através da cadeia ilegal de abastecimento, sendo a internet uma via provável de acesso. Contudo não é apenas na cadeia ilegal de abastecimento que se corre o risco de obter produtos falsificados. A cadeia de abastecimento legal tornou-se complexa e o controlo e fiscalização da mesma começou a ser mais difícil de realizar. Esta complexidade e o facto do sistema regulamentar não estar ainda bem implementado, levou ao aparecimento de produtos falsificados na cadeia legal. Para o controlo regulamentar deste problema, ao fim de alguns anos de debate e modificações à proposta existente, foi lançada na União Europeia a Directiva 2011/62/EU que pretende impedir a introdução de medicamentos falsificados na cadeia de abastecimento legal. A nível europeu existem iniciativas e organizações, tais como a International Medical Products Anti-Counterfeiting Taskforce(IMPACT), a Medicrime, Working Group of Enforcement Officers(WGEO), Pharmaceutical Security Institute(PSI), entre outras,cujo objectivo principal é o combate à contrafacção. São organizações e iniciativas com um grau de importância elevado devido ao trabalho que realizam. Para além destas acções as entidades reguladoras dos vários países europeus têm os Single Points of Contact (SPOCs) que permitem a troca de informação e colaboração internacional para que todos tenham acesso à mesma informação e a casos detectados. Em Portugal, o INFARMED I.P. é a Autoridade Nacional do Medicamento e Produtos de saúde e desta autoridade depende a fiscalização e controlo dos diversos intervenientes no ciclo do medicamento. Existe no INFARMED I.P. um departamento designado de Célula 3C que trabalha diariamente para o combate à contrafacção de medicamentos a nível nacional. São pontos essenciais no combate à contrafacção de medicamentos, que a Directiva seja implementada a nível nacional e que os esforços e cooperação entre os vários países perdurem para que haja uma diminuição do risco nos próximos anos.<br>The variety of drugs and health products on the market is huge and there is a wide choice for consumers. However, sometimes the prices are high, the product that the consumer wants is not legal in his country, the consumer, for shame, doesn´t buy at licensed places, or the country doesn’t have access to a particular innovative drug. And for these reasons the consumer can get counterfeit drugs through illegal supply chain, and the Internet is a likely route of access. However, it isn’t just in the illegal supply chain that the consumer can get counterfeiting products. The legal supply chain has become complex and the supervision difficult to accomplish. This complexity and the fact that the regulatory system isn’t well implemented yet, has led to the appearance of counterfeit goods in the legal chain. For the regulatory control of this problem, after several years of debate and amendments to the first proposal, was launched in the EU the 2011/62/EU Directive which aims to prevent the introduction of counterfeit medicines in the legal supply chain. In Europe exists many initiatives and organizations such as the International Medical Products Anti-Counterfeiting Taskforce (IMPACT), Medicrime, Working Group of Enforcement Officers (WGEO), Pharmaceutical Security Institute (PSI), among others, whose main objective is to combat counterfeiting. They are organizations and initiatives with a high level of importance due to their work. Beyond these actions, Drug Regulatory Authority (DRA) have the Single Points of Contact (SPOCs) that enable information exchange and international collaboration so that everyone has access to the same information and cases detected. In Portugal, INFARMED I.P is the National Authority of Medicines and Health Products, and this authority has a duty to supervision and controls the stakeholders in the product cycle. In Infarmed, a department called 3C Cell is working daily to combat counterfeit medicines nationally. Some points are essential in combating counterfeiting medicines such as the implementation of the new Directive nationally and the continuation of cooperation between countries.

Ce projet de maitrise implique le développement et l’optimisation de deux méthodes utilisant la chromatographie liquide à haute performance couplée à la spectrométrie de masse en tandem (HPLC-MS/MS). L'objectif du premier projet était de séparer le plus rapidement possible, simultanément, 71 médicaments traitant la dysfonction érectile (ED) et 11 ingrédients naturels parfois retrouvés avec ces médicaments dans les échantillons suspectés d’être adultérés ou contrefaits. L'objectif du deuxième projet était de développer une méthode de dépistage permettant l'analyse rapide simultanée de 24 cannabinoïdes synthétiques et naturels pour une grande variété d'échantillons tels que les mélanges à base de plantes, des bâtons d'encens, de sérums et de cannabis. Dans les deux projets, la séparation a été réalisée en moins de 10 min et cela en utilisant une colonne C18 à noyau solide 100 x 2,1 mm avec des particules de 2,6 µm de diamètre couplée à un système MS avec trappe ionique orbitale fonctionnant en électronébulisation positive. En raison du nombre élevé de composés dans les deux méthodes et de l’émergence de nouveaux analogues sur le marché qui pourraient être présents dans les échantillons futurs, une méthode de dépistage LC-MS/MS ciblée/non-ciblée a été développée. Pour les deux projets, les limites de détection étaient sous les ng/mL et la variation de la précision et de l’exactitude étaient inférieures de 10,5%. Le taux de recouvrement à partir des échantillons réels variait entre 92 à 111%. L’innovation des méthodes LC-MS/MS développées au cours des projets est que le spectre de masse obtenu en mode balayage lors de l'acquisition, fournit une masse exacte pour tous les composés détectés et permet l'identification des composés initialement non-ciblés, comme des nouveaux analogues. Cette innovation amène une dimension supplémentaire aux méthodes traditionnellement utilisées, en permettant une analyse à haute résolution sur la masse de composés non-ciblés.<br>This master’s project involved the development and optimization of two rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. The objective of the first project was to simultaneously separate, as rapidly as possible, 71 erectile dysfunction (ED) treatment drugs and 11 natural ingredients sometimes found alongside ED drugs present in suspected adulterated or counterfeit samples. The objective of the second project was to develop a screening method allowing rapid, simultaneous analysis of 24 synthetic and natural cannabinoids for a wide variety of samples such as herbal smoking mixtures, incense sticks, serums and Cannabis plant material. In both projects, the separations were achieved in ≤ 10 min using 2.6 µm fused-core C18 particles packed into a 100 x 2.1 mm column coupled to an LTQ Orbitrap XL mass spectrometer operated in positive electrospray mode. Because of the very high number of compounds in both methods and the knowledge that future analogues are always immerging on the market that could thus be present in samples, a targeted/untargeted LC-MS/MS screening method was developed. For both projects, detection limits were in the sub ng/mL range and intra- and inter-assay precisions were below 10.5%. Recovery from real samples ranged from 92 to 111%. The innovation of the developed LC-MS/MS methods is that the full scan event in the MS acquisition provides accurate masses for all detected species and thus allows post-analysis identification of initially untargeted compounds, i.e., the immerging analogues. This innovation adds an additional dimension to traditional MS/MS methods, allowing high mass resolution of untargeted compounds.