Pharmaceutical Industry in Uganda: A Review of the Common GMP Non-conformances during Regulatory Inspections

The prevalence of substandard medicines in Africa is high but not well documented. Low and Middle-Income Countries (LMICs) are likely to face considerable challenges with substandard medications. Africa faces inadequate drug regulatory practices, and in general, compliance with Good Manufacturing Practices (GMP) in most of the pharmaceutical industries is lacking. The majority of pharmaceutical manufacturers in developing countries are often overwhelmed by the GMP requirements and therefore are unable to operate in line with internationally acceptable standards. Non-conformances observed during regulatory inspections provide the status of the compliance to GMP requirements. The study aimed to identify the GMP non-conformances during regulatory inspections and gaps in the production of pharmaceuticals locally manufactured in Uganda by review of the available 50 GMP reports of 21 local pharmaceutical companies in Uganda from 2016. The binary logistic generalized estimating equations (GEE) model was applied to estimate the association between odds of a company failing to comply with the GMP requirements and non-conformances under each GMP inspection parameter. Analysis using dummy estimation to linear regression included determination of the relationship that existed between the selected variables (GMP inspection parameters) and the production capacity of the local pharmaceutical industry. Oral liquids, external liquid preparations, powders, creams, and ointments were the main categories of products manufactured locally. The results indicated that 86% of the non-conformances were major, 11% were minor, and 3% critical. The majority of the non-conformances were related to production (30.1%), documentation (24.5%), and quality control (17.6%). Regression results indicated that for every non-conformance under premises, equipment, and utilities, there was a 7-fold likelihood of the manufacturer failing to comply with the GMP standards (aOR=6.81, P=0.001). The results showed that major non-conformances were significantly higher in industries of small scale (B=6.77, P=0.02) and medium scale (B=8.40, P=0.04), as compared to those of large scale. This study highlights the failures in quality assurance systems and stagnated GMP improvements in these industries that need to be addressed by the manufacturers with support from the regulator. The addition of risk assessment to critical production and quality control operations and establishment of appropriate corrective and preventive actions as part of quality management systems are required to ensure that quality pharmaceuticals are manufactured locally.

Falsified and Substandard Medicines in Developing Countries: Seeking for The Sampling Procedure to Find them

Falsified and substandard medicines is a very important issue, especially in developing countries including Indonesia. World Health Organization (WHO) stated that 1 in 10 medicines in developing countries are substandard or falsified. It is result in risks for patients and health systems relating to ineffective drugs, prolong treatment times, possible side effects, increased healthcare spending, even the risk of serious illness and death. There are many factors responsible for this situation, namely the effectiveness of government control, public drug procurement policies, market and economic competition, the depletion of entry barriers driven by free and online trade, availability of raw materials, and mastery of technology on pharmaceuticals. The problem is how to find falsified and substandard medicines amidst so many kinds of medicines in market. If the sampling is done randomly on all types of medicines in all market, it will be less likely to find them. In addition, this kind of sampling technique will be expensive because it requires a lot of resources. Therefore, a risk-based systematic mechanism is needed to guide sampling procedure. This research was aimed to design a model that could be used as a reference. Using the system thinking method, we mapped out relationships between various factors and phenomena surrounding the issue. Then, the system dynamics modelling was developed with a focus on sentinel groups that were most at risk of drug counterfeiting cases. All relevant variables were discussed, and some recommendations were provided in this paper. We hope, using this recommendation, the sampling procedure becomes faster, more efficient, and more likely to find cases. It is because the more effective the way to control falsified and substandard medicines, the higher the protection that consumers or patients may get.

CandyCodes: Simple universally unique edible identifiers for confirming the authenticity of pharmaceuticals

Counterfeit or substandard medicines adversely affect the health of millions of people and cost an estimated $200 billion USD annually. Their burden is greatest in developing countries, where the World Health Organization estimates that one in ten medical products are fake. In this work, I describe a simple addition to the existing drug manufacturing process that imparts an edible universally unique physical identifier to each pill, tablet, capsule, caplet, etc. This technique uses nonpareils (also called sprinkles and “hundreds and thousands”), tiny inexpensive multicolor candy spheres that are normally added to other candies or desserts as decorations. If nonpareils are applied at random to a pill immediately after manufacture, the specific pattern they form is unlikely to ever be repeated by random chance; this means that the pattern (or “CandyCode”) can be used to uniquely identify the pill and distinguish it from all other pills. By taking a photograph of each CandyCoded pill after manufacture and recording the location and color of each nonpareil, a manufacturer can construct a database containing the CandyCodes of all known-authentic pills they produce. A consumer can then simply use a cellphone to photograph a pill and transfer its image to the manufacturer’s server, which determines whether the pill’s CandyCode matches a known-good CandyCode in their database (meaning that the pill is authentic) or does not have a match in the database (in which case the consumer is warned that the pill may be counterfeit and should not be consumed). To demonstrate the feasibility of using random particles as universal identifiers, I performed a series of experiments using both real CandyCodes (on commercially produced chocolate candies) and simulated CandyCodes (generated by software). I also developed a simple method for converting a CandyCode photo to a set of strings for convenient storage and retrieval in a database. Even after subjecting CandyCodes to rough handling to simulate shipping conditions, the CandyCodes were still easily verifiable using a cellphone camera. A manufacturer could produce at least 1017 CandyCoded pills—41 million for each person on Earth—and still be able to uniquely identify each CandyCode. By providing universally-unique IDs that are easy to manufacture but hard to counterfeit, require no alteration of the existing drug formation and minimal alteration of the manufacturing process, and need only a cameraphone for verification, CandyCodes could play an important role in the fight against fraud in pharmaceuticals and many other products.

Criminal liability for illegal production and circulation of medicines, medical devices and dietary supplements: issues of legislative technique and law enforcement

The article is devoted to the criminal law means of countering the illegal production and circulation of medicines, medical devices and dietary supplements. The importance of the pharmaceutical industry has increased in the face of the global pandemic of the novel coronavirus infection (COVID-19), and the demand for medicines has led to an increase in the turnover of counterfeit medicines and medical devices. Among the criminal law means that prevent the appearance of counterfeit and substandard medicines on the market, a special place is occupied by criminal repression, the possibilities of which have significantly expanded in recent years. So in 2014, the Criminal Code of the Russian Federation was supplemented with three articles providing for liability for the illegal production and circulation of counterfeit, substandard medicines and Сетевой научно-практический журнал частного и публичного права 97 Стратегическая роль фармацевтического производства определяется не только экономической привлекательностью выпускаемого продукта, спрос на который ежегодно растет в связи увеличением численности населения, повышением продолжительности жизни, популяризацией здорового образа жизни, но и его ведущей ролью при реализации мер, направленных на повышение рождаемости, сдерживание заболеваемости и снижение смертности. Ключевое значение фармацевтической отрасли стало заметным в условиях мировой пандемии COVID-19, вызываемой коронавирусом SARS-CoV-2. Слабый рост реальных доходов населения ориентирует потребителя на поиск более бюджетных лекарственных препаратов, снижая требовательность к их качеству. При этом подстегиваемый коронавирусной паникой растущий спрос на лекарственные средства и ослабление государственного контроля за фармрынком в форме разрешения онлайн-продаж безрецептурных препаратов через интернет-аптеки определяют увеличение оборота фальсифицированных лекарственных средств и медицинский изделий. Отмечая расширение нелегального рынка медицинских препаратов, который по масштабам сопоставим с оборотом наркотиков, представители уголовно-правовой науки обращают внимание на то, что в отличие от наркоторговли потребителем некачественного лекарства может стать любой, независимо от социального статуса и уровня доходов1 . При этом повышенная общественная опасность криминального оборота лекарственных препаратов определяется не только экономическими потерями государства, легальных производителей (которые несут и репутационный урон), потребителей, но и реальной угрозой не только здоровью, но и жизни человека (а с учетом масштабов и распространения – населения), поскольку применение подделок может не только стать непосредственной причиной наносимого вреда, но и повлечь нарушение схемы лечения, что особенно критично в случаях использования пациентами жизненно необходимых препаратов2. Среди средств, препятствующих появлению на рынке фальсифицированных и недоброкачественных медикаментов, особое место занимает уголовная репрессия, возможности которой в последние годы заметно увеличились. Так, Федеральным законом от 31.12.2014 № 532-ФЗ «О внесении изменений в отдельные законодательные акты Российской Федерации в части противодействия обороту фальсифицированных, контрафактных, недоброкачественных и незарегистрированных лекарственных средств, медицинских изделий и фальсифицированных биологически активных добавок»3 УК РФ был дополнен тремя статьями, предусматривающими ответственность за незаконное производство лекарственных средств и медицинских изделий (ст. 235.1 УК РФ), обращение фальсифицированных, недоброкачественных и незарегистрированных лекарственных средств, медицинских изделий и оборот фальсифицированных биологически активных добавок (ст. 238.1 УК РФ) и подделку документов на лекарственные средства или медицинские изделия или упаковки лекарственных средств или медицинских изделий (ст. 327.2 УК РФ). До этого момента виновных в производстве недоброкачественных и фальсифицированных лекарств привлекали к ответственности по ст. 238 УК РФ «Производство, хранение, перевозка или сбыт товаров, не отвечающих требованиям безопасности», при этом подавляющее большинство уголовных дел прекращалось по нереабилитирующим основаниям, так как деяния, предусмотренные ч. 1 ст. 238 УК РФ, являются преступлениями небольшой medical devices, forgery of documents for medicines or medical devices (Articles 235.1, 238.1, 327.2 of the Criminal Code of the Russian Federation). The implementation of the new norms in practice posed the questions of not only differentiating the relevant acts from related and competing acts, but also defining the key features of the offenses for law enforcement officials. The article indicates certain provisions that require permission at the legislative level and clarifications of the Plenum of the Supreme Court of the Russian Federation.

Comparative Quality Evaluation of Selected Brands of Cefuroxime Axetil Tablets Marketed in the Greater Accra Region of Ghana

The ever-growing commercialization of poor-quality and substandard medicines, especially anti-infectives characterized by inadequate postmarket surveillance by stakeholders remains a major global health challenge, particularly in developing countries, where antibiotic drug resistance and its repercussions on human health remain dominant. This research sought to evaluate the pharmaceutical quality of six randomly selected brands of cefuroxime axetil tablets (250 mg) marketed in the Greater Accra region of Ghana. The selected brands were coded and subjected to both compendial and noncompendial tests. Statistical analysis and model-independent parameter (similarity factor, f2) were employed in analyzing the dissolution profiles of all the brands. All brands including the reference brand conformed to the pharmacopeial specifications for both compendial and noncompendial tests, indicating that they were of good quality. However, there were significant variations ( p < 0.05 ) in the disintegration time amongst the various brands. All the brands had ƒ2 values > 50 indicating similarity of their drug release profiles with the innovator. Hence, all the sampled cefuroxime axetil brands can be considered as pharmaceutical equivalents to the innovator drug. These brands can, therefore, be used as a substitute for the innovator drug by physicians to patients in cases of unaffordability or unavailability of the innovator brand.

Quality and Authenticity of Metformin Tablets Circulating on Japanese Websites

Background Low-quality medicines and falsified medicines represent long-standing problems in developing countries. In Southeast Asia, the circulation of low-quality diabetes drugs (metformin) has been confirmed. It is possible that low-quality metformin has entered Japan via personal import through the Internet. This study evaluated the pharmaceutical quality and authenticity of metformin tablets obtained via the Internet in Japan. Methods In total, 33 samples of 500-mg metformin tablets and 7 samples of extended-release/sustained-release tablets (500, 750, and 1,000 mg) were purchased via personal import in January 2017. Confirmation of a prescription was never requested purchase. The obtained samples were subjected to visual observations and authenticity investigations. Additionally, quantitative analysis, content uniformity and dissolution tests were performed using HPLC–PDA. Results Our authenticity investigations revealed that seven samples were genuine products, whereas the authenticity of the remaining 33 samples was unclear. Referring to United States Pharmacopeia 2014 for validation, four samples failed quality testing, five samples failed content uniformity testing, and two samples failed dissolution testing. Conclusions Our findings illustrate that metformin tablets of poor-quantity and unregistered/unlicensed doses are available online and that it is important to increase consumer awareness about the presence of these medicines on the Internet to prevent the purchase of substandard medicines.

Counterfeit/Fake and Substandard Medicines – A Global Bioethical Issue Requiring A Global Approach

Counterfeit drugs are a global problem and a public health hazard. Nearly 10 percent of all medicines sold worldwide are fake, leading to an estimated 100,000 deaths each year, equating to an additional economic burden of close to $200 billion annually. Counterfeit medicines also thwart public health efforts to control infectious diseases like Covid-19 and Tuberculosis and lead to the worsening of other public health crises such as anti-microbial resistance (AMR). According to the CDC, more than 2.8 million antibiotic-resistant infections in the U.S each year, with more than 35,000 people dying, have been reported. Globalization and the internet's expansion have led to the rapid spreading of poor-quality medicines due to the high demand for cheap goods and lack of access - before adequate detection and intervention are possible. Moreover, selling counterfeit medicine is more profitable with lesser penalties, even in the U.S. As a clandestine market, there is no precise magnitude of how the counterfeit-medicine market flows. The WHO is alarmed by the lack of available data to demonstrate the extent and impact of fake/substandard medicines. Controlling counterfeit drugs' availability will not be easy; however, it has become necessary to protect public and global health. Through the lens of a case in Bangladesh that demonstrates how easy it is to sell and get away with selling fake medicines in developing countries - this paper discusses how counterfeit medicines negatively contribute significantly to human lives and sufferings in developing and developed countries. No single policy will be effective based on the different issues faced on multiple fronts due to fake/substandard medicines. However, a broad-based concerted effort across the various stakeholders to combat this counterfeit drug problem and secure the global supply chain is urgently needed.

From the laboratory to the end-user: a primary packaging study for microneedle patches containing amoxicillin sodium

As microneedle (MN) patches progress towards commercialisation, there is a need to address issues surrounding their translation from the laboratory to the end-user. One important aspect of MN patches moving forward is appropriate primary packaging. This research focuses on MN patches containing amoxicillin (AMX) sodium for the potential treatment of neonatal sepsis in hot and humid countries. A MN patch consists of a hydrogel-forming MN array and a drug-containing reservoir. Improper primary packaging in hot and humid countries may result in degradation of active pharmaceutical ingredients, with the use of substandard medicines a major health concern. The research presented here, for the first time, seeks to investigate the integrity of MN patches in different primary packaging when stored under accelerated storage conditions, according to international guidelines. At pre-defined intervals, the performance of the MN patch was investigated. Major causes of drug instability are moisture and temperature. To avoid unnecessary degradation, suitable primary packaging was sought. After 168 days, the percentage of AMX sodium recovered from drug-containing reservoirs packaged in Protect™ 470 foil was 103.51 ± 7.03%. However, packaged in poly(ester) foil, the AMX sodium content decreased significantly (p = 0.0286), which is likely due to the degradation of AMX sodium by the imbibed moisture. Therefore, convincing evidence was provided as to the importance of investigating the stability of MN patches in primary packaging intended for MN-mediated transdermal delivery so that they are ‘fit for purpose’ when it reaches the end-user. Future work will include qualitative studies to assess MN patch usability. Graphical abstract

Quality of oxytocin and misoprostol in health facilities of Rwanda

Sustainable Development Goal 3.1 calls for a reduction of the maternal mortality ratio to less than 70 per 100,000 live births by 2030. The most important cause of maternal mortality is post-partum haemorrhage (PPH). Oxytocin injections and misoprostol tablets are medicines of first choice for the management of PPH in low- and middle-income countries (LMICs). Unfortunately, both substances are chemically unstable, and previous studies have revealed serious quality problems of these medicines in LMICs. The present study is the first report on their quality in Rwanda. From 40 randomly selected health facilities (hospitals, health centers, retail pharmacies and private clinics) in different parts of Rwanda, as well as from six wholesalers and government stores, oxytocin injections and misoprostol tablets were collected. Oxytocin storage temperatures in the health facilities were monitored for six months using temperature data loggers, and found to correctly follow the storage requirements stated by the manufacturers (2–8°C, or room temperature) with few minor deviations. Oxytocin injections (57 samples, representing seven batches of four brands) were tested for their oxytocin content and pH value according to the United States Pharmacopeia. Twenty-four samples from three European manufacturers passed all tests. However, all nine samples of one batch of a Chinese manufacturer showed an excessive content of oxytocin (range 117.2–121.5% of the declared amount). Another batch of the same manufacturer showed extreme variations of the concentration of the preservative benzyl alcohol. Misoprostol tablets (25 samples, representing ten batches of six brands) were tested for content and dissolution according to the International Pharmacopoeia. Fifteen samples passed, but all 10 samples of two brands from India failed with extreme deviations, containing only 42.5–48.7% of the stated amount of misoprostol. In conclusion, oxytocin quality in Rwanda was better than reported from other African countries. However, two extremely substandard brands of misoprostol tablets were found. The Rwandan authorities reacted quickly and efficiently, and recalled these substandard medicines from the market. For oxytocin and misoprostol, with their well-known problems of quality and stability, procurement should possibly be restricted to medicines which are WHO-prequalified or which have been manufactured in countries with stringent regulatory authorities.

Medicine quality in high-income countries: The obstacles to comparative prevalence studies

The entry of falsified and substandard medicines into the legitimate pharmaceutical supply chain has negative impacts on healthcare systems, patient safety, and patient access to medicine. The COVID-19 pandemic has highlighted the importance of access to safe medicine through legitimate pharmaceutical supply chains and the willingness of criminals to target medical products such as PPE (personal protective equipment) and COVID-19 treatments. In this article, we analyse data from the United Kingdom (UK) national medicine alert and recall database to identify and understand recent cases of substandard and falsified medicine in the UK’s healthcare systems. Using the UK as a case study, we describe that national drug alert and recall data are useful in their current form to record and understand cases of substandard and falsified medicines in the supply chain. However, if regulatory agencies published further data, these drug recall databases may be useful to support longitudinal and international comparative medicine quality studies. We suggest that regulatory agencies publish the number of affected medicine packs in each recalled batch, as part of the recall process. This will help policy makers, practitioners, and researchers to better understand, monitor and compare the quality of medicines within legitimate supply chains.