Mutagenic Azido Impurities in Drug Substances: A Perspective.

Contamination of drug products and substances containing impurities is a significant concern in the pharmaceutical industry because it may impact the quality and safety of medicinal products. Special attention is required when mutagenic impurities are present in pharmaceuticals, as they may pose a risk of carcinogenicity to humans. Therefore, controlling potential mutagenic impurities in active pharmaceutical ingredients to an acceptable safety limit is mandatory to ensure patient safety. As per the International Council for Harmonization (ICH) M7 (R2)3 Guideline, mutagenic impurities are those compounds or materials that induce point mutations. In 2018, the sartan class of drugs was recalled due to the presence of N-nitrosamine impurities, which are potential mutagens. In addition to the primary impurities being detected, this class of products, especially losartan, irbesartan and valsartan, have been identified as having organic azido contaminants, which are again highly reactive toward DNA, leading to an increased risk of cancer. These azido impurities form during the preparation of the tetrazole moiety via the reaction of a nitrile intermediate with sodium azide. Given that this is a newly raised issue in the pharmaceutical world, it should be noteworthy to review the related literature. Thus, this review article critically accounts for (i) the toxicity of azido impurities and the proposed mechanism of mutagenicity, (ii) the regulatory perspective, and (iii) the sources and control strategies used during the preparation of drug substances and (iv) future perspectives.

Veterans Health Administration response to 2021 recall of Philips Respironics devices: A case study.

This case study describes, for the time frame of June 2021 through August 2022, the U.S. Veterans Health Administration (VHA) organizational response to a manufacturer's recall of positive airway pressure devices used in the treatment of sleep disordered breathing. VHA estimated it could take over a year for Veterans to receive replacement devices. Veterans awaiting a replacement faced a dilemma. They could continue using the recalled devices and bear the product safety risks that led to the recall, or they could stop using them and bear the risks of untreated sleep disordered breathing. Using a program monitoring approach, we report on the processes VHA put in place to respond to the recall. Specifically, we report on the strategic, service, and operational plans associated with VHA's response to the recall for Veterans needing replacement devices. In program monitoring, the strategic plan reflects the internal process objectives for the program. The service plan articulates how the delivery of services will intersect the customer journey. The operational plan describes how the program's resources and actions must support the service delivery plan. VHA's strategic plan featured a clinician-led, as opposed to primarily legal or administrative response to the recall. The recall response team also engaged with VHA's medical ethics service to articulate an ethical framework guiding the allocation of replacement devices under conditions of scarcity. This framework proposed allocating scarce devices to Veterans according to their clinical need. The service plan invited Veterans to schedule visits with sleep providers who could assess their clinical need and counsel them accordingly. The operational plan distributed devices according to clinical need as they became available. Monitoring our program processes in real time helped VHA launch and adapt its response to a recall affecting more than 700,000 Veterans.

A robust drug recall supply chain management system using hyperledger blockchain ecosystem.

Drug recall is a critical issue for manufacturing companies, as a manufacturer might face criticism and severe business downfall due to a defective drug. A defective drug is a highly detrimental issue, as it can cost several lives. Therefore, recalling the drug becomes one of the most sensitive issues in the pharmaceutical industry. This paper presents a blockchain-enabled network that allows manufacturers to effectively monitor a drug while in the supply chain with improved security and transparency throughout the process. The study also tries to minimize the cost and time sustained by the manufacturing company to transfer the drug to the end-user by proposing forward and backward supply chain mathematical models. Specifically, the forward chain model supports drug delivery from the manufacturer to the end-user in less time with a reliable transport mode. The backward supply chain model explicitly focuses on reducing the extra time and cost incurred to the manufacturer in pursuit of recalling the defective drug. Moreover, a real-time implementation of the proposed blockchain-enabled supply chain management system using the Hyperledger Composer is done to demonstrate the transparency of the process.

Monitoring the manufacturing and quality of medicines: a fundamental task of pharmacovigilance.

The collection and assessment of individual case safety reports (ICSRs) is important to detect unknown adverse drug reactions particularly in the first decade after approval of new chemical entities. However, regulations require that these activities are routinely undertaken for all medicinal products, including older medicines such as generic medicinal products with a well-established safety profile. For the latter, the risk management plans no longer contain important risks, considered important safety concerns, on the basis that routine pharmacovigilance activity would not allow their further characterisation. Society assumes that unexpected adverse reactions causally related to pharmacological activity are very unlikely to be detected for such well-established medicines, but important risks can still occur. For these products, a change in the safety profile which is brand or source specific and usually local in nature, associated with failures with the adequate control of quality of manufacturing or distribution are important safety issues. These may be the consequence of manufacturing and pharmacovigilance quality systems that are not fully integrated over the product life cycle (e.g. inadequate control of quality defects affecting one or multiple batches; inadequate impact assessment of change/variation of manufacturing, quality control testing, storage and distribution processes; inadequate control over the distribution channels including the introduction of counterfeit or falsified products into the supply chain). Drug safety hazards caused by the above-mentioned issues have been identified with different products and formulations, from small molecules to complex molecules such as biological products extracted from animal sources, biosimilars and advanced therapy medicinal products. The various phases of the drug manufacturing and distribution of pharmaceutical products require inputs from pharmacovigilance to assess any effects of quality-related issues and to identify proportionate risk minimisation measures that often have design implications for a medicine which requires a close link between proactive vigilance and good manufacturing practice. To illustrate our argument for closer organisational integration, some examples of drug safety hazards originating from quality, manufacturing and distribution issues are discussed. PLAIN LANGUAGE SUMMARY: Monitoring the manufacturing and quality of medicines: the fundamental task of pharmacovigilance Pharmacovigilance is the science relating to the collection, detection, assessment, monitoring, and prevention of adverse reactions with pharmaceutical products. The collection and assessment of adverse reactions are particularly important in the first decade after marketing authorisation of a drug as the information gathered in this period could help, for example, to identify complications from its use which were unknown before its commercialization. However, when it comes to medicines that have been on the market for a long time there is general acceptance that their safety profile is already well-established and unknown adverse reactions unlikely to occur. Nevertheless, even older medicines, such as generic drugs, can generate new risks. For these drugs a change in the safety profile could be the result of inadequate control of their quality, manufacturing and distribution systems. To overcome such an obstacle, it is necessary to fully integrate manufacturing and pharmacovigilance quality systems in the medicine life-cycle. This could help detect safety hazards and prevent the development of new complications which may arise due to the poor quality of a drug. Pharmacovigilance activities should indeed be included in all phases of the drugs' manufacturing and distribution process, regardless of their chemical complexity to detect quality-related matters in good time and reduce the risk of safety concerns to a minimum.

El Problema de la Recogida de Productos Defectuosos en el Mercado: Enfoques Académicos y Legales / The Product Recall Problem: Academic and Legal Approaches / O Problema da Recolha de Produtos Defeitos no Mercado: Abordagens Acadêmicas e Jurídicas

Resumen Introducción: el estudio de las campañas de retiro de productos defectuosos del mercado {recalls} es un tema vigente y complejo en el contexto de la gestión de la calidad en cadenas de suministro para garantizar la seguridad y la protección de los consumidores. Objetivo: identificar los principales enfoques académicos y legales utilizados a nivel nacional e internacional para el diseño y ejecución de estrategias de retiro de productos. Materiales y métodos: se aplicó un enfoque exploratorio de la investigación, a través de una revisión de literatura y análisis bibliométrico con Vosviewer, considerando los artículos publicados en el periodo entre 1999 y 2019, en las bases de datos Taylor and Francis, EBSCO, Science Direct, Scopus, Springer Link, IEEE, Google académico y Proquest. Resultados: se evidenció un crecimiento en el número de recalls en los últimos 20 años, especialmente en la industria de juguetes (161 %), sector automotriz (140%), productos de belleza (70 %) y suministros eléctricos (64 %). Las principales metodologías para el estudio de los recalls son de naturaleza cualitativa. Conclusiones: son requeridos nuevos aportes académicos orientados al desarrollo de modelos y metodologías que permitan involucrar a todos los miembros de la cadena de suministro en el diseño y ejecución de estrategias coordinadas para disminuir los riesgos de ocurrencia de productos defectuosos o inseguros en el mercado.

Abstract Introduction: the recall study is a current and complex issue of supply chain quality management to ensure the safety and protection of consumers. Objective: identify the main national and international academic and legal approaches used to design and perform product recall strategies. Materials and Methods: an exploratory research approach was applied, through a literature review and bibliometric analysis with the Vosviewer software, by considering the articles published between 1999 and 2019 in the databases Taylor and Francis, EBSCO, Science Direct, Scopus databases, Springer Link, IEEE, Google Scholar, and Proquest. Results: there was an increase in the number of recalls in the last 20 years, especially in the toy industry (161 %), the automotive sector (140 %), beauty products (70 %) and electrical supplies (64 %). The main methodologies for studying product recalls are qualitative ones. Conclusions: new academic contributions are required for developing models and methodologies that allow all the supply chain members to be involved in designing and performing coordinated strategies to reduce the risks of defective or unsafe products in the market.

Resumo Introdução: o estudo de recolha de produtos defeitos é uma questão actual e complexa de gestão da qualidade da cadeia de abastecimento para garantir a segurança e a protecção dos consumidores. Objetivo: identificar as principais abordagens acadêmicas e jurídicas nacionais e internacionais utilizadas para conceber e executar estratégias de recolha de produtos. Materiais e métodos: foi aplicada uma abordagem de pesquisa exploratória, por meio de uma revisão da literatura e análise bibliométrica com Vosviewer, considerando os artigos publicados no período entre 1999 e 2019, nas bases de dados de Taylor e Francis, EBSCO, Science Direct, Scopus, Springer Link, IEEE, Google Scholar e Proquest. Resultados: houve um aumento no número de recalls nos últimos 20 anos, principalmente na indústria de brinquedos (161 %), no setor automotivo (140 %), produtos de beleza (70 %) e suprimentos elétricos (64 %). As principais metodologias para o estudo de recalls são de natureza qualitativa. Conclusões: são necessárias novas contribuições académicas para o desenvolvimento de modelos e metodologias que permitam a todos os membros da cadeia de fornecimento estarem envolvidos na concepção e execução de estratégias coordenadas para reduzir os riscos de produtos defeituosos ou inseguros no mercado.

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.

Lesson Learnt from Recall of Valsartan and Other Angiotensin II Receptor Blocker Drugs Containing NDMA and NDEA Impurities.

The presence of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) impurities in angiotensin II receptor blocker (ARB) drugs containing tetrazole ring has triggered worldwide product recalls. The purpose of this article is to identify the potential gap area in current pharmaceutical industry practice that might have led to the NMDA and NDEA impurities escaping the drug manufacturer's and FDA's attention. The impact of process change was not adequately assessed by the manufacturer of contaminated APIs (active pharmaceutical ingredients), and potential for generation of mutagenic or other toxic impurities was not considered. The safety and risk associated with a chemical synthetic process was also not evaluated. This is primarily due to current industry practice which focuses on controlling the impurities above reporting threshold. ICH Q3A and FDA guidance on genotoxic and carcinogenic impurities in drug substances and products need to be integrated so that the ICH Q3A decision tree (attachment 3) begins by checking whether the synthetic process has been evaluated for the potential to generate toxic impurities. The compliance with ICH Q3A limits should be carried out only after the process has been determined to be safe without the risk of generating mutagenic and carcinogenic impurities.

An investigation into online videos as a source of safety hazard reports.

INTRODUCTION: Despite the advantages of video-based product reviews relative to text-based reviews in detecting possible safety hazard issues, video-based product reviews have received no attention in prior literature. This study focuses on online video-based product reviews as possible sources to detect safety hazards. METHODS: We use two common text mining methods - sentiment and smoke words - to detect safety issues mentioned in videos on the world's most popular video sharing platform, YouTube. RESULTS: 15,402 product review videos from YouTube were identified as containing either negative sentiment or smoke words, and were carefully manually viewed to verify whether hazards were indeed mentioned. 496 true safety issues (3.2%) were found. Out of 9,453 videos that contained smoke words, 322 (3.4%) mentioned safety issues, vs. only 174 (2.9%) of the 5,949 videos with negative sentiment words. Only 1% of randomly-selected videos mentioned safety hazards. CONCLUSIONS: Comparing the number of videos with true safety issues that contain sentiment words vs. smoke words in their title or description, we show that smoke words are a more accurate predictor of safety hazards in video-based product reviews than sentiment words. This research also discovers words that are indicative of true hazards versus false positives in online video-based product reviews. Practical applications: The smoke words lists and word sub-groups generated in this paper can be used by manufacturers and consumer product safety organizations to more efficiently identify product safety issues from online videos. This project also provides realistic baselines for resource estimates for future projects that aim to discover safety issues from online videos or reviews.

Twenty-Two Years of U.S. Meat and Poultry Product Recalls: Implications for Food Safety and Food Waste.

The U.S. Department of Agriculture, Food Safety and Inspection Service maintains a recall case archive of meat and poultry product recalls from 1994 to the present. In this study, we collected all recall records from 1994 to 2015 and extracted the recall date, meat or poultry species implicated, reason for recall, recall class, and pounds of product recalled and recovered. Of a total of 1,515 records analyzed, the top three reasons for recall were contamination with Listeria, undeclared allergens, and Shiga toxin-producing Escherichia coli . Class I recalls (due to a hazard with a reasonable probability of causing adverse health consequences or death) represented 71% (1,075 of 1,515) of the total recalls. The amounts of product recalled and recovered per event were approximately lognormally distributed. The mean amount of product recalled and recovered was 6,800 and 1,000 lb (3,087 and 454 kg), respectively (standard deviation, 1.23 and 1.56 log lb, respectively). The total amount of product recalled in the 22-year evaluation period was 690 million lb (313 million kg), and the largest single recall involved 140 million lb (64 million kg) (21% of the total). In every data category subset, the largest recall represented >10% of the total product recalled in the set. The amount of product recovered was known for only 944 recalls. In 12% of those recalls (110 of 944), no product was recovered. In the remaining recalls, the median recovery was 29% of the product. The number of recalls per year was 24 to 150. Recall counts and amounts of product recalled over the 22-year evaluation period did not regularly increase by year, in contrast to the regular increase in U.S. meat and poultry production over the same time period. Overall, these data suggest that (i) meat and poultry recalls were heavily skewed toward class I recalls, suggesting recalls were focused on improving food safety, (ii) numbers of products and amounts of each product recalled were highly variable but did not increase over time, and (iii) the direct contribution of recalls to the food waste stream was associated with the largest recalls.

Recall en la industria alimentaria: una estrategia sanitaria por implementar en Colombia / Recall in the food industry: a health strategy to implement in Colombia

Resumen Las medidas sanitarias y fitosanitarias en los mercados internacionales han llevado a que la industria alimentaria cuente con alarmas técnicas durante sus procesos de comercialización; una de las estrategias utilizadas por algunos estados para regular las alarmas es el Recall. Este proceso, que consiste en el retiro de productos del mercado, previene impactos negativos en la salud de la población y en la reputación de la industria del sector alimentario ya que garantiza la inocuidad y calidad de los alimentos que llegan al consumidor. El Recall obliga a un plan de retiro en anaquel en los sitios de venta o en alguna de las fases de producción, para lo cual se debe implementar un sistema de trazabilidad que permita rastrear un producto durante toda la cadena productiva a través de una adecuada codificación. Del mismo modo, esta estrategia demanda un marco jurídico y regulatorio en cada país que requiere colaboración de la industria, el consumidor y las ligas y asociaciones de consumidores. Colombia tiene acciones de gestión de alerta sanitaria para tomar decisiones a fin de proteger la salud pública del país, pero están limitadas a dos sistemas de alerta que trabajan en coordinación con las alertas sanitarias emitidas por organismos reguladores internacionales que cuentan con un sistema propio.

Abstract Sanitary and phytosanitary measures taken by international markets have led the food industry to develop technical warnings during marketing processes. Recall is one of the strategies used by some states to regulate such warnings. This process, which involves withdrawal of products from the market, prevents negative impacts on the health of the population and the reputation of the food industry, since safety and quality of food that reaches the consumer is ensured. Recall requires a withdrawal plan from shelves at retail sites or at any of the stages of production; therefore, a tracking system must be implemented to track products throughout the entire production chain by using proper coding. Similarly, this strategy requires a legal and regulatory framework in each country and collaboration from the industry, consumers and consumer associations and leagues. Colombia has developed a management system for health warnings to make decisions in order to protect public health in the country, but they are limited to two warning systems working in coordination with the health warnings issued by international regulatory bodies with their own systems.

Halo and spillover effect illustrations for selected beneficial medical devices and drugs.

BACKGROUND: Negative news media reports regarding potential health hazards of implanted medical devices and pharmaceuticals can lead to a 'negative halo effect,' a phenomenon whereby judgments about a product or product type can be unconsciously altered even though the scientific support is tenuous. To determine how a 'negative halo effect' may impact the rates of use and/or explantation of medical products, we analyzed the occurrence of such an effect on three implanted medical devices and one drug: 1) intrauterine contraceptive devices (IUDs); 2) silicone gel-filled breast implants (SGBI); 3) metal-on-metal hip implants (MoM); and 4) the drug Tysabri. METHODS: Data on IUD use from 1965 to 2008 were gathered from the Department of Health and Human Services Vital and Health Statistics and peer-reviewed publications. Data regarding SGBI implant and explantation rates from 1989 to 2012 were obtained from the Institute of Medicine and the American Society of Plastic Surgeons. MoM implant and explantation data were extracted from the England and Wales National Joint Registry and peer-reviewed publications. Tysabri patient data were reported by Elan Corporation or Biogen Idec Inc. Data trends for all products were compared with historical recall or withdrawal events and discussed in the context of public perceptions following such events. RESULTS: We found that common factors altered public risk perceptions and patterns of continued use. First, a negative halo effect may be driven by continuing patient anxiety despite positive clinical outcomes. Second, negative reports about one product can spill over to affect the use of dissimilar products in the same category. Third, a negative halo effect on an entire category of medical devices can be sustained regardless of the scientific findings pertaining to safety. Fourth, recovery of a product's safety reputation and prevalent use may take decades in the U.S., even while these products may exhibit widespread use and good safety records in other countries. CONCLUSIONS: We conclude that the 'negative halo effect' associated with a stigma, rather than an objective risk-benefit assessment of medical products can increase negative health outcomes for patients due to reduced or inappropriate product usage.

An Empirical Study of the Volkswagen Crisis in China: Customers' Information Processing and Behavioral Intentions.

Product-harm crises usually lead to product recalls, which may cause consumers concern about the product quality and safety. This study systematically examines customers' immediate responses to the Volkswagen product recall crisis in China. Particular attention was given to customers' responses to the risk information influencing their behavioral intentions. By combining the protective action decision model and the heuristic-systematic model, we constructed a hypothetical model to explore this issue. A questionnaire survey was conducted to collect data involving 467 participants drawn from the customers of Volkswagen. We used structural equation modeling to explore the model. The results show that customers' product knowledge plays an important role in their responses to the crisis. Having more knowledge would make them perceive a lower risk, but they might need even more information, making them more likely to seek and process information, and subsequently increasing their positive behavioral intentions toward the firm (that is pro-firm behavioral intentions). Risk perception increased customers' information needs, information seeking, and information processing but decreased their pro-firm behavioral intentions. In addition to promoting information seeking, information needed to also facilitate customers' systematic processing and thus increase their behavioral intentions to take corrective action. Customers' behavioral intentions were also spurred by systematic processing, but failed to be predicted by information seeking. In summary, theoretical and practical implications and suggestions for further research are also discussed.

Drug recall: An incubus for pharmaceutical companies and most serious drug recall of history.

There has been an increasing trend in the number of prescribed and over-the-counter drug recall over the last few years. The recall is usually due to company's discovery, customer's complaint or Food and Drug Administration (FDA) observation. The process of recall involves a planned specific course of action, which addresses the depth of recall, need for public warning, and the extent of effectiveness checks for the recall. The FDA review and/or recommend changes to the firm's recall strategy, as appropriate. The critical recall information list includes the identity of the product; summary of the failure; amount of product produced in the distribution chain and direct account. Product recalls clashes thousands of companies every year affecting: sales, testing customer relationships and disrupting supply chains. Drug recall is incubus for pharmaceutical companies. It effects the reputation of the company. The reason for the recall can be divided into two categories: manufacturing affined and safety/efficacy affined. It is essential to follow all the guidelines related to drug development and manufacturing procedure so as to minimize drug recall.

Toy-related injuries among children treated in US Emergency Departments, 1990-2011.

This study investigates the epidemiology of injuries associated with toys among US children by analyzing data from the National Electronic Injury Surveillance System. During 1990-2011, an estimated 3278073 (95% confidence interval = 2762281-3793865) children <18 years old were treated in US emergency departments for toy-related injuries, averaging 149003 cases annually. The annual injury rate per 10000 children increased significantly by 39.9% from 18.88 in 1990 to 26.42 in 2011. The number and rate of injuries peaked at age 2 years; 63.4% of patients were male; and 80.3% of injuries occurred at home. Ride-on toys accounted for 34.9% of injuries and 42.5% of hospital admissions. This study is the first to comprehensively investigate toy-related injuries among children using a nationally representative data set. The increasing number and rate of toy-related injuries to children, especially those associated with ride-on toys, underscore the need for increased efforts to prevent these injuries.