N-Nitrosamines Impurities in Pharmaceuticals the Abrupt Challenges They Bring and Approaches to Tackle the Risk

1. Download : Download high-res image (84KB)
2. Download : Download full-size image

     

Regulatory Experiences with Root Causes and Risk Factors for Nitrosamine Impurities in Pharmaceuticals

N-Nitrosamines (also referred to as nitrosamines) are a class of substances, many of which are highly potent mutagenic agents which have been classified as probable human carcinogens. Nitrosamine impurities have been a concern within the pharmaceutical industry and by regulatory authorities worldwide since June 2018, when regulators were informed of the presence of N-nitrosodimethylamine (NDMA) in the angiotensin-II receptor blocker (ARB) medicine, valsartan.  Since that time, regulatory authorities have collaborated to share information and knowledge on issues related to nitrosamines with a goal of promoting convergence on technical issues and reducing and mitigating patient exposure to harmful nitrosamine impurities in human drug products. This paper shares current scientific information from a quality perspective on risk factors and potential root causes for nitrosamine impurities, as well as recommendations for risk mitigation and control strategies.     

英国脱欧后药品医疗器械监管体制机制探究

目的:了解脱欧后英国在药品和医疗器械监管的最新进展,为开展双边贸易合作和监管科学研究提供有益参考.方法:查阅英国药品与健康产品管理局网站信息和其发布的药品医疗器械监管指南文件,搜集英国脱欧后药品医疗器械监管体制机制主要改革情况及现状,包括其机构职责、组织架构、法律依据、监管机制等.结果与结论:英国脱欧后,确立了新的中央...     

Paediatric Medicines – Regulatory Drivers,Restraints, Opportunities and Challenges

The investment in the pharmaceutical development of medicines for paediatric use represents a minority when compared to that one made for adult population. Which reasons lie behind this status quo? Which policies have been implemented to reverse such asymmetry? Is there room to new regulatory initiatives? The creation of regulations establishing the obligation to conduct paediatric trials was deemed necessary as a means of producing products of proven quality, safety and efficacy and, in addition, to set forth financial incentives for the pharmaceutical industry reduce this delay. The first regulatory initiatives were carried out by the Food and Drug Administration (FDA) at the end of the 20^th century. Later on, the European Medicines Agency (EMA) issued the Paediatric Regulation, which has boosted a closer collaboration between both regulatory agencies. Along with the implemented legislation, pharmaceutical dosage forms, more adapted to the paediatric population have emerged, increasing the availability of age-appropriate formulations. However, a case-by-case analysis is required to ensure the best therapeutic option for the specific child. This review aims at discussing the development of medicines for paediatric use from a regulatory perspective, comparing the policies adopted by the EMA and FDA, following an overview of the drivers, restraints, opportunities and challenges.     

Challenges in DNA Microarray Studies from the Regulatory Perspective

Genomic classifiers using DNA microarrays are becoming powerful tools in the medical community with the potential to revolutionize the diagnosis and treatment of disease. However, despite the tremendous interest in using these classifiers in diagnosis and the management of disease, few genomic classifiers have made it into clinical practice. Some of the major challenges for the development and validation of genomic classifiers will be discussed in this article together with some of their difficulties.     

Hormesis in Regulatory risk assessment - Science and Science Policy

This brief commentary will argue that whether hormesis is considered in regulatory risk assessment is a matter less of science than of science policy. I will first discuss the distinction between science and science policy and their roles in regulatory risk assessment. Then I will focus on factors that influence science policy, especially as it relates to the conduct of risk assessments to inform regulatory decisions, with a focus on the U.S. Environmental Protection Agency (EPA). The key questions will then be how does hormesis interact with current concepts of science and science policy for risk assessment? Finally, I look ahead to factors that may increase, or decrease, the likelihood of hormesis being incorporated into regulatory risk assessment.     

新时代药品监管科学研究与思考

本文对监管科学的发展历程和价值进行了系统阐述,并对新时代我国药品监管科学的应用进行了深入思考。探讨了监管科学的萌芽与起步、监管科学的发展与成就、监管科学的本质与特征、监管科学的作用和任务,通过对药品监管科学的战略规划以及实施方法路径的研究,提出了打造具有中医药特色的监管科学体系以及构建接轨世界的中国现代药物监管科学体系。     

监管科学的学科建设和人才培养

监管科学是被世界卫生组织和美欧日等制药强国高度重视和发展的一门前沿交叉学科,有力提升了药品创新能力和监管效能,已被美国教育部门明确认定为大门类一级学科,初步形成本科、硕士和博士层面完备的教育培养体系.为提高我国药品监管的科技化、法治化、现代化和国际化水平,2019年国家药监局启动"中国药品监管科学行动计划".明确监管科...     

Workshop Overview: Scientific and Regulatory Challenges for the Reduction, Refinement, and Replacement of Animals in Toxicity Testing

Public concern for animal welfare has been expressed throughlegislative control of animal use for experimental purposessince the first legislation was introduced in 1876 in the UnitedKingdom. Legislative control of animal use has been introducedin virtually every developed country, with major initiativesin Europe (1986) and the United States (1966 and 1985). Advancesin scientific thinking resulted in the development of the conceptof the three Rs—refinement, reduction, and replacement—byRussell and Burch in 1959. The field has expanded substantiallysince, with specialist scientific journals dedicated to alternatives,World Congresses organized to discuss the scientific and philosophicalissues, and European and U.S. validation organizations beinglaunched. Current scientific attention is focused on validationof alternative methods. The underlying scientific principlesof chemical toxicity are complicated and insufficiently understoodfor alternative methods for all toxicity endpoints of importancein protecting human health to be available. Important lessonshave been learned about how to validate methods, including theneed to have prediction models available before the validationis undertaken, the need to understand the variability of theanimal-based data which is to be used as the validation standard,and the need to have well-managed validation programs. Futureprogress will depend on the development of novel methods, whichcan now be validated through international collaborative efforts.     

A Regulatory Framework for Controlling Effluent Discharges Using Toxicity Testing in The UK

Legislation designed to regulate effluent discharges is expressed in terms of minimising the risk of harm of that discharge to the environment. Practical implementation is usually based on the control and measurement of a limited number of individual chemicals. However, this is not always effective because of the complex nature of some discharges or the lack of data for some chemicals, preventing the definition of acceptable levels in the environment. Direct Toxicity Assessment (DTA) clearly has a role in such circumstances because it avoids the need for a comprehensive chemical characterisation of effluent discharges. Several scenarios in which DTA can play a useful role in water quality management under current legislation have been identified. A 'generic' framework for the implementation of bioassays for effluent control is proposed. This provides a number of options in terms of the level of environmental protection afforded and the 'starting point' for a DTA programme (i.e. whether it is based on local measurable impacts on water quality or directed from the outset towards the risk assessment of particular discharges). A DTA programme can be developed that meets both the technical and regulatory requirements of these different scenarios. Guidance on the design of such programmes for different scenarios is provided.     

Investigation of Carcinogenic Impurities of N-Nitrosamines in Sartan Pharmaceutical Products Marketed in Brazil: Development and Validation of Method Based on High-Performance Liquid Chromatography-Tandem Mass Spectrometry

N-nitrosamines (NA) impurities have unexpectedly been found in sartan products, angiotensin II receptor antagonists that are used to control hypertension, representing an urgent concern for industry, global regulators and for the patients. In this study, an HPLC-MS/MS method was developed and validated for the quantification of six NA (N-nitrosodimethylamine, N-Nitroso-N-methyl-4-aminobutyric acid, N-Nitrosodiethylamine, N-ethyl-N-nitroso-2-propanamine, N-nitroso-diisopropylamine and N-nitroso-di-n-butylamine) in losartan, valsartan, olmesartan, irbesartan, candesartan and telmisartan products. The method was validated in terms of sensitivity, linearity, accuracy, precision, robustness and stability. The limits of quantification were 100, 31.25, 250, 33, 312.5 and 125 µg kg⁻¹ in losartan, valsartan, olmesartan, irbesartan, candesartan and telmisartan samples, respectively, which met the sensitivity requirements for the limits set by Food and Drug Administration of the United States. The standard curves showed good linearity. The recoveries ranged from 93.06 to 102.23% in losartan matrix, 83 to 85.9% in valsartan, 96.1 to 101.2% in olmesartan, 89.2 to 97.5% in irbesartan, 93.4 to 132.0% in candesartan and 62.3 to 106.2% in telmisartan matrix. The other parameters met the validation criteria, the good sensitivity and precision, high accuracy and simple and fast analysis provides a reliable method for quality control of NA in sartan pharmaceutical products. The developed method was successfully applied for the determination of N-nitrosamines in 71 sartan products marketed in Brazil.     

我国药品政府定价办法

与普通商品不同,药品是一种关系人们生命安全的特殊商品.因此,其定价一般受到政府的指导和干预,我国药品的定价即属此类.它的好处是可最大限度的保持药品市场价格的稳定,有利于普通民众的健康安全.     

The BCS,BDDCS, and Regulatory Guidances

Pharmaceutical Research -     

Nitrosamine Contamination in Pharmaceuticals: Threat,Impact, and Control

Nitrosamine-contaminated medicinal products have raised safety concerns towards the use of various drugs, not only valsartan and all tetrazole-containing angiotensin II receptor blockers, but also ranitidine, metformin, and other medicines, many of which have been recalled and prone to shortage. At any stages, from drug substance synthesis throughout each product's lifetime, these impurities may evolve if an amine reacts with a nitrosating agent coexisting under appropriate conditions. Consequently, drug regulatory authorities worldwide have established stringent guidelines on nitrosamine contamination for all drug products in the market. This review encompasses various critical elements contributing to successful control measures against current and upcoming nitrosamine issues, ranging from accumulated knowledge of their toxicity concerns and potential root causes, precise risk evaluation, as well as suitable analytical techniques with sufficient sensitivity for impurity determination. With all these tools equipped, the impact of nitrosamine contamination in pharmaceuticals should be mitigated. An evaluation aid to tackle challenges in risk identification, as well as suitable industry-friendly analytical techniques to determine nitrosamines and other mutagenic impurities, are among unmet needs that will significantly simplify the risk assessment process.     

The Science of USP 1 and 2 Dissolution: Present Challenges and Future Relevance

Since its inception, the dissolution test has come under increasing levels of scrutiny regarding its relevance, especially to the correlation of results to levels of drug in blood. The technique is discussed, limited to solid oral dosage forms, beginning with the scientific origins of the dissolution test, followed by a discussion of the roles of dissolution in product development, consistent batch manufacture (QC release), and stability testing. The ultimate role of dissolution testing, “to have the results correlated to in vivo results or in vivo in vitro correlation,” is reviewed. The recent debate on mechanical calibration versus performance testing using USP calibrator tablets is presented, followed by a discussion of variability and hydrodynamics of USP Apparatus 1 and Apparatus 2. Finally, the future of dissolution testing is discussed in terms of new initiatives in the industry such as quality by design (QbD), process analytical technology (PAT), and design of experiments (DOE).     

The International Conference on the Freeze-Drying of Pharmaceuticals and Biologicals

The stability of pharmaceuticals and biological products is a major challenge for the industry. While some preparations have adequate stability as a liquid formulation, many biological molecules must be dried in order to achieve shelf-lives compatible with a commercial product. In addition, the technology for conducting freeze-drying and sample analysis is continually improving. Researchers from all relevant areas discussed critical aspects and new developments at the conference of Freeze-Drying of Pharmaceuticals and Biologicals.     

新时期医事法学面临的挑战及机遇

本文首先分析了医事法学在学科建设中学科特点的复杂性、团队建设实力不足、复合型人才培养、学科建设所面临的挑战、机遇及学科建设的现状。其次阐述了要加强研究的力度,提高医事法学学科建设的研究水平,学科定位、复合型人才培养的解决方案。     

国外药品监管科学技术支撑体系研究及思考

药品监管科学于上世纪90年代初步完成学科构建,并受到世界卫生组织认可,世界各主要发达国家均高度重视并积极推动成为一门新兴前沿科学;是一个高度交叉融合、支撑服务监管的学科理论体系、知识体系和学术体系;核心是研发评价药品安全有效性的新技术、新工具和新方法的创新实践活动;重点是建设药品监管治理体系和治理能力现代化、科技化、法治化和国际化的系列工程。笔者通过对国外监管科学技术支撑机构和合作单位等有关情况的调研,初步厘清了当前世界监管科学技术支撑体系发展的现状和成就,并对我国药品监管科学机构的发展进行思考,提出建议。