亚硝胺类遗传毒性杂质的监管策略及思考

如何对药品中存在致癌风险的亚硝胺类杂质进行控制,已成为企业和监管部门关注的热点。本文对亚硝胺类杂质的常见类型、来源、致癌性作用特点进行梳理,并结合EMA、FDA、ICH及我国相关遗传毒性杂质控制指导原则,对制定符合我国国情的亚硝胺类杂质的监管限度和监管工作提出建议。尽管国外已陆续出台了一系列针对药品中亚硝胺类杂质的含量限定的指南性文件,但众多亚硝胺类杂质的毒性剂量、人体暴露量尚不明确,且药物合成工艺存在差异,我国无法完全照搬欧美等国的监管方法。当前应深入研究亚硝胺类杂质的遗传毒性和致癌性,从而制定符合我国国情的监管限度值和药品中亚硝胺杂质监管策略;此外,本文从解决实际问题的角度出发,讨论如何根据已有指导原则,确定在已知毒理学数据、毒理学数据不足和短期使用药物不同情况下亚硝胺类杂质的监管限度。本文将为药物生产和杂质评价与研究和监管领域相关人员提供借鉴。     

亚硝胺类遗传毒性杂质的监管策略及思考

如何对药品中存在致癌风险的亚硝胺类杂质进行控制,已成为企业和监管部门关注的热点。本文对亚硝胺类杂质的常见类型、来源、致癌性作用特点进行梳理,并结合EMA、FDA、ICH及我国相关遗传毒性杂质控制指导原则,对制定符合我国国情的亚硝胺类杂质的监管限度和监管工作提出建议。尽管国外已陆续出台了一系列针对药品中亚硝胺类杂质的含量限定的指南性文件,但众多亚硝胺类杂质的毒性剂量、人体暴露量尚不明确,且药物合成工艺存在差异,我国无法完全照搬欧美等国的监管方法。当前应深入研究亚硝胺类杂质的遗传毒性和致癌性,从而制定符合我国国情的监管限度值和药品中亚硝胺杂质监管策略;此外,本文从解决实际问题的角度出发,讨论如何根据已有指导原则,确定在已知毒理学数据、毒理学数据不足和短期使用药物不同情况下亚硝胺类杂质的监管限度。本文将为药物生产和杂质评价与研究和监管领域相关人员提供借鉴。     

原料药国际注册中基因毒性杂质的法规解读

遗传毒素是一类极富挑战性的杂质,并已被证明即便在低浓度条件下依然具有毒性。因此美国和欧盟的药品监管机构以及人用药品注册技术要求国际协调会（ICH）都特别指定了它们在原料药和成品药中的限量。通过解析原料药在美国和欧盟注册中涉及到的关于基因毒性杂质控制的法规,为中国制药企业提供相关技术指导以推动中国药品出口事业的增长。     

基于计算毒理学的遗传毒性评价研究进展

计算毒理学是一种使用计算方法分析、模拟、可视化或预测化学品毒性的毒性评估方法,在时间、成本和动物福利方面具有明显优势。近年来,使用计算工具预测遗传毒性正受到监管机构更多的关注,ICH M7指南表明在药品监管中认可应用(Q)SAR模型预测药物杂质的Ames致突变性。本文讨论了经典的遗传毒性计算评估方法及其原理,总结目前常用的遗传毒性评价模型及模型的构建现状,回顾计算毒理学在药物杂质、纳米材料和化妆品成分的遗传毒性评价中的应用,旨在为评价遗传毒性的计算模型的构建和优化提供一定参考,进一步促进计算毒理学在国家遗传毒性监管中的应用。     

药物杂质的毒理学评价要求及进展

 药物原料或制剂中的杂质可能引起临床不良反应。杂质毒理学评价是药物研究的重要内容。ICH关于药物及制剂杂质方面指导原则规定了杂质的报告、鉴定和质控限度,含量超过质控限度的杂质应进行毒理学评价。但指导原则对于研发阶段的药物杂质和遗传毒性杂质的限度未作明确要求。EMEA对于遗传毒性杂质制定了专门的指导原则,引入了毒理学担忧阈值（TTC）的概念对遗传毒性杂质限度进行控制,遗传毒性杂质每日接触量应小于1.5 μg。FDA也推荐采用TTC原则控制遗传毒性和致癌性杂质。本文结合ICH,EMEA及美国FDA等指导原则,对药物杂质毒理学评价的要求及其进展进行了综述。     

《药物生殖毒性研究技术指导原则》与ICH S5(R2)指导原则的对比研究及实施建议

介绍国家食品药品监督管理总局药品审评中心(CDE)和人用药品注册技术要求国际协调会(ICH)对药物生殖毒性研究指导原则的内容,比较不同机构对生殖毒性非临床评价要求,包括ICH S5(R2)指导原则和国内相关领域指导原则的对应关系、我国指导原则与ICH S5(R2)的差异等内容,对ICH S5(R2)在我国实施的可行性存在的技术困难和法规方面的障碍进行了讨论,并根据CDE和ICH指导原则的差异对比情况对我国实施ICH S5(R2)给出了建议,以期为国内新药的生殖毒性评价提供借鉴。     

仿制药中遗传毒性杂质的研究进展

我国是仿制药大国,在整个化学药品市场中仿制药占比约三分之二,其质量控制尤为重要。杂质控制是药品质量控制的重要一环,仿制药在杂质控制方面不仅要关注其参比药物中存在的杂质,更应结合实际生产工艺确定可能存在的需要加以控制的杂质。近年来,行业内对于仿制药中遗传毒性杂质的关注度不断提升。本文在宏观上对遗传毒性杂质的来源、检测方法等进行总结,以期对行业内的仿制药研发分析提供参考。     

突破性治疗药物程序在药品注册体系中的作用及展望

目的：进一步完善我国突破性治疗药物程序并发挥其在药品注册体系中的作用。方法：通过梳理美国食品药品管理局(FDA)突破性治疗认定(BTD)、欧洲药品管理局(EMA)优先药物计划 (PRIME)和我国国家药品监督管理局(NMPA)突破性治疗药物程序和案例,进一步探索优化我国突破性治疗药物程序在药品注册体系中的发展方向。结果与结论：FDA、EMA和NMPA的药品注册体系中均具有突破性药物治疗程序。FDA自2012年7月实行加快程序中的突破性治疗认定,通过大量案例积累了相对完善的管理经验,EMA的PRIME专人专管的政策支持以及明确的资格申请数据要求,均具有借鉴意义。我国突破性治疗药物法规于2020年落地实施后,至今也积累了一定案例。通过对FDA、EMA和 NMPA关于BTD的法规对比,为我国突破性治疗药物程序实施提供建议。     

化学药品中杂质的基因毒性评估策略以及相关分析方法研究进展

基因毒性杂质是受到药品监管机构和制药企业重点关注和控制的对象,由于其较一般杂质具有微量水平就存在潜在致突变性和致癌性风险的特点,需要严格控制其在药物中的含量以保证药物质量与临床应用的安全性。本文从识别警示结构、文献及数据库检索、量化构效关系软件预测、体内外遗传毒性试验、依照法规和指南要求制定合理限度等方面综述了评估杂质基因毒性的研究策略,并总结了目前为了应对其含量低,稳定性较差,结构多样等特点开发的各类前处理技术及分析方法,为基因毒性杂质的研究提供参考。     

当前新药非临床安全性评价的趋势(英文)

非临床药物安全性评价为新药的研发发挥了重要作用。人用药品注册技术要求国际协调会(ICH)新药研发指南M3(R2)是非临床药物安全性评价的方向性指导文献。正确的评价策略和相关毒理学研究应该一起综合考虑,以促进新药候选物高效、及时地向前发展,从而支持临床试验计划和市场登记进展。然而,随着发展成本增加和行业的竞争,毒性预测、动物模型和法规遵从性也是新药深入研发过程中非常重要的因素。此外,ICH其他指导文献,例如ICH S6和ICH S9,也是给新药深入研发带来冲击力很大的指导文献。因此,深入理解所有这些文献的本质意义对从事新药安全评价人员来说是很重要的,增强综合使用各方面总体知识的能力将促进新药深入研发更快、更好地实施。     

Analytical control of genotoxic impurities in the pazopanib hydrochloride manufacturing process

Pharmaceutical regulatory agencies are increasingly concerned with trace-level genotoxic impurities in drug substances, requiring manufacturers to deliver innovative approaches for their analysis and control. The need to control most genotoxic impurities in the low ppm level relative to the active pharmaceutical ingredient (API), combined with the often reactive and labile nature of genotoxic impurities, poses significant analytical challenges. Therefore, sophisticated analytical methodologies are often developed to test and control genotoxic impurities in drug substances. From a quality-by-design perspective, product quality (genotoxic impurity levels in this case) should be built into the manufacturing process. This necessitates a practical analysis and control strategy derived on the premise of in-depth process understanding. General guidance on how to develop strategies for the analysis and control of genotoxic impurities is currently lacking in the pharmaceutical industry. In this work, we demonstrate practical examples for the analytical control of five genotoxic impurities in the manufacturing process of pazopanib hydrochloride, an anticancer drug currently in Phase III clinical development, which may serve as a model for the other products in development. Through detailed process understanding, we implemented an analysis and control strategy that enables the control of the five genotoxic impurities upstream in the manufacturing process at the starting materials or intermediates rather than at the final API. This allows the control limits to be set at percent levels rather than ppm levels, thereby simplifying the analytical testing and the analytical toolkits to be used in quality control laboratories.     

Analytical Method Capable of Quantifying Eight Nitrosamine Impurities from Five Different Commercially Available Metformin Formulations with Glipizide,Glibenclamide, Gliclazide,Evogliptin, and Glimepiride by Ultra High Performance Liquid Chromatography Tripple Quadrupole Mass Spectrometry

Metformin and its combinations are widely used to treat type 2 diabetes. The drugs commonly used in combination with Metformin are Glipizide, Glibenclamide, Gliclazide, Evogliptin, and Glimepiride. Combination therapy is preferred over monotherapy of Metformin in most diabetics. About eighteen pharmaceutical manufacturers have lately recalled metformin formulation batches from the U.S. market due to N-nitrosodimethylamine (NDMA) impurities based on the food and drug administration (USFDA) guideline “Control of Nitrosamine in Human Drugs.” European Medicines Agency (EMA) and Health Canada have also established guidelines for nitrosamine impurities. Nitrosamines are well-known mutagenic impurities and probable human carcinogens found in pharmaceutical formulations. Thus, global regulatory agencies require pharmaceutical and formulation manufacturers to complete risk assessments for nitrosamine impurities for patient safety. Therefore, drug manufacturers must develop analytical techniques for monitoring trace nitrosamine impurities. Quantifying nitrosamine impurities in formulations requires modern equipment like LC-MS/MS and great intellect. The present study intends to give a single pre-packaged LC-MS/MS method parameters, including liquid chromatography and triple quadrupole mass spectrometer configuration. This method could quantify eight nitrosamine impurities from five different Metformin combinations (Metformin with Glipizide, Glibenclamide, Gliclazide, Evogliptin, and Glimepiride). The atmospheric pressure chemical ionisation (APCI) was used as an ionisation source, and the mass spectrometer was set to multiple reaction monitoring (MRM) mode for all eight nitrosamine impurities. A unified pre-packaged analytical setup allows analytical chemists to develop a reliable, sensitive, robust, and precise method for quantifying eight nitrosamine impurities from five different Metformin formulations of varying manufacturers. This analytical method saves time, money, and the environment using fewer pharmaceutical chemicals.     

The use of electrocardiograms in clinical trials: a public discussion of the proposed ICH E14 regulatory guidance

This meeting, jointly sponsored by the FDA, Drug Information Association and Heart Rhythm Society, examined crucial issues on nonclinical and clinical evaluation of the potential of new drugs to prolong the QT interval of an electrocardiogram (ECG). It gathered ～ 350 attendees from pharmaceutical industry, academia, core ECG analysis laboratories, regulatory agencies (FDA, European Medicines Agency, Japanese Ministry of Health, Labour and Welfare, and Health Canada) and the International Conference on Harmonisation (ICH). Key issues discussed included the reliability of the S7B guideline strategy, design and usefulness of the ‘thorough QT/QTc study’ recommended by ICH E14 guideline, choice of 5 ms QTc prolongation as a threshold for regulatory concern, ECG reading, and statistical analysis. This report is restricted to the two main presentations dealing with the predictability of nonclinical tests for clinical outcomes – one defending the prognostic value of nonclinical tests and the other, from the FDA, which casts reservations on the predictive value of nonclinical studies. Commentary on the recent finalisation of ICH S7B and E14 guidelines are also provided.     

The use of electrocardiograms in clinical trials: a public discussion of the proposed ICH E14 regulatory guidance. April 11-12, 2005, Bethesda, MD, USA

This meeting, jointly sponsored by the FDA, Drug Information Association and Heart Rhythm Society, examined crucial issues on nonclinical and clinical evaluation of the potential of new drugs to prolong the QT interval of an electrocardiogram (ECG). It gathered approximately 350 attendees from pharmaceutical industry, academia, core ECG analysis laboratories, regulatory agencies (FDA, European Medicines Agency, Japanese Ministry of Health, Labour and Welfare, and Health Canada) and the International Conference on Harmonisation (ICH). Key issues discussed included the reliability of the S7B guideline strategy, design and usefulness of the 'thorough QT/QTc study' recommended by ICH E14 guideline, choice of 5 ms QTc prolongation as a threshold for regulatory concern, ECG reading, and statistical analysis. This report is restricted to the two main presentations dealing with the predictability of nonclinical tests for clinical outcomes--one defending the prognostic value of nonclinical tests and the other, from the FDA, which casts reservations on the predictive value of nonclinical studies. Commentary on the recent finalisation of ICH S7B and E14 guidelines are also provided.     

欧美药典及ICH元素杂质指导原则增修订历程及对中国药典的启示

目的：为2020年版《中华人民共和国药典》四部元素杂质通则及指导原则的增修订提供借鉴和参考。方法：查阅ICH Q3D及欧美药典中收载的元素杂质通则及指导原则的增修订背景,梳理它们的增修订历程。结果：欧美药典均制定了详细的ICH Q3D指导原则本地区实施策略,元素杂质通则和指导原则几经修订完善,目前已与ICH Q3D一致。结论：《中华人民共和国药典》可借鉴欧美药典实施元素杂质相关控制要求的时机及策略,结合我国国情,增订相关通则及指导原则。     

Guidelines and pharmacopoeial standards for pharmaceutical impurities: Overview and critical assessment

ICH/regional guidances and agency scrutiny provide the regulatory framework for safety assessment and control of impurities in small-molecule drug substances and drug products. We provide a critical assessment of the principal impurity guidances and, in particular, focus on deficiencies in the derivation of the threshold of toxicological concern (TTC) as applied to genotoxic impurities and the many toxicological anomalies generated by following the current guidelines on impurities. In terms of pharmacopoeial standards, we aim to highlight the fact that strictly controlling numerous impurities, especially those that are minor structural variants of the active substance, is likely to produce minimal improvements in drug safety. It is believed that, wherever possible, there is a need to simplify and rebalance the current impurity paradigm, moving away from standards derived largely from batch analytical data towards structure-based qualification thresholds and risk assessments using readily available safety data. Such changes should also lead to a minimization of in vivo testing for toxicological qualification purposes. Recent improvements in analytical techniques and performance have enabled the detection of ever smaller amounts of impurities with increased confidence. The temptation to translate this information directly to the regulatory sphere without any kind of safety evaluation should be resisted.     

Capsule review on bioanalytical method transfer: opportunities and challenges for chromatographic methods

With the globalization of drug development activities, transferring a validated bioanalytical procedure to a different site within a pharmaceutical company, or to one or multiple contract research organizations has been dramatically increased in recent years. Undeniably, bioanalytical method transfer is the needed step prior to routine sample analysis at the receiving laboratory. It is clearly stated in the 2001 US FDA Guidance on Bioanalytical Method Validation that a partial validation is needed for method transfer between laboratories. In the current EMA draft guidelines on method validation, the necessity of a method transfer is also emphasized. However, the above guidelines do not give many details on how and when a method transfer validation should be conducted. There is a need for a step-by-step deliberation on the overall strategies, procedures and even technical details for a successful bioanalytical method transfer. In this article, we review the contemporary information available in the scientific literature on method transfer and illustrate various bioanalytical method transfer scenarios using case studies. A 'flexible and fit-for-purpose' bioanalytical method transfer strategy is proposed.