Q1a(R2)-2003-新原料药及新制剂稳定性研究(中英文)

Stability Testing of New Drug Substances and Products 新原料药及新制剂稳定性研究 Q1a R2 第 1 页 共 21 页 INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED TRIPARTITE GUIDELINE STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS Q1A R2 Current Step 4 version dated 6 February 2003 This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties in accordance with the ICH Process At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union Japan and USA Stability Testing of New Drug Substances and Products 新原料药及新制剂稳定性研究 Q1a R2 第 2 页 共 21 页 ICH 指导原则 新药物与新产品稳定性研究 Q1A R2 2003 2 6 现行第 4 版 Q1A R2 Document History First Codification History Date New Codification November 2005 Q1 Approval by the Steering Committee under Step 2 and release for public consultation 16 September 1992 Q1 Q1A Approval by the Steering Committee under Step 4 and recommendation for adoption to the three ICH regulatory bodies Q1 was renamed Q1A 27 October 1993 Q1A Q1A R Approval by the Steering Committee of the first revision under Step 2 and release for public consultation 7 October 1999 Q1A R1 Q1A R Approval by the Steering Committee of the first revision under Step 4 and recommendation for adoption to the three ICH regulatory bodies 8 November 2000 Q1A R1 Current Step 4 version Q1A R2 Approval by the Steering Committee of the second revision directly under Step 4 without further public consultation to include consequences of the adoption of Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV and recommendation for adoption to the three ICH regulatory bodies 6 February 2003 Q1A R2 Stability Testing of New Drug Substances and Products 新原料药及新制剂稳定性研究 Q1a R2 第 3 页 共 21 页 Cover Note for Revision of Q1A R Stability Testing of New Drug Substances and Products 新药物与新产品稳定性研究 Q1A R 修正说明 The purpose of this note is to outline the changes made in Q1A R that result from adoption of ICH Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV These changes are 本注释的目的是概述 R1A R 的变化 这些变化是因采纳了 ICH Q1F 即 在气候带 III 和 IV 地区注册申请的稳定性研究要求 这一指导原则而产生的 内容包括 1 The intermediate storage condition has been changed from 30 C 2 C 60 RH 5 RH to 30 C 2 C 65 RH 5 RH in the following sections 2 1 7 1 Drug Substance Storage Conditions General Case 2 2 7 1 Drug Product Storage Conditions General Case 2 2 7 3 Drug products packaged in semi permeable containers 3 Glossary Intermediate testing 下列章节中 中间放置环境由 30 2 60 RH 5 修正为 30 2 65 RH 5 2 1 7 1 原料药 放置条件 一般情况 2 2 7 1 制剂 放置条件 一般情况 2 2 7 3 半渗透容器包装的制剂 3 术语 中间试验 2 30 C 2 C 65 RH 5 RH can be a suitable alternative long term storage condition to 25 C 2 C 60 RH 5 in the following sections 2 1 7 1 Drug Substance Storage Conditions General Case 2 2 7 1 Drug Product Storage Conditions General Case 在下列章节中 30 2 65 RH 5 可作为长期试验放置条件 25 2 60 RH 5 的合适替代条件 2 1 7 1 原料药 放置条件 一般情况 2 2 7 1 制剂 放置条件 一般情况 3 30 C 2 C 35 RH 5 RH has been added as a suitable alternative long term storage condition to 25 C 2 C 40 RH 5 and the corresponding example for the ratio of water loss rates has been included in the following section 2 2 7 3 Drug products packaged in semi permeable containers 在下列章节中 30 2 35 RH 5 已作为长期放置条件 5 2 40 RH 5 的合 适替代条件 相应的计算失水率比值的例子已包括其中 2 2 7 3 半渗透容器包装的制剂 Stability Testing of New Drug Substances and Products 新原料药及新制剂稳定性研究 Q1a R2 第 4 页 共 21 页 Mid stream switch of the intermediate storage condition from 30 C 2 C 60 RH 5 RH to 30 C 2 C 65 RH 5 RH can be appropriate provided that the respective storage conditions and the date of the switch are clearly documented and stated in the registration application 中间放置条件可从 30 2 60 RH 5 转为 30 2 65 RH 5 但必须清楚记录转 换前后的放置条件和转换日期并在注册申请中阐明 It is recommended that registration applications contain data from complete studies at the intermediate storage condition 30 C 2 C 65 RH 5 RH if applicable by three years after the date of publication of this revised guideline in the respective ICH tripartite region 本修正指南颁布三年内 建议向各 ICH 机关提交的注册申请内容包括中间放置条件 30 2 65 RH 5 的全部试验数据 Stability Testing of New Drug Substances and Products 新原料药及新制剂稳定性研究 Q1a R2 第 5 页 共 21 页 TABLE OF CONTENTS 目 录 1 INTRODUCTION 引言 6 1 1 Objectives of the Guideline 目的 6 1 2 Scope of the Guideline 范围 6 1 3 General Principles 通则 7 2 GUIDELINES 指导原则 7 2 1 Drug Substance 原料药 7 2 1 1 General 通则 7 2 1 2 Stress Testing 影响因素试验 7 2 1 3 Selection of Batches 批的选择 8 2 1 4 Container Closure System 包装容器 9 2 1 5 Specification 规范 9 2 1 6 Testing Frequency 检测频率 9 2 1 7 Storage Conditions 放置条件 10 2 1 8 Stability Commitment 稳定性承诺 14 2 1 9 Evaluation 样品评价 15 2 1 10 Statements Labeling 说明 标签 16 2 2 Drug Product 制剂 略 16 3 GLOSSARY 术语 17 4 REFERENCES 参考文献 略 20 Stability Testing of New Drug Substances and Products 新原料药及新制剂稳定性研究 Q1a R2 第 6 页 共 21 页 Stability Testing of New Drug Substances and Products 新原料药及新制剂稳定性研究 1 INTRODUCTION 引言 1 1 Objectives of the Guideline 目的 The following guideline is a revised version of the ICH Q1A guideline and defines the stability data package for a new drug substance or drug product that is sufficient for a registration application within the three regions of the EC Japan and the United States It does not seek necessarily to cover the testing for registration in or export to other areas of the world 本指南为 ICH Q1A 修订版 界定了向欧盟 日本 美国三大机构提交新原料药和新制剂注册申 请的稳定性数据包 无意满足向世界其他地区申报或出口药物之需 The guideline seeks to exemplify the core stability data package for new drug substances and products but leaves sufficient flexibility to encompass the variety of different practical situations that may be encountered due to specific scientific considerations and characteristics of the materials being evaluated Alternative approaches can be used when there are scientifically justifiable reasons 本指南致力于解释新原料药和新制剂稳定性数据包 鉴于所考察药物的性质和特定科研用途 针 对各种不同实际情况本指南留有充足的可变通之处 只要有正当的科学依据就可以采用这些变通 1 2 Scope of the Guideline 范围 The guideline addresses the information to be submitted in registration applications for new molecular entities and associated drug products This guideline does not currently seek to cover the information to be submitted for abbreviated or abridged applications variations clinical trial applications etc 本指南介绍了用于新化合物及其相关制剂提交注册申请的信息 目前版本不包括简化或删节申请 申请变更及临床试验申请等所需提交的信息 Specific details of the sampling and testing for particular dosage forms in their proposed container closures are not covered in this guideline 已包装制剂的取样和检测细节问题在本指南中没有涉及到 Further guidance on new dosage forms and on biotechnological biological products can be found in ICH guidelines Q1C and Q5C respectively 新剂型 生物技术产品及生物制品分别参见 ICH Q1C 和 Q5C Stability Testing of New Drug Substances and Products 新原料药及新制剂稳定性研究 Q1a R2 第 7 页 共 21 页 1 3 General Principles 通则 The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature humidity and light and to establish a re test period for the drug substance or a shelf life for the drug product and recommended storage conditions 稳定性研究的目的是考察温度 湿度和光对原料药和制剂质量的影响随时间的变化 建立原料药复验期和制剂有效期 以供储存条件作参考 The choice of test conditions defined in this guideline is based on an analysis of the effects of climatic conditions in the three regions of the EC Japan and the United States The mean kinetic temperature in any part of the world can be derived from climatic data and the world can be divided into four climatic zones I IV This guideline addresses climatic zones I and II The principle has been established that stability information generated in any one of the three regions of the EC Japan and the United States would be mutually acceptable to the other two regions provided the information is consistent with this guideline and the labeling is in accord with national regional requirements 本指南中样品储存条件的选择是在对欧盟 日本 美国气候条件进行分析的基础上 建立的 世界各地的动态温度可以从气候数据中得到 全世界可以划分为 四个 气候带 本指南选择气候带 和 原则上 如果稳定性数据与本指南一致 且标 记符合当地要求 在欧盟 日本和美国任一地区做的稳定性数据都可以在另两个地 区通用 2 GUIDELINES 指南 2 1 Drug Substance 原料药 2 1 1 General 概论 Information on the stability of the drug substance is an integral part of the systematic approach to stability evaluation 原料药稳定性信息是稳定性系统评价的一个组成部分 2 1 2 Stress Testing 影响因素试验 Stress testing of the drug substance can help identify the likely degradation products which can in turn help establish the degradation pathways and the intrinsic stability of the molecule and validate the stability indicating power of the analytical procedures used The nature of the stress testing will depend on the individual drug substance and the type of drug product involved Stability Testing of New Drug Substances and Products 新原料药及新制剂稳定性研究 Q1a R2 第 8 页 共 21 页 原料药影响因素试验可以帮助确定可能降解产物 反过来又可以帮助建立降解途径 以及分子内在稳定性 验证所用分析方法的稳定性指示能力 影响因素试验的种类 取决于所用原料药以及制剂类型 Stability Testing of New Drug Substances and Products 新原料药及新制剂稳定性研究 Q1a R2 第 9 页 共 21 页 Stress testing is likely to be carried out on a single batch of the drug substance It should include the effect of temperatures in 10 C increments e g 50 C 60 C etc above that for accelerated testing humidity e g 75 RH or greater where appropriate oxidation and photolysis on the drug substance The testing should also evaluate the susceptibility of the drug substance to hydrolysis across a wide range of pH values when in solution or suspension Photostability testing should be an integral part of stress testing The standard conditions for photostability testing are described in ICH Q1B 影响因素试验最好以原料药单批样品进行 应该包括温度 比加速试验高 10 如 50 60 等 需要时再加上湿度 如 75 RH 或更高 氧气和光照对原料药 的影响 对于溶液或混悬液 检验还应包括在一个较宽 pH 范围内对原料药水解可能 性的评价 光学稳定性试验应该是影响因素试验的一个组成部分 光学稳定性试验标 准条件见 ICH Q1B Examining degradation products under stress conditions is useful in establishing degradation pathways and developing and validating suitable analytical procedures However it may not be necessary to examine specifically for certain degradation products if it has been demonstrated that they are not formed under accelerated or long term storage conditions 影响因素试验中对样品降解产物的研究有助于建立降解途径 建立和验证可行的分 析方法 然而 如果确定影响因素试验中的降解产物在加速试验和长期实验中不会 产生 则不必特定研究这些 Results from these studies will form an integral part of the information provided to regulatory authorities 以上研究的结果应整理成文并报告给管理部门 2 1 3 Selection of Batches 批的选择 Data from formal stability studies should be provided on at least three primary batches of the drug substance The batches should be manufactured to a minimum of pilot scale by the same synthetic route as and using a method of manufacture and procedure that simulates the final process to be used for production batches The overall quality of the batches of drug substance placed on formal stability studies should be representative of the quality of the material to be made on a production scale 正式的稳定性研究数据应由至少三批原料药得出 这些批次应达到中放最低量 所 采用的合成路线应与大生产一致 制备工艺和操作流程模拟最终生产过程 用于正 式稳定性研究的原料药批次应具有代表性 产品质量可以代表最终产品 Other supporting data can be provided 其他有用数据也可以提供 Stability Testing of New Drug Substances and Products 新原料药及新制剂稳定性研究 Q1a R2 第 10 页 共 21 页 2 1 4 Container Closure System 包装容器 The stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution 用于稳定性研究的原料药应包装于与药物储存及运输相同或相似包装内 2 1 5 Specification 规范 Specification which is a list of tests reference to analytical procedures and proposed acceptance criteria is addressed in ICH Q6A and Q6B In addition specification for degradation products in a drug substance is discussed in Q3A 规格作为检验 分析方法参考 预期验收标准的一系列要求 在 ICH Q6A 中有详细 描述 关于药物降解产物规格的讨论在 Q3A 中 Stability studies should include testing of those attributes of the drug substance that are susceptible to change during storage and are likely to influence quality safety and or efficacy The testing should cover as appropriate the physical chemical biological and microbiological attributes Validated stability indicating analytical procedures should be applied Whether and to what extent replication should be performed will depend on the results from validation studies 稳定性研究应该包括对有可能造成改变药物包装的因素 以及可能影响药物质量 安全性或药效的因素的考察 检验内容应该涵盖物理 化学 生物及微生物方面 所采用的分析方法应该经过稳定性指示验证的 试验是否需要重复以及重复次数应 该取决于验证性研究结果 2 1 6 Testing Frequency 检验频率 For long term studies frequency of testing should be sufficient to establish the stability profile of the drug substance For drug substances with a proposed re test period of at least 12 months the frequency of testing at the long term storage condition should normally be every 3 months over the first year every 6 months over the second year and annually thereafter through the proposed re test period 长期稳定性研究中检验频率以能够建立原料药稳定性特征为宜 对于预设复验期至 少 12 个月的原料药 长期稳定性研究检验频率为 第 1 年每 3 个月一次 第二年每 6 个月一次 以后每年一次 Stability Testing of New Drug Substances and Products 新原料药及新制剂稳定性研究 Q1a R2 第 11 页 共 21 页 At the accelerated storage condition a minimum of three time points including the initial and final time points e g 0 3 and 6 months from a 6 month study is recommended Where an expectation based on development experience exists that results from accelerated studies are likely to approach significant change criteria increased testing should be conducted either by adding samples at the final time point or by including a fourth time point in the study design 在加速试验放置条件为期 6 个月的研究中 至少进行包括初次和末次的 3 个时间点 如 0 3 6 月 根据研发经验 预计加速试验结果可能会接近显著变化限度 则应在最后一个时间点增加样本数或在研究设计中增加第 4 个时间点 When testing at the intermediate storage condition is called for as a result of significant change at the accelerated storage condition a minimum of four time points including the initial and final time points e g 0 6 9 12 months from a 12 month study is recommended 当加速试验结果产生了显著变化 则应进行中间放置条件下的试验 建议进行为期 12 个月的研究 取样时间点包括起始和结束在内的四个时间点 如 1 6 9 12 月 2 1 7 Storage Conditions 放置条件 In general a drug substance should be evaluated under storage conditions with appropriate tolerances that test its thermal stability and if applicable its sensitivity to moisture The storage conditions and the lengths of studies chosen should be sufficient to cover storage shipment and subsequent use 通常 药物需要在储存条件下评价 测试其热稳定性 必要时也检验其对湿度的敏 感性 放置条件及考察时间的选择应考虑到储存 运输及应用的整个过程 The long term testing should cover a minimum of 12 months duration on at least three primary batches at the time of submission and should be continued for a period of time sufficient to cover the proposed re test period Additional data accumulated during the assessment period of the registration application should be submitted to the authorities if requested Data from the accelerated storage condition and if appropriate from the intermediate storage condition can be used to evaluate the effect of short term excursions outside the label storage conditions such as might occur during shipping 长期稳定性试验应届时提交至少包括三批最初样品 12 个月的数据 试验应继续进行 以达到设定的复验期 如果需要 申报期间的实验数据也应该提交审批机构 如果 可以 中间条件下的加速实验数据可以用于评价储存条件偏差对药物的影响 如运 输过程中可能发生的情况 Stability Testing of New Drug Substances and Products 新原料药及新制剂稳定性研究 Q1a R2 第 12 页 共 21 页 Long term accelerated and where appropriate intermediate storage conditions for drug substances are detailed in the sections below The general case applies if the drug substance is not specifically covered by a subsequent section Alternative storage conditions can be used if justified 长期 加速或中间放置条件下药物实验安排具体如以下部分 如果下面个部分中没 有准确包括适合该药物的情况 可以采用通常条件 经评价 试验条件可更改 2 1 7 1 General case 一般情况 Study Storage condition Minimum time period covered by data at submission Long term 25 C 2 C 60 RH 5 RH or 0 C 2 C 65 RH 5 RH 12 months Intermediate 30 C 2 C 65 RH 5 RH 6 months Accelerated 40 C 2 C 75 RH 5 RH 6 months 研究内容 放置条件 申报文件涵盖的 最少时间周期 长期实验 25 2 60 RH 5 RH 或 30 2 65 RH 5 RH 12 月 中间条件 30 2 65 RH 5 RH 6 月 加速试验 40 2 75 RH 5 RH 6 月 It is up to the applicant to decide whether long term stability studies are performed at 25 2 C 60 RH 5 RH or 30 C 2 C 65 RH 5 RH 取决于申报人所选择的长期稳定性试验是在 25 2 60 RH 5 RH 还是 30 2 65 RH 5 RH 条件下进行的 If 30 C 2 C 65 RH 5 RH is the long term condition there is no intermediate condition 如果长期稳定性试验是在 30 2 65 RH 5 RH 条件下进行的 则无需中间条件 试验 Stability Testing of New Drug Substances and Products 新原料药及新制剂稳定性研究 Q1a R2 第 13 页 共 21 页 If long term studies are conducted at 25 C 2 C 60 RH 5 RH and significant change occurs at any time during 6 months testing at the accelerated storage condition additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria Testing at the intermediate storage condition should include all tests unless otherwise justified The initial application should include a minimum of 6 months data from a 12 month study at the intermediate storage condition 如果长期稳定性试验是在 25 度 相对湿度 65 下进行 加速试验 6 个月内发生 显 著变化 则中间条件实验样品需增加针对 显著变化 的检测项目 若无修正 中间 条件实验样品的检测应包括所有项目 初步申报应包括中间条件下实验样品 12 个月 数据中的至少 6 个月数据 Significant change for a drug substance is defined as failure to meet its specification 针对原料药的 显著变化 指的是可以造成样品专属性不符的变化 2 1 7 2 Drug substances intended for storage in a refrigerator 拟冷藏的药物 Study Storage condition Minimum time period covered by data at submission Long term 5 C 3 C 12 months Accelerated 25 C 2 C 60 RH 5 RH 6 months 研究内容 放置条件 申报文件涵盖的最少时间周期 长期实验 5 3 12 月 加速试验 25 2 60 RH 5 RH 6 月 Data from refrigerated storage should be assessed according to the evaluation section of this guideline except where explicitly noted below 若非下文明确指出 冷藏储存样品实验数据应照本指导原则评价部分进行评估 If significant change occurs between 3 and 6 months testing at the accelerated storage condition the proposed re test period should be based on the real time data available at the long term storage condition 如果加速试验 3 6 个月期间发生显著变化 预设的再检测应基于长期实验实际时间 所得数据 Stability Testing of New Drug Substances and Products 新原料药及新制剂稳定性研究 Q1a R2 第 14 页 共 21 页 If significant change occurs within the first 3 months testing at the accelerated storage condition a discussion should be provided to address the effect of short term excursions outside the label storage condition e g during shipping or handling This discussion can be supported if appropriate by further testing on a single batch of the drug substance for a period shorter than 3 months but with more frequent testing than usual It is considered unnecessary to continue to test a drug substance through 6 months when a significant change has occurred within the first 3 months 如果加速试验 3 个月以内发生显著性变化 应讨论短时储存条件偏差 如运输或处 理 对药物的影响 如果条件允许 可以采用单批药物进行 3 个月之内的试验 试 验期间增加检测频率 以使佐证讨论内容 如果加速试验 3 个月以内发生显著性变 化 则认为不必继续完成 6 个月的试验 2 1 7 3 Drug substances intended for storage in a freezer 需冷冻贮藏的药物 Study Storage condition Minimum time period covered by data at submission Long term 20 C 5 C 12 months 研究内容 放置条件 申报文件涵盖的最少时间周期 长期实验 20 5 12 月 For drug substances intended for storage in a freezer the re test period should be based on the real time data obtained at the long term storage condition In the absence of an accelerated storage condition for drug substances intended to be stored in a freezer testing on a single batch at an elevated temperature e g 5 C 3 C or 25 C 2 C for an appropriate time period should be conducted to address the effect of short term excursions outside the proposed label storage condition e g during shipping or handling 需冷冻保存的药物 再检测周期应基于长期放置条件下具体时间数据 需冷冻储存 的药物若无加速实验数据 则应取一批样品在升高温度 如 5 3 或 25 2 条件下适当时间间隔内进行试验 以测试短时放置条件偏差 如运输或处理 对药 物的影响 2 1 7 4 Drug substances intended for storage below 20 C 拟 20 以下贮藏的药物 Drug substances intended for storage below 20 C should be treated on a case by case basis 需 20 以下储存的药物应视情况而定 Stability Testing of New Drug Substances and Products 新原料药及新制剂稳定性研究 Q1a R2 第 15 页 共 21 页 2 1 8 Stability Commitment 稳定性承诺 When available long term stability data on primary batches do not cover the proposed re test period granted at the time of approval a commitment should be made to continue the stability studies post approval in order to firmly establish the re test period 如果最初批次长期稳定性研究可得数据未能涵盖批准时预设的复验期 为严格建立 复验期 应在批准后做出继续进行稳定性研究的承诺 Where the submission includes long term stability data on three production batches covering the proposed re test period a post approval commitment is con