1、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 USEICH HARMONISED TRIPARTITE GUIDELINESTABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTSQ1A(R2)C
2、urrent Step 4 versiondated 6 February 2003This 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 regu
3、latory 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 HistoryFirst CodificationHistory Date New CodificationNovember 2005Q1 Approval by the Steering Commi
4、ttee under Step 2 and release for public consultation.16 September 1992Q1Q1A Approval by the Steering Committee under Step 4 and recommendation for adoption to the three ICH regulatory bodies.Q1 was renamed Q1A.27 October 1993Q1AQ1A(R) Approval by the Steering Committee of the first revision under S
5、tep 2 and release for public consultation.7 October 1999Q1A(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 2000Q1A(R1)Current Step 4 versionQ1A(R2) Approval by the Steering Committee of the
6、 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 2003Q1A(R2)Sta
7、bility 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 “St
8、ability 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 30C 2C/60% RH 5% RH to 30C 2C/65% RH 5% RH in the follo
9、wing sections:2.1.7.1 Drug Substance - Storage Conditions - General Case2.2.7.1 Drug Product - Storage Conditions - General Case2.2.7.3 Drug products packaged in semi-permeable containers3 Glossary - “Intermediate testing”下列章节中，中间放置环境由 302/60%RH5%修正为 302/65%RH5%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-
10、 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. 30C 2C/65% RH 5% RH can be a suitable alternative long-term storage condition to 25C 2C/60% RH 5% in the following sections:2.1.7.1 Drug Substance - Storage Conditions - General Case2.2.7.1 Drug Product - Storage Conditions - General Case在下列章节中，302 /65%RH5%可作为
11、长期试验放置条件 252/60%RH5%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. 30C 2C/35% RH 5% RH has been added as a suitable alternative long-term storage condition to 25C 2C/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 p
12、roducts packaged in semi-permeable containers在下列章节中，302 /35%RH5%已作为长期放置条件 52/40%RH5%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 30C 2C/60% RH 5% RH to
13、30C 2C/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 302/60%RH5%转为 302/65%RH5%，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 conta
14、in data from complete studies at the intermediate storage condition 30C 2C/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 302/65%RH5%的全部试验数据。Stability Testing of New D
15、rug 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 61.1. Objectives of the Guideline 目的 61.2. Scope of the Guideline 范围 61.3. General Principles 通则 .72. GUIDELINES 指导原则 .72.1. Drug Substance 原料药 .72.1.1. General 通则 72.1.2. Stress Testing 影响因素试验 72.1.
16、3. Selection of Batches 批的选择 82.1.4. Container Closure System 包装容器 .92.1.5. Specification 规范 .92.1.6. Testing Frequency 检测频率 .92.1.7. Storage Conditions 放置条件 102.1.8. Stability Commitment 稳定性承诺 .142.1.9. Evaluation 样品评价 152.1.10. Statements/Labeling 说明/标签 .162.2. Drug Product 制剂（略） .163. GLOSSARY 术语
17、 174. REFERENCES 参考文献（略） 20Stability 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 guidel
18、ine 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 th
19、e 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 encount
20、ered 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
21、 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 applicat
22、ions, 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 biotechnolog
23、ical/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 qual
24、ity 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、
25、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 fro
26、m 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
27、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. G
28、UIDELINES 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 degrada
29、tion 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 produ
30、ct 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 t
31、o be carried out on a single batch of the drug substance. It should include the effect of temperatures (in 10C increments (e.g., 50C, 60C, etc.) above that for accelerated testing), humidity (e.g., 75% RH or greater) where appropriate, oxidation, and photolysis on the drug substance. The testing sho
32、uld 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
33、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 analytica
34、l 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
35、 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
36、 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 qu
37、ality 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.
38、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
39、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 s
40、hould 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 stabilit
41、y-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 F
42、requency 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 mo
43、nths 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
44、 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 ap
45、proach 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 test
46、ing 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
47、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 length
48、s 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 c
49、ontinued 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
