Q1aR22003新原料药及新制剂稳定性研究中英文

1、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)Current Step 4 versiondated 6 February 2003This Guideline has been developed by the appr

2、opriate 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.ICH指导原则 新药物与新产品稳定性研究Q1A（R2） 2003.2.6

3、现行第4版Q1A(R2)Document HistoryFirst CodificationHistoryDateNew CodificationNovember 2005Q1Approval by the Steering Committee under Step 2 and release for public consultation.16 September 1992Q1Q1AApproval by the Steering Committee under Step 4 and recommendation for adoption to the three ICH regulator

4、y bodies.Q1 was renamed Q1A.27 October 1993Q1AQ1A(R)Approval by the Steering Committee of the first revision under Step 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

5、ICH regulatory bodies.8 November 2000Q1A(R1)Current Step 4 versionQ1A(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 Climat

6、ic Zones III and IV), and recommendation for adoption to the three ICH regulatory bodies.6 February 2003Q1A(R2)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 fro

7、m 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

8、77; 5% RH to 30°C ± 2°C/65% RH ± 5% RH in the following sections:.1 Drug Substance - Storage Conditions - General Case Drug Product - Storage Conditions - General Case Drug products packaged in semi-permeable containers3 Glossary - “Intermediate testing”下列章节中，中间放置环境

9、由30±2/60%RH±5%修正为30±2/65%RH±5%.1 原料药-放置条件-一般情况 .1 制剂-放置条件-一般情况 .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:.1 Drug Subs

10、tance - Storage Conditions - General Case.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：.1 原料药放置条件 一般情况.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

11、 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:.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

12、已包括其中：.3半渗透容器包装的制剂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 state

13、d 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 applic

14、able, 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。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 P

15、rinciples 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72.1.3.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

16、样品评价152.1.10.Statements/Labeling 说明/标签162.2.Drug Product 制剂（略）163.GLOSSARY 术语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

17、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

18、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 specif

19、ic 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 add

20、resses 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

21、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 pr

22、oducts 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.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 fa

23、ctors 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 b

24、ased 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 climat

25、ic 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 a

26、ccord 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 General概论 Information on the stability of the drug substance is an integral

27、 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。 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 val

28、idate 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.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。 Stress testing is likely

29、 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 substa

30、nce. 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 Q

31、1B.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 suita

32、ble 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

33、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。. 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 manuf

34、actured 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

35、 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。. Container Closure System包装容器 The stability studies should be conducted on the dru

36、g 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。. Specification规范 Specification, which is a list of tests, reference to analytical procedures, and proposed acceptance criteria, is

37、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 du

38、ring 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 shou

39、ld 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。. Testing Frequency检验频率 For long term studies, frequency of testing should be sufficient to establish the stabili

40、ty 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 prop

41、osed 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。 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 expec

42、tation (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，

43、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.

44、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）。 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 a

45、nd, 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

46、 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 reque

47、sted. 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

48、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） 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 secti

49、on. 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。.1 General case一般情况StudyStorage conditionMinimum time period covered by data at submissionLong term*25°C ± 2°C/60% RH ± 5% RH or0°C ± 2

50、6;C/65% RH ± 5% RH 12 monthsIntermediate*30°C ± 2°C/65% RH ± 5% RH6 monthsAccelerated40°C ± 2°C/75% RH ± 5% RH6 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%RH12月中间条件30±2/65%RH±5%RH6月加速试验40±2/75%RH±5

51、%RH6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

52、77; 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。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 sto

53、rage 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 mo

54、nths 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

55、是可以造成样品专属性不符的变化。.2 Drug substances intended for storage in a refrigerator拟冷藏的药物StudyStorage conditionMinimum time period covered by data at submissionLong term5°C ± 3°C12 monthsAccelerated25°C ± 2°C/60% RH ± 5% RH6 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±312月加速试验25&

56、#177;2/60%RH±5%RH6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, th

57、e 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。If significant change occurs within the first 3 months testing at the accelerated storage condition, a discussion should be provided to address the e

58、ffect 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 cons

59、idered 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。.3 Drug substances intended for storage in a freezer需冷冻贮藏的药物StudyStorage conditionMinimum time period covered by data at submissionLong term- 20°C ± 5°C12 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±512月For d