INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE
人用药品注册技术要求国际协调会
ICH HARMONISED TRIPARTITE GUIDELINE
ICH三方协调指导原则
STABILITY TESTING OF
NEW DRUG SUBSTANCES AND PRODUCTS
Q1A(R2)
新原料药和制剂的稳定性试验
Current Step 4 version
dated 6 February 2003
在2003.02.06由ICH指导委员会推荐进入ICH进程第四阶段
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.
根据ICH进程,本指导原则由相应的ICH专家工作组提出,并交给管理当局征询过意见。在ICH第四阶段,最后的草案被推荐给欧盟、日本和美国当局采纳。
Q1A(R2)
Document History
文件修订历史
COVER NOTE FOR REVISION OF Q1A(R)
STABILITY TESTING OF
NEW DRUG SUBSTANCES AND PRODUCTS
新原料药与制剂的稳定性试验
Q1A(R)修订本的注释
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Q1A(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℃±2℃/60%RH±5%RH to 30℃ ±2℃/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”
1.下列章节中,中间放置条件由30℃±2℃/60%RH±5%变为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 储藏在半渗透包装容器中的制剂
★ 3 术语-“中间试验”
2. 30℃±2℃/65%RH±5%RH can be a suitable alternative long-term storage condition to 25℃ ±2℃/60%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.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%RH的合适替代条件
★ 2.1.7.1 原料药-储存条件-一般情况
★ 2.2.7.1 制剂-储存条件-一般情况
3. 30℃±2℃/35%RH±5%RH has been added as a suitable alternative long-term storage condition to 25℃±2℃/40%RH±5%RH 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
3. 下列章节中,30℃±2℃/35%RH±5%已作为长期试验放置条件25℃±2℃/40%RH±5%的合适替换条件,其相应的计算失水率比值的例子已包括其中:
★ 2.2.7.3 包装在半渗透包装容器中的制剂
Mid-stream switch of the intermediate storage condition from 30℃±2℃/60%RH±5%RH to 30℃±2℃/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%切换为30℃±2℃/65%RH±5%,但必须清楚记录切换前后的放置条件和切换日期,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℃±2℃/65%RH±5%RH, if applicable, by three years after the date of publication of this revised guideline in the respective ICH tripartite region.
在本次修订的指导原则出版三年后,建议在ICH三地区注册申请中包括中间放置条件30℃±2℃/65%RH±5%试验的全部数据。
STABILITY TESTING OF
NEW DRUG SUBSTANCES AND PRODUCTS
新原料药和制剂的稳定性试验
ICH Harmonised Tripartite Guideline
ICH三方协调指导原则
First Recommended for Adoption at Step 4 of the ICH Process on 27 October 1993.
Revised under Step 2 of the ICH Process on 7 October 1999 and Recommended for
Adoption at Step 4 of the ICH Process on 8 November 2000.
This guideline has been Revised a second time and has reached Step 4 of the ICH
Process at the ICH Steering Committee meeting on 6 February 2003. It is
recommended for adoption to the three regulatory parties to ICH
1993.10.27 被首次推荐进入ICH进程第四阶段。
1999.10.07于ICH进程第二阶段被修订,并于2000.11.08进入ICH进程第四阶段被推荐使用。
2003.02.06在ICH指导委员会会议上,本指导原则被进行第二次修订,并进入第四阶段,推荐给ICH三方管理当局采纳。
TABLE OF CONTENTS
1. INTRODUCTION.....................................................................................................1
1.1. Objectives of the Guideline........................................................................................1
1.2. Scope of the Guideline................................................................................................1
1.3. General Principles......................................................................................................1
2. GUIDELINES .......................................................................................................1
2.1. Drug Substance .......................................................................................................1
2.1.1. General .......................................................................................................1
2.1.2. Stress Testing.................................................................................................1
2.1.3. Selection of Batches........................................................................................2
2.1.4. Container Closure System.............................................................................2
2.1.5. Specification....................................................................................................2
2.1.6. Testing Frequency..........................................................................................3
2.1.7. Storage Conditions.........................................................................................3
2.1.8. Stability Commitment....................................................................................5
2.1.9. Evaluation .......................................................................................................5
2.1.10. Statements/Labeling......................................................................................6
2.2. Drug Product .......................................................................................................6
2.2.1. General .......................................................................................................6
2.2.2. Photostability Testing.....................................................................................6
2.2.3. Selection of Batches........................................................................................6
2.2.4. Container Closure System..............................................................................7
2.2.5. Specification.....................................................................................................7
2.2.6. Testing Frequency...........................................................................................7
2.2.7. Storage Conditions..........................................................................................8
2.2.8. Stability Commitment...................................................................................12
2.2.9. Evaluation .....................................................................................................12
2.2.10. Statements/Labeling.....................................................................................13
3. GLOSSARY .....................................................................................................13
4. REFERENCES .....................................................................................................17
目录
1.引言
1.1指导原则的目的
1.2 指导原则的范围
1.3一般原则
2.指导原则
2.1原料药
2.1.1总则
2.1.2 强制破坏试验
2.1.3 批的选择
2.1.4 包装容器
2.1.5 规范
2.1.6 试验频率
2.1.7 放置条件
2.1.8 稳定性承诺
2.1.9 样品评价
2.1.10 说明书/标签
2.2 制剂
2.2.1 总则
2.2.2光稳定性试验
2.2.3 批的选择
2.2.4 包装容器
2.2.5 规范
2.2.6 试验频率
2.2.7 放置条件
2.2.8 稳定性承诺
2.2.9 样品评价
2.2.10 说明书/标签
3. 术语
4. 参考文献
STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS
新原料药和制剂的稳定性试验
1. INTRODUCTION
1. 介绍
1.1. Objectives of the Guideline
1.1 指导原则的目的
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.
下述的指导原则是ICH Q1A指导原则的修订版,它规定了在欧盟、日本、美国三个地区注册申请新原料药或所需的一整套稳定性资料的要求,它不包括到世界其他国家和地区注册或出口所要求的试验内容。
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.
本指导原则旨在列举新原料药及其新制剂稳定性试验主要资料要求,鉴于所考察药物的性质和特定的科学技术考虑,它对不同的实际情况中可能发生的变化保留了充分的灵活性。当有足够的科学依据时,也可使用其他方法。
1.2. Scope of the Guideline
1.2 指导原则的范围
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.
本指南主要阐述新分子实体及其制剂注册申请时要提交的稳定性资料,目前尚不包括简略申请、变更申请及临床试验申请等所要求的资料。
Specific details of the sampling and testing for particular dosage forms in their proposed container closures are not covered in this guideline.
对于特殊剂型,对在其建议的包装容器中进行取样及试验的特定要求不包括在本指导原则中。
Further guidance on new dosage forms and on biotechnological/biological products can be found in ICH guidelines Q1C and Q5C, respectively.
生物工程/生物制品的新制剂的指导原则,分别见ICH Q1C和Q5C.
1.3. General Principles
1.3 一般原则
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.
稳定性试验的目的是提供原料药和制剂在各种环境因素,如温度、湿度和光等条件的影响下,其质量随时间变化的情况,并且由此建立原料药的复验期或制剂有效期,以及推荐的贮存条件。
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.
本指南是根据欧盟、日本、美国的气候条件来选择试验条件的。世界各地的平均动力学温度可以从气候资料中获得,全世界可以划分为Ⅰ-Ⅳ四个气候带。本指南仅阐述气候带Ⅰ和Ⅱ。已经建立了这样一个原则,即对欧盟、日本和美国中任何一方提供的稳定性数据,只要它与本指南一致,并且其标签符合国家/地区的规定,则该资料可被其他两方接受。
2. GUIDELINES
2. 指导原则
2.1. Drug Substance
2.1 原料药
2.1.1. General
2.1.1 总则
Information on the stability of the drug substance is an integral part of the systematic approach to stability evaluation.
原料药稳定性资料是系统性的稳定性评价的一个组成部分。
2.1.2. Stress Testing
2.1.2 强制破坏试验
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.
原料药的强制破坏试验有助于确定可能的降解产物,而这些降解产物又可帮助了解降解途径和分子内在的稳定性,并论证使用的分析方法是否能反映产品的稳定性。强制破坏试验的类型将取决于各种原料药的性质及其所包含的制剂类型。
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℃ increments (e.g., 50℃, 60℃, 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.
强制破坏试验通常仅需对一批原料药进行试验,它包括温度(高于加速试验温度10℃,如50℃、60℃等)、湿度(如RH 75%或更大)、氧化、光解对原料药的影响;该试验也应评估原料药在溶液或混悬液状态时,在一较宽pH值范围内对水解的敏感程度。光稳定性试验是强制破坏试验的一部分,关于它的标准条件在ICH Q1B中讲述。
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.
在强制破坏条件下检查降解产物,对于了解降解途径和建立并论证所使用的分析方法的有效性是有用的。然而,如果在加速或长期放置条件下已证明某些降解产物并不形成,则可不必再专门检查。
Results from these studies will form an integral part of the information provided to regulatory authorities.
这些研究的结果应整理成文并报告给管理部门。
2.1.3. Selection of Batches
2.1.3 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.
进行正式的稳定性研究,应提供至少三批申报批次原料药的稳定性资料,申报批次应是中试规模生产的批次,其合成路线和生产工艺应与最终生产时的相同。用于正式稳定性研究的各批次的总体质量应能代表规模生产时的质量。
Other supporting data can be provided.
还可提供其他支持性资料。
2.1.4. Container Closure System
2.1.4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.
进行稳定性研究的原料药应放置在与所建议的贮存和销售相同的或相似的包装容器中。
2.1.5. Specification
2.1.5 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.
规范就是一系列的试验、分析方法和建议的认可标准,在ICH的Q6A和Q6B中阐述。此外,原料药降解产物的规范在Q3A中阐述。
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.
稳定性研究应检验那些在贮藏期间易变化的、可能影响其质量、安全性和/或有效性的项目。检验项目应包括物理、化学、生物和微生物特性。应采用经论证能指示稳定性的分析方法。稳定性研究是否需重复及重复程度取决于论证研究的结果。
2.1.6. Testing Frequency
2.1.6试验频率
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.
对于长期试验,试验的频率应足以确定原料药的稳定性状况。对建议的再试验期至少为12个月的原料药,在长期放置条件下的试验频率一般为:第一年每3个月一次,第二年每6个月一次,以后每年一次,直到建议的再试验期。
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下为期六个月的研究中,至少进行包括初次和末次的3个时间点(如0、3、6月)的试验。根据研究开发的经验,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试验。建议进行为期12个月的研究,其中至少包括初次和末次的四个时间点(如0、6、9、12个月)的试验。
2.1.7. Storage Conditions
2.1.7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.
一般,原料药应在一定的放置条件下(在适当的范围内)进行评价,以检验其热稳定性,必要时也检验其对湿度的敏感性。选择的放置条件和研究时间的长短要充分考虑到的贮藏、运输及其使用的整个过程。
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).
申报时的长期试验应至少包括三批申报批次的至少12个月的试验,并应继续考察足够的时间以涵盖建议的再试验日期。当管理当局要求时,在注册申请评价期间积累的其他资料也应呈报。从加速试验和必要时进行的中间试验放置条件下得到的数据可用于评价短期偏离标签上所建议的贮藏条件的影响(如在运输途中可能发生的情况)。
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 section. Alternative storage conditions can be used if justified.
原料药长期试验、加速试验及必要时的中间试验放置条件在下节中详细列出,除另有规定外,原料药应采用下述“一般情况”的放置条件,经说明,也可使用其他放置条件。
2.1.7.1. General case
2.1.7.1一般情况
研究 | 放置条件 | 申报数据涵盖的最少时间周期 |
长期试验﹡ | 25℃±2℃/60%RH±5%RH或30℃±2℃/65%RH±5%RH | 12个月 |
中间试验﹡﹡ | 30℃±2℃/65%RH±5%RH | 6个月 |
加速试验 | 40℃±2℃/75%RH±5%RH | 6个月 |
﹡长期试验在25℃±2℃/60%RH±5%RH还是在30℃±2℃/65%RH±5%RH条件下进行,由申请者决定。
﹡﹡如果把30℃±2℃/65%RH±5%RH作为长期试验条件,则无中间试验条件。
If long-term studies are conducted at 25℃±2℃/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.
如果在25℃±2℃/60%RH±5%RH条件下进行长期试验,而在加速放置条件下的6个月期间的任何时间点发生“显著变化”,则增加中间放置条件下的试验,并对照显著变化的标准进行评价。除非另有规定,中间试验应包括所有试验项目。初次申报应包括在中间试验条件下进行的12个月研究中的至少6个月的数据。
“Significant change” for a drug substance is defined as failure to meet its specification.
原料药“显著变化”即指不符合规定。
2.1.7.2. Drug substances intended for storage in a refrigerator
2.1.7.2拟冷藏的原料药
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