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1、ICHICH指导建议原则稳指导建议原则稳定性定性主要内容主要内容ICH简介简介ICH指导原则指导原则 Q1A(R2)ICH指导原则指导原则 Q1BICH简介简介说明说明ICH的论题主要分为四类，因此ICH根据论题的类别不同而进行相应的编码分类：1.“Q”类论题：Q代表QUALITY，指那些与化工和医药，质量保证方面的相关的论题。2.“S”类论题：S代表SAFETY，指那些与实验室和动物实验，临床前研究方面的相关的论题。3.“E”类论题：E代表EFFICACY，指那些与人类临床研究相关的课题。4.“M”类论题：M代表MULTIDISCIPLINARY,指那些不可单独划入以上三个分类的交叉涉及的论
2、题。同时M又细分为5个小类M1:常用医学名词（MedDRA）M2:药政信息传递之电子标准M3:与临床试验相关的临床前研究时间的安排M4:常规技术文件(CTD)M5:药物词典的数据要素和标准Q1A-Q1F Stability稳定性稳定性Q1A(R2)StabilityTestingofNewDrugSubstancesandProducts新原料药和制剂的稳定性试验Q1B StabilityTesting:PhotostabilityTestingofNewDrugSubstancesandProducts新原料药和制剂的光稳定性试验Q1C StabilityTestingforNewDosag
3、eForms新剂型的稳定性试验Q1D BracketingandMatrixingDesignsforStabilityTestingofNewDrugSubstancesandProducts原料药和制剂稳定性试验的交叉和矩阵设计Q1EEvaluationofStabilityData稳定性数据的评估Q1F StabilityDataPackageforRegistrationApplicationsinClimaticZonesIIIandIV在气候带III和IV，药物注册申请所提供的稳定性数据Q1A(R2)Stability Testing of New Drug Substances
4、and Products1、Drug Substance2、Drug ProductsStress Testing强力破坏试验是通过建立降解途径，鉴定可能的降解产物，以确定分子的内在稳定性，并论证所使用的分析方法是否能反映产品的稳定性。Drug SubstanceStress Testing可以是单批原料药，包括温度（一般比加速试验温度高10）、湿度（75%或者更高）、氧化、光照。Drug SubstanceSelection of Batches 批的选择批的选择三批以上样品的数据试产规模生产的批次，应与在最终规模生产时的合成路线和生产工艺相同。用于稳定性研究的各批次原料药的总体质量应既能代
5、表临床前研究的质量，又能代表临床研究以及规模生产时的质量。Drug SubstanceContainer Closure System 包装包装与储存和运输的包装相同或相似Drug SubstanceSpecification稳定性研究应检验在储存期间容易变化的原料药的属性，并且可能影响原料药的质量，安全性和/或功效。检验应适当地涵盖物理，化学，生物和微生物方面。应采用经验证的分析方法。Drug SubstanceTesting Frequency For long term studies,frequency of testing should be sufficient to establ
6、ish 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 throu
7、gh the proposed re-test period.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
8、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.Drug SubstanceTesting Frequency When testing at the intermediate storage condition is called for as a resu
9、lt 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.Drug SubstanceStorage Conditions 1、General case*有有显著著变化化时，增加中，增加中间条件条件Drug SubstanceStudyStorage conditio
10、n Minimum time period covered by data at submission Long term 25C2C/60%RH5%RHor30C2C/65%RH5%RH12monthsIntermediate30C2C/65%RH5%RH6monthsAccelerated40C2C/75%RH5%RH6monthsStorage Conditions 2、Drug substances intended for storage in a refrigerator If significant change occurs within the first 3 months
11、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.可以进一步考察单批原料药在少于3个月内的稳定性，提高检样频率。Drug SubstanceStudyStorage condition Minimum time period covered by data at
12、submission Long term 5C 3C 12 months Accelerated 30C 2C/65%RH 5%RH 6 months Storage Conditions 3、Drug substances intended for storage in a freezer 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 temper
13、ature(e.g.,5C 3C or 25C 2C)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.Drug SubstanceStudyStorage condition Minimum time period covered by data at submission Long term-
14、20C 5C 12 months Storage Conditions 4、Drug substances intended for storage below-20C Drug substances intended for storage below-20C should be treated on a case-by-case basis.Drug SubstanceGeneral The design of the formal stability studies for the drug product should be based on knowledge of the beha
15、vior and properties of the drug substance and from stability studies on the drug substance and on experience gained from clinical formulation studies.The likely changes on storage and the rationale for the selection of attributes to be tested in the formal stability studies should be stated.成品稳定性试验设
16、计应以原料药的性质以及从临床处方研究和原料药稳定性研究中得到的经验为基础，应阐述贮存中可能发生的变化以及将产品可变因素选入试验方案的理由。Drug Product Selection of Batches Data from stability studies should be provided on at least three primary batches of the drug product.The primary batches should be of the same formulation and packaged in the same container closure system as proposed for marketing.The manufacturing process used for primary batches should simulate that to be applied to production batches and should provide product of the same quality and meeting
