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1、ICH指导原则指导原则 稳定性稳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题。同时M又
2、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 StabilityTestingforNewDosageForms
3、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 and Pr
4、oducts1、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表临床前研究
5、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 establish th
6、e 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
7、 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 are li
8、kely 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 result of
9、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*有有显显著著变变化化时时，增加中，增加中间间条件条件Drug SubstanceStudyStorage condition
10、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 te
11、sting 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 su
12、bmission 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 temperat
13、ure(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-20
14、C 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 behavi
15、or 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.成品稳定性试验设计应
16、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 s
17、ystem 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 the same specification as that intended for marketing.Two of the three batches should be at least pil
18、ot scale batches and the third one can be smaller,if justified.Where possible,batches of the drug product should be manufactured by using different batches of the drug substance.Drug Product Selection of Batches 加速和长期试验的稳定性资料至少应包括与上市产品具有相同处方、剂型和容器及闭塞物的三批样品的数据，三批中至少有两批样品应是试生产规模生产的，第三批可以少一些(如：固体口服剂型可以
19、2500050000 片剂或胶囊)。长期试验至申报时至少应进行12 个月。所用生产工艺应尽可能模拟用于上市药品大规模生产的工艺，该生产工艺应能提供与上市质量相同的药品，同时也要符合与出厂产品相同的质量要求。若可能，应该用不同批号的原料药生产几批成品。Drug Product Container Closure System Stability testing should be conducted on the dosage form packaged in the container closure system proposed for marketing(including,as app
20、ropriate,any secondary packaging and container label).Drug Product Specification Stability studies should include testing of those attributes of the drug product that are susceptible to change during storage and are likely to influence quality,safety,and/or efficacy.The testing should cover,as appro
21、priate,the physical,chemical,biological,and microbiological attributes,preservative content(e.g.,antioxidant,antimicrobial preservative),and functionality tests(e.g.,for a dose delivery system).Analytical procedures should be fully validated and stability indicating.Whether and to what extent replic
22、ation should be performed will depend on the results of validation studies.试验项目应该包括在贮存期内易于改变和可能影响质量、安全性和(或)药效的那些因素。试验范围应包括物理、化学、生物以及微生物稳定性，还应包括防腐剂含量（抗氧剂，抗菌防腐剂）。分析方法应经过充分论证。Drug Product Testing Frequency（同（同Drug Substance原料原料药药）For long term studies,frequency of testing should be sufficient to establ
23、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
24、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
25、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 Product Testing Frequency（同（同Drug Substance原料原料药药）When testing at the intermediate storage condition
26、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.Drug Product Storage Conditions 1、General case*有有显显著著变变化化时时，增加中，增加中间间条件条件Drug Prod
27、uct StudyStorage condition Minimum time period covered by data at submission Long term 25C2C/60%RH5%RHor30C2C/65%RH5%RH12monthsIntermediate30C2C/65%RH5%RH6monthsAccelerated40C2C/75%RH5%RH6monthsIn general,“significant change”for a drug product is defined as:1.A 5%change in assay from its initial val
28、ue;or failure to meet the acceptance criteria for potency when using biological or immunological procedures;2.Any degradation products exceeding its acceptance criterion;3.Failure to meet the acceptance criteria for appearance,physical attributes,and functionality test(e.g.,color,phase separation,re
29、suspendibility,caking,hardness,dose delivery per actuation);however,some changes in physical attributes(e.g.,softening of suppositories,melting of creams)may be expected under accelerated conditions;and,as appropriate for the dosage form:4.Failure to meet the acceptance criterion for pH;or 5.Failure
30、 to meet the acceptance criteria for dissolution for 12 dosage units.（12粒胶囊或片剂的溶出度超出了规定限度；）Drug Product Storage Conditions 2、Drug products packaged in impermeable containers（药品包装在不渗透容器中）Sensitivity to moisture or potential for solvent loss is not a concern for drug products packaged in impermeable c
31、ontainers that provide a permanent barrier to passage of moisture or solvent.Thus,stability studies for products stored in impermeable containers can be conducted under any controlled or ambient humidity condition.Drug Product Storage Conditions 3、Drug products intended for storage in a refrigerator
32、 Drug Product StudyStorage condition Minimum time period covered by data at submission Long term 5C 3C 12 months Accelerated 25C 2C/60%RH 5%RH 6 months Storage Conditions 4、Drug products intended for storage in a freezer Drug Product StudyStorage condition Minimum time period covered by data at submission Long term 5C 3C 12 months Storage Conditions 4、Drug products intended for storage below-20C Drug substances intended for storage below-20C should be treated on a case-by-case basis.Drug Substance谢谢聆听！