稳定性考察SOP

1、标准操作规程SOP文件号/版本号SOP Number制订部门Department质量检验室文件页数Pages24/24文件名称SOP Title稳定性考察SOP Stability study SOP 稳定性考察SOP stability study SOP1. 目的 Objective/Purpose32. 适用范围Scope33. 责任部门（人）及权限 Responsible department (person)33.1 处于临床和注册阶段的研发产品development products in clinical and registration phase33. 2 对于商业化产品co

2、mmercial products45. 物料和设备 Materials and equipment57. 规程 Procedure56.1 稳定性方案stability protocol56.2 成品稳定性研究 Drug Product stability66.2.1 批次和数量 Number and Size of Batches66.2.2 加速稳定性accelerated stability76.2.3贮存条件Storage Conditions76.2.4检测方法和标准Test methods and specifications76.2.5 容器密封系统Container-Clos

3、ure System86.2.6 防腐剂 Preservatives86.2.7 变更引起的稳定性研究 Stability study for change control86.3原料及中间体Bulk Drug Substances and Intermediates96.3.1 考察批次和样品量 Number and Size of Batches96.3.2 加速稳定性研究Accelerated Studies96.3.3 贮存条件Storage Conditions96.3.4 检测方法和标准Test methods and specifications106.3.5 容器密封系统Con

4、tainer-Closure System106.3.6 防腐剂检测Preservatives116.3.7 变更引起的稳定性研究 Stability study for change control116.4 实际贮存条件下长期稳定性稳定性试验计划 real storage conditions long term stability plan126.5 加速和强力稳定性试验研究Accelerated and stress study126.6取样检测时间点和检测窗Timepoints for sampling and testing window136.7 可接收标准 Acceptance

5、 criteria136.8 偏差管理和它们在稳定性报告中的追朔Deviations Management and their traceability in the stability report136.9稳定性数据趋势分析和统计分析Stability Data trending and Statistical Analysis146.10 上市产品的稳定性研究后续产品的稳定性研究 Time point frequency for Follow-up Stability Studies156.11 和药政部门沟通 Communication with Health Authorities1

6、56.12 稳定性试验箱/稳定性试验房间管理 stability chamber or stability room166.13 稳定性样品留样 stability samples retention166.14 稳定性样品送检 stability samples delivery166.15 稳定性结果汇总166.16 稳定性报告 stability report176.17 稳定性中期报告Interim Study Report176.18 稳定性方案和报告的编号stability protocol and report number177 记录报告Reporting178 参考文献 Re

7、ference documents179 附件 attachment1810注意事项 Notes181. 目的 Objective/Purpose本文的主要目的是按照WHO，ICH,中国药典和GMP要求，管理研发和上市疫苗产品稳定性研究，确定产品的复验期/有效期，贮存和运输条件。The purpose of this document is to describe the requirements for stability testing, re-test period / shelflife declaration, determination of storage/ transport

8、conditions of development and marketed products according to WHO, ICH and Chinese Pharmacopeia and GMP requirement. 2. 适用范围Scope2.1本文适用于稳定性研究的研发和上市产品的的菌毒种，原液，中间体和成品疫苗的稳定性考察。溶液，缓冲液和生产用培养基的稳定性考察不在本范围之内。This document describes the Standards to be applied for Stability Studies performed for both develop

9、ment and commercial products applicable to bacterial (viral) seed, bulk solutions, intermediates and vaccine in the context of current industry practices, regulatory agency guidance documents, inspectional findings and * corporate quality expectations for such programs. Solutions, Buffers and Media

10、Holding Time Studies are out of scope. 2.2 稳定性数据可以用于以下几个方面：确定临床研究时，产品或中间体的复检时间；确定中间体得存放时间；建立产品存贮，运输以及包装的条件，特殊情况下还可用于针对不同气候带的包装类型设计。Stability data are used to: determine clinical retest period for products or intermediates; assign holding time for intermediates; establish product storage and transpor

11、t conditions and packaging conditions, if appropriate, and to select a suitable packing configuration for each climatic zone.2.3 通常，对于不同规格或不同包装类型的产品应分别进行稳定性研究。但是，如果有恰当的文件记录，解释以及QA部门的批准，一个稳定性研究计划将被用于覆盖所有规格和包装的同类产品，例如括号法或矩阵法。In generally, the products should be put into stability program individually

12、per different potency or different package type. However, a bracketing and/or matrixing approach may be applied to cover all of the potencies and packaging presentations if properly documented, justified and approved by Quality department.3. 责任部门（人）及权限 Responsible department (person)3.1 处于临床和注册阶段的研发

13、产品development products in clinical and registration phase 1）稳定性方案和报告的起草：QCEstablishing of stability study protocol and report: QC2）稳定性方案以及报告的复核：研发部门，注册部门以及研发QAReview of stability study protocol and report: R&D, development QA, registration department3）稳定性方案执行：QCImplementation of stability study

14、protocol: QC4）稳定性方案以及报告的批准：研发QA或被指定的稳定性专家Approval of stability study protocol and report: development QA or designated stability expert3. 2 对于商业化产品commercial products 1）稳定性方案和报告的起草：QCEstablishing of stability study protocol and report: QC2）稳定性方案以及报告的复核：生产QAReview of stability study protocol and repo

15、rt: manufacturing QA3）稳定性方案执行：QCImplementation of stability study protocol: QC4）稳定性方案以及报告的批准：manufacturing QAApproval of stability study protocol and report: manufacturing QA4. 定义、符号和缩略语 Definition，signal and abbreviation4.1 定义4.1.1 加速试验 Accelerated testing加速试验是通过超常的贮存条件，评估活性原料药或制剂的化学降解水平或物理变化。它是常规稳

16、定性研究的一部分。这些数据也可作为长期稳定性研究的补充，评估在非加速试验条件下长期时间内的化学变化，也可作为支持数据用于评估短实践内非标示储存条件下暴露对产品的影响，例如可能在储运过程中发生的异常情况，加速试验研究的结果有时不能预示物理变化。Studies designed to increase the rate of chemical degradation or physical change of a drug substance or drug product by using exaggerated storage conditions as part of the formal

17、stability studies. Data from these studies, in addition to long term stability studies, can be used to assess longer term chemical effects at non-accelerated conditions and as supportive data to evaluate the effect of short term excursions outside the label storage conditions such as might occur dur

18、ing shipping or storage. Results from accelerated testing studies are not always predictive of physical changes4.1.2 强力破坏试验Stress testing (Drug Substance)这些研究是为了揭示原料药内在稳定性的特性，它是开发研究的一部分。这些试验通常是在比加速试验更剧烈的条件下进行 Studies are undertaken to elucidate the intrinsic stability of the drug substance. Such tes

19、ting is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing.4.1.3 强力破坏试验(制剂) Stress testing (Drug Product)光照试验是强力破坏试验的一部分(见单独的附件)。对于特定产品(如计量给药的吸入剂和乳膏及乳剂)的特殊试验条件，可能要求附加其他的强力破坏研究Studies are undertaken to assess the effect of

20、 severe conditions on the drug product. Such studies include photo stability testing (see ICH Q1B) and specific testing on certain products, (e.g., metered dose inhalers, creams, emulsions, refrigerated aqueous liquid products).4.2 简写 abbreviationsICH：International conference on harmonization of tec

21、hnical requirements for registration of pharmaceuticals for human use药品注册技术要求世界协调组织SP：stability protocol 稳定性方案SR：stability report 稳定性报告DP： Drug products 成品5. 物料和设备 Materials and equipment无none。6. 规程 Procedure6.1 稳定性方案stability protocol 对于每项稳定性研究均应起草对应的稳定性考察方案，稳定性方案模板见附件1，稳定性方案需要QA批准后，方可执行稳定性考察。Stabi

22、lity protocol should be prepared for each stability study, attachment 1 is the stability protocol, the stability protocol should be approved before execution the stability study. 稳定性考察方案内容有the stability protocol should include the following information简介（稳定性研究的原因的简单描述和相关的一些细节）Introduction (brief des

23、cription of the reason for the stability studies along with any relevant details).需要检测批次的描述（包括生产日期和批量）及包装方式的描述Description of batches tested (including manufacturing date and batch quantity ) and description of packaging tested.稳定性计划：长期和加速稳定性计划（包括贮存条件和贮存时间）和具体的检测项目Stability Program: long-term and acc

24、elerated testing plan (including storage conditions and storage time in months), and special tests planned if applicable.质量控制和微生物控制程序和检测要求及可接受标准Quality Control and Microbiology procedure and test requirements and acceptance criteria. 稳定性方案的变更历史，备注，取样量和分发清单 Chronology and changes to previous version,

25、 remarks, sample quantity and distribution list.6.2 成品稳定性研究 Drug Product stability6.2.1 批次和数量 Number and Size of Batches用于新药注册申请批准或新产品正式生产的首三批产品必须进行长期稳定研究Three initial batches used for registration application approval or the first three commercial products should be placed into the long term stabil

26、ity program.对于后续的产品，只要每年有生产，每年应保证至少一批产品进行长期稳定性的研究，如果因变更评估的需要或偏差，额外批次产品的稳定性试验考察也必须执行。Minimally one batch per year should be placed on follow-up stability after approval provided that manufacturing campaigns are run; additional batches are required based on changes (triggered by the change control sys

27、tem) and/or deviations (triggered by the deviation management system). 年度产品稳定性的考察应有完整的包装，以评估包装材料对产品的影响。但如果在第一次时间点之前，产品无法包装完成，可以采用没有包装的产品进行稳定性，并将该原因在稳定性研究中说明。稳定性考察检测试验，研发阶段的产品不需要此项研究。Annual stability studies should be performed using the packed product in order to evaluate the impact of the packaging

28、 materials on the product. If it is not possible to have the final product before the first timepoint expiration, in order to avoid missing timepoints the filled product can be used to perform the study and a note will be put in the stability project. For logistics reasons, this is not required for

29、development products稳定性样品留样量应该在稳定性方案中进行规定，以确保能够稳定性考察，应至少包括有25%的富余样品，以便于有额外的测试发生，富余量可以根据稳定性研究的要求而改变。The total number of samples required to complete the stability study must be stated within the stability protocol. This should include a reserve allocation of 25% for filled products thereby allowing a

30、dditional testing to occur. This reserve allocation percentage may be altered depending on the stability study requirements6.2.2 加速稳定性accelerated stability加速和强力稳定性应按照ICH的标准来执行，他们应该根据ICH来执行，加速和强力稳定性应该于开发阶段用于注册的产品的研究，以确认产品的降解，和稳定性检测方法Accelerated and stressed studies are strongly suggested according to

31、 ICH. They should be performed during development for registration purpose on Drug Product (DP) to identify degradation products, pathways and stability indicating methods for DP.采用很高的温度来进行加速稳定性研究以便于在短期内得到结果并进行外推得到很长的效期时间是不合适的，因为在高温和推荐的储存温度，产品的降解机理是不同的。It is not reasonable to perform accelerated tes

32、ting at very high temperatures for a very short time and expect to extrapolate results to a very long expiration dating period since the actual mechanism of degradation at high temperature may be different than at recommended storage temperature对于加速稳定性，采用1批产品来进行稳定性考察，并和长期稳定性考察的数据来支持得到效期的数据，因为加速稳定性考察

33、的目的是考察动态的降解，而不是评估批间产品的一致性。One batch may be adequateThree batches needed in Ch.P 2010. in order to support and extend the expiration date together with long term real storage conditions data. This is acceptable since it is not the purpose of an accelerated test to determine batch uniformity but rathe

34、r to test for kinetic degradation.6.2.3贮存条件Storage Conditions 稳定性研究的样品应该根据推荐的贮存条件或加速考察的条件存放Stability studies must be conducted on product stored under recommended storage conditions (temperature and humidity) and under exaggerated (accelerated and stressed) conditions.上市产品批次的稳定性考察应在实际贮存条件下进行，不需要进行加速

35、或强力考察Follow-up Stability Studies for commercial batches have to be performed at the recommended storage conditions. Accelerated or stressed studies are not needed.6.2.4检测方法和标准Test methods and specifications 所有采用的检测方法均应通过验证，检测程序应包括稳定性指示性的检查，该检测能够区分活性成分和其他降解成分，并能够得到任何降解数量的正确评估All testing methods used

36、shall be validated under actual conditions of use. Testing procedures must include a stability indicating test which will distinguish the active ingredient from any degradation products and be able to make a reliable estimate of the quantity of any degradation.从三期临床开始研发产品的放行标准和稳定性考察标准应该得以建立， “只报告结果”

37、标准不可接受，研发团队负责建议开发阶段的产品的放行和稳定性标准Starting from Clinical Phase III batches, all release and stability specifications for Drug Product (DP) have to be set, “report results” specification is not acceptable anymore. The Development Project Team is responsible to propose the release and stability specifica

38、tions during the development of the product. 6.2.5 容器密封系统Container-Closure System稳定性样品的考察应该采用贮存或上市产品同样的包装，对于液体产品，样品应平躺放置，以确保产品和密封系统接触。Stability testing has to be performed in the same container/closure system as that in which the drug product is stored/marketed. For liquid product sample have to be

39、stored in horizontal position to ensure product contact with the closure material. 6.2.6 防腐剂 Preservatives含有防腐剂的产品应该检测防腐剂的有效性，一旦最低防腐剂含量水平已经建立，可采用化学方法进行防腐剂含量的检测，防腐剂含量的检测应该和稳定性的检测同时进行。Products formulated to contain preservatives to inhibit microbial growth should be monitored throughout their shelf li

40、fe to assure the effectiveness of the preservative system. Once a minimally effective level of preservative is established, chemical testing for the preservative(s) may be performed. The preservative system should be monitored at the same stability testing times as other ingredients are monitored.6.

41、2.7 变更引起的稳定性研究 Stability study for change control对于上市后的产品如果发生以下变更需要进行额外的稳定性研究 For marketed products, below changes will require additional stability study：1）变更内包材供应商或类型, 需要对变更后的首三批对应规格的产品进行稳定性研究 Changing the vendor or type of the primary package, samples from three of the first production batches of

42、 each potency should be put into stability study.2）变更原辅料种类，或关键物料供应商或关键工艺，需要对变更的首三批对应规格的产品进行稳定性研究 Changing the type of raw materials, excipents or the vendor of critical raw materials, excipients or process steps, samples from three of the first production batches of each potency should be put into s

43、tability study.3）变更次要物料供应商，工艺或外包装，通常需要对首批产品进行长期稳定性研究；如有特殊情况，需在变更控制中说明并得到QA部门的批准 Changing the vendor of subordinate materials, uncritical process step or secondary package material, samples from the first production batch of each potency should be put into stability study; if there is any special cas

44、es, it need to be justified in the change control and get approval by QA.6.3原液和中间体Bulk Drug Substances and Intermediates6.3.1 考察批次和样品量 Number and Size of Batches 初步研究应对三批产品进行，对于常规的稳定性考察，通常不需要对原液进行考察，如果除非必须（如流感），通过评价可用的数据，可以对1批产品每x月（x月为原液的效期）进行稳定性考察， Three batches are required for initial studies. A

45、routine stability program (FUST) is not required for vaccine Drug Substances, if not otherwise required (e.g. Flu). After evaluation of available data, it is advisable to put one batch on stability study every x months, where x is the shelf life.中间体的存放时间以及存放条件应根据稳定性研究获得。所有的中间体的稳定性考察应该根据产品的实际储存温度和容器来

46、执行，短时间的稳定性（少于1个月）的考察应该作为保存时间的验证来执行，该研究应该不少于3批产品，稳定性方案应该定义检测的项目，方法和可接受标准。Holding time and storage conditions of intermediates should be based on stability studies. All stability studies on intermediates have to be performed in the real storage containers and condition (real time studies) where applic

47、able. Short storage period (less than 1 month) have to be performed as Holding Time Validation Study. The study has to be performed on not less than 3 representative batches. The Stability Protocol has to define the tests, methods and acceptance range to be applied.稳定性样品留样量应该在稳定性方案中进行规定，以确保能够完成稳定性考察

48、，对每个时间点应至少包括有3 x 25 ml的富余样品，以便于有额外的测试发生，富余量可以根据稳定性研究的要求而改变。The total number of volume required to complete the stability study must be stated within the stability protocol. This should include a reserve allocation of 3 x 25 ml per time point for bulk materials thereby allowing additional testing to

49、occur. This reserve allocation percentage may be altered depending on the stability study requirements6.3.2 加速稳定性研究Accelerated Studies 加速和强力试验研究：如需要，应在开发阶段，以识别降解的杂质Accelerated and stressed studies, if necessary, should be conducted during the development of the Drug Substance to identify degradation

50、 impurities.6.3.3 贮存条件Storage Conditions 稳定性研究应该将产品放置在推荐的贮存条件下 （温度和湿度）Stability studies must be conducted on product stored under recommended storage conditions (temperature and humidity).对于贮存在生产部门的冰箱或冰柜中的中间体和原液，但在生产部门，温度需要受到严格控制和监控，稳定性研究应该在相同的温度和环境条件下或最差情况下执行，但是，采用最差情况，应在方案中说明理由For intermediates an

51、d drug substances stored not in a refrigerator or freezer，but in manufacturing department the temperature has to be strictly under control and monitored. Stability studies should be conducted at the same temperature and environmental conditions, or in worst conditions. In the last case the worst con

52、ditions should be explained with a rational in the protocol.稳定性研究需要在实际贮存条件下考察，或在更恶劣的条件下考察。Stability studies should be conducted on product stored under normal storage conditions or, preferably, under exaggerated conditions.6.3.4 检测方法和标准Test methods and specifications 所有采用的检测方法均应通过验证，检测程序应包括稳定性指示性的检查

53、，该检测能够区分活性成分和其他降解成分，并能够得到任何降解数量的正确评估对于原辅料成分，“报告结果”是不可接受的，开发组负责建议放行和稳定性的标准对于中间体，如果“报告结果”这种方法应该在程序中报告，应说明理由All testing methods used shall be validated under actual conditions of use. Testing procedures must include a stability indicating test which will distinguish the active ingredient from any degra

54、dation products and be able to make a reliable estimate of the quantity of any degradation。从三期临床开始研发产品的放行标准和稳定性考察标准应该得以建立，“只报告结果”标准不可接受，研发团队负责建议开发阶段的产品的放行和稳定性标准Starting from Clinical Phase III batches, all release and stability specifications for Drug Substance (DS) have to be set, “report results”

55、specification is not acceptable anymore. The Development Project Team is responsible to propose the release and stability specifications, during the development of the product. 对于中间产品的可接受标准应该制定，如果需要采用“只报告结果”标准，应该说明理由For intermediates the acceptance range should be set. In case “report result” specif

56、ication is set, a rationale should be given. 6.3.5 容器密封系统Container-Closure System 当对中间体或原液进行稳定性研究时，该产品应存放在于实际包装一致的容器中。When stability studies are performed on intermediate (bulk) product, bulk preparations should be packed in containers which simulate the original bulk pack。如有需要，可选择较小的容器（相同的材料和密封系统）作

57、为稳定性研究，任何最差条件的采用都要科学的合理的解释。Scaled down containers can be selected (same material and closure system) to perform the study where possible. Any worst case approach has to be explained by a scientifically sound rationale. 如果一个产品贮存在多种规格的包装中，可以通过比较容器的内在面积与体积的比值，最小的容器是最可能导致产品降解的因素，其他的包装容器可以通过括号/举证方法来选择作为稳

58、定性考察的方法。When the same product is stored in more than one size, it can be demonstrated, by comparing the ratio of the surface area of the container to the internal volume, that smaller containers have a higher ratio than larger containers. This indicates that the smallest container is the most critical in terms of the container properties contributing to product degradation. All other container sizes are subjected to bracketing/matrixing stability testing approach.6.3.6 防腐剂检测P