20 / 10 / 16
关于“医学翻译学习-ICH指导原则-新原料药和制剂的稳定性试验-ICH三方协调指导原则”，学习内容记录于此。
本指导原则是ICH QⅠA指导原则的修订版，它规定了在欧盟、日本和美国三个地区注册申请新原料药或制剂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 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.
本指导原则旨在列举新原料药及其制剂稳定性试验主要研究内容，它对实际情况中要求有特定的技术和具有特殊性的药品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。
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。
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.
对于特殊剂型，其试验样品及试验的特定要求不包括在本指导原则中。
Specific details of the sampling and testing for particular dosage forms in their proposed container closures are not covered in this guideline.
生物技术 / 生物制品的新制剂的指导原则,分别见ICH Q1C和Q5C。
Further guidance on new dosage forms and on biotechnological/biological products can be found in ICH guidelines Q1C and Q5C, respectively.
稳定性试验的目的是提供原料药或制剂在各种环境因素如温度、湿度和光等条件影响下，其质量随时间变化的情况，并且由此建立原料药的再试验期或制剂的货架期以及推荐的贮存条件。
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.
本原则是根据欧盟、日本和美国的气侯条件来选择试验条件的。世界上任何地区的平均动力学温度可从气侯资料获得，世界可分成Ⅰ~Ⅳ四个气侯带。本指导原则仅阐述气侯带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资料，只要它与本指导原则保持一致，而且其标签符合国家/地区的规定，则该资料可被其他两方接受。
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.
原料药稳定性研究是系统性的稳定性评价内容的一个组成部分。
Information on the stability of the drug substance is an integral part of the systematic approach to stability evaluation.
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 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.
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RH75%或更大）、氧化、光照对原料药的影响；该试验也应评估原料药在溶液或混悬液状态时，及在较宽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。
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°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 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.
在强制破坏条件下检查降解产物，对于了解降解途经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，则可不必再做专门检查。
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.
这些研究的结果应整理成文并报告给管理部门。
Results from these studies will form an integral part of the information provided to regulatory authorities.
进行正式的稳定性研究，应提供至少三个批次原料药的稳定性资料，这三个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样品质量应能代表规模化生产时的产品的质量。
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.
还可提供其他支持性资料。
Other supporting data can be provided.
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。
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.
质量标准就是一系列的试验、分析方法和建议认可的限度要求，在ICH的Q6A和Q6B中阐述。此外，对原料药降解产物的控制要求在Q3A中阐述。
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.
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。应采用经验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验证研究的结果。
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.
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。
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.
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。
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.
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。
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.
一般，原料药应在一定的放置条件下（在适当的范围内）进行考察，以考察其热稳定性，必要时也考察其对湿度的敏感性。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。
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.
申报时的长期试验应至少包括 三个批次的至少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)。
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).
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。
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.
★ 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。
*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.
★ ★ 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 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate 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,并对照显著变化的限度标准进行评价。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。
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 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.
原料药“显著变化”即指不符合规定。
“Significant change” for a drug substance is defined as failure to meet its specification.
除以下情况外，应根据本指导原则评价冷藏条件下的稳定性试验数据。
Data from refrigerated storage should be assessed according to the evaluation section of this guideline, except where explicitly noted below.
在加速试验条件下，如果在3个月到6个月之间出现了显著变化，则应根据在长期试验条件下实际时间的数据来确定建议的再试验日期。
If significant change occurs between 3 and 6 months’ testing at the accelerated storage condition, the proposed re-test period should be based on the real time data available at the long term storage condition.
在加速试验条件下，如果在前3个月内产生显著变化，则应讨论短期偏离标签上贮藏条件（如在运输途中或搬运中）对药物的影响。必要时，可对一批原料药进行少于3个月但取样更频繁的测试来论证。如果前3个月已产生显著变化,就不必再继续进行6个月的试验了。
If significant change occurs within the first 3 months’ 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. 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 considered unnecessary to continue to test a drug substance through 6 months when a significant change has occurred within the first 3 months.
对于拟冷冻储存的原料药，应根据在长期试验放置条件下实际时间的数据来确定再试验期。虽然没有加速试验放置条件，但应取一批样品,在略高的温度(如:5℃±3℃或25℃±2℃)下放置适当的时间进行试验，以了解短期偏离标签上的所建议的贮藏条件(如在运输或搬运时)对药物的影响。
For drug substances intended for storage in a freezer, the re-test period should be based on the real time data obtained at the long term storage condition. 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 temperature (e.g., 5°C ± 3°C or 25°C ± 2°C) 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.
2.1.7.4拟在-20℃以下贮藏的原料药
2.1.7.4. Drug substances intended for storage below -20°C
应酌情处理。
Drug substances intended for storage below -20°C should be treated on a case-by-case basis.
当申报批次的长期稳定性数据在批准时还无法涵盖所建议的再试验日期时，应承诺在批准后继续进行稳定性研究，以建立确切的再试验日期。
When available long term stability data on primary batches do not cover the proposed re-test period granted at the time of approval, a commitment should be made to continue the stability studies post approval in order to firmly establish the re-test period.
当申报的三批生产批次长期稳定性数据已涵盖了所建议的再试验日期，则认为不需进行批准后的承诺。否则，有下列情况之一的也应承诺：
Where the submission includes long term stability data on three production batches covering the proposed re-test period, a post approval commitment is considered unnecessary. Otherwise, one of the following commitments should be made:
如果递交资料包含了至少三批生产批次的稳定性研究数据但未至再试验日期，应承诺继续这些研究直到建议的再试验日期。
If the submission includes data from stability studies on at least three production batches, a commitment should be made to continue these studies through the proposed re-test period.
如果递交资料包含的生产批次的稳定性研究数据少于三批，应承诺继续进行这些长期稳定性研究直到建议的再试验日期，并补充生产规模的批次至少到三批，进行直到所建议的再试验期的长期稳定性研究。
If the submission includes data from stability studies on fewer than three production batches, a commitment should be made to continue these studies through the proposed re-test period and to place additional production batches, to a total of at least three, on long term stability studies through the proposed re-test period.
如果递交的资料不包含生产批次稳定性数据，则应承诺用生产规模生产的前三批样品进行长期稳定性研究，直到所建议的再试验日期。
If the submission does not include stability data on production batches, a commitment should be made to place the first three production batches on long term stability studies through the proposed re-test period.
除非另有充分的科学依据，用于研究承诺批次的长期稳定性研究方案应与研究初始批次的方案相同。
The stability protocol used for long term studies for the stability commitment should be the same as that for the primary batches, unless otherwise scientifically justified.
稳定性研究的目的是通过对至少三批原料药的试验和对稳定性资料（包括物理、化学、生物和微生物等试验结果）的评价，建立适合将来所有在相似条件下生产出来的原料药的再试验日期。批次间变异的程度将会影响将来生产的产品在再试验日期内质量符合标准的可靠程度。
The purpose of the stability study is to establish, based on testing a minimum of three batches of the drug substance and evaluating the stability information (including, as appropriate, results of the physical, chemical, biological, and microbiological tests), a re-test period applicable to all future batches of the drug substance manufactured under similar circumstances. The degree of variability of individual batches affects the confidence that a future production batch will remain within specification throughout the assigned re-test period.
有时数据表明降解和变异非常小，以致于从数据上就可以明显看出所申请的再试验期是合理的，这时通常不必进行正式的统计分析，只要提供省略的理由即可。
The data may show so little degradation and so little variability that it is apparent from looking at the data that the requested re-test period will be granted. Under these circumstances, it is normally unnecessary to go through the formal statistical analysis; providing a justification for the omission should be sufficient.
分析那些可能会随时间变化的定量参数的一个方法是：将平均曲线的95%单侧置信限与认可标准的相交点所对应的时间点作为再试验期。如果分析表明批间变异较小，最好将数据合并进行整体评估。具体做法是：先对每批样品的回归曲线的斜率和截距进行统计检验（如P值＞0.25表示无显著性差异）。如果不能合并，总的再试验期可以根据其中那批再试验期最短的时间来定。
An approach for analyzing the data on a quantitative attribute that is expected to change with time is to determine the time at which the 95% one-sided confidence limit for the mean curve intersects the acceptance criterion. If analysis shows that the batch-to-batch variability is small, it is advantageous to combine the data into one overall estimate. This can be done by first applying appropriate statistical tests (e.g., p values for level of significance of rejection of more than 0.25) to the slopes of the regression lines and zero time intercepts for the individual batches. If it is inappropriate to combine data from several batches, the overall re-test period should be based on the minimum time a batch can be expected to remain within acceptance criteria.
降解关系的性质将决定是否可将数据转换为线性回归分析。通常这种关系可表示为算术或对数的一次、二次或三次函数关系。各批次及合并批次（当适当时）的数据与假定降解直线或曲线拟合程度的好坏，应该用统计方法进行检验。
The nature of any degradation relationship will determine whether the data should be transformed for linear regression analysis. Usually the relationship can be represented by a linear, quadratic, or cubic function on an arithmetic or logarithmic scale. Statistical methods should be employed to test the goodness of fit of the data on all batches and combined batches (where appropriate) to the assumed degradation line or curve.
如果合理，在报批阶段，可依据长期储藏条件下获得的实测数据，有限外推得到超出观察时间范围外的再试验期。其合理性应基于已知的降解机制、加速试验的结果、数学模型的良好的拟合度、批次规模及所获得的支持性的稳定性数据等。然而，外推法的应用建立在确信“在观察范围外也存在着相同的降解关系”的基础上的。
Limited extrapolation of the real time data from the long term storage condition beyond the observed range to extend the re-test period can be undertaken at approval time, if justified. This justification should be based on what is known about the mechanism of degradation, the results of testing under accelerated conditions, the goodness of fit of any mathematical model, batch size, existence of supporting stability data, etc. However, this extrapolation assumes that the same degradation relationship will continue to apply beyond the observed data.
任何评价不仅应考虑含量，还应考虑降解产物的量和其他有关的属性。
Any evaluation should cover not only the assay, but also the levels of degradation products and other appropriate attributes.
应按照相应的国家/地区的要求，在标签上说明贮藏条件。该说明应建立在原料药稳定性评价的基础上。必要时，应有特殊说明，尤其是对不能冷冻的原料药。应避免使用如“环境条件”或“室温”这一类术语。
A storage statement should be established for the labeling in accordance with relevant national/regional requirements. The statement should be based on the stability evaluation of the drug substance. Where applicable, specific instructions should be provided, particularly for drug substances that cannot tolerate freezing. Terms such as “ambient conditions” or “room temperature” should be avoided.
从稳定性资料中可得出再试验日期，如必要，应在容器的标签上注明再试验日期。
A re-test period should be derived from the stability information, and a retest date should be displayed on the container label if appropriate.
制剂正式稳定性研究的设计应根据对原料药性质和特点的了解、原料药的稳定性试验和从临床处方研究中获得的结果而定。应说明在贮藏时可能产生的变化和在正式稳定性试验中试验项目的选择原则。
The design of the formal stability studies for the drug product should be based on knowledge of the behavior 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.
如必要，至少应用一批样品进行光稳定性试验，其标准条件在ICH Q1B项下有专述。
Photostability testing should be conducted on at least one primary batch of the drug product if appropriate. The standard conditions for photostability testing are described in ICH Q1B.
应提供至少三个批次样品的稳定性资料，申报批次的处方和包装应与拟上市产品相同，其生产工艺应与拟上市产品相似，其质量应与拟上市产品相同，符合相同的质量标准。如证明合理，其中两批必须至少在中试规模下生产，另一批可在较小规模下生产。可能的话，生产不同批次的制剂应采用不同批号的原料。
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 the same specification as that intended for marketing. Two of the three batches should be at least pilot 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.
制剂的每一种规格和包装规格都应进行稳定性研究，除非应用了括号法和矩阵化设计。
Stability studies should be performed on each individual strength and container size of the drug product unless bracketing or matrixing is applied.
可提供其他支持性的资料。
Other supporting data can be provided.
应对装在上市包装容器（必要时，包括次级包装和容器上的标签）中的制剂进行稳定性试验。除去内包装的制剂或装在其他包装材料中的制剂所进行的稳定性研究，可以作为制剂强制试验的一部分或其它支持性资料。
Stability testing should be conducted on the dosage form packaged in the container closure system proposed for marketing (including, as appropriate, any secondary packaging and container label). Any available studies carried out on the drug product outside its immediate container or in other packaging materials can form a useful part of the stress testing of the dosage form or can be considered as supporting information, respectively.
质量标准就是一系列的试验，分析方法和建议的限度要求，包括两种：放行标准和货架期期标准，在ICH的Q6A和 Q6B中有阐述。此外，制剂中降解产物的控制要求在Q3B中有阐述。
Specification, which is a list of tests, reference to analytical procedures, and proposed acceptance criteria, including the concept of different acceptance criteria for release and shelf life specifications, is addressed in ICH Q6A and Q6B. In addition, specification for degradation products in a drug product is addressed in Q3B.
稳定性研究应检验那些在贮藏期间易变化的、可能影响质量、安全性和/或有效性的项目。检验应包括物理、化学、生物、微生物学特性 、保护剂含量（如：抗氧剂、抑菌剂）和功能性测试(如定量给药系统)。应采用充分验证的、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将取决于验证研究的结果。
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 appropriate, 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 replication should be performed will depend on the results of validation studies.
根据所有稳定性资料来制定货架期的标准。根据稳定性结果和贮藏期观察到的变化， 允许货贺期标准和放行标准存在差异。放行标准和货架期标准中抑菌剂含量限度的任何不同，都应该在药物研发阶段中，对拟上市的最终处方（除保护剂含量外）中化合物含量与保护剂有效性之间的相互关系进行验证，以支持这两种标准中限度的制定。不管放行标准和货架期标准中保护剂含量限度是否不同，都要取一批进行稳定性试验的申报制剂，在建议的货架期测定和证实抑菌剂的有效性（除测定抑菌剂含量外）。
Shelf life acceptance criteria should be derived from consideration of all available stability information. It may be appropriate to have justifiable differences between the shelf life and release acceptance criteria based on the stability evaluation and the changes observed on storage. Any differences between the release and shelf life acceptance criteria for antimicrobial preservative content should be supported by a validated correlation of chemical content and preservative effectiveness demonstrated during drug development on the product in its final formulation (except for preservative concentration) intended for marketing. A single primary stability batch of the drug product should be tested for antimicrobial preservative effectiveness (in addition to preservative content) at the proposed shelf life for verification purposes, regardless of whether there is a difference between the release and shelf life acceptance criteria for preservative content.
对长期稳定性研究，应有足够的试验频率，以了解制剂稳定性的总体情况。对于建议货架期至少为12个月的制剂 ，在长期试验放置条件下的试验频率一般为第一年每3个月1次，第二年每6个月1次，以后每年一次，直到建议的货架期期满。
For long term studies, frequency of testing should be sufficient to establish the stability profile of the drug product. For products with a proposed shelf life 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 shelf life.
在加速试验放置条件下，为期6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。根据开发研究的经验，预计加速试验结果可能会接近显著变化的限度，就应在最后一次时间点增加样本数或在研究设计中增加第4个时间点。
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 testing 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.
如果在加速试验放置条件下产生显著变化，则要增加中间放置条件试验。建议进行为期12个月的研究，其中至少进行包括初次和末次的4个时间点（如：0、6、9、12月）的试验。
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.
合理的情况下，可采用减少试验次数的设计，如：采用矩阵化法设计或括号法设计，试验次数可减少或不试验某些因素的组合。
Reduced designs, i.e., matrixing or bracketing, where the testing frequency is reduced or certain factor combinations are not tested at all, can be applied, if justified.
通常,制剂应在一定的放置条件下（在适当的范围内）进行考察，以考察其热稳定性，必要时考察其对湿度的敏感性或潜在的溶剂损失。选择的放置条件和研究时间长短应充分考虑贮藏、运输和使用的整个过程。
In general, a drug product should be evaluated under storage conditions (with appropriate tolerances) that test its thermal stability and, if applicable, its sensitivity to moisture or potential for solvent loss. The storage conditions and the lengths of studies chosen should be sufficient to cover storage, shipment, and subsequent use.
必要时，对配制或稀释后使用的制剂应进行稳定性试验，可为标签上的配制、贮藏条件和配制或稀释后的使用期限提供依据。申报批次应在配制和稀释后的初始和建议的使用期末进行稳定性试验，作为正式稳定性试验的一部分。如果申报前不能提供整个货架期试验数据，应提供第12个月或最近一次测定的这些数据。通常，对承诺的批次不必重复这项试验。
Stability testing of the drug product after constitution or dilution, if applicable, should be conducted to provide information for the labeling on the preparation, storage condition, and in-use period of the constituted or diluted product. This testing should be performed on the constituted or diluted product through the proposed in-use period on primary batches as part of the formal stability studies at initial and final time points and, if full shelf life long term data will not be available before submission, at 12 months or the last time point for which data will be available. In general, this testing need not be repeated on commitment batches.
申报时的长期试验应至少包括三个批次的至少连续12个月的试验，并应继续试验至足以涵盖建议的货架期。注册申报考察期间积累的其他数据，如有关管理当局需要，也要呈报。由加速试验和中间试验放置条件所得到的数据，可用于评价短期偏离标签贮藏条件的影响（如运输途中可能发生的情况）。
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 shelf life. 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).
制剂长期试验、加速试验及必要时中间试验的放置条件在下节详述，除另有规定外，可采用下节所述的“一般情况”的放置条件。经说明也可使用其他放置条件。
Long term, accelerated, and, where appropriate, intermediate storage conditions for drug products are detailed in the sections below. The general case applies if the drug product is not specifically covered by a subsequent section. Alternative storage conditions can be used, if justified.
长期稳定性研究在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。
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.
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 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate 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，并对照显著性变化的情况进行评价。初次申报应包括在中间放置条件下进行12个月研究中的至少6个月数据。
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 storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria. The initial application should include a minimum of 6 months’ data from a 12-month study at the intermediate storage condition.
通常制剂的“显著性变化”定义为：
In general, “significant change” for a drug product is defined as:
含量与初始值相差5%；或采用生物或免疫法测定时效价不符合规定；
A 5% change in assay from its initial value; or failure to meet the acceptance criteria for potency when using biological or immunological procedures;
任何降解产物超过标准限度要求；
Any degradation product’s exceeding its acceptance criterion;
外观、物理常数、功能试验（如颜色、相分离、再分散性、粘结、硬度、每揿剂量）不符合标准要求。然而，一些物理性能（如：栓剂的变软、霜剂的熔化）的变化可能会在加速试验条件下出现；
Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, resuspendibility, 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;
另外，对于某些剂型：
and, as appropriate for the dosage form:
pH值不符合规定；
Failure to meet the acceptance criterion for pH; or
12个剂量单位的溶出度不符合标准的规定；
Failure to meet the acceptance criteria for dissolution for 12 dosage units.
对包装在非渗透容器中的药物制剂可不考虑药物的湿敏感性或可能的溶剂损失，因为这种容器具有防止潮湿和溶剂通过的永久屏障。因此，包装在非渗透容器中的制剂稳定性研究可在任何湿度下进行。
Sensitivity to moisture or potential for solvent loss is not a concern for drug products packaged in impermeable containers 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.
包装在半渗透容器中的水溶液制剂，除物理、化学、生物和微生物稳定性考察外，应考察潜在的失水性。这种考察可在如下所述的低相对湿度条件下进行，以证明其可以放在低相对湿度的环境中。
Aqueous-based products packaged in semi-permeable containers should be evaluated for potential water loss in addition to physical, chemical, biological, and microbiological stability. This evaluation can be carried out under conditions of low relative humidity, as discussed below. Ultimately, it should be demonstrated that aqueous-based drug products stored in semi-permeable containers can withstand low relative humidity environments.
对于非水或溶剂型基质的药物，可建立其他可比较的方法并报告。
Other comparable approaches can be developed and reported for non-aqueous, solvent-based products.
如果在25℃±2℃/40%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除失水外的显著变化，应增加按“一般情况”下所述的中间试验，以考察30℃时温度的影响。在加速试验放置条件下，仅失水一项发生显著性变化，不必进行中间试验。然而，应有数据证明制剂在建议的货架期贮藏在25℃，40%RH时无明显失水。
For long-term studies conducted at 25°C ± 2°C/40% RH ± 5% RH, additional testing at the intermediate storage condition should be performed as described under the general case to evaluate the temperature effect at 30°C if significant change other than water loss occurs during the 6 months’ testing at the accelerated storage condition. A significant change in water loss alone at the accelerated storage condition does not necessitate testing at the intermediate storage condition. However, data should be provided to demonstrate that the drug product will not have significant water loss throughout the proposed shelf life if stored at 25°C and the reference relative humidity of 40% RH.
包装在半渗透容器中的制剂，在40℃、不超过25%RH的条件下放置3个月，失水量与原始值相差5%，可认为有显著性变化。然而，对小容器（≤1ml）或单剂量包装容器，只要说明理由，40℃不超过25%RH放置3个月失水5%或以上是可以的。
A 5% loss in water from its initial value is considered a significant change for a product packaged in a semi-permeable container after an equivalent of 3 months’ storage at 40°C/NMT 25% RH. However, for small containers (1 mL or less) or unit-dose products, a water loss of 5% or more after an equivalent of 3 months’ storage at 40°C/NMT 25% RH may be appropriate, if justified.
可用另一种方法来进行上表推荐的参比相对湿度条件下的研究（无论是长期还是加速试验），即在高湿情况下进行稳定性研究，然后通过计算算出参比相对湿度时的失水率。具体方法是通过实验测定包装容器的渗透因子，或如下例所示，利用计算得到的同一温度下不同湿度的失水率之比得出。一个包装容器的渗透因子可以用拟包装的制剂在最差的情况下（如：系列浓度中最稀的一种）经实验测定而得。
An alternative approach to studying at the reference relative humidity as recommended in the table above (for either long term or accelerated testing) is performing the stability studies under higher relative humidity and deriving the water loss at the reference relative humidity through calculation. This can be achieved by experimentally determining the permeation coefficient for the container closure system or, as shown in the example below, using the calculated ratio of water loss rates between the two humidity conditions at the same temperature. The permeation coefficient for a container closure system can be experimentally determined by using the worst case scenario (e.g., the most diluted of a series of concentrations) for the proposed drug product.
测定失水的例子：
Example of an approach for determining water loss:
对于包装在一定包装容器、一定大小尺寸、一定装量的制剂，计算其在参比相对湿度下的失水率的方法，是用在相同温度下和实测相对湿度下测得的失水率与下表中的失水率之比相乘。但应证明在贮藏过程中，实测时的相对湿度与失水率之间呈线性关系。
For a product in a given container closure system, container size, and fill, an appropriate approach for deriving the water loss rate at the reference relative humidity is to multiply the water loss rate measured at an alternative relative humidity at the same temperature by a water loss rate ratio shown in the table below. A linear water loss rate at the alternative relative humidity over the storage period should be demonstrated.
例如，在温度40℃下，计算放置在不超过25%RH时的失水率，就是将75%RH时测得的失水率乘以3（相应的失水率之比）。
For example, at a given temperature, e.g., 40°C, the calculated water loss rate during storage at NMT 25% RH is the water loss rate measured at 75% RH multiplied by 3.0, the corresponding water loss rate ratio.
如果制剂包装在半渗透容器中，应提供适当的信息以考察失水程度。
If the drug product is packaged in a semi-permeable container, appropriate information should be provided to assess the extent of water loss.
除以下情况外，应根据本指导原则考察冷藏条件下的稳定性实验数据。
Data from refrigerated storage should be assessed according to the evaluation section of this guideline, except where explicitly noted below.
如果加速试验3至6个月期间发生显著变化，建议的货架期应根据长期试验中实际时间的数据而定。
If significant change occurs between 3 and 6 months’ testing at the accelerated storage condition, the proposed shelf life should be based on the real time data available from the long term storage condition.
如果加速试验前三个月发生显著性变化，应讨论短期偏离标签上的贮藏条件（如在运输途中或搬运中）对药物的影响。必要时可对一批制剂进行少于3个月但更频繁的测试来验证。如果前3个月已发生了显著变化，就不必继续进行6个月的试验。
If significant change occurs within the first 3 months’ 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 shipment and handling. This discussion can be supported, if appropriate, by further testing on a single batch of the drug product for a period shorter than 3 months but with more frequent testing than usual. It is considered unnecessary to continue to test a product through 6 months when a significant change has occurred within the first 3 months.
对拟冷冻贮藏的制剂，货架期应根据长期试验放置条件下实际时间的数据而定。虽然没有加速试验放置条件，但应对一批样品在略高的温度下（如：5℃±3℃或25℃±2℃）放置适当时间进行考察，以了解短期偏离标签贮藏条件对该制剂的影响。
For drug products intended for storage in a freezer, the shelf life should be based on the real time data obtained at the long term storage condition. In the absence of an accelerated storage condition for drug products intended to be stored in a freezer, testing on a single batch at an elevated temperature (e.g., 5°C ± 3°C or 25°C ± 2°C) for an appropriate time period should be conducted to address the effect of short term excursions outside the proposed label storage condition.
应酌情处理。
Drug products intended for storage below -20°C should be treated on a case-by-case basis.
当申报批次的长期稳定性数据在批准时还无法涵盖所建议的货架期时，应承诺在批准后继续进行稳定性研究，以建立确切的货架期。
When available long term stability data on primary batches do not cover the proposed shelf life granted at the time of approval, a commitment should be made to continue the stability studies post approval in order to firmly establish the shelf life.
当申报的三批生产批次长期稳定性数据已涵盖了所建议的货架期，则认为不需进行批准后的承诺。否则，有下列情况之一的也应承诺：
Where the submission includes long term stability data from three production batches covering the proposed shelf life, a post approval commitment is considered unnecessary. Otherwise, one of the following commitments should be made:
如果递交资料包含了至少三批生产规模批次的稳定性研究数据但未至货架期，应承诺继续这些研究直到建议的货架期和进行六个月的加速试验。
If the submission includes data from stability studies on at least three production batches, a commitment should be made to continue the long term studies through the proposed shelf life and the accelerated studies for 6 months.
如果递交的稳定性研究数据资料包含的生产批次少于三批，应承诺继续进行这些长期稳定性研究直到建议的货架期和进行六个月的加速试验，并补充试验的批次到至少三批，进行直到所建议的货架期的长期稳定性试验和进行六个月的加速试验。
If the submission includes data from stability studies on fewer than three production batches, a commitment should be made to continue the long term studies through the proposed shelf life and the accelerated studies for 6 months, and to place additional production batches, to a total of at least three, on long term stability studies through the proposed shelf life and on accelerated studies for 6 months.
如果递交的资料不包含生产批次稳定性数据，则应承诺用生产规模生产的前三批进行长期稳定性研究直到所建议的货架期和进行六个月的加速试验。
If the submission does not include stability data on production batches, a commitment should be made to place the first three production batches on long term stability studies through the proposed shelf life and on accelerated studies for 6 months.
除非有其他的科学依据，用于研究承诺批次的长期稳定性研究方案应与研究申报批次的方案相同。
The stability protocol used for studies on commitment batches should be the same as that for the primary batches, unless otherwise scientifically justified.
当申报批次的加速试验有显著变化而需进行中间试验时，承诺批次可进行中间试验，也可进行加速试验。然而，如果承诺批次的加速试验有显著性变化，也要进行中间试验。
Where intermediate testing is called for by a significant change at the accelerated storage condition for the primary batches, testing on the commitment batches can be conducted at either the intermediate or the accelerated storage condition. However, if significant change occurs at the accelerated storage condition on the commitment batches, testing at the intermediate storage condition should also be conducted.
申报时应采用系统评估方法来评价稳定性资料，包括物理、化学、生物和微生物测定等的结果，以及制剂的特殊性能指标（如：固体口服制剂的溶出度）。
A systematic approach should be adopted in the presentation and evaluation of the stability information, which should include, as appropriate, results from the physical, chemical, biological, and microbiological tests, including particular attributes of the dosage form (for example, dissolution rate for solid oral dosage forms).
稳定性研究的目的是根据至少三批制剂的测定结果，确定将来所有在相似条件下生产和包装的制剂的货架期和标签上的贮藏条件。批次间变异的程度有可能产生产品质量的差异，但产品在货架期内应符合质量标准的要求。
The purpose of the stability study is to establish, based on testing a minimum of three batches of the drug product, a shelf life and label storage instructions applicable to all future batches of the drug product manufactured and packaged under similar circumstances. The degree of variability of individual batches affects the confidence that a future production batch will remain within specification throughout its shelf life.
有时数据表明降解和变异非常小，以致于从数据上就可以明显看出所申请的货架期是合理的，这时通常不必进行正式的统计分析，只要提供省略的理由即可。
Where the data show so little degradation and so little variability that it is apparent from looking at the data that the requested shelf life will be granted, it is normally unnecessary to go through the formal statistical analysis; providing a justification for the omission should be sufficient.
分析那些可能会随时间变化的定量参数的一个方法是：将平均曲线的95%单侧置信限与认可标准的相交点所对应的时间点作为货架期。如果分析表明批间变异较小，最好将数据合并进行整体评估。具体做法是：先对每批样品的回归曲线的斜率和截距进行统计检验（如P值＞0.25表示无显著性差异）。如果不能合并，总的货架期可以根据其中那批货架寿命最短的时间来定。
An approach for analyzing data of a quantitative attribute that is expected to change with time is to determine the time at which the 95 one-sided confidence limit for the mean curve intersects the acceptance criterion. If analysis shows that the batch-to-batch variability is small, it is advantageous to combine the data into one overall estimate. This can be done by first applying appropriate statistical tests (e.g., p values for level of significance of rejection of more than 0.25) to the slopes of the regression lines and zero time intercepts for the individual batches. If it is inappropriate to combine data from several batches, the overall shelf life should be based on the minimum time a batch can be expected to remain within acceptance criteria.
降解关系的性质将决定是否可将数据转换为线性回归分析。通常这种关系可表示为算术或对数的一次、二次或三次函数关系。各批次及合并批次（如有必要）的数据与假定降解直线或曲线拟合程度的好坏，应该用统计方法进行检验。
The nature of the degradation relationship will determine whether the data should be transformed for linear regression analysis. Usually the relationship can be represented by a linear, quadratic, or cubic function on an arithmetic or logarithmic scale. Statistical methods should be employed to test the goodness of fit on all batches and combined batches (where appropriate) to the assumed degradation line or curve.
如果合理，在报批阶段，可依据长期储藏条件下获得的实测数据，有限外推得到超出观察时间范围外的货架期。这合理性应基于已知的降解机制、加速试验的结果、数学模型的良好的拟合度、批次规模、稳定性数据的支持程度等。然而，外推法的应用是建立在确信 “在观察范围外也存在着相同的降解关系”的基础上的。
Limited extrapolation of the real time data from the long term storage condition beyond the observed range to extend the shelf life can be undertaken at approval time, if justified. This justification should be based on what is known about the mechanisms of degradation, the results of testing under accelerated conditions, the goodness of fit of any mathematical model, batch size, existence of supporting stability data, etc. However, this extrapolation assumes that the same degradation relationship will continue to apply beyond the observed data.
任何评价不仅要考虑含量，还要考虑降解产物和其他有关的性能指标。如有必要，应注意考察质量平衡情况和不同的稳定性及降解特性。
Any evaluation should consider not only the assay but also the degradation products and other appropriate attributes. Where appropriate, attention should be paid to reviewing the adequacy of the mass balance and different stability and degradation performance.
应按照相应的国家/地区的要求，在标签上说明贮藏条件。该说明应建立在制剂稳定性研究的基础上。必要时，应有特殊说明，尤其是对不能冷冻的制剂。应避免使用如“环境条件”或“室温”这一类术语。
A storage statement should be established for the labeling in accordance with relevant national/regional requirements. The statement should be based on the stability evaluation of the drug product. Where applicable, specific instruction should be provided, particularly for drug products that cannot tolerate freezing. Terms such as “ambient conditions” or “room temperature” should be avoided.
标签上的贮藏条件直接反映制剂稳定性。失效期应标在容器标签上。
There should be a direct link between the label storage statement and the demonstrated stability of the drug product. An expiration date should be displayed on the container label.