WHO 第992号技术报告 附录4：保存时间研究通用指南

WHO 第992号技术报告 附录4：保存时间研究通用指南
Annex 4
General guidance on hold?time studies
1. Introduction and background 概述和背景
2. Glossary 术语
3. Scope 范围
4. Aspects to be considered 要考虑的方面
Reference 参考文献

1. Introduction and background 概述和背景
Manufacturers should ensure that the products that they manufacture are safe, effective and of the quality required for their intended use. Systems should be in place to ensure that pharmaceutical products are produced according to validated processes and to defined procedures. Manufacturing processes should be shown to be capable of consistently manufacturing pharmaceutical products that are of the required quality and that comply with their specifications.
生产商必须保证其生产的产品安全有效，具有其既定用途所需要的质量。应有一个系统来保证药品是根据经过验证的工艺和既定的程序生产的。生产工艺应具备持续生产出具有所需的质量，并符合其质量标准的药品的能力。
Good manufacturing practices (GMP) require that arrangements should be made to ensure that the dispensed raw materials and packaging materials, intermediate products, bulk and finished products are stored under appropriate conditions. Storage arrangements should not have deleterious effects on the subsequent processing, stability, safety, efficiency or quality of starting materials, intermediate products and bulk products prior to final packing. Maximum acceptable holding periods should therefore be established to ensure that intermediates and bulk product can be held, pending the next processing step, without producing results outside the acceptance criteria for the quality of the material. Normally, intermediate and bulk products should not be stored beyond the established hold time.
优良生产规范（GMP）要求必须做出适当的安排来保证分好的原料、包材、中间产品、散装产品和包装后的成品存贮在适当的条件下。存贮条件不应对随后的工艺、稳定性、安全性、有效性或起始原料、中间体产品和包装前的散装产品的质量产生不良影响。因此应设定最长的可接受保存时间来保证中间体和散装产品可以在下一工序前的保存不会使得原料质量超出可接受标准。通常，中间体和散装产品存贮时间不应超过设定的保存时间。
The choice of maximum holding period should be supported by relevant data. Studies may extend beyond the chosen maximum but it is not necessary to extend testing to determine the extreme limits at which failure occurs.
最长保存时间的选择应有相应的数据来支持。研究可以延长超过所选的最长时间，但没有必要将检测延长直到检验结果超出标准。
2. Glossary 术语
Some important terms used in these guidelines are defined below. They may have different meanings in other contexts.
本指南中所用的一些重要术语定义如下。他们可能在其它语境中有不同含义。
Bulk product. Any pharmaceutical product that has completed all processing stages up to, but not including, final packaging.
散装产品：完成了所有工序直到，但还没有完成最终包装的制剂成品。
Intermediate. Partly processed product that must undergo further manufacturing steps before it becomes a bulk product.
中间体：完成部分工序，必须要经过进一步生产工序才能成为散装成品的部分加工产品。
3. Scope 范围
These guidelines focus primarily on aspects that should be considered in the design of the hold?time studies during the manufacture of non?sterile solid dosage forms. Many of the principles described here also apply to other dosage forms such as liquids, creams and ointments. These guidelines do not cover aspects for hold times in cleaning validation, or the manufacturing of active pharmaceutical ingredients (APIs) or biological.
这些指南主要关注非无菌固体制剂保存时间研究设计中要考虑的问题。其中描述的许多原则也适用于其它剂型，例如液体、乳霜和软膏。这些指南不包括清洁验证或原料药或生物制剂的生产中保留时间的问题。
These guidelines are intended as a basic guide for use by manufacturers of pharmaceuticals and by GMP inspectors. This document is not intended to prescribe a process for establishing hold times, but reflects aspects that should be considered in the design of the hold?time study.
这些指南意在作为一个药品生产商和GMP检查员使用的基本指南。本文件无意描述建立保存时间的流程，而只是反映在保存时间研究设计中所需考虑的问题。
Manufacturers should gather scientific and justifiable data to demonstrate that the dispensed raw materials and packaging materials, intermediate and bulk products:
生产商应收集可以论证的科学数据来证明分装后的原料和包材、中间体和散装产品：
-     remain of appropriate quality before processing to the next stage;
-     在加工至下一工序时保持适当的质量
-     meet the acceptance criteria.
-     符合可接受标准
The finished product should meet the release specifications.
制剂成品应符合放行标准。
4. Aspects to be considered 要考虑的问题
Hold time can be considered as the established time period for which materials (dispensed raw materials, intermediates and bulk dosage form awaiting final packaging) may be held under specified conditions and will remain within the defied specifications.
保存时间可以认为是已建立的某种物料（分装后的原料、中间体和散装待包装的制剂）在指定条件下可以保存并能维持其质量在既定质量标准内的时间长度。
Hold?time studies establish the time limits for holding the materials at different stages of production to ensure that the quality of the product does not produce results outside the acceptance criteria during the hold time. The design of the study should reflect the holding time at each stage.
保存时间研究建立不同生产工序物料保存的时间限度，以保证产品的质量不会在保存时间内超出可接受标准。研究设计应反映各工序的保存时间。
Hold times should normally be determined prior to marketing of a product. The risk assessment of changes in processes, equipment, storage conditions, starting or packaging materials should include an assessment of whether further hold?time studies should be performed. Hold?time studies may be included during development on pilot?scale batches or during scale?up, and should be confirmed during process validation of commercial?scale processing (1). Further data can also be collected as part of an investigation of a deviation that occurred during manufacture.
保存时间通常应在产品上前确定。工艺、设备、存贮条件、起始物料或包材变更的风险评估应包括是否需要进一步进行保存时间研究的评估。保存时间研究可以包括在研发过程中的中试规模中，也可以是在放大生产过程中，还应该包括在商业规模工艺验证中。也可以从生产过程发生的偏差调查中收集更多信息。
Manufacturers may use a flow chart to review the manufacturing procedure for a product and then break up the critical stages of the manufacturing process on the basis of the time period required for the particular storage and processing stages, typical pauses in the manufacturing campaign, and the potential impact of storage with reference to environmental and storage conditions. An example of a flow chart is given in Figure A4.1.
生产商可以使用工艺流程图对生产过程进行审核，将生产工艺的关键工序根据需要特殊存贮和加工过程的时间，以及环境和存贮条件的潜在影响进行划分，通常物料会在生产周期中进行停顿。
As an example, for oral tablets that are coated, the following stages may be considered:
例如对于要包衣的口服片剂，可以考虑以下工序：
-     binder preparation to granulation – consider the granulate;
-     粘合剂制备到制粒---考虑颗粒
-     wet granulation to drying – consider the dried granulate;
-     湿法制粒到干燥----考虑干燥后的颗粒
-     dried granules to lubrication/blending – consider the lubricated blend;
-     干燥后的颗粒到润滑混合---考虑有润滑的混合
-     blend to compression;
-     混合到压片
-     compression to coating – consider the tablet cores;
-     压片到包衣----考虑片芯
-     coating solution to preparation – consider the coating solution;
-     包衣溶液到制备---考虑包衣溶液
-     coating to packing – consider the bulk coated tablets;
-     包衣到包装---考虑散装包衣片
-     coating to packing in bulk;
-     包衣到包装至散装成品
-     packing of bulk to finished packed dosage form.
-     散装包装至制剂成品


Figure A4.1 Example of a flow chart for reviewing the manufacturing procedure

WHO 第992号技术报告 附录4：保存时间研究通用指南 - Julia - 成功是永远的追逐，追逐是永远的成功

A written protocol, procedure or programme should be followed, which includes, for example, the activities to be performed, test parameters and acceptance criteria appropriate to the material or product under test. The protocol and report should generally include the following: a title; reference number; version; date; objective; scope; responsibility; procedure; description of the material or product; sample quantities; sampling method and criteria; acceptance limits; frequency of sampling; sampling locations; pooling of samples; storage conditions; type of container; methods of analysis; results; conclusion; recommendation; signatures; and dates. Acceptance criteria are typically more stringent than registered specifications, to provide assurance that the material is well within control. When setting the specifications, any known stability trends will need to be taken into account.
应遵守一份书面的方案、程序或计划，其中应包括，例如，要实施的活动、适合于物料或产品的检验项目和可接受标准。方案和报告通常应包括以下内容：标题、文件编号、版本号、日期、目标、范围、职责、流程、物料或产品的描述、样品量、取样方法和标准、可接受限度、取样频次、取样点、取样规则、存贮条件、容器类型、分析方法、结果、结论、建议、签名和日期。可接受标准通常会比注册的质量标准更严格，以保证原料很好地受到控制。在设定质量标准时，需要考虑所有已知的稳定性趋势。
For certain products, microbiological aspects should also be considered and included where appropriate.
对于特定的产品，还需要考虑微生物方面的问题，适当时应包括在研究中。
All testing of bulk intermediates and product should be performed using validated stability?indicating methods.
所有散装中间体和产品的检测应使用经过验证的可以指示稳定性的方法。
Typically one or more batches of a material, intermediate or product can be used for determining hold times. A risk?based approach can be used to determine the appropriate number of batches, considering the characteristics of the materials and other relevant aspects. A representative sample of the batch of material or product subjected to the hold?time study should be held for the defined hold period. The hold period for each category of material should be established on the basis of the study by keeping the material in either the original or simulated container used in production. The containers in which hold?time samples are stored should be the same pack as is used in production unless the pack is exceptionally large, in which case one that is equivalent (constructed of the same material and using the same closure system as the production packaging system) may be used. Reducing the size of container, when this is necessary for testing holding time, should be justified.
通常可以使用一批或多批物料、中间体或产品来确定保存时间。可以使用基于风险的方法来确定批次数，同时考虑物料的特性和其它相关方面。进行保存时间研究的物料或产品批次的代表性样品要保存至指定的时长。每类物料的保存时间应根据保存在生产中使用的原装或模拟容器中的物料的研究制订。用于保存时间研究的样品存贮所用的容器应与生产中所用的包装相同，除非该包装实在太大，这时应使用一个相等同的容器（材质相同，使用与生产相同的密闭系统）。如果在保存时间测试中必须减小容器尺寸，则应进行论证。
Where the headspace of containers used for bulk storage in manufacturing and/or quarantine is important, for example, because of a risk of potential degradation as a result of oxidation, then the hold?time studies should represent worst?case conditions. In such cases, the ratio of headspace to contents in the test containers should be at least as great as the maximum that is possible in routine production (especially taking into account part?filed containers). The environmental conditions for sample storage should be the same as those of the quarantine area/manufacture stage. A sampling plan should be established and followed for taking samples for testing at the different intervals. The amount of sample required should be calculated based on the batch size, the intervals, and the tests to be performed. Results should be compared with the initial baseline data on the control sample. Samples may be pooled for analysis where appropriate, e.g. when the analysis of a composite sample will not lead to issues that would be detectable in single samples being missed when the samples are pooled.
如果生产和/或暂存过程中用于散装存贮的容器的顶部空间非常重要，例如，因为氧化引起可能的降解风险，则保存时间研究应代表最差情形时的条件。在这种情况下，顶部空间与受试容器容量的比例应至少大于常规生产中可能的最大情形（特别要考虑半满容器）。样品存贮的环境条件应与暂存区域/生产工序的条件相同。应建立并遵守取样计划，以在不同时间间隔取样检测。应根据批量、时间间隔和要检验的项目计算所需的样品数量。应装结果与受控样品的初始数据进行比较。适当时，样品可以放在一起分析，例如，将样品合并分析不会导致单独样品分析可检出的问题被忽略时。
Where appropriate, statistical analysis of the data generated should be performed to identify trends and to justify the limits and hold time set.
适当时，应将所获得的数据进行统计学研究，以找出趋势，判定限度和保存时间对应关系。
Batches of finished products made from intermediates or bulk products and subjected to a hold?time study should be considered for long?term stability testing if data show adverse trending or shifting patterns during the intermediate time points up to the end of the shelf?life. The shelf?life of the product – irrespective of hold times – should be measured from the time the active ingredients are mixed with other ingredients. Normally, intermediate and bulk products should not be stored beyond the established hold time.
从中间体或散装产品生产，并经过保存时间研究的制剂批次可以考虑用作长期稳定性试验，以查看在中间时间点到货架期结束时的数据是否显示出不良趋势。产品的货架时间---不考虑保存时间---应从活性成分与其它成分混合的时间开始计算。通常，中间体和散装产品的存贮时间不应超过所建立的保存时间。
Table A4.1 provides examples of stages, study times and tests that may be considered for a coated tablet.
表A4.1给出了在包衣片中可以考虑的工序、研究时间和检测的例子。
Table A4.1 Examples of stages, study times and tests that may be considered, based on risk assessment and specific product needs
表A4.1： 根据风险评估和特定的产品需求拟定的工序、研究时间点举例
Stage
Test to be carried out as per specification
Study time
工序
根据质量标准要检测的项目
研究时间点
Binder preparation
Microbial test, appearance, viscosity, if applicable
Initial, 2, 5, 8 hours. In case of starch: initial, 2, 5 hours
粘合剂制备
微生物测试、外观、粘度，适用时
第0、2、5、8小时
淀粉：第0、2、5小时
Dispersions prepared (including granulation pastes, coating solution and coating suspension
Physical appearance, specific gravity, viscosity, sedimentation, pH, microbial test
Initial, 12, 24, 36, 48, 60, 72 hours
分散剂制备（包括制粒糊、包衣溶液和包衣混悬液）
物理外观、比重、粘度、沉淀、微生物测试
第0、12、24、36、48、60、72小时
Granule
Description, assay, related substances, loss on drying, water content, particle size distribution, bulk density, tap density, angle of repose
Initial, 15th day, 30th day, 45th day
颗粒
性状、含量、降解产品/相关物质、干燥失策重、水分、粒径分布、堆密度、击拍密度、休止角
第0、15、30、45天
Blend
Microbial test, loss on drying, blend uniformity, particle size, bulk/tapped density
Initial, 15th day, 30th day, 45th day
混合
微生物测试、干燥失重、混合均一性、粒径分布、堆密度/击拍密度
第0、15、30、45天
Core tablets – uncoated (in bulk container)
Description, hardness, thickness, friability, disintegration, dissolution or dissolution profile, assay, degradation products/related substance, uniformity of dosage units, microbial test
Initial, 30th day, 45th day, 60th day and 90th day
素片---未包衣（在散装容器中）
性状、硬度、厚度、脆碎度、分散度、溶出度或溶出概况、含量、降解产品/相关物质、剂量均匀性、微生物测试
第0、30、45、60、90天
Coated tablets (in bulk container)
Description, appearance or visual examination, hardness, thickness, friability, disintegration, dissolution or dissolution profile, assay, degradation products/related substance, moisture content, microbial test
Initial, 30th day, 45th day, 60th day and 90th day
包衣后片剂（散装容器内）
性状、外观或目视检查、硬度、厚度、脆碎度、分散度、溶出度或溶出概况、含量、降解产品/相关物质、水分、微生物测试
第0、30、45、60、90天

Reference 参考文献
1. Supplementary guidelines on GMP: validation, non-sterile process validation. In: WHO Expert Committee on Specifiations for Pharmaceutical Preparations: forty-ninth report. Geneva: World Health Organization; 2015: Annex 3 (WHO Technical Report Series, No. 992).
GMP补充指南：验证，非无菌工艺验证。WHO专家委员会制剂质量标准：第49号报告，日内瓦，WHO，2015：附录3（WHO技术报告第992号）。

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