1、Zhulikou431 内部培训 2012 中国 In use stability专题研究谨记 纸上得来终觉浅， 绝知此事要躬行！ -陆游 1.本培训资料参考文献更新至20121101. 2.本专题资料主要针对药品 in use stability研究。 3.任何宝贵建议，请联系.目录（contents） 第01章：概念解析 第02章：中国药典对药品使用期间稳定性要求 第03章：cde指导原则对药品使用期间稳定性要求 第04章：EMA指南对药品使用期间稳定性要求 第05章：WHO对药品使用期间稳定性要求 第06章：cde电子刊物对药品使用期间稳定性要求 第07章：其他法规文献阐述In use
2、stability专题研究 第01章：in use stability概念解析 In use stability，顾名思义，指的是药品使用期间稳 定性研究项目。 对于如下使用条件的药品，需要考察in use stability 项目： -药品使用前，需要重新配置或者稀释； -药品标签声明，和其他药品混合仍然具有稳定性； -药品包装多次打开以后，药品需要继续保持质量稳 定性。In use stability专题研究 第02章：中国药典对药品使用期间稳定性要求 中国药典2010版附录XIX C原料药与药物制剂 稳定性试验指导原则也要求： 此外，有些药物制剂还应考察临用时配制和使用 过程中的稳定性。
3、In use stability专题研究 第03章：cde指导原则对药品使用期间稳定性要求 中国cde2005年发布了化学药物稳定性研究技术指导 原则，其中对于in use stability，进行了明确规 定： 稳定性试验要求在一定的温度、湿度、光照条件下进 行，这些放置条件的设置应充分考虑到药品在贮存、 运输及使用过程中可能遇到的环境因素。 对于需要溶解或者稀释后使用的药品，如注射用无菌粉 末、溶液片剂等，还应考察临床使用条件下的稳定性。In use stability专题研究 第04章：EMA指南对药品使用期间稳定性要求 2001年3月，EMA发布了NOTE FOR GUIDANCE O
4、N IN-USE STABILITY TESTING OF HUMAN MEDICINAL PRODUCTS，专门对此问题进行法 规阐述。In use stability专题研究 4.1-Objective 4.2-Scope 4.3-Introduction 4.4-Selection of batches 4.5-Test design 4.6-Test storage conditions 4.7-Test parameters 4.8-Analytical procedures 4.9-Presentation of the results 4.10-Evaluation 4.11-L
5、abelling of the primary container 4.12-SPC, leaflet and labelling of the secondary containerIn use stability专题研究 Objective The purpose of in-use stability testing is to establish - where applicable - a period of time during which a multidose product can be used whilst retaining quality within an acc
6、epted specification once the container is opened.In use stability专题研究 Scope This guideline refers to medicinal products in multidose containers which - by nature of their physical form and chemical composition - due to repeated opening and closing, may pose a risk to its content with regard to micro
7、biological contamination, proliferation and/or physicochemical degradation once the closure system has been breached.In use stability专题研究 Introduction The continued integrity of products in multidose containers after the first opening is an important quality issue. While this principle is acknowledg
8、ed in the Ph. Eur. and EU Guidelines, no specific guidance is available on defining test design and conduct of studies to be undertaken to define in-use shelf life in a uniform fashion. Therefore, this document attempts to define a framework for selection of batches, test design, test storage condit
9、ions, test parameters, test procedures etc., taking into consideration the broad range of products concerned.In use stability专题研究 Nevertheless should this Note for guidance also be read in connection with the Notes for guidance on Development pharmaceutics (CPMP/QWP/155/96), Stability testing of exi
10、sting active substances and related finished products (CPMP/QWP/556/96) and Stability testing of new drug substances and products (CPMP/ICH/2736/99).In use stability专题研究 The registration dossier for a multi-dose product should include either the in-use stability data on which the in-use shelf life i
11、s based or a justification why no in-use shelf life is established. This justification can also be based on experimental results.In use stability专题研究 Selection of batches批次选择 A minimum of two batches, at least pilot scale batches, should be subjected to the test. At least one of the batches should b
12、e chosen towards the end of its shelf life. If such results are not available, one batch should be tested at the final point of the submitted stability studies. The batch number, date of manufacture and size of each batch should be stated. The container and closure of the product and, if present, th
13、e medicinal device should be equivalent to that proposed for marketing. 这项测试，需要批次要求：最少2批次，最低要求是中试规模批 次。最少其中1批的研究要进行到有效期结束。如果不能获得 这样的数据，应该在稳定性研究终点进行测试。In use stability专题研究 If the product is to be supplied in more than one container size or in different strengths, the inuse stability test should be ap
14、plied to the product which presents the greatest susceptibility to change. The choice of the tested product should always be justified.In use stability专题研究 Test design As far as possible the test should be designed to simulate the use of the product in practice taking into consideration the filling
15、volume of the container and any dilution/reconstitution before use. At intervals comparable to those which occur in practice appropriate quantities should be removed by the withdrawal methods normally used and described in the product literature. Sampling should take place under normal environmental
16、 conditions of use.In use stability专题研究 The appropriate physical, chemical and microbial properties of the product susceptible to change during storage should be determined over the period of the proposed in- use shelf life. If possible, testing should be performed at intermediate time points and at
17、 the end of the proposed in-use shelf life on the final remaining amount of the product in the container.In use stability专题研究 Test storage conditions The product should be stored under the conditions as recommended in the product literature (SPC and PIL) throughout the in-use stability test period.
18、Any other storage conditions should be justified.In use stability专题研究 Test parameters The appropriate physical, chemical and microbial properties of the product susceptible to change during use should be monitored. The tests used must be appropriate to individual dosage forms, however, examples of p
19、arameter types which may need to be studied are given below: Physical: colour, clarity, closure integrity, particulate matter, particle size Chemical: active substance assay(s), antimicrobial preservative and antioxidant content(s), degradation product level(s), pH Microbial: Total viable count, ste
20、rilityIn use stability专题研究 Analytical procedures The analytical procedures used in the study should be described and fully validated. Stability indicating assays should be employed.In use stability专题研究 Presentation of the results The results should be summarized and tabulated.If relevant, the result
21、s should be presented graphically.In use stability专题研究 Evaluation Conclusions reached based on the data provided should be stated. In the case of anomalous results these should be explained.Where applicable and justified an in-use shelf life specification should be given. In-use stability data shoul
22、d be used to determine whether or not a declaration of an in-use shelf life and additional storage conditions are necessary.In use stability专题研究 Labelling of the primary container The in-use shelf life should be stated on the label. In addition (if space allows) there should be a space for the user
23、to write the date of opening or the “use-by“ date.In use stability专题研究 SPC, leaflet and labelling of the secondary container The in-use shelf life and in-use storage recommendations - if applicable - should be included in SPC, leaflet and outer carton text.In use stability专题研究 第05章：WHO对药品使用期间稳定性要求 在
24、2009年，WHO发布了Technical Report Series, No. 953。其中，附录2Stability testing of active pharmaceutical ingredients and fi nished pharmaceutical products对药 品使用期间稳定性进行了明确要求。In use stability专题研究 2.2.10 In-use stability The purpose of in-use stability testing is to provide information for the labelling on the pr
25、eparation, storage conditions and utilization period of multidose products after opening, reconstitution or dilution of a solution, e.g. an antibiotic injection supplied as a powder for reconstitution.In use stability专题研究 As far as possible the test should be designed to simulate the use of the FPP
26、in practice, taking into consideration the fi lling volume of the container and any dilution or reconstitution before use. At intervals comparable to those which occur in practice appropriate quantities should be removed by the withdrawal methods normally used and described in the product literature
27、.In use stability专题研究 The physical, chemical and microbial properties of the FPP susceptible to change during storage should be determined over the period of the proposed in-use shelf-life. If possible, testing should be performed at intermediate time points and at the end of the proposed in-use she
28、lf-life on the fi nal amount of the FPP remaining in the container. Specifi c parameters, e.g. for liquids and semi-solids, preservatives, per content and effectiveness, need to be studied.In use stability专题研究 A minimum of two batches, at least pilot-scale batches, should be subjected to the test. A
29、t least one of these batches should be chosen towards the end of its shelf-life. If such results are not available, one batch should be tested at the fi nal point of the submitted stability studies.In use stability专题研究 This testing should be performed on the reconstituted or diluted FPP throughout t
30、he proposed in-use period on primary batches as part of the stability studies at the initial and final time points and, if full shelf-life,long-term data are not available before submission, at 12 months or the last time point at which data will be available. In general this testing need not be repe
31、ated on commitment batches (see 2.2.10).In use stability专题研究 第06章：cde电子刊物对药品使用期间稳定性要求 20051206关于化学药品稳定性试验的五个问题，其中提到： 4、注射剂配伍试验稳定性考察的要求是什么？ 答：针对部分药品，如小针、粉针，在临床上需与其它输液 配伍后使用，需进行配伍试验，以考察药品在与输液配伍后 的稳定性。 一般情况下，配伍试验需考察8小时内样品的稳定性。取样点 的设置通常为0.5、1、2、4、6、8小时。如果样品在4小时测 定结果不稳定，2小时内稳定，那么必须在说明书上明确注 明，样品应在配伍后2小时内滴
32、完，以保证药品的稳定性，保 证临床用药的安全。In use stability专题研究 2010年，药物使用期间稳定性试验的技术要求 探讨对此问题进行比较全面的阐述。In use stability专题研究 第07章：其他法规文献阐述 7.1 VICH 指南Stability Testing of New Veterinary Drug Substances and Medicinal Products (Revision) ，这是兽药研究的权威指南。 7.2-1998年，资深法规专家Scott Sutton在THE REGULATORY AFFAIRS JOURNAL杂志上面撰文，论述 此问
33、题。IN-USE STABILITY TESTING:WHAT DATA ARE REQUIRED ANDWHEN?。 7.3-TGAAustralian regulatory guidelines for prescription medicines-Appendix 14: Stability testing 指南也对此问题进行了阐述。In use stability专题研究 例如，TGA指南提到： In-use stability data should be generated where relevant, for example: where the product must be
34、 reconstituted or diluted prior to use; where the product is claimed to be stable when mixed with other products; where the product may be labile once the container is opened.In use stability专题研究 The stability of the in-use form of the product should be established for the period of time and under t
35、he conditions for which storage is recommended. Published papers may be submitted as evidence of in-use stability provided they can be shown to be relevant to the formulation proposed for registration, and they include sufficient detail to allow independent evaluation. In use stability专题研究 Where it
36、is claimed (on the label or in the Product Information, PI) that the product may be diluted with a range of solutions, the most common example being parenteral medicines diluted in large volume intravenous infusions, stability data should establish compatibility with each recommended diluent at the extremes of the recommended dilution ratios for the permitted duration of storage.感谢聆听！ Have any questions, please contact me at
