鼻腔和口腔吸入制剂指导原则-EMA（翻译版）.pdf

1、 7 Westferry Circus,Canary Wharf,London,E14 4HB,UK Tel.(44-20)74 18 84 00 Fax(44-20)74 18 85 95 E-mail:mailemea.eu.int http:/www.emea.eu.int EMEA 2006 Reproduction and/or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged European Medicines

2、 Agency Inspections London,21 June 2006 Doc Ref.:EMEA/CHMP/QWP/49313/2005 Corr COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP)GUIDELINE ON THE PHARMACEUTICAL QUALITY OF INHALATION AND NASAL PRODUCTS DRAFT AGREED BY QUALITY WORKING PARTY October 2004 ADOPTION BY CHMP FOR RELEASE FOR CONSULTATIO

3、N 19 January 2005 END OF CONSULTATION(DEADLINE FOR COMMENTS)30 July 2005 AGREED BY QUALITY WORKING PARTY February 2006 ADOPTION BY CHMP 23 March 2006 DATE FOR COMING INTO EFFECT 1 October 2006 Note:This Guideline has been prepared in collaboration with Health Canada and represents a harmonised guide

4、line.It replaces the QWP Guidelines on pressurised Metered Dose Inhalation Products(pMDIs)and Dry Powder Inhalers(DPI)and is complementary to the existing Efficacy Working Party Guideline on Orally Inhaled Products(OIP).The final Guideline has been adapted to the EU template for Guidelines.MEA/CHMP/

5、QWP/49313/2005 Corr EMEA 2006 GUIDELINE ON THE PHARMACEUTICAL QUALITY OF INHALATION AND NASAL PRODUCTS TABLE OF CONTENTS COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP).1 1.INTRODUCTION .1 2.SCOPE.1 4.1 DRUG SUBSTANCE SPECIFICATION .2 4.2 DRUG PRODUCT PHARMACEUTICAL DEVELOPMENT .3 4.2.1 Inhala

6、tion Products .4 4.2.1.1 Physical characterisation(CTD 3.2.P.2.1.1 and 3.2.P.2.1.2).7 4.2.1.2 Minimum Fill Justification(CTD 3.2.P.2.2.2).7 4.2.1.3 Extractables/Leachables(CTD 3.2.P.2.4).7 4.2.1.4 Delivered dose uniformity and fine particle mass through container life (CTD 3.2.P.2.4).8 4.2.1.5 Deliv

7、ered dose uniformity and fine particle mass over patient flow rate range（CTD 3.2.P.2.4)9 4.2.1.6 Fine particle mass with spacer/holding chamber use(CTD 3.2.P.2.4).9 4.2.1.7 Single dose fine particle mass(CTD 3.2.P.2.4).10 4.2.1.8 Particle/droplet size distribution(CTD 3.2.P.2.4).11 4.2.1.9 Actuator/

8、Mouthpiece deposition(CTD 3.2.P.2.4).11 4.2.1.10 Drug delivery rate and total drug delivered(CTD 3.2.P.2.4).12 4.2.1.11 Shaking requirements(CTD 3.2.P.2.4).12 4.2.1.12 Initial priming of the container(CTD 3.2.P.2.4).12 4.2.1.13 Re-priming of the container(CTD 3.2.P.2.4).12 4.2.1.14 Cleaning requirem

9、ents(CTD 3.2.P.2.4).13 4.2.1.15 Low temperature performance(CTD 3.2.P.2.4).13 4.2.1.16 Performance after temperature cycling(CTD 3.2.P.2.4).14 4.2.1.17 Effect of environmental moisture(CTD 3.2.P.2.4).14 4.2.1.18 Robustness(CTD 3.2.P.2.4).14 4.2.1.19 Delivery device development(CTD 3.2.P.2.4 and 3.2.

10、R).15 4.2.1.20 Preservative effectiveness/efficacy(CTD 3.2.P.2.5).16 4.2.1.21 Compatibility(CTD 3.2.P.2.6).16 4.2.2 Nasal Products .16 4.3 DRUG PRODUCT MANUFACTURE.19 4.4 EXCIPIENTS .19 4.4.1 Pharmacopoeial Excipients .20 4.4.2 Non-Pharmacopoeial Excipients .21 4.5 DRUG PRODUCT SPECIFICATION(S).21 4

11、.5.1 Inhalation Products .22 4.5.1.1 Description .23 4.5.1.2 Assay .23 4.5.1.3 Moisture Content .23 4.5.1.4 Mean Delivered Dose .24 4.5.1.5 Delivered Dose Uniformity .24 4.5.1.6 Content Uniformity/Uniformity of Dosage Units .24 MEA/CHMP/QWP/49313/2005 Corr EMEA 2006 4.5.1.7 Fine Particle Mass .24 4.

12、5.1.8 Leak Rate .25 4.5.1.9 Microbial/Microbiological Limits .25 4.5.1.10 Sterility .25 4.5.1.11 Leachables .25 4.5.1.12 Preservative content .26 4.5.1.13 Number of actuations per container .26 4.5.2 Nasal Products .26 4.5.2.1 Particle/Droplet Size Distribution.26 4.6 DRUG PRODUCT CONTAINER CLOSURE

13、SYSTEM .28 4.7 DRUG PRODUCT STABILITY .29 APPENDIX I:.33 APPENDIX II:.36 APPENDIX III:.39 MEA/CHMP/QWP/49313/2005 Corr EMEA 2006 page 1/39 译文：魏利军 邮箱： 1.INTRODUCTION 介绍介绍 This guidance document applies to human medicinal products intended for delivery of the drug substance into the lungs,or to the na

14、sal mucosa,with the purpose of evoking a local or systemic effect.该指南文件适用于递送药物到肺部或鼻腔引起局部或全身效应的人用药品。The document outlines expected quality aspects of drug products to be marketed,but the general principles described here should also be considered for products used in clinical trials.It is not expecte

15、d that all described testing would be conducted on all clinical trial batches.However,extensive characterisation of the drug substance and drug product batches used in pivotal clinical trials is necessary to qualify the product proposed for marketing.文件概述了上市药品预期的质量，对于临床试验所用药品，此文件描述的一般原则也应加以考虑。并不希望每一

16、批用于临床试验的药品都开展每一项所述的测试，然而在关键性临床试验中，广泛地表征药品及其原料药以明确其上市后的特性是有必要的。Only quality aspects specific to inhalation and nasal products are discussed,although the need for safety testing(e.g.,for excipients and leachables)is also addressed.Additional quality aspects(e.g.,impurities,process validation,stability

17、 testing,specifications)as well as safety and efficacy aspects,are described in other guidance documents,including ICH guidelines.在此只对吸入制剂和鼻药产品质量方面的特殊问题进行讨论，尽管安全性测试（如辅料和析出物）也亟待解决。更多质量方面（如杂质、工艺验证、稳定性试验、质量标准）、安全性方面和有效性方面的内容，已在其它指南中描述，包括 ICH 指南。Detailed guidance on pharmaceutical development study desi

18、gns(e.g.,priming studies)and the analytical procedures used primarily for inhalation and nasal products(e.g.,cascade impactor analysis)has not been provided.Some of this information may be found in other publications(e.g.,United States Pharmacopeia,European Pharmacopoeia,ISO standards).It is also re

19、cognised that the wide diversity of inhalation and nasal products with respect to formulation and delivery device characteristics necessitates some flexibility in testing methodology.有关药学开发研究设计（如灌注研究）和主要用于吸入制剂和鼻药产品的分析过程的详细指南已在文中列出，其中某些部分信息也可能在其它出版物（如美国药典、欧洲药典、国际标准）中发现。人们已意识到吸入制剂和鼻药产品在处方和递送装置特性的巨大差异，

20、而这种差异早就了测试方法学的灵活性。2.SCOPE 范围范围 The document addresses new marketing authorisation applications(including for generic products)and does not outline expected quality aspects related to changes in existing inhalation and nasal products.However,the general principles described here should also be consid

21、ered when making changes to existing products.MEA/CHMP/QWP/49313/2005 Corr EMEA 2006 page 2/39 译文：魏利军 邮箱： 文件提出新药上市批准申请（也包括仿制药品），并没有作有关吸入制剂和鼻药产品的质量方面发生变化的概述。然而在当更改现有的产品时，此处描述的一般原则也应考虑。This guidance document has been developed for products containing drug substances of synthetic or semi-synthetic orig

22、in.However,the general principles described here should also be considered for other inhalation and nasal products.对于含合成和半合成原料药来源的产品，该指南文件已经发展成熟。然而对于其它类型的吸入制剂和鼻药产品，此处描述的一般原则应该考虑。This document includes products for administration of the drug substance to the lungs,such as pressurised metered dose inh

23、alers,dry powder inhalers,products for nebulisation,and nonpressurised metered dose inhalers,as well as pressurised metered dose nasal sprays,nasal powders,and nasal liquids.Liquid inhalation anaesthetics and nasal ointments,creams and gels are excluded.该文件涵盖了除液体吸入型麻醉剂、鼻腔软膏、霜剂和凝胶剂以外的各种肺部给药产品，如加压计量型气

24、雾剂、干粉吸入剂、喷雾剂、非加压计量型气雾剂、加压计量型鼻腔气雾剂、鼻腔粉剂、滴鼻液。3.LEGAL BASIS Directive 2001/83/EC,as amended.4.MAIN GUIDELINE TEXT 4.1 DRUG SUBSTANCE SPECIFICATION 原料药标准 For all inhalation and nasal products containing a drug substance that is not in solution at any time during drug product manufacture,storage or use,t

25、he drug substance specification should include a particle size test and limits.A validated particle sizing method(e.g.,laser diffraction),with acceptance criteria set at multiple points across the size distribution,should be employed.所有吸入剂和鼻药产品在生产、储存或使用过程中原料药并非一直是溶液状态存在，原料药质量标准中应规定粒度检测项和相应的限度，应使用经过验

26、证的粒度测定方法（比如激光散射）进行粒度检测，而且在粒度分布范围内应指定多个粒径下的检验标准。Acceptance criteria should assure a consistent particle size distribution in terms of the percentage of total particles in given size ranges.The median,upper,and/or lower particle size limits should be well-defined.Acceptance criteria should be set base

27、d on the observed range of variation,and should take into account the particle size distribution of batches that showed acceptable performance in vivo,as well as the intended use of the product.Process capability and stability data may also be considered,provided the proposed acceptance criteria hav

28、e been suitably qualified.MEA/CHMP/QWP/49313/2005 Corr EMEA 2006 page 3/39 译文：魏利军 邮箱： 检验标准应包括在规定粒度范围下粒子数占总粒子数的百分比，中间，最大和最小等粒度限度都需要明确规定。检验标准的确定应基于实测的粒度范围差异之上，综合考虑多批不同粒度分布的产品在体内表现出的可接受性能差异，其也包括将要用在临床上的产品。工艺的批量和稳定性数据也应该关注，提供的拟定标准应经过适当资质的确证。If alternative sources of drug substance are proposed,evidence

29、of equivalence should include appropriate physical characterisation and in vitro performance studies(see also Drug Product Pharmaceutical Development).如果是申请变更原料药来源，应提供包括适当的物理性质和体外性能研究（参见药品药物开发）在内的等效性证据。4.2 DRUG PRODUCT PHARMACEUTICAL DEVELOPMENT 药品开发 Pharmaceutical development studies are conducted

30、to establish that the dosage form,formulation,manufacturing process,container closure system,microbiological attributes and instructions for use are appropriate and result in acceptable product performance.药品开发是指确立剂型，处方，工艺，储药器和密封系统，微生物属性，合理使用说明的整个过程，以及符合以上要求的产品性能。It is generally expected that the de

31、velopment tests be conducted on more than one batch,so that batch variability is taken into account.For a single strength and a single container closure system,testing two batches should be sufficient.For products packaged in container closure systems that also serve as the delivery device,tests tha

32、t involve delivery of the formulation should also be conducted on more than one batch of the container closure system.In the case of multiple strengths and multiple package sizes,a bracketing and/or matrixing design may be used to limit the number of test samples necessary.Justification should be pr

33、ovided.普遍认为药品开发时应对多批产品进行检验，以分析批间的差异。对于单规格和单储药器的产品，检测两批即可。对于产品密封在递送装置中的多剂量型产品，应在多批次储药器的基础上研究递送配方的性能。如果是多个规格和多个包装尺寸的产品，有必要用括号法或矩阵化设计来限制样本数量，同时提供相应的理由。Sufficient data should be provided to support the specifications proposed or to give adequate assurance that those performance characteristics which may not be routinely tested(e.g.,priming and testing to exhaustion)have been adequately investigated.It