Guidance 11: Drug Master Files and Certificates of Suitability of a Monograph of the European Pharmacopoeia for drug substances
指南11：药用物质的药物主文件（DMF）和欧洲药典适用性证书（CEP）
Version 1.0, August 2013
版本：1.0，2013年8月
About the Therapeutic Goods Administration (TGA) 关于TGA
l The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health and Ageing, and is responsible for regulating medicines and medical devices.
l TGA是澳大利亚政府健康和老龄部下的一个部门，负责药品和医疗器械的法规管理。
l ? The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary.
l TGA管理“治疗产品法案1989”，采用风险管理方法，该方法被设计来保证在供应给澳大利亚的治疗产品符合质量、安全和有效性（性能）可接受标准。
l ? The work of the TGA is based on applying scientific and clinical expertise to decision-making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices.
l TGA的工作是基于要求各学科和临床专家做出决定，来保证药品和医疗器械使用者的利益重于使用所带来的风险。
l ? The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action.
l TGA依赖公众、卫生专业人员和企业报告与药品或医疗器械相关的问题。TGA会对收到的报告进行调查，决定需要采取什么法规行动。
l ? To report a problem with a medicine or medical device, please see the information on the TGA website <
http://www.tga.gov.au>.
l 要报告药品或医疗器械相关的问题，请参见TGA官网信息。
Copyright 版权声明
? Commonwealth of Australia 2013 This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the
Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to <
tga.copyright@tga.gov.au>.
Version history 版本历史
Version 版本号 | Description of change 变更摘要 | | |
| | Office of Medicines Authorisation | |
| | | |
Contents 目录
Introduction | |
11.1 Drug Master Files and certificates of suitability | |
11.1.1 For drug substance sourced from a third party manufacturer | |
11.1.2 For ingredients of animal or human origin | |
11.2 What substances require a Drug Master File | |
11.2.1 Acceptable format for Drug Master Files | |
| |
11.2.2 Letters of access to Drug Master Files | |
| |
11.3 Sponsor's obligations regarding Drug Master Files | |
11.3.1 Updating drug master files | |
11.4 Additional information in Drug Master Files for some drug substances: guidance for manufacturers | |
11.4.1 Drug substances with a default standard monograph | |
11.4.2 What to include in a Drug Master File for sterile drug substances | |
11.4.3 Products of human or animal origin | |
11.4.3.1 Heparin products | |
| |
11.4.4 Substances produced wholly or in part by fermentation_ | |
11.4.4.1 Manufacturing facilities | |
11.4.4.2 Manufacturing process and controls | |
11.4.4.3 Control of materials | |
11.4.4.4 Control of critical steps and intermediates | |
11.4.4.5 Noncritical in-process controls | |
11.4.4.6 Process validation and/or evaluation | |
11.4.4.7 Characterisation | |
11.4.4.8 Control of intermediates and drug substances | |
11.4.4.9 Container/closure system | |
| |
11.4.4.11 Stability summary and conclusions | |
11.5 When to include a certificate of suitability in an application | |
For ingredients of animal or human origin | |
11.6 How to include a certificate of suitability in an application | |
11.7 Sponsor's obligations regarding certificates of suitability | |
11.8 Additional information regarding certificates of suitability for some drug substances | |
11.8.1 Nonsterile drug substances | |
11.8.2 Sterile drug substances | |
11.9 Other information that may be requested by the TGA in relation to certificates of suitability | |
Introduction 介绍
This guidance is intended for manufacturers of drug substances for prescription medicines, and sponsors of prescription medicines sourcing drug substances from a third party manufacturer.
本指南针对的是采用第三方生产商提供的原料药生产处方药品的申请人，以及处方药原料药生产商。
11.1 Drug Master Files and certificates of suitability DMF和CEP
11.1.1 For drug substance sourced from a third party manufacturer 第三方生产商来源原料药
There are two mechanisms by which a sponsor can provide information about a drug substance sourced from a third-party manufacturer:
如果申报人采用第三方生产商提供的原料药，可以有两种方式进行申报：
l a DMF or
l 使用DMF，或
l a CEP issued by the European Directorate for the Quality of Medicines & HealthCare (EDQM).
l 使用由EDQM签发的CEP
11.1.2 For ingredients of animal or human origin人或动物来源成分
A CEP does not contain sufficient information and will not alone be accepted.
CEP所包括的资料不够充分，仅有CEP是不能被接受的
Related information and guidance 相关资料和指南 l Therapeutic goods that contain or are produced from human blood or plasma l 含有人血或血浆或由人血或血浆制成的治疗产品 l Adventitious agent safety of medicines l 药品的外源性试剂安全性 |
11.2 What substances require a Drug Master File 什么样的物质需要提交DMF
A DMF is required for all drug substances that are sourced from a third-party manufacturer, except for the following substances:
除以下物质外，所有源自第三方生产商的原料药均需要DMF，
l common inorganic salts that are used and regarded as drug substances in products such as:
l 在药品中用作原料药的常规无机盐
— injections
— 注射剂
— dialysis solutions (e.g. sodium chloride and other common electrolytes)
— 透析液（例如，氯化钠和其它常见电解液）
l simple organic compounds that are commercially available in high purity e.g. naturally occurring organic acids and their salts, including:
l 可商业采购到高纯度的简单有机化合物， 例如自然存在的有机酸及其盐类，包括：
— ascorbic acid
— 抗坏血酸
— sodium citrate
— 柠檬酸钠
— simple monosaccharides
— 简单单糖类
— disaccharides, such as glucose and sucrose
— 双糖类，如葡萄糖和蔗糖
l when a CEP has been provided in lieu of a DMF.
l 采用了CEP代替DMF
Note 注 l Any nonpharmacopoeial specifications need to be assessed by the TGA to determine their appropriateness and adequacy to ensure the quality of the substance. l 任何非药典质量标准均需要由TGA评估后确定是否恰当，是否能充分保证物质的质量 l The evaluation of an application will not commence until the TGA receives the DMF. l 在收到DMF之前，TGA不会对申报资料做出评估， l Mention the specific version number of the DMF in the application l 在申报中要指出特定的DMF版本号 |
For a drug substance and drug product manufactured by the same company, include information on the production, quality control and stability of the drug substance as either:
如果同一公司生产药用物质和制剂，可以将药用物质的生产、质量控制和稳定性资料包括以下述任一方式提交：
l part of the application for the drug product, or
l 制剂申报资料的一部分，或
l in a separate DMF.
l 在单独的DMF中
11.2.1 Acceptable format for Drug Master Files 可接受的DMF方式
Guidance for sponsors 申报者指南
The preferred format for DMF is the European Common Technical Document (CTD) format or the European format. However if the manufacturer has not used either of these formats, the TGA will accept a drug master file in the United States format.
推荐的DMF格式是欧洲CTD格式，或欧洲格式。但是，如果生产商未使用上述两种格式，TGA接受美国格式的DMF。
Related information and guidance相关资料和指南 l Guideline on active substance master file procedure (CPMP/QWP/227/02 Rev 1), adopted with annotation. l 活性物质主文件（ASMF）程序指南 |
11.2.2 Letters of access to Drug Master Files DMF授权信
Guidance for sponsors 申报者指南
A Proforma Letter of Access to DMF is available in Module 1.6.3 of the CTD.
应在CTD的模块1.6.3中包括DMF形式授权信。
l Obtain written permission (i.e. a Letter of Access) from of the DMF owner to enable the TGA to access the current version of the DMF.
l 从DMF所有人那里获得书面许可（即授权信）以使TGA可以审阅DMF的现行版本
Request the manufacturer to:
要求生产商：
l use the proforma in Module1.6.3 of the CTD prepare the Letter of Access to DMF
l 使用CTD模块1.6.3中的格式准备DMF授权信
l clearly identify the sponsor the letter relates to
l 清楚指出授权信所指的申请人
l ?provide information and assurances required by the TGA in Module 1.6 of the CTD
l 在CTD模块1.6中提供TGA所要求的信息和保证TGA
l send the letter directly to the TGA, either with the DMF or separately.
l 向TGA直接发送授权信，与DMF一起发送或分开发送
Note 注 l The proforma for Letters of Access used in Europe is not acceptable. l 不接受欧洲格式的授权信 |
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