WHO现场主文件编写指南

1、© World Health OrganizationWHO Technical Report Series, No.961, 2011附件14Annex 14WHO现场主文件编写指南1WHO guidelines for drafting a site master file11. 介绍Introduction2. 目的Purpose3. 范围Scope4. 现场主文件的内容Content of site master file附件Appendix现场主文件的内容Content of a site master file1 基于制药检查会议对药品生产商编写现场主文件的注释 Base

2、d on the Explanatory notes for pharmaceutical manufacturers on the preparation of a site master file of the Pharmaceutical Inspection Convention.1. 介绍Introduction1.1 现场主文件是由药品制药商编写的，应当包含下列具体的信息：生产厂区的质量管理方针及活动、在指定的生产厂区实行的对药品生产操作的生产和/或质量控制以及在与其相邻的建筑物内所进行的任何紧密的完整的操作。如果只有一部分药品生产操作在此厂区内进行，那么在现场主文件中只需要描述这

3、些操作，例如分析、包装等。The site master file (SMF) is prepared by the pharmaceutical manufacturer and should contain specific information about the quality management policies and activities of the site, the production and/or quality control of pharmaceutical manufacturing operations carried out at the named s

4、ite and any closely integrated operations at adjacent and nearby buildings. If only part of a pharmaceutical operation is carried out on the site, an SMF need only describe those operations, e.g. analysis, packaging, etc.1.2 当提交给监管机构时，现场主文件中应当包含对常规监督、有效计划及进行GMP检查有用的、关于制造商与GMP相关的活动的清晰信息。When submitte

5、d to a regulatory authority, the SMF should provide clear information on the manufacturers good manufacturing practices (GMP)-related activities that can be useful in general supervision and in the efficient planning and undertaking of GMP inspections.1.3 现场主文件中应当包含足够的信息，但加上附件尽量不要超过2530页。用简单的计划、轮廓图或

6、示意图来替代叙述性的文字是更可取的。当用A4纸张打印出时，现场主文件及其附件应当是可读的。An SMF should contain adequate information but, as far as possible, not exceed 2530 pages plus appendices. Simple plans, outline drawings or schematic layouts are preferred instead of narratives. The SMF, including appendices, should be readable when prin

7、ted on A4 paper sheets.1.4 现场主文件应是制造商质量管理体系文件的一部分，且应持续更新。现场主文件应有版本号、生效期和必须对其进行审核的日期。应当定期对现场主文件进行回顾以保证其包含了最新的信息和代表了当前所进行的活动。每个附件可以有单独的生效期，以便进行独立的更新。The SMF should be a part of documentation belonging to the quality management system of the manufacturer and kept updated accordingly. The SMF should hav

8、e an edition number, the date it becomes effective and the date by which it has to be reviewed. It should be subject to regular review to ensure that it is up to date and representative of current activities. Each annex can have an individual effective date, allowing for independent updating.2. 目的Pu

9、rpose这些注释的目的是：在药品制造商编写现场主文件时提供指导，现场主文件在监管机构计划和进行GMP检查时有用的。The aim of these explanatory notes is to guide the manufacturer of medicinal products in the preparation of an SMF that is useful to the regulatory authority in planning and conducting GMP inspections.3. 范围Scope这些注释适用于现场主文件的编写及内容的确定。制造商应参照区域性

10、的和/或国家监管要求来确定编写现场主文件是否是强制性的要求。These explanatory notes apply to the preparation and content of the SMF. Manufacturers should refer to regional and or national regulatory requirements to establish whether it is mandatory for manufacturers of medicinal products to prepare an SMF.这些注释适用于各种制造操作，例如各种药品的生产

11、、包装和贴签、检测、重新贴签和重新包装。本指南中的概述也可用于指导血液和组织制品和原料药（API）制造商编写现场主文件或相应的文件。These explanatory notes apply for all kinds of manufacturing operations such as production, packaging and labelling, testing, relabelling and repackaging of all types of medicinal products. The outlines of this guide could also be use

12、d in the preparation of an SMF or corresponding document by blood and tissue establishments and manufacturers of active pharmaceutical ingredients (APIs).4. 现场主文件的内容Content of site master file格式参照附件。Refer to the Appendix for the format to be used.附件Appendix场主文件的内容Content of a site master file1. 制造商基

13、本信息General information on the manufacturer 1.1制造商联系信息Contact information on the manufacturer - 制造商名称及官方地址；name and official address of the manufacturer;- 生产厂地名称及街道地址，在生产厂地内的建筑物和生产单元；names and street addresses of the site, buildings and production units located on the site;- 制造商联系信息，包括在产品缺陷或召回时，相关联系人

14、的24小时联系号码；以及contact information of the manufacturer including 24-hour telephone number of the contact personnel in the case of product defects or recalls; and- 生产厂地的识别码，例如全球地位系统（GPS）详细信息、生产厂地或其它地理系统D-U-N-S（数据通用编号系统）编号（由Dun & Bradstreet提供的识别码）。identification number of the site as e.g. global posi

15、tioning system (GPS) details, D-U-N-S (Data Universal Numbering System) number (a unique identification number provided by Dun & Bradstreet) of the site or any other geographical location system.1.2生产厂地被授权的药品生产活动Authorized pharmaceutical manufacturing activities of the site- 主管部门颁发的有效的生产许可证的复印件作

16、为附件一；或者当适用时，索引到EudraGMP数据库。如果主管部门不颁发生产许可证，应当进行声明。copy of the valid manufacturing authorization issued by the relevant competent authority in Annex 1; or when applicable, reference to the EudraGMP database. If the competent authority does not issue manufacturing authorizations, this should be stated;

17、- 如果没有涵盖在生产许可证范围时，简述由相关主管部门，包括国外监管机构授权的制造、进口、出口、分发和其他活动，授权的剂型/活动，应根据许可的剂型/活动分别叙述；brief description of manufacture, import, export, distribution and other activities as authorized by the relevant competent authorities including foreign authorities with authorized dosage forms/activities, respectively

18、; where not covered by the manufacturing authorization;- 在超出附件一或EudraGMP数据库范围时，将目前在生产厂地生产的所有产品类型列出（附件二）；type of products currently manufactured on-site (list in Annex 2) where not covered by Annex 1 or the EudraGMP database; and- 列出最近5年内接受的所有GMP检查，包括进行检查的监管部门名称/国家和检查日期。如果有的话，应将现行GMP证书的复印件作为附件三或索引到Eu

19、draGMP数据库。list of GMP inspections of the site within the last five years; including dates and name/country of the competent authority having performed the inspection. A copy of the current GMP certificate (Annex 3) or reference to the EudraGMP database should be included, if available.1.3 在生产厂地进行的其他

20、生产活动Any other manufacturing activities carried out on the site- 如果有的话，对生产厂地内的非药品生产活动进行描述。description of non-pharmaceutical activities on site, if any.2. 质量管理Quality management 2.1 制造商的质量管理体系The quality management system of the manufacturer- 公司质量管理体系简介以及采取的标准；brief description of the quality manageme

21、nt systems run by the company and reference to the standards used;- 包括高层管理人员在内的与维护质量体系相关的人员的职责；以及 responsibilities related to the maintaining of the quality system including senior management; and- 生产厂地被认证和确认的活动信息，包括认证的日期和内容，认证机构的名称；information on activities for which the site is accredited and cert

22、ified, including dates and contents of accreditations, and names of accrediting bodies.2.2 成品放行程序Release procedure of finished products- 负责批确认的质量受权人资质要求（教育背景和工作经验）和放行程序的详细描述；detailed description of qualification requirements (education and work experience) of the authorized person(s)/qualified perso

23、n(s) responsible for batch certification and releasing procedures;- 批确认和放行程序的总体描述；general description of batch certification and releasing procedure;- 质量受权人在成品待验和放行、评价上市许可时所扮演的角色；role of authorized person/qualified person in quarantine and release of finished products and in assessment of compliance

24、 with the marketing authorization;- 当有多个质量受权人时，不同质量受权人之间职责的分工；以及the arrangements between authorized persons/qualified persons when several authorized persons/qualified persons are involved; and- 声明控制策略中是否包括过程分析技术（PAT）和实时放行或参数放行。statement on whether the control strategy employs process analytical tec

25、hnology (PAT) and/or real-time release or parametric release.2.3 供应商和承包商的管理Management of suppliers and contractors - 对供应链的建立/知识和外部审计程序进行小结；a brief summary of the establishment/knowledge of supply chain and the external audit programme;- 简述承包商、API制造商和其它关键物料供应商的确认系统；a brief description of the qualific

26、ation system of contractors, manufacturers of APIs and other critical materials suppliers;- 为保证所生产的产品符合传染性动物海绵状脑病（TSE）相关指南所采取的措施；measures taken to ensure that products manufactured are compliant with transmitting animal spongiform encephalopathy (TSE) guidance;- 当怀疑或确认有不合格的/假的/错误贴标签/伪造的/仿冒的药品、待包装产品（

27、例如未包装的片剂）、API或辅料时所采取的措施；measures adopted where substandard/spurious/falsely-labelled/falsified/counterfeit medical products, bulk products (i.e. unpacked tablets), APIs or excipients are suspected or identified;- 采用的与生产和分析相关外部的科学、分析或其它的技术支持；use of outside scientific, analytical or other technical as

28、sistance in relation to manufacture and analysis;- 委托生产商和实验室清单，包括外包的生产和QC活动的地址和联系信息、供应链流程图，例如无菌工艺中使用的内包材的灭菌、起始物料的检验等，上述信息在附件四中进行描述；以及list of contract manufacturers and laboratories including the addresses and contact information and flowcharts of supply chains for outsourced manufacturing and QC act

29、ivities, e.g. sterilization of primary packaging material for aseptic processes, testing of starting raw materials, etc., should be presented in Annex 4; and- 合同双方关于上市许可符合性职责的概述（如果没有在2.2中进行描述的话）brief overview of the responsibility sharing between the contract giver and acceptor with respect to compl

30、iance with the marketing authorization (where not included under 2.2).2.4 质量风险管理Quality risk management - 简述制造商采用的质量风险管理（QRM）方法学；以及brief description of quality risk management (QRM) methodologies used by the manufacturer; and- 质量风险管理（QRM）的范围和聚焦点，包括在公司层面进行的和局部进行的风险管理活动的简述。应对任何运用质量风险管理（QRM）系统评价供应连续性的活

31、动进行描述。scope and focus of QRM including brief description of any activities which are performed at corporate level, and those which are performed locally. Any application of the QRM system to assess continuity of supply should be mentioned.2.5产品质量回顾 Product quality reviews - 简述采用的产品质量回顾的方法学。brief des

32、cription of methodologies used.3. 人员Personnel - 组织机构图，显示出质量管理、生产和质量控制之间的安排，在附件五中列出，包括高管和质量受权人，应列出职位/职务；以及organization chart showing the arrangements for quality management, production and quality control positions/titles in Annex 5, including senior management and authorized person(s)/qualified pers

33、on(s); and- 分别列出参与质量管理、生产、质量控制、储存和分发的员工人数；number of employees engaged in the quality management, production, quality control, storage and distribution, respectively.4. 设施和设备Premises and equipment 4.1设施 Premises - 对生产车间的简短描述：尺寸和建筑物清单。如果供应到不同市场的产品在不同的建筑物内进行生产，例如国内或区域所属经济区，则应在建筑物清单中列出并标明生产的产品所供应的市场（如果没

34、有在1.1中说明的话）short description of plant: size of the site and list of buildings. If the production for different markets, i.e. for local country or regional economic areas, takes place in different buildings on the site, the buildings should be listed with destined markets identified (if not identifie

35、d under 1.1);- 生产区域的简短描述或计划，并标示出相应的规模（不要求提供建筑或工程图纸）simple plan or description of manufacturing areas with indication of scale (architectural or engineering drawings are not required);- 生产区域平面图和流程图（在附件六中列出），标示出房间洁净级别、相邻区域之间的压差以及房间内的生产活动（例如配药、灌装、储存、包装等）；layouts and flowcharts of the production areas (

36、in Annex 6) showing the room classification and pressure differentials between adjoining areas and indicating the production activities (i.e. compounding, filling, storage, packaging, etc.) in the rooms;- 仓库和存储区平面图，如果有的话，平面图中应标示出储存和处理高毒性、高危害性和高敏感性的物料的特殊区域；以及layouts of warehouses and storage areas, w

37、ith special areas for the storage and handling of highly toxic, hazardous and sensitizing materials indicated, if applicable; and- 如果有的话，简述没有在平面图中标出的特殊储存条件。brief description of specific storage conditions if applicable, but not indicated on the layouts.4.1.1采暖、通风和空调（HVAC）系统的简述Brief description of he

38、ating, ventilation and air-conditioning (HVAC) systems- 确定空气供应量、温度、湿度、压差、换气率和空气再循环方针的原则。principles for defining the air supply, temperature, humidity, pressure differentials and air-change rates, policy of air recirculation (%).4.1.2 水系统简述Brief description of water systems - 使用的水的质量参照；以及quality refe

39、rences of water produced; and- 在附件七中列出水系统原理图。schematic drawings of the systems in Annex 7.4.1.3其他相关公用设施，例如蒸汽、压缩空气和氮气系统等的简述Brief description of other relevant utilities such as steam, compressed air, nitrogen, etc.4.2 设备Equipment 4.2.1主要生产和控制实验室设备清单作为附件八，并标示出关键设备。Listing of major production and contr

40、ol laboratory equipment with critical pieces of equipment identified should be provided in Annex 8.4.2.2 清洁和卫生Cleaning and sanitation - 描述与产品接触的表面的清洁和卫生方法（例如手工清洁、自动在线清洁等）brief description of cleaning and sanitation methods of product contact surfaces (i.e. manual cleaning, automatic clean-in-place,

41、etc.).4.2.3良好生产规范关键计算机化系统Good manufacturing practices critical computerized systems- GMP关键计算机化系统的描述（除设备的可编程逻辑控制器（PLC）外）。description of GMP critical computerized systems (excluding equipment specific programmable logic controllers (PLCs).5. 文件记录Documentation - 文件记录系统的描述（例如电子、手工）；以及description of docu

42、mentation system (i.e. electronic, manual); and- 当文件和记录不在生产厂地保存或存档（如果适用的话，包括药物警戒数据）时：列出文件/记录的种类；储存地的名称和地址；从储存地取回文件所需要的预计时间。When documents and records are stored or archived off-site (including pharmacovigilance data, when applicable): list of types of documents/records; name and address of storage s

43、ite; and an estimate of time required to retrieve documents from the off-site archive.6. 生产Production 6.1产品种类 Type of products References to Annex 1 or 2 can be made.可索引到附件一或附件二。- 生产产品的类型包括：type of products manufactured including:· 列出在生产厂地生产的人用药和兽用药的剂型；list of dosage forms of both human and vet

44、erinary products which are manufactured on the site；· 列出在生产厂地生产的用于临床研究的研究药用产品（IMP）的剂型，当其生产不同于商业化生产时，还应对生产区域和人员进行描述；list of dosage forms of investigational medicinal products (IMP) manufactured for any clinical trials on the site, and when different from the commercial manufacturing, information

45、 on production areas and personnel;· 处理的有毒或有害物质（例如有高药理活性和/或高致敏性）；toxic or hazardous substances handled (e.g. with high pharmacological activity and/or with sensitizing properties);· 如果适用的话，在专用区域内或基于阶段性生产的产品类型product types manufactured in a dedicated facility or on a campaign basis, if appl

46、icable; and· 如果适用的话，PAT应用：相关技术的总体声明；及相关的计算机化系统。· PAT applications, if applicable: general statement of the relevant technology; and associated computerized systems.6.2 工艺验证Process validation - 工艺验证总方针简述；以及brief description of general policy for process validation; and- 返工或重新加工方针。policy for

47、 reprocessing or reworking.6.3 物料管理和仓库Material management and warehousing - 起始物料、包装材料、待包装品和成品的处理，包括取样、待验、放行和储存；以及arrangements for the handling of starting materials, packaging materials, bulk and finished products including sampling, quarantine, release and storage; and- 不合格物料和产品的处理arrangements for

48、the handling of rejected materials and products.7. 质量控制Quality control - 描述在生产厂地的QC活动，包括物理、化学、微生物和生物检测。description of the QC activities carried out on the site in terms of physical, chemical and microbiological and biological testing.8. 分发、投诉、产品缺陷和召回Distribution, complaints, product defects and reca

49、lls 8.1分发（生产商的职责部分）Distribution (to the part under the responsibility of the manufacturer)- 接收产品的公司的类型（批发许可证持有者、生产许可证持有者等）和位置（国家或区域经济区）；types (wholesale licence holders, manufacturing licence holders, etc.) and locations (countries or regional economic areas) of the companies to which the products are shipped from the site;- 用于核实每位客户/接收者具有合法的资质来接收从生产商运送过来的药品的系统；description of the system used to verify that each customer/recipient is legally entitled to receive medicinal products from the manufacturer;- 简述在运输过程中用于保证适当的环境条件的系统，例如温度监控/控制；brief description of the system to ensure appro