HC:《药品生产企业场地主文件编制说明注释》

4月10日，加拿大卫生部发布《GUI-0005：药品生产企业场地主文件编制说明注释》。

1. Purpose

1. 目的

The aim of this document is to guide the preparation of the site master file. This guide will help drug establishments comply with Part C, Division 2 of the Food and Drug Regulations (the Regulations).

本文档旨在指导场地主文件的编制。本指南将帮助药品生产企业遵守《食品药品条例》C 部分第 2 分部的要求。

2. Scope

2. 适用范围

These Explanatory Notes apply to the preparation of the site master file by any person who conducts any of the licensable activities listed below with respect to a drug:

本说明适用于从事以下药品持证活动的任何主体编制场地主文件：

• fabrication

• 生产

• packaging

• 包装

• labelling

• 贴签

• testing

• 检验

3. Introduction

3. 引言

These guidelines interpret the requirements for good manufacturing practices (GMP) in Part C, Division 2 of the Food and Drug Regulations.

本指南对《食品药品条例》C 部分第 2 分部中的药品生产质量管理规范（GMP）要求进行解读。

Guidance documents like this one are meant to help industry and health care professionals understand how to comply with regulations. They also provide guidance to Health Canada staff, so that the rules are enforced in a fair, consistent and effective way across Canada.

此类指南文件旨在帮助行业及医疗专业人员理解如何遵守法规，同时为加拿大卫生部工作人员提供指导，确保在加拿大全国范围内公平、统一、有效地执行相关规定。

Health Canada inspects establishments to assess their compliance with the Food and Drugs Act (the Act) and associated regulations.

加拿大卫生部对企业进行检查，评估其是否符合《食品药品法》及相关法规要求。

These guidelines are not the only way GMP regulations can be interpreted, and are not intended to cover every possible case. Other ways of complying with GMP regulations will be considered with proper scientific justification. Also, as new technologies emerge, different approaches may be called for.

本指南并非解读 GMP 法规的唯一方式，也无意涵盖所有可能情形。具备充分科学依据的其他合规方式将予以考虑。此外，随着新技术出现，可能需要采用不同方法。

Guidance documents are administrative and do not have the force of law. Because of this, they allow for flexibility in approach. So use this guide to help you develop specific approaches that meet your unique needs.

指南文件为行政指导性文件，不具有法律效力。因此，执行方式可灵活掌握。请使用本指南制定满足自身特定需求的具体方案。

This guide is based on the Pharmaceutical Inspection Cooperation Scheme (PIC/S) document Explanatory Notes for Pharmaceutical Manufacturers on the Preparation of a Site Master File (SMF) (PE 008-4). This guide reflects changes necessary to adapt the text to meet Canadian requirements.

本指南基于药品检查合作计划（PIC/S）文件《药品生产企业场地主文件编制说明》（PE 008-4）制定，并根据加拿大监管要求进行了必要调整。

The content of the site master file provides information about Canadian and foreign buildings in the planning and conducting of GMP inspections. The site master file supports pre-market authorizations and applications for drug establishment licenses.

场地主文件内容为加拿大及境外厂房的 GMP 检查策划与实施提供信息，支持药品上市许可及药品生产企业许可证申请。

A site master file should be prepared to contain specific information about the quality management policies and activities of the site, the production and/or quality control of drug manufacturing operations carried out at the named site and any closely integrated operations at adjacent and nearby buildings. If only part of these operations is carried out on the site, a site master file need only describe those operations, e.g. analysis, packaging, etc.

场地主文件应包含该场地质量管理方针与活动、指定场地开展的药品生产及 / 或质量控制操作，以及相邻及附近建筑内紧密整合操作的具体信息。若仅开展部分操作，场地主文件只需描述该部分操作，如检验、包装等。

When submitted to Health Canada, the site master file should provide clear information on the manufacturer’s GMP related activities that can be useful in general supervision and in the efficient planning and undertaking of GMP inspections.

提交至加拿大卫生部时，场地主文件应清晰说明生产企业与 GMP 相关的活动，为日常监管及高效策划与实施 GMP 检查提供支持。

A site master file should contain adequate information but, as far as possible, not exceed 25-30 pages plus appendices. Simple plans outline drawings or schematic layouts are preferred instead of narratives. The site master file, including appendices, should be readable when printed on letter size paper sheets.

场地主文件应包含充分信息，但正文尽量不超过 25–30 页，可附附录。优先使用简易平面图、示意图或布局图，而非文字叙述。场地主文件（含附录）应能在信纸尺寸纸张上清晰打印阅读。

The site master file should be a part of documentation belonging to the quality management system of the manufacturer and kept updated accordingly. The site master file should have 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 Appendix can have an individual effective date, allowing for independent updating.

场地主文件应作为生产企业质量管理体系文件的一部分，并及时更新。文件应注明版本号、生效日期及复审日期，定期复审以确保内容最新且反映当前操作。各附录可单独设定生效日期，实现独立更新。

4. Content of site master file

4. 场地主文件内容

You are requested to prepare a site master file for each location where you fabricate, package/label or test drugs. A list of Appendices to include with the site master file is provided at the end of this document.

要求在每个药品生产、包装 / 贴签或检验场所分别编制场地主文件。本文档末尾列出场地主文件需包含的附录清单。

You may refer to other related documents such as Site master file (SMF) for source plasma establishments PI 019-3 and Site master file (SMF) for plasma warehouses PI 020-3 for alternate formats to use.

可参考其他相关文件，如《原料血浆企业场地主文件》（PI 019-3）和《血浆仓库场地主文件》（PI 020-3）采用替代格式。

4.1 General information on the manufacturer

4.1 生产企业基本信息

4.1.1 Contact information of the manufacturer

4.1.1 生产企业联系方式

• Name and official address of the manufacturer.

• 生产企业名称及法定地址。

• Names and street addresses of the site, buildings and production units located on the site.

• 场地、建筑物及生产单元名称与街道地址。

• Contact information of the manufacturer including a 24 hour telephone number of the contact personnel in the case of product defects or recall.

• 生产企业联系方式，包括产品缺陷或召回时联系人的 24 小时联系电话。

• Geographic location of the site as e.g. GPS details or any other geographic location system.

• 场地地理位置，如 GPS 坐标或其他地理定位系统信息。

4.1.2 Authorized drug manufacturing activities of the site

4.1.2 场地获准药品生产活动

• Copy of the valid manufacturing authorization issued by the relevant Regulatory Authority in Appendix 1; or when applicable, reference to the appropriate Regulatory Authority’s database (e.g., Drug and Health Products Inspection Database, EudraGMP database, FDA Inspection Classification Database). If the Regulatory Authority does not issue manufacturing authorizations, this should be stated.

• 附录 1 中附上相关监管机构核发的有效生产许可文件复印件；或适用时引用相关监管机构数据库（如药品及健康产品检查数据库、EudraGMP 数据库、FDA 检查分类数据库）。若监管机构不核发生产许可，应予以说明。

• Brief description of manufacture, import, export, distribution and other activities as authorized by the relevant Regulatory Authorities including foreign authorities with authorized dosage forms/activities, respectively; where not covered by the manufacturing authorization.

• 简要说明生产许可未涵盖的、经相关监管机构（含境外机构）分别批准的生产、进口、出口、分销及其他活动，以及获准剂型 / 活动。

• Type of products currently manufactured on-site (list in Appendix 2) where not covered by Appendix 1 or other Regulatory Authority’s database.

• 附录 1 或其他监管机构数据库未涵盖的、当前场地生产的产品类型（列入附录 2）。

• List of GMP inspections of the site within the last 5 years; including dates and name/country of the Regulatory Authority having performed the inspection. A copy of current GMP certificate (Appendix 3) or reference to the Regulatory Authority’s database should be included, if available.

• 近 5 年场地 GMP 检查清单，包括检查日期及实施检查的监管机构名称 / 国家。如有现行有效 GMP 证书，应附上复印件（附录 3）或引用监管机构数据库。

4.1.3 Any other manufacturing activities carried out on the site

4.1.3 场地开展的其他生产活动

• Description of non-drug related activities on-site, if any.

• 场地内非药品相关活动（如有）的说明。

4.2 Quality management system of the manufacturer

4.2 生产企业质量管理体系

4.2.1 The quality management system of the manufacturer

4.2.1 生产企业质量管理体系

• Brief description of the quality management systems run by the company and reference to the standards used.

• 简要说明公司运行的质量管理体系及所依据的标准。

• Responsibilities related to the maintaining of quality system including senior management.

• 包括高级管理层在内的质量体系维护相关职责。

• Information of activities for which the site is accredited and certified, including dates and contents of accreditations, names of accrediting bodies.

• 场地获得认可与认证的活动信息，包括认可日期、内容及认可机构名称。

4.2.2 Release procedure of finished products

4.2.2 成品放行程序

• Detailed description of qualification requirements (education and work experience) of the Authorized Person (s) / Qualified Person (s) responsible for batch certification and releasing procedures.

• 详细说明负责批次认证与放行程序的受权人 / 质量受权人的资质要求（教育背景及工作经验）。

• General description of batch certification and releasing procedure.

• 批次认证与放行程序概述。

• Role of Authorized Person / Qualified Person in quarantine and release of finished products and in assessment of compliance with the market authorization requirements.

• 受权人 / 质量受权人在成品待验与放行、评估是否符合上市许可要求中的职责。

• The arrangements between Authorized Persons / Qualified Persons when several Authorized Persons / Qualified Persons are involved.

• 多名受权人 / 质量受权人参与时的分工安排。

• Statement on whether the control strategy employs Process Analytical Technology (PAT) and/or Real Time Release or Parametric Release.

• 说明控制策略是否采用过程分析技术（PAT）及 / 或实时放行或参数放行。

4.2.3 Management of suppliers and contractors

4.2.3 供应商与承包商管理

• A brief summary of the establishment/knowledge of supply chain and the external audit program.

• 供应链建立 / 认知及外部审计计划简要总结。

• Brief description of the qualification system of contractors, manufacturers of active ingredients and other critical materials suppliers.

• 承包商、原料药生产商及其他关键物料供应商的资质确认体系简要说明。

• Measures taken to ensure that products manufactured are compliant with TSE (Transmissible spongiform encephalopathy) guidelines.

• 为确保生产产品符合传染性海绵状脑病（TSE）指南所采取的措施。

• Measures adopted where counterfeit/falsified products, bulk products (i.e. unpacked tablets), active ingredients or excipients are suspected or identified.

• 怀疑或确认存在假冒 / 伪造产品、散装产品（如未包衣片剂）、原料药或辅料时所采取的措施。

• Use of outside scientific, analytical or other technical assistance in relation to manufacture and analysis.

• 生产与检验相关外部科学、分析或其他技术支持的使用情况。

4.2.4 Quality risk management (QRM)

4.2.4 质量风险管理（QRM）

• Brief description of QRM methodologies used by the manufacturer.

• 简要说明生产企业采用的质量风险管理方法。

• 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.

• 质量风险管理范围与重点，包括公司层面及场地层面开展的活动简要说明。应提及质量风险管理体系用于评估供应持续性的情况。

4.2.5 Product quality reviews

4.2.5 产品质量回顾

• Brief description of methodologies used.

• 简要说明所采用的方法。

4.3 Personnel

4.3 人员

• Organization chart showing the arrangements for quality management, production and quality control positions/titles in Appendix 5, including senior management and Authorized Person (s) / Qualified Person (s).

• 附录 5 中附上展示质量管理、生产及质量控制岗位 / 职务设置的组织架构图，包括高级管理层及受权人 / 质量受权人。

• Number of employees engaged in the quality management, production, quality control, storage and distribution respectively.

• 分别从事质量管理、生产、质量控制、仓储及分销的员工人数。

4.4 Premises and equipment

4.4 厂房与设备

4.4.1 Premises

4.4.1 厂房

• Short description of plant; size of the site and list of buildings. If the production for different markets, i.e. for local, EU, USA, etc. takes place in different buildings on the site, the buildings should be listed with destined markets identified (if not identified under 1.1).

• 厂房简要说明、场地规模及建筑物清单。若针对不同市场（如本地、欧盟、美国等）的生产在场地内不同建筑物开展，应列出建筑物并注明目标市场（若 1.1 未注明）。

• Simple plan or description of manufacturing areas with indication of scale (architectural or engineering drawings are not required).

• 生产区域简易平面图或说明，注明规模（无需建筑或工程图纸）。

• Layouts and flow charts of the production areas (in Appendix 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.

• 附录 6 中附上生产区域布局图及流程图，标明房间洁净级别、相邻区域压差及房间内生产活动（如配制、灌装、仓储、包装等）。

• Layouts of warehouses and storage areas, with special areas for the storage and handling of highly toxic, hazardous and sensitizing materials indicated, if applicable.

• 仓库及仓储区域布局图，适用时标明剧毒、高危及致敏性物料的专用储存与处理区域。

• Brief description of specific storage conditions if applicable, but not indicated on the layouts.

• 布局图未注明的特定储存条件（如适用）简要说明。

4.4.1.1 Brief description of heating, ventilation and air conditioning (HVAC) systems

4.4.1.1 采暖、通风与空调（HVAC）系统简要说明

• Principles for defining the air supply, temperature, humidity, pressure differentials and air change rates, policy of air recirculation (%).

• 送风、温度、湿度、压差及换气次数的确定原则，空气回流比例（%）规定。

4.4.1.2 Brief description of water systems

4.4.1.2 水系统简要说明

• Quality references of water produced.

• 产水质量标准。

• Schematic drawings of the systems in Appendix 7.

• 附录 7 中附上系统示意图。

4.4.1.3 Brief description of other relevant utilities, such as steam, compressed air, nitrogen, etc.

4.4.1.3 其他相关公用工程简要说明，如蒸汽、压缩空气、氮气等

4.4.2 Equipment

4.4.2 设备

4.4.2.1 Listing of major production and control laboratory equipment with critical pieces of equipment identified should be provided in Appendix 8.

4.4.2.1 附录 8 中附上主要生产及检验实验室设备清单，并标明关键设备。

4.4.2.2 Cleaning and sanitation

4.4.2.2 清洁与卫生

• Brief description of cleaning and sanitation methods of product contact surfaces (i.e. manual cleaning, automatic Clean-in-Place, etc).

• 产品接触表面清洁与卫生方法简要说明（如人工清洁、自动在位清洗等）。

4.4.2.3 GMP critical computerized systems

4.4.2.3 GMP 关键计算机化系统

• Description of GMP critical computerized systems (excluding equipment specific Programmable Logic Controllers (PLCs)).

• GMP 关键计算机化系统说明（不包括设备专用可编程逻辑控制器（PLC））。

4.5 Documentation

4.5 文件

• Description of documentation system (i.e. electronic, manual).

• 文件系统说明（如电子、纸质）。

• 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 site and an estimate of time required retrieving documents from the off-site archive.

• 文件与记录异地储存或存档时（如适用，包括药物警戒数据）：文件 / 记录类型清单；储存场所名称及地址，以及从异地档案调取文件的预估时间。

4.6 Production

4.6 生产

For this section, you can reference Appendix 1 or 2.

本节可引用附录 1 或附录 2。

4.6.1 Type of products

4.6.1 产品类型

• Type of products manufactured including:

• 生产产品类型包括：

o List of dosage forms of both human and veterinary products which are manufactured on the site.

o 场地生产的人用及兽用产品剂型清单。

o List of dosage forms of investigational drugs manufactured for any clinical trials on the site, and when different from the commercial manufacturing, information of production areas and personnel.

o 场地为临床试验生产的研究用药物剂型清单，若与商业化生产不同，需说明生产区域及人员信息。

• Toxic or hazardous substances handled (e.g. with high pharmacological activity and/or with sensitizing properties).

• 处理的有毒或高危物料（如高药理活性及 / 或致敏性物料）。

• Product types manufactured in a dedicated facility or on a campaign basis, if applicable.

• 专用设施或阶段性生产的产品类型（如适用）。

• Process Analytical Technology (PAT) applications, if applicable: general statement of the relevant technology, and associated computerised systems.

• 过程分析技术（PAT）应用情况（如适用）：相关技术及配套计算机化系统概述。

4.6.2 Process validation

4.6.2 工艺验证

• Brief description of general policy for process validation.

• 工艺验证总体方针简要说明。

• Policy for reprocessing or reworking.

• 返工或重新加工方针。

4.6.3 Material management and warehousing

4.6.3 物料管理与仓储

• Arrangements for the handling of starting materials, packaging materials, bulk and finished products including sampling, quarantine, release and storage.

• 原料、包装材料、中间产品及成品的处理安排，包括取样、待验、放行及储存。

• Arrangements for the handling of rejected materials and products.

• 不合格物料及产品的处理安排。

4.7 Quality control (QC)

4.7 质量控制（QC）

• Description of the Quality Control (QC) activities carried out on the site in terms of physical, chemical, and microbiological and biological testing.

• 场地开展的理化、微生物及生物学检验等质量控制（QC）活动说明。

4.8 Distribution, complaints, product defects and recalls

4.8 分销、投诉、产品缺陷与召回

4.8.1 Distribution (to the part under the responsibility of the manufacturer)

4.8.1 分销（生产企业责任范围内部分）

• Types (wholesale licence holders, manufacturing licence holders, etc) and locations (EU/EEA, USA, Canada etc.) of the companies to which the products are shipped from the site.

• 产品从场地发往的公司类型（批发许可证持有者、生产许可证持有者等）及地区（欧盟 / 欧洲经济区、美国、加拿大等）。

• Description of the system used to verify that each customer /recipient is legally entitled to receive drugs from the manufacturer.

• 用于核实每位客户 / 接收方具备合法接收药品资格的系统说明。

• Brief description of the system to ensure appropriate environmental conditions during transit, e.g. temperature monitoring/control.

• 确保运输过程环境条件适宜的系统简要说明，如温度监测 / 控制。

• Arrangements for product distribution and methods by which product traceability is maintained.

• 产品分销安排及产品可追溯性维持方法。

• Measures taken to prevent manufacturers’ products to fall in the illegal supply chain.

• 防止产品流入非法供应链的措施。

4.8.2 Complaints, product defects and recalls

4.8.2 投诉、产品缺陷与召回

• Brief description of the system for handling complaints, product defects and recalls.

• 投诉、产品缺陷与召回处理系统简要说明。

4.9 Self-inspections

4.9 自检

• Short description of the self-inspection system with focus on criteria used for selection of the areas to be covered during planned inspections, practical arrangements and follow-up activities.

• 自检体系简要说明，重点说明计划检查范围的选取标准、实际安排及跟踪活动。

4.10 Appendices accompanying a site master file

4.10 场地主文件附录

The following list of appendices should be referenced and provided with the site master file:

场地主文件应引用并提供以下附录：

Appendix A – Glossary

附录 A – 术语表

Acronyms

缩写

EU: European Union

欧盟：欧洲联盟

EMA: European Medicines Agency

欧洲药品管理局：欧洲药品管理局

FDA: Food and Drugs Administration

美国食品药品监督管理局：美国食品药品监督管理局

GMP: Good manufacturing practices

药品生产质量管理规范：良好生产规范

PIC/S: Pharmaceutical Inspection Cooperation/Scheme

药品检查合作计划：药品检查合作计划

PAT: Process Analytical Technology

过程分析技术：过程分析技术

PLC: Programmable Logic Controller

可编程逻辑控制器：可编程逻辑控制器

QRM: Quality Risk Management

质量风险管理：质量风险管理

QC: Quality Control

质量控制：质量控制

TSE: Transmissible animal spongiform encephalopathy

传染性动物海绵状脑病：传染性动物海绵状脑病

USA: United States of America

美国：美利坚合众国

Terms

术语

These definitions explain how terms are used in this document. If there is a conflict with a definition in the Food and Drugs Act or associated regulations, the definition in the Act or regulations prevails.

以下定义说明本文档中术语的用法。若与《食品药品法》或相关法规中的定义冲突，以法规定义为准。

Site master file: also known as a site reference file is prepared by the pharmaceutical manufacturer or the holder of an establishment licence. It 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 site and any closely integrated operations at adjacent and nearby buildings.

场地主文件：又称场地参考文件，由药品生产企业或生产许可证持有者编制。文件应包含该场地质量管理方针与活动、指定场地开展的药品生产及 / 或质量控制操作，以及相邻及附近建筑内紧密整合操作的具体信息。