重新加工和返工的區別;返工和重新加工

PHARMACEUTICAL INSPECTION CONVENTION PHARMACEUTICAL INSPECTION CO-OPERATION SCHEME

藥品檢查協定和藥品檢查合作計劃組織

PE 008-4

1 Annex

1 January 2011

PE 0084

附件一

2011年1月1日

EXPLANATORY NOTES FOR PHARMACEUTICAL MANUFACTURERS ON THE PREPARATION OF A SITE MASTER FILE

制藥工廠現場主文件編寫說明

TABLE OF CONTENTS

目錄

1 Document History/文件歷史...................................................................................2

2 Introduction/簡介....................................................................................................2

3 Purpose/目的.........................................................................................................2

4 Scope/范圍............................................................................................................3

5 Content of Site Master File/現場主文件內容..........................................................3

6 Revision History/修訂歷史.....................................................................................3

1 DOCUMENT HISTORY 文件歷史

2 INTRODUCTION 簡介

2.1 The Site Master File 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 site and any closely integrated operations at adjacent and nearby buildings. If only part of a pharmaceutical operation is carried out on the site, a Site Master File need only describe those operations, e.g. analysis, packaging, etc. 現場主文件是由制藥廠家編寫，并包含以下信息：質量管理方針及現場活動、在對在指定現場進行生產或/和對在指定現場的制藥生產操作進行的質量控制以及在臨近及附近建筑內進行的一體化操作。如果僅有一部份制藥操作在該現場進行，那么SMF僅需描敘該類操作即可，如：分析、包裝、等。

2.2 When submitted to a regulatory authority, 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. 提交至監管機構時，SMF需提供明確信息，說明廠家進行的有助于一般監管和GMP審查有效計劃和應對的相關GMP活動

2.3 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 A4 paper sheets. SMF應包含足夠的信息，但是加上附件不得超過25-30頁。相較于詳述，簡單性計劃、簡略的原理圖布局圖為首選。SMF，包括附件，用A4紙打印出來應當可讀。

2.4 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.SMF廠家質量管理系統文件的一部分，應進行相應更新。SMF應當有一個版本號、生效日期以及需進行審核的日期。應對SMF進行定期審核以保證其為最新版本并體現最新行動。每個附件可有單獨的生效日期，允許單獨對附件進行更新。

3 PURPOSE目的

The aim of these Explanatory Notes is to guide the manufacturer of medicinal products in the preparation of a Site Master File that is useful to the regulatory authority in planning and conducting GMP inspections.

本說明的目的是指導醫藥生產廠家進行SMF的編寫。SMF在監管機構進行GMP審查計劃和執行GMP審查中是有用的。

4 SCOPE 適用范圍

These Explanatory Notes apply to the preparation and content of the Site Master File. Manufacturers should refer to regional / national regulatory requirements to establish whether it is mandatory for manufacturers of medicinal products to prepare a Site Master File.

本說明使用與SMF的編寫及內容。廠家應參考地區／國家法規要求以確定是否強制要求醫藥用品廠家編寫SMF。

These Explanatory Notes apply for all kind 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 used in the preparation of a Site Master File or corresponding document by Blood and Tissue Establishments and manufacturers of Active Pharmaceutical Ingredients.

本說明適用于下述此類生產操作：所有類型醫藥產品的生產、包裝和貼標、檢驗、再貼標和再包裝。本指南的大綱也可以用于編寫SMF或API血液和組織制造機構以及生產廠家相關文件的編寫。

5 CONTENT OF SITE MASTER FILE ＳＭＦ內容

Refer to Annex for the format to be used.

SMF格式見附件。

6 REVISION HISTORY 修訂歷史

Annex to PE 008-4

CONTENT OF SITE MASTER FILE

現場主文件內容

1 GENERAL INFORMATION ON THE MANUFACTURER工廠一般信息

1.1 Contact information on the manufacturer生產商聯系信息

— Name and official address of the manufacturer;

— 生產商名稱和辦公地址；

— Names and street addresses of the site, buildings and production units located on the site;

— 廠址名稱和街道地址、廠內建筑和生產單元的名稱；

— Contact information of the manufacturer including 24 hrs telephone number of the contact personnel in the case of product defects or recalls;

— 生產商聯系信息，包括產品缺陷或召回時聯系人的24小時電話號碼；

— Identification number of the site as e.g. 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 geographic location system.

— 工廠識別信息，如全球定位信息（GPS信息）或其他的地理定位系統，以及鄧氏編號。

1.2 Authorised pharmaceutical manufacturing activities of the site. 授權的藥物生產活動

— Copy of the valid manufacturing authorisation issued by the relevant Competent - Authority in Appendix 1; or when applicable, reference to the EudraGMP database. If the Competent Authority does not issue manufacturing authorisations, this should be stated;

— 在附件1中，附上相關主管當局頒發的有效生產許可證的復件；或者可能的話，引用歐洲GMP數據庫；如果主管當局不頒發生產許可證，這應該加以說明。

— Brief description of manufacture, import, export, distribution and other activities as authorised by the relevant Competent Authorities including foreign authorities with authorised dosage forms/activities, respectively; where not covered by the manufacturing authorisation;

— 藥政機構許可的生產、進口、出口、分銷和其他活動的簡要描述，包括生產許可證上沒有的國外當局許可的劑型/活動；

— Type of products currently manufactured on-site (list in Appendix 2) where not covered by Appendix 1 or the EudraGMP database;

— 目前在廠生產的產品類型（在附件2中列出），如果未被包含在附件1中或歐洲GMP準入中

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

— 列出過去5年的現場GMP檢查清單，包括日期和進行檢驗的藥政機構的名稱/國家。如果有，應當提供現行的GMP證書（附件3）或引用歐洲GMP數據庫中的副本。

1.3 Any other manufacturing activities carried out on the site廠區內進行的任何其他生產活動

— Description of non-pharmaceutical activities on-site, if any.

— 如果有的話，描述廠區內的非制藥活動。

2 QUALITY MANAGEMENT SYSTEM OF THE MANUFACTURER公司的質量管理體系

2.1 The quality management system of the manufacturer公司質量管理體系

— Brief description of the quality management systems run by the company and reference to the standards used;

— 公司質量管理運行系統的簡要說明和所參考的標準;

— Responsibilities related to the maintaining of quality system including senior management;

— 包括高級管理層在內的質量體系維護職責；

— Information of activities for which the site is accredited and certified, including datas and content of accreditations, name of accrediting bodies.

— 公司認證的活動信息，包括日期和認證內容，認證機構名稱。

2.2 Release procedure of finished products最終產品放行程序

— Detailed description of qualification requirements (education and work experience) of the Authorised Person(s) / Qualified Person(s) responsible for batch certification and releasing procedures;

— 負責批量證明和放行程序的授權人/有資質人（簡稱：QP）的資格要求（教育/工作經驗）的詳細說明；

— General description of batch certification and releasing procedure;

— 批合格和放行過程的一般描述；

— Role of Authorised Person / Qualified Person in quarantine and release of finished products and in assessment of compliance with the Marketing Authorisation;

— 授權人/有資質人（簡稱：QP）在待驗、放行最終產品、上市授權符合性評估中的角色。

— The arrangements between Authorised Persons / Qualified Persons when several Authorised Persons / Qualified Persons are involved;

— 涉及到多個授權人/有資質人時，他們之間的安排

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

— 采用PAT（過程分析技術）控制策略和/或實時放行或參數放行的描述

2.3 Management of suppliers and contractors承包商和供應商的管理

— A brief summary of the establishment/knowledge of supply chain and the external audit program;

— 供應鏈和外部審計程序建立和信息的一個簡要介紹;

— Brief description of the qualification system of contractors, manufacturers of active pharmaceutical ingredients (API) and other critical materials suppliers;

— 簡要說明承包商、活性藥物成分（API供應商）和其他關鍵材料供應商的資格審查系統；

— Measures taken to ensure that products manufactured are compliant with TSE (Transmitting animal spongiform encephalopathy) guidelines.

— 采取的措施，以確保生產出的產品符合TSE（動物海綿狀腦病傳染）指南

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

— 假冒/偽造產品，散裝產品（即拆開的片劑），藥物活性成分或輔料的懷疑或確定方法

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

— 外部研究、分析或其他有關生產的技術支援;

— List of contract manufacturers and laboratories including the addresses and contact information and flow charts of supply-chains for outsourced manufacturing and Quality Control activities; e.g. sterilisation of primary packaging material for aseptic processes, testing of starting raw-materials etc, should be presented in Appendix 4;

— 合同生產商和實驗室的名單，包括地址和聯系方式，以及外包生產和質量控制活動的供應鏈流程圖。如無菌工藝的內包裝材料滅菌，起始物料的檢測，應顯示附件4

— Brief overview of the responsibility sharing between the contract giver and acceptor with respect to compliance with the Marketing Authorisation (where not included under 2.2).

— 上市授權符合性中，合同雙方責任劃分（如果未在2.2項下描述）的簡要概述。

2.4 Quality Risk Management (QRM) 生產商質量風險管理（QRM）

— Brief description of QRM methodologies used by the manufacturer;

— 生產商QRM方針的簡要描述

— 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.

— QRM的范圍和關注點的詳細描述，包括全體公司層所有活動和僅在局部執行活動的簡要描述。任何采用QRM體系對供應連續性進行的評估，都應當被討論。

2.5 Product Quality Reviews產品質量回顧

— Brief description of methodologies used

— 方法的簡要描述

3 PERSONNEL人員

— - Organisation chart showing the arrangements for quality management, production and quality control positions/titles in Appendix 5, including senior management and Authorised Person(s) / Qualified Person(s);

— 顯示質量管理、生產和質量控制安排以及職位/職稱的圖表附于附件5，包括高級管理人員和QP的安排;

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

— 參與質量管理、生產、質量控制、儲存和發放的各自員工數目；

4 PREMISES AND EQUIPMENT廠房和設施

4.1 Premises廠房

— 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);

— 廠房的簡單描述：場地大小和建筑清單。如果不同市場的產品，如本地、歐盟、美國等地，在不同的建筑中生產，清單中應在建筑上列出目標市場（如果未在1.1中描述）；

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

— 示意圖或生產區的簡單描述，要指出生產規模（不要求建筑或工程圖紙）;

— Lay outs 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;

— 應在附件6提供生產區域的布局圖和流程圖。圖上應當顯示房間級別，相鄰區域之間的壓差，并指出房間內進行的生產活動即混合、填料、儲存、包裝等。

— Lay-outs of warehouses and storage areas, with special areas for the storage and handling of highly toxic, hazardous and sensitising materials indicated, if applicable;

— 倉庫和儲存區域的示意圖和高毒高危害高敏感物料儲存和處理區域的描述，如果適用。

— Brief description of specific storage conditions if applicable, but not indicated on the lay-outs.

— 特定儲存條件（如果適用）的簡要描述，不需要在示意圖中指出。

4.1.1 Brief description of heating, ventilation and air conditioning (HVAC) systems供暖，通風和空調（HVAC）系統的簡要描述

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

— 系統設計標準，例如，空氣供應、溫度、濕度、壓差和換氣次數、空氣循環方法（%）;

4.1.2 Brief description of water systems水系統的簡要描述

— - Quality references of water produced;

— 產水的質量標準

— - Schematic drawings of the systems in Appendix 7.

— 水系統的示意圖附于附件7

4.1.3 Brief description of other relevant utilities, such as steam, compressed air, N2, etc. 其他相關單元的簡要描述，如蒸汽??，壓縮空氣，氮氣等。

4.2 Equipment設備

4.2.1 Listing of major production and control laboratory equipment with critical pieces of equipment identified should be provided in Appendix 8. 在附件8中列出生產和實驗室控制設備中已確定的關鍵設備4.2.2 Cleaning and sanitation清潔和衛生

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

— 產品接觸表面的清潔和衛生方法的簡要描述（即人工清洗，自動清潔等）。

4.2.3 GMP critical computerised systems GMP的關鍵電腦系統

— Description of GMP critical computerised systems (excluding equipment specific Programmable Logic Controllers (PLCs)). GMP關鍵電腦系統的描述（不包括特定設備的可編程邏輯控制器PLC）

5 DOCUMENTATION文件

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

— 公司文件體系的描述

— 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.

— 文件和記錄在廠外存儲或歸檔（包括藥物警戒的數據，如果適用）：文件/記錄的類型列表，存儲地點的名稱和地址以及異地存檔時檢索取回文件所需時間的評估。

6 PRODUCTION生產

6.1 Type of products產品類型

(references to Appendix 1 or 2 can be made可參考附件1或2):

— Type of products manufactured including

— 生產的產品類型包括

n list of dosage forms of both human and veterinary products which are manufactured on the site;

n 工廠生產的人用和獸用產品的劑型的列表

n 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 of production areas and personnel;

n 臨床試驗用的研究性新藥（IMP）的劑型列表，如果不同于商業生產工藝，要給出生產區域和人員信息

— Toxic or hazardous substances handled (e.g. with high pharmacological activity and/or with sensitising properties);

— 有毒有害物質處理（如，高藥物活性或致敏物質）

— Product types manufactured in a dedicated facility or on a campaign basis, if applicable;

— 在專用車間生產的產品劑型，如果適用

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

— 過程分析技術（簡稱：PAT）的應用，如果適用：相關計算機系統和相關技術的簡要描述。

6.2 Process validation工藝驗證

— Brief description of general policy for process validation;

— 工藝驗證方法的簡要描述。如適用，連續的驗證方法；

— Policy for reprocessing or reworking.

— 返工或再加工的方法

6.3 Material management and warehousing物料管理和倉儲

— Arrangements for the handling of starting materials, packaging materials, bulk and f inished products including sampling, quarantine, release and storage;

— 起始物料、包裝材料、原料藥和成品的處置管理，包括取樣、待驗、放行和儲存。

— Arrangements for the handling of rejected materials and products.

— 不合格物料和產品處置管理

7 QUALITY CONTROL (QC) 質量控制

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

— 關于物理、化學、微生物和生物檢測項目，在工廠執行的質量控制活動的描述。

8 DISTRIBUTION, COMPLAINTS, PRODUCT DEFECTS AND RECALLS分銷，投訴，偏差和召回

8.1 Distribution (to the part under the responsibility of the manufacturer) 分銷（生產商所承擔的責任）

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

— 工廠生產的產品發往的公司類型（零售證持有者、生產許可證持有者等）和位置（歐盟、美國等），

— Description of the system used to verify that each customer / recipient is legally entitled to receive medicinal products from the manufacturer;

— 描述：確認每個客戶/接收人是合法的從生產商處接收醫藥產品

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

— 簡要描述運輸過程中環境條件的監測控制，例如溫度監測/控制；

— Arrangements for product distribution and methods by which product traceability is maintained;

— 產品分銷和產品追蹤性的管理方法

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

— 防止生產商的產品進入非法供應鏈的措施

8.2 Complaints, product defects and recalls投訴、偏差和召回

— Brief description of the system for handling complains, product defects and recalls.

— 處置投訴、偏差和召回的體系的簡要描述

9 SELF INSPECTIONS自檢

— 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.

— 自檢體系的簡要描述，重點描述在計劃檢查、實際安排和跟蹤活動中檢查區域選擇的標準。