WHO現(xiàn)場(chǎng)主文件編寫指南

1、© World Health OrganizationWHO Technical Report Series, No.961, 2011附件14Annex 14WHO現(xiàn)場(chǎng)主文件編寫指南1WHO guidelines for drafting a site master file11. 介紹Introduction2. 目的Purpose3. 范圍Scope4. 現(xiàn)場(chǎng)主文件的內(nèi)容Content of site master file附件Appendix現(xiàn)場(chǎng)主文件的內(nèi)容Content of a site master file1 基于制藥檢查會(huì)議對(duì)藥品生產(chǎn)商編寫現(xiàn)場(chǎng)主文件的注釋 Base

2、d on the Explanatory notes for pharmaceutical manufacturers on the preparation of a site master file of the Pharmaceutical Inspection Convention.1. 介紹Introduction1.1 現(xiàn)場(chǎng)主文件是由藥品制藥商編寫的，應(yīng)當(dāng)包含下列具體的信息：生產(chǎn)廠區(qū)的質(zhì)量管理方針及活動(dòng)、在指定的生產(chǎn)廠區(qū)實(shí)行的對(duì)藥品生產(chǎn)操作的生產(chǎn)和/或質(zhì)量控制以及在與其相鄰的建筑物內(nèi)所進(jìn)行的任何緊密的完整的操作。如果只有一部分藥品生產(chǎn)操作在此廠區(qū)內(nèi)進(jìn)行，那么在現(xiàn)場(chǎng)主文件中只需要描述這

3、些操作，例如分析、包裝等。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 當(dāng)提交給監(jiān)管機(jī)構(gòu)時(shí)，現(xiàn)場(chǎng)主文件中應(yīng)當(dāng)包含對(duì)常規(guī)監(jiān)督、有效計(jì)劃及進(jìn)行GMP檢查有用的、關(guān)于制造商與GMP相關(guān)的活動(dòng)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 現(xiàn)場(chǎng)主文件中應(yīng)當(dāng)包含足夠的信息，但加上附件盡量不要超過2530頁(yè)。用簡(jiǎn)單的計(jì)劃、輪廓圖或

6、示意圖來替代敘述性的文字是更可取的。當(dāng)用A4紙張打印出時(shí)，現(xiàn)場(chǎng)主文件及其附件應(yīng)當(dāng)是可讀的。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 現(xiàn)場(chǎng)主文件應(yīng)是制造商質(zhì)量管理體系文件的一部分，且應(yīng)持續(xù)更新?，F(xiàn)場(chǎng)主文件應(yīng)有版本號(hào)、生效期和必須對(duì)其進(jìn)行審核的日期。應(yīng)當(dāng)定期對(duì)現(xiàn)場(chǎng)主文件進(jìn)行回顧以保證其包含了最新的信息和代表了當(dāng)前所進(jìn)行的活動(dòng)。每個(gè)附件可以有單獨(dú)的生效期，以便進(jìn)行獨(dú)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這些注釋的目的是：在藥品制造商編寫現(xiàn)場(chǎng)主文件時(shí)提供指導(dǎo)，現(xiàn)場(chǎng)主文件在監(jiān)管機(jī)構(gòu)計(jì)劃和進(jìn)行GMP檢查時(shí)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. 范圍Scope這些注釋適用于現(xiàn)場(chǎng)主文件的編寫及內(nèi)容的確定。制造商應(yīng)參照區(qū)域性

10、的和/或國(guó)家監(jiān)管要求來確定編寫現(xiàn)場(chǎng)主文件是否是強(qiáng)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.這些注釋適用于各種制造操作，例如各種藥品的生產(chǎn)

11、、包裝和貼簽、檢測(cè)、重新貼簽和重新包裝。本指南中的概述也可用于指導(dǎo)血液和組織制品和原料藥（API）制造商編寫現(xiàn)場(chǎng)主文件或相應(yīng)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. 現(xiàn)場(chǎng)主文件的內(nèi)容Content of site master file格式參照附件。Refer to the Appendix for the format to be used.附件Appendix場(chǎng)主文件的內(nèi)容Content of a site master file1. 制造商基

13、本信息General information on the manufacturer 1.1制造商聯(lián)系信息Contact information on the manufacturer - 制造商名稱及官方地址；name and official address of the manufacturer;- 生產(chǎn)廠地名稱及街道地址，在生產(chǎn)廠地內(nèi)的建筑物和生產(chǎn)單元；names and street addresses of the site, buildings and production units located on the site;- 制造商聯(lián)系信息，包括在產(chǎn)品缺陷或召回時(shí)，相關(guān)聯(lián)系人

14、的24小時(shí)聯(lián)系號(hào)碼；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- 生產(chǎn)廠地的識(shí)別碼，例如全球地位系統(tǒng)（GPS）詳細(xì)信息、生產(chǎn)廠地或其它地理系統(tǒng)D-U-N-S（數(shù)據(jù)通用編號(hào)系統(tǒng)）編號(hào)（由Dun & Bradstreet提供的識(shí)別碼）。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生產(chǎn)廠地被授權(quán)的藥品生產(chǎn)活動(dòng)Authorized pharmaceutical manufacturing activities of the site- 主管部門頒發(fā)的有效的生產(chǎn)許可證的復(fù)印件作

16、為附件一；或者當(dāng)適用時(shí)，索引到EudraGMP數(shù)據(jù)庫(kù)。如果主管部門不頒發(fā)生產(chǎn)許可證，應(yīng)當(dāng)進(jìn)行聲明。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、- 如果沒有涵蓋在生產(chǎn)許可證范圍時(shí)，簡(jiǎn)述由相關(guān)主管部門，包括國(guó)外監(jiān)管機(jī)構(gòu)授權(quán)的制造、進(jìn)口、出口、分發(fā)和其他活動(dòng)，授權(quán)的劑型/活動(dòng)，應(yīng)根據(jù)許可的劑型/活動(dòng)分別敘述；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數(shù)據(jù)庫(kù)范圍時(shí)，將目前在生產(chǎn)廠地生產(chǎn)的所有產(chǎn)品類型列出（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年內(nèi)接受的所有GMP檢查，包括進(jìn)行檢查的監(jiān)管部門名稱/國(guó)家和檢查日期。如果有的話，應(yīng)將現(xiàn)行GMP證書的復(fù)印件作為附件三或索引到Eu

19、draGMP數(shù)據(jù)庫(kù)。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 在生產(chǎn)廠地進(jìn)行的其他

20、生產(chǎn)活動(dòng)Any other manufacturing activities carried out on the site- 如果有的話，對(duì)生產(chǎn)廠地內(nèi)的非藥品生產(chǎn)活動(dòng)進(jìn)行描述。description of non-pharmaceutical activities on site, if any.2. 質(zhì)量管理Quality management 2.1 制造商的質(zhì)量管理體系The quality management system of the manufacturer- 公司質(zhì)量管理體系簡(jiǎn)介以及采取的標(biāo)準(zhǔn)；brief description of the quality manageme

21、nt systems run by the company and reference to the standards used;- 包括高層管理人員在內(nèi)的與維護(hù)質(zhì)量體系相關(guān)的人員的職責(zé)；以及 responsibilities related to the maintaining of the quality system including senior management; and- 生產(chǎn)廠地被認(rèn)證和確認(rèn)的活動(dòng)信息，包括認(rèn)證的日期和內(nèi)容，認(rèn)證機(jī)構(gòu)的名稱；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- 負(fù)責(zé)批確認(rèn)的質(zhì)量受權(quán)人資質(zhì)要求（教育背景和工作經(jīng)驗(yàn)）和放行程序的詳細(xì)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;- 批確認(rèn)和放行程序的總體描述；general description of batch certification and releasing procedure;- 質(zhì)量受權(quán)人在成品待驗(yàn)和放行、評(píng)價(jià)上市許可時(shí)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;- 當(dāng)有多個(gè)質(zhì)量受權(quán)人時(shí)，不同質(zhì)量受權(quán)人之間職責(zé)的分工；以及the arrangements between authorized persons/qualified persons when several authorized persons/qualified persons are involved; and- 聲明控制策略中是否包括過程分析技術(shù)（PAT）和實(shí)時(shí)放行或參數(shù)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 供應(yīng)商和承包商的管理Management of suppliers and contractors - 對(duì)供應(yīng)鏈的建立/知識(shí)和外部審計(jì)程序進(jìn)行小結(jié)；a brief summary of the establishment/knowledge of supply chain and the external audit programme;- 簡(jiǎn)述承包商、API制造商和其它關(guān)鍵物料供應(yīng)商的確認(rèn)系統(tǒng)；a brief description of the qualific

26、ation system of contractors, manufacturers of APIs and other critical materials suppliers;- 為保證所生產(chǎn)的產(chǎn)品符合傳染性動(dòng)物海綿狀腦病（TSE）相關(guān)指南所采取的措施；measures taken to ensure that products manufactured are compliant with transmitting animal spongiform encephalopathy (TSE) guidance;- 當(dāng)懷疑或確認(rèn)有不合格的/假的/錯(cuò)誤貼標(biāo)簽/偽造的/仿冒的藥品、待包裝產(chǎn)品（

27、例如未包裝的片劑）、API或輔料時(shí)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;- 采用的與生產(chǎn)和分析相關(guān)外部的科學(xué)、分析或其它的技術(shù)支持；use of outside scientific, analytical or other technical as

28、sistance in relation to manufacture and analysis;- 委托生產(chǎn)商和實(shí)驗(yàn)室清單，包括外包的生產(chǎn)和QC活動(dòng)的地址和聯(lián)系信息、供應(yīng)鏈流程圖，例如無菌工藝中使用的內(nèi)包材的滅菌、起始物料的檢驗(yàn)等，上述信息在附件四中進(jìn)行描述；以及l(fā)ist 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- 合同雙方關(guān)于上市許可符合性職責(zé)的概述（如果沒有在2.2中進(jìn)行描述的話）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 質(zhì)量風(fēng)險(xiǎn)管理Quality risk management - 簡(jiǎn)述制造商采用的質(zhì)量風(fēng)險(xiǎn)管理（QRM）方法學(xué)；以及brief description of quality risk management (QRM) methodologies used by the manufacturer; and- 質(zhì)量風(fēng)險(xiǎn)管理（QRM）的范圍和聚焦點(diǎn)，包括在公司層面進(jìn)行的和局部進(jìn)行的風(fēng)險(xiǎn)管理活動(dòng)的簡(jiǎn)述。應(yīng)對(duì)任何運(yùn)用質(zhì)量風(fēng)險(xiǎn)管理（QRM）系統(tǒng)評(píng)價(jià)供應(yīng)連續(xù)性的活

31、動(dòng)進(jìn)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產(chǎn)品質(zhì)量回顧 Product quality reviews - 簡(jiǎn)述采用的產(chǎn)品質(zhì)量回顧的方法學(xué)。brief des

32、cription of methodologies used.3. 人員Personnel - 組織機(jī)構(gòu)圖，顯示出質(zhì)量管理、生產(chǎn)和質(zhì)量控制之間的安排，在附件五中列出，包括高管和質(zhì)量受權(quán)人，應(yīng)列出職位/職務(wù)；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- 分別列出參與質(zhì)量管理、生產(chǎn)、質(zhì)量控制、儲(chǔ)存和分發(fā)的員工人數(shù)；number of employees engaged in the quality management, production, quality control, storage and distribution, respectively.4. 設(shè)施和設(shè)備Premises and equipment 4.1設(shè)施 Premises - 對(duì)生產(chǎn)車間的簡(jiǎn)短描述：尺寸和建筑物清單。如果供應(yīng)到不同市場(chǎng)的產(chǎn)品在不同的建筑物內(nèi)進(jìn)行生產(chǎn)，例如國(guó)內(nèi)或區(qū)域所屬經(jīng)濟(jì)區(qū)，則應(yīng)在建筑物清單中列出并標(biāo)明生產(chǎn)的產(chǎn)品所供應(yīng)的市場(chǎng)（如果沒

34、有在1.1中說明的話）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);- 生產(chǎn)區(qū)域的簡(jiǎn)短描述或計(jì)劃，并標(biāo)示出相應(yīng)的規(guī)模（不要求提供建筑或工程圖紙）simple plan or description of manufacturing areas with indication of scale (architectural or engineering drawings are not required);- 生產(chǎn)區(qū)域平面圖和流程圖（在附件六中列出），標(biāo)示出房間潔凈級(jí)別、相鄰區(qū)域之間的壓差以及房間內(nèi)的生產(chǎn)活動(dòng)（例如配藥、灌裝、儲(chǔ)存、包裝等）；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;- 倉(cāng)庫(kù)和存儲(chǔ)區(qū)平面圖，如果有的話，平面圖中應(yīng)標(biāo)示出儲(chǔ)存和處理高毒性、高危害性和高敏感性的物料的特殊區(qū)域；以及l(fā)ayouts 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- 如果有的話，簡(jiǎn)述沒有在平面圖中標(biāo)出的特殊儲(chǔ)存條件。brief description of specific storage conditions if applicable, but not indicated on the layouts.4.1.1采暖、通風(fēng)和空調(diào)（HVAC）系統(tǒng)的簡(jiǎn)述Brief description of he

38、ating, ventilation and air-conditioning (HVAC) systems- 確定空氣供應(yīng)量、溫度、濕度、壓差、換氣率和空氣再循環(huán)方針的原則。principles for defining the air supply, temperature, humidity, pressure differentials and air-change rates, policy of air recirculation (%).4.1.2 水系統(tǒng)簡(jiǎn)述Brief description of water systems - 使用的水的質(zhì)量參照；以及quality refe

39、rences of water produced; and- 在附件七中列出水系統(tǒng)原理圖。schematic drawings of the systems in Annex 7.4.1.3其他相關(guān)公用設(shè)施，例如蒸汽、壓縮空氣和氮?dú)庀到y(tǒng)等的簡(jiǎn)述Brief description of other relevant utilities such as steam, compressed air, nitrogen, etc.4.2 設(shè)備Equipment 4.2.1主要生產(chǎn)和控制實(shí)驗(yàn)室設(shè)備清單作為附件八，并標(biāo)示出關(guān)鍵設(shè)備。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 清潔和衛(wèi)生Cleaning and sanitation - 描述與產(chǎn)品接觸的表面的清潔和衛(wèi)生方法（例如手工清潔、自動(dòng)在線清潔等）brief description of cleaning and sanitation methods of product contact surfaces (i.e. manual cleaning, automatic clean-in-place,

41、etc.).4.2.3良好生產(chǎn)規(guī)范關(guān)鍵計(jì)算機(jī)化系統(tǒng)Good manufacturing practices critical computerized systems- GMP關(guān)鍵計(jì)算機(jī)化系統(tǒng)的描述（除設(shè)備的可編程邏輯控制器（PLC）外）。description of GMP critical computerized systems (excluding equipment specific programmable logic controllers (PLCs).5. 文件記錄Documentation - 文件記錄系統(tǒng)的描述（例如電子、手工）；以及description of docu

42、mentation system (i.e. electronic, manual); and- 當(dāng)文件和記錄不在生產(chǎn)廠地保存或存檔（如果適用的話，包括藥物警戒數(shù)據(jù)）時(shí)：列出文件/記錄的種類；儲(chǔ)存地的名稱和地址；從儲(chǔ)存地取回文件所需要的預(yù)計(jì)時(shí)間。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. 生產(chǎn)Production 6.1產(chǎn)品種類 Type of products References to Annex 1 or 2 can be made.可索引到附件一或附件二。- 生產(chǎn)產(chǎn)品的類型包括：type of products manufactured including:· 列出在生產(chǎn)廠地生產(chǎn)的人用藥和獸用藥的劑型；list of dosage forms of both human and vet

44、erinary products which are manufactured on the site；· 列出在生產(chǎn)廠地生產(chǎn)的用于臨床研究的研究藥用產(chǎn)品（IMP）的劑型，當(dāng)其生產(chǎn)不同于商業(yè)化生產(chǎn)時(shí)，還應(yīng)對(duì)生產(chǎn)區(qū)域和人員進(jìn)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;· 處理的有毒或有害物質(zhì)（例如有高藥理活性和/或高致敏性）；toxic or hazardous substances handled (e.g. with high pharmacological activity and/or with sensitizing properties);· 如果適用的話，在專用區(qū)域內(nèi)或基于階段性生產(chǎn)的產(chǎn)品類型product types manufactured in a dedicated facility or on a campaign basis, if appl

46、icable; and· 如果適用的話，PAT應(yīng)用：相關(guān)技術(shù)的總體聲明；及相關(guān)的計(jì)算機(jī)化系統(tǒng)。· PAT applications, if applicable: general statement of the relevant technology; and associated computerized systems.6.2 工藝驗(yàn)證Process validation - 工藝驗(yàn)證總方針簡(jiǎn)述；以及brief description of general policy for process validation; and- 返工或重新加工方針。policy for

47、 reprocessing or reworking.6.3 物料管理和倉(cāng)庫(kù)Material management and warehousing - 起始物料、包裝材料、待包裝品和成品的處理，包括取樣、待驗(yàn)、放行和儲(chǔ)存；以及arrangements for the handling of starting materials, packaging materials, bulk and finished products including sampling, quarantine, release and storage; and- 不合格物料和產(chǎn)品的處理arrangements for

48、the handling of rejected materials and products.7. 質(zhì)量控制Quality control - 描述在生產(chǎn)廠地的QC活動(dòng)，包括物理、化學(xué)、微生物和生物檢測(cè)。description of the QC activities carried out on the site in terms of physical, chemical and microbiological and biological testing.8. 分發(fā)、投訴、產(chǎn)品缺陷和召回Distribution, complaints, product defects and reca

49、lls 8.1分發(fā)（生產(chǎn)商的職責(zé)部分）Distribution (to the part under the responsibility of the manufacturer)- 接收產(chǎn)品的公司的類型（批發(fā)許可證持有者、生產(chǎn)許可證持有者等）和位置（國(guó)家或區(qū)域經(jīng)濟(jì)區(qū)）；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;- 用于核實(shí)每位客戶/接收者具有合法的資質(zhì)來接收從生產(chǎn)商運(yùn)送過來的藥品的系統(tǒng)；description of the system used to verify that each customer/recipient is legally entitled to receive medicinal products from the manufacturer;- 簡(jiǎn)述在運(yùn)輸過程中用于保證適當(dāng)?shù)沫h(huán)境條件的系統(tǒng)，例如溫度監(jiān)控/控制；brief description of the system to ensure appro