下载文档原格式
ANNEX 1附录ⅠMANUFACTURE OF STERILE MEDICINAL PRODUCTS无菌药品的生产Principle原则The manufacture of sterile products is subject to special requirements in order to minimize risks of microbiological contamination, and of particulate and pyrogen contamination. Much depends on the skill, training and attitudes of the personnel involved. Quality Assurance is particularly important, and this type of manufacture must strictly follow carefully established and validated methods of preparation and procedure. Sole reliance for sterility or other quality aspects must not be placed on any terminal process or finished product test.为将微生物、微粒和热原污染的风险降低至最小限度，无菌药品的生产应有各种特殊要求。
这在很大程度上取决于生产人员的技能、所接受的培训及其工作态度。
质量保证极为重要，无菌药品的生产必须严格按照精心制订并经验证的方法及规程进行。
产品的无菌或其它质量特性绝不能仅依赖于任何形式的最终操作或成品检验。
Note:注：This guidance does not lay down detailed methods for determining the microbiological and particulate cleanliness of air, surfaces etc. Reference should be made to other documents such as the EN/ISO Standards.本指南没有制定详细的空气和物体表面等的微生物和微粒的测定方法，相关事项可以参照其他文件，诸如欧洲/国际标准。
PHARMACEUTICAL INSPECTION CONVENTIONPHARMACEUTICAL INSPECTION CO-OPERATION SCHEMEPE 008-41 Annex1 January 2011© PIC/S January 2011Reproduction prohibited for commercial purposes.Reproduction for internal use is authorised,provided that the source is acknowledged.Editor: PIC/S Secretariate-mail: info@web site: TABLE OF CONTENTSPage1. Document History (2)2. Introduction (2)3. Purpose (2)4. Scope (3)5. Content of Site Master File (3)6. Revision History (3)1. DOCUMENT HISTORY2. INTRODUCTION2.1 The Site Master File is prepared by the pharmaceutical manufacturer andshould 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.2.2 When submitted to a regulatory authority, the Site Master File should provideclear 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.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. 2.4 The Site Master File should be a part of documentation belonging to the qualitymanagement 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.3. PURPOSEThe 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.4. SCOPEThese 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.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.5. CONTENT OF SITE MASTER FILERefer to Annex for the format to be used.6. REVISION HISTORYAnnex toPE 008-4CONTENT OF SITE MASTER FILE1. GENERAL INFORMATION ON THE MANUFACTURER1.1 Contact information on the manufacturer- Name and official address of the manufacturer;- Names and street addresses of the site, buildings and production units located on the site;- Contact information of the manufacturer including 24 hrs telephone number of the contact personnel in the case of product defects orrecalls;- Identification number of the site as e.g. GPS details, D-U-N-S (Data Universal Numbering System) Number (a unique identification numberprovided by Dun & Bradstreet) of the site or any other geographiclocation system1.1.2 Authorised pharmaceutical manufacturing activities of the site.- Copy of the valid manufacturing authorisation issued by the relevant Competent Authority in Appendix 1; or when applicable, reference to theEudraGMP database. If the Competent Authority does not issuemanufacturing authorisations, this should be stated;- Brief description of manufacture, import, export, distribution and other activities as authorised by the relevant Competent Authorities includingforeign authorities with authorised dosage forms/activities, respectively;where not covered by the manufacturing authorisation;- Type of products currently manufactured on-site (list in Appendix 2) where not covered by Appendix 1 or the EudraGMP database;- List of GMP inspections of the site within the last 5 years; including dates and name/country of the Competent Authority having performedthe inspection. A copy of current GMP certificate (Appendix 3) orreference to the EudraGMP database should be included, if available. 1.3 Any other manufacturing activities carried out on the site- Description of non-pharmaceutical activities on-site, if any.2. QUALITY MANAGEMENT SYSTEM OF THE MANUFACTURER2.1 The quality management system of the manufacturer- Brief description of the quality management systems run by the company and reference to the standards used;1A D-U-N-S reference is required for Site Master Files submitted to EU/EEA authorities for manufacturing sites located outside of the EU/EEA.- Responsibilities related to the maintaining of quality system including senior management;- Information of activities for which the site is accredited and certified, including dates and contents of accreditations, names of accreditingbodies.2.2. Release procedure of finished products- Detailed description of qualification requirements (education and work experience) of the Authorised Person(s) / Qualified Person(s)responsible for batch certification and releasing procedures;- General description of batch certification and releasing procedure;- Role of Authorised Person / Qualified Person in quarantine and release of finished products and in assessment of compliance with theMarketing Authorisation;- The arrangements between Authorised Persons / Qualified Persons when several Authorised Persons / Qualified Persons are involved;- Statement on whether the control strategy employs Process Analytical Technology (PAT) and/or Real Time Release or Parametric Release. 2.3Management of suppliers and contractors- A brief summary of the establishment/knowledge of supply chain and the external audit program;-Brief description of the qualification system of contractors, manufacturers of active pharmaceutical ingredients (API) and othercritical materials suppliers;-Measures taken to ensure that products manufactured are compliant with TSE (Transmitting animal spongiform encephalopathy) guidelines.-Measures adopted where counterfeit/falsified products, bulk products(i.e. unpacked tablets), active pharmaceutical ingredients or excipientsare suspected or identified;-Use of outside scientific, analytical or other technical assistance in relation to manufacture and analysis;-List of contract manufacturers and laboratories including the addresses and contact information and flow charts of supply-chains for outsourcedmanufacturing and Quality Control activities; e.g. sterilisation of primarypackaging material for aseptic processes, testing of starting raw-materials etc, should be presented in Appendix 4;-Brief overview of the responsibility sharing between the contract giver and acceptor with respect to compliance with the MarketingAuthorisation (where not included under 2.2).2.4 Quality Risk Management (QRM)- Brief description of QRM methodologies used by the manufacturer;- Scope and focus of QRM including brief description of any activities which are performed at corporate level, and those which are performedlocally. Any application of the QRM system to assess continuity ofsupply should be mentioned.2.5 Product Quality Reviews- Brief description of methodologies used3. PERSONNEL- Organisation chart showing the arrangements for quality management, production and quality control positions/titles in Appendix 5, includingsenior management and Authorised Person(s) / Qualified Person(s);- Number of employees engaged in the quality management, production, quality control, storage and distribution respectively.4. PREMISES AND EQUIPMENT4.1Premises- 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 placein different buildings on the site, the buildings should be listed withdestined markets identified (if not identified under 1.1);- Simple plan or description of manufacturing areas with indication of scale (architectural or engineering drawings are not required);- Lay outs and flow charts of the production areas (in Appendix 6) showing the room classification and pressure differentials betweenadjoining areas and indicating the production activities (i.e.compounding, filling, storage, packaging, etc.) in the rooms;- Lay-outs of warehouses and storage areas, with special areas for the storage and handling of highly toxic, hazardous and sensitisingmaterials indicated, if applicable;- Brief description of specific storage conditions if applicable, but not indicated on the lay-outs.4.1.1 Brief description of heating, ventilation and air conditioning (HVAC) systems- Principles for defining the air supply, temperature, humidity, pressure differentials and air change rates, policy of air recirculation (%).4.1.2 Brief description of water systems- Quality references of water produced;- Schematic drawings of the systems in Appendix 7.4.1.3. Brief description of other relevant utilities, such as steam, compressed air,nitrogen, etc.4.2 Equipment4.2.1Listing of major production and control laboratory equipment with critical piecesof equipment identified should be provided in Appendix 8.4.2.2Cleaning and sanitation- Brief description of cleaning and sanitation methods of product contact surfaces (i.e. manual cleaning, automatic Clean-in-Place, etc).4.2.3GMP critical computerised systems- Description of GMP critical computerised systems (excluding equipment specific Programmable Logic Controllers (PLCs)).5. DOCUMENTATION- Description of documentation system (i.e. electronic, manual);- When documents and records are stored or archived off-site (including pharmacovigilance data, when applicable): List of types ofdocuments/records; Name and address of storage site and an estimateof time required retrieving documents from the off-site archive.6. PRODUCTION6.1. Type of products(references to Appendix 1 or 2 can be made):- Type of products manufactured including§list of dosage forms of both human and veterinary productswhich are manufactured on the site§list of dosage forms of investigational medicinal products (IMP)manufactured for any clinical trials on the site, and when differentfrom the commercial manufacturing, information of productionareas and personnel- Toxic or hazardous substances handled (e.g. with high pharmacological activity and/or with sensitising properties);- Product types manufactured in a dedicated facility or on a campaign basis, if applicable;- Process Analytical Technology (PAT) applications, if applicable: general statement of the relevant technology, and associated computerisedsystems.6.2 Process validation- Brief description of general policy for process validation;- Policy for reprocessing or reworking.6.3 Material management and warehousing-Arrangements for the handling of starting materials, packaging materials, bulk and finished products including sampling, quarantine,release and storage;-Arrangements for the handling of rejected materials and products.7. QUALITY CONTROL (QC)- Description of the Quality Control activities carried out on the site in terms of physical, chemical, and microbiological and biological testing. 8. DISTRIBUTION, COMPLAINTS, PRODUCT DEFECTS AND RECALLS8.1 Distribution (to the part under the responsibility of the manufacturer)- Types (wholesale licence holders, manufacturing licence holders, etc) and locations (EU/EEA, USA, etc.) of the companies to which theproducts are shipped from the site;- Description of the system used to verify that each customer / recipient is legally entitled to receive medicinal products from the manufacturer;- Brief description of the system to ensure appropriate environmental conditions during transit, e.g. temperature monitoring/ control;- Arrangements for product distribution and methods by which product traceability is maintained;- Measures taken to prevent manufacturers’ products to fall in the illegal supply chain.8.2 Complaints, product defects and recalls- Brief description of the system for handling complains, product defects and recalls.9. SELF INSPECTIONS- Short description of the self inspection system with focus on criteria used for selection of the areas to be covered during plannedinspections, practical arrangements and follow-up activities.___________Appendix 1 Copy of valid manufacturing authorisationAppendix 2 List of dosage forms manufactured including the INN-names or common name (as available)of active pharmaceutical ingredients(API) usedAppendix 3 Copy of valid GMP CertificateAppendix 4 List of contract manufacturers and laboratories including the addresses and contact information, and flow-charts of the supply-chains for these outsourced activitiesAppendix 5 Organisational chartsAppendix 6 Lay outs of production areas including material and personnel flows, general flow charts of manufacturing processes of eachproduct type (dosage form)Appendix 7 Schematic drawings of water systemsAppendix 8 List of major production and laboratory equipment*********。
附件1Annex 1确认与验证Qualification and Validation（征求意见稿）(Draft for Comments)第一章范围Chapter One Scope第一条本附录适用于《药品生产质量管理规范》中涉及的所有确认与验证活动。
Article 1 This appendix applies to all qualification and validation activities involved in Good Manufacturing Practice.第二章原则Chapter Two Principles第二条企业应当确定需要进行的确认或验证工作，以证明有关操作的关键要素能够得到有效控制。
确认和验证的范围和程度应根据风险评估的结果确认。
确认与验证应当贯穿于产品生命周期的全过程。
Article 2 A manufacturer should determine the required qualification or validation activities to prove that the critical aspects of relevant operations can be effectively controlled. The scope and extent of qualification and validation should be determined based on risk assessment results. Qualification and validation activities should be throughout the entire life cycle of a product.第三章验证计划Chapter Three Validation Plan第三条所有的确认与验证活动都应当事先计划。
确认与验证的关键要素都应在验证总计划或同类文件中详细说明。
Annex 1 : Manufacture of Sterile Products无菌药品的生产Document map 目录8 Production and Specific Technologies生产与具体技术 (2)Terminally sterilized products 最终灭菌产品 (2)Aseptic preparation and processing 无菌准备和处理 (2)Finishing of sterile products无菌产品的最终处理 (6)Sterilization 灭菌 (8)Sterilization by heat 热力灭菌 (10)Moist heat sterilization 湿热灭菌 (11)Dry heat sterilization 干热灭菌 (13)Sterilization by radiation 辐射灭菌 (15)Sterilization with ethylene oxide环氧乙烷灭菌 (15)Filter sterilization of products which cannot be sterilized in their final container非最终灭菌药品的无菌过滤 (16)Form-Fill-Seal 成型-灌-封 (20)Blow-Fill-Seal 吹-灌-封 (20)Lyophilization 冻干 (22)Closed systems 密封系统 (23)Single use systems (SUS) 一次性使用系统 (24)9 Viable and non-viable environmental & process monitoring 活性和非活性环境和工艺监测 (26)General 综述 (26)Environmental monitoring 环境检测 (26)Environmental monitoring- non-viable particles 非活性粒子的环境检测 (27)Environmental and personnel monitoring-viable particles 环境和人员的监测—活粒子 (29)Aseptic process simulation (APS) (also known as media fill) 无菌模拟灌装 (31)10 Quality Control (QC) 质量控制 (38)Glossary 术语 (40)8 Production and Specific Technologies生产与具体技术Terminally sterilized products 最终灭菌产品8.1 Preparation of components and materials should be performed in at least a Grade D cleanroom in order to limit the risk of microbial, pyrogen and particulate contamination, so that the product is suitable for sterilization. Where the product is at a high or unusual risk of microbial contamination (e.g. the product actively supports microbial growth, the product must be held for long periods before filling or the product is not processed mostly in closed vessels), then preparation should be carried out in a Grade C environment. Preparation of ointments, creams, suspensions and emulsions should be carried out in a Grade C environment before terminal sterilization.部件和物料的准备工作至少应在D级洁净室中进行，以限制微生物、热原和微粒污染的风险，以便使产品适合灭菌。
化学药品注射剂灭菌/无菌工艺研究及验证指导原则的起草和考虑国家药品监督管理局药品审评中心2020年7月概述湿热灭菌工艺的研究和验证一二目录CONTENTS 无菌生产工艺的研究和验证三小结四无菌药品和无菌保证水平的定义无菌药品是指法定药品标准中列有无菌检查项目的制剂和原料。
特定批次物品的无菌保证水平系指无菌药品中存在活微生物的概率。
终端灭菌工艺：不超过一百万分之一。
无菌生产工艺：以培养基灌装零污染为目标。
《药品生产质量管理规范》附录无菌药品•无菌药品的生产必须严格按照精心设计并经过验证的方法及规程进行，产品的无菌或其他质量特性绝不能依赖于任何形式的最终处理或成品检验。
《中国药典》2015年版1421 灭菌法•灭菌物品的无菌保证不能依赖于最终产品的无菌检验，而是取决于生产过程中采用合格的灭菌工艺、严格的GMP管理和良好的无菌保证体系。
质量源于设计《总局关于发布化学药品新注册分类申报资料要求（试行）的通告（2016年第80号）》•提供无菌工艺步骤的工艺验证报告（编号：--，版本号：--），工艺必须在预定的参数范围内进行。
M4Q（R1）：人用药物注册通用技术文档：药学部分•3.2.P.3.5 工艺验证和/或评价（名称、剂型）•对于生产工艺中的关键步骤或关键检验项目，应提供验证和/或评价研究的说明、文件和结果（例如灭菌工艺、无菌工艺或灌装的验证）。
《化学药品注射剂仿制药质量和疗效一致性评价技术要求》•注射剂灭菌/无菌工艺的研究和选择应参考国内外灭菌/无菌工艺相关的指导原则进行。
•2、工艺验证：灭菌/无菌工艺验证•对于终端灭菌药品：药品终端灭菌工艺验证。
目的•对注射剂的灭菌工艺研究和验证的要点进行阐述。
•促进现阶段化学药品注射剂的研究和评价工作的开展。
适用范围•化学药品注射剂-终产品•湿热灭菌工艺•无菌生产工艺•注册申报过程中需要提供的研究及验证内容。
•GMP要求的相关器具、设备等的验证及常规再验证不在本指导原则的范围内。
