欧洲药品GMP检查指南.docVIP

肁羆薁蒂螁膁蒇薁袃羄莃薀羆膀艿薀蚅羃芅蕿袈芈薄薈羀肁蒀薇肂芆莆薆螂聿节薅袄芅膈蚄羇肇蒆蚄蚆芃莂蚃蝿肆莈蚂羁莁芄蚁肃膄薃蚀螃羇葿虿袅膂莅蚈羇羅芁螈蚇膁膇螇蝿羃蒅螆袂腿蒁螅肄羂莇螄螄芇芃螃袆肀薂螃羈芅蒈螂肁肈莄袁螀芄芀蒇袃肇膆蒆羅节薄蒆螅肅蒀蒅袇莀莆蒄罿膃节蒃肁羆薁蒂螁膁蒇薁袃羄莃薀羆膀艿薀蚅羃芅蕿袈芈薄薈羀肁蒀薇肂芆莆薆螂聿节薅袄芅膈蚄羇肇蒆蚄蚆芃莂蚃蝿肆莈蚂羁莁芄蚁肃膄薃蚀螃羇葿虿袅膂莅蚈羇羅芁螈蚇膁膇螇蝿羃蒅螆袂腿蒁螅肄羂莇螄螄芇芃螃袆肀薂螃羈芅蒈螂肁肈莄袁螀芄芀蒇袃肇膆蒆羅节薄蒆螅肅蒀蒅袇莀莆蒄罿膃节蒃肁羆薁蒂螁膁蒇薁袃羄莃薀羆膀艿薀蚅羃芅蕿袈芈薄薈羀肁蒀薇肂芆莆薆螂聿节薅袄芅膈蚄羇肇蒆蚄蚆芃莂蚃蝿肆莈蚂羁莁芄蚁肃膄薃蚀螃羇葿虿袅膂莅蚈羇羅芁螈蚇膁膇螇蝿羃蒅螆袂腿蒁螅肄羂莇螄螄芇芃螃袆肀薂螃羈芅蒈螂肁肈莄袁螀芄芀蒇袃肇膆蒆羅节薄蒆螅肅蒀蒅袇莀莆蒄罿膃节蒃肁羆薁蒂螁膁蒇薁袃羄莃薀羆膀艿薀蚅羃芅蕿袈芈薄薈羀肁蒀薇肂芆莆薆螂聿节 GUIDE TO GOOD MANUFACTURINGPRACTICE FOR MEDICINAL PRODUCTS药品GMP检查指南. PIC/S July 2004Reproduction prohibited for commercial purposes.Reproduction for internal use is authorised,provided that the source is acknowledged.Editor: PIC/S SecretariatP.O. Box 5695CH-1211 Geneva 11e-mail: web site: 1 July 2004 PE 009-2TABLE OF CONTENT目录INTRODUCTION介绍1CHAPTER 1 QUALITY MANAGEMENT 质量管理4PRINCIPLE 原则4QUALITY ASSURANCE 质量保证4GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (GMP) 药品GMP6QUALITY CONTROL 质量控制7CHAPTER 2 PERSONNEL 人员10PRINCIPLE 原则10GENERAL 通则10KEY PERSONNEL 关键人员10TRAINING 培训13PERSONAL HYGIENE 个人卫生14CHAPTER 3 PREMISES AND EQUIPMENT 厂房和设备16PRINCIPLE 原则16PREMISES General总则16Production Area 生产区域17Storage Areas 储存区域19Quality Control Areas 质量控制区域20Ancillary Areas 辅助区域20EQUIPMENT 设备21CHAPTER 4 DOCUMENTATION 文件23PRINCIPLE 原则23GENERAL 总则23DOCUMENTS REQUIRED 必需的文件25MANUFACTURING FORMULA AND PROCESSING INSTRUCTIONS 生产方法和加工指示27PACKAGING INSTRUCTIONS 包装指示28BATCH PROCESSING RECORDS 批加工记录29BATCH PACKAGING RECORDS 批包装记录30PROCEDURES AND RECORDS 程序和记录32CHAPTER 5 PRODUCTION 生产36PRINCIPLE 原则36GENERAL 通则36PREVENTION OF CROSS-CONTAMINATION IN PRODUCTION 生产过程中防止交叉污染38VALIDATION 验证39STARTING MATERIALS 起始物料40PROCESSING OPERATIONS - INTERMEDIATE AND BULK PRODUCTS 加工操作：中间体和散装产品42PACKAGING MATERIALS 包装材料42PACKAGING OPERATIONS 包装操作43FINISHED PRODUCTS 最终成品45REJECTED, RECOVERED AND RETURNED MATERIALS 拒绝的，回收的和退回的物料46CHAPTER 6 QUALITY CONTROL 质量控制48PRINCIPLE 原则48GENERAL 通则48GOOD QUALITY CONTROL LABORATORY PRACTICE 优良质量控制实验室实践49DOCUMENTATION 文件49SAMPLING 取样50TESTING 检测52CHAPTER 7 CONTRACT MANUFACTURE AND ANALYSIS 合同加工和分析55PRINCIPLE 原则55GENERAL 通则55THE CONTRACT GIVER 合同提供人55THE CONTRACT ACCEPTOR 合同接受人56THE CONTRACT 合同57CHAPTER 8 COMPLAINTS AND PRODUCT RECALL 抱怨和产品召回59PRINCIPLE 原则59COMPLAINTS 抱怨59RECALLS 召回60CHAPTER 9 SELF INSPECTION 自检61PRINCIPLE 原则61ANNEX 1 MANUFACTURE OF STERILE MEDICINAL PRODUCTS无菌药品的生产63PRINCIPLE63GENERAL63BLOW/FILL/SEAL TECHNOLOGY67TERMINALLY STERILISED PRODUCTS67ASEPTIC PREPARATION68PERSONNEL68PREMISES70EQUIPMENT71SANITATION71PROCESSING71STERILISATION73STERILISATION BY HEAT74MOIST HEAT75DRY HEAT75STERILISATION BY RADIATION75STERILISATION WITH ETHYLENE OXIDE76FILTRATION OF MEDICINAL PRODUCTS WHICH CANNOT BE STERILISED IN THEIR FINAL CONTAINER77FINISHING OF STERILE PRODUCTS77QUALITY CONTROL78ANNEX 2 MANUFACTURE OF BIOLOGICAL MEDICINAL PRODUCTS FOR HUMAN USE人用生物药品的生产79SCOPE79PRINCIPLE79PERSONNEL80PREMISES AND EQUIPMENT81ANIMAL QUARTERS AND CARE82DOCUMENTATION82PRODUCTION83QUALITY CONTROL84ANNEX 3 MANUFACTURE OF RADIOPHARMACEUTICALS 放射性药品的生产85PRINCIPLE85PERSONNEL85PREMISES AND EQUIPMENT85PRODUCTION86QUALITY CONTROL86DISTRIBUTION AND RECALLS86ANNEX 4 MANUFACTURE OF VETERINARY MEDICINAL PRODUCTS OTHER THAN IMMUNOLOGICALS MANUFACTURE OF PREMIXES FOR MEDICATED FEEDING STUFFS 除为预混合加药饲料原料生产的免疫产品以外的，兽药产品的生产87THE MANUFACTURE OF ECTOPARASITICIDES88THE MANUFACTURE OF VETERINARY MEDICINAL PRODUCTS CONTAINING PENICILLINS88RETENTION OF SAMPLES (point 1.4. viii and point 6.14.)88STERILE VETERINARY MEDICINAL PRODUCTS88ANNEX 5 MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS免疫兽药产品的生产89PRINCIPLE89PERSONNEL89PREMISES90EQUIPMENT93ANIMALS AND ANIMAL HOUSES94DISINFECTION - WASTE DISPOSAL94PRODUCTION95STARTING MATERIALS95QUALITY CONTROL98ANNEX 6 MANUFACTURE OF MEDICINAL GASES药用气体的生产991. PRINCIPLE992. PERSONNEL993. PREMISES AND EQUIPMENT994. DOCUMENTATION1005. PRODUCTION1016. QUALITY CONTROL1047. STORAGE AND RELEASE105ANNEX 7 MANUFACTURE OF HERBAL MEDICINAL PRODUCTS草药产品的生产108PRINCIPLE108PREMISES108DOCUMENTATION108SAMPLING109QUALITY CONTROL110ANNEX 8 SAMPLING OF STARTING AND PACKAGING MATERIALS起始物料和包装材料的取样111PRINCIPLE111PERSONNEL111STARTING MATERIALS111PACKAGING MATERIAL112ANNEX 9 MANUFACTURE OF LIQUIDS, CREAMS AND OINTMENTS流体，霜体和膏体药品的生产113PRINCIPLE113PRODUCTION113ANNEX 10 MANUFACTURE OF PRESSURISED METERED DOSE AEROSOL PREPARATIONS FOR INHALATION吸入式剂量仪的气雾剂的生产115PRINCIPLE115GENERAL115PREMISES AND EQUIPMENT115PRODUCTION AND QUALITY CONTROL116ANNEX 11 COMPUTERISED SYSTEMS 计算机化系统117PRINCIPLE117PERSONNEL117VALIDATION117ANNEX 12 USE OF IONISING RADIATION IN THE MANUFACTURE OF MEDICINAL PRODUCTS使用离子放射生产药品120INTRODUCTION120RESPONSIBILITIES120DOSIMETRY121VALIDATION OF THE PROCESS121COMMISSIONING OF THE PLANT122PREMISES124PROCESSING124DOCUMENTATION126MICROBIOLOGICAL MONITORING126ANNEX 13 MANUFACTURE OF INVESTIGATIONAL MEDICINAL PRODUCTS观察期药品的生产127PRINCIPLE127GLOSSARY128QUALITY MANAGEMENT130PERSONNEL130PREMISES AND EQUIPMENT130DOCUMENT ATION131PRODUCTION132QUALITY CONTROL136RELEASE OF BATCHES137SHIPPING139COMPLAINTS139RECALLS AND RETURNS139DESTRUCTION140ANNEX 14 MANUFACTURE OF PRODUCTS DERIVED FROM HUMAN BLOOD OR HUMAN PLASMA生产自人类血液或人体组织分离的产品143PRINCIPLE143GLOSSARY144QUALITY MANAGEMENT144PREMISES AND EQUIPMENT145BLOOD AND PLASMA COLLECTION145TRACEABILITY AND POST COLLECTION MEASURES146PRODUCTION AND QUALITY CONTROL147RETENTION OF SAMPLES148DISPOSAL OF REJECTED BLOOD, PLASMA OR INTERMEDIATES148ANNEX 15 QUALIFICATION AND VALIDATION 确认和验证149PRINCIPLE149PLANNING FOR VALIDATION149DOCUMENTATION150QUALIFICATION150PROCESS VALIDATION151CLEANING VALIDATION153CHANGE CONTROL154REVALIDATION154GLOSSARY154ANNEX 16 QUALIFIED PERSON AND BATCH RELEASE*经授权的人员和批放行157ANNEX 17 PARAMETRIC RELEASE参数放行1581. PRINCIPLE1582. PARAMETRIC RELEASE1583. PARAMETRIC RELEASE FOR STERILE PRODUCTS1584. GLOSSARY160ANNEX 18 GMP GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS 17原料药GMP指南161GLOSSARY术语表162GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS药品GMP指南INTRODUCTION介绍为进一步消除药品贸易壁垒，促进许可证的一致性，以及确保整个欧洲在研发，生产和控制药品中保持高标准的质量保证，根据药品检查协会（PIC）同意，药品检查使用一致的GMP原则，和药品检查合作计划表中的欧洲药品GMP及其附录。In order to further facilitate the removal of barriers to trade in medicinal products, to promote uniformity in licensing decisions and to ensure the maintaining of high standards of quality assurance in the development, manufacture and control of medicinal products throughout Europe, it was agreed to harmonise the rules of GMP applied under Pharmaceutical Inspection Convention (PIC) and the Pharmaceutical Inspection Co-operation Scheme (PIC/S) to those of the EU Guide to Good Manufacturing Practice for Medicinal Products and its Annexes. 为了将欧洲指南改编成适合协会的要求和目的，进行了最小的编辑变化。这些变化如下： 药品的定义 （参见本指南对药品的定义），保留了药品检查协会的第一章的定义； 删除了对欧洲法规的参考； 由于药品检查协会没有“有资质人员”的定义，这个定义被替换成“经授权人员”（见术语表）； 由于药品检查协会的参与国或参与的官方机构不是欧洲药典委员会的成员，本指南中的“欧洲药典”应理解成“欧洲药典或其他相关药典”。A minimum of editorial changes have, however, been necessary to adapt the text of the EU Guide to the Conventions purposes and requirements. Those changes are the following: . the definition of Pharmaceutical Product (referred to as “Medicinal Product” in this Guide) which is found in Article 1 of the Pharmaceutical Inspection Convention has been retained; . references to the EU Directives have been deleted; . as the expression Qualified Person does not exist under the PIC or PIC/S , it has been replaced by authorised person (see Glossary) . since all the Contracting States to the PIC Convention or Participating Authorities under the PIC Scheme are not parties to the European Pharmacopoeia Convention, the mention of European Pharmacopoeia in the Guide has been amended to read European or other relevant Pharmacopoeia. 本指南所包括的标准和原则是按照药品检查协会或药品检查合作计划表的要求进行生产实践的参考信息。The standards and principles contained in this Guide are intended to serve as a reference for the preparation of information on manufacturing practice as requested under the Pharmaceutical Inspection Convention or the Pharmaceutical Inspection Cooperation Scheme. 各国卫生部的行政措施应本着应用这些标准于实践的方针，任何新的或修订的各国GMP法规应至少符合本标准的水平。Administrative measures of national health authorities should be directed towards the application of these standards in practice, and any new or amended national regulations for good manufacturing practice should at least meet their level. 这些标准也是生产企业的基本工业管理原则。These standards are also intended to serve manufacturers as a basis for the elaboration of specific rules adapted to their individual needs. 在本指南包括的GMP基本章节外，尚有补充指南。补充指南的目的是对特殊领域的活动提供详细的指南，并且不一定适用于所有生产企业。In addition to the general matters of Good Manufacturing Practice outlined in the chapters of this Guide, supplementary guidelines have been incorporated. The purpose of the supplementary guidelines on other subjects is to provide details about specific areas of activity which may not necessarily apply to all manufacturers. 这里陈述的标准适用于人用药品或类似产品。然而，建议兽药生产也采用类似的指南。The standards set out herein, apply to medicines and similar products intended for human use. It is recommended, however, that the same kind of attention be given to the manufacture of veterinary products. 当然也有一些在本指南描述以外的可以接受的方法，同样也能达到本指南的原则要求。本指南不阻止新概念或新技术的发展，只要其经过验证，能提供至少和本指南相同的质量保证水平。It is recognised that there are acceptable methods, other than those describes in this Guide, which are capable of achieving the principles of the Guide. This Guide is not intended to place any restraint upon the development of new concepts or new technologies, which have been validated and provide a level of Quality Assurance at least equivalent to those set out in this Guide. REVISION HISTORY 修订记录Date Version Number Reasons for revision 21 December 2000 PH 1/97 (Rev.) . Revision of Annex 14 . Renumbering of all annexes . Change in the editors address and insertion of copyright statement . Inclusion of revision history 10 August 2001 PH 1/97 (Rev. 2) . Amendment of para. 42 of Annex 1 . Revision of Annex 6 . New Annex 15 . New Annex 17 . Amendment to the glossary 15 January 2002 PH 1/97 (Rev. 3) . New Annex 4 . New Annex 5 . Reference to Annex 18 of EC GMP Guide 1 September 2003 PE 009-1 . Amendment of Annex 1 (mainly section 3) 1 July 2004 PE 009-2 . Revision of Annex 13 . Change in the Editors co-ordinates CHAPTER 1 QUALITY MANAGEMENT 质量管理PRINCIPLE 原则生产许可的持有人必须生产药品并确保产品符合用途，符合上市许可的要求，防止将病人置于安全，质量或疗效不充分的药品风险之下。达到这个质量目标，是高级管理层的责任，并且要求不同部门的员工参与和承担义务，包括公司上下各级员工，公司的供应商和经销商。为可靠的达到这个质量目标，必须建立一个有计划的，能正确执行的质量保证系统以具体体现GMP和进行质量控制。该系统应当有足够的人力资源，合适和足够的厂房，设备和设施来支持。另外对生产许可的持有人和经授权人员还有法律责任。The holder of a manufacturing authorization must manufacture medicinal products so as to ensure that they are fit for their intended use, comply with the requirements of the marketing authorization and do not place patients at risk due to inadequate safety, quality or efficacy. The attainment of this quality objective is the responsibility of senior management and requires the participation and commitment by staff in many different departments and at all levels within the company, by the companys suppliers and by the distributors. To achieve the quality objective reliably there must be a comprehensively designed and correctly implemented system of Quality Assurance Incorporating Good Manufacturing Practice and thus Quality Control. It should be fully documented and its effectiveness monitored. All parts of the Quality Assurance systems should be adequately resourced with competent personnel, and suitable and sufficient premises, equipment and facilities. There are additional legal responsibilities for the holder of the manufacturing authorization and for the authorised person(s). 1.1. 质量保证，GMP和质量控制的基本概念是互相联系的。它们在这里描述时强调的是它们的关系和它们在生产和控制药品中的基本原则。1.1. The basic concepts of Quality Assurance, Good Manufacturing Practice and Quality Control are inter-related. They are described here in order to emphasise their relationships and their fundamental importance to the production and control of medicinal products. QUALITY ASSURANCE 质量保证1.2. 质量保证是一个广泛的概念，它覆盖所有的单独或连续进行的可以影响药品质量的活动。它是为确保药品质量符合其用途这一目标而组织的所有安排的总结。因此，质量保证具体体现GMP和其他超出本指南范围的因素。1.2. Quality Assurance is a wide ranging concept which covers all matters which individually or collectively influence the quality of a product. It is the sum total of the organised arrangements made with the object of ensuring that medicinal products are of the quality required for their intended use. Quality Assurance therefore incorporates Good Manufacturing Practice plus other factors outside the scope of this Guide. 恰当的药品生产的质量保证系统应确保：i. 药品的设计和研发符合GMP和GLP要求；ii. 生产和操作控制有明确的指示并符合GMP；iii. 管理层的责任有明确说明；iv. 生产，供应和使用正确的原料和包装材料都有安排；v. 所有必要的对中间体的控制，任何其他的过程控制和验证都执行了；vi. 成品按照规定的程序正确的加工和检查了；vii. 药品在经授权人员证明每批的生产和控制符合上市许可要求和任何其他有关生产，控制和放行药品的法规之前，不得销售或供应。viii. 应当有满意的安排来尽可能的确保药品在储存，销售和后续过程中，能保证整个有效期的质量。ix. 应当有自检和/或质量审计程序，定期评价质量保证系统的效力和适用性。The system of Quality Assurance appropriate for the manufacture of medicinal products should ensure that: i. medicinal products are designed and developed in a way that takes account of the requirements of Good Manufacturing Practice and Good Laboratory Practice; ii. production and control operations are clearly specified and Good Manufacturing Practice adopted; iii. managerial responsibilities are clearly specified; iv. arrangements are made for the manufacture, supply and use of the correct starting and packaging materials; v. all necessary controls on intermediate products, and any other inprocess controls and validations are carried out; vi. the finished product is correctly processed and checked, according to the defined procedures; vii. medicinal products are not sold or supplied before an authorised person has certified that each production batch has been produced and controlled in accordance with the requirements of the marketing authorization and any other regulations relevant to the production, control and release of medicinal products; viii. satisfactory arrangements exist to ensure, as far as possible, that the medicinal products are stored, distributed and subsequently handled so that quality is maintained throughout their shelf life; ix. there is a procedure for self-inspection and/or quality audit which regularly appraises the effectiveness and applicability of the quality assurance system. GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (GMP) 药品GMP1.3. GMP是质量保证的一部分，确保产品是按照恰当的符合产品用途的质量标准，始终如一的生产和控制的，符合上市许可或产品质量标准的要求。GMP包括生产和质量控制。GMP的基本要求是：i. 所有的生产过程都有明确说明，根据经验进行系统的回顾，并体现其始终如一的生产所要求的质量的产品和符合其质量标准的能力；ii. 生产过程中的关键步骤和这些过程的重要变更是验证过的；iii. 提供所有符合GMP的设施，包括：a. 经适当的培训并有资格的人员；b. 足够的厂房和空间；c. 合适的设备和服务；d. 正确的物料，容器和标签；e. 经批准的程序和指示；f. 合适的储存和运输；iv. 程序和指示是书面的指令形式，其语言明确清晰，明确能应用于所提供的设施；v. 操作人得到如何正确执行程序的培训；vi. 生产过程中进行记录，手工的和/或记录仪都可以。该记录证明程序和指示明确要求的每一步都如实执行，产品的数量和质量符合预期要求。任何重大偏差都有完整的记录和调查；vii. 生产过程记录包括销售，成为完整的一批，可以被追溯，该记录以可理解和易于评估的形式保存；viii. 产品的销售（批发）对其质量的风险应最小化；ix. 应建立从市场和供应商处召回任何一批产品的系统；x. 已销售产品的抱怨应得到检查，造成质量缺陷的原因应调查并对这些有缺陷的产品采取恰当的措施，同时防止其重复发生。1.3. Good Manufacturing Practice is that part of Quality Assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization or product specification. Good Manufacturing Practice is concerned with both production and quality control. The basic requirements of GMP are that: i. all manufacturing processes are clearly defined, systematically reviewed in the light of experience and shown to be capable of consistently manufacturing medicinal products of the required quality and complying with their specifications: ii. critical steps of manufacturing processes and significant changes to the process are validated; iii. all necessary facilities for GMP are provided including: a. appropriately qualified and trained personnel; b. adequate premises and space; c. suitable equipment and services; d. correct materials, containers and labels; e. approved procedures and instructions; f. suitable storage and transport; iv. instructions and procedures are written in an instructional form in clear and unambiguous language, specifically applicable to the facilities provided; v. operators are trained to carry out procedures correctly; vi. records are made, manually an/or by recording instruments, during manufacture which demonstrate that all the steps required by the defined procedures and instructions were in fact taken and that the quantity and quality of the product was as expected. Any significant deviations are fully recorded and investigated; vii. records of manufacture including distribution which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form; viii. the distribution (wholesaling) of the products minimises any risk to their quality; ix. a system is available to recall any batch of product, from sale or supply; x. complaints about marketed products are examined, the causes of quality defects investigated and appropriate measures taken in respect of the defective products and to prevent re-occurrence. QUALITY CONTROL 质量控制1.4. 质量控制GMP的一部分，其涉及取样，质量标准和检测，以及通过组织，文件和放行程序确保必要的和相关的检测如实执行，确保在得到满意的评价之前，物料不得放行使用，产品不得放行销售或供应。质量控制的基本要求是：i. 有足够的设施，经培训的人员和经批准的程序用于取样，检查和检测起始物料，包装材料，中间体，散装成品和最终成品，适当的话，还监视GMP要求的环境条件；ii. 起始物料，包装材料，中间体，散装成品和最终成品的取