1、GMP502.1,De-mystifying GMP 解疑GMPDr Bob Pietrowski Bob Pietrowski 博士David Begg Associates,GMP502.2,De-mystifying GMP 解疑GMP,Introduction 介绍 Quality Assurance, GMP and Quality Control质量保证，GMP与质量控制 What is GMP ? 什么是GMP ? Legal Status of GMP GMP的法律地位 GMP : The Industry and the RegulatorsGMP：行业与法规制定者 Esse
2、ntial Elements of GMP： GMP的基本元素 Summary 摘要 Essential Messages 基本信息,GMP502.3,MORAL and LEGAL Obligations of Manufacturers 制造商的道德与法律责任,To organize their activities so that 规范业界的行为以使得 Products are FIT FOR INTENDED USE产品符合指定的用途 Comply with REGULATORY COMMITMENTS遵守对法规的承诺 Patients not at risk because of i
3、nadequate:防止由于以下的不当，使患者处于风险中: SAFETY安全 QUALITY质量 EFFICACY功效,GMP502.4,EU Guide to GMP . 欧盟关于GMP的指南,ATTAINMENT of QUALITY OBJECTIVE 达到质量目标 Is responsibility of SENIOR MANAGEMENT 是高层管理者的责任 Requires PARTICIPATION and COMMITMENT by :要求下列人员的共同参与及承诺: Staff in many Departments and at all levels多数的部门和各个级别的员工
4、 The Companys Suppliers公司的供应商 The Companys Distributors公司的销售商,GMP502.5,To Achieve the Quality RELIABLY there must be a . 要达到质量可靠性，必须有.,COMPREHENSIVELY DESIGNED and CORRECTLY IMPLEMENTED system of QUALITY MANAGEMENT incorporating .全面设计的与正确实施的质量管理系统, 它综合了 QUALITY ASSURANCE 质量保证 GOOD MANUFACTURING PRAC
5、TICE良好操作规范（或称:生产质量管理规范） QUALITY CONTROL质量控制,GMP502.6,Quality Assurance . 质量保证.,The CREATION and OPERATION of :建立并实施: STANDARDS 标准 PROCEDURES 过程 MANAGEMENT SYSTEMS管理系统 To GUARANTEE the QUALITY of a PRODUCT throughout its “LIFE CYCLE ” 保证产品在整个“生命期” 的质量,GMP502.7,GMP502.8,ALL FACTORS. inside and outside
6、 the factory 工厂内部的与外部的所有的因素. BEFORE, DURING AND AFTER MANUFACTURE 在生产之前，生产期间和生产之后,GMP502.9,Good Manufacturing Practice 良好操作规范,Part of Quality Assurance aimed at ensuring that products are CONSISTENTLY MANUFACTURED to the REQUIRED QUALITY within the FACTORY质量保证的一个目的是确保工厂按照要求的质量始终如一地生产合格的产品。,GMP502.10
7、,GMP502.11,Tests, inspections and measurements carried out on SAMPLES taken before, during and after MANUFACTURING and PACKAGING to provide evidence that a starting material or a finished product will or will not meet its WRITTEN SPECIFICATION 对生产与包装之前，期间和之后的样品进行测试、检验与测量，以提供原始材料或最终产品是否能够符合书面技术规范的证据。
8、,Quality Control. Part of GMP 质量控制.GMP的一部分,GMP502.12,Quality Control is Concerned With 质量控制涉及,Sampling programmes 采样程序Specifications 规范Testing 检测PHYSICAL CHEMICAL BIOLOGICAL 物理的、化学的与生物方面的测试Documentation 文件Standards 标准Release procedures 放行程序 and GOOD CONTROL LABORATORY PRACTICE 及良好的实验室控制规范,GMP502.13,
9、GMP502.14,What is GMP ? GMP 是什么？,GMP502.15,GMP stems from recognition that QUALITY can be of TWO types . GMP起源于认识到质量可以分为两种类型.,INTRINSIC 内在的 inherent suitability of active in a particular formulation特定配方中的有效成分固有的适宜性 safety and efficacy of the formulated product when made correctly and used as indicat
10、ed正确制造并按规定使用的配方产品的安全性与功效性 EXTRINSIC 外在的 suitability of any batch of a manufactured product任何生产批次产品的适合性quality determined by the manufacturing practices由操作规范决定的质量,GMP502.16,Extrinsic Quality depends on : 外在质量依赖于：,Quality of starting materials原材料的质量 Quality of Premises and Plant工厂设施及其环境的质量 Suitability
11、 of the Process过程的适宜性 Absence of Processing Problems没有加工生产问题 Quality of In-Process Controls过程控制的质量 Training and Attitude of People人员的培训与态度 . in short GMP GMP简而言之,GMP502.17,GMP is concerned with . GMP涉及.,All activities .所有的活动 Delivery of materials a Release of products原料的运送a 产品的放行 All processes .所有的过
12、程 Logistics a Manufacturing Packaging物流a 加工包装 Quality Control .质量控制 Materials a In-process a Finished Products原料a加工a成品 Good Management .良好的管理 People a Data a Communications人员a 数据a 沟通,GMP502.18,Principles of GMP . GMP 的原理.,People人员 Premises场地 Products产品 Processes过程 Procedures程序,GMP502.19,The Legal St
13、atus of GMP GMP的法律地位,GMP502.20,Legally binding regulations in USA在美国，是法律意义上的规章 Updated annually - hence “current”年度更新 - 因此标明为“动态”,GMP has been LAW since 1962 从1962年开始，GMP已经立法,“Current” Good Manufacturing Practice Regulations (cGMPs) detailed in CODE of FEDERAL REGULATIONS (Title 21 - Food and Drugs
14、- Parts 210 and 211) 在联邦法规中对动态良好操作规范cGMPs的规章作了详细描述 （标题21-食品与药品-210与211部分）,Legal Status of GMP in USA . GMP在美国的法律地位,GMP502.21,GMPs mean the requirements found in the respective legislations, regulations, and administrative provisions for methods to be used in, and the facilities or controls to be use
15、d for, the manufacturing, processing, packing, and/or holding of a drug to assure that such drug meets the requirements as to safety, and has the identity and strength, and meets the quality and purity characteristics that it purports or is represented to possess GMPs是指在法律、法规与行政规定中对制造、加工、包装和/或扣留药品的过
16、程所使用的方法、使用的设施或控制措施的要求，以确保药品的安全性，并具有识别特性与浓度，符合其声称或描述的质量与纯度的特性 。,GMP -Good Manufacturing Practice GMP- 良好操作规范,21 CFR 210.1(a) 21-联邦法规- 210.1(a),GMP502.22,Legal Status of GMP in USA . GMP在美国的法律地位.,Regulations cover . 法规包含. ORGANISATION and PERSONNEL组织与人员 BUILDINGS and FACILITIES建筑物与工厂设施 EQUIPMENT设备 CON
17、TROL of Components, Drug Product Containers and Closures组分，药物产品容器与密封的控制 PRODUCTION and PROCESS CONTROLS生产与过程的控制 PACKAGING and LABELLING CONTROLS包装与标签的控制 HOLDING and DISTRIBUTION保留与配送 LABORATORY CONTROLS实验室控制 RECORDS and REPORTS记录与报告 RETURNED and SALVAGED DRUG PRODUCTS退回和剩余产品,GMP502.23,Directives . T
18、HE LAW GMP Guidelines . INTERPRETATION 指示 . GMP导则的法律 .解释,Legal Status of GMP in EU. GMP在欧盟的法律地位,1970s European Countries publish GMP guides 20世纪70年代 欧洲国家出版了GMP导则 First EC Guide to GMP 1989 第一部欧盟的GMP导则 Compliance with GMP made compulsory in all member states 1992 所有成员国内符合GMP的强制性要求 Compliance with GMP
19、 extended to cover IMPs 2004 GMP要求扩展到IMP（工业管理程序）上,GMP502.24,That part of QUALITY ASSURANCE which ensures that products are consistently produced and controlled to the quality standards appropriate to their INTENDED USE 是质量保证的一部分，目的是确保产品按照与用途相适应的质量标准稳定进行生产和控制的 EU Volume IV of the Rules “Good Manufact
20、uring Practice for Medicinal Products” 欧盟规则的IV卷 药品良好操作规范,GMP . Good Manufacturing Practice GMP .良好操作规范,GMP502.25,Legal Status of GMP in EU. GMP在欧盟的法律地位,GMP Guidelines . interpretation of GMP directives GMP指导方针.GMP指导的解释 QUALITY MANAGEMENT质量管理 PERSONNEL人员 PREMISES and EQUIPMENT场地与设备 DOCUMENTATION文件 PR
21、ODUCTION生产 QUALITY CONTROL质量控制 WORK CONTRACTED OUT工作的外包 COMPLAINTS and PRODUCT RECALL投诉与产品召回 SELF-INSPECTION自检 + Annexes on specialised topics +专题的附件,GMP502.26,EU and US GMP Requirements？ 欧盟与美国GMP的要求？,Underlying PRINCIPLES and PHILOSOPHY of GMP are similar . and especially concerned withGMP的根本原理与指导思
22、想是相似的.特别是涉及 PEOPLE人员 PREMISES场地 PROCESSES过程 PRODUCTS产品 PROCEDURES程序,GMP502.27,GMP . the way in which appropriate product quality is reliably achieved ! GMP .实现产品质量可靠的方法 THERE is NOTHING MYSTERIOUS about GMP ! 关于GMP，没有任何神秘的事情! Nor is it simply the figment of the imagination of the REGULATORY AUTHORIT
23、IES 它也不是简单的法规部门凭空想象出来的,GMP . Industry and Regulators GMP . 行业与规范制定者,GMP502.28,It is a DISTILLATION of ACCEPTED GOOD PRACTICES agreed between Industry and Regulators 它是被行业与法规部门公认的可接受的良好操作的精髓,GMP . Industry and Regulators GMP . 行业与规范制定者,GMP502.29,etc,Perusal of GMP Guidelines . GMP导则的精读.,Nothing which
24、 responsible manufacturers do not负责任的制造商不能 agree with不同意 strive to comply with - in practice不在实践中努力遵守操作规范 Why should GMP INSPECTION sometimes turn into a PAINFUL and CATACLYSMIC event ? 为什么GMP检查有时会成为一次痛苦的和非常大的事件？,WHO 世界卫生组织,EU 欧盟,PICS 药品检查合作计划,FDA 食品药物管理局,GMP502.30,Reason ? 原因？,No difference in phil
25、osophy and principles of GMP . GMP的指导思想与原理上没有分歧. BUT.但是 Difference in INTERPRETATION of HOW to achieve these principles in practice . and the WAY in which manufacturers RESPOND 在实际中怎样实现这些原理的解释. 与制造者响应的方式存在差异,GMP502.31,The Secret of Success 成功的秘密Getting the Basics Right 获得正确的认识,GMP502.32,Essential El
26、ements of GMP GMP的基本元素,All manufacturing processes are : 所有制造过程应： Clearly defined 明确地定义 Systematically reviewed in the light of experience依据经验，进行系统性的评审 Shown to be capable of consistently manufacturing medicinal products of the required quality and complying with their specifications表明能够稳定地制造符合质量要求与
27、满足规格的医药产品 Critical steps of manufacturing processes and significant changes to the process are validated 制造过程的关键步骤与过程的重大变化应被确认,Basic requirements 基本要求,GMP502.33,Essential Elements of GMP GMP的基本元素,All necessary facilities for GMP are provided, including : 提供有关GMP所有必需的设施，包括: Appropriately qualified an
28、d trained personnel具有适当资格与受训的人员 Adequate premises and space 足够的场地与空间 Suitable equipment and services 合适的设备与服务 Correct materials, containers and labels 正确的材料，容器与标签 Approved procedures and instructions 批准的程序与指令 Suitable storage and transport 合适的储存与运输 Instructions and procedures are written in an instr
29、uctional form in clear and unambiguous language, specifically applicable to the facilities provided 指令单上的指令与程序应是清楚、明确的语言书面叙述，特别是与之提供的设施相适应。,Basic requirements基本要求,GMP502.34,Essential Elements of GMP GMP的基本元素,Operators are trained to carry out procedures correctly 操作工应经培训，正确地按作业指导书进行操作。 Records are m
30、ade, manually and/or by recording instruments, during manufacture which demonstrate that :在制造过程中，不论是用手工还是记录仪进行记录，它应能表明：All the steps required by the defined procedures and instructions were in fact taken按既定程序要求的所有步骤与指令已执行 The quantity and quality of the product was as expected已达到预期的产品数量与质量 Any signi
31、ficant deviations are fully recorded and investigated任何明显的偏离，已被完整的记录并进行调查,Basic requirements基本要求,GMP502.35,Essential Elements of GMP GMP的基本元素,Records of manufacture and distribution, which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form 生产和销售
32、记录，应确保每批次都可追溯，并以易识别和易得到的方式保留 The distribution of products minimises any risk to their quality产品的配送方式应使它们的质量风险减到最小 A system is available to recall any batch of product from sale or supply有从销售或库存可召回任何一批产品的系统 Complaints about marketed products are examined, the causes of quality defects investigated an
33、d appropriate measures taken in respect of the defective products and to prevent reoccurrence.检查市场产品的投诉，调查质量缺陷的原因，对于缺陷产品采取适当的措施以预防再次发生,Basic requirements基本要求,GMP502.36,Specific Requirements for Quality Control 质量控制的特殊要求,Samples are taken by methods and by personnel approved by QC取样方法和人员应经质量控制部门批准和授权
34、。 Test methods are validated测试方法应是有效的 Product assessment shall be performed, including a review and evaluation of relevant production documentation and an assessment of deviations from specified procedures进行产品的评估，包括对相关生产文件的评估和评价，以及评估特定程序的偏离等。,GMP502.37,Specific Requirements for Quality Control 质量控制的
35、特殊要求,No material shall be released for manufacture, or product released for supply, if it fails to meet its approved quality specification如果不能满足经批准的质量要求，原料不准予用于生产，产品不能放行 Sufficient reference samples of Starting materials Productsshall be retained to permit future examination if necessary应当有足够的原料 产品的
36、样品应当被保留，以便于将来可能的检查。,GMP502.38,Additionally 附加,Regular or rolling quality review of all products shall be conducted 必须对所有产品进行日常的或滚动的质量评估 To verify 以验证 The consistency of the existing process已有过程的一致性 The appropriateness of current specifications当前技术规范的适宜性 To highlight any trends 以显示可能的趋势 To identify t
37、he need for improvements to Products Processes以识别对 产品与 过程改进的需要,GMP502.39,And Finally 最后,There shall be a procedure for Self- Inspection and/or Quality Audit to appraise the effectiveness relevanceof the Quality Assurance System必须建立评价质量保证体系有效性与适宜性的自检和/或质量审核的程序。,GMP502.40,SUMMARY 摘要,GMP502.41,GMP is a
38、 natural consequence of the central role that PEOPLE and the PROCESS play in the achievement of QUALITY GMP是实现质量中两大要素：人员与过程的自然结果 It is GUIDELINES and GOOD PRACTICES developed via CONSULTATION and CONSENSUS between MANUFACTURERS and REGULATORS GMP是通过咨询和制造商与法规制定者的共同意愿发展起来的导则与良好规范,Summary . 摘要.,GMP502.
39、42,Summary . 摘要.,GMP seeks to minimise the VARIABLES which affect quality such as :GMP寻求影响质量的变数的最小化，如： Materials原料 Processes/methods of manufacture制造过程和加工方法 Equipment设备 Environment/Premises环境/场地 People人员,GMP502.43,Summary . 摘要.,These VARIABLES may be controlled by : 这些变数可以通过以下因素进行控制： Testing, inspec
40、ting, measuring测试，检验与测量 Documenting 记录 Validating 确认 Calibrating 校准 Monitoring 监控 Maintaining (eg Planned Preventative Maintenance) 维护 (譬如有计划的维修保养） Self-Inspection and Auditing 自检与审核 Housekeeping 清洁管理 Training 培训,GMP502.44,Essential Message . 基本信息.,GMP is about : GMP 是有关 People 人员 Premises 场地 Proces
41、ses 过程 Products 产品 Procedures 程序,GMP502.45,Assurance of the required quality cannot be achieved by testing alone 质量保证不能单独依靠测试实现,Essential Message . 基本信息.,GMP502.46,GMP is only one important element that determines the total quality of a product GMP是决定产品全面质量的唯一的一个重要因素,Essential Message . 基本信息.,GMP502
42、.47,Achievement of quality assurance doesnt happen by accident质量保证的实现不是偶然发生的 - it is the result of careful planning and installation of a QUALITY SYSTEM,它是质量系统精密的计划和安装的结果but a system is like a chain - only as strong as its weakest link ! 但是一个系统就像一个链条-它的强度只和它最薄弱的一环相同,Essential Message . 基本信息.,GMP502.48,Essential Message . 基本信息.,Quality Assurance is : 质量保证是 an attitude of mind ! 一种思想态度 a team job ! 一个团体的工作 the responsibility of everyone in the company ! 公司内每一个人员的责任,STAND E1C13,rapDBA-,
