1、2018年10月2日,Pharmaceutical Services Corporation 美国医药服务有限公司,How GMPs are regulated in Europe 欧洲药品生产管理规范,What Is GMP? 什么是GMP？,Definition: 定义：The part of Quality Assurance which ensures products are consistently produced and controlled in accordance with the quality standards appropriate for their inten
2、ded use质量保证的一部分，它确保按产品预定用途持续稳定地控制生产，保证产品符合质量标准要求。,2,What Is GMP? 什么是GMP？,The procedures employed to ensure that the drug product or substance is manufactured under a quality management system and meets the claimed requirements for purity, identity, safety and quality遵循标准操作规程，以确保药品的生产在质量管理系统的控制中并符合注册
3、的纯度、鉴别、安全和质量 Continuously evolving “feasible and valuable” industry practices designed to ensure the above持续地发展“可行性和有用性”的工业规范，以确保达到以上要求,3,A Brief History of GMP GMP历史简介,1962 The food drug and cosmetic act requires that drugs must be made in accordance with good manufacturing practices食品、药品和化妆品法要求药品必
4、须符合药品生产管理规范 1969 WHO publishes Good Practices in the Manufacture and Quality control of drugs世界卫生组织出版了药品生产和质量控制的管理规范 1971 The guide to good pharmaceutical manufacturing practice (orange guide) published 药品生产管理规范指南(orange guide)出版英国GMP 1976 FDA publishes proposed cGMPS美国食品药物管理局出版了提议的药品生产管理规范,4,A Brie
5、f History of GMP GMP历史简介,1978 Major revision in FDA 21 CFR 210 and 211. 美国食品药物管理局的21 CFR 210 和 211重大版本变更 1989 European guide to GMP published 欧盟出版药品生产管理规范指南 1991 European commission adopts two directives on principles and guidelines for GMP欧洲委员会在药品生产管理规范原则和指南上采用两种条令 1992 European guide to GMP revise
6、d. Further annexes added. Some Chapters revised 2008欧洲药品生产管理规范指南更新，添加了新的附录。2008 年更新了一些章节。 2003 Commission Directive replaced by 2003/94/EC欧洲委员会条令由2003/94/EC取代,5,GMP Variations GMP的差异,The overall principles of Good Manufacturing Practice are similar whether we follow the WHO Guidelines, the EU Guidel
7、ines or the FDA guidelines不管是世界卫生组织指南、欧洲指南，还是美国食品药物管理局指南，药品生产管理规范的总体原则是相似的 There are numerous variations in the application of these principles这些原则在应用上有些差异 The enforcement of the guidelines varies between different regulatory authorities不同法规组织在指南的实施上存在差异 The approach taken by individual inspectors v
8、aries不同检查人员所采用的方法存在差异 The approach taken by different regulatory authorities varies不同法规组织所采用的方法存在差异,6,The GMPs tell us what to do, they do not tell us how to do it.药品生产管理规范告诉我们做什么，而不告诉我们怎样做。How comes from:怎样来源于： industry standard practice and guidelines工业标准规范和指南,7,Commission Directive 2003/94/EC 委员会
9、条令2003/94/EC,Replaced original directive 91/356/EEC替代原有条令91/356/EEC Lays down principles and guidelines of GMP for medicinal products for human use规定了人用药品的生产管理规范的原则和指南 Member states must ensure respect for GMP by means of repeated inspections通过反复检查，成员国必须确保遵守药品生产管理规范 Interpretation of Principles and
10、guidelines shall be by reference to the “Guide for good manufacturing practice for medicinal products and for investigational medicinal products”原则和指南的解释应参考“药品和在研药品的生产管理规范指南”,8,Commission Directive 2003/94/EC 委员会条令2003/94/EC,For products imported from third country, the importer shall ensure product
11、s are manufactured to a standard at least equivalent to GMP as laid down by EU由第三国进口的药品，进口商要确保药品的生产达到至少等同于欧盟规定的药品生产管理规范 Importer shall ensure that products have been manufactured by authorised manufacturers进口商要确保药品是授权生产厂家生产的 Must be manufactured in compliance with Marketing Authorisation药品的生产必须符合药品注
12、册批准的要求。,9,Commission Directive 2003/94/EC 委员会条令2003/94/EC,The rest of the Directive briefly summarises the aspects of GMP that must be in place. These are addressed in more detail in the GMP Guide.条令的其余部分总结了药品生产管理规范必须执行的方面。这些在药品生产管理规范指南中有更详细地说明。,10,EU Guidelines to GMP 欧洲GMP指南,Published as Vol 4 of
13、EudraLex by the European Commission 由欧洲委员会出版，共4卷。 This comprises: 这包括： Introduction引言 Chapter 1 Quality Management第一章 质量管理 Chapter 2 Personnel第二章 人员 Chapter 3 Premises and Equipment第三章 厂房和设备,11,EU Guidelines to GMP 欧洲GMP指南,Chapter 4 Documentation第四章 文件 Chapter 5 Production第五章 生产 Chapter 6 Quality Co
14、ntrol第六章 质量控制 Chapter 7 Contract Manufacturing and Analysis第七章 外包生产和样品分析 Chapter 8 Complaints and Product Recall第八章 投诉和成品召回 Chapter 9 Self Inspection第九章 自检,12,EU Guidelines to GMP 欧洲GMP指南,Annex 1 Manufacture of Sterile Medicinal Products附录一 无菌药品的生产 Annex 2 Manufacture of Biological Medicinal Product
15、s for Human Use附录二 人用生物药品的生产 Annex 3 Manufacture of Radiopharmaceuticals附录三 放射药品的生产 Annex 4 Manufacture of Veterinary Medicinal Products other than Immunological Veterinary Medicinal Products附录四 非免疫动物药品的生产 Annex 5 Manufacture of Immunological Veterinary Medicinal Products附录五 免疫动物药品的生产,13,EU Guidelin
16、es to GMP 欧洲GMP指南,Annex 6 Manufacture of Medicinal Gases附录六 医用气体的生产 Annex 7 Manufacture of Herbal Medicinal Products附录七 草本药品的生产 Annex 8 Sampling of Starting and Packaging Material附录八 原材料和包装材料的取样 Annex 9 Manufacture of Liquids, Creams and Ointments附录九 液体、乳剂和膏剂的生产 Annex 10 Manufacture of Pressurised M
17、etered Dose Aerosol Preparations for Inhalation附录十 压力计量喷雾状吸入式药剂的生产,14,Annex 11 Computerised Systems附录十一 计算机系统 Annex 12 Use of Ionising Radiation in the Manufacture of Medicinal Products附录十二 药品生产过程中电离辐射的使用 Annex 13 Manufacture of Investigational Medicinal Products附录十三 研究用药品的生产 Annex 14 Manufacture of
18、 Medicinal Products derived from Human Blood or Plasma附录十四 来源于人体血液或血浆药品的生产,EU Guidelines to GMP 欧洲GMP指南,15,Annex 15 Qualification and Validation附录十五 确认和验证 Annex 16 Certification by a Qualified Person and Batch Release附录十六 药品放行责任人签发证书和放行批产品 Annex 17 Parametric Release附录十七 参数放行 Annex 18 Not Used (was
19、used for GMP for API)附录十八 未使用（以前用于合成制药的生产管理规范） Annex 19 Reference and Retention samples附录十九 对照样品和留样 Annex 20 Quality Risk Management附录二十 质量风险管理,EU Guidelines to GMP 欧洲GMP指南,16,Who are the Regulators 法规管理者是谁,European Medicines Agency (EMEA)欧洲药品管理局（ EMEA） decentralised body of the European Union with
20、headquarters in London.欧盟的分散机构，其总部在伦敦 The EMEA is responsible for the scientific evaluation of applications for European marketing authorisation for medicinal products (centralised procedure). Under the centralised procedure, companies submit one single marketing authorisation application to the EME
21、A.EMEA负责对拟在欧洲上市的药品申请进行科学评估（集中审评）。在集中审评程序下，公司要向EMEA提交单独的上市许可申请。,17,All medicinal products for human and animal use derived from biotechnology and other high-technology processes must be approved via the centralised procedure. The same applies to all human medicines intended for the treatment of HIV/A
22、IDS, cancer, diabetes or neurodegenerative diseases and for all designated orphan medicines intended for the treatment of rare diseases. 所有由生物技术及其它高科技工艺制备的人用药品和兽药产品，都必须通过集中审评程序报批。治疗艾滋病、肿瘤、糖尿病、神经退化以及罕见病的药物，也须按照集中审评程序报批。,Who are the Regulators 法规管理者是谁,18,For medicinal products that do not fall under a
23、ny of the above-mentioned categories companies can submit an application for a centralised marketing authorisation to the EMEA, provided the medicinal product constitutes, a significant therapeutic, scientific or technical innovation or the product is in any other respect in the interest of patient
24、or animal health. 对于不属于上述类型的药品，如果药效十分明显，科学或工艺上有创新，或产品的其它方面对病人及动物的健康十分有益时，企业也可向EMEA递交集中审评程序的申请。,Who are the Regulators 法规管理者是谁,19,For a generic, the centralised procedure can be used if the innovator product was centrally authorised对于仿制药，如果创新药已由集中审评程序批准，那么也可以按集中审评程序申请。 Responsible for coordinating GM
25、P inspections when centralised application process is used. The responsibility for carrying out inspections rests with the Competent Authority under whose responsibility the manufacturer falls.当集中申请程序适用时，负责协调GMP检查。进行检查的责任取决于生产厂家隶属于哪家主管当局管辖。,Who are the Regulators 法规管理者是谁,20,EMEA Coordinated GMP Insp
26、ections EMEA 协调的GMP检查,21,22,From 1995 to 2006, a total of 9465 deficiencies, comprising 193 critical (2%), 989 major (10%) and 8283 other deficiencies (88%) were recorded in the EMEA database during the 435 inspections carried out by EMEA inspectors during the above referenced period. 根据EMEA数据库的记录，从
27、1995年至2006年，EMEA检查人员共进行了435次检查，并共发现了9465项缺陷。其中包括193项重要缺陷（2%）， 989项主要缺陷（10%）和8283项其他缺陷（88%）。,EMEA Coordinated GMP Inspections EMEA 协调的GMP检查,TOP GMP Deficiencies GMP缺陷排名,23,MHRA A Competent Authority MHRA 一个主管当局,24,The Medicines and Healthcare products Regulatory Agency (MHRA) is the government agency
28、 in the UK which is responsible for ensuring that medicines and medical devices work, and are acceptably safe.药品和健康产品管理局（MHRA）是英国的政府机构，其负责确保药品和医疗器械工作正常且安全性令人满意。The GMP Inspectorate division has a team of over 30 inspectors based at the MHRA headquarters in London (Market Towers) and at two MHRA outs
29、tations (Welwyn Garden City and York )GMP检查部门有30多名检查员。其总部在伦敦，另外两个分部在Welwyn Garden City 和约克。,25,MHRA：- Responsible for UK inspections when a company is named on a Manufacturing license or has applied for one负责对英国区域内已取得生产许可证的公司或提交申请的公司进行检查- Responsible for inspecting Overseas manufacturing sites when
30、they are named on a specific Marketing Authorisation. Overseas inspections focus on product to be imported负责检查已获准特定市场授权的国外生产厂家。国外检查着重于进口的产品。,MHRA A Competent Authority MHRA 一个主管当局,GMP and Business GMP和商业,Why should we comply with GMP apart from the fact that the Regulators tell us we must do so?除了法规
31、管理者要求我们必须这样做之外，我们为什么应该遵循GMP呢？,26,Business Objectives 商业目的,Provide consistent quality product提供质量持续稳定的产品 Maintain consistent, reproducible processes维持持续稳定的、可再现的生产工艺 Reduce the need of extensive testing of each batch through quality assurance通过质量保证，减少每批产品扩延检测的需要 Maintain the ability to reconstruct pas
32、t production through accurate records通过精确的记录，维持以前生产的再现能力 Develop the ability to predict future process performance based on past results依据过去的结果，形成预见未来工艺性能的能力,27,Business Objectives = GMP Objectives 商业目的 = GMP目的,28,GMP and Good Business Practise GMP和商业管理规范,Meeting our GMP objectives is not only a Reg
33、ulatory requirement but is makes good business sense because:满足GMP目标不只是法定管理部门的要求，也是好的商业意识，因为： the amount of product failure should decrease不合格产品的数量减少 the process should be more efficient and reproducible生产工艺更加有效，再现性更强 the equipment should be well maintained and able to consistently operate within pr
34、ocess specifications设备得到良好的维护保养，能够在工艺标准范围内持续稳定运行,29,future performance should be predictable未来的性能是可以预见的 amount of recalls and complaints should decrease产品召回和投诉的数量减少 investigations of deviations should be enhanced by the right level of documentation通过适合的文件，强化了对偏差的调查,30,GMP and Good Business Practise
35、GMP和商业管理规范,Conclusion 结论,Compliance with GMP is a regulatory requirement and makes good business sense遵循GMP是法定管理部门的要求，也是好的商业意识 The general principles of GMP are consistent irrespective of the specific regulator除去特定的法规之外，GMP的总体原则是一致的 The application and enforcement of specific aspects of GMP are vari
36、able GMP的特定方面的应用和实施具有差异性 There are specific differences in some areas between the various guidelines不同指南的一些条款具有差异性,31,2018年10月2日,Pharmaceutical Services Corporation 美国医药服务有限公司,Good Documentation Practices (GDP) 文件管理规范(GDP),Good Documentation Practice 文件管理规范The handling of written or pictorial inform
37、ation describing, defining, specifying and/or reporting of certifying activities, requirements, procedures or results in such a way as to ensure data integrity ISPE 描述、定义、规定或报告特定的活动、要求、规程或结果的记录或图片的管理，以确保数据的完整性 国际医药工程协会,Definition 定义,In many cases Documentation is the only evidence that an activity h
38、as taken place in a specific way or even at all. Therefore the documents must be reliable. 大多数情况下，文件是记录发生在某特定场合下某项活动的唯一证据。因此，文件一定要可靠。List some examples of where the only evidence for activity is the documentation 实例说明,Why do we need GDP 为什么需要文件管理规范,Documentation 文件,To perform a GMP task, you must kn
39、ow the requirements, what to do, how to do it and you must record that you have done it. 为执行一项GMP任务，必须知道要求，做什么，怎样做，以及记录所做的。Requirements: Policies, Specifications, URS 要求：政策、规范、用户需求 What to do (Instructions): Plans, Procedures, Protocols 做什么（指令）：计划、规程、方案 How to do it (Training): Training records 怎么做（
40、培训）：培训记录 What you did: Records 做过什么：记录,Types of Documents 文件种类,36,Exercise: List as many Document types as you can for: 练习：列出以下部门的文件种类：Purchasing 采购 Production 生产 Engineering 工程,Types of Documents 文件种类,37,Document Control 文件控制 Labeling and packaging 标签和包装 Handling, storage and distribution 装卸、存放和分发
41、Quality Control 质量控制 Quality Assurance 质量保证,Documented evaluation of suppliers, contractors and consultants记录在案的对供应商、承包商和咨询公司的评估 Records of acceptable suppliers, contractors and consultants批准的供应商、承包商和咨询公司的记录 Purchasing requirements for products and services产品和服务的采购要求,Purchasing 采购,SOPs for Manufactu
42、ring, monitoring of process parameters, compliance with specified standards, approval of process and process equipment标准操作规程，包括生产、工艺参数监测、内部标准的符合性、工艺及工艺设备的批准 Environmental control specifications if it could have adverse impact on product环境控制标准（如对产品有不良影响） Policies on Training, Health, Hygiene, Gowning
43、培训、健康、卫生和更衣的规定 Validation Documents验证文件,Production 生产,Design documents for Buildings, Utilities and Equipment厂房、公用工程和设备的设计文件 Documented Maintenance and Calibration schedule记录在案的维修和校正计划表 Calibration and control of testing and measuring equipment including procedures, records, limits and tolerances, r
44、emedial action, traceable standards.测试测量仪器的校正和控制，其包括标准操作规程、记录、接受限度、弥补行动、可追踪的标准,Engineering 工程,Procedures to control document distribution and approval 文件分发及批准的标准操作规程 Procedures for Approval of changes to documents and communication of changes to personnel文件变更批准及通知人员有关变更的标准操作规程,Document Control 文件控制,
45、Documented Inspection and test of incoming, in process and finished goods记录在案的原料、中控样品和成品的检查和测试Identification of acceptance status throughout manufacturing, packaging and labeling贯穿生产、包装和贴标签整个过程中批准状态的识别,Quality Control 质量控制,Label storage procedure so as to prevent mix ups防止混淆的标签储存规程 Documented Label
46、inspection before use记录在案的使用前标签的检查 Documented Labeling operations记录在案的贴标签操作 Label legibility and integrity during normal handling after fixing.正常操作过程中贴标后标签的清晰性和完整性,Labeling and Packaging 标签和包装,Procedures for control of storage areas to prevent mix ups, deterioration, contamination and to ensure no o
47、bsolete, reject or deteriorated product is distributed.储存区域的控制规程 - 防止物品混淆、变质及污染和确保不合格或已变质的产品不被发放。 Procedures for receipt and dispatch from and to storage areas.储存区域的收货和发货的规程 Distribution records分发记录,Handling, Storage and distribution 装卸、存储和分发,Procedures for control and disposition of nonconforming p
48、roducts including review and disposition process, evaluation and investigation.不合格产品的控制及处理规程，其包括审核、处理工艺过程、评估和调查 Procedures for rework再加工规程 Procedures for Investigating non conformities, identifying actions to correct and prevent reoccurrence and verifying actions were effective对不符合规定事件调查、制定纠正和防范行动及确
49、认行动有效性的规程,Quality Assurance 质量保证,Procedures for Implementing changes to correct quality problems为纠正质量问题而实施变更的规程 Analyzing quality data to detect reoccurring quality problems质量数据分析，以检测可能再发生的质量问题 Quality policy understood, implemented. 质量方针 - 理解及实施 Quality Plans and procedures质量计划和规程,Quality Assurance
50、 质量保证,Documented Quality Audits记录在案的质量审计 Must maintain a complaint file. Review and evaluate complaints in a timely fashion必须建立投诉档案，随时审核和评估投诉。,Quality Assurance 质量保证,All records must be available for inspection by Regulators for at least the expected life of the product or in any case not less than 2 years from date of release.所有记录必须保留以供法规人员检查。记录保留期限至少为产品的有效期限，或从产品的放行日起算，不少于2年。 Regulators is not entitled to see internal quality audits, supplier audits, evaluation of contractors etc and management review records.法规人员无权审阅公司内部的质量审计、供应商审计、承包商评估和管理层的审核记录。,
