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欧洲药品生产管理规范 2021/7/1What Is GMP?什么是什么是GMP？Definition:定义：定义：The part of Quality Assurance which ensures products are consistently produced and controlled in accordance with the quality standards appropriate for their intended use 质质量量保保证证的的一一部部分分，它它确确保保按按产产品品预预定定用用途途持持续续稳稳定定地控制生产，保证产品符合质量标准要求。地控制生产，保证产品符合质量标准要求。2What Is GMP?什么是什么是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 遵遵循循标标准准操操作作规规程程，以以确确保保药药品品的的生生产产在在质质量量管管理理系系统的控制中并符合注册的纯度、鉴别、安全和质量统的控制中并符合注册的纯度、鉴别、安全和质量Continuously evolving “feasible and valuable” industry practices designed to ensure the above 持续地发展持续地发展“可行性和有用性可行性和有用性”的工业规范，以确保的工业规范，以确保达到以上要求达到以上要求3A Brief History of GMPGMP历史简介历史简介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须符合药品生产管理规范食品、药品和化妆品法要求药品必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药品生产管理规范指南(orange guide)出版出版英国英国GMP1976 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美国食品药物管理局出版了提议的药品生产管理规范4A Brief History of GMPGMP历史简介历史简介1978 Major revision in FDA 21 CFR 210 and 211. 美国食品药物管理局的美国食品药物管理局的21 CFR 210 和和 211重大版本变更重大版本变更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 revised. 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。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。年更新了一些章节。2003 Commission Directive replaced by 2003/94/EC 欧洲委员会条令由欧洲委员会条令由2003/94/EC取代取代5GMP VariationsGMP的差异的差异The overall principles of Good Manufacturing Practice are similar whether we follow the WHO Guidelines, the EU Guidelines or the FDA guidelines 不不管管是是世世界界卫卫生生组组织织指指南南、欧欧洲洲指指南南，还还是是美美国国食食品品药药物物管管理理局局指指南南，药品生产管理规范的总体原则是相似的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不同法规组织在指南的实施上存在差异The approach taken by individual inspectors varies 不同检查人员所采用的方法存在差异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药品生产管理规范告诉我们做什么什么，而不告诉我们，而不告诉我们怎样怎样做。做。 How comes from: 怎样怎样来源于：来源于：industry standard practice and guidelines 工业标准规范和指南工业标准规范和指南7Commission Directive 2003/94/EC委员会条令委员会条令2003/94/ECReplaced original directive 91/356/EEC 替代原有条令替代原有条令91/356/EECLays 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 guidelines shall be by reference to the “Guide for good manufacturing practice for medicinal products and for investigational medicinal products” 原原则则和和指指南南的的解解释释应应参参考考“药药品品和和在在研研药药品品的的生生产产管管理理规规范范指指南南”8Commission Directive 2003/94/EC委员会条令委员会条令2003/94/ECFor products imported from third country, the importer shall ensure products are manufactured to a standard at least equivalent to GMP as laid down by EU 由由第第三三国国进进口口的的药药品品，进进口口商商要要确确保保药药品品的的生生产产达达到到至至少少等等同同于于欧欧盟规定的药品生产管理规范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册批准的要求。药品的生产必须符合药品注册批准的要求。9Commission Directive 2003/94/EC委员会条令委员会条令2003/94/ECThe 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。在药品生产管理规范指南中有更详细地说明。10EU Guidelines to GMP欧洲欧洲GMP指南指南Published as Vol 4 of EudraLex by the EuropeanCommission由欧洲委员会出版，共由欧洲委员会出版，共4卷。卷。 This comprises:这包括：这包括：Introduction 引言引言Chapter 1 Quality Management 第一章第一章 质量管理质量管理Chapter 2 Personnel 第二章第二章 人员人员Chapter 3 Premises and Equipment 第三章第三章 厂房和设备厂房和设备11EU Guidelines to GMP欧洲欧洲GMP指南指南Chapter 4 Documentation 第四章第四章 文件文件Chapter 5 Production 第五章第五章 生产生产Chapter 6 Quality Control 第六章第六章 质量控制质量控制Chapter 7 Contract Manufacturing and Analysis 第七章第七章 外包生产和样品分析外包生产和样品分析Chapter 8 Complaints and Product Recall 第八章第八章 投诉和成品召回投诉和成品召回Chapter 9 Self Inspection 第九章第九章 自检自检12EU Guidelines to GMP欧洲欧洲GMP指南指南Annex 1 Manufacture of Sterile Medicinal Products 附录一附录一 无菌药品的生产无菌药品的生产Annex 2 Manufacture of Biological Medicinal Products for Human Use 附录二附录二 人用生物药品的生产人用生物药品的生产Annex 3 Manufacture of Radiopharmaceuticals 附录三附录三 放射药品的生产放射药品的生产Annex 4 Manufacture of Veterinary Medicinal Products other than Immunological Veterinary Medicinal Products 附录四附录四 非免疫动物药品的生产非免疫动物药品的生产 Annex 5 Manufacture of Immunological Veterinary Medicinal Products 附录五附录五 免疫动物药品的生产免疫动物药品的生产13EU Guidelines to GMP欧洲欧洲GMP指南指南Annex 6 Manufacture of Medicinal Gases 附录六附录六 医用气体的生产医用气体的生产Annex 7 Manufacture of Herbal Medicinal Products 附录七附录七 草本药品的生产草本药品的生产 Annex 8 Sampling of Starting and Packaging Material 附录八附录八 原材料和包装材料的取样原材料和包装材料的取样Annex 9 Manufacture of Liquids, Creams and Ointments 附录九附录九 液体、乳剂和膏剂的生产液体、乳剂和膏剂的生产Annex 10 Manufacture of Pressurised Metered Dose Aerosol Preparations for Inhalation 附录十附录十 压力计量喷雾状吸入式药剂的生产压力计量喷雾状吸入式药剂的生产14Annex 11 Computerised Systems 附录十一附录十一 计算机系统计算机系统Annex 12 Use of Ionising Radiation in the Manufacture of Medicinal Products 附录十二附录十二 药品生产过程中电离辐射的使用药品生产过程中电离辐射的使用Annex 13 Manufacture of Investigational Medicinal Products 附录十三附录十三 研究用药品的生产研究用药品的生产Annex 14 Manufacture of Medicinal Products derived from Human Blood or Plasma 附录十四附录十四 来源于人体血液或血浆药品的生产来源于人体血液或血浆药品的生产 EU Guidelines to GMP欧洲欧洲GMP指南指南15Annex 15 Qualification and Validation 附录十五附录十五 确认和验证确认和验证Annex 16 Certification by a Qualified Person and Batch Release 附录十六附录十六 药品放行责任人签发证书和放行批产品药品放行责任人签发证书和放行批产品Annex 17 Parametric Release 附录十七附录十七 参数放行参数放行Annex 18 Not Used (was used for GMP for API) 附录十八附录十八 未使用（以前用于合成制药的生产管理规范）未使用（以前用于合成制药的生产管理规范）Annex 19 Reference and Retention samples 附录十九附录十九 对照样品和留样对照样品和留样Annex 20 Quality Risk Management 附录二十附录二十 质量风险管理质量风险管理EU Guidelines to GMP欧洲欧洲GMP指南指南16Who are the Regulators法规管理者是谁法规管理者是谁European Medicines Agency (EMEA) 欧洲药品管理局（欧洲药品管理局（ EMEA）decentralised body of the European Union with headquarters in London. 欧盟的分散机构，其总部在伦敦欧盟的分散机构，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 EMEA. EMEA负负责责对对拟拟在在欧欧洲洲上上市市的的药药品品申申请请进进行行科科学学评评估估（集集中中审审评评）。在在集集中中审审评评程程序序下下，公公司司要要向向EMEA提提交交单单独独的的上上市许可申请。市许可申请。 17All 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/AIDS, cancer, diabetes or neurodegenerative diseases and for all designated orphan medicines intended for the treatment of rare diseases. 所所有有由由生生物物技技术术及及其其它它高高科科技技工工艺艺制制备备的的人人用用药药品品和和兽兽药药产产品品，都都必必须须通通过过集集中中审审评评程程序序报报批批。治治疗疗艾艾滋滋病病、肿肿瘤瘤、糖糖尿尿病病、神经退化以及罕见病的药物，也须按照集中审评程序报批。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法规管理者是谁法规管理者是谁18For medicinal products that do not fall under any 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 or animal health. 对对于于不不属属于于上上述述类类型型的的药药品品，如如果果药药效效十十分分明明显显，科科学学或或工工艺艺上上有有创创新新，或或产产品品的的其其它它方方面面对对病病人人及及动动物物的的健健康康十十分分有有益时，企业也可向益时，企业也可向EMEA递交集中审评程序的申请。递交集中审评程序的申请。Who are the Regulators法规管理者是谁法规管理者是谁19For a generic, the centralised procedure can be used if the innovator product was centrally authorised 对对于于仿仿制制药药，如如果果创创新新药药已已由由集集中中审审评评程程序序批批准准，那那么么也也可以按集中审评程序申请。可以按集中审评程序申请。Responsible for coordinating GMP inspections when centralised application process is used. The responsibility for carrying out inspections rests with the Competent Authority under whose responsibility the manufacturer falls. 当当集集中中申申请请程程序序适适用用时时，负负责责协协调调GMP检检查查。进进行行检检查查的的责任取决于生产厂家隶属于哪家主管当局管辖。责任取决于生产厂家隶属于哪家主管当局管辖。Who are the Regulators法规管理者是谁法规管理者是谁20EMEA Coordinated GMP InspectionsEMEA 协调的协调的GMP检查检查21From 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.根据根据EMEA数据库的记录，从数据库的记录，从1995年至年至2006年，年，EMEA检查人员共检查人员共进行了进行了435次检查，并共发现了次检查，并共发现了9465项缺陷。其中包括项缺陷。其中包括193项重要缺项重要缺陷（陷（2%），）， 989项主要缺陷（项主要缺陷（10%）和）和8283项其他缺陷（项其他缺陷（88%）。）。EMEA Coordinated GMP InspectionsEMEA 协调的协调的GMP检查检查22TOP GMP DeficienciesGMP缺陷排名缺陷排名Category of GMP deficiency GMP缺陷种类缺陷种类Number数量 Incidence百分比 (%) Documentation - quality system elements/procedures文件- 质量系统因素/规程 134114.1Design and maintenance of premises 厂房的设计和维修6346.7Design and maintenance of equipment 设备的设计和维修5946.2Documentation - manufacturing 文件 - 生产5265.5Contamination, microbiological - potential for 交叉污染，微生物 潜在4634.923MHRA A Competent AuthorityMHRA 一个主管当局一个主管当局 The Medicines and Healthcare products Regulatory Agency (MHRA) is the government agency 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（药品和健康产品管理局（MHRA）是英国的政府机构，其负责）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。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 outstations (Welwyn Garden City and York ) GMP检查部门有检查部门有30多名检查员。其总部在伦敦，多名检查员。其总部在伦敦， 另外两个分部在另外两个分部在Welwyn Garden City 和约克。和约克。24 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 进行检查进行检查- Responsible for inspecting Overseas manufacturing sites when 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。于进口的产品。 MHRA A Competent AuthorityMHRA 一个主管当局一个主管当局25GMP and BusinessGMP和商业和商业Why should we comply with GMP apart from the fact that the Regulators tell us we must do so? 除了法规管理者要求我们必须这样做之外，我们为什么除了法规管理者要求我们必须这样做之外，我们为什么应该遵循应该遵循GMP呢？呢？26Business Objectives商业目的商业目的Provide consistent quality product 提供质量持续稳定的产品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通过质量保证，减少每批产品扩延检测的需要Maintain the ability to reconstruct past production through accurate records 通过精确的记录，维持以前生产的再现能力通过精确的记录，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依据过去的结果，形成预见未来工艺性能的能力27Business Objectives = GMP Objectives商业目的商业目的 = GMP目的目的28GMP and Good Business PractiseGMP和商业管理规范和商业管理规范Meeting our GMP objectives is not only a Regulatory requirement but is makes good business sense because: 满满足足GMP目目标标不不只只是是法法定定管管理理部部门门的的要要求求，也也是是好好的的商商业意识，因为：业意识，因为：the amount of product failure should decrease 不合格产品的数量减少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 process specifications 设设备备得得到到良良好好的的维维护护保保养养，能能够够在在工工艺艺标标准准范范围围内内持持续续稳稳定定运运行行 29future performance should be predictable 未来的性能是可以预见的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通过适合的文件，强化了对偏差的调查GMP and Good Business PractiseGMP和商业管理规范和商业管理规范30Conclusion结论结论Compliance with GMP is a regulatory requirement and makes good business sense 遵循遵循GMP是法定管理部门的要求，也是好的商业意识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，除去特定的法规之外，GMP的总体原则是一致的的总体原则是一致的The application and enforcement of specific aspects of GMP are variable GMP的特定方面的应用和实施具有差异性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不同指南的一些条款具有差异性31Pharmaceutical Services Corporation美国医药服务有限公司Good Documentation Practices (GDP)文件管理规范文件管理规范(GDP) 2021/7/1Good Documentation Practice文件管理规范文件管理规范The handling of written or pictorial information 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果的记录或图片的管理，以确保数据的完整性 国际国际医药工程协会医药工程协会Definition 定义定义In many cases Documentation is the only evidence that an activity has 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。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实例说明实例说明Why do we need GDP为什么需要文件管理规范为什么需要文件管理规范Documentation文件文件To perform a GMP task, you must know the requirements, what to do, how to do it and you must record that you have done it.为为执执行行一一项项GMP任任务务，必必须须知知道道要要求求，做做什什么么，怎怎样样做做，以及记录所做的。以及记录所做的。Requirements: Policies, Specifications, URS要求：政策、规范、用户需求要求：政策、规范、用户需求What to do (Instructions): Plans, Procedures, Protocols做什么（指令）：计划、规程、方案做什么（指令）：计划、规程、方案How to do it (Training): Training records 怎么做（培训）：培训记录怎么做（培训）：培训记录What you did: Records做过什么：记录做过什么：记录Types of Documents文件种类文件种类Exercise: List as many Document types as you can for:练习：列出以下部门的文件种类：练习：列出以下部门的文件种类：Purchasing采购采购Production生产生产Engineering工程工程36Types of Documents文件种类文件种类Document Control文件控制文件控制Labeling and packaging标签和包装标签和包装Handling, storage and distribution装卸、存放和分发装卸、存放和分发Quality Control质量控制质量控制Quality Assurance质量保证质量保证37Documented 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产品和服务的采购要求Purchasing采购采购SOPs for Manufacturing, monitoring of process parameters, compliance with specified standards, approval of process and process equipment 标标准准操操作作规规程程，包包括括生生产产、工工艺艺参参数数监监测测、内内部部标标准准的的符合性、工艺及工艺设备的批准符合性、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）环境控制标准（如对产品有不良影响）Policies on Training, Health, Hygiene, Gowning 培训、健康、卫生和更衣的规定培训、健康、卫生和更衣的规定Validation Documents 验证文件验证文件Production生产生产Design documents for Buildings, Utilities and Equipment 厂房、公用工程和设备的设计文件厂房、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, remedial action, traceable standards. 测测试试测测量量仪仪器器的的校校正正和和控控制制，其其包包括括标标准准操操作作规规程程、记记录、接受限度、弥补行动、可追踪的标准录、接受限度、弥补行动、可追踪的标准Engineering工程工程Procedures to control document distribution and approval 文件分发及批准的标准操作规程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文件控制文件控制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质量控制质量控制Label storage procedure so as to prevent mix ups 防止混淆的标签储存规程防止混淆的标签储存规程Documented Label inspection before use 记录在案的使用前标签的检查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标签和包装标签和包装Procedures for control of storage areas to prevent mix ups, deterioration, contamination and to ensure no obsolete, reject or deteriorated product is distributed. 储储存存区区域域的的控控制制规规程程 - 防防止止物物品品混混淆淆、变变质质及及污污染染和和确确保不合格或已变质的产品不被发放。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储存区域的收货和发货的规程Distribution records 分发记录分发记录Handling, Storage and distribution装卸、存储和分发装卸、存储和分发Procedures for control and disposition of nonconforming products including review and disposition process, evaluation and investigation. 不不合合格格产产品品的的控控制制及及处处理理规规程程，其其包包括括审审核核、处处理理工工艺艺过程、评估和调查过程、评估和调查Procedures for rework 再加工规程再加工规程Procedures for Investigating non conformities, identifying actions to correct and prevent reoccurrence and verifying actions were effective 对对不不符符合合规规定定事事件件调调查查、制制定定纠纠正正和和防防范范行行动动及及确确认认行行动有效性的规程动有效性的规程Quality Assurance质量保证质量保证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. 质量方针质量方针 - 理解及实施理解及实施Quality Plans and procedures 质量计划和规程质量计划和规程Quality Assurance质量保证质量保证Documented Quality Audits 记录在案的质量审计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。必须建立投诉档案，随时审核和评估投诉。Quality Assurance质量保证质量保证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. 所所有有记记录录必必须须保保留留以以供供法法规规人人员员检检查查。记记录录保保留留期期限限至至少少为为产产品品的的有有效效期期限限，或或从从产产品品的的放放行行日日起起算算，不不少少于于2年。年。Regulators is not entitled to see internal quality audits, supplier audits, evaluation of contractors etc and management review records. 法法规规人人员员无无权权审审阅阅公公司司内内部部的的质质量量审审计计、供供应应商商审审计计、承包商评估和管理层的审核记录。承包商评估和管理层的审核记录。Records记录记录Good Documentation Practice文件质量管理规范文件质量管理规范General:一般原则：一般原则：Always use ink of suitable darkness to ensure copying will accurately transcribe the numbers 用适合深度的墨水，以确保复印件清晰用适合深度的墨水，以确保复印件清晰Written entries must be clear, concise and legible using indelible ink (ballpoint pen preferred in most cases) 记记录录必必须须清清楚楚、简简要要，字字迹迹清清晰晰。要要用用持持久久的的墨墨水水笔笔记记录录 （建议使用圆珠笔）。（建议使用圆珠笔）。Records containing photocopied information (e.g. data ) must reference the original source and date, the information was generated. 记记录录中中若若包包含含复复印印件件（如如数数据据），其其复复印印件件上上必必须须标标明明文文件件的原始出处及颁布日期。的原始出处及颁布日期。Good Documentation Practice文件质量管理规范文件质量管理规范Data must be entered each time. No words (e.g.“As above”) or symbols (e.g., ditto marks or arrows) indicating repeated entries are permitted 必必须须每每次次记记录录数数据据。对对于于重重复复的的数数据据记记录录，不不允允许许使使用用 “如上所示如上所示”、同上符号或箭头。、同上符号或箭头。Complete documentation at the time the activity is being executed 当工作完成时，及时完成记录当工作完成时，及时完成记录Ensure that data entered is accurate and unambiguous 确保记录的数据准确、清晰确保记录的数据准确、清晰50Good Documentation Practice文件质量管理规范文件质量管理规范Report actual readings and in addition round numbers to the number of decimal places stated in the requirements 报告实际读数，并将其修约至规定的小数点位数报告实际读数，并将其修约至规定的小数点位数Ensure that you understand the revision numbering system and always use latest revision 确保理解版本编号系统并始终使用最新版本确保理解版本编号系统并始终使用最新版本Good Documentation Practice文件质量管理规范文件质量管理规范Dates日期日期Date Format to be used : DD-MMM-YY or DD-MMM-YYYY 日期表示方式：日期表示方式： DD-MMM-YY 或或 DD-MMM-YYYYEnter the date when you executed the work and signed the document. Back-dating or forward dating is not permitted. 执执行行工工作作和和签签署署文文件件时时记记录录日日期期。不不允允许许签签署署以以前前或或未未来来的的日期。日期。When a signature and date is required, the date cannot be stamp dated, it should be hand written 当当签签名名和和日日期期同同时时需需要要时时，其其日日期期不不允允许许用用图图章章，而而应应手手工工记录。记录。Good Documentation Practice文件质量管理规范文件质量管理规范Corrections更正更正White-out fluid or tape should never be used 不允许使用白色修正液或修正带不允许使用白色修正液或修正带Original entries should not be obliterated or erased 不允许涂掉或擦掉原来记录不允许涂掉或擦掉原来记录Corrections should be made with a single line through the error followed by the initials and date of the person making the correction 更正时，在错误处画一条线，更正人签名并记录日期。更正时，在错误处画一条线，更正人签名并记录日期。Good Documentation Practice文件质量管理规范文件质量管理规范the correction shall be signed and dated by the originator, 更正人应在更正处签名并记录日期更正人应在更正处签名并记录日期the date shall be the date the correction is made 日期应是执行更正的日期日期应是执行更正的日期explanation for correction shall be provided, if it is not obvious why the correction is made e.g.: “Entry Error” 如更正原因不显而易见，应注明更正原因，如如更正原因不显而易见，应注明更正原因，如“记录错误记录错误”always cross out the full number/word, when making correction 更正时，应删除整个数字或字词更正时，应删除整个数字或字词54Good Documentation Practice文件质量管理规范文件质量管理规范Transcribing誊写誊写Do not transcribe data with the intention of discarding the original 誊写时，不要有意去除原始数据誊写时，不要有意去除原始数据Do not record data on post it note, scraps of paper, notebooks etc 不要将数据记录在及时贴、废纸及笔记本上不要将数据记录在及时贴、废纸及笔记本上Generally avoid transcribing data as it is a large source of errors. If you have to transcribing data, always double check it! 一一般般来来说说，应应避避免免誊誊写写，因因为为它它是是错错误误的的来来源源。如如果果不不得不誊写，应有人审核。得不誊写，应有人审核。Good Documentation Practice文件质量管理规范文件质量管理规范Calculations and weights计算和称量计算和称量If calculations are performed by an validated automatic system, then a single verification is all that is required 如如果果计计算算由由一一个个已已经经过过验验证证的的自自动动化化系系统统进进行行，单单一一的的确认即可确认即可Manual calculations should be verified by a second person 人工计算需由第二人审核人工计算需由第二人审核Good Documentation Practice文件质量管理规范文件质量管理规范If weights are printed out by a validated system then a single verification is all that is required 如如果果重重量量由由一一个个已已经经过过验验证证的的系系统统打打印印出出来来，单单一一的的确确认即可认即可Weights read manually must be verified by a second person 人工记录重量，需由第二人审核人工记录重量，需由第二人审核57Good Documentation Practice文件质量管理规范文件质量管理规范Blank Spaces空白空白Blanks (e.g. empty fields, empty pages, or partially empty pages) that are not required should be crossed through or otherwise indicated that they are not required (e.g. use N.A) 不不使使用用的的空空白白处处（如如空空白白表表格格、空空白白页页或或部部分分空空白白页页）应划掉或用其它方式注明不需要（如注明应划掉或用其它方式注明不需要（如注明“N.A”）Good Documentation Practice文件质量管理规范文件质量管理规范Identification定性定性A document with incomplete entries or without signature and date will not be considered as proof that the activity has been carried out 一个含有不完整记录或无签名及日期的文件不能作为某一个含有不完整记录或无签名及日期的文件不能作为某项活动已进行的依据项活动已进行的依据Prepare signature record sheet that identifies signature and initials against name and function 准备签名记录以识别签名人的名字和职务准备签名记录以识别签名人的名字和职务Ensure Authorized Signatories sign the relevant documentation 确保授权的人员签署有关的文件确保授权的人员签署有关的文件Good Documentation Practice文件质量管理规范文件质量管理规范Correction of a previously approved record requires the review and approval of all original signatories or the same or higher level of management. (If the correction changes the original conclusion of the record, potential impact must be evaluated and evaluation and decision must be documented.) 对对已已批批准准的的记记录录进进行行更更正正，其其更更正正需需要要同同样样人人员员或或高高一一级级的的管管理理人人员员进进行行审审核核和和批批准准。如如更更正正改改变变了了原原始始记记录录的的结结论论，则则应应对对潜潜在在的的影影响响进进行行评评估估，并并书书面面记记录录评评估估的结果和决定。的结果和决定。60Good Documentation Practice文件质量管理规范文件质量管理规范Photocopies复印件复印件Records containing photocopied information must reference the original source. 含有复印件的记录必须注明原始出处含有复印件的记录必须注明原始出处Where the original is not available, then an explanation must be provided 如无原件，应注明原因如无原件，应注明原因Records on thermal paper must be photocopied because the original record will fade 热敏纸上的记录必须复印，因为原始记录会消失热敏纸上的记录必须复印，因为原始记录会消失Copies should be identified as such (e.g., Certified true copy) 复印件本身应能识别，如证明复印件本身应能识别，如证明“与原件相符与原件相符”Good Documentation Practice文件质量管理规范文件质量管理规范Attachments附件附件Where a document is attached to a record, the record must refer to the attachment (e.g. refer to Attachment A, Page 2 of 10) 如如果果一一个个文文件件附附在在一一个个记记录录后后，此此记记录录中中必必须须注注明明所所有有的附件（如指出附件的附件（如指出附件A，第，第2页共页共10页）。页）。The attachment must be traceable to the record. (e.g. Form XXX, Attachment A, Page 2 of 10) 附附件件必必须须有有可可追追踪踪性性。如如表表格格XXX，附附件件A，第第2页页共共10页。页。 Good Documentation Practice文件质量管理规范文件质量管理规范Attachments must be signed, dated and numbered in such a way that the document can be taken apart and reassembled in the correct order (survives the “drop test”) 附附件件上上必必须须有有签签名名、日日期期和和编编号号。这这样样当当文文件件分分离离时时，易于将文件重新整理好易于将文件重新整理好 （经过（经过“落地测试落地测试”）。）。Printouts attached to a page should be signed so that the signature crosses the page and the printout 贴贴在在记记录录上上的的打打印印输输出出结结果果，应应有有签签名名及及日日期期。签签名名应应跨越打印出的记录和其所在记录。跨越打印出的记录和其所在记录。 63Good Documentation Practice文件质量管理规范文件质量管理规范Do not sign work until it is completed 直至工作完成再签名直至工作完成再签名Only document work that has been performed 只记录执行过的工作只记录执行过的工作Clearly record the data 清楚地记录数据清楚地记录数据Use a Blue/Black pen 使用蓝色使用蓝色/黑色钢笔黑色钢笔Make sure the time and date are correct 确保时间和日期正确确保时间和日期正确Good Documentation Practice文件质量管理规范文件质量管理规范Ensure legible handwriting 确保书写字迹清晰确保书写字迹清晰Never delete or change any records without reason 不要无原因的删除或更改任何记录不要无原因的删除或更改任何记录Take time to check and double check your work 花一些时间审核并再次检查自己的工作花一些时间审核并再次检查自己的工作 65Pharmaceutical Services Corporation美国医药服务有限公司Premises and Equipment厂房和设备厂房和设备 2021/7/1Layout and design of premises and equipment must aim to minimise the risk of errors and permit effective cleaning and maintenance in order to avoid cross contamination, build up of dust or dirt and, in general, any adverse effect on the quality of products 厂厂房房、设设备备的的布布局局及及设设计计必必须须旨旨在在将将错错误误的的风风险险降降低低至至最最低低程程度度并并允允许许对对它它们们进进行行有有效效地地清清洗洗和和维维修修，以以达达到到避避免免交交叉叉污污染染、尘尘粒粒集集结结、对对产产品品质质量量产产生生任任何何不不良良影影响的目的。响的目的。Principle原则原则67Premises厂房厂房In an environment that presents minimal risk of causing contamination to products 所处的环境应能最大限度降低产品交叉污染风险所处的环境应能最大限度降低产品交叉污染风险Maintained, cleaned, disinfected according to procedures 根据规程进行维修、清洁和消毒根据规程进行维修、清洁和消毒 Lighting, temperature, humidity, ventilation does not affect product or accurate functioning of equipment 照照明明、温温度度、湿湿度度和和通通风风对对产产品品质质量量或或设设备备的的正正确确运运行行不会造成影响不会造成影响68Designed and equipped so as to protect against insects or other animals 设计和装备应能有效防止昆虫或其他动物进入设计和装备应能有效防止昆虫或其他动物进入Steps to prevent entry of unauthorised people 应采取适当措施防止未经批准的人员进入应采取适当措施防止未经批准的人员进入Production, storage and QC not to be used as right of way by people who dont work there 生生产产、贮贮存存和和质质量量控控制制区区不不应应作作为为非非本本区区工工作作人人员员的的通通道。道。Premises厂房厂房69Production生产生产Dedicated and self contained facilities must be available for the production of particular medicinal products, such as highly sensitising materials (e.g. penicillins) or biological preparations (e.g. from live micro-organisms). 特特殊殊药药品品如如：高高致致敏敏药药品品（青青霉霉素素）或或生生物物制制品品（如如用用活活的的微微生生物物制制备备而而成成）必必须须采采用用专专用用的的、独独立立的的生生产设施。产设施。70The production of certain additional products, such as certain antibiotics, certain hormones, certain cytotoxics, certain highly active drugs and non-medicinal products should not be conducted in the same facilities. For those products, in exceptional cases, the principle of campaign working in the same facilities can be accepted provided that specific precautions are taken and the necessary validations are made. 某某些些抗抗生生素素、激激素素、细细胞胞毒毒素素、高高活活性性药药不不应应和和非非医医药药产产品品使使用用相相同同的的生生产产设设施施。特特殊殊情情况况下下，如如采采取取特特别别防防护护措措施施并并经经过过必要的验证，则可能过阶段生产方式共用同一生产设施。必要的验证，则可能过阶段生产方式共用同一生产设施。 Production生产生产71The manufacture of technical poisons, such as pesticides and herbicides, should not be allowed in premises used for the manufacture of medicinal products. 药药品品的的生生产产厂厂房房不不能能用用于于杀杀虫虫剂剂和和除除草草剂剂等等工工业业毒毒性性物物品的生产。品的生产。Production生产生产72Laid out in logical order corresponding to sequence of operations 根据生产操作顺序进行合理布局根据生产操作顺序进行合理布局Adequate space to permit orderly and logical positioning of equipment and materials 足够的空间以合理地、有秩序地放置设备和物料足够的空间以合理地、有秩序地放置设备和物料Interior services smooth, easy to clean 内部设施光滑，容易清洗内部设施光滑，容易清洗Pipework, light fittings etc sited to avoid recesses 管道、灯具等的安装要避免凹凸管道、灯具等的安装要避免凹凸Production生产生产73Open drains avoided where possible 应尽可能避免明沟排水应尽可能避免明沟排水Effectively ventilated appropriate to products handled 适合产品操作的有效的通风系统适合产品操作的有效的通风系统Separate weighing room for starting materials 原辅料的称量应在单独的称量室中进行原辅料的称量应在单独的称量室中进行Provisions to avoid cross contamination from dust generation 有相关的措施避免产尘区域内的交叉污染有相关的措施避免产尘区域内的交叉污染Production生产生产74Packaging designed to avoid mix up 包装区的设计应避免物料混淆包装区的设计应避免物料混淆Well lit production areas 生产区域应有足够的照明生产区域应有足够的照明In process control can be carried out in production as long as no risk to product 生生产产区区内内可可设设中中间间控控制制，但但中中间间控控制制操操作作不不能能对对产产品品带带来风险来风险Production生产生产75Storage Areas储存区储存区Storage areas should be of sufficient capacity to allow orderly storage of the various categories of materials and products: starting and packaging materials, intermediate, bulk and finished products, products in quarantine, released, rejected, returned or recalled. 储储存存区区应应有有足足够够的的空空间间，以以允允许许有有序序地地存存放放多多种种物物料料和和成成品品：原原材材料料和和包包材材、中中间间体体、待待包包装装产产品品和和成成品品、待待检检产产品品、放放行行产产品品、不不合合格格品品、退退回回产产品品或或召召回回产产品品76Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean and dry and maintained within acceptable temperature limits. Where special storage conditions are required (e.g. temperature, humidity) these should be provided, checked and monitored. 储储存存区区的的设设计计和和建建造造应应确确保保良良好好的的储储存存条条件件。应应特特别别注注意意清清洁洁和和干干燥燥，温温度度应应保保持持在在控控制制限限度度内内。如如需需要要特特殊殊的的储储存存条条件件（如如温温湿湿度度），应应予予满满足足，并并进进行行检检查查和和监监测。测。Storage Areas储存区储存区77Receiving and dispatch bays should protect materials and products from the weather. Reception areas should be designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage. 收收货货和和发发货货台台应应能能保保护护物物料料和和产产品品不不受受天天气气的的影影响响。收收货货区区的设计应允许原料在移到储存区前可进行必要的清洁。的设计应允许原料在移到储存区前可进行必要的清洁。Where quarantine status is ensured by storage in separate areas, these areas must be clearly marked and their access restricted to authorised personnel. 若若待待检检状状态态的的物物料料储储存存在在隔隔离离区区，该该区区域域必必须须清清楚楚标标明明状状态态并只限于经批准的人员进入。并只限于经批准的人员进入。Storage Areas储存区储存区78There should normally be a separate sampling area for starting materials. If sampling is performed in the storage area, it should be conducted in such a way as to prevent contamination or cross-contamination. 通通常常，应应有有一一个个单单独独的的原原料料取取样样区区域域。如如果果取取样样在在储储存存区进行，要防止污染或交叉污染。区进行，要防止污染或交叉污染。Segregated areas should be provided for the storage of rejected, recalled or returned materials or products. 不合格、召回或退回的物料或产品应隔离存放。不合格、召回或退回的物料或产品应隔离存放。Storage Areas储存区储存区79Highly active materials or products should be stored in safe and secure areas. 高活性物料或成品应储存在安全的区域内。高活性物料或成品应储存在安全的区域内。Printed packaging materials are considered critical to the conformity of the medicinal product and special attention should be paid to the safe and secure storage of these materials. 印印刷刷包包材材是是确确保保药药品品标标识识正正确确的的关关键键，应应特特别别注意安全贮存。注意安全贮存。Storage Areas储存区储存区80QC Areas质量控制区质量控制区Quality Control laboratories should be separated from production areas. This is particularly important for laboratories for the control of biologicals, microbiologicals and radioisotopes, which should also be separated from each other. 质质量量控控制制实实验验室室应应与与生生产产区区隔隔离离。这这点点对对于于生生物物实实验验室室、微微生生物物实实验验室室和和放放射射性性同同位位素素实实验验室室尤尤为为重重要要。这这三三个个实验室也应互相隔离。实验室也应互相隔离。81Control laboratories should be designed to suit the operations to be carried out in them. Sufficient space should be given to avoid mix-ups and cross-contamination. There should be adequate suitable storage space for samples and records. 质质量量控控制制实实验验室室的的设设计计应应便便于于操操作作的的运运行行。应应有有足足够够的的空空间间以以避免混杂和交叉污染。样品和记录的储存区域应足够大。避免混杂和交叉污染。样品和记录的储存区域应足够大。Separate rooms may be necessary to protect sensitive instruments from vibration, electrical interference, humidity, etc. 如如必必要要，设设置置专专门门的的仪仪器器室室以以保保护护敏敏感感仪仪器器免免受受振振动动、静静电电、潮湿等因素的干扰。潮湿等因素的干扰。QC Areas质量控制区质量控制区82Ancillary Areas辅助区辅助区Rest and refreshment rooms should be separate from other areas. 休息室和茶点室应与其他区域隔离。休息室和茶点室应与其他区域隔离。Facilities for changing clothes, and for washing and toilet purposes should be easily accessible and appropriate for the number of users. Toilets should not directly communicate with production or storage areas. 更更衣衣室室和和盥盥洗洗室室应应方方便便人人员员出出入入，并并与与使使用用人人数数相相适适应应。卫生间不应与生产区或储存区直接相通。卫生间不应与生产区或储存区直接相通。83Maintenance workshops should as far as possible be separated from production areas. Whenever parts and tools are stored in the production area, they should be kept in rooms or lockers reserved for that use. 机机修修间间近近可可能能与与生生产产区区分分开开。当当维维修修用用的的零零件件和和工工具具储存在生产区内，应把它们放在预定的房间或锁橱中。储存在生产区内，应把它们放在预定的房间或锁橱中。Ancillary Areas辅助区辅助区84Equipment设备设备Manufacturing equipment should be designed, located and maintained to suit its intended purpose. 生生产产设设备备的的设设计计、安安装装位位置置和和维维修修都都应应适适合合它它的的预预定定用用途。途。Repair and maintenance operations should not present any hazard to the quality of the products. 修理和维修操作不应给产品的质量带来任何危害。修理和维修操作不应给产品的质量带来任何危害。85Manufacturing equipment should be designed so that it can be easily and thoroughly cleaned. It should be cleaned according to detailed and written procedures and stored only in a clean and dry condition. 生生产产设设备备的的设设计计应应使使其其易易于于全全面面清清洗洗。设设备备的的清清洗洗应应按按照照详详细细的的、书书面面规规程程进进行行。清清洗洗后后的的设设备备只只能能储储存存在在干干净净及及干燥的环境中。干燥的环境中。Washing and cleaning equipment should be chosen and used in order not to be a source of contamination. 应应注注意意洗洗涤涤、清清洁洁设设备备的的选选择择和和使使用用方方式式，以以避避免免这这类类设设备成为污染源。备成为污染源。Equipment设备设备86Equipment should be installed in such a way as to prevent any risk of error or of contamination. 设备的安装应有利于防止差错或污染。设备的安装应有利于防止差错或污染。Production equipment should not present any hazard to the products. The parts of the production equipment that come into contact with the product must not be reactive, additive or absorptive to such an extent that it will affect the quality of the product and thus present any hazard. 生生产产设设备备不不能能给给产产品品带带来来任任何何危危害害。与与产产品品接接触触的的设设备备部部件件不不应应与与药药品品发发生生反反应应、不不应应吸吸附附或或向向药药品品中中释释放放物物质质而而影影响产品的质量并因此带来危害。响产品的质量并因此带来危害。Equipment设备设备87Balances and measuring equipment of an appropriate range and precision should be available for production and control operations. 生产和控制操作应配有适当量程和精度的天平和测量仪器生产和控制操作应配有适当量程和精度的天平和测量仪器Measuring, weighing, recording and control equipment should be calibrated and checked at defined intervals by appropriate methods. Adequate records of such tests should be maintained. 测测量量、称称量量、记记录录和和控控制制设设备备应应按按照照规规定定的的时时间间间间隔隔根根据据适适当的方法进行校正和检查。这些测试的纪录应保留。当的方法进行校正和检查。这些测试的纪录应保留。Equipment设备设备88Fixed pipework should be clearly labelled to indicate the contents and, where applicable, the direction of flow. 固固定定管管道道上上应应清清楚楚地地贴贴有有标标明明管管道道内内容容物物的的标标签签，必必要要时时，应应标明流向。标明流向。Distilled, deionized and, where appropriate, other water pipes should be sanitised according to written procedures that detail the action limits for microbiological contamination and the measures to be taken. 蒸蒸馏馏水水、去去离离子子水水和和其其他他水水的的管管道道应应按按照照书书面面的的规规程程进进行行消消毒毒。规程中应详细地规定了微生物污染的纠偏限度及要采取的措施。规程中应详细地规定了微生物污染的纠偏限度及要采取的措施。Equipment设备设备89Defective equipment should, if possible, be removed from production and quality control areas, or at least be clearly labelled as defective. 如如可可能能，将将有有故故障障的的设设备备移移出出生生产产和和质质量量控控制制区区。或或至至少贴上醒目的标识。少贴上醒目的标识。Equipment设备设备90Pharmaceutical Services Corporation美国医药服务有限公司Computerised Systems计算机系统计算机系统 2021/7/1Annex 11 EU GMP Guide 欧洲欧洲GMP指南，附录十一指南，附录十一Introduction介绍介绍92Where a computerised system replaces a manual operation, there should be no resultant decrease in product quality or quality assurance. 计计算算机机系系统统替替代代手手工工操操作作，不不得得造造成成降降低低产产品品质质量量或或影影响质量保证的后果响质量保证的后果Principle原则原则93Validation验证验证The extent of validation necessary will depend on a number of factors including the use to which the system is to be put, whether the validation is to be prospective or retrospective and whether or not novel elements are incorporated. Validation should be considered as part of the complete life cycle of a computer system. This cycle includes the stages of planning, specification, programming, testing, commissioning, documentation, operation, monitoring and modifying. 应应根根据据多多种种因因素素来来决决定定必必要要的的验验证证范范围围，包包括括系系统统要要在在哪哪里里使使用用、是是前前验验证证还还是是回回顾顾性性验验证证、是是否否结结合合新新元元件件等等。验验证证应应作作为为计计算算机机系系统统完完整整生生命命周周期期的的一一部部分分。生生命命周周期期包包括括：计计划划、设定标准、编程、测试、调试、文件、操作、监测和更改。设定标准、编程、测试、调试、文件、操作、监测和更改。94System系统系统A written detailed description of the system should be produced (including diagrams as appropriate) and kept up to date. It should describe the principles, objectives, security measures and scope of the system and the main features of the way in which the computer is used and how it interacts with other systems and procedures. 应应准准备备一一个个书书面面的的系系统统详详细细描描述述（包包括括图图表表），并并随随时时更更新新以以反反映映现现有有的的情情况况。该该文文件件应应描描述述原原则则、目目的的、安安全全措措施施、范范围围、计计算算机机的的主主要要使使用用特特性性和和如如何何与与其其它它系系统统及及程程序序相相互互作用。作用。95The software is a critical component of a computerised system. The user of such software should take all reasonable steps to ensure that it has been produced in accordance with a system of Quality Assurance. 软软件件是是计计算算机机系系统统的的关关键键部部份份。软软件件的的使使用用者者要要采采取取合合理理的的步骤以确保编制的软件符合质量保证系统要求。步骤以确保编制的软件符合质量保证系统要求。System系统系统96Data should only be entered or amended by persons authorised to do so. Suitable methods of deterring unauthorised entry of data include the use of keys, pass cards, personal codes and restricted access to computer terminals. There should be a defined procedure for the issue, cancellation, and alteration of authorisation to enter and amend data, including the changing of personal passwords. 只只有有授授权权的的人人员员可可以以输输入入或或改改正正数数据据。应应采采用用适适当当的的措措施施防防止止外外来来人人员员输输入入数数据据，如如使使用用钥钥匙匙、通通行行卡卡、个个人人密密码码和和权权限限对对计计算算机机终终端端的的访访问问。应应有有一一个个规规程程规规定定授授权权人人的的批批准准、取消、更改和个人密码的更换。取消、更改和个人密码的更换。 System系统系统97When critical data are being entered manually (for example the weight and batch number of an ingredient during dispensing), there should be an additional check on the accuracy of the record which is made. This check may be done by a second operator or by validated electronic means 当当关关键键数数据据由由人人工工输输入入时时（如如配配料料过过程程中中，某某种种成成份份的的重重量量和和批批号号），应应复复核核输输入入记记录录的的准准确确性性。该该复复核核可可由由第第二二个个操操作作人人员员执执行行或或根根据据验验证证过过的的电电子子方法。方法。System系统系统98The system should record the identity of operators entering or confirming critical data. Authority to amend entered data should be restricted to nominated persons. Any alteration to an entry of critical data should be authorised and recorded with the reason for the change. Consideration should be given to building into the system the creation of a complete record of all entries and amendments (an audit trail). 系系统统应应能能确确认认输输入入或或证证实实关关键键数数据据的的操操作作人人员员。应应禁禁止止给给指指定定的的人人员员授授权权更更改改已已输输入入的的数数据据。对对已已输输入入数数据据进进行行任任何何更更改改，应应该该事事先先得得到到批批准准并并记记录录更更改改的的原原因因。应应考考虑虑安安装装一一个个系系统统，以以能能够够产产生生一一个个记记有有所所有有输输入入和和更更改改记记录录的的报报告告（即即“审审计计追追踪踪”）。）。 System系统系统99Alterations to a system or to a computer program should only be made in accordance with a defined procedure which should include provision for validating, checking, approving and implementing the change. 对对系系统统或或计计算算机机程程序序的的更更改改应应按按照照规规定定的的规规程程进进行行。该该规规程程应包括对变更的批准、实施、检查和验证。应包括对变更的批准、实施、检查和验证。For quality auditing purposes, it should be possible to obtain clear printed copies of electronically stored data. 为为达达到到质质量量审审计计的的目目标标，应应能能获获得得电电子子储储存存数数据据的的清清晰晰打打印印记录。记录。System系统系统100Data should be secured by physical or electronic means against wilful or accidental damage. 采采用用的的现现场场措措施施或或电电子子措措施施应应能能保保护护数数据据的的安安全全，以以防防止止人人为或意外的数据毁坏。为或意外的数据毁坏。Data should be protected by backing-up at regular intervals. Back-up data should be stored as long as necessary at a separate and secure location. 应对数据定期地进行备份。备份的数据应储存在一个分离及应对数据定期地进行备份。备份的数据应储存在一个分离及安全的地方，并保存尽可能长的时间。安全的地方，并保存尽可能长的时间。System系统系统101The procedures to be followed if the system fails or breaks down should be defined and validated. Any failures and remedial action taken should be recorded. 如如果果系系统统失失败败或或损损坏坏，要要准准备备所所要要遵遵守守的的规规程程并并对对其其进进行行验验证。要记录所有的故障和进行的弥补措施。证。要记录所有的故障和进行的弥补措施。System系统系统102Pharmaceutical Services Corporation美国医药服务有限公司Qualification and Validation确认和验证确认和验证 2021/7/1Introduction介绍介绍Annex 15 EU GMP Guide 欧洲欧洲GMP指南附录十五指南附录十五Based on PIC/S recommendations 根据根据PIC/S建议建议Principle原则原则It is a requirement of GMP that manufacturers identify what validation work is needed to prove control of the critical aspects of their particular operations. Significant changes to the facilities, the equipment and the processes, which may affect the quality of the product, should be validated. A risk assessment approach should be used to determine the scope and extent of validation GMP要要求求生生产产厂厂家家搞搞清清楚楚为为了了证证明明其其操操作作的的关关键键方方面面得得到到控控制制应应需需要要哪哪些些验验证证工工作作。对对可可能能影影响响产产品品质质量量的的厂厂房房、设设备备和和工工艺艺进进行行的的显显著著变变更更，要要经经过过验验证证。应应使使用用风风险险评评估估方方法法来来决决定定验验证证的的范围和程度。范围和程度。Planning计划计划All validation activities should be planned. The key elements of a validation programme should be clearly defined and documented in a validation master plan (VMP) or equivalent documents 所所有有的的验验证证活活动动都都应应事事先先计计划划。验验证证程程序序的的关关键键要要素素应应在在验验证证主主计计划划（VMP）或或等等同同的的文文件件中中清清楚楚的的定定义义和和阐明阐明The VMP should contain data on at least the following: VMP应至少包括以下信息：应至少包括以下信息：validation policy 验证原则验证原则 organisational structure of validation activities 验证活动的组织结构验证活动的组织结构summary of facilities, systems, equipment and processes to be validated 需验证的厂房、系统、设备和工艺的汇总需验证的厂房、系统、设备和工艺的汇总Planning计划计划documentation format: the format to be used for protocols and reports 文件格式：验证方案和报告的格式文件格式：验证方案和报告的格式planning and scheduling 计划和时间表计划和时间表change control 变更控制变更控制reference to existing documents 参考的现有文件参考的现有文件Planning计划计划108Protocol方案方案A written protocol should be established that specifies how qualification and validation will be conducted. The protocol should be reviewed and approved. The protocol should specify critical steps and acceptance criteria. 应应准准备备一一个个书书面面方方案案规规定定确确认认和和验验证证如如何何执执行行。方方案案应应经过审核和批准，并规定关键步骤和接收标准。经过审核和批准，并规定关键步骤和接收标准。Report报告报告A report that cross-references the qualification and/or validation protocol should be prepared, summarising the results obtained, commenting on any deviations observed, and drawing the necessary conclusions, including recommending changes necessary to correct deficiencies. Any changes to the plan as defined in the protocol should be documented with appropriate justification. 应应按按照照确确认认和和验验证证方方案案编编写写报报告告。总总结结收收集集的的结结果果，评评估估发发现现的的偏偏差差，得得出出必必要要的的结结论论并并建建议议必必要要的的变变更更以以纠纠正正偏偏差差。任任何何与与即即定方案不符的偏差也应在报告中记录并有适当解释。定方案不符的偏差也应在报告中记录并有适当解释。After completion of a satisfactory qualification, a formal release for the next step in qualification and validation should be made as a written authorisation. 确确认认完完成成且且结结果果令令人人满满意意后后，应应准准备备一一个个书书面面的的文文件件正式批准进入确认和验证的下一步。正式批准进入确认和验证的下一步。Report报告报告Design Qualification设计确认设计确认The first element of the validation of new facilities, systems or equipment could be design qualification (DQ). 新的厂房、系统或设备验证的第一个因素是设计确认（新的厂房、系统或设备验证的第一个因素是设计确认（DQ）The compliance of the design with GMP should be demonstrated and documented 符合符合GMP的设计应经过论证并记录在案的设计应经过论证并记录在案Installation Qualification安装确认安装确认Installation qualification (IQ) should be performed on new or modified facilities, systems and equipment. 新的或改动过厂房、系统和设备要进行安装确认新的或改动过厂房、系统和设备要进行安装确认IQ should include, but not be limited to the following: IQ至少包括以下方面：至少包括以下方面：installation of equipment, piping, services and instrumentation checked to current engineering drawings and specifications; 根根据据现现有有的的图图纸纸和和规规格格，检检查查设设备备、管管道道、公公共共设设施施、仪仪表表的的安装安装collection and collation of supplier operating and working instructions and maintenance requirements; 供应商的操作和工作指南以及维修需要的收集和核对供应商的操作和工作指南以及维修需要的收集和核对calibration requirements; 校正要求校正要求verification of materials of construction. 材质证实材质证实Installation Qualification安装确认安装确认114Operational Qualification运行确认运行确认Operational qualification (OQ) should follow Installation qualification. 运行确认（运行确认（OQ）应在）应在IQ批准后进行批准后进行OQ should include, but not be limited to the following: OQ至少包括以下方面：至少包括以下方面： - Tests that have been developed from knowledge of processes, systems and equipment; 根据对工艺、系统和设备的了解准备测试方法根据对工艺、系统和设备的了解准备测试方法 - Tests to include a condition or a set of conditions encompassing upper and lower operating limits, sometimes referred to as “worst case” conditions. 测试包括操作的上、下限，有时称为测试包括操作的上、下限，有时称为“最坏最坏”条件条件The completion of a successful Operational qualification should allow the finalisation of calibration, operating and cleaning procedures, operator training and preventative maintenance requirements. It should permit a formal release of the facilities, systems and equipment. OQ包包括括：进进行行校校准准、操操作作运运行行和和清清洁洁，对对操操作作人人员员进进行行培培训训和和制制定定预预防防性性维维护护保保养养，这这些些结结束束后后，运运行行确确认认才才算算完完成成。经经运运行确认的厂房、系统和设备应有一个正式的批准手续。行确认的厂房、系统和设备应有一个正式的批准手续。 Operational Qualification运行确认运行确认Performance Qualification性能确认性能确认Performance qualification (PQ) should follow successful completion of Installation qualification and Operational qualification. 性能确认（性能确认（PQ）应在）应在IQ和和OQ完成后进行完成后进行PQ should include, but not be limited to the following: PQ至少包括以下方面：至少包括以下方面：tests, using production materials, qualified substitutes or simulated product, that have been developed from knowledge of the process and the facilities, systems or equipment; 根根据据对对工工艺艺、厂厂房房、系系统统和和设设备备的的了了解解准准备备测测试试方方法法，测测试试使用生产物料、批准的替代物或模拟产品使用生产物料、批准的替代物或模拟产品 tests to include a condition or set of conditions encompassing upper and lower operating limits. 测试包括操作的上、下限测试包括操作的上、下限Although PQ is described as a separate activity, it may in some cases be appropriate to perform it in conjunction with OQ. 虽虽然然对对PQ作作为为一一个个单单独独的的行行动动进进行行描描述述，但但是是，有有些些情情况况下，也可与下，也可与OQ结合进行。结合进行。Performance Qualification性能确认性能确认Process Validation工艺验证工艺验证Process validation should normally be completed prior to the distribution and sale of the medicinal product (prospective validation). In exceptional circumstances, where this is not possible, it may be necessary to validate processes during routine production (concurrent validation). Processes in use for some time should also be validated (retrospective validation). 工工艺艺验验证证通通常常需需要要在在药药品品上上市市前前完完成成（前前验验证证）。但但是是，有有些些情情况况下下，这这是是不不可可能能的的。它它需需要要在在日日常常生生产产时时对对工工艺艺进进行行验验证证（同同步步验验证证）。已已投投入入使使用用一一段段时时间间的的工工艺艺也也应应进进行行验验证证（回回顾顾性性验验证）。证）。Prospective and concurrent validation should include, but not be limited to the following: 前验证和同步验证应至少包括以下方面：前验证和同步验证应至少包括以下方面：short description of the process; 工艺的简要描述工艺的简要描述summary of the critical processing steps to be investigated; 工艺关键步骤的汇总工艺关键步骤的汇总list of the equipment/facilities to be used (including measuring/monitoring/recording equipment) together with its calibration status 所用设备所用设备/设施清单（包括测量设施清单（包括测量/监测监测/记录设备）及其校正状态记录设备）及其校正状态Process Validation工艺验证工艺验证finished product specifications for release; 成品的放行规格成品的放行规格list of analytical methods, as appropriate; 分析方法清单（如适用）分析方法清单（如适用）proposed in-process controls with acceptance criteria; 建议的中间控制及其接收标准建议的中间控制及其接收标准additional testing to be carried out, with acceptance criteria and analytical validation, as appropriate; 执行的附加测试及其接收标准和分析方法验证（如适用）执行的附加测试及其接收标准和分析方法验证（如适用）sampling plan; 取样计划取样计划Process Validation工艺验证工艺验证methods for recording and evaluating results 记录和评价结果的方法记录和评价结果的方法functions and responsibilities 职能部门和职责职能部门和职责proposed timetable. 建议的时间表建议的时间表Process Validation工艺验证工艺验证Using this defined process (including specified components) a series of batches of the final product may be produced under routine conditions. 使使用用规规定定的的工工艺艺（包包括括规规定定的的原原辅辅料料），可可以以在在日日常常生生产产的的条条件件下可以生产出一系列批次的产品下可以生产出一系列批次的产品 Batches made for process validation should be the same size as the intended industrial scale batches. 工艺验证批的数量应与预计生产的工业批的数量一致工艺验证批的数量应与预计生产的工业批的数量一致Process Validation工艺验证工艺验证In theory the number of process runs carried out and observations made should be sufficient to allow the normal extent of variation and trends to be established and to provide sufficient data for evaluation. It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters, would constitute a validation of the process. 理理论论上上，工工艺艺验验证证的的批批数数和和观观察察到到的的结结果果应应足足以以建建立立一一般般的的偏偏离离程程度度和和趋趋势势，并并能能提提供供足足够够的的数数据据以以供供评评估估。总总体体来来说说，按按照照最最终终制制定定的的参参数数，进进行行连连续续三三批批的的生生产产以以对对工工艺艺进进行行验验证证是是可可以以接接受的。受的。Process Validation工艺验证工艺验证Retrospective validation is only acceptable for well-established processes and will be inappropriate where there have been recent changes in the composition of the product, operating procedures or equipment. 回回顾顾性性验验证证只只适适用用于于已已建建立立良良好好的的工工艺艺。如如果果产产品品的的组组成成、操操作作规规程程或设备在最近有所变更，那么回顾性验证则不适用。或设备在最近有所变更，那么回顾性验证则不适用。Validation of such processes should be based on historical data. The steps involved require the preparation of a specific protocol and the reporting of the results of the data review, leading to a conclusion and a recommendation 这这种种工工艺艺的的验验证证应应根根据据历历史史数数据据。其其做做法法是是准准备备一一个个特特定定的的方方案案，报报告审阅数据的结果，并给出一个结论和建议。告审阅数据的结果，并给出一个结论和建议。Retrospective Validation回顾性验证回顾性验证The source of data for this validation should include, but not be limited to batch processing and packaging records, process control charts, maintenance log books, records of personnel changes, process capability studies, finished product data, including trend cards and storage stability results 这这种种验验证证数数据据的的来来源源应应该该至至少少包包括括批批生生产产和和包包装装记记录录、工工艺艺控控制制图图表表、维维修修记记录录簿簿、人人员员变变化化记记录录、工工艺艺能能力力研研究究、成成品品数数据据（包括趋势图和储存稳定性结果（包括趋势图和储存稳定性结果Retrospective Validation回顾性验证回顾性验证Batches selected for retrospective validation should be representative of all batches made during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency. Additional testing of retained samples may be needed to obtain the necessary amount or type of data to retrospectively validate the process. 回回顾顾性性验验证证所所选选择择的的产产品品批批应应具具有有代代表表性性（包包括括失失败败批批），批批的的数数量量应应充充足足，以以能能论论证证工工艺艺的的一一致致性性。可可能能需需要要对对留留样样进进行行附附加加测试，以获得必要数量或特性的数据来回顾性验证工艺。测试，以获得必要数量或特性的数据来回顾性验证工艺。Retrospective Validation回顾性验证回顾性验证Retrospective Validation回顾性验证回顾性验证For retrospective validation, generally data from ten to thirty consecutive batches should be examined to assess process consistency, but fewer batches may be examined if justified. 对对回回顾顾性性验验证证而而言言，一一般般选选取取十十到到三三十十连连续续批批的的数数据据进进行行审审阅阅以以评评价价工工艺艺的的一一致致性性。但但是是，如如果果有有判判断断依依据据，那那么么审审阅阅较较少少的的批批次也是可以接受的。次也是可以接受的。Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure. The rationale for selecting limits of carry over of product residues, cleaning agents and microbial contamination should be logically based on the materials involved. The limits should be achievable and verifiable. 清清洗洗验验证证的的执执行行是是为为证证实实清清洗洗规规程程的的有有效效性性。选选择择产产品品残残留留物物限限度度、清清洗洗试试剂剂限限度度和和微微生生物物污污染染限限度度的的合合理理性性应应基基于于所所涉涉及及的的物物料。这些限度应该是可以达到的，能够证实的。料。这些限度应该是可以达到的，能够证实的。Cleaning Validation清洗验证清洗验证Validated analytical methods having sensitivity to detect residues or contaminants should be used. 应应使使用用验验证证过过的的分分析析方方法法，并并且且该该分分析析方方法法的的灵灵敏敏度度能能检检测测残留残留Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. 一般来说，只有接触产品的设备表面的清洗规程需要验证一般来说，只有接触产品的设备表面的清洗规程需要验证Cleaning Validation清洗验证清洗验证For cleaning procedures for products and processes which are similar, it is considered acceptable to select a representative range of similar products and processes. A single validation study utilising a “worst case” approach can be carried out which takes account of the critical issues 可可以以从从相相似似产产品品及及工工艺艺中中选选择择一一个个具具有有代代表表性性的的产产品品和和工工艺艺进进行行验验证证。可可以以应应用用“最最坏坏条条件件”理理论论而而进进行行单单独独的的验验证证，在在验验证证中中应考虑关键因素。应考虑关键因素。Cleaning Validation清洗验证清洗验证Cleaning Validation清洗验证清洗验证Typically three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated. 为为证证明明清清洗洗方方法法已已得得到到验验证证，应应在在连连续续三三批批产产品品上上执执行行清清洗洗规程并检验合格果规程并检验合格果Revalidation再验证再验证Facilities, systems, equipment and processes, including cleaning, should be periodically evaluated to confirm that they remain valid. Where no significant changes have been made to the validated status, a review with evidence that facilities, systems, equipment and processes meet the prescribed requirements fulfils the need for revalidation. 应应对对厂厂房房、系系统统、设设备备和和工工艺艺（包包括括清清洗洗）进进行行阶阶段段性性评评估估，以以证证实实它它们们维维持持在在有有效效状状态态。如如果果已已验验证证的的状状态态没没有有发发生生过过显显著著变变更更，那那么么一一个个能能证证明明厂厂房房、系系统统、设设备备和和工工艺艺能能够够满满足足规规定定要要求求的、有事实依据的回顾就可以达到再验证的需要的、有事实依据的回顾就可以达到再验证的需要Pharmaceutical Services Corporation美国医药服务有限公司Production生产生产 2021/7/1Production operations must follow clearly defined procedures; they must comply with the principles of Good Manufacturing Practice in order to obtain products of the requisite quality and be in accordance with the relevant manufacturing and marketing authorisations. 生生产产操操作作必必须须按按照照规规定定的的规规程程执执行行。它它们们必必须须遵遵循循GMP原原则则，以以得得到到符符合合要要求求质质量量的的产产品品并并符符合合相相关关生生产和市场注册要求。产和市场注册要求。Principle原则原则135General概述概述All handling of materials and products, such as receipt and quarantine, sampling, storage, labelling, dispensing, processing, packaging and distribution should be done in accordance with written procedures or instructions and, where necessary, recorded. 所所有有物物料料和和产产品品的的处处理理（如如接接收收、待待检检、取取样样、储储存存、贴贴标标、配配料料、工工艺艺、包包装装和和分分发发）都都应应按按照照书书面面的的规规程程或指示执行。如必要，还要进行记录。或指示执行。如必要，还要进行记录。136All incoming materials should be checked to ensure that the consignment corresponds to the order. 对所有原料进行检查以确保接收物符合订单。对所有原料进行检查以确保接收物符合订单。Damage to containers and any other problem which might adversely affect the quality of a material should be investigated, recorded and reported to the Quality Control Department. 应应对对容容器器破破损损和和其其他他可可能能影影响响物物料料质质量量的的问问题题进进行行调调查、记录，并报告给质量控制部。查、记录，并报告给质量控制部。General概述概述137Incoming materials and finished products should be physically or administratively quarantined immediately after receipt or processing, until they have been released for use or distribution. 接接收收物物料料或或完完成成生生产产后后，原原料料和和成成品品在在实实地地或或管管理理系系统统中应立即处于待检状态，直至它们被放行。中应立即处于待检状态，直至它们被放行。General概述概述138All materials and products should be stored under the appropriate conditions established by the manufacturer and in an orderly fashion to permit batch segregation and stock rotation. 所所有有物物料料和和产产品品都都应应储储存存在在厂厂家家建建议议的的适适合合条条件件下下，有有有序分批贮存和周转。有序分批贮存和周转。General概述概述139Checks on yields, and reconciliation of quantities, should be carried out as necessary to ensure that there are no discrepancies outside acceptable limits. 应检查产量和数额平衡，以确保它们在可接受的限度内应检查产量和数额平衡，以确保它们在可接受的限度内Operations on different products should not be carried out simultaneously or consecutively in the same room unless there is no risk of mix-up or cross-contamination. 不不同同产产品品的的操操作作不不能能在在同同一一房房间间内内同同时时或或连连续续进进行行，除除非没有混杂或交叉污染的风险。非没有混杂或交叉污染的风险。General概述概述140At every stage of processing, products and materials should be protected from microbial and other contamination. 在在生生产产的的每每一一步步，都都要要保保护护产产品品和和物物料料避避免免微微生生物物和和其其他他污污染。染。When working with dry materials and products, special precautions should be taken to prevent the generation and dissemination of dust. This applies particularly to the handling of highly active or sensitising materials. 干干燥燥的的物物料料或或产产品品的的生生产产中中，尤尤其其是是高高活活性性或或高高致致敏敏性性物物料料的生产中，要采取特殊措施防止粉尘的产生和扩散。的生产中，要采取特殊措施防止粉尘的产生和扩散。General概述概述141At all times during processing, all materials, bulk containers, major items of equipment and where appropriate rooms used should be labelled or otherwise identified with an indication of the product or material being processed, its strength (where applicable) and batch number. Where applicable, this indication should also mention the stage of production. 生生产产期期间间，所所有有的的物物料料、半半成成品品容容器器、设设备备的的主主要要部部件件及及相相关关的的房房间间都都要要有有标标签签或或标标识识，以以识识别别正正在在进进行行生生产产的的产产品品或物料名称、规格和批号。如适用，也应显示生产的工序。或物料名称、规格和批号。如适用，也应显示生产的工序。General概述概述142Labels applied to containers, equipment or premises should be clear, unambiguous and in the companys agreed format. It is often helpful in addition to the wording on the labels to use colours to indicate status (for example, quarantined, accepted, rejected, clean, .). 容容器器、设设备备或或厂厂房房的的标标签签应应清清楚楚并并符符合合公公司司批批准准的的模模板板格格式式。除除了了标标签签上上的的字字迹迹以以外外，颜颜色色也也是是很很有有帮帮助助的的（如待检、批准、不合格、清洁等）（如待检、批准、不合格、清洁等）General概述概述143Any deviation from instructions or procedures should be avoided as far as possible. If a deviation occurs, it should be approved in writing by a competent person, with the involvement of the Quality Control Department when appropriate. 任任何何违违背背指指令令或或规规程程的的偏偏差差都都应应尽尽量量避避免免。如如果果发发生生偏偏差差，该该偏偏差差应应由由有有主主管管人人员员签签字字批批准准，必必要要时时，质质量量控控制制部部门门参参与调查处理。与调查处理。Access to production premises should be restricted to authorised personnel. 生产厂房应只限于经批准的人员进入。生产厂房应只限于经批准的人员进入。General概述概述144Prevention of Cross Contamination交叉污染的预防交叉污染的预防Products in which contamination is likely to be most significant are those administered by injection, those given in large doses and/or over a long time. 对对注注射射产产品品、大大剂剂量量给给药药和和/或或长长期期使使用用的的药药品品而而言言，产产品品污污染的危害性最为严重。染的危害性最为严重。Cross-contamination should be avoided by appropriate technical or organisational/measures, for example: 应采取适当的技术手段或管理措施避免交叉污染，如：应采取适当的技术手段或管理措施避免交叉污染，如：production in segregated areas 隔离区域进行生产隔离区域进行生产providing appropriate air-locks and air extraction 提供适当的气闸室和排风提供适当的气闸室和排风145using cleaning and decontamination procedures of known effectiveness, as ineffective cleaning of equipment is a common source of cross-contamination 应应用用已已知知效效果果的的清清洁洁规规程程。设设备备清清洁洁不不充充分分是是交交叉叉污污染染的的常常见见来源。来源。testing for residues and use of cleaning status labels on equipment. 应对残留物进行测试及并使用设备清洁状态标签应对残留物进行测试及并使用设备清洁状态标签Prevention of Cross Contamination交叉污染的预防交叉污染的预防146Starting Materials原料原料Starting materials should only be purchased from approved suppliers named in the relevant specification and, where possible, directly from the producer. It is recommended that the specifications established by the manufacturer for the starting materials be discussed with the suppliers. It is of benefit that all aspects of the production and control of the starting material in question, including handling, labelling and packaging requirements, as well as complaints and rejection procedures are discussed with the manufacturer and the supplier. 应应只只从从批批准准的的供供应应商商处处购购买买原原料料。如如可可能能，最最好好直直接接从从生生产产厂厂家家购购买买。原原辅辅料料的的质质量量标标准准，建建议议由由药药品品生生产产企企业业与与供供应应商商共共同同商商定定，所所购购的的原原辅辅料料生生产产和和控控制制的的各各个个方方面面，包包括括加加工工，处处理理、贴贴签签，包包装装要要求求、投投诉诉以以及及产产品品不不合合格格的的判判定定等等，最最好好也也由由药药品品生生产企业与生产商及供应商共同商定。产企业与生产商及供应商共同商定。147For each delivery, the containers should be checked for integrity of package and seal and for correspondence between the delivery note and the suppliers labels. 每每次次收收货货都都要要检检查查包包装装的的完完整整性性、密密封封性性及及交交货货单单与与供供应应商商标签的一致性。标签的一致性。If one material delivery is made up of different batches, each batch must be considered as separate for sampling, testing and release. 如如果果收收到到的的物物料料含含有有不不同同的的批批号号，对对每每一一批批都都要要单单独独取取样样、测试、放行。测试、放行。Starting Materials原料原料148Starting material labels should bear at least the following information: 原料标签应包含下列信息：原料标签应包含下列信息：the designated name of the product and the internal code reference where applicable; 产品名称和内部编号（如适用）产品名称和内部编号（如适用）a batch number given at receipt; 收货后给出的批号收货后给出的批号where appropriate, the status of the contents (e.g. in quarantine, on test, released, rejected); 如可能，产品的状态（如待检、在检、放行、不合格）如可能，产品的状态（如待检、在检、放行、不合格）where appropriate, an expiry date or a date beyond which retesting is necessary. 如可能，有效期或复验期如可能，有效期或复验期Starting Materials原料原料149There should be appropriate procedures or measures to assure the identity of the contents of each container of starting material. Bulk containers from which samples have been drawn should be identified 有有适适当当的的规规程程或或措措施施保保证证每每个个容容器器中中原原料料正正确确无无误误。取过样的容器应做好标记。取过样的容器应做好标记。Only starting materials which have been released by the Quality Control Department and which are within their shelf life should be used 只能使用质量控制部放行的、在有效期内的原辅料。只能使用质量控制部放行的、在有效期内的原辅料。Starting Materials原料原料150Starting materials should only be dispensed by designated persons, following a written procedure, to ensure that the correct materials are accurately weighed or measured into clean and properly labelled containers. 应应由由指指定定的的人人员员根根据据书书面面的的规规程程进进行行配配料料，确确保保正正确确原原料料经经过过准准确称重，装入洁净的容器中，并进行适当标记。确称重，装入洁净的容器中，并进行适当标记。Each dispensed material and its weight or volume should be independently checked and the check recorded. 对每个配制的物料及其重量或体积都应由他人独立复核并记录。对每个配制的物料及其重量或体积都应由他人独立复核并记录。Materials dispensed for each batch should be kept together and conspicuously labelled as such. 用用于于同同一一批批药药品品生生产产的的所所有有配配料料应应集集中中存存放放，并并标标上上相相应应的的明明显显标识。标识。Starting Materials原料原料151Processing Operations生产工艺操作生产工艺操作Before any processing operation is started, steps should be taken to ensure that the work area and equipment are clean and free from any starting materials, products, product residues or documents not required for the current operation. 生生产产操操作作前前，应应先先确确保保工工作作区区域域和和设设备备干干净净，没没有有其其他他任何与本次操作无关的原料、产品、产品残留物和文件任何与本次操作无关的原料、产品、产品残留物和文件152Intermediate and bulk products should be kept under appropriate conditions. 中间体和待包装产品应存放在适宜的条件下中间体和待包装产品应存放在适宜的条件下Any necessary in-process controls and environmental controls should be carried out and recorded. 应执行必要的中间控制和环境监测，并记录应执行必要的中间控制和环境监测，并记录Any significant deviation from the expected yield should be recorded and investigated. 实实际际产产量量明明显显偏偏离离预预期期产产量量时时，应应有有记记录录并并进进行行调查。调查。Processing Operations生产工艺操作生产工艺操作153Packaging Materials包装材料包装材料The purchase, handling and control of primary and printed packaging materials shall be accorded attention similar to that given to starting materials. 内包材和印刷包材的采购、管理和控制与原料相似。内包材和印刷包材的采购、管理和控制与原料相似。Particular attention should be paid to printed materials. They should be stored in adequately secure conditions such as to exclude unauthorised access. Cut labels and other loose printed materials should be stored and transported in separate closed containers so as to avoid mix-ups. Packaging materials should be issued for use only by authorised personnel following an approved and documented procedure. 应应特特别别注注意意印印刷刷包包材材。它它们们应应存存放放在在足足够够安安全全的的地地方方以以防防止止未未经经批批准准的的人人员员进进入入。断断的的标标签签和和其其他他散散装装印印刷刷包包材材应应存存放放在在隔隔离离的的密密闭闭容容器器中中以以防防止止混混淆淆。包包装装材材料料的的发发放放只只能能由由指指定定人人员员根根据据批批准准的的书书面面规规程进行。程进行。154Each delivery or batch of printed or primary packaging material should be given a specific reference number or identification mark. 每每批批或或每每次次发发放放的的基基本本或或印印刷刷包包装装材材料料都都应应有有一一个个特特定定的参考编号或识别标识。的参考编号或识别标识。Outdated or obsolete primary packaging material or printed packaging material should be destroyed and this disposal recorded. 失失效效或或废废除除的的内内包包材材或或印印刷刷包包装装材材料料应应被被销销毁毁，销销毁毁过过程应被记录程应被记录Packaging Materials包装材料包装材料155Packaging Operations包装操作包装操作Different products should not be packaged in close proximity unless there is physical segregation. 未经隔离，不同产品不应在相邻区域内包装。未经隔离，不同产品不应在相邻区域内包装。Line-clearance should be performed according to an appropriate check-list. 应按照适当的检查表进行清场应按照适当的检查表进行清场The name and batch number of the product being handled should be displayed at each packaging station or line. 进行包装的产品名称和批号应显示在每个包装台或包装线上进行包装的产品名称和批号应显示在每个包装台或包装线上All products and packaging materials to be used should be checked on delivery to the packaging department for quantity, identity and conformity with the Packaging Instructions. 应应检检查查所所有有发发放放到到包包装装部部门门的的产产品品和和包包装装材材料料。检检查查包包括括数数量量、产产品品、与包装指令的一致性。与包装指令的一致性。156Normally, filling and sealing should be followed as quickly as possible by labelling. If it is not the case, appropriate procedures should be applied to ensure that no mix-ups or mislabelling can occur. 一一般般来来说说，灌灌装装和和密密封封后后应应尽尽可可能能快快地地进进行行贴贴标标。如如果果不不能能做做到到这一点，应有适当的规程以确保不会发生混杂或贴错标签。这一点，应有适当的规程以确保不会发生混杂或贴错标签。Special care should be taken when using cut-labels and when over-printing is carried out off-line. Roll-feed labels are normally preferable to cut-labels, in helping to avoid mix-ups. 当当使使用用剪剪贴贴式式标标签签和和离离线线进进行行打打印印时时，应应特特别别小小心心。一一般般来来说说，建议使用卷筒式标签以避免混杂。建议使用卷筒式标签以避免混杂。 Packaging Operations包装操作包装操作157Checks should be made to ensure that any electronic code readers, label counters or similar devices are operating correctly. 为为确确保保电电子子条条码码识识读读器器、标标签签计计数数器器或或相相似似仪仪器器的的正正确确操作，要进行必要的检查操作，要进行必要的检查Printed and embossed information on packaging materials should be distinct and resistant to fading or erasing. 包包装装材材料料上上的的印印刷刷和和压压印印信信息息应应清清楚楚，不不退退色色，不不易易擦擦去去Packaging Operations包装操作包装操作158On-line control of the product during packaging should include at least checking the following: 包装过程中，对产品的在线控制检查应至少包括以下方面：包装过程中，对产品的在线控制检查应至少包括以下方面：general appearance of the packages; 包装的外观包装的外观whether the packages are complete; 包装是否完整包装是否完整whether the correct products and packaging materials are used; 是否使用了正确的产品和包装材料是否使用了正确的产品和包装材料whether any over-printing is correct; 打印是否正确打印是否正确correct functioning of line monitors. 在线监测的正确功能在线监测的正确功能Samples taken away from the packaging line should not be returned. 不应返还从包装线取走的样品不应返还从包装线取走的样品Packaging Operations包装操作包装操作159Products which have been involved in an unusual event should only be reintroduced into the process after special inspection, investigation and approval by authorised personnel. Detailed record should be kept of this operation. 涉涉及及不不正正常常事事件件的的产产品品，要要经经过过特特定定的的检检查查、调调查查并并被被有有资资质质人人员员批准后，才能再次使用。该过程的详细记录应保留。批准后，才能再次使用。该过程的详细记录应保留。Any significant or unusual discrepancy observed during reconciliation of the amount of bulk product and printed packaging materials and the number of units produced should be investigated and satisfactorily accounted for before release. 在在核核对对待待包包装装产产品品和和印印刷刷包包材材的的数数量量及及成成品品的的数数量量时时，如如发发现现明明显显的的或或不不正正常常的的偏偏差差，应应对对其其进进行行调调查查。只只有有得得到到满满意意的的答答复复后后，该该产品才能放行。产品才能放行。Packaging Operations包装操作包装操作160Upon completion of a packaging operation, any unused batch-coded packaging materials should be destroyed and the destruction recorded. A documented procedure should be followed if uncoded printed materials are returned to stock. 包包装装操操作作完完成成后后，所所有有没没有有用用过过的的、印印有有批批号号的的包包装装材材料料都都应应被被销销毁毁并并且且记记录录。如如果果把把没没有有打打印印批批号号的的印印刷刷材材料退回仓库，应按照书面的规程进行。料退回仓库，应按照书面的规程进行。Packaging Operations包装操作包装操作161Finished Product成品成品Finished products should be held in quarantine until their final release under conditions established by the manufacturer. 成成品品应应处处于于待待检检状状态态，直直至至它它们们满满足足了了生生产产厂厂家家的的标标准准而批准放行而批准放行After release, finished products should be stored as usable stock under conditions established by the manufacturer. 放行后，成品应作为合格品在生产厂家规定的条件存放放行后，成品应作为合格品在生产厂家规定的条件存放162Rejected and Returned Material不合格品和退回品不合格品和退回品Rejected materials and products should be clearly marked as such and stored separately in restricted areas. They should either be returned to the suppliers or, where appropriate, reprocessed or destroyed. Whatever action is taken should be approved and recorded by authorised personnel. 不不合合格格的的物物料料和和产产品品应应清清楚楚标标明明并并存存放放在在单单独独的的控控制制区区内内，既既可可退退还还给给供供应应商商，也也可可在在一一定定条条件件眄眄进进行行返返工工，或或销销毁毁。不不管管采采取取何何种种方方式式处处理理，都都必必须须得得到到有有资质人员的批准并进行记录。资质人员的批准并进行记录。163The reprocessing of rejected products should be exceptional. It is only permitted if the quality of the final product is not affected, if the specifications are met and if it is done in accordance with a defined and authorised procedure after evaluation of the risks involved. Record should be kept of the reprocessing. 不不合合格格产产品品的的返返工工除除外外。只只有有经经过过了了风风险险评评估估，并并确确保保返返工工按按照照规规定定的的规规程程进进行行、最最终终成成品品可可以以符符合合质质量量标标准准、其质量不受影响时，才允许进行返工。返工应有记录。其质量不受影响时，才允许进行返工。返工应有记录。Rejected and Returned Material不合格品和退回品不合格品和退回品164The recovery of all or part of earlier batches which conform to the required quality by incorporation into a batch of the same product at a defined stage of manufacture should be authorised beforehand. This recovery should be carried out in accordance with a defined procedure after evaluation of the risks involved, including any possible effect on shelf life. The recovery should be recorded. 只只有有经经预预先先批批准准，方方可可将将以以前前生生产产的的所所有有或或部部分分批批次次的的合合格格产产品品，在在某某一一确确定定的的生生产产工工序序合合并并到到同同一一产产品品的的一一个个批批次次中中予予以以回回收收。应应对对相相关关的的质质量量风风险险（包包括括可可能能对对产产品品有有效效期期的的影影响响）进进行行适适当当的的评评估估后后，方方可可按按照照预预定定的的规规程程进进行行回回收收处处理。回收应有记录。理。回收应有记录。 Rejected and Returned Material不合格品和退回品不合格品和退回品165The need for additional testing of any finished product which has been reprocessed, or into which a recovered product has been incorporated, should be considered by the Quality Control Department. 质质量量控控制制部部门门应应考考虑虑对对返返工工的的成成品品或或掺掺杂杂了了回回收收产产品品的的成品进行额外测试。成品进行额外测试。Rejected and Returned Material不合格品和退回品不合格品和退回品166Products returned from the market and which have left the control of the manufacturer should be destroyed unless without doubt their quality is satisfactory; they may be considered for re-sale, re-labelling or recovery in a subsequent batch only after they have been critically assessed by the Quality Control Department in accordance with a written procedure. 从从市市场场上上退退回回并并已已脱脱离离药药品品生生产产企企业业的的控控制制的的产产品品应应予予以以销销毁毁，除除非非对对其其质质量量无无可可置置疑疑;只只有有经经质质量量控控制制部部门门根根据据书书面面规规程程进进行行了了严严格格评评估估后后，方方可可考考虑虑将将这这些些退退回回产产品品重重新新发发放放销售、重新贴标签或在其后的批次生产中回收。销售、重新贴标签或在其后的批次生产中回收。Rejected and Returned Material不合格品和退回品不合格品和退回品167The nature of the product, any special storage conditions it requires, its condition and history, and the time elapsed since it was issued should all be taken into account in this assessment. Where any doubt arises over the quality of the product, it should not be considered suitable for re-issue or re-use, although basic chemical reprocessing to recover active ingredient may be possible. Any action taken should be appropriately recorded. 评评价价时时，应应考考虑虑产产品品的的特特性性、它它需需要要的的特特殊殊储储存存条条件件、它它的的现现状状和和历历史史以以及及发发放放和和退退回回之之间间间间隔隔的的时时间间等等等等因因素素。即即使使有有可可能能利利用用基基础础化化学学从从退退货货中中回回收收原原料料，如如果果对对产产品品的的质质量量存存有有任任何何怀怀疑疑时时，就就不不应应再再考考虑虑产产品品的的重重新新发发放放或或重重新新使使用用。任任何何退退货货处处理理均均应有相应记录。应有相应记录。Rejected and Returned Material不合格品和退回品不合格品和退回品168 结结束束语语若有不当之处，请指正，谢谢！若有不当之处，请指正，谢谢！