SIX SYSTEM APPROACH TO GMP IN MANUFACTURINGOF SOLID DOSAGE FORM固体制剂的六大体系固体制剂的六大体系Presented bysFDA & Alliance Pharmon& & 美国洲际药业美国洲际药业17, 18 March 2006Hangzhou, ChinaSpeakerSimon Rusmin, Ph.D.1cGMP培训 SEMINAR CONTENTS 研讨会内容 Quality System Approach to GMP Microbes in non-sterile manufacturing Validation Principles and Practices Preparing for regulatory inspection 2cGMP培训QUALITY SYSTEM APPROACH TO GMP GMP的质量系统3cGMP培训The FDA experts studied all quality systems includingthose of non-pharmaceutical.FDA认证专家研究了所有的包括非制药的质量系统认证专家研究了所有的包括非制药的质量系统In August 2002 the USA-FDA initiatedscience-based & risk-base quality systemapproach to CGMP.2002年八月，美国年八月，美国FDA成立了以科学和风险为基础的成立了以科学和风险为基础的CGMP质量系统质量系统To be in compliance with USA CGMP & EU GMP, we need to understand the approaches & to know how to implement them. 为了达到美国为了达到美国CGMP &欧盟欧盟GMP要求，我们需要知道方法及如何执行要求，我们需要知道方法及如何执行。First we need to understand the concept and science of QUALITY and the present day QUALITY SYSTEMS.首先我们需要了解质量理念和知识及现行的质量系统首先我们需要了解质量理念和知识及现行的质量系统1.1 Why Quality System Approach为什么使用质量系统法?4cGMP培训Unlike adult wild animals, human beings need products (goods and services) provided by others.不同于成年的野生动物，人类需要由别人提供的产品（不同于成年的野生动物，人类需要由别人提供的产品（物品和服务）物品和服务）QUALITY is the characteristicsof Goods and Services that the users LIKE.质量是使用者对物品和服务喜欢的特征质量是使用者对物品和服务喜欢的特征In the science of manufacturingQuality is documented as measurable SPEFICIATIONS生产质量知识已被当作可测量的规格写成了文件生产质量知识已被当作可测量的规格写成了文件1.2 What is Quality什么是质量?5cGMP培训1.3 History of Quality 质量的历史 1850sBefore the INDUSTRIAL REVOLUTION在工业革命以前在工业革命以前Product is UNIQUE(one of a kind).产品是唯一的（一种一个）产品是唯一的（一种一个）Personal skills & pridemake QUALITY人类的技能和自尊心造就了质量人类的技能和自尊心造就了质量High variability.可变化性高可变化性高After工业革命后工业革命后 Product is UNIFORM产品是统一的产品是统一的Scientific controlsmake QUALITY科学控制造就了质量科学控制造就了质量Low variability 可变化性低可变化性低6cGMP培训1.4 Statistical Quality Control统计质量控制 1920sNature is inherently non-UNIFORM. Its variability is of Normally Distribution.本质上不再统一，其可变性有了正态分布本质上不再统一，其可变性有了正态分布In 1920s Schewart pioneered the science of statistical quality controls:在二十年代，休哈特倡导了统计质量控制在二十年代，休哈特倡导了统计质量控制Statistical Sampling统计抽样统计抽样Statistical Process control统计工艺控制统计工艺控制Process Capability加工能力加工能力Design of Experiment实验设计实验设计World War II 二次世界大战二次世界大战(1945) - the PEAK of Industrial Revolution, and the subsequent flood of consumer goods afterward.工业革命的鼎盛时期，出现了后来的生活工业革命的鼎盛时期，出现了后来的生活消费品潮消费品潮7cGMP培训1.5 The Race of Quality质量的赛跑 1970sAfter WWII, Deming taught Japanese industry methodsand techniques of qualitymanagement & improvement.第二次世界大战后，戴明教给了日本人工业方法和质量管理第二次世界大战后，戴明教给了日本人工业方法和质量管理及改进方法及改进方法Japan perfected quality into Total Quality Management日本把质量完善为总的质量管理日本把质量完善为总的质量管理:Top management commits to quality主管管理质量主管管理质量Everyone participate in quality人人参与质量人人参与质量Processes are continuously improved工艺不断改进工艺不断改进In 1976 the USA-FDA issued Good Manufacturing Practices.1976年美国年美国FDA发布了质量生产规范发布了质量生产规范GMP8cGMP培训In the 1980s the USA industry learned the Japanese ways of manufacturing and caught up in quality.在八十年代，美国工业学习了日本的生产方式并且引发了质量在八十年代，美国工业学习了日本的生产方式并且引发了质量Motorola & General Electric initiatedthe Six-Sigma Manufacturingquality system, followedby Lean-Manufacturing.摩托罗拉及通用电气根据精益生产，发起了六西格码质量系统摩托罗拉及通用电气根据精益生产，发起了六西格码质量系统 Six sigma六西格码六西格码= defect of 3/106 3/106的缺陷的缺陷Lean精益精益 = highest value at lowest cost 以最小的成本得到最大的价值以最小的成本得到最大的价值Current quality system concepts are the baseof FDAs Quality System Approach to CGMP.当前的质量系统理念是FDA的CGMP质量系统的基础1.6 Quality in the 21th Century21世纪的质量9cGMP培训 QUALITY IS 质量是质量是 What the CustomersLike 消费者喜欢什么消费者喜欢什么 measured by Specifications根据规格进行测量根据规格进行测量 got by Reducing Variability of manufacturing通过减少生产可变性通过减少生产可变性得到得到1.6a QUICK SUMMARY快速总结10cGMP培训1.7 What is a Process什么是过程?Changing low-value INPUT into high-value OUTPUTChanging low-value INPUT into high-value OUTPUT把低价值的输入变成高价值的输出把低价值的输入变成高价值的输出11cGMP培训1.8 Knowledge is Power知识就是力量Process Knowledge is the power Process Knowledge is the power to control the processto control the process工艺知识是控制过程的力量工艺知识是控制过程的力量Alvin TofflerAlvin Toffler托夫勒托夫勒 The THIRD WAVE The THIRD WAVE 第三次第三次浪潮浪潮-1980-198012cGMP培训1.9 Process Three Factors过程的三个因素Factors contribute to Process variabilityFactors contribute to Process variability影响过程可变性的因素影响过程可变性的因素13cGMP培训1.10 The Business Process Flow商业的工艺流程Business is a change of processes the output of Business is a change of processes the output of one process is the input of the next processone process is the input of the next process商业是过程的变更一个过程的输出是商业是过程的变更一个过程的输出是下一个过程的输入下一个过程的输入14cGMP培训qProduct Development leads to Manufacturing Authorization (NDA, ANDA, DMF process/product specs) Facility, Utility, Equipment mapping, qualification and validation.产品的发展导致了生产核准（ NDA, ANDA, DMF 工艺/产品规格），设备，公共设施的系统图，确认和验证 q Establish maintenance/calibration.建立维护/校准qProcess-mapping, Risk-analysis (FMEA, HACCP), & establish Process-controls.q工艺描述，风险分析(FMEA, HACCP), & 建立工艺控制qEstablish Material-testing and Process-monitoring, In-process, intermediate, and finished product testing. Set-up Testing-laboratories.q建立材料检验和工艺监测，内控标准，中间体和成品检验，建立测试实验室qDocumentation and Knowledge-transfer to operators & managers through continuous training.q不断的对操作者&管理者进行文件建立及知识培训qChange-control & Problem-solving (Deviation, OOS, & conformance), and establish CAPA.q变更控制& 问题解决（偏差，超标&一致性），建立CAPAqAudit (self-inspection ) & Annual Quality Review (health-check).q审核（自我检查） &年度质量审阅（健康检查）1.11 Creating Process Knowledge创造性的工艺知识15cGMP培训1.12 FDA Six Quality Systems ApproachFDA的六个质量系统方法16cGMP培训 QUALITY SYSTEM 质量系统是质量系统是 is the MEANS to control process variability, by Mapping & Analyzing the Process, and Establishing Six Control Points是通过工艺描述、分析及建立六个控制点来控制过程变化的方法是通过工艺描述、分析及建立六个控制点来控制过程变化的方法1.12a QUICK SUMMARY快速总结17cGMP培训1.13 Document Pyramid文件金字塔18cGMP培训qAs a SHOWCASE to introduce the quality operations of qthe company.把企业的质量操作当作一种优势介绍qThe QUALITY POLICY statement is the commitment of the highest management to QUALITY质量方针陈述是质量的最高管理承诺qDisplays the sites of manufacturing and the products manufactured in the sites.把生产的位置和所在位置生产的产品显示出来qDefine the organization and personnel involved in quality, and each function responsibilities (Quality Unit (Qualified Person of EU) is independent of Manufacturing.q定义包含在质量中的组织和人员，及每种职责（质量单位（EU有资格的人）和生产无关）qAppended with List of other manuals (Manufacturing / Analytical Labs), SOPs, and other documents as a GATEWAY to view the complete quality systems.q附加的有：其它手册（生产/分析实验室）， SOPs，及其它可以浏览到全部质量系统的文件1.14 Quality Policy质量方针19cGMP培训qThe very first SOP describing how to writean SOP and manage GMP documents.q第一份SOP描述的是如何编写SOP和管理GMP文件qFORMAT格式Software to use and template使用的软件和模版; Numbering system 编号系统- Example例如: JS1013: J=co. code; S =SOP (F=form构成, L=logbook日志, T=test method检验方法, P=protocol方案); 1 = quality assurance质量保证 (2=quality control lab质量控制实验室, 3=manufacturing生产, 4=engineering工程); 013=Serial number序号. qCONTENTS内容Purpose目的; Scope范围; (Background背景); Responsibilities职责; Procedure规程; Appendix附录; Approval批准; Revision history修订记录qPROCESS工艺Creation制造, Approval批准, Distribution分布, Change变更, Periodic review定期审阅, Absolution无限制, Archiving存档.qCONTROL控制The Document Controller functions in SOPs & Records. SOPs & 记录中的文件管理者作用 1.15 Quality System Documentation质量系统文件20cGMP培训qMajor SYSTEM SOPs created by QU include： qQU创造的主要SOPS系统包括:1 Quality system documentation (grand-father SOP)质量系统文件（起始SOP）1 Personnel & contactors人员&承包商2 Facility, utility, and equipment设施，公用设备，设备3 Incoming materials and suppliers来料和供应商4, 5 Manufacturing and controls生产和控制5 Distribution, complaints, & recalls分发，投诉和召回6 Quality control & testing laboratories质量控制&测试实验室 Process validation and improvement工艺验证和改进qCreation of INSTRUCTION SOPs are by the users of each organizational functions (begin with flowcharting).q指令是由行为组织者创造的（从流程图开始）qHandling of RECORDS is described in grand-father SOP.q有关记录的处理在起始中有描述1.16 SOPs and Records SOPs和记录21cGMP培训qSOP: “Manufacturing and Control Personnel & Responsibilities生产和控制人员&职责”, containing包括:Sufficient personnel to do the tasks with education (knowledge), skills, and experience用足够的有文化（知识），技能及经验的人员来执行任务Clear authorities and responsibilities明确权利和职责Responsibilities of QA/QP (release product), QC, & Manufacturing unitsQA/QP (产品放行）， QC, & 生产单位的职责qSOP: “Workplace Attire 工作场所服装& Operating Rules操作规则” (safeguards of product quality and personal safety产品质量和人员安全保障)qSOP: “Training Program培训计划& documentation文件”qSOP: “Consultants and Contracted Works顾问和签约工作”, containing包括:Selection and qualification挑选和确认Contract agreements on responsibilities and transactions职责和事务的合同协议Evaluating results and auditing Quality System评估结果和质量系统审核1.17 Personnel & Contractors人员&承包商22cGMP培训1.17a QUICK SUMMARY快速总结 SOFTWARE软件软件 & LIVEWARE 生生命件命件 Quality System (software) are rules to keep Process Variability low.质量系统（软件）是把过程变化保持到最低的准则质量系统（软件）是把过程变化保持到最低的准则 Personnel (liveware) is the operator of the Quality System.人员（生命件）是质量系统的操作者人员（生命件）是质量系统的操作者 Rules must be good and correctly followed by people.准则必准则必须是有益的并且由人来正确执行须是有益的并且由人来正确执行23cGMP培训1.18 Hardware Pyramid硬件金字塔24cGMP培训qSituation, Design, Construction位置，设计，建造Situated at suitable surrounding, enclosed to prevent vermin放在合适的环境中，并且封起来以预防害虫等Design with sufficient space to prevent product mix-up, cross-contamination, & contamination. 要设计成足够的空间，以防止产品混淆，交叉污染和污染Dedicated facility for penicillin, hormones, cytotoxins对青霉素，激素，细胞毒素类要用专用设备qCEILINGs and WALLs do not contribute dust, easy to maintained and cleaned. FLOORs are resistant to use, no dust / moisture collection, drains are easily cleaned and sanitized.q天花板和墙壁不允许有灰尘，应容易维护和清洗，地板耐用，没有灰尘水堆积，排水装置应容易打扫和清洁qHVAC provide clean and dry air suitable for operations with sufficient LIGHT. qHVAC利用充足的光，提供了适合操作的干净、干燥的空气qAREAs for rest / toilet, weighing, in-process storage etc.休息厕所，称重，内控标准储藏等区域qSOP: “Facility Maintenance & Repair设备维护和维修” (logbook日志).qVAL: IQ/OQ & Warehouse qualification仓库确认 (as equipment) 1.19 FACILITY设备25cGMP培训qUtilities are suitable and well designed and constructed. Utilities consists of:公用设备都是相配的，而且设计和制造都很好，其包括下面的内容HVAC, Chiller冷却器, and Electricity电流Water systems水系统 (raw materials原料): City, Purified, WFICompressed Air压缩空气, Nitrogen氮Boilers and steam generators (clean steam)锅炉和蒸汽产生器（干净的蒸汽）qQA/QC understand the principles and operationsq QA/QC理解法规和操作qSOP: “Utilities Maintenance 公用设施维护& Repair维修”qPiping in Manufacturing Area protected and identified (type & flow direction).被保护和选定的生产区域内的管道系统（种类及流向）qMONITOR监测: Output contributing to product quality must be monitored.和产品质量有关的输出必须被监测qVAL: IQ/OQ 1.20 UTILITIES公共事业设备26cGMP培训qEquipment are to be designed and installed correctly to be suitable for their purposes and ease of cleaning.q设备的设计和安装要适用于其使用，且容易清洗。qEquipment are to be identified and the identity displayed when necessary during manufacturing.q设备要被鉴定并且当生产中有必要时把特性显示出来qProduct-contact-surfaces are not to be reactive, adsorptive, or additive to the products.q产品的接触面对产品没有反应，吸附或附加作用。qSOP: “Cleaning Procedures for XXX” qXXX清洁规程Cleaning tool and equipment清洁工具和设备Cleaning agent清洗剂 Documentation制成文件 (logbook日志, label标签) qSOP: “Measuring Instrument Calibration测量仪器校准”qSOP: “Equipment Maintenance & Repair设备维护和维修”qVAL: IQ/OQ, and Electronic-Controller validated有效的电子控制器.1.21 EQUIPMENT设备27cGMP培训1.21a QUICK SUMMARY快速总结 HARDWARE 硬件硬件 Processes CANNOT run without Hardware没有硬件工艺就无法运行没有硬件工艺就无法运行 Hardware deteriorates with time causing VARIABILITIES To Clean, Maintain, Repair & Calibrate硬件随着时间会变坏，并硬件随着时间会变坏，并引起清洁，维护，维修及校准的变化引起清洁，维护，维修及校准的变化28cGMP培训qPurchase from reliable vendors with good Quality Systems (known original manufacturer) and defined specs. q供应商应可靠，且拥有良好的质量系统（已知的起始生产商）和确定的规格qAgreed on supply, delivery, reject returns.q在供货，运货，拒收应意见一致qThree store areas: Receiving, Quarantine, Release, Reject (locked); Identify materials with stickers (info).q三种储藏区域：接收，待验，放行，拒收（锁定）；使用标签进行材料鉴别qExamine package, invoice and CoA; QC samples & test (must ID-test), and determines to release or reject.q检查包装，货物和化验报告； QC样品& 检验（必须是ID检验）及决定放行或拒收qRetain Reference-Samples for Critical Materialsq保持主要物料的相关样品qLabels must be kept locked.标签须被上锁保存qSOP: “Incoming Materials Storage来料储藏 & Release放行”qVendor auditing, evaluation, and rating买主审核，评估及评价.qWATER is a raw materials for most products.水是大多数产品的原料1.22 INCOMING MATERIALS进厂物料Bad Materials make Bad Products坏原料制造出坏产品坏原料制造出坏产品29cGMP培训qMANUFACTURING MANUAL contains:生产手册包括q1. Purpose目的, 2. Site map位置地图, 3. Organization组织, Manufacturing lines生产线,4. Major Equipment list主要设备清单, q5. SOPs list qSOPs清单qMANUFACTURING consists of Production of Intermediate & Bulk, and Packaging of Finished products.q生产包括中间体及批量的生产和成品包装qPROCESS KNOWLEDGE transferred from Development is designed into Batch Record = SOPof making & recording productsconsistent with Marketing Authorization (NDA or ANDA).q工艺知识被设计成批记录制造及记录与上市批准(NDA or ANDA)一致的产品的SOPqMaster Batch Record is approved and controlled by Q-Unit, who also review completed Batch Record. qQ-Unit批准和控制主要的批记录，及审阅所有的批记录。qSOP: “Batch Record Issuance, Use & Review批记录发布，使用及审阅” (QU).qVAL: Manufacturing Process Validation生产工艺验证1.23 MANUFACTURING生产30cGMP培训qWeighing of formula materials are verifiable (electronic or 2nd person).原料的称重是可确认的（电子秤必须用外置二级标准砝码进行校正）qRecord data at the end of each process step directly on the Batch Record, sign and date each record.q在批记录上直接记录每一工序结束时的数据，标上标记和日期qRecord the start-end time of TIME-DURATION parameters or END-POINT parameters.q记录持续参数或终点参数的起始结束时间qSign and date any mechanically generated records.q给任何的机械生产记录标上标记及日期qStore results (intermediate or bulk) in assigned container and location.在指定的容器和位置存储结果（中间体或批量）qReconcile results against input materials.所得结果和所用材料相协调qRecord all deviations and discuss 记录所有的偏差和讨论(with supervisor/QU和管理人员).qClose-out Batch Record and submit to QU.停止批记录并听从于QU.qDis-assemble the equipment. Clean the equipment and facility.把设备拆卸，进行清洗1.24 BULK PRODUCTION批量生产31cGMP培训qObtain and verify the correct packaging materials and labels.获取及检验正确的包装材料和标签qVerify line-clearance 检验清除线(by QU由QU).qRecord start-end time of a filling/packaging process.记录填充包装工艺的起始结束时间qConduct in-process control testing. Record any unusual line-stoppage and its reasons.做内控标准试验，记录任何异样的线中断和其原因qStore the Packaged Product in the designated place; Reconcile the product against the bulk.在指定位置储存包装好的产品；使得产品和批量相协调qReconcile labels and other critical packaging materials.使得标签和其它主要包装材料相协调qRecord deviations in processing and reconciliation.记录工艺和协调中的偏差qClose-out Batch Record and submit to QU.停止批记录并听从于QU.qDis-assemble equipment. Clean equipment and lines.把设备拆卸，进行清洗1.25 FINISHED PACKAGING最终包装32cGMP培训qCorrectly design and assign facility and work flow.正确地设计、分配工具及工作流程qAssign dedicated operators for one process.对于一个工艺指定操作者qTrain personnel (operators, mechanics, QC analysts) on hazards of causing mix-up, cross-contamination, and contamination; and on proper attire & behavior.对人员（机械操作人员， QC 分析人员）在混淆，交叉污染和污染的危险性及合适的服装及行为方面进行培训qRestrict the entry of persons into the production and packaging areas.对于进入生产及包装区域的人员进行限制qMaintained the integrity and cleanliness of the facility and equipment.保证设施和设备的完整和清洁qMonitor facility and equipment cleanliness through auditing and microbial testing.通过审核及微生物检验来监测设施和设备的清洁qImplement 5S (sort, set-in-order, shine, standardize, sustain) workshop rules.使用车间规定（分门别类，归类，发亮，标准化，持续发展） 1.26 Prevent mix-up & Contamination 防止混淆及污染33cGMP培训qDEVIATIONS may cause bulk, intermediate, and finished products not meeting specifications, called “non-conformance”.q偏差可能引起批生产，中间体及成品不符合规格，叫做“不符合”qREWORK is treating the non-conformance with another process to correct. REPROCESSING is repeating the process to correct.q重新加工是用另外的工艺来处理改正“不符合”，再加工是重复用同一种工艺改正qQU pre-approves rework/reprocessing based agreed protocol, and reviews & approves/rejects the results. Therework/reprocessing is documented. QU 根据方案提前进行重新加工再加工批准及审阅& 支持反对结果。重新加工再加工被写成文件qIf rework/reprocessing is very often, correct and validate the process.如果重新加工再加工很频繁，对工艺进行改正和验证qSOP: “Rework and Reprocessing重新加工和再加工” 1.27 Rework & Reprocessing重新加工及再加工34cGMP培训qDISTRIBUTION is done by Marketing/Sales departments.q分发由市场销售部来做qThe distribution of products per lot numbers must be traceable for the purpose of recalling the products. q为了方便召回产品，每批量的产品分发都必须有可追溯性。qRECALL is caused by defective products discovered after release. Is voluntary or a regulatory action. Voluntary recall must be reported.q召回是由放行后出现的有缺陷产品引起的，是自发的或常规的行为，自发的召回必须作报告qFDAs Type I, II, III recalls (from most to least serious).qFDA召回种类I, II, III（从最严重的到最不严重的） qSOP: “Product Recall and Reporting产品召回和报告”.qRETURN is bringing product back to the plant because the products are unsold or damaged.退货是因为产品没有卖出去或被损坏而把产品退回到工厂qReturns are documented and stored separately, and must be inspected/ tested before re-release by QU.退货产品必须分开备案和储存，在重新放行前必须由QU进行检查检验qSOP: “Product Return and Re-releasing产品退货和再放行” 1.28 Distribution, Return, Recall分发，退货，召回35cGMP培训QC “SEE” if the materials (INPUT) and the products (OUTPUT) meet Specifications. QC来检查原料（输入）和产品（输出）是否符合规格 1.29 Quality Control Tasks质量控制任务36cGMP培训qQC LAB MANUAL be prepared, containing: 1. Purpose, 2. Site map, 3. Organization, 3. Sample Flows, 4. Major Test Instrument, 5. List of SOPs qQC实验室手册包括：目的，位置图，组织，样品流程， SOPs清单qHas sufficient qualified equipment/ instrument and qualified analysts to run the labs.q要有足够的合格设备工具和合格的分析人员来运作实验室qThere is a Calibration Program for measuring instrumentsq对于测量工具有一个校准程序qThere are Specification Sheets for Materials, In-process, intermediates, Bulk, and Finished products.q对于材料，内控，中间体，批量和成品有规格表qSamples are collected according to Sampling Plan to be representative of items tested (ANSI/ASQC Z1.4 -1993).q根据检测项目的有代表性的取样计划取样（ ANSI/ASQC Z1.4 -1993).qSOP: “Sample Collection, Testing, and Results Reporting样品收集，检验及结果报告”. 1.30 QC Laboratories -1 QC实验室37cGMP培训qReserved samples are taken of Bulk and Finished for problem investigation and Stability Studies.q用于问题和稳定性研究的保留样品来自于批量和成品qSOP: “Product Long Term Stability Program产品长期稳定性计划”qMicrobiology laboratory needs a biologist to run微生物实验室需要有一位生物学家.qHazardous Waste Disposal is controlled.对危险废品处理进行控制qVAL: IQ/OQ of Lab Facility, Utilities, Equipment / Instrument,q实验室设施的IQ/OQ，公用设施，设备仪器qVAL: Qualification of compendia analytical methods; Validation of product specific analytical methods.q分析方法概略的确认；产品细节分析方法的验证qReference to Good Laboratory Practices根据实验室操作规范: US-FDA 21 CFR Part 50, & EU Directive87/18/EEC 1.31 QC Laboratories -2 QC实验室38cGMP培训 QC IS 是是 The EARS and EYES of MANUFACTURING.生产的耳朵和眼睛生产的耳朵和眼睛 QCs DATA must be Accurate and Timely.QC的数据必须是准确及时的的数据必须是准确及时的1.31a QUICK SUMMARY快速总结39cGMP培训 1.32 Maintain & Improve Systems维护和改进系统40cGMP培训qVALIDATION - a new process must be confirmed that it works as designed (see Part 3 of Seminar)q验证必须保证新的工艺按照所设计的进行（见研讨会Part 3 ）qCHANGE CONTROL any changes to a process have to be evaluated and approved by the QU before implementation. Changes include: input materials, the procedures, the facility and equipment, the testing and monitoring. q变更控制在使用前，工艺的任何变化都必须经过QU 评估和批准。变更包括：所用材料，规程，设备和设施，检验和监测qSOP: “Manufacturing Changes Evaluation and Approval生产变更的评估和批准” (QU 批准approvals).qCAPA Investigation of deviations and non-conformance, resulting in Corrective Actions and Preventative Actions.q偏差和不符合研究，形成了矫正和预防措施qOOS Investigation of doubtful analytical test results to determine causes of Out-of-Specifications either from the test operation or as a product failure. 试验操作或产品过失中的超标是对需测定的有疑问的试验结果进行研究的原因 1.33 Maintain & Improve -1维护和改进系统41cGMP培训qMONITORING 监测 Continuous or at fixed frequency measurement of factors that may effect product quality (cleanliness of areas, manufacturing machines, input water quality)连续的或因素在固定频率的测量可能影响产品质量（区域清洁，生产机器，所用水质量）qTRENDING 趋向 Results of monitoring is not release criteria. Results are displayed to observe trends.q监测的结果不是放行标准，而是为了观察趋向qNON-CONFORMANCE are situations or actions not in accordance to GMP elements or requirements. q不符合是指位置或措施和GMP要素或要求不一致qAUDIT Periodic examination of Quality System implementation, resulting in corrections of non-conformance (inspection of self, supplier/contractor) SOP.q审核执行质量系统的定期检查，对不符合（自我检查，及供应商承包商检查）的纠正SOPqCOMPLAINT from customers are investigated and corrected. SOP.顾客的投诉被调查并改正SOP.qANNUAL REVIEW 年度审阅 Periodic review of the whole manufacturing operations related to Quality.有关质量的总体生产操作 的定期审阅 1.34 Maintain & Improve -2维护及改进42cGMP培训qANNUAL REVIEW to include年度审阅包括:CHANGES to quality organization & personnel; facility, utilities, equipment; materials; processes; testing and monitoring; new product introduction质量机构及人员的变更，设施，公用设施，设备，原料，工艺，检验和监测，新产品介绍Summary of material & product released/rejected and trends; rework / reprocessing / returns / recall; monitoring trends; investigation of deviations / non-conformance / OOS, customer complaints/ other quality problems/ regulator inspections.有关原料及产品发放拒收和趋向；重新加工再加工退货召回；监测趋向；偏差不符合超标的调查研究，顾客投诉其它质量问题校准仪的检查总结Summary of Stability Studies稳定性研究的总结.COMPANY TOTAL QUALITY HEALTH EXAMINATION公司总的质量健康检查qCONTINUOUS IMPROVEMENT 不断提高 Using knowledge from Annual Review to plan and execute improvement projects. 利用从年度审阅中获得的知识做计划，并改进项目。1.35 Maintain & Improve -3维护及改进43cGMP培训MICROBES IN NON-STERILE MANUFACTURING非无菌生产中的微生物44cGMP培训2.1 Microbes in Manufacturing Areas生产区域中的微生物qThere are two groups of micro-organisms commonly found in pharmaceutical plant: 在制药工厂里常见的有两组微生物q The BACTERIA & the FUNGI:细菌和真菌45cGMP培训2.2 Fungus, Bacteria, Virus真菌，细菌，病毒qMicroscopic look显微镜观察:46cGMP培训2.3 Prokaryotes & Eukaryotes原核生物和真核细胞qAn organism must have two capabilities to stay alive and propagate: 一个生物体必须有生存和繁殖的能力q a) METABOLSIM新陈代谢作用 changing inorganic H2O and CO2 into organics by plant, and eating other organics to become its own by other organisms; and b) GENETICS DNA molecules that record the characteristic of the organism that can be reproduced to make more of itself. qa) 新陈代谢作用 通过种植把无机的水和二氧化碳转化成有机物，通过食用别的有机物，在其它生物作用下变成无机物， b)遗传 可以表现生物特性的DNA能够进行自我繁殖qThe DNA and metabolic machinery are packaged into a CELL.qDNA和新陈代谢器官在同一个细胞里qThe Cell of a bacteria is simple where the DNA is loosely stored inside the cell called Prokaryote. The cell of fungus has a nucleus where the DNA is tightly packed called Eukaryote.qDNA松散存储在简单细胞里面的细菌，称作原核生物，菌类的DNA紧密排列在有细胞核的细胞里面，称作真核细胞qVirus is a piece of DNA packaged into a box of protein, therefore it cannot metabolize. It finds other organisms to make more of itself. 病毒具有蛋白质外壳的基因组 ，它利用其它生物来满足自身需求47cGMP培训2.4 How a Virus Propagate病毒如何繁殖48cGMP培训2.5 Roles of Microbes in Nature微生物在自然中的角色qBacteria can be found in more places than other organisms on earth. Fungus is the main component of soil. Microbes recycle the organics of dead plants and animals.相对于其它生物来说，细菌可以在地球上的更多地方被发现，菌类是土壤的主要成分，生物可以对死亡的动植物进行分解49cGMP培训2.6 The Five Kingdoms on Earth地球上的五大区域50cGMP培训2.7 Evolution of Life on Earth地球上的生物演变51cGMP培训2.8 Human are Microbe Carrier人类是微生物的载体52cGMP培训2.9 Human Shed Microbes人类传播微生物53cGMP培训2.10 Microbe Prevention微生物预防qMICROBES need water to live and cannot be in too high or too low temperature. Microbes are also susceptible to many chemicals.q微生物的生存需要水，它们不能在高温或低温中存活，而且对很多化学品也很敏感qMICROBES thrive in dirt of organic substances and are carried by dust in the air. q微生物在有机泥土中存活旺盛，并且通过空气进行传播qHUMAN are the main carrier of microbes in the manufacturing plant after the places are made clean. q在干净的厂区，人类是微生物的主要载体qWith the above principles, preventing microbes in the plant areas is by根据上面几点，厂区里微生物的预防可通过以下方面:Keeping the Workplace DRY and CLEAN保持车间干燥、洁净TRAIN the operators in personal cleanliness, wear proper clothing and hair protection, and handling products with gloved hands and correct techniques.操作人员要注意个人清洁，穿着得体，头发不能外露，处理产品时要戴手套，并使用正确的技术54cGMP培训2.11 Microbe Prevention in Products产品中的微生物预防 The technologies to prevent microbes from growing in products are预防产品中的微生物生长技术有:qPRESERVATION预防 To keep foods and drugs from allowing microbes growing on/in it, by drying, refrigerating, freezing, adding high salt/sugar/acid, or adding preservative chemicalsq为了预防食品和药品的表面或里面没有微生物生长，采取干燥，冷却，冷冻，添加高盐/糖/酸或防腐剂等措施qSANITATION卫生 To reduce the number of bacterial by cleaning and killing using chemicals (sanitants), and leaving the area/equipment DRY and PROTECTED from dust and human touching.通过清洁，使用化学品杀菌，保持生产区域/设备干燥而且没有灰尘及人员接触的方式来减少细菌的数量qDISINFECTION 消毒 To reduce harmful microbes by using chemical killing microbes, but not harming human body parts or equipment.通过使用化学杀菌剂来减少有害的微生物，但是不能危害到人或设备55cGMP培训2.12 Complete Elimination完全消灭qEliminating microbes from product, objects, or space is called STERILIZTION. Methods are:q把产品，物体或空间中的微生物消灭掉被称为灭菌，方法有：qSTEAM STERILIZTION 蒸汽灭菌法 steam at high pressure, e.g. Autoclave.高压蒸汽，举例说：高压锅qDRY HEAT STERILATION干热灭菌法 air at high temperature, e.g. Oven.高温气体，举例说，烤箱qGAS STERILIZATION气体灭菌法 gas with killing power, e.g. ETO (ethylene oxide) and hydrogen peroxide gases.有杀伤力的气体，举例说ETO （环氧乙烷 ）和过氧化氢气体qIRRADIATON STERILIZATION放射灭菌法 high power electro-magnetic waves, e.g. gamma rays.高杀伤力的电磁波，如伽马射线qFILTRATION STERILIZATION过滤灭菌法 exclude but not kill the microbes; 0.22 micrometer pore size filters.去除但不杀死微生物，0.22微米孔径过滤器56cGMP培训VALIDATION PRINCIPLES & PRACTICES验证法则和规范57cGMP培训3.1 What is Validation什么是验证58cGMP培训3.2 What are IQ, OQ, PQ什么是IQ, OQ, PQ59cGMP培训3.3 Definition of Validation验证的定义qDEFINITION定义: To establish documented evidence that a process or system will do what it purports to do.q建立工艺或系统要做什么的文件性证据qRATIONALE基本原理: The adherence to GMP does not assure product quality unless the systems or processes are correctly designed to consistently produce products meeting the desired quality. q执行GMP并不能保证产品质量，除非系统或工艺的设计符合达标质量的要求qHISTORY历史: In the late 1970s a companys venous infusion sterile product was contaminated on the cap with microbes. This prompted the FDA requiring “validation” of sterilization processes. Followed, throughout the years, by validation of water systems, solid dosage form process validation, computerized systems, aseptic filling validation, equipment cleaning validation, analytical method validation.q70年代末期，一个厂家的无菌静脉注射产品被微生物污染，这促使了FDA采取了无菌工艺验证，后来的一些年里，形成了水系统验证、固体制剂工艺验证、计算机系统验证、无菌填充物验证、设备清洁验证、分析方法验证。60cGMP培训3.4 Validation Items Diagram验证项目图标61cGMP培训3.5 Validation Principle -1验证法则qPROSPECTIVE Validation前瞻性验证: for a process where the final test results cannot reliably indicate the performance of the process, (e.g. steam sterilization).用于最终结果不能可靠反映工艺运行的工艺（如蒸汽灭菌法）qRETROSPECTIVE Validation回顾性验证: for a process where final test results can reliably indicate the performance is usually preliminary validated prospectively, followed by reviewing historical data (water system, long marketed solid dosage forms)q用于最终结果能够可靠反映运行的工艺，通常是根据历史数据审阅，事先对工艺进行前瞻性验证（水系统，长期上市的固体制剂）qCONCURRENT Validation同步验证: for a processes with reliable test results and are of limited validation scope is validated during the manufacturing of products (single lots for clinical study).q用于有可靠性结果和有限的验证范围的工艺，验证在产品生产期间进行（留出一批用于临床研究）62cGMP培训3.6 Validation Principle -2验证法则qRISK BASE风险基础: Validating every types and of every dose levels of products is not economical feasible; therefore validation is done on selected products. 把每种类型和每种剂量标准的产品都进行验证从经济上讲是不可行的，因此，只对选定的产品进行验证。q The selection is based two approaches根据两种方法进行选择:a) REPRESENTATIVE Products, using Bracketing and Matrix methods, and对于有代表性的产品，采用交叉和矩阵法b) WORSE CASE Process Parameters, selecting parameters at the edge of Operating Range.对于更坏的工艺参数选择，在运行范围的边沿进行63cGMP培训3.7 Validation Principle -3验证法则qThe LIFE-CYCLE concept of Validation consists of 验证的生命周期理念包括. qDQ设计确认: The design of the process is suitable for its use.q 是对工艺的设计适于使用的确认qIQ安装确认: The hardware, e.g. facility & equipment, used are installed as designed.是对硬件，如设备实施按照设计安装的确认qOQ运行确认: The facility & equipment operates as designedq 是对设备设施按照设计运行的确认qPQ性能确认: The processing of input materials using the facility & equipment, and operated by trained personnel result in products meeting the specifications. q 通过设备设施及合格人员的操作把进料变成符合规格产品的工艺确认qCQ持续性确认: The process is continuously maintained & monitored, changes are controlled, and the process is periodically re-validated (to be “In its validated state”). 持续对工艺进行维持和监测，变更受到控制，工艺要定期复验证（保持在有效状态）Q=qualification, D=design, I=installation, O=operation, P=performance, C=continuous64cGMP培训3.8 Validation 验证= Process Knowledge工艺知识qThe main OBJECTIVE of Validation is to gain process knowledge, with which to control process variability.q验证的主要目的是为了获得用于控制工艺可变性的工艺知识。qThe BENEFITS of process knowledge are 工艺知识的用途. Increases the probability that the manufactured products are acceptable.提高生产产品符合要求的可能性Reduces dependency on in-process and finished product testing.减少对内控标准和成品检验的依赖性Reduces costs due to scrap and rework.减少废料和返工的成本Expands process knowledge beneficial for trouble shooting, improvement, automation, and PAT扩展对问题解决，改进，自动化和PAT 有用的知识(Process Analytical Technology工艺分析方法)65cGMP培训3.9 Validation Master Plan验证主计划qDesign a VALIDATION MASTER PLAN to consists of 验证主计划包括：COVER PAGE 封面 title and approvals标题和批准POLICY & ORGANIZATION 方针和机构- company policy, validation organization & assignment of responsibilities公司方针，验证机构及职责OVERVIEW of what needs to be validated and steps to conduct validation.关于需要验证的事物和验证工序的提纲ITEM BY ITEM description of validation approach, methods and acceptance criteria (for qualification of Facility, Utilities & Equipment, validation of Water System, Manufacturing Processes, Equipment Cleaning, Analytical Method, & Computerized Systems)验证方法的逐条描述，方法和可接受标准（对设备，公用设备设施，水系统验证，生产工艺，设备清洁，分析方法及计算机系统的确认）VALIDATION SUPPORTS 验证支持(SOPs, change control变更控制, personnel training人员培训, process maintenance / monitoring工艺维持/监测, revalidation再验证). 66cGMP培训3.10 Validation Documentation验证文件67cGMP培训3.11 Plan Execution -1计划执行qVALIDATION TEAM验证组 - organize & assign responsibilities. 组织分配任务(Most big firms have a validation group. Some small firms use contractors大多数大公司有验证小组，一些小公司用承包商).qSTUDY DIRECTORS研究主管 - it is a good practice to assign a focal person for each validation study. q每一项验证研究都分配一个主要人员，这是很好的习惯qDETERMINE测定 list the systems to be qualified / validated including the components, operations, procedures, parameters to be measured, analytical methods, and Acceptance Criteria of measurements.把要确认/验证的系统列出来，包括成分，运行，规程，要测量的参数，分析方法和测量的可接受标准方面qVALIDATION PROTOCOL 验证方案 to be prepared with validation work plan and scheduling.按照验证工作计划和安排编写qCalibrate all measuring instrument, and qualify/validate analytical methods to be used. 把所有的测量仪器进行校准，并把要使用的分析方法进行确认/验证。68cGMP培训3.12 Plan Execution -2计划执行qCONDUCT实施 the validation according to protocols within the time frame planned.按照方案在计划时间内进行验证qANALYZE分析 the resulting data, observations, and deviations from the protocol.从方案中所得的结果数据，观测，偏离qRESOLVE偏离度 deviations to judge validity of the study.用于判断研究有效性的偏离qEVALUATE分析 the results against Acceptance Criteria, and determine if the process is “Validated”.q背离可接受标准的结果及测定工艺是否有效qREPORT 报告 the results and conclusion and obtain approvals, store and make available for inspection. q结果，结论，获得的批准，储存，检查的有效性qASSIGN分配 the need of next re-validation. 下一个再验证的需求69cGMP培训3.13 Water System Validation outline水系统验证-概要qAssure that the system has been IQ/OQ-ed; Study the water systems & analyze risks of failure to water quality and set control and monitoring point.q确保系统已经进行过安装和执行确认，研究水系统及分析水质量系统失误，建立控制和监测点qEstablish sampling points to monitor the purification systems and points of use.q建立净化系统及使用点监测的取样点qPerform extensive sample testing for 2 to 3 month.q样品试验执行2-3个月qEvaluate the results; make correction to the system if Acceptance Criteria are not met.q分析结果；如果不符合可接受标准，进行更正qIf Acceptance Criteria are met, reduce the sampling points and continue as regular monitoring of the system.q如果符合可接受标准，减少取样点，继续系统的常规监测qAfter one year of system operations/maintenance, and water usage, review the one year data to conclude the validation study.q进行系统执行/维持，水使用法一年后，审阅这一年内的数据以给验证研究做出结论70cGMP培训3.14 Manufacturing Process Validation outline生产工艺验证-概要qStudy the product types, dosage, and packaging.q研究产品型号，剂量和包装qSelect representative, worse case processing of the products by bracketing/ matrixing.q选择有代表性的，更坏的工艺通过交叉/矩阵方法选择qMake sure that the facility, utilities, and equipment are IQ/OQ-ed; and the operators are trained.q确保设施，公用设施，设备都进行过安装/执行确认，且操作者都经过培训。qPrepare process validation protocols based on Batch Records.q在批记录基础上准备工艺验证方案qExecute the protocol by recording the process parameters as the products are manufactured, including in-process, and finished product testing.q用和已生产产品相同的方法，记录工艺参数来实施文件，包括内控标准，成品检验qAnalyze results and evaluate against Acceptance Criteria; Determine the disposition of the study.分析偏离可接受标准的结果和评估，测定研究的部署qRepeat on other lots of the same product; the process is validated when three consecutive studies of the SAME lots all meet Acceptance Criteria.在同种产品的其它批进行重复，当同批的三个连续研究都符合可接受标准时，工艺有效71cGMP培训3.15 Equipment Cleaning Validation outline1设备清洁验证-概要qThe OBJECTIVE of cleaning validation is to assure that the first product A is not carried over to the next product B higher than an acceptable level (there is no concern for dedicated equipment).q清洁验证的目的是为了确保在下一个高于可接受产品标准产品B的生产中不会出现前一个产品A（不涉及专用设备）72cGMP培训3.16 Equipment Cleaning Validation outline2设备清洁验证-概要qStudy the equipment to be cleaned and products made with the same equipment.q研究要清洁的设备和用同一设备生产的产品qStudy the surface contact configuration of the equipment, measure the surface area, and evaluate the ease of cleaning.q研究设备的接触面构造，测量其表面积，评估清洁的难易程度。qStudy the method of cleaning, the chemicals used for cleaning, and the training/experience of the cleaning operators.q研究清洁的方法、用于清洁的化学品和清洁人员的培训/经验。qSelect representative products: the Largest dose of product A and the smallest dose of product B (worse case conditions).q选择有代表性的产品：最大剂量的产品A和最小剂量的产品B（较差的情况下）73cGMP培训3.17 Equipment Cleaning Validation outline3设备清洁验证-概要qAfter the cleaning, dis-assemble the equipment and swab the representative surfaces.q清洁后，把设备拆卸，擦洗个别的面qThe swabs are analyzed for the Active Drug of product A.q把抹布进行产品A活性药物分析qCalculate the milligram of Active A left on the surfaces (Need to know: one-swab area, % recovery of swabbing, the total product contact surface)q计算残留在表面的活性A的毫克数（需要知道的是：一块抹布的面积，通过擦洗回收的百分数%，总的产品接触面）74cGMP培训3.18 Equipment Cleaning Validation outline4设备清洁验证-概要qFinally, calculate the concentration of the A in product B case (Need to know the volume of product B).q最后，计算产品A在产品B中的浓度（需要知道产品B的体积）qNote: The smallest batch size of B is the worse case.q标注：产品B的批号最小时情况最坏qTWO Acceptance Criteria is used of concentration of A in B, whichever is the smaller:q产品B中的产品A浓度的两种可接受标准，选择较小的一个：(1)A is NOT MORE THAN the 1/1000 the maximal daily dose of B. A不大于B的最大日常剂量1/1000(2)A is NOTR MORE THAN 10 ppm of B. A不大于B的10 ppm qIn practice, the Acceptance Criteria is calculated to be expressed as mg of A per swab assay.q实际中，可接受标准被计算表示成每块抹布的A含量；mg75cGMP培训HOW TO PREPARE FOR REGULATORY INSPECTION如何准备常规检查76cGMP培训4.1 The USA-FDA -1Is one of the government agencies, established to enforce the law, Food & Drug Act, passed by Congress in 1906是一个政府机构，为了执行法律和食品&药品条例而建立的，由议会在1906年通过. revised in 1938 to the . revised in 1938 to the Food, Drug, and Cosmetic Act Food, Drug, and Cosmetic Act 19381938年进行了食品，药品和化妆品条例修订年进行了食品，药品和化妆品条例修订77cGMP培训4.2 The USA-FDA -2qThe FDA is organized intoqFDA有以下几个机构： OC = Office of Commissioner专员办公室CBER = Center for Biologics Evaluation and Research 生物制品评价和研究中心CDER = Center for Drug Evaluation and Research 药品评价和研究中心CDRH = Center for Devices and Radiological Health 器械和辐射健康中心CVM = Center for Veterinary Medicine兽药中心CFSAN = Center for Food Safety and Applied Nutrition食品安全和应用营养中心ORA = Office of Regulatory Affairs法律事务部qNew pharmaceutical approval and marketed product surveillance are conducted by CDER.新药批准和上市产品监督由CDER执行qRegulatory enforcement (e.g. regulatory inspection) is conducted by ORA.q法规要求由ORA执行（如常规检查）Regulations are published in 21 CFR (code of federal regulations No. 21 is assigned for the FDA)法规出版在21 CFR（联邦法规代码 No. 21，FDA分配）78cGMP培训4.3 FDA Foreign EnforcementFDA对国外的强制要求qMISSION of the FDA is to . FDA的使命是to protect and promote the health of the citizen保护并提高人民健康to ensure that: foods are safe and wholesome and sanitary; human and veterinary drugs, biological products and medical devices are safe and effective; cosmetics are safe; and electronic products that emit radiation are safe; and regulated products are honestly, accurately, and informatively represented.确保：食品是安全、卫生、有益健康的；兽药，生物制品和医疗器械是安全和有效的；化妆品是安全的；有辐射性的电子产品是安全的；常规产品具有公开、准确、广泛的代表性。qThe FDA does not deal directly with foreign drug manufacturers, but through the sponsoring US company or a US agent (including plant inspection).qFDA不直接处理国外药品生产厂家的事情，而是通过美国赞助公司或美国的代理商进行（包括现场检查）qAny foreign companies can deposit a Drug Master File with the FDA, but will only be reviewed for the benefit of a sponsoring US company without disclosing trade secrets (Freedom of Information Act). FDA要求国外的任何一个厂家须存放一份DMF文件，仅在美国赞助公司要使用这种药物的时候才进行审阅79cGMP培训4.4 FDA Plant Inspection -1现场检查qBEFORE: find info about plant, purpose of inspection, contact local authority and the inspected plant.q检查前：要知道厂区信息和检查目的，联系好地方当局，准备好进行检查的厂区。qFIRST DAY: Show form 482 and credential and indicate purpose and identify company representative. q第一天：拿出482表格和委托书，表明目的，对有代表性的公司进行鉴别qDURING在期间Tactful得体的, persuasive有说服力的, patient有耐心的, diplomacy外交的.Personal safety and protect company property.保护好人员安全和公司财产Not to use company product on site.不要在现场使用公司产品Sample collection with form 484; End of day advice. 用484表格进行样品汇集；结束当日计划Objectionably & timely record potential problems.有目的地且即时地记录可能问题NOT report opinion, conclusion, characterization, & quotation of regulation during inspection, consult how to be done. 不要报告观点，结论，描述和常规的报价，商量好如何去做Follow Code of Ethics要按照道德规范去做 In Chapter 5 of IOM (Inspections Operations Manual) of ORA q 在ORA的第五章IOM (检查手册）80cGMP培训4.5 FDA Plant Inspection -2FDA现场检查qLAST DAY最后一天: Discussion of findings with highest ranking manager of objectionable situations listed in Form 483 and the expected response (to be frank, courteous, & responsive). q和最高级别的经理讨论483表格中列出的一些问题，采取应该有的举动（坦率，有礼貌的做出回答）qAFTER: Preparation of EIR (Establishment Inspection Report) for internal documentation with a copy to the firm.q结束后：准备内部文件EIR（设施检查报告），公司留有备份。qREGULATORY ACTIONS常规行为:WARNING LETTER: pointing out repeated uncorrected objections and the consequences if not corrected to be responded within 15 days.警告信：指出重复未纠正的缺陷和15日内没有更正的结果。INJUNCITON命令: stopping the manufacturing operations.停止生产操作SEIZURE查封: confiscating products被没收的产品PROSECUTION起诉: criminal actions directed against responsible individuals.被检举出来的犯法行为(For Foreign Inspection: Denial of Sponsor Requests对于国外检查：拒绝赞助者请求). 81cGMP培训4.6 EUDRA欧盟药品法规机关& EMEA -1The European Union was establish by the Treaty of Maastricth in 1992 by 12 members (15 in 1995, 25 in 2004)欧盟是1992年由12个成员国通过马斯特里条约成立的（1995年15个，2004年25个）82cGMP培训4.7 EUDRA欧盟药品法规机关& EMEA -2qEU is governed by three interdependent bodies: the Parliament, the Council, & the Commission with the Court of Justice.q欧盟是由三个相互关联的部分统治：国会，理事会及法院qUnder the European Commission are 40 Directorate Generals; one is DG Enterprise, one of the units, F2 is Pharmacos (Pharmaceutical & Cosmetics).q欧委会下面有40个理事；一个是DG 企业，其中一个单位， F2是制药和化妆品协会qEarly in 1965, the European Economic Council established EUDRA (European Union Drug Regulatory Authority), triggered by the Thalidomide incident.In 1992 it is incorporated under Pharmacos.q在1965年早期，欧洲经济理事会建立了EUDRA（欧盟药品法规机关），源于镇静剂事件。1992年制药和化妆品协会成立。qIn 1995, to unify the Marketing Authorization processing, EMEA (European Medicinal Agency) was established; It is an independent body but works closely with EUDRA.q在1995年，为了统一上市授权， EMEA (欧洲药品评价局）成立了，这是一个独立的部分，但是服务于EUDRA83cGMP培训4.8 The EUDRA欧盟药品法规机关qEUDRA使命 mission:assure a high level of protection of public health确保大众健康更高一级的保护bring about a single market in pharmaceutical打造制药方面的单一市场foster a stable and predictable environment for pharmaceutical innovation.为药物研发打造一个稳定可预测的环境qEUDRA tasks covers: EUDRA 业务范围Labeling标签 & advertising广告Marketing Authorization approval 上市批准(on EMEAs advice参考EMEA建议)Established Directive 2003/94/EC, Volume 4 Medicinal Product for Human Veterinary Use GMP.建立指示2003/94/EC，4 卷-人兽药使用的GMPqEMEA 使命mission:Coordinate scientific evaluation of safety, efficacy, & quality of products.产品安全，功效及质量评估Establish coordinated centralized procedure for marketing authorization investigation, and regulatory inspection.建立上市核准调研，常规检查的集中手续。84cGMP培训4.9 EMEA Plant Inspection -1 EMEA 现场检查qPURPOSE of inspection is determine that检查的目的是为了测定:Elements of the quality system are effective and suitable to achieve compliance with GMP.质量系统的原理是有效的，且适于达到GMP标准Products comply with master batch formula approve by the licensing authority.产品符合许可部门批准的主料方qPERFORMED by the Competent Authority of the EU member state, coordinated by EMEA.q由EU成员国权威人士执行qFOREIGN MANUFACTURER for importation requires equivalent GMP & inspection will also be Competent Authority of the State and coordinated by EMEA.q用于进口的国外生产厂家需要通过GMP 及主管当局的检查qGUIDELINE TO INSPECTION检查方针: Conduct of Inspections of Pharmaceutical Manufacturers (similar to FDAs)药品生产者的检查指南（和FDA检查指南类似）85cGMP培训4.10 EMEA Plant Inspection -2 EMEA 现场检查qOPENING MEETING & CONDUCT OF INSPECTIONq公开会议及检查指南Inform the firm in advance for an inspection检查前提前通知公司Opening meeting with management and key persons, who are to explain quality policy and systems.和管理者及解释质量方针、系统的主要人员一起召开公开会议Strive to create positive educational and motivational atmosphere.努力创造积极的教育、动机氛围。Should answer questions but avoid entering the role of a consultant.要回答问题，但要避免进入咨询者的角色qFINAL MEETING最终会议Agree with firm on facts & observations; indicate necessary corrections and schedule.公司对于事实& 观察应达成一致，说明必要的修改和时间表。In serious cases, immediate actions should be taken.对于一些严重情况，应立即采取措施Inspection检查q INSPECTION REPORT summarize findings and concludes levels of compliance with GMP.检查报告要对发现的问题作出总结，并对和GMP的 一致程度作出结论。86cGMP培训4.11 EUDRA Regulatory Actions欧盟药品法规机关的常规行为qEUDRA/EMEA can stop the process of giving GMP license or approving the Marketing Authorization.q欧盟/EMEA可以暂停能够通过GMP认证或获取上市核准批准的工艺qEMEA is drafting Vol 9, on Pharmacos Vigilance regulations and the regulatory actions in cases of product failures.qEMEA起草了药理学不良反应法规，9卷及产品故障的常规措施。87cGMP培训4.12 WHO, PIC/S, ISO, USP, EP, ICHOther regulatory bodies and standard institutions其它法规体系和标准机构:qWHO: World heath Organization assists GMP in developing countries.世界卫生组织制定了发展中国家实施的GMPqPIC/S: Pharmaceutical Inspection Convention & Pharmaceutical Inspection Cooperation Scheme, inspection validity agreement between member countries.q制药检查草案，成员国间达成的有效的一致检查意见qISO: International Standard Organization, issued quality system ISO 9000 and many other standards for e.g. clean room specificationsq国际标准化组织，发布了质量体系ISO 9000和其它很多标准，如洁净室规格qUSP: United States Pharmacopoeia since 1803; monographs of medicines and testing standardsq美国药典，从1803年开始使用，药学专论和检验标准qEP: European Pharmacopoeia, similar to USP英国药典，和USP相似qICH: International (USA-EU-JAPAN) Conference on Harmonization of pharmaceutical quality standards in the areas of:q关于制药质量标准调和化的国际会议（ USA-EU-JAPAN) Q quality质量; S safety安全; E efficacy效率; M miscellaneous其它各项88cGMP培训4.13 Preparation for Inspection -1检查的准备qPreparing a regulatory inspection is based on SUBSTANCE and APPEARANCE, both as important, but Substance is FIRST.q以本质和表面为基础，准备常规检查，两者都很重要，但是本质是最重要的qSUBSTANCES本质Upper management is committed to Quality.质量要有很好的管理CGMP quality systems are established and fully & correctly implemented.CGMP质量系统完全建立并正确使用Everyone working and managing product manufacturing and controls are trained on CGMP and perform the tasks accordingly.每位工作，管理产品生产和控制的人员都要受到CGMP 培训，并按照相应的CGMP 去执行任务Establish internal audit (self inspection) program and campaign periodic audit.建立内部审计（自我检查）计划和定期审计Establish and maintain documentation storage system.建立并维持文件储存系统Establish Inspection Response Team and rehearse regulatory mock inspections.成立检查审计组并预先进行常规模拟检查89cGMP培训4.14 Preparation for Inspection -2检查的准备qAPPEARANCE表面The plant ground, facilities (manufacturing, offices, and labs) are well-kept, organized and clean.工厂地面，设施（生产，办公室和实验室）要做好保持，组织和清洁工作People are in work uniform and are in proper places and act properly.人员要穿工作制服，并且要在适当的位置扮演适当的角色。Managers and workers are knowledgeable of their tasks and the related GMP.经理和工人要对他们的任务和相关GMP有很好的了解Available updated Quality Manual, Manufacturing Manual, and QC Lab Manual as gateway to all other documents.通过可用的最新质量手册，生产手册，QC实验室手册可以了解其它所有文件Available a comfortable isolated room for the inspector to work, to meet and ask questions.要有一个舒适的独立房间给检查人员进行工作，接见和问问题用Available a comfortable conference room for final discussion of inspection findings. 要有一个舒适的会议室用于检查所发现问题的最终讨论90cGMP培训4.15 Inspection Response Team检查审计组qORGANIZATION 组成- Headed by QA Person; members are有QA人员领到，组员有:QA person QA人员Plant Manager (highest responsible person in plant)总经理（工厂的最高负责人）Selected managers / supervisor from each operation从每一操作中选取经理/监督人Legal council of the company公司的法律顾问qRESPONSIBILITIES 职责QA person coordinates the inspection and is the company representative to lead the inspector.QA人员安排检查，并作为公司代表来引导检查人员Selected managers/supervisor prepare the area for inspection and provide information and documentation.选定的经理/监督人员把进行检查的区域贮备好，并提供信息和文件Plant Manager and Council attend final meeting & commit to GMP correction.总经理和法律顾问参加最后的会议& 答应按照GMP进行修改91cGMP培训4.16 Conduct of Inspection检查指南qRECEIVE接待 Upon arrival take the Inspector to the Inspector Room. QA receives the purpose of inspection and immediately alert the team. QA accompany the Inspector ALL the time.q当检查人员来到时，把他们接到住处。QA知道检查目的时，立即提醒全体组员，而且要一直陪着检查人员qCONFINE限制 Bring the information requested by the Inspector into room and answer questions there.q 把检查人员提出的问题带到指定房间里面回答qCoordinate 整理 The team coordinate the gathering of oral or written information promptly.q立即把口头或书面的信息整理出来qCONTAIN During inspection of plant areas, confine the Inspector to the area inspected in proper clothing.q 在生产区域检查期间，使得进入区域的检查人员穿上合适的衣服qCONCLUDE/CLARIFY做出结论/阐明 In the last day meeting, understand clearly all cited findings, correct any mis-observations. Make NO promises of correction at that time.q在会议的最后一天，把发现的所有问题理解清楚，改正任何观察到的过失，但当时不要做出任何承诺。92cGMP培训4.17 The DO/DONT in Inspection检查中的能/不能qTrain the team, the managers, and the operators of the DO and DONT when the plant areas are inspected.q当检查生产区域时，对组员，经理和操作人员进行能和不能培训qWhen an operation is inspected DO continue working normally.q当操作被检查为能时，继续正常工作qWhen asked, DO answer the question to the point, DONT ramble. If the question is not clear, DO ask for clarification. If you cannot answer DO just say “I do not know”, the QA person will help. DONT make things up.q当被问时，一定要扼要地回答问题，不要随意，如果问题不清楚，一定要问清楚，如果你不会回答，只能说“我不知道”，QA的人可以帮忙回答，不要拼凑。qWhen an objectionable situation is observed, DONT give reasons or apologize, DO assure the observation is correct.q当观测到负面情况时，不要给出理由或道歉，一定要确保观测是正确的qDO be calm, polite, professional, and DO smile.q一定要保持冷静，有礼貌，专业和微笑93cGMP培训4.18 Respond to Inspection对检查的回复qWhile memories are fresh, team discuss the findings and how to remedy the shortcomings. q趁刚刚记住，小组讨论出现的问题及如何补救缺陷qFormulate a GMP remediation plan and timeline. Consult with pertinent areas and person on the feasibility of accomplishing within the timeline.q做出GMP补救计划和时间，在计划时间内，咨询相关人员完成计划。qDraft a response letter including the plan and timeline. Describe the corrective actions point-by-point correspond to the each finding.q起草一份回复信，包括计划和时间，点对点的描述和每个问题相关的纠正措施qWhen the official EIR (Establishment Inspection Report) is received from the FDA, verify the suitability of the response letterq当职员从FDA拿到EIR (设施检查报告）时，检验回复信的可行性。qAllow the Plant Manager and company Legal Council to approve the letter, and mail the letter promptly.q允许总经理和法律顾问批准回复信，并立即把信寄出。qShare with every one in the plant about the inspection and the remediation plan.厂区里的每个人都要参与检查和补救计划。94cGMP培训ANDA & BIOEQUIVALENCY STUDY 简略新药上市申请&生物等效性研究95cGMP培训5.1 The Waxman-Hatch Act非专利药Waxman-Hatch法案qIn 1984, Congress passed - Drug Price Competition & Patent Term Restoration Act. Also known as Waxman-Hatch Act.q1984年，议会通过了药物竞价及专利权恢复法案，也叫做Waxman-Hatch法案qThis Act expedites the availability of less costly generic drugs by permitting FDA to approve applications to market generic versions of brand-name drugs without conducting costly and duplicative clinical trials.q对于那些品牌药,这个法案允许FDA加快批准其价格低廉的非专利药上市申请,而不需要通过昂贵而且手续复杂的临床试验.qAt the same time, the brand-name companies can apply for up to five additional years longer patent protection for the new medicines they developed to make up for time lost while their products were going through FDAs approval process.q同时，品牌药厂商可以再申请最多五年的新药专利保护期以弥补产品通过FDA批准所耗费的时间96cGMP培训5.2 What is ANDA什么是ANDAqGeneric drug applications are termed abbreviated because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness.q非专利药申请用简化的术语表示，因为它们通常不需要临床前（动物）和临床（人）数据来建立安全性和有效性。qInstead, generic applicants must scientifically demonstrate that their product is bioequivalent (i.e., performs in the same manner as the innovator drug).q相反的，非专利药申请者必须科学阐明他们的产品具有生物等效性（如：按照与创新药相同的方式进行）qOne way scientists demonstrate bioequivalence is to measure the time it takes the generic drug to reach the bloodstream in 24 to 36 healthy, volunteers, giving the rate of absorption, or bioavailability, of the generic drug, compared to that of the innovator drug.q科学家阐明生物等效性的一种方式是：在24-36个健康的自愿者中，测量非专利药到达血流的时间，通过和创新药物进行比较，得出非专利药的吸收率或生物利用度qThe generic version must deliver the same amount of active ingredients into a patients bloodstream in the same amount of time as the innovator drug. 非专利药中能进入病人血流的活性成分数量必须和创新药物的一样多97cGMP培训5.3 Product Development产品开发98cGMP培训5.4 Pharmaceutics & Pharmacokinetic药剂学&药物代谢动力学qPHARMACEUTICS is the science concerning:药剂学是包含下面内容的科学Physical/chemical property of drug药品的物理/化学特性The characteristics of dosage form to deliver the drug制剂的特性The physiology of the body in absorbing, distribution, metabolism, and elimination of drug to design a dosage form to deliver the drug to the site of action in the body.有关药品吸收，分布，代谢，去除的人体生理学PHARMACOKINTICS is a branch of pharmaceutics concerning the quantitative study of the absorption, distribution, metabolism, and excretion of the drug metabolite in the body. 药代动力学是包含药品代谢物在人体中如何被吸收、分布、代谢和排泄的药剂学分支qPHARMACODYNAMICS is the study how drug biochemically interact with cells and organs; thus, while a drug heals a disease. q药效学是针对药物如何对细胞、器官进行作用的研究，因此，药品可以治愈疾病99cGMP培训5.5 Passage of Drug in the Body药品在身体中经过的通道100cGMP培训5.6 Bioavailability Study药物的生物利用度研究qBioavailability (BA) studies focus on determining the process by which a drug is released from the oral dosage form and moves to the site of action.q药物的生物利用度研究集中在对过程的测定，即药品从口服后到发挥作用的位置qBA data provide an estimate of the fraction of the drug absorbed, as well as its subsequent distribution and elimination.qBA数据提供了药品吸收部分及其后来的分布和去除的评估qBA can be generally studied by selecting a group of human subjects who will be taking the drug, and over time, blood or urine is taken from the subject and analyzed for the drug and/or metabolites concentration in the blood serum or urine, and create a systemic exposure profile. qBA一般通过选择一组人进行实验，待他们服用药品到达一定的时间后，把他们的血液和尿液进行采样，并分析药物和/或代谢物在血液或尿液中的浓度，来达到全面了解这样的一种方式进行研究qStudy shows that in VIVO bioavailability correlates well with data of in VITRO Disintegration and Dissolution studies of the same product.研究表明VIVO生物利用度研究和同种产品的VITRO分离和溶解研究密切相关101cGMP培训5.7 Disintegration & Dissolution分离和溶解qMean plasma level of a drug of 10 personscorrelates well with disintegration & dissolution. q进行药物实验的十个人表明，他们的平均血浆水平和药物的分离及溶解密切相关102cGMP培训5.8 Bioequivalence Study生物等效性研究qBioequivalence (BE) studies are to establish that two drug products containing the same drug ingredient and of the same dosage form are equal in its bio-availability in the human body.q生物等效性研究是为了证明含有相同成分和制剂的两种药品在人体中有相同的生物利用度。qBE between two products is done on altered brand-name product with NDA, and for submission of generic products wit ANDA.q两种产品的BE 是为了改变后的品牌药的新药上市申请和非专利药的简略新药上市申请 qAlso, BE is important for changes after the products have been approved for both NDAs and ANDAs products.q同时，BE对于产品的NDAs 和 ANDAs批准后的变更很重要 qIn BE studies, an applicant compares the systemic exposure profile of a test drug product to that of a reference drug product.q在BE研究中，申请者把试验药品和参照药品进行全面的比较qFor two orally administered drug products to be bioequivalent, the active drug ingredient or active moiety in the TEST product should exhibit the same rate and extent of absorption as the REFERENCE drug product. q对于进行生物等效性研究的两种口服药品，试验药品的药物活性成分或活性团的吸收率和范围应和参照药品的相同103cGMP培训5.9 What is EqualqThe common design of Bioequivalent Study is called Randomized two-way Cross-over method.q生物等效性研究方法通常被称为随机双向交叉法qTwenty four to thirty six healthy persons are randomly separated into two groups. When Group-1 takes the TEST drug, Group-2 takes the REFEREMCE drug. After one week of “Washout Period” the experiment is repeated by Group-1 taking the REFERENCE and Group-2 the TEST.q随机抽取24-36个健康人分成两组，当第一组服用试验药品时，第二组服用参照药品，一个星期的洗脱期后，两组服用的药品交换重复实验qThe group average time course of drug/metabolite concentration in the blood / serum of the TEST and REFERENCE studies are presented in graphs.q用图表表示试验和参照研究过程中药品/代谢物在血液/尿液中的浓度qThe three parameters: peak time, peak height, and Area-under-curve, are statistically analyzed to determine the significance of differences, and conclude the BIOEQUIVALENCY between the Test and Reference drugs. (21 CFR 320)q三个参数：对“峰时间，峰高，曲线下的面积”进行统计研究，以测定差值的重要性，对试验和参照药品的生物等效性做出推论. (21 CFR 320)104cGMP培训5.10 Unequal Bioavailability -1不相等的生物利用度105cGMP培训5.11 Unequal Bioavailability -2不相等的生物利用度 106cGMP培训5.12 ANDA Application简略新药上市申请qSelecting what product to make as generic and how to apply for the USA-FDA or European Union require special expertise to avoid mistakes and waste time.q对非专利产品的选择和如何申请USA-FDA 或 European Union-EMEA需要专家指导，以避免出现失误和浪费时间qApplication for ANDA in the USA is governed 21 CFR (codes of federal regulations) part 314. The documents to be submitted are:在美国， ANDA的申请是根据21 CFR (联邦法规代码）314部分进行的，需要递交的文件有：NDA application formNDA申请表; Table of contents目录; Basics要素: information on the generic and the brand-name product as the basis for bioequivalence; 用作生物等效性实验的非专利药和品牌药信息 Conditions of product use产品使用的条件; Active ingredients;活性成分 Route of administration管理途径; Bio- equivalence studies生物等效性研究; Labeling标签; Chemistry， Manufacturing & Control化学，生产及控制; Samples when asked;列举的样品 Patent certification 专利证明(to show meeting one of the 4 submission conditions为了显示满足4个递交条件中的一个) qIt usually takes two or more years for approval.申请一般需要二年或更长时间107cGMP培训5.13 NDA versus ANDA 108cGMP培训5.14 Application Review对申请的审阅qCDERs Manual of Policy and Procedure (MaPPs) provides official instructions for internal practices and procedures followed by CDER staff to help standardize the drug review process and other activities, both internal and external. Chapter 5200 of the Manual is for Generic Drugs.q药物评价与研究中心（ CDER）的方针和规程手册为CDER职员提供了内部方针和规程指导，用于帮助标准化药品审阅过程和其它内部及外部活动。 手册的第5200章是针对非专利药的qThe following FDA guidance describes how a Bio-equivalent study can be conducted satisfying the FDA requirement for filing NDA or ANDA:q下面的FDA指导描述了如何进行生物等效性研究才能符合FDA对NDA 或 ANDA的要求q GUIDANCE FOR INDUSTRY行业指南 Bioavailability and Bioequivalence Studies for Orally Administered Drug Products General Consideration , July 2002 口服药品的生物利用度和生物等效性研究-总的事项， 2002.07 109cGMP培训Attachment附件Example1-Grandfather-SOP总SOPExample2-SOP-ChangeControl变更控制SOPExample3-SOP-ChangeControl-Form变更控制SOP列表Example4-Validation-Master-Plan验证主计划Example5-Equipment-IOPQ-Protocol设备IOPQ验证方案Example6-Process-Validation-Worksheet工艺验证工作表110cGMP培训