cGMP培训讲解学习.ppt

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Simon Rusmin,March 17 and 18,2006,浙江省食品药品监督管理局培训中心,ZJFDA,SIX SYSTEM APPROACH TO GMP IN MANUFACTURINGOF SOLID DOSAGE FORM,固体制剂的六大体系,Presented bysFDA&Alliance Pharmon,浙江省药监局,&,美国洲际药业,17,18 March 2006Hangzhou,China,SpeakerSimon Rusmin,Ph.D.,Simon Rusmin,March 17 and 18,2006,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,Simon Rusmin,March 17 and 18,2006,QUALITY SYSTEM APPROACH TO GMP GMP,的质量系统,Simon Rusmin,March 17 and 18,2006,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,In August 2002 the USA-FDA initiatedscience-based&risk-base quality systemapproach to CGMP.,2002,年八月，美国,FDA,成立了以科学和风险为基础的,CGMP,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,CGMP&,欧盟,GMP,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,1.1 Why Quality System Approach,为什么使用质量系统法,?,Simon Rusmin,March 17 and 18,2006,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（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,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,1.2 What is Quality,什么是质量,?,Simon Rusmin,March 17 and 18,2006,1.3 History of Quality,质量的历史,1850s,Before the INDUSTRIAL REVOLUTION,在工业革命以前,Product is UNIQUE(one of a kind).,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,High variability.,可变化性高,After,工业革命后,Product is UNIFORM,产品是统一的,Scientific controlsmake QUALITY,科学控制造就了质量,Low variability,可变化性低,Simon Rusmin,March 17 and 18,2006,1.4 Statistical Quality Control,统计质量控制,1920s,Nature 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,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,Statistical Sampling,统计抽样,Statistical Process control,统计工艺控制,Process Capability,加工能力,Design of Experiment,实验设计,World War II,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,消费品潮,Simon Rusmin,March 17 and 18,2006,1.5 The Race of Quality,质量的赛跑,1970s,After 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,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,:,Top management commits to quality,主管管理质量,Everyone participate in quality,人人参与质量,Processes are continuously improved,工艺不断改进,In 1976 the USA-FDA issued,Good Manufacturing Practices,.,1976,年美国,FDA,发布了质量生产规范,GMP,Simon Rusmin,March 17 and 18,2006,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,Motorola&General Electric initiatedthe,Six-Sigma,M,anufacturing,quality 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,Six sigma,六西格码,=defect of 3/10,6,3/10,6,的缺陷,Lean,精益,=highest value at,lowest cost,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,Simon Rusmin,March 17 and 18,2006,QUALITY IS,质量是,What the Customers,Like,消费者喜欢什么,measured by,Specifications,根据规格进行测量,got by,Reducing Variability,of manufacturing,通过减少生产可变性得到,1.6a QUICK SUMMARY,快速总结,Simon Rusmin,March 17 and 18,2006,1.7 What is a Process,什么是过程,?,Changing low-value INPUT into high-value OUTPUT,把低价值的输入变成高价值的输出,Simon Rusmin,March 17 and 18,2006,1.8 Knowledge is Power,知识就是力量,Process Knowledge,is the power to control the process,工艺知识是控制过程的力量,Alvin Toffler,托夫勒,The THIRD WAVE,第三次,浪潮,-1980,Simon Rusmin,March 17 and 18,2006,1.9 Process Three Factors,过程的三个因素,Factors contribute to Process variability,影响过程可变性的因素,Simon Rusmin,March 17 and 18,2006,1.10,The Business Process Flow,商业的工艺流程,Business is a change of processes the output of one process is the input of the next process,商业是过程的变更一个过程的输出是下一个过程的输入,Simon Rusmin,March 17 and 18,2006,Product 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,Establish,maintenance/calibration,.,建立维护,/,校准,Process-mapping,Risk-analysis(FMEA,HACCP),&establish,Process-controls,.,工艺描述，风险分析,(FMEA,HACCP),&,建立工艺控制,Establish Material-testing and Process-monitoring,In-process,intermediate,and finished product testing.Set-up,Testing-laboratories,.,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,Documentation and Knowledge-transfer to operators&managers through continuous,training,.,不断的对操作者,&,管理者进行文件建立及知识培训,Change-control,&Problem-solving(Deviation,OOS,&conformance),and establish,CAPA,.,变更控制,&,问题解决（偏差，超标,&,一致性），建立,CAPA,Audit(self-inspection)&Annual Quality Review(health-check).,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,Simon Rusmin,March 17 and 18,2006,1.12 FDA Six Quality Systems ApproachFDA,的六个质量系统方法,Simon Rusmin,March 17 and 18,2006,QUALITY SYSTEM,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,1.12a QUICK SUMMARY,快速总结,Simon Rusmin,March 17 and 18,2006,1.13 Document Pyramid,文件金字塔,Simon Rusmin,March 17 and 18,2006,As a SHOWCASE to introduce the quality operations of,the company.,把企业的质量操作当作一种优势介绍,The 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,Displays 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,Define the organization and personnel involved in quality,and each function responsibilities(,Quality Unit,(,Qualified Person,of EU)is independent of Manufacturing.,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）,Appended with List of other manuals(Manufacturing/Analytical Labs),SOPs,and other documents as a GATEWAY to view the complete quality systems.,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,Simon Rusmin,March 17 and 18,2006,The very first SOP describing how to writean SOP and manage GMP documents.,第一份,SOP,描述的是如何编写,SOP,和管理,GMP,文件,FORMAT,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,.,CONTENTS,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,PROCESS,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,.,CONTROL,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,Simon Rusmin,March 17 and 18,2006,Major,SYSTEM SOPs,created by QU include,：,QU,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,Creation of,INSTRUCTION SOPs,are by the users of each organizational functions(begin with flowcharting).,指令是由行为组织者创造的（从流程图开始）,Handling of RECORDS is described in grand-father SOP.,有关记录的处理在起始中有描述,1.16 SOPs and Records SOPs,和记录,Simon Rusmin,March 17 and 18,2006,SOP:“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 units,QA/QP(,产品放行），,QC,&,生产单位的职责,SOP:“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,),SOP:“Training Program,培训计划,&documentation,文件”,SOP:“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,Simon Rusmin,March 17 and 18,2006,1.17a QUICK SUMMARY,快速总结,SOFTWARE,软件,&LIVEWARE,生命件,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,Personnel(liveware)is the operator of the Quality System.,人员（生命件）是质量系统的操作者,Rules must be good and correctly followed by people.,准则必须是有益的并且由人来正确执行,Simon Rusmin,March 17 and 18,2006,1.18 Hardware Pyramid,硬件金字塔,Simon Rusmin,March 17 and 18,2006,Situation,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,CEILINGs 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.,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,HVAC provide clean and dry air suitable for operations with sufficient LIGHT.,HVAC,利用充足的光，提供了适合操作的干净、干燥的空气,AREAs for rest/toilet,weighing,in-process storage etc.,休息厕所，称重，内控标准储藏等区域,SOP:“Facility Maintenance&Repair,设备维护和维修”,(logbook,日志,).,VAL:IQ/OQ&Warehouse qualification,仓库确认,(as equipment),1.19 FACILITY,设备,Simon Rusmin,March 17 and 18,2006,Utilities 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,WFI,Compressed 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）,QA/QC understand the principles and operations,QA/QC,理解法规和操作,SOP:“Utilities Maintenance,公用设施维护,&Repair,维修”,Piping 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）,MONITOR,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,VAL:IQ/OQ,1.20 UTILITIES,公共事业设备,Simon Rusmin,March 17 and 18,2006,Equipment are to be designed and installed correctly to be suitable for their purposes and ease of cleaning.,设备的设计和安装要适用于其使用，且容易清洗。,Equipment are to be identified and the identity displayed when necessary during manufacturing.,设备要被鉴定并且当生产中有必要时把特性显示出来,Product-contact-surfaces are not to be,reactive,adsorptive,or,additive,to the products.,产品的接触面对产品没有反应，吸附或附加作用。,SOP:“Cleaning Procedures for XXX”,XXX,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,),SOP:“Measuring Instrument Calibration,测量仪器校准”,SOP:“Equipment Maintenance&Repair,设备维护和维修”,VAL:IQ/OQ,and Electronic-Controller validated,有效的电子控制器,.,1.21 EQUIPMENT,设备,Simon Rusmin,March 17 and 18,2006,1.21a QUICK SUMMARY,快速总结,HARDWARE,硬件,Processes CANNOT run without Hardware,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，并引起清洁，维护，维修及校准的变化,Simon Rusmin,March 17 and 18,2006,Purchase from reliable vendors with good Quality Systems(known original manufacturer)and defined specs.,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,Agreed on supply,delivery,reject returns.,在供货，运货，拒收应意见一致,Three store areas:,Receiving,Quarantine,Release,Reject,(locked);Identify materials with stickers(info).,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,Examine package,invoice and CoA;QC samples&test(must ID-test),and determines to release or reject.,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,Retain Reference-Samples for Critical Materials,保持主要物料的相关样品,Labels must be kept locked.,标签须被上锁保存,SOP:“Incoming Materials Storage,来料储藏,&Release,放行”,Vendor auditing,evaluation,and rating,买主审核，评估及评价,.,WATER 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,Simon Rusmin,March 17 and 18,2006,MANUFACTURING MANUAL contains:,生产手册包括,1.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,5.SOPs list,SOPs,清单,MANUFACTURING consists of Production of Intermediate&,Bulk,and Packaging of Finished,products.,生产包括中间体及批量的生产和成品包装,PROCESS KNOWLEDGE transferred from Development is designed into,Batch Record,=SOPof making&recording products,consistent with,Marketing Authorization,(NDA or ANDA).,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,SOP,Master Batch Record is approved and controlled by Q-Unit,who also review completed Batch Record.,Q-Unit,批准和控制主要的批记录，及审阅所有的批记录。,SOP:“Batch Record Issuance,Use&Review,批记录发布，使用及审阅”,(QU).,VAL:Manufacturing Process Validation,生产工艺验证,1.23 MANUFACTURING,生产,Simon Rusmin,March 17 and 18,2006,Weighing of formula materials are verifiable(electronic or 2,nd,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）,Record data at the end of each process step directly on the Batch Record,sign and date each record.,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,Record the start-end time of TIME-DURATION parameters or END-POINT parameters.,记录持续参数或终点参数的起始结束时间,Sign and date any mechanically generated records.,给任何的机械生产记录标上标记及日期,Store 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）,Reconcile results against input materials.,所得结果和所用材料相协调,Record all deviations and discuss,记录所有的偏差和讨论,(with supervisor/QU,和管理人员,).,Close-out Batch Record and submit to QU.,停止批记录并听从于,QU.,Dis-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,Simon Rusmin,March 17 and 18,2006,Obtain and verify the correct packaging materials and labels.,获取及检验正确的包装材料和标签,Verify line-clearance,检验清除线,(by QU,由,QU).,Record start-end time of a filling/packaging process.,记录填充包装工艺的起始结束时间,Conduct 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,Store 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,Reconcile labels and other critical packaging materials.,使得标签和其它主要包装材料相协调,Record deviations in processing and reconciliation.,记录工艺和协调中的偏差,Close-out Batch Record and submit to QU.,停止批记录并听从于,QU.,Dis-assemble equipment.Clean equipment and lines.,把设备拆卸，进行清洗,1.25 FINISHED PACKAGING,最终包装,Simon Rusmin,March 17 and 18,2006,Correctly design and assign facility and work flow.,正确地设计、分配工具及工作流程,Assign dedicated operators for one process.,对于一个工艺指定操作者,Train 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,Restrict 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,M