美国FDA验证高级培训

null 美国FDA验证高级 培训 焊锡培训资料ppt免费下载焊接培训教程 ppt 下载特设培训下载班长管理培训下载培训时间表下载 Denis Kluba 博士 吴培栋 博士目录Table Of Contents目录Table Of Contents验证定义 CGMP对验证的要求 验证历史与期望 验证综述 验证主 方案 气瓶 现场处置方案 .pdf气瓶 现场处置方案 .doc见习基地管理方案.doc关于群访事件的化解方案建筑工地扬尘治理专项方案下载 与 规划 污水管网监理规划下载职业规划大学生职业规划个人职业规划职业规划论文 实施验证的方法 验证的技术内容要求 执行验证方案 工作流程 改变控制 再验证 总结 Part One: What is Validation?Part One: What is Validation??第一部分：验证定义What is Validation?What is Validation?For this Seminar it refers to two things: 1. The USA FDA requirements that must be met in order to successfully and continually sell drug products in the USA 2. Activities that will contribute to the success of the company in the manufacture of drug products验证的含义？ValidationValidation“Anything which you cannot understand is indistinguishable from magic.” Arthur C. Clark “Validation may not be magic!” C. Edwards业内对验证的理解Validation Is.....Validation Is.....“Documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes.”FDA对验证的定义Why Do We Validate?Why Do We Validate?To Consistently Produce A Desired Known ProductConfirm DesignEstablish Operating BoundariesEstablish BaselinesProduct ComplianceTest within Specification验证的作用/目的How Do We Validate?How Do We Validate?Details Will Follow But This is the General ModelIdentify Equipment SystemsDevelop TestsWrite ProtocolsConduct TestsEvaluate DataReport ResultsResults OK?yesNoAmend ProtocolAmend TestCollect DataValidated SystemSystem Modified?验证流程图First three steps to CGMP complianceFirst three steps to CGMP compliancedocument document document符合CGMP要求的头三步Boundaries of ValidationBoundaries of ValidationCOMMISSIONING START-UP TROUBLE SHOOTING TRIAL RUNS CYCLE DEVELOPMENT PROCESS DEVELOPMENT ENGINEERING STUDIES VENDOR SERVICE REPORTS FACTORY ACCEPTANCE TEST “AS-BUILT” DRAWINGS STANDARD OPERATING PROCEDURES MFG BATCH RECORDS PERSONNEL TRAINING CALIBRATION PREVENTATIVE MTCE CHANGE CONTROL COMPLIANCE VENDOR AUDITS ANNUAL REVIEWS COMPLAINTS SAFETY验证的界限/范围Validation Life Cycle ApproachValidation Life Cycle ApproachProspective / ConcurrentDefine Specifications Equipment Process RequirementsProceduresNew / Revised Process / Product验证生命周期: 新的/修改过的工艺/产品Validation Life Cycle ApproachValidation Life Cycle ApproachRetrospectiveDefine System Specifications Equipment ProceduresExisting Process / Product验证生命周期: 现有工艺/产品Benefits of ValidationBenefits of ValidationIncreased Throughput Reduction In Rejections and Reworks Reduction In Utility Costs Avoidance Of Capital Expenditures Fewer Complaints About Process Related Failures Reduced Testing – In-process and Finished Goods More Rapid / Accurate Investigations Into Process Upsets More Rapid and Reliable Startup Of New Equipment Easier Scale-up From Development Work Easier Maintenance Of The Equipment Improved Employee Awareness Of Processes More Rapid Automation验证带来的好处Elements Of Contemporary Validation In The USElements Of Contemporary Validation In The USEquipment Calibration - Process and Validation Equipment Equipment Qualification - Installation and Operational Process Development Process Documentation Performance Qualification - "Validation" Maintenance of Validation - Process and Equipment Change Control 当今美国验证包含的内容cGMP and ISO-9000 - SimilaritiescGMP and ISO-9000 - SimilaritiesAimed at Quality Require Documentation Require Specific Quality Program QA and QC IncludedCGMP和 ISO 9000的相似之处cGMP and ISO-9000 - DifferencescGMP and ISO-9000 - DifferencescGMP Aimed at Product ISO-9000 Includes Design and Service, as well cGMP Covers Activities Directly Related to Manufacturing ISO-9000 Covers Broader Range of Activities (e.g.. Purchasing) cGMP Requires Formal Validation ISO-9000 Requires Applicable Statistical MethodsCGMP和 ISO 9000的不同之处Benefits of the Systems Approach to ValidationBenefits of the Systems Approach to ValidationMore Rigorous Control Over Operations Centralized Planning for all Validation Related Aspects Ties Existing Sub-elements into Cohesive System Establishes Validation as a Program, not a Project Provides for Continuity of Approach Affirms Validation as a Discipline Much like Others Allows For Personnel Growth within the Validation Expertise Usually Results in Centralization of Validation Expertise More Compatible with the Accomplishment of a Corporate Objective for Validation系统验证方法的好处The Validation ProgramThe Validation ProgramEstablish Goals and Objectives as to What Must be Validated Qualify or Re-qualify the Equipment Establish Validation Protocols for each, and obtain Approval of the Protocols Establish Personnel Requirements and Training Records Procedure Design and Conduct Experiments. Collect Data Evaluate the Data Prepare Summary Reports Outlining the Results of the Experiments. Obtain the Necessary Approvals Establish and Maintain Validation Files Including Raw Data Institute a Change Control Procedure to Insure the Ongoing Acceptability of the Work 验证项目/规划Part Two: GMP RequirementsPart Two: GMP Requirements第二部分：GMP对验证的要求GMP requirementsGMP requirementsPart 211: Current good manufacturing practice for finished pharmaceuticals   §211.68 - Automatic, mechanical, and electronic equipment.   §211.84 - Testing and approval or rejection of components, drug product containers, and closures.   §211.110 - Sampling and testing of in-process materials and drug products.   §211.113 - Control of microbiological contamination.   §211.165 - Testing and release for distribution.   §211.166 - Stability testing. GMP要求cGMP in the Pharmaceutical IndustrycGMP in the Pharmaceutical IndustryGMP is the abbreviation of “Good Manufacturing Practice” which is adopted by the medical and health related industries including the pharmaceutical industry in an effort to maintain the highest standards of quality in the development, manufacture and control of medicinal products. Since the industry standards are subject to continuous improvement, the letter ‘c’ in the abbreviation “cGMP” refers more specifically to the current or the latest version of the GMP requirements. 制药行业的cGMPRegulatory Requirements for Validation.....Regulatory Requirements for Validation.....The requirement of process validation is implicit in the language of 21 CFR 211.100 of the Current Good Manufacturing regulations which states: “There shall be written procedures for product and process control to assure that drug products have the identity, strength, quality, and purity they purport or are represented to possess." 监管部门对验证的要求GMP Regulatory Requirements for Cleaning ValidationGMP Regulatory Requirements for Cleaning Validation1978 cGMP Regulations (part 211.67(a)) Equipment cleaning and maintenance states: “Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements”. GMP条例对清洗验证的要求GMP Regulatory Requirements for Test Method ValidationGMP Regulatory Requirements for Test Method ValidationLaboratory Controls 21 CFR 211.165(e) states: The accuracy, sensitivity, specificity and reproducibility of test methods employed by the firm shall be established and documented. Such validation and documentation may be accomplished in accordance with Part 211.194(a)(2). GMP条例对化验方法验证的要求GMP Regulatory Requirements for Test Method ValidationGMP Regulatory Requirements for Test Method ValidationPart 211.194(a)(2) states: A statement of each method used. . . shall indicate the location of data that establish that the methods used in the testing of the sample meet proper standards of accuracy and reliability as applied to the product tested. The suitability of all testing methods used shall be verified under actual conditions of use.GMP条例对化验方法验证的要求GMP Regulatory Requirements for Test Method ValidationGMP Regulatory Requirements for Test Method ValidationU.S. Federal Court decision: United States vs Barr Labs Cleaning Validation: . . . it was ruled for cleaning to be effective, the specific test methods had to be shown to be effective.GMP条例对化验方法验证的要求PROCESS VALIDATIONPROCESS VALIDATION21 CFR 211.110 “such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product” 工艺验证Part Three: History and ExpectationsPart Three: History and ExpectationsAs applied by the FDA and Implemented by Industry第三部分：验证历史与FDA和制药行业对验证的期望History and expectationsHistory and expectationsLearn for the experiences of the USA manufacturers and industry organizations Current applications Past citations Industry guidelines ICH Q7A ISPE PDA Etc.历史与期望Validation TargetsValidation TargetsEarly Years Sterilization Aseptic Operations Middle Years Non-sterile Processes Oral Dosage Forms Recent Years Biological Processes Bulk Organic Synthesis Developmental and Pilot Operations Supporting Services Currently Total Operations Review by Systems Quality System Production System Laboratory Controls Packaging and Labeling, Materials and Facilities Equipment Manufacturing. 验证目标History of ValidationHistory of ValidationValidation in The Early Years - 1972 to 1978 Regulatory Based to Satisfy FDA Pressures Defensive to Protect Product Line Validation in Its' Adolescence - 1978 To 1983 Primarily Defensive Some Efforts at Process Optimization Includes Some Peripheral Concerns Validation in the US Today - 1983 to Present Non- Regulatory in Many Areas Geared Towards Optimization and focused on Systems 验证历史"validation" vs. "VALIDATION""validation" vs. "VALIDATION""validation" Defensive Testing Oriented Costly Quality Control Narrow Focus"VALIDATION" Optimization Total Process Control Cost Effective Quality Assurance Diverse Application如何正确理解验证Elements of Contemporary Validation in the USElements of Contemporary Validation in the USEquipment Calibration - Process and Validation Equipment Equipment Qualification - Installation and Operational Process Development Process Documentation Performance Qualification - "Validation" Maintenance of Validation - Process and Equipment Change Control 当今美国验证所包含的内容/要素ExpectationsExpectationsValidation is a Program not a Project Validation Contributes to the Stability of the Operations Validation is not Someone Else's Job!对验证的期望Part Four: ValidationPart Four: ValidationAn Overview第四部分：验证概述Who Validates?Who Validates?Validation StaffEngineeringQuality AssuranceQuality ControlManufacturing谁进行验证？ValidationValidationvDesignTestingOperation验证运作ValidationValidationvVendorSystems IntegratorOwner/User验证系统集成者ValidationValidationvEngineering R&D Validation Team MaintenanceManufacturing Quality Assurance验证制造质量保障Write ProtocolsWrite Protocols起草方案Example Data SheetsExample Data Sheets数据单样品Conduct TestingConduct TestingChemical TestsCareful Review and Markup of Prints, SpecsMicrobiological TestsPhysical Tests (Temp., Press., Flow)Computer Tests进行测试Installation Qualification (IQ)Installation Qualification (IQ)IQ documents that system is installed in accordance with approved design, specification and regulatory codes manufacturers installation recommendation have been taken into consideration IQs implemented concurrently with construction of each system 安装合格确认Operational Qualification (OQ)Operational Qualification (OQ)OQ documents that the equipment: can operate as designed and intended is capable of repeatable operation over the entire operating range of process variables OQ executed when equipment can be started up 运转/运作合格确认Process Qualification (PQ)Process Qualification (PQ)PQ documents critical systems which can be challenged test procedures product quality attributes to be evaluated acceptance criteria alert/action levels system validated under "worst case conditions" generally 3 consecutive successful runs required 工艺合格确认Definition of Process ValidationDefinition of Process ValidationValidation is: Documented evidence that provides a high degree of assurance that a specific process will consistently produce a product of a certain predetermined quality. 1978工艺验证定义Definition of Process ValidationDefinition of Process ValidationIn addition to documented evidence that a process will perform reliably and repeatedly, validation, in its highest form, provides an understanding of why.1993工艺验证定义Stages of the Life-CycleStages of the Life-CycleR&DDesignConstructionTestingSOPs/MaintenanceChange Control生命周期的阶段Benefits of ValidationBenefits of ValidationIncreased Throughput Reduction in Rejections and Reworks Reduction in Utility Costs Avoidance Of Capital Expenditures Fewer Complaints About Process Related Failures Reduced Testing – In-process and Finished Goods More Rapid / Accurate Investigations Into Process Upsets More Rapid and Reliable Startup Of New Equipment Easier Scale-up From Development Work Easier Maintenance Of The Equipment Improved Employee Awareness Of Processes More Rapid Automation 验证的好处Documentation of ValidationDocumentation of ValidationMaster Plan Protocol Data Sheets Report Procedures验证文件Validation ProtocolsValidation ProtocolsProvide an Outline of the Validation Effort Include a Clear Definition of What Will Be Validated Is Uniquely Identified Is Dated Approved By Competent Individuals In Responsible Areas Are Suitable For Review By Regulatory Agencies验证方案Validation Protocol Essential ElementsValidation Protocol Essential ElementsIntroduction/Abstract Description of Process or System Test Plan Responsibilities Acceptance Criteria Approvals Append Data Sheets, Etc.验证方案的核心要素Validation Reports – FunctionsValidation Reports – FunctionsRestrict to One Task or Subject Has a Unique Identification Is Dated Formally Reviewed and Approved Identifies Protocol(s) Used in the Study Is Suitable for Review by FDA验证报告－功能Validation Report - ContentsValidation Report - ContentsAbstract Or Summary Conclusion Plan Of Study Experimental Results Conclusions Protocol Reference Diagrams Any Miscellaneous Information Approvals验证报告－内容Installation Qualification (IQ)Installation Qualification (IQ)IQ Documents That The: System is Installed in Accordance with Approved Design, Specifications and Regulatory Codes Manufacturers Installation Recommendations have been taken into Consideration IQ is Implemented Concurrently with Construction of Each System安装合格确认Design DocumentationDesign DocumentationDesign and Procurement Documentation Support of IQ: PFDs/P&IDs Critical System Installation Drawings (E.G. Water System Isometrics, Sanitary Duct Drawings) Purchase and Installation Specifications Vendor Manuals and Prints Computer Software Documentation 设计 领导形象设计圆作业设计ao工艺污水处理厂设计附属工程施工组织设计清扫机器人结构设计 文件Construction DocumentationConstruction DocumentationConstruction Documents In Support Of IQ: Slope Checks Piping Pressure Test Reports Motor Checkout Reports Weld Inspection Reports Cleaning, Passivation and Sanitization Procedures and Reports HVAC Test and Balance Reports Other Appropriate Construction Documentation建造文件The P&IDThe P&IDProcess Equipment Support Vessels Interconnecting Lines Utility Lines Instruments/Instrument Functions Schematic No Scale - Not Spatially Precise Shows Relationships and Relative Position(Piping & Instrumentation Diagram, Engineering Flow Diagram)管线和仪器图Operational Qualification (OQ)Operational Qualification (OQ)OQ Documents That The Equipment: Can Operate as Designed and Intended Is Capable of Repeatable Operation Over the Entire Operating Range of Process Variables OQ Implemented After Equipment has been Started Up or Commissioned运作合格确认Process Qualification (PQ)Process Qualification (PQ)PQ Documents That: Processes Operate as Required at the Normal Operating Limits of Critical Parameters Systems Operate Consistently and Reliably Appropriate Challenges Are Employed工艺合格确认Review and ApprovalsReview and ApprovalsDesign Drawings and Specifications Master Plan Protocols Reports Procedures审阅和批准Part Five: Validation Master PlanningPart Five: Validation Master Planning第五部分：主验证规划PlanningPlanning“If you don’t know where you are going, you are likely to end up someplace else!” - Lewis Carroll Like any other important activity in a complex organization validation must be managed. This is especially true given the multi-disciplined nature of many validation activities.规划Existing PlantsExisting PlantsThe same level of management is necessary for the validation of an existing facility, whether fully validated or not. Validation is easier when it is an integral part of the day-to-day operation of the facility. 现有工厂Master PlanMaster PlanDefines and Establishes the Validation Approach and the Acceptance Criteria and more!主方案Facilities, Processes or ProductsFacilities, Processes or ProductsWhat needs to be done? Who will do it? How will they do it? How long will it take? How much will it cost?设施，工艺或产品Master Plan - GeneralMaster Plan - GeneralIntroduction to Facility Purpose and Design Intent Facility/Process Description Process Control Considerations System Definitions Planning/Scheduling主方案概述Master Plan - WhyMaster Plan - WhyProject Familiarization/Training Management Introduction FDA Introduction/Familiarization Validation Program Foundation Basic Procedures Protocol Outlines/Bases Resource Planning/Scheduling Contract Execution Interaction Codifies Prior Decisions Structures Validation Activities Facilitates Regulatory Compliance Useful in Regulatory and Client Interactions Use With 3rd Parties Convertible Into Drug Master File Internal Audit Preparation为什么需要主方案？Master Plan - WhatMaster Plan - WhatIntroduction Facility / Process / Product Description Process Control Considerations System Definition Protocol Outlines/Acceptance Criteria Formats SOPs Planning/Scheduling什么是主方案？Master Plan - Getting StartedMaster Plan - Getting StartedFacility Layout Process Description(s) Product Description(s) Equipment List Utility List Controlled Environment Requirements Control Philosophy Schedule主方案的起点Master Plan – Facility DescriptionMaster Plan – Facility DescriptionLayout/Equipment Arrangement People/Material/Component Flow Controlled Environments Materials of Construction Sketches主方案中的设施描述Master Plan - Process DescriptionMaster Plan - Process DescriptionMajor Process Steps Block Diagram Process Flow Diagram(s) Utilities (WFI, DI, CIP, Etc.) Major Support Equipment (Autoclaves, Ovens, Etc.)主方案中的工艺描述Master Plan - Process ControlMaster Plan - Process ControlGeneral Architecture Central/Distributed Control System PLCs/Individual Control Systems Building Automation System Higher Level Systems (LIMS, EBR, Etc.) Integrate into other Sections if Minimal主方案中的工艺控制Master Plan - Validated SystemsMaster Plan - Validated SystemsLists Of Systems To Be Validated General Acceptance Criteria Specific Acceptance Criteria Basic Protocol Outlines主方案中验证过的系统Master Plan - Procedures and FormatsMaster Plan - Procedures and FormatsProtocol Format SOP Format Basic Procedures Validation Program Responsibilities Calibration Change Control List Of SOPs 主方案的流程和格式Master Plan - Planning and Scheduling Master Plan - Planning and Scheduling Manpower Resources Document Preparation Field Execution Calibration Lab Support Test & Balance/Filter Certification Start-Up/Commissioning主方案的规划与 计划 项目进度计划表范例计划下载计划下载计划下载课程教学计划下载 Master Plan - FocusMaster Plan - FocusSterile Products Facility Emphasis On Facility and Environment People, Component, Product Flows Automation May Or May Not Be Central Support Systems Critical (Autoclaves, Ovens, WFI, Etc.) 主方案的集中点Master Plan - FocusMaster Plan - FocusSolids Facility In-process Controls Tests Examinations to be Conducted on Appropriate Samples of In-process Materials of Each Batch 主方案的集中点Master Plan - FocusMaster Plan - FocusAPI Facility Emphasis On Chemical Process Identify API Step Cross-c