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1、1,美国FDA验证高级培训 Denis Kluba 博士 吴培栋 博士,2,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 验证主方案与规划 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,3,Part One: What is Validation?,?,第一部分：验证定义,4,What is Validation?,For this Seminar it refers to two things: 1. The USA FDA requirements that must be met in order
2、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？,5,Validation,“Anything which you cannot understand is indistinguishable from magic.” Arthur C. Clark “Validation may not be magic!
3、” C. Edwards,业内对验证的理解,6,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,7,To Consistently Produce A Desired Known Product,Why Do We Va
4、lidate?,Confirm Design,Establish Operating Boundaries,Establish Baselines,Product Compliance,Test within Specification,验证的作用/目的,8,How Do We Validate?,Details Will Follow But This is the General Model,Identify Equipment Systems,Develop Tests,Write Protocols,Conduct Tests,Evaluate Data,Report Results,
5、Results OK?,yes,No,Amend Protocol,Amend Test,Collect Data,Validated System,System Modified?,验证流程图,9,First three steps to CGMP compliance,document document document,符合CGMP要求的头三步,10,Boundaries of Validation,Engineering,COMMISSIONING START-UP TROUBLE SHOOTING TRIAL RUNS CYCLE DEVELOPMENT PROCESS DEVELO
6、PMENT 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,Operations / QA,Validation,验证的界限/范围,1
7、1,Validation Life Cycle Approach,Prospective / Concurrent,Define Specifications Equipment Process Requirements,Procedures,New / Revised Process / Product,验证生命周期: 新的/修改过的工艺/产品,12,Validation Life Cycle Approach,Retrospective,Define System Specifications Equipment Procedures,Existing Process / Product,
8、验证生命周期: 现有工艺/产品,13,Benefits of Validation,Increased 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 Proc
9、ess 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,14,Elements Of Contemporary Validation In The US,Equipment Calibration - Process and Validation
10、 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,15,cGMP and ISO-9000 - Similarities,Aimed at Quality Require Documentation
11、 Require Specific Quality Program QA and QC Included,CGMP和 ISO 9000的相似之处,16,cGMP and ISO-9000 - Differences,cGMP 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 R
12、equires Formal Validation ISO-9000 Requires Applicable Statistical Methods,CGMP和 ISO 9000的不同之处,17,Benefits of the Systems Approach to Validation,More Rigorous Control Over Operations Centralized Planning for all Validation Related Aspects Ties Existing Sub-elements into Cohesive System Establishes V
13、alidation 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 O
14、bjective for Validation,系统验证方法的好处,18,The Validation Program,Establish 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 De
15、sign 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 Wor
16、k,验证项目/规划,19,Part Two: GMP Requirements,第二部分：GMP对验证的要求,20,GMP requirements,Part 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 microbiolog
