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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,Design/Specify Equipment,Define Process,Develop Procedure Spec.,Install Equipment,Verify Procedure Specifications,Qualify Equipment,Develop Validation Protocol,Obtain Data on Pro
8、cess,Obtain Data on Process,Validation Report,Three Lots Prospective,Acceptance,Ongoing Evaluation,Change Control,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,Qualify Equipment,Review Process Ca
9、pability, Specifications, Procedures, Operating Instructions,Develop Validation Protocol,Validation Report,Acceptance,Ongoing Evaluation,Data,Conduct Testing (If Needed),Change Control,Existing Process / Product,验证生命周期: 现有工艺/产品,13,Benefits of Validation,Increased Throughput Reduction In Rejections a
10、nd 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 Develop
11、ment 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 Equipment Equipment Qualification - Installation and Operational Process Development Pr
12、ocess 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 Require Specific Quality Program QA and QC Included,CGMP和 ISO 9000的相似之处,16,cGMP and ISO
13、-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 Requires Formal Validation ISO-9000 Requires Applicable Statistical Methods,CGMP和 ISO 900
14、0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 Validation as a Program, not a Project Provides for Continuity of Approach Affirms Valida
15、tion 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,18,The Validation Program,Establish Goals and Objectiv
16、es 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 Out
17、lining 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,19,Part Two: GMP Requirements,第二部分：GMP对验证的要求,20,GMP requirements,Part 211: Cur
18、rent 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 -
19、 Control of microbiological contamination. 211.165 - Testing and release for distribution. 211.166 - Stability testing.,GMP要求,21,cGMP in the Pharmaceutical Industry,GMP is the abbreviation of “Good Manufacturing Practice” which is adopted by the medical and health related industries including the ph
20、armaceutical 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 th
21、e latest version of the GMP requirements.,制药行业的cGMP,22,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 co
22、ntrol 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,23,GMP Regulatory Requirements for Cleaning Validation,1978 cGMP Regulations (part 211.67(a) Equipment cleaning and maintenance states: “Equipment and utensils
23、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,24,GMP Regulatory Requirements f
24、or Test Method Validation,Laboratory 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).,GM
25、P条例对化验方法验证的要求,25,GMP Regulatory Requirements for Test Method Validation,Part 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 t
26、o 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,26,GMP Regulatory Requirements for Test Method Validation,U.S. Federal Court decision: United States vs Barr Labs Cleaning Validation: . . . it was ruled for cleaning t
27、o 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,27,PROCESS VALIDATION,21 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 var
28、iability in the characteristics of in-process material and the drug product”,工艺验证,28,Part Three: History and Expectations,As 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,29,History and expectations,Learn for the experiences of the USA manufacturers and industry organizatio
29、ns Current applications Past citations Industry guidelines ICH Q7A ISPE PDA Etc.,历史与期望,30,Validation Targets,Early Years Sterilization Aseptic Operations Middle Years Non-sterile Processes Oral Dosage Forms,Recent Years Biological Processes Bulk Organic Synthesis Developmental and Pilot Operations S
30、upporting 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,31,History of Validation,Validation in The Early Years - 1972 to 1978 Regulatory Based to Satisfy FDA Pr
31、essures 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 Syst
32、ems,验证历史,32,“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,33,Elements of Contemporary Validation in the US,Equipment Calibration -
33、 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,34,Expectations,Validation is a Program not a P
34、roject Validation Contributes to the Stability of the Operations Validation is not Someone Elses Job!,对验证的期望,35,Part Four: Validation,An Overview,第四部分：验证概述,36,Who Validates?,Validation Staff,Engineering,Quality Assurance,Quality Control,Manufacturing,谁进行验证？,37,Validation,v,Design,Testing,Operation,验
35、证,运作,38,Validation,v,Vendor,Systems Integrator,Owner/User,验证,系统集成者,39,Validation,v,Engineering R&D,Validation Team Maintenance,Manufacturing Quality Assurance,验证,制造质量保障,40,Write Protocols,起草方案,41,Example Data Sheets,数据单样品,42,Conduct Testing,Chemical Tests,Careful Review and Markup of Prints, Specs,M
36、icrobiological Tests,Physical Tests (Temp., Press., Flow),Computer Tests,进行测试,43,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 I
37、Qs implemented concurrently with construction of each system,安装合格确认,44,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 starte
38、d up,运转/运作合格确认,45,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
39、,46,Definition of Process Validation,1978,Validation is: Documented evidence that provides a high degree of assurance that a specific process will consistently produce a product of a certain predetermined quality.,工艺验证定义,47,Definition of Process Validation,In addition to documented evidence that a p
40、rocess will perform reliably and repeatedly, validation, in its highest form, provides an understanding of why.,1993,工艺验证定义,48,Stages of the Life-Cycle,R&D,Design,Construction,Testing,SOPs/Maintenance,Change Control,生命周期的阶段,49,Benefits of Validation,Increased Throughput Reduction in Rejections and R
41、eworks 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
42、 Work Easier Maintenance Of The Equipment Improved Employee Awareness Of Processes More Rapid Automation,验证的好处,50,Documentation of Validation,Master Plan Protocol Data Sheets Report Procedures,验证文件,51,Validation Protocols,Provide an Outline of the Validation Effort Include a Clear Definition of What
43、 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,52,Validation Protocol Essential Elements,Introduction/Abstract Description of Process or System Test Plan Responsibilities Acceptance Criteri
44、a Approvals Append Data Sheets, Etc.,验证方案的核心要素,53,Validation Reports Functions,Restrict 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,54,Validation Report - Contents,Abstract Or
45、 Summary Conclusion Plan Of Study Experimental Results Conclusions Protocol Reference Diagrams Any Miscellaneous Information Approvals,验证报告内容,55,Installation Qualification (IQ),IQ Documents That The: System is Installed in Accordance with Approved Design, Specifications and Regulatory Codes Manufact
46、urers Installation Recommendations have been taken into Consideration IQ is Implemented Concurrently with Construction of Each System,安装合格确认,56,Design Documentation,Design and Procurement Documentation Support of IQ: PFDs/P&IDs Critical System Installation Drawings (E.G. Water System Isometrics, San
47、itary Duct Drawings) Purchase and Installation Specifications Vendor Manuals and Prints Computer Software Documentation,设计文件,57,Construction Documentation,Construction Documents In Support Of IQ: Slope Checks Piping Pressure Test Reports Motor Checkout Reports Weld Inspection Reports Cleaning, Passi
48、vation and Sanitization Procedures and Reports HVAC Test and Balance Reports Other Appropriate Construction Documentation,建造文件,58,The P&ID,(Piping & Instrumentation Diagram, Engineering Flow Diagram),Process Equipment Support Vessels Interconnecting Lines Utility Lines Instruments/Instrument Functio
49、ns Schematic No Scale - Not Spatially Precise Shows Relationships and Relative Position,管线和仪器图,59,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,60,Process Qualification (PQ),PQ Documents That: Processes Operate as Required at the Normal O