美国FDA 验证高级培训Denis Kluba 博士吴培栋博士目录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Part One: 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 Validation Validation Is..... Why Do We Validate? To Consistently Produce A Desired Known Product How Do We Validate? Details Will Follow But This is the General Model First three steps to CGMP compliance document document document Boundaries of Validation Validation Life Cycle Approach Validation Life Cycle Approach 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 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 Elements Of Contemporary Validation In The US Equipment 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 cGMP and ISO-9000 - Similarities Aimed at Quality Require Documentation Require Specific Quality Program QA and QC Included 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 Requires Formal Validation ISO-9000 Requires Applicable Statistical Methods 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 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 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 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 		 Part Two: GMP Requirements 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 microbiological contamination.  §211.165 - Testing and release for distribution.  §211.166 - Stability testing. 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 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. 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." GMP Regulatory Requirements for Cleaning Validation 1978 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 Regulatory Requirements for 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). 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 to the product tested. The suitability of all testing methods used shall be verified under actual conditions of use. GMP Regulatory Requirements for Test Method Validation U.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. 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 variability in the characteristics of in-process material and the drug product”Part Three: History and Expectations As applied by the FDA and Implemented by Industry History and expectations Learn for the experiences of the USA manufacturers and industry organizations Current applications Past citations Industry guidelines ICH Q7A ISPE PDA Etc. 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 	Supporting Services Currently 	Total Operations 	Review by Systems 		Quality System 		Production System 	Laboratory Controls 		Packaging and Labeling, 	Materials and Facilities 		Equipment Manufacturing. History of Validation Validation 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	 "validation" vs. "VALIDATION" "validation" Defensive Testing Oriented Costly Quality Control Narrow Focus Elements of Contemporary Validation in the US Equipment 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 Expectations Validation is a Program not a Project Validation Contributes to the Stability of the Operations Validation is not Someone Else's Job! Part Four: Validation An Overview Who Validates? Validation Validation Validation Write Protocols Example Data Sheets Conduct Testing Installation Qualification (IQ) IQ documents that system is installed in accordance with approved design, specification and regulatory codes manufacturers installation recommendation have been