1、1,美國FDA驗證高級培訓 Denis Kluba 博士 吳培棟 博士,2,目錄Table Of Contents,驗證定義 CGMP對驗證的要求 驗證歷史與期望 驗證綜述 驗證主方案與規(guī)劃 實施驗證的方法 驗證的技術內容要求 執(zhí)行驗證方案 工作流程 改變控制 再驗證 總結,3,Part One: What is Validation?,?,第一部分：驗證定義,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,驗證的含義？,5,Validation,“Anything which you cannot understand is indistinguishable from magic.” Arthur C. Clark “Validation may not be magic!

3、” C. Edwards,業(yè)內對驗證的理解,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對驗證的定義,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,驗證的作用/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?,驗證流程圖,9,First three steps to CGMP compliance,document document document,符合CGMP要求的頭三步,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,驗證的界限/范圍,1

7、1,Validation Life Cycle Approach,Prospective / Concurrent,Define Specifications Equipment Process Requirements,Procedures,New / Revised Process / Product,驗證生命周期: 新的/修改過的工藝/產品,12,Validation Life Cycle Approach,Retrospective,Define System Specifications Equipment Procedures,Existing Process / Product,

8、驗證生命周期: 現(xiàn)有工藝/產品,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,驗證帶來的好處,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,當今美國驗證包含的內容,15,cGMP and ISO-9000 - Similarities,Aimed at Quality Require Documentation R

11、equire Specific Quality Program QA and QC Included,CGMP和 ISO 9000的相似之處,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 Re

12、quires Formal Validation ISO-9000 Requires Applicable Statistical Methods,CGMP和 ISO 9000的不同之處,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 Va

13、lidation 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 Ob

14、jective for Validation,系統(tǒng)驗證方法的好處,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 Des

15、ign 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

16、,驗證項目/規(guī)劃,19,Part Two: GMP Requirements,第二部分：GMP對驗證的要求,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 closur

17、es. 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,21,cGMP in the Pharmaceutical Industry,GMP is the abbreviation of “Good Manufacturing P

18、ractice” 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

19、, the letter c in the abbreviation “cGMP” refers more specifically to the current or the latest version of the GMP requirements.,制藥行業(yè)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

20、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.,監(jiān)管部門對驗證的要求,23,GMP Regulatory Requirements for Cleaning Validation,1978 cGMP Regulatio

21、ns (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 offic

22、ial or other established requirements”.,GMP條例對清洗驗證的要求,24,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 vali

23、dation and documentation may be accomplished in accordance with Part 211.194(a)(2).,GMP條例對化驗方法驗證的要求,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 th

24、e 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條例對化驗方法驗證的要求,26,GMP Regulatory Requirements for Test Method Validation,U.S. Federal Court decis

25、ion: 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條例對化驗方法驗證的要求,27,PROCESS VALIDATION,21 CFR 211.110 “such control procedures shall be established to monitor the output and to validate th

26、e performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product”,工藝驗證,28,Part Three: History and Expectations,As applied by the FDA and Implemented by Industry,第三部分：驗證歷史與FDA和制藥行業(yè)對驗證的期望,29,History and ex

27、pectations,Learn for the experiences of the USA manufacturers and industry organizations Current applications Past citations Industry guidelines ICH Q7A ISPE PDA Etc.,歷史與期望,30,Validation Targets,Early Years Sterilization Aseptic Operations Middle Years Non-sterile Processes Oral Dosage Forms,Recent

28、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.,驗證目標,31,History of Vali

29、dation,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

30、 Present Non- Regulatory in Many Areas Geared Towards Optimization and focused on Systems,驗證歷史,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

31、確理解驗證,33,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 Cha

32、nge Control,當今美國驗證所包含的內容/要素,34,Expectations,Validation is a Program not a Project Validation Contributes to the Stability of the Operations Validation is not Someone Elses Job!,對驗證的期望,35,Part Four: Validation,An Overview,第四部分：驗證概述,36,Who Validates?,Validation Staff,Engineering,Quality Assurance,Qual

33、ity Control,Manufacturing,誰進行驗證？,37,Validation,v,Design,Testing,Operation,驗證,運作,38,Validation,v,Vendor,Systems Integrator,Owner/User,驗證,系統(tǒng)集成者,39,Validation,v,Engineering R -Analog Inputs; -Analog Outputs; -Digital Inputs; -Digital Outputs; -One Speed Motor; -Two speed Motor. The appropriate procedur

34、e to follow when performing Tag Checkouts, is described on the forms mentioned above. A list of instruments to be tag checked will be attached to the package OQ Protocol. The completion of Instrument tag checkout for a specific package is confirmed on package OQ Checkout Sheet.,EXAMPLE,標簽校驗,126,Cons

35、truction Cleaning - Process Production Problems; Production Failures,工藝驗證,227,CGMP Annual Review,21 CFR 211.180(e) Requires a Retrospective Overall Evaluation of the Adequacy of the Quality Standards At Least Annually Drug Products Directly Impacted Drug Substances Impacted Per Preamble (1978),CGMP

36、年度評審,228,CGMP Annual Review,95 Retrospective Review Representative # of Batches for Ea. Product If Check Reveals an Adverse Quality Go to 100% Review Computers Use Encouraged As a Compliment to Human Judgment & Intervention,CGMP 年度評審,229,CGMP Annual Review,95 Proposed Revisions -Validation Implement

37、 Revalidation Procedures Whenever There Are Changes, Including Reprocessing, That Could Affect Product Effectiveness or Characteristics,CGMP 年度評審,230,Planned Changes,Propose Change, Document Reason (Manufacturing, Development, Etc.) File Formal Request Determine Need For Validation Of Process With C

38、hange Implemented Implement Change Execute and Report Validation Testing Review and Approve Update Drawings, SOPs and Operating Records,計劃的改變,231,Emergency Changes,Only To Save Product In Process Impound Product Pending Evaluation Of Change Document Change - Formal Request Form Determine Need For Va

39、lidation Of Change Determine If Change Should Be Permanent Validation Testing, If Necessary Accept Or Reject Impounded Product Update Drawings and Procedures, As Required,緊急狀況下的改變,232,Part Eleven: Revalidation, etc,Calibration Program Preventative Maintenance Change Control Program Software Equipmen

40、t Logs SOPs Regular QA Reviews,第十一部分：再驗證等,233,Revalidation,Validation of a Previously Validated System that has been Changed or Modified Need to perform is Established in the Change Control Program Event Based Time Based,再驗證,234,Calibration,Define Critical Process Variables - Effect On Quality - Eff

41、ect On Yield Or Accountability - Effect On Operator Safety SOP - General Procedure For Critical Variables - Specific Procedure For Each Instrument - Acceptable Range Definition - Frequency Of Recalibration - Exception Reporting Traceability - NIST Traceable Standards - Recalibration Of Standards,校準,

42、235,Essential Parts of a Calibration Program,Statement Of Purpose and Scope Criteria For Training Personnel Written Calibration Procedures Metrology Laboratory Calibration Records System For Instrument Recall For Calibration Alert Procedure For Out Of Calibration Instruments,校準項目的核心部分,236,Maintenanc

43、e,Corrective Adaptive Preventative,維護,237,Preventative Maintenance,Housekeeping Filters Temperature, RH Routine Diagnostics Mfg. Recommended Program,預防性維護,238,Software,Changes made to correct errors and faults in the software are corrective maintenance. Changes made to the software to improve the pe

44、rformance, maintainability, or other attributes of the software system are perfective maintenance. Software changes to make the software system usable in a changed environment are adaptive maintenance. When changes are made to a software system, either during initial development or during post relea

45、se maintenance, sufficient regression analysis and testing should be conducted to demonstrate that portions of the software not involved in the change were not adversely impacted. This is in addition to testing that evaluates the correctness of the implemented change(s).,軟件,239,Equipment Logs,A writ

46、ten record of major equipment cleaning, maintenance (except routine maintenance such as lubrication and adjustments), and use shall be included in individual equipment logs that show the date, time, product, and lot number of each batch processed. If equipment is dedicated to manufacture of one prod

47、uct, then individual equipment logs are not required, provided that lots or batches of such product follow in numerical order and are manufactured in numerical sequence. In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use shall be part of the batch record. T

48、he persons performing and double-checking the cleaning and maintenance shall date and sign or initial the log indicating that the work was performed. Entries in the log shall be in chronological order.,設備記錄,240,SOPs,Established to Ensure that Activities are Performed the Same Way at all Times Period

49、ic Review and Updating Defined Approval Process, which includes Signatory Responsibility Training on the SOP Content A System of Archiving and Version Control,標準操作規(guī)程,241,Regular QA Reviews,There shall be a quality control unit that shall have the responsibility and authority to approve or reject all

50、 components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. The quality control unit s

51、hall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company.,QA定期審閱,242,Regular QA Reviews,All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the qu

52、ality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control r

53、ecords) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation shall extend to other batches of the same drug product and other drug products that may have been as

54、sociated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and follow up.,QA定期審閱,243,QA Reviews21 CFR 211.180(e), General requirements Subpart J - Records and Reports,The cGMP regulations call for at least an annual evalua

55、tion of each drug products quality standards to determine the need for changes in product specifications or manufacturing or control procedures. The rule also requires firms to establish and follow written procedures for conducting those evaluations. Such an evaluation would be incomplete if the sta

56、ndard operating procedures for production and process controls were themselves not reviewed. During Your establishment inspections, when auditing for compliance with section 211.180, determine if the firm has established, and is following, those evaluation procedures. Also check to see if the proced

57、ures call for reviewing SOPs.,QA審閱,244,Part Twelve: SHOWSTOPPERS,第十二部分：總結,245,SHOWSTOPPERSGeneral Quality Assurance,The failure to have written procedures in place that have been approved by the quality unit. Personnel performing critical operations who lack adequate training or experience The failu

58、re to have a quality unit review for product release that includes review of failures, yield discrepancies, and deviations from procedures.,質量保障,246,SHOWSTOPPERSLaboratory Controls,Analytical method not validated Not Stability Indicating Related compounds not distinguished Failure to test finished p

59、roduct Stability program inadequate/not observed Poor investigation of out of spec. findings Analysts and/or equipment not qualified Preservative/media effectiveness testing,實驗控制,247,SHOWSTOPPERSFacilities and Equipment,No cleaning validation No environmental monitoring Obvious avenues of contamination Equipment operating parameters not documented Batch size exceeds capacity of equipment Water and air systems not validated,設施和設備,248,SHOWSTOPPERSProduction and Process Contro