美国FDA顾问药品生产企业验证基础及实质培训(中英对照)

1、美国FDA顾问药品生产企业验证基础及实质培训(中英对照)FUNDAMENTALS AND ESSENTIALS OF VALIDATION验证基础及实质Michael Anisfeld（Dr.麦克.安斯菲尔得）Globepharm Consulting1?Copyright Globepharm, 2005课程安排COURSE SCHEDULEINTRODUCTION + REGULATORY ENVIRONMENT介绍法规环境VALIDATION BASICS 验证基础知识VALIDATION MASTER PLANS 验证主文件PROCESS VALIDATION 工艺验证UTILITIE

2、S VALIDATION 公用系统验证CLEANING VALIDATION 清洁验证COMPUTER VALIDATION 计算机系统验证ANALYTICAL METHOD VALIDATION 分析方法验证CASE STUDY 案例研究2?Copyright Globepharm, 2005HousekeepingCourse Notes 课程注意Master List SurveysAre You Lost ?English American ?Mobile PhoneBeepers-PagersRestroomsFire DrillBreaks and EndingMessages f

3、rom OfficeAirport ?3?Copyright Globepharm, 2005培训期间During this Training SessionIf如果:1.I go too fast我讲的太快2.I use strange words我使用陌生词语3.I get too technical我讲的太专业Please Interrupt and Ask .There Is No Such Thing As A Silly Question 请随时打断我，并提问。4?Copyright Globepharm, 2005请大家自我介绍WHO ARE YOU?Tell Us Your N

4、AME 告诉我你的名字Tell Us Your COMPANY告诉我你的公司Tell Us Your JOB 你的职务Tell Us The PRODUCTS YOUR COMPANY MAKES你公司生产的产品Tell Us YourEXPERIENCE WITH VALIDATION有关验证的经验Tell Us What SPECIFICALLY YOU CAME TO LEARN你想了解的内容5?Copyright Globepharm, 2005Dr.麦克.H.安斯菲尔得MICHAEL H.ANISFELDIndustrial Pharmacist 执业约师Industrial Pha

5、rmacy Faculty University of Illinois毕业于伊利诺伊州州立大学药学系Has trained FDA and MCA inspectors培训过FDA MCA检查官Perform audits on behalf of UN agencies and governments代表联合国政府部门进行审计Performs 25 35 full scale audits annually每年进行2535个审计Has audited in 32 countries 对32个国家的医药企业进行过审计Guides clients through FDA, MCA, TGA,

6、HPFBI and other inspections 帮助客户通过FDA,MCA, TGA, HPFBI及其他官方机构的现场检查6?Copyright Globepharm, 20057?Copyright Globepharm, 2005验证VALIDATIONDefinition非常Very 定义辛苦Arduous周期长L engthy棘手I nvolvedand详细的D etailedAttemptto 试图要Test测试所有事务Everything8?Copyright Globepharm, 2005验证原理及要素FUNDAMENTALS AND ESSENTIALS OF VAL

7、IDATIONSREGULATORY ENVIRONMENT法规环境9?Copyright Globepharm, 2005质量QUALITY“a comprehensive system,designed, documented, implemented and controlled,furnished with personnel, equipment and resources,to provide assurance that products will be consistently fit for, and appropriate to, the intended use”一个全面

8、的质量体系，包含了设计，文件，执行，控制，以及提供足够的人员、仪器、资源，为了确保产品能持续达到既定目标。10?Copyright Globepharm, 2005工艺验证PROCESS VALIDATIONFDA“establishing, through documented evidence, a high degree of assurance that a specific process will consistently produce a product that meets its predetermined specifications and quality charac

9、teristics”通过文档记录，建立一个高水平的保证，既在特定的工艺下能生产出符合既定标准的产品。FDA: Proposed cGMP Rules (21CFR211.3b24), May 199611?Copyright Globepharm, 2005验证目的VALIDATION OBJECTIVEASSURANCE OF CONSISTENCY确保连续性3Consistency Is Great 连续性很重要Inconsistency, or Poor Consistency, Is Terrible 不连续或连续性不好是很糟糕的12?Copyright Globepharm, 200

10、5概念性定义CONCEPTUAL DEFINITIONInstrumentsEquipmentProcessesAreAreIsValidatedCalibratedQualified工艺被验证仪器被校验设备被确认13?Copyright Globepharm, 2005验证不是Validation IS NOT:Validation is not developing the process验证不是工艺研发Validation is not an experiment 验证不是试验Validation is not process optimization验证不是工艺优化Validation

11、 is not a process capability study验证不是生产能力研究Validation is not “worst case testing”验证不是最坏条件测试Validation is not writing the SOP验证不是写SOPValidation is not re-inventing the wheel验证不是彻底重来做Validation is not a voyage of discovery验证不是探索记录验证应该是令人很郁闷的！14?Copyright Globepharm, 2005验证VALIDATION PIC“action of pro

12、ving, in accordance with the principles ofGMP, that any procedure, process, equipment,material, or system actually leads to expected results”符合GMP原则的校对，既所有程序、工艺过程、设备、物料、系统实际上导致预期的结果。Pharmaceutical Inspection Convention GMPs, 199115?Copyright Globepharm, 2005验证VALIDATION PICPIC 5.21“validation studie

13、s should reinforce GMPand be conducted in accordance to defined procedures.Results and conclusions should be recorded”PIC 5.21 验证研究应强化GMP，应遵照既定程序执行。所有结果结论应进行记录。PIC 5.22“when any new manufacturing formula ormethod of preparation is adopted, steps should betaken to demonstrate suitability for routine

14、processing”PIC 5.22 当新生产配方或制备方法被采用时，应采取措施表明常规操作的适用性。Pharmaceutical Inspection Convention GMPs, 199116?Copyright Globepharm, 2005验证VALIDATION PICPIC 5.23“significant amendments to the manufacturing process, including any changes in equipment or materials which may affect product quality and/or the re

15、producibility of the process should be validated”PIC 5.23 生产过程中的显著变更应进行验证。这些变更包括所有可能影响产品质量或影响工艺过程重复性的设备和物料方面的任何变更。PIC 5.24“processes and procedures shouldundergo periodic critical revalidation to ensure thatthey remain capable of achieving the intended results”PIC 5.24 工艺过程和程序应进行周期性临界再验证，以确保这些过程和程序能

16、保持完成既定的结果的能力。Pharmaceutical Inspection Convention GMPs, 199117?Copyright Globepharm, 2005FDA 关于验证的要求FDA REGULATORY REQUIREMENTS FOR VALIDATION21CFR211.10 SAMPLING AND TESTING 取样测试“establish control procedures to monitor the output and to validate the performance of those manufacturing processes that

17、 may be responsible for causing variability in the characteristics of in-process material and drug product”建立控制程序，以监控产品和验证关键生产工艺过程，既可能导致中间体及成品性质的变动的生产过程。21CFR211.68b AUTOMATIC + ELECTRONIC EQUIPMENT 自动电子设备“a written record of the (computer) program shall be maintained along with appropriate validati

18、on data”记录和验证数据应该进行保存及维护。18?Copyright Globepharm, 2005FDA 关于验证的要求FDA REGULATORY REQUIREMENTS FOR VALIDATION21CFR211.84d2 TESTING OF COMPONENTS 测试原辅料“the manufacturer shall establish the reliability of the suppliers analyses through appropriate validation of the suppliers test results生产商通过对供应商分析测试结果的

19、适当验证，来建立对供应商的分析结果可信性评价。21CFR211.165e TESTING + RELEASE OF PRODUCTS 测试放行产品“the accuracy, sensitivity, specificity and reproducibility of test methods employed by the firm shall be established and documented. Such validation and documentation .”生产商使用的成品测试方法的准确性、灵敏度、专署性和重复性应当被建立和文档化。如验证和文件。19?Copyright

20、 Globepharm, 2005工艺验证PROCESS VALIDATION FDA21CFR211.220athe manufacturer shall validate all drug product manufacturing processes including, but not limited to, computerized systems that monitor and/or control the manufacturing process. The manufacturing process includes all manufacturing steps in th

21、e creation of the finished product including, but not limited to: cleaning, weighing, measuring, mixing, blending, compressing, filling, packaging and labeling生产商应对所有产品的生产过程进行验证，包括，但不局限于，监控或控制生产过程的计算机处理系统验证。生产过程应该包括所有接触最终产品的过程，包括，单不局限于：清洗、称量、测量、混合、混批、压缩、填充、包装及贴签。20?Copyright Globepharm, 2005工艺验证PROC

22、ESS VALIDATION FDA21CFR211.220bvalidation protocols that identify the product and product specifications and specify the procedures and acceptance criteria for the tests to be conducted and the data to be collected during process validation shall be developed and approved. 识别产品、产品标准、写明工艺过程及所要进行的测试以及

23、可接受的标准，注明工艺验证过程中需要收集的数据的验证方案应该被建立和批准。The protocol shall specify a sufficient number of replicate process runs to demonstrate reproducibility of the process and provide an accurate measure of variability among successive runs.验证方案中应规定需要足够数量的批次，以证明生产工艺的可重复性，以及准确评估连续批次之间的变化。Validation documentation sha

24、ll include evidence of material suitability and the performance and reliability of equipment and systems.验证文件中应包括物料适用性的证据，和设备、体系性能和可信度的证据。21?Copyright Globepharm, 2005工艺验证PROCESS VALIDATION FDA21CFR211.220cthe manufacturer shall design or select equipment and processes to ensure product specificatio

25、ns are consistently achieved. The manufacturers determination of equipment suitability shall include testing to verify that the equipment is capable of operating satisfactorily within the operating limits required by the process.生产商应该设计或选择合适的设备、工艺过程，以确保能持续生产出达到既定标准的产品。生产商关于设备使用性的决定，应当包括测试设备以确认在生产过程中

26、所需的操作限度下能够进行满意的操作。Process suitability shall include documented rigorous testing todemonstrate the effectiveness and reproducibility of the process. Parts of the process that may cause variability or otherwise affect the product shall be tested.工艺过程的适用性应包括文档化的严格测试，以证明生产工艺的有效性和可重复性。应对可能影响产品质量的部分工艺过程进行

27、测试。22?Copyright Globepharm, 2005工艺验证PROCESS VALIDATIONFDA21CFR211.220dthere shall be a quality assurance system in place which requires revalidation whenever there are changes in packaging, component characteristics, formulation, equipment, or processes, including reprocessing that could affect prod

28、uct effectiveness or product characteristics, and whenever changes are observed in product characteristics.应当建立质量保障体系，无论何时，当包装、原辅料性质、配方、设备、或工艺过程（包括可能影响产品效价或产品性质的再加工）发生变更时；无论何时发现产品性质发生变化时，确保进行再验证。23?Copyright Globepharm, 2005分析方法验证METHOD VALIDATION FDA21CFR211.222the accuracy, sensitivity, specificit

29、y, and reproducibility of test methods used by a manufacturer shall be validated and documented. Such validation shall be accomplished in accordance with 21CFR211.194a2生产商应对所使用的分析方法的精密度、灵敏性、专属性及重复性要进行验证以及文档化。分析方法验证应参考21CFR211.194a2。24?Copyright Globepharm, 2005验证VALIDATION South Africa9In manufactur

30、ing no two objects are ever made exactly alike.Five factors contribute to variation: inherent process methods, raw materials, environment, human element, testing methods (9.1.2)在生产中，没有2个产品是能够完全一致地生产出来的。5个因素导致可变性：生产工艺，原辅料，环境，人为因素，测试方法。9When all assignable causes of variation are eliminated, and onlyc

31、hance causes remain, the process is validated (9.1.3)当所有影响因素被消除，生产工艺是验证过的。9SPC may be used to demonstrate that a process has been validated(9.1.4)SPC可用来证明生产工艺是验证过的。9A process in a state of control contributes to productivity and profitability by reducing waste; increasing the yield of salableproduct

32、; and reducing the cost of inspection and test activities (9.1.5)处于控制状态的生产过程可以有助于减少浪费，提高收率，降低检查以及测试的成本。Source: South Africa GMPs, 199525?Copyright Globepharm, 2005验证阶段VALIDATION PhasesCovers all Activities in: 包括所有活动Development + Formulation 研发阶段Pilot Batches + Scale-Up Studies中试放大生产Tech transfer to

33、 Commercial Scale转移到工业化规模Equipment Qualifications IQ, OQStage设备确认IQ,OQMaster Production Documents1工艺规程文件Process Capability Studies生产能力研究Source: Canadian Validation Guidelines, 2000.hc-sc.gc.ca/hpb-dgps/therapeut26?Copyright Globepharm, 2005验证阶段VALIDATION PhasesCovers all Activities in:包括所有活动Process

34、Validation (PV) 工艺验证Verification that all critical parameters are valid and can be reproduced even in “worst case”Stageconditions2确认所有的关键工艺参数是有效的，能在最苛刻条件下重复生产的。Canadian Validation Guidelines, 200027?Copyright Globepharm, 2005验证阶段VALIDATION PhasesCovers All Activities In:包括所有活动Validation Maintenance

35、验证维护?Review of Process Related Documents回顾与工艺有关的所有文件?Review of Validation Audit Reports回顾验证审计报告Deviations 偏差Changes 变更StageFailures 失败Modifications 修改3?Review That SOPs Have Been Validated回顾已经验证的SOPS。?Effectiveness of Change Control评估变更结果?Re-Validation / Revalidation Need 再验证/评定是否需要再验证Canadian Valid

36、ation Guidelines, 200028?Copyright Globepharm, 2005文档化DOCUMENTEDWritten 起草by a knowledgeable and trained person由经过培训的、有相应知识的人起草Reviewed 审核by someone equally proficient由精通的人审核approved批准at an appropriate level of management由适当的管理人员批准Retained 保存kept on file and available forreference文件归档保存。29?Copyright

37、 Globepharm, 2005FDA 座右铭FDA Maximsif it is not documented, it is a rumor如果没有文档化，那就是谣言！if its documented, but not signed its graffiti如果文档化了，但没有签名，那就是乱写！in God we trust .all others provide data30?Copyright Globepharm, 2005问题Questions?31?Copyright Globepharm, 2005FUNDAMENTALS AND ESSENTIALSOF VALIDATIO

38、NVALIDATIONBASICS验证基础知识32?Copyright Globepharm, 2005验证策略VALIDATION STRATEGIESPROSPECTIVE VALIDATION 前性验证CONCURRENT VALIDATION 同步验证RETROSPECTIVE VALIDATION 回顾性验证DEVELOPMENT VALIDATION 研发验证33?Copyright Globepharm, 2005研发验证DEVELOPMENT VALIDATIONa series of documented evidences demonstrating that the de

39、velopment process followed a development plan, and that each phase of the development plan was formally reviewed and approved at suitable milestones一系列的文件证明研发过程是基于研发计划进行的，以及每一阶段研发计划是经过审核和批准的。note: the end result of development validation is typically a technology transfer document, formally reviewed

40、 and approved by research+development personnel; and formally accepted by facilities manufacturing, engineering and quality personnel注意：研发验证的最终结果是技术转移文件，要经过RD人员审核和批准，生产、工程和质量人员的接受。34?Copyright Globepharm, 2005技术转移文件TECHNOLOGY TRANSFER DOCUMENTTechnology Transfer Document (TTD) signifies the end of p

41、roduct or process development activities, and includes:技术转移文件TTD意味着产品或工艺研发的结束，包括：?Bills of Materials 物料列表?Development Plan + Rationale研发计划基本原理?Actives + Excipients?Critical Parameter Listing?Specifications 标准关键参数列表?+ Test Methods 测试方法?Batch Comparisons 批对照?Raw Materials 原料?Formulation Batches 制剂批?In

42、-Process 中间控制?Stability Batches 稳定性批?Finished Product 成品?Clinical / Bio Batches 临床试验批?Equipment Recommendations?Scale-Up Batches 放大批建议使用的设备?Validation Batches 验证批大批?Product Methods 工艺过程?Stability Reports 稳定性报告35?Copyright Globepharm, 2005关键参数列表Critical Parameter ListingTTD -The Validation Teams Star

43、ting Point 起始点Identifies Validation Activities 确认验证内容Sequences Validation Activities 验证次序Prioritizes Validation Activities 验证优先顺序36?Copyright Globepharm, 2005技术转移Technology TransferTransfer -Phase 1第一阶段Development meets with Production / QC / QAexplains technology研发与生产部门/QC/QA开会，说明技术资料Transfer Phase

44、 2Development demonstrates technology ensures production/QC understands研发讲解技术资料，确保生产部门/QC理解Transfer Phase 3Production/QC apply technology 生产部门/QC接受技术资料development monitor -assure adequate skill levels demonstrated37?Copyright Globepharm, 2005TTD活动顺序TTD -Sequence of Activity (1)InputActivityOutputPla

45、nning; Purchasing; Vendor SCHEDULING Agreed Scale-up Campaign Scheduling; Regulatory; Compliance; Strategy (Number of Batches, SCALE-UP Validation; ArtworkBatch Sizes); Raw Materials BATCHESOrdered 准备放大生产计划安排Development Specifications, Methods; PREPARATION PQ Protocols; Cleaning Documentation; Valid

46、ation; Compliance; FOR Validation Protocols; Batch Production; QualityMANUFACTURERecords-Manufacture/Cleaning; SOPs For Plant/Equipment; 准备生产Personnel Training; QC Specifications And Methods; QA Compliance AuditDevelopment; Technical/Engineering; MANUFACTURINGScale-up Of Finished ProductProduction;

47、Compliance; Validation; 生产Completed Batch DocumentationQACompleted PQCompleted Cleaning Study38?Copyright Globepharm, 2005TTD活动顺序TTD -Sequence of Activity (2)InputActivityOutputSpecifications; Methods; Scale-up FINISHED Approved Finished Product Batches Of Finished Product; PQ Packaging; COAs; OOS R

48、eportsPRODUCT CriteriaTESTING成品测试Completed Batch Documentation; SCALE-UP Changes -Additional Scale UpIncident Reports; Validation; APPROVALOR Compliance Reports; QA/QC Test 同意放大Product TransferResultsPost Approval StabilityProduct Transfer Sign-offsTTD COMPLETION TTD完成39?Copyright Globepharm, 2005TT

49、D接受TTD AcceptanceOnly accepted by production + quality control if:Methodology is shown to be robustProcess is optimized (or is as best as its going to get for now)At least one batch has been run on production+qc equipmentTTD needs to be formally accepted by production, quality control, engineering a

50、nd quality assuranceTTD acceptance is formal end to development activities40?Copyright Globepharm, 2005技术转移Technology TransferFormal technology transfer is a vital element in speedy and efficient product start-up正式的技术转移是否能快速、有效地生产中至关重要地一步。41?Copyright Globepharm, 2005预验证PROSPECTIVE VALIDATION“valida

51、tion of a process, procedure, etc., beforeproduction begins is a part of orderly product orprocess development”预验证是生产前验证工艺、过程等，是生产或工艺研发的一部分。Australian Code of GMP, 199342?Copyright Globepharm, 2005预验证PROSPECTIVE VALIDATION“establishing documented evidence that a process orsystem will do what it purp

52、orts to do based on apre-planned protocol”建立文件体系，工艺或系统会按照预先制定的方案中要求的去做。FDA Guidelines on Process Validation, 198743?Copyright Globepharm, 2005预验证PROSPECTIVE VALIDATION“establishing documented evidence that a process orsystem will do what it purports to do based on apre-planned protocol”FDA Guideline

53、s on Process Validation, 1987note: considered to be complete when a minimum of 3successive experimental runs are shown to meet predetermined specifications注意：至少3个连续批次的产品能满足预先设定的标准，则认为完成了预验证。44?Copyright Globepharm, 2005为什么WHY 3 ?3 BLIND MICE?3 MUSKETEERS?3 STOOGES?3 WISE MEN?3 LITTLE PIGS?3 KINGS?3

54、STRIKES AND YOU ARE OUT?3 COINS IN A FOUNTAIN?3 POINTS ON A GRAPHetc. etc. MINIMUM OF 3 RUNS45?Copyright Globepharm, 2005How Many Validation Runs?/./cder/guidance/cGMPs/production.htm46?Copyright Globepharm, 2005CPG 7132c08 of Mar 12, 2004: Forget 347?Copyright Globepharm, 2005CPG 7132c08: Pr

55、ocess Validation Requirements for Drug Products and Active Pharmaceutical IngredientsA validated manufacturing process has a high level of scientificassurance that it will reliably produce acceptable product. 一个经过验证的工艺应具有高度的科学的保证，确保能可靠的生产出可接受的产品。The proof of validation is obtained through rational e

56、xperimental design and the evaluation of data, preferably beginning from the process development phase and continuing through commercial production phase验证的证据来自于合理的设计以及对数据的评估，最好从工艺研发阶段开始持续到工业生产阶段。Before commercial distribution begins, a manufacturer is expected to have accumulated enough data and knowledge about the commercial production process to support post-approval product dis