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UTILITIES 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, 2005
HousekeepingCourse Notes 课程注意Master List SurveysAre You Lost ?English –American ?Mobile Phone–Beepers-PagersRestroomsFire DrillBreaks and EndingMessages from OfficeAirport ?3©Copyright Globepharm, 2005
培训期间During this Training SessionIf如果: go too fast我讲的太快 use strange words我使用陌生词语 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 NAME 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, 2005
Dr.麦克.H.安斯菲尔得MICHAEL Pharmacist 执业约师Industrial Pharmacy 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25－35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, 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, 2005
7©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 VALIDATIONSREGULATORY 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 VALIDATION[FDA]“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 characteristics”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 (), 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, 2005
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 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 proving, 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 [PIC]PIC “validation studies should reinforce GMPand be conducted in accordance to defined and conclusions should be recorded”PIC 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 “when any new manufacturing formula ormethod of preparation is adopted, steps should betaken to demonstrate suitability for routine processing”PIC 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 [PIC]PIC “significant amendments to the manufacturing process, including any changes in equipment or materials which may affect product quality and/or the reproducibility of the process should be validated”PIC 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 “processes and procedures shouldundergo periodic critical revalidation to ensure thatthey remain capable of achieving the intended results”PIC 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保持完成既定的结果的能力。Pharmaceutical Inspection Convention GMPs, 199117©Copyright Globepharm, 2005
FDA 关于验证的要求FDA REGULATORY REQUIREMENTS FOR SAMPLING AND TESTING 取样＆测试“establish control procedures 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 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。 AUTOMATIC + ELECTRONIC EQUIPMENT 自动＆电子设备“a written record of the (computer) program shall be maintained along with appropriate validation data”记录和验证数据应该进行保存及维护。18©Copyright Globepharm, 2005
FDA 关于验证的要求FDA REGULATORY REQUIREMENTS FOR TESTING OF COMPONENTS 测试原辅料“the manufacturer shall establish the reliability of the supplier’s analyses through appropriate validation of the supplier’s test results生产商通过对供应商分析测试结果的适当验证，来建立对供应商的分析结果可信性评价。 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 Globepharm, 2005
工艺验证PROCESS VALIDATION [FDA] 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 the 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PROCESS VALIDATION [FDA] 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 shall 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 [FDA] manufacturer shall design or select equipment and processes to ensure product specifications are consistently achieved. The manufacturer’s 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测试。22©Copyright Globepharm, 2005
工艺验证PROCESS VALIDATION[FDA] 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 product 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 [FDA] accuracy, sensitivity, specificity, and reproducibility of test methods used by a manufacturer shall be validated and documented. Such validation shall be accomplished in accordance with 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。24©Copyright Globepharm, 2005
验证VALIDATION [South Africa]9In manufacturing no two objects are ever made exactly factors contribute to variation: inherent process methods, raw materials, environment, human element, testing methods ()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 onlychance causes remain, the process is validated ()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()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; and reducing the cost of inspection and test activities ()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 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[ Globepharm, 2005
验证阶段VALIDATION PhasesCovers all Activities in:包括所有活动Process 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 –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3Review 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 Validation 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 Globepharm, 2005
FDA 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 it’s 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, 2005
FUNDAMENTALS AND ESSENTIALSOF VALIDATIONVALIDATIONBASICS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 development 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 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 product 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 + ExcipientsCritical Parameter ListingSpecifications 标准关键参数列表+ Test Methods 测试方法Batch Comparisons 批对照Raw Materials 原料¾Formulation Batches 制剂批In-Process 中间控制¾Stability Batches 稳定性批Finished Product 成品¾Clinical / Bio Batches 临床试验批Equipment Recommendations¾Scale-Up Batches 放大批建议使用的设备¾Validation 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 Team’s Starting 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 / QA–explains technology研发与生产部门/QC/QA开会，说明技术资料Transfer –Phase 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, 2005
TTD活动顺序TTD -Sequence of Activity (1)InputActivityOutputPlanning; 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; Validation; 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; Compliance; Validation; 生产Completed Batch DocumentationQACompleted PQCompleted Cleaning Study38©Copyright Globepharm, 2005
TTD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 ReportsPRODUCT 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, 2005
TTD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 and 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“validation 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 purports 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 Guidelines 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 MICE3 MUSKETEERS3 STOOGES3 WISE MEN3 LITTLE PIGS3 KINGS3 STRIKES AND YOU ARE OUT3 COINS IN A FOUNTAIN3 POINTS ON A GRAPHetc. etc. MINIMUM OF 3 RUNS45©Copyright Globepharm, 2005
How Many Validation Runs? Globepharm, 2005
CPG 7132c08 of Mar 12, 2004: Forget ‘3’’47©Copyright Globepharm, 2005
CPG 7132c08: Process 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 experimental 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 distribution商业销售前，生产商被要求积累关于改产品工业生产的足够的数据和知识，以便支持批准后的产品销售。Conformance batches (sometimes referred to as “validation”batches and “demonstration”batches) are prepared to demonstrate that under normal conditions and defined ranges of operating parameters, the commercial scale process appears to make acceptable product.验证批次的生产用以证实在正常条件下和设定的操作参数范围内，商业规模的生产能够制造出合格的产品。Prior to the manufacture of conformance batches the manufacturershould have identified and controlled all critical sources of variability在工业生产之前，生产商应鉴别和控制所有关键的可变性来源。48©Copyright Globepharm, 2005
CPG 7132c08: Process Validation Requirements for Drug Products and Active Pharmaceutical IngredientsConformance Batches:验证批New drug applications may be approved prior to completion of theinitial conformance batch phase of process validation新药申请在完成首批的工艺验证前可能被批准。Completion of Initial Conformance Batch:完成首批工艺验证For some products, the completion of the initial conformance batch phase of process validation before the distribution of any one batch would require the manufacture of unneeded batches (. certain orphan drugs), which would not be in the interest of public health.对一些产品来说，在销售任何一批不需要再生产的批次（如：罕用药）前完成完成首批工艺验证，不是为了公共健康。In addition the completion of multiple batches before first distribution may also be impractical for a product with a very short shelf-life or one that is intended for limited use (. radio-pharmaceuticals). Therefore the need to manufacture multiple conformance batches in advance of initial product distribution may not be needed. In such cases product distribution may have occurred concurrently with release of the conformance batch另外，对于效期很短的药物或限制使用的药物（如：放射性药物），在首批商业销售前完成多批生产验证是很不实际的。因此，在销售前完成多批工艺验证是没有必要的。这种情况下，商业销售会与工艺验证同步进行。49©Copyright Globepharm, 2005
CPG 7132c08: Process Validation Requirements for Drug Products and Active Pharmaceutical IngredientsThe FDA’s evaluation of a firm’s decision to release batches concurrent with the manufacture of the initial conformance batch should include review of:FDA会评估生产商关于销售产品伴随首批工艺验证的决定 firm’s basis for justifying the distribution of individual batches prior to completion of the initial conformance batches生产商在完成首批工艺验证前销售生产批的依据 firm’s protocol/plan and available data to verify that there are adequate batch controls and testing prior to release for distribution of each batch, and provision of adequate and timely assessment of the process validity once all initial conformance batches have been manufactured, and公司的方案/计划以及可得到的数据用以证明这些批次是经过适当的控制，每批产品在放行前经过测试，一旦首次的工艺验证完成后，能对工艺有效性提供足够的、及时的评估。 firm’s program for monitoring distributed batches and provisions for a rapid response to information suggesting the process is not under control ( batch failures, production problems related to process design or equipment performance)公司50©Copyright Globepharm, 2005
设备确认EQUIPMENT QUALIFICATION“the process of determining that a device, apparatus,or piece of manufacturing or control equipment meets all design and performance specificationsincluding ‘boundary’, ‘worst case’, and ‘power failure’conditions”设备确认是确定装置、仪器，或生产的一部分或控制设备符合所有设计和性能标准的过程，包括“临界点”、“最坏情况”和“动力失灵”的情况。“equipment qualification is a necessary preliminary toprocess validation”设备确认是在工艺验证之前的必需的准备阶段。Australian Code of GMP, 199351©Copyright Globepharm, 2005
最坏情况Worst CaseWorst Case最坏情况A condition or set of conditions encompassing upper and lower processing limits and circumstances, within standard operating procedures, which pose the greatest chance of product or process failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure.是一种包括工艺极限上限和下限的情况以及环境状况，不超出当与理想条件相对比下提出的使产品或工艺有最大几率失败的标准操作规程。这种情况不是诱发产品或工艺的失败的必要条件EU GMPs –Annex 15, 200152©Copyright Globepharm, 2005
回顾性验证RETROSPECTIVE VALIDATION“conducting validation studies performed afterproduction has begun, and designed to show that theprocess, procedures, etc., are effective and robust(insensitive to variation) within the likely ranges ofvariables affecting them”实施验证研究在生产开始以后进行，并设计来显示工艺、规程等，在可能会产生影响的的变量范围之内是有效的和耐用的。Australian Code of GMP, 199353©Copyright Globepharm, 2005
回顾性验证RETROSPECTIVE VALIDATION“conducting validation studies performed afterproduction has begun, and designed to show that theprocess, procedures, etc., are effective and robust(insensitive to variation) within the likely ranges ofvariables affecting them”实施验证研究在生产开始以后进行，并设计来显示工艺、规程等，在可能会产生影响的的变量范围之内是有效的和耐用的。Australian Code of GMPNote: Evaluation of a minimum of 30 successive runs is considered statistically significant 评估至少30个连续批次被认为是有统计学意义的。Note: The collection of data showing that batchesalways meet specifications is not, in itself, validation注意：收集的数据显示批次总是符合预定的标准，这不是验证的本身。54©Copyright Globepharm, 2005
回顾性验证RETROSPECTIVE VALIDATIONEvaluation of a minimum of 30successive prior runs (considered to be statistically significant), is acceptable when:评估至少30个连续批次被认为是有统计学意义的，在以下情况下是可接受的：all batches meet all specifications,所有的批符合标准，no unacceptable deviations, corrective actions, or changes to manufacturing/packaging documents have occurred in the data set在已设定的数据中，生产/包装文件中没有出现不可接受的偏差，修正措施，或变更。and no changesare seen in:并且在以下的情况中不能出现变更Raw Materials And Finished Product Specifications 原料和成品的标准Master Manufacturing/Packaging Records主要的生产/包装记录Stability Profiles Of The Batches 批稳定性试验Trend Analysis Of Quality Related Complaints与质量相关的投诉的趋势分析cPkAnalysis shows acceptability (value > )cPK分析显示可接受性（〉）55©Copyright Globepharm, 2005
56©Copyright Globepharm, 2005
同步验证CONCURRENT VALIDATIONwhere product is:当产品是：a. very low production volume (one batch a year), 产量非常的低（一年一批）b. very expensive, 非常昂贵c. the manufacturing process is very lengthy (several months),生产过程非常长（几个月）then validation is performed simultaneous to production and product release验证是在与生产和产品放行同时进行的Note:注意：FDA requires where product is to be released to market under a concurrent validation plan, that FDA has reviewed and approved the validation plan prior to its implementation FDA要求FDA在验证计划施行之前审核和批准了验证计划，产品在进行同步验证计划时不能放行进入市场。57©Copyright Globepharm, 2005
同步验证CONCURRENT VALIDATIONTypically performed with:典型的同步验证Clinical trial manufacture 用于临床研究的生产Reprocessing –Rework Situations 再加工－返工情形58©Copyright Globepharm, 2005
验证总结VALIDATION CONCLUSIONWe Have Demonstrated What the Protocol Called For:We Did Not Demonstrate What the Protocol Called For:59©Copyright Globepharm, 2005
BACK-TO-BASICS Remember the ScienceACTIVITYPARAMETERIMPACT活动参数影响/结果dryingair flowmoisture content干燥气流速度水份millingfeed ratecrystal size / shape磨粉进料速率晶体大小/形状blendingtimemixing / demixing混批时间混合均匀/没有混合均匀tabletingfeed levelfeed flow / compression制片进料高度进料速度/压缩stabilityshelf designtemperature distribution稳定性货架期温度分布Theory and Practice of Industrial PharmacyHPLCmobile phaseassay accuracyEditors: Lachman, Lieberman and KoenigHPLC流动相分析精密度Publisher: Lea and Febiger60©Copyright Globepharm, 2005
工程Engineering 101CommissioningQualification试生产确认61©Copyright Globepharm, 2005
确认－试生产Qualification –Commissioning Commonalities9Calibration Records 校验报告9Equipment Lists 设备列表9Input/Output Testing 输入输出测试9Component Lists 物料列表9Loop Checks 检查回路9Utility Verification Reports 9Alarm Testing 报警器测试公用设施确认报告9Operations Sequencing 操作先后顺序9System Drawings 系统草图/流程图9Integrated System Testing9Operating Procedures 操作过程整个系统进行测试62©Copyright Globepharm, 2005
确认－试生产Qualification –Commissioning DifferencesQUALIFICATION 确认COMMISSIONING 试生产User Responsibility 用户职责Supplier Responsibility 供应商职责Demonstrate that process operated under controlObjective –to identify and fix 证明工艺操作是在可控条件下进行problemsMust follow protocol目的－识别＆安装必须安装方案进行No protocol required 不需要协议User generated 由用户进行Supplier generated 由供应商进行All data and changes to be reviewed and approvedNot all data recorded or reviewed所有的数据以及变更都需要审核、批准。不需要记录或审核所有的数据Written report requiredUsually no written report需要报告通常没有报告Reviewed/Accepted by QAReviewed/Accepted by Engineers由QA审核/接受由工程部审核/接受63©Copyright Globepharm, 2005
FATs–Factory Acceptance TestsFATS-工厂验收测试SATs –Site Acceptance TestsSATS-安装验收测试HATs–Hardware Acceptance TestsHATS-硬件验收测试64©Copyright Globepharm, 2005
THE VALIDATION LOOP验证评估设计确认QDESIGN VALIDATION UVQUALIFICATIONEAAASSESSMENT校验PQLLRCALIBRATIONU验II校验O证IFD过CPINSTALLATION IA程CHANGE EMCTQUALIFICATIONSCONTROLEAI安装确认S变更控制NTOTIN设PERFORMANCE O备确NVALIDATIONOPERATIONAL认运行确认性能确认QUALIFICATION65©Copyright Globepharm, 2005
概念性定义Conceptual Definitions确认是基于工程学验证是基于研发QualificationValidationIsIsEngineeringDevelopmentBasedBased66©Copyright Globepharm, 2005
验证循环THE VALIDATION LOOPDESIGNQUALIFICATION设计确认67©Copyright Globepharm, 2005
DESIGN QUALIFICATION [DQ]a documented process that summarizes design documents developed for the equipment, or system, together with approvals granted, dates and copies of signaturesthe DQ is the company’s guarantee that the company has properly developed design criteria, and that GMPs have been followed68©Copyright Globepharm, 2005
Dish Washer DQParameter 参数QAC69©Copyright Globepharm, 2005
Dish Washer DQParameterQACDish Washer Size 洗碗机的尺寸36”H x 24”D x 24”W Load –Typical (self, spouse, kids) 特殊负荷(本人,4 plates + 4 mugs四配偶,小孩)个盘子+四个杯子18 plates + 18 glassesLoad –Maximal (neighbors, in-laws, friends)十八个盘子+十八个杯子最高负荷(邻居,亲家,朋友)Cycle Time时间周期30 minutes三十分钟Energy Usage (cost/cycle) 耗费精力(成本/周期)$ –Typical (cereal; veggies; tea)squeaky clean特殊清洁(谷类食品,素食,茶)清洁的响声Cleanliness –Maximal (egg-sausage; lasagna)squeaky clean70最高清洁(蛋黄香肠,烤面条)清洁的响声©Copyright Globepharm, 2005
Design Qualification [DQ]The longer you spend on the DQThe quicker the IQ / OQ / PV在DQ上花的时间较长IQ/OQ/PV就会较快71©Copyright Globepharm, 2005
Design Qualification [DQ]P roper 适当的P rior优先的Planning计划Prevents预防P itiful怜悯P erformance执行72©Copyright Globepharm, 2005
THE VALIDATION LOOPDESIGN QUALIFICATION设计条件CALIBRATION校准73©Copyright Globepharm, 2005
CALIBRATION [METROLOGY]documented evidence that a measuring device produces results within specified limits over its operating range一个计量器具明确文件产生是以详细的说明测量限度即测量范围为结果的.74©Copyright Globepharm, 2005
THE VALIDATION LOOPDESIGN QUALIFICATION设计条件CALIBRATION校准INSTALLATION QUALIFICATION安装确认75©Copyright Globepharm, 2005
INSTALLATION QUALIFICATION [IQ]documented evidence that installation of a piece of equipment conforms to the specifications of the equipment manufacturer, or equipment user, or both (static attributes)一个明确的文件要有一件设备安装应该遵照设备的厂商,使用者的标准the IQ captures key baseline information about systems or equipment installed and verifies that the installed equipment is what was specified关于系统或设备安装,校验等要战胜IQ的关键信息是设备安装需要什么样的标准76©Copyright Globepharm, 2005
Does Every Piece of Equipment Need IQ?Consider IQ as needed if the equipment:设备是否是IQ必须考虑的comes with a manual that needs to be marked and kept一个工作手册需要标记和受控is to be marked with a tag number.标签的数量被做记号impacts product fitness –form –function产品的使用因素-外观-功效requires precautions for installation,安装是必要的预防shall be included on calibration or maintenance schedules包括校验和维护时间carries a serial number.进行编号is required by GMP to have its own usage-maintenance log根据GMP的需要有自己的使用记录requires operator training to be used使用时需要操作培训77©Copyright Globepharm, 2005
THE VALIDATION LOOPDESIGN QUALIFICATION设计确认CALIBRATION校验INSTALLATION QUALIFICATION安装确认OPERATIONALQUALIFICATION运行确认78©Copyright Globepharm, 2005
OPERATIONAL QUALIFICATION [OQ]documented evidence that the system operates as intended to control the specified operating parameters. OQ testing is specifically defined for each system or equipment and may include testing of controls, indicators, and alarms (dynamic attributes)明确的操作系统文件必须要求控制特定的参数,作为每个系统或设备,也包括控制的检测,指示剂和警告.79©Copyright Globepharm, 2005
运行确认Operational Qualification [OQ]Operational Qualification is the documentation of the specific dynamic equipment attributes 运行确认是特定的动态设备属性的文件。to prove that the equipment operates as expected throughout its specified operating range来证明设备从始至终在规定的运行范围内预期的运行。OQ is verification of the DQ运行确认是设计确认的验证80©Copyright Globepharm, 2005
什么需要确认What Needs to Be Qualified?Assess Criticality确定关键点Risk is intolerable风险是不能忍受的Risk undesirable风险是不合需要的(FMEA / HACCP)Risk very low –considered negligible 风险非常低——考虑忽略Assess Regulatory Requirements确定法规需求What do regulations mandate must be validated什么是法律规定要验证的81©Copyright Globepharm, 2005
FMEA -Example82©Copyright Globepharm, 2005
Hazard Analysis of Critical Control Points (HACCP)validationneeded83©Copyright Globepharm, 2005
验证圈THE VALIDATION LOOPDESIGN 设计确认QUALIFICATIONCALIBRATION校验INSTALLATION QUALIFICATION安装确认(calibration)校验OPTIMIZATION最优化84©Copyright Globepharm, 2005
最优化OPTIMIZATIONprocess by which the optimum parameters for manufacture are determined, including those parameters, or combinations of parameters providing the most consist process resulting in:确定了最优化生产参数的工艺，包括、或整合最一致的工艺的参数，可导致：the lowest levels of impurities / degradation product最低量的杂质/降解产物the optimum yield 最佳收率the most efficient / economical operation 最有效/经济的运行85©Copyright Globepharm, 2005
THE VALIDATION LOOPDESIGN 设计确认QUALIFICATIONCALIBRATION校验PERFORMANCE INSTALLATION QUALIFICATION安装确认VALIDATION性能验证OPERATIONAL 运行确认QUALIFICATION86©Copyright Globepharm, 2005
工艺验证－性能确认PV –PQPQ –Performance Qualification 性能确认-Process Qualification工艺确认PV –Performance Validation性能验证-Process Validation工艺验证Depends Which Book You Read !Depends When the Book Was Written !Depends Where the Book was Written !Depends on Who Wrote the Book !87©Copyright Globepharm, 2005
工艺验证Process ValidationQualifiedQualifiedEquipmentUtilities确认过的设备确认过的公用设施PVPeopleProvenTrained SOPsIn SOPs确认过的SOPS接受过SOPS培训的人员88©Copyright Globepharm, 2005
性能验证PERFORMANCE VALIDATION [PV]documented evidence that the process, or product, conforms to expectations as determined through independent parameter measurement and / or through intensive sampling, or challenge性能确认：是通过对每个参数的测试、评估/或全面的取样/或挑战试验，来证明产品或工艺是符合预期目标的文件化的活动。PV may be used in cases where performance data are gathered over a long period of time. Under these circumstances, it is difficult to “approve”the OQ as complete. PV可能被用于性能数据需要在很长一段时间里收集的情况下。在这种情况下，很难证明OQ是完全的。One solution is to define and approve the OQ as a single point in time, and to create a PV protocol which is then used as the vehicle to amass the on-going data一个解决方法是及时把运行确认（OQ）定义为一个点，同时建立一个PV方案,可用于收集持续数据的载体。89©Copyright Globepharm, 2005
性能验证Performance Validation [PV]Performance validationis used where performance data needs to be gathered over long time periods性能验证：适用于性能数据需要较长时间收集的情况下。The OQ may be a “point-in-time”, an early stage of the PV 运行确认可以是一个点，PV的前一阶段。90©Copyright Globepharm, 2005
OQ + PVGrowing industry trend to combine OQ + PV逐渐形成OQ和PV结合起来的趋势Very few true system-challenge PV¾Aseptic media filling 无菌装填¾Filter Integrity 过滤器完整性¾Seal Integrity 密封圈完整性¾Bar Code Readability 条形码的可读性¾Software Code Testing 软件代码测试91©Copyright Globepharm, 2005
回顾OverviewEQDQPV设计确认IQOQ性能验证安装确认运行确认92©Copyright Globepharm, 2005
The Qualification-Validation Relationship确认－验证之间的联系93©Copyright Globepharm, 2005
回顾OverviewThe qualification and validation process should establish and provide documentary evidence that:确认和验证过程必须确立和提供如下文件化资料： The premises, the supporting utilities, the equipment and the processes have been designed in accordance with the requirements of GMP.按照GMP要求进行了厂房、公用设施、设备和工艺的设计。This normally constitutes Design Qualification or DQ.通常这些设计构成了设计确认。 The premises, supporting utilities and the equipment have been built and installed in compliance with their design specifications.按照设计要求，厂房、公用设施和设备进行了建造和安装。This constitutes Installation Qualification or IQ.这些构成了安装确认。 The premises, supporting utilities and the equipment operate in accordance with their design specifications.厂房、公用设施、设备和工艺的运行符合其设计要求。This constitutes Operational Qualification or OQ.这些构成了运行确认。 A specific process will consistently produce a product meeting its predetermined specifications and quality attributes.一个特定的工艺将持续生产出符合既定的标准和质量特性的产品。This constitutes Process Validation or PV.这些构成了工艺验证。The term Performance Qualification or PQ may be used Validation Master Plan Installation And Operational Qualification, 200194©Copyright Globepharm, 2005
验证THE VALIDATION LOOPDESIGN QUALIFICATION设计确认CALIBRATION校验CHANGE INSTALLATION CONTROLQUALIFICATION变更控制安装确认PERFORMANCE OPERATIONAL VALIDATIONQUALIFICATION性能确认运行确认95©Copyright Globepharm, 2005
验证的变更控制VALIDATION CHANGE CONTROLformal monitoring system, by trained personnel from appropriate disciplines, who review proposed or actual changes that might impact the validated status and define and authorize appropriate action to assure that the process, or system, or equipment, remains in a validated state由经过培训的、有相应学科背景的人员来审核提出的或者实际存在的会影响验证状态的变更；阐释和批准适当的措施以确保工艺、系统、设备维持在验证的状态的正式的监控体系。96©Copyright Globepharm, 2005
验证循环THE VALIDATION LOOPVALIDATIONDESIGN QUALIFICATION设计确认ASSESSMENTCALIBRATION校验验证评估CHANGE INSTALLATION CONTROLQUALIFICATION变更控制安装确认PERFORMANCE OPERATIONALVALIDATIONQUALIFICATION性能确认运行确认97©Copyright Globepharm, 2005
验证评估VALIDATION ASSESSMENTTO MONITOR THE IMPACT OF CHANGE ON THE VALIDATED SYSTEM, AND TO ASSESS CORRECTIVE ACTION / RE-VALIDATION REQUIREMENTS: 验证评估：监控基于验证系统的变更而产生的影响，并评估纠正措施/再验证要求equipment calibration reviewchange control review设备校验审核变更控制回顾equipment usage logs 设备使用台帐batch record reviewequipment preventive maintenance / 批记录审核inspection reportsannual product review设备预防性维护/检查报告产品年度回顾personnel changes (?)deviation/product failure 人员变更？investigationCpk analysis Cpk（工艺性能指数）分析偏差或不合格品的调查data / trend analysis数据/趋势分析audit reports审计报告98©Copyright Globepharm, 2005
工艺性能指数Process Capability Index-CpkA measure of how well data is centered within specification limits:Cpk：一项关于数据在标准限度内如何很好集中的测试方法。Cpk > X –LSL USL –XFavorable processCpk = min,良好工艺3σ3σCpk – Marginal processLSL = lower specification limit低于指标限度边际工艺USL = upper specification limit高于指标限度Cpk < Unfavorable process不适宜工艺99©Copyright Globepharm, 2005
再验证Re-ValidationRe-Validation can be necessary when:当存在如下情况时再验证是有必要的：Change in characteristics of raw material原料性质发生了改变Change in source of active raw material活性（主要）原料来源发生了变化Change in primary packaging material内包材发生了变化Change in critical process parameters关键工艺参数发生了变化Change in equipment设备变更Change in facility location 设施、设备位置变更Change in regulatory environment法规环境发生变更A decision not to re-validate needs a written full justification.不进行再验证的决定需要一份书面的全面的解释说明100©Copyright Globepharm, 2005
瓶标签机BOTTLE LABELER [IQ]标签机LABELER文件要求公共设施主要部件部件材质润滑剂安全功能EQUIPMENTDOCUMENTATIONUTILITIESMAJORCOMPONENTLUBRICANTSSAFETYIDENTIFICATIONREQUIREMENTSCOMPONENTSMATERIALSFUNCTIONS设备确定MANUALSELECTRICALSMETERING转轮WHEEL操作手册DRAWINGSCOMPRESSED AIRBARCODE草图READER条形码电气设备SOPs压缩空气101©Copyright Globepharm, 2005
瓶标签机BOTTLE LABELER [OQ]LABELER标签机Type title here型号CALIBRATIONEQUIPMENTEQUIPMENT设备控制设备运行REQUIREMENTSCONTROLSOPERATION校验要求设备转速发动机标签发放SWITCHES设定速度EQUIPMENTMOTORLABEL DISPENSER开关ROTATION[fixed speed]PUSH BUTTONSLITERATURE DISPENSER按钮METERINGMETERING资料（标签机）发放WHEELWHEELLOT IMPRINTER测量轮测量轮批号打印机BARCODE READER条形码102©Copyright Globepharm, 2005
瓶标签机[PV] BOTTLE LABELER [PV]标签机LABELER标签机系统运行发动机设定速度LABELERMOTORSYSTEMFIXED SPEEDOPERATION瓶子尺寸标签尺寸BOTTLE SIZELABELS SIZEMETERING WHEEL测量轮宽度SMALLESTSMALLEST宽度LARGESTLARGEST长度长度103©Copyright Globepharm, 2005
V-SHELL混合机[IQ] V-SHELL BLENDER [IQ]V-SHELL 混合机V-SHELL BLENDER设备确定文件要求公共设施主要部件部件材质润滑剂安全性能EQUIPMENTDOCUMENTATIONUTILITIESMAJORCOMPONENTLUBRICANTSSAFETYIDENTIFICATIONREQUIREMENTSCOMPONENTSMATERIALFEATURESMANUALSELECTRICALSMOTORS操作手册发动机DRAWINGSCOMPRESSED AIR绘图BLENDERINTENSIFIER BARSOPs电气设备压缩空气104©Copyright Globepharm, 2005
V-SHELL BLENDER [OQ]V-SHELL混合机[OQ]V-SHELL BLENDERV-SHELL 混合机校验要求设备控制功能设备运行CALIBRATIONEQUIPMENTEQUIPMENTREQUIREMENTSCONTROLSOPERATIONFUNCTIONALITY设备转速发动机SWITCHESEQUIPMENTMOTORS开关ROTATIONBLENDER EMPTY混合机空载PUSH BUTTONSBLENDER ++BLENDER搅拌器按钮INTENSIFIER --TIP SPEED叶片速度INTENSIFIER搅拌器调速器调速器105©Copyright Globepharm, 2005
V-SHELL BLENDER [PV]V-SHELL混合机[PV]V-SHELL 混合机V-SHELL BLENDER混合机运行搅拌桨全速BLENDERMOTORSOPERATIONBLENDER FULLBLENDINGBLENDERINTENSIFYING混合介质MEDIUMBAR搅拌桨调速器安全阀PLACEBOCOLORING空白介质有色介质106©Copyright Globepharm, 2005
验证：时间表很重要VALIDATION: CHRONOLOGY IS CRITICALraw materials purchased原料的采购April 18, 2004raw materials tested/released原料的分析/放行April 20, 2004validation batch manufactured验证批号的生产April 21, 2004(using fluid bed dried no. 5使用5号流化床干燥)validation batch tested/released验证批号的分析/放行April 24, 2004validation protocol written验证方案的撰写April 16, 2004validation protocol approved验证方案的批准April 26, 2004validation report approved验证报告的批准Aug 17, 2004fluid bed drier 5 installed 5号流化床干燥器的安装May 7, 2004fluid bed drier 5 qualified 5号流化床干燥器的确认June 29, 2004107©Copyright Globepharm, 2005
验证文件VALIDATION DOCUMENTATIONPolicies and Procedures (SOPs) need to be written and approved to cover:规章和规程（SOPs）需要撰写并批准，包括：specifications and validation implementation验证执行specification development标准和标准的开发validation maintenance验证的维护Purchasing采购deviation recording and validation organization验证组织evaluation偏差记录和评估protocol creation and corrective action approval方案的建立和批准implementation整改措施的执行tests and test methods分auditing practices and 析和分析方法reports审计的实行和记录personnel training人员培训change control变更控制equipment calibration and maintenance设备校验和保养108©Copyright Globepharm, 2005
文件的标准化Standardize DocumentationStandardized Protocol Format建立标准化的方案格式Minimizes omissions简介Speeds review and approval快速的审核和批准Creates good impression with regulators给检查官留下良好的印象Standardized Data Entry Sheets建立标准化数据输入表Standardized Review Formats建立标准化审核格式109©Copyright Globepharm, 2005
文件的标准化Standardize DocumentationCreate logical document numbering systems建立合乎逻辑的文件编号系统Design for document retrieval为文件检索而设计Scan all documents扫描所有文件Makes loses impossible使遗漏不可能发生On-line review speeds qualification + validation在线审核加速了确认和验证Keyword all documents为所有文件建立关键词Enhances document retrieval增强文件检索110©Copyright Globepharm, 2005
AdobeThe easiest way to electronicize your SOPsand qualification/validationdocuments最简单的方法来电子化你的SOPs和确认/验证文件Speed up document distribution提高文件分发的速度Speed up document review提高文件审核的速度Eliminate out-dated documents from system从系统中排出过时文件Accurately control your documents精确控制你的文件111©Copyright Globepharm, 2005
112©Copyright Globepharm, 2005
验证文件层次Validation Documentation Hierarchysite validation master plan设定验证主计划project/product specificABCvalidation master plan项目/产品具体的验证主计划discipline specificDQIQOQPVmaster plan各专业的具体验证计划validation protocol / reports验证方案/报告validation summary验证总结113©Copyright Globepharm, 2005
验证文件VALIDATION DOCUMENTATIONValidation Documents Are:验证文件是：the baseline for operations 操作的基准the starting point for change control变更控制的起点an objective basis for corrective / out-of-limit decisions 整改/超标判定的客观基准the basis for regulatory submissions [ANDA/NDA/PL]文件递报的基础a living entity一个不断更新以应对变更的有机体-constantly updated to reflect change114©Copyright Globepharm, 2005
文件的等級DOCUMENTATION LEVELSlevel of documentation文件的等級too much太多no added value沒有加入值sufficient足夠的recommended –company policy建議——公司方針too little太少risky / non-GMP compliant風險O/沒P有T依I从MGUMPM 優化115©Copyright Globepharm, 2005
驗證的花費VALIDATION COSTS1998 costs of 81,000 small volume parenteralfacility1998年小規模的注射用药物的工廠花費+EQUIPMENT COSTS:工廠+設備花費STRUCTURAL COSTS建築花費US$9,750PROCESS EQUIPMENT COSTS工藝設備花費8,220sub-total 小計US$ 17,970VALIDATION ACTIVITY COST:驗證活動花費METROLOGY/VALIDATION EQUIPMENT计量/验证设备340 MANPOWER人力1,772MATERIALS原料410sub-total 小计US$ 2,522TOTAL COST 总计US$ 20,492VALIDATION AS % OF TOTAL START-UP 验证占总启动百分比%VALIDATION AS % OF PROCESS EQUIPMENT 验证占工艺设备的百分比%116©Copyright Globepharm, 2005
API工厂：GMP+验证花费API Facility: GMP+Validation CostsProject End --1996Project Start --1993项目结束于——1996项目开始于——1993US + worldwide sales美国+全球销售2nd World Sales第2世界销售GMP CultureGMP文化Entrepreneurial Culture企业文化Effective QA有效的QANo QA没有QACalibration/Validation In Place适当的No Calibration/Validation没有校验/校验/验证验证Maintenance Effective有效维护No Preventive Maintenance没有预防性维护Too many (?) Documents太多（？）文件Little Documentation很少文件Products With Expiry Dates产品有失No Stability / Expiry Dates没有稳效期定性/失效期Passed FDA --no observation通过No Chance of FDA Approval没有FDA——没有观察FDA批准117©Copyright Globepharm, 2005
API项目：以色列的ChemAgisAPIProject: ChemAgis, IsraelUpgrade facility with no GMPs, manufacturing 5 APIs to pass FDA inspection and sell product to USA将工厂从没有GMPs，制造5种APIs升级至通过FDA检查，并将产品销往美国Strategy:策略Build dedicated line for Pentoxiphylline, USP为pentoxiphylline建立专用的系统，USPValidation of one product only仅验证一个产品Eliminating cleaning validation issues解决清洗验证问题Make infrastructure to support PentoxiphyllineUSP, 建立基础部门来支持PentoxiphyllineUSPUS cGMPcompliant遵循美国cGMPQC LabsQC实验室QA OperationsQA的运作Maintenance, Engineering, Warehouse, etc. etc.维护，工程，仓库等等118©Copyright Globepharm, 2005
ChemAgis:人力资源ChemAgis: Staff ResourcesFunctionProject Start 1993Project End 1996项目结束1996项目开始1993职责Administration行政67Development开发2020Production生产2224Warehousing入库24Engineering/Maintenance37工程/维护Quality Assurance质保¼5Quality Control质量控制2¾7总计Total5672119©Copyright Globepharm, 2005
ChemAgis: 项目花费ChemAgis: Project CostsOriginal 1993 Facility原1993年的工厂US$ 4,000,000Original 1993 Equipment原1993年的设备2,500,000原厂总计Total Original FacilityUS$ 6,500,000Upgrade –Facilities升级-工厂1,470,000Upgrade –Equipment升级-设备370,000Upgrade –Staff (during project period)升级-人员1,390,000（在项目期间）Upgrade –Validation Materials升级-验证资源135,000总计TotalUS$ 3,365,000120©Copyright Globepharm, 2005
ChemAgis: 项目利润ChemAgis: Project BenefitsBenefit利润Project Start Project End 1993项目开始19931996项目结束1996Improved Throughput TimeConfidential20% decrease提高产量的时间保密减少20%Improved Production Yield提高产品收率80%> 90%Improved Yield Range (Hi-Lo)提高收率45%< 10%范围（高-低）Decrease Batch Failures减少批不合格%< %Increase Client Audits增加客户审计2-3 / year2-3 /month2-3/年2-3/月Increase Sales增加销售Confidential> 130%保密121©Copyright Globepharm, 2005
验证领导：产品开发阶段VALIDATION LEADERSHIPproduct development phaseQUALITY ASSURANCE质量保证DEVELOPMENT研发PRODUCTION产品122©Copyright Globepharm, 2005
VALIDATION LEADERSHIPequipment phaseQUALITY ASSURANCE质量保证ENGINEERING工程PRODUCTION产品123©Copyright Globepharm, 2005
工作职责Job RolesDEVELOPMENT’S JOB IS TO DEVELOP研发部门的任务是研发A robust and validatableproduction process一个健全和可验证的生产工艺A robust and validated analytical method一个健全和已验证的分析方法PRODUCTION’S JOB IS TO PRODUCE生产部门的职责是生产As speedily/efficiently as possible尽可能快速/有效Product meeting specification 产品符合标准In accordance with GMPs与GMPs要求一致124©Copyright Globepharm, 2005
验证实践：2004年工业调查Validation Practices: Industry Survey, 2004197 responses from 4,974 surveyed125©Copyright Globepharm, 2005
验证实践：2004年工业调查Validation Practices: Industry Survey, 2004197 responses from 4,974 surveyed126©Copyright Globepharm, 2005
验证组织机构VALIDATION ORGANIZATIONQUALITY ASSURANCE质量保证ENGINEERING SERVICES工程服务document review + approval文件project managers项目经理审核+批准architects, designers, draftsmenbatch release批放行建筑师，设计师，绘图人Auditing审计engineers, mechanics工程师，机械维护人员INFORMATION SERVICES信息calibration specialists专业校验人员服务data management systems数据管理系统VALIDATION SERVICES验证服务Scheduling计划人员MANUFACTURING生产validation leadership验证领导人technical writers (sop)技术文件撰写人（sop）ANALYTICAL SERVICES分析服务operators/technicianssampling technicians取样技术人员操作人员/技术人员environmental / microbial testing环REGULATORY AFFAIRS法律事务境/微生物测试chemistry testing化学分析PRODUCT DEVELOPMENT产品研发部门127©Copyright Globepharm, 2005
验证批准VALIDATION APPROVALSNOT TOO LOW IN THE ORGANIZATION不能在组织机构中地位太低NOT TOO HIGH IN THE ORGANIZATION不能在组织机构中地位太高128©Copyright Globepharm, 2005
验证成果Validation EffortsOne day’s people costs One day’s(salaries + benefits)每天的delayed 人员费用（薪金+福利）marketing ($$$$)延迟一天销售129©Copyright Globepharm, 2005
验证方案[FDA]VALIDATION PROTOCOL [FDA]“a written plan describing the process to be validated, including production equipment, and how validation will be conducted, including objective test parameters, product and/or process characteristics, and factors which will determine acceptable results”一个书面计划描述了需验证的过程，包括生产设备，和如何去进行验证，包括目标的分析参数，产品和/或工艺参数，和可确定可接受结果的因素。FDA: Proposed cGMPRules (), May 1996130©Copyright Globepharm, 2005
高中科学High School 名字日期题目方法结果6.(Discussion)（讨论）结论8.(QED) 131©Copyright Globepharm, 2005
方案格式PROTOCOL FORMATPROTOCOL OBJECTIVE + INTRODUCTION方案目的+介绍QUALITY ACCEPTANCE CRITERIA (QAC)质量可接受标准SAMPLING + TESTING METHODOLOGY取样+分析方法MANAGEMENT REVIEW + APPROVAL管理层审核+批准132©Copyright Globepharm, 2005
方案的目的+介绍PROTOCOLobjective + introductionthe protocol objective + introduction describes:方案的目的+介绍叙述了provides reference links product, process of interest产品，工艺的重要性to all subsidiary documentation:提供所有辅助文protocol objective方案的目的件的参考的链接equipment or system设备或系统¾Drawings图纸operating principles操作原理¾Specifications标准validation methodology验证方法¾production methods生产方法test methods分析方法¾company policies公司方针degree of replication重复的程度¾company SOPs公司SOPsfunctional groups involved包括的¾test methods分析方法功能组¾development reports研发who approves protocol谁批准方案报告who approves final report谁批准最后的报告133©Copyright Globepharm, 2005
方案的质量可接受标准PROTOCOLQuality Acceptance Criteria (QAC)the quality acceptance criteria are based onand are sometimes a compromise between :质量可接受标准是基于或有些时候是以下内容的折中：regulatory requirements法规需求national standards (. pharmacopeia monographs)国家标准（例如：药典专论）industry practices (. insurance codes)工业标准（例如：安全代码）marketing requirements市场与需要process capability生产能力Be Warned!If QAC is outside process capabilityValidation IS IMPOSSIBLE如果质量可接受标准超出了生产能力，验证是不可能的134©Copyright Globepharm, 2005
QUALITY ACCEPTANCE CRITERIAvial washing machineoperate at 100 vials / minute for sizes 1mL -100mLwhen machine drained retains <100mL of WFI after 10 min. drainageroom free from condensation throughout production shiftglass breakage < 1% throughout production shiftair used to blow dry vials meets ISO 14644 class 100135©Copyright Globepharm, 2005
QUALITY ACCEPTANCE CRITERIAvial washing machineoperate at 100 vials / minute washed vial < 1 EU/vialfor sizes 1mL -100mLwashed vial < 10 particles when machine drained retains per vial of size > micron<100mL of WFI after 10 min. washed vial < 50ppb drainageTOC residue room free from condensation residual water < production shiftglass breakage < 1% throughout production shiftair used to blow dry vials meets ISO 14644 class 100136©Copyright Globepharm, 2005
QUALITY ACCEPTANCE CRITERIAvial washing machineoperate at 100 vials / minute washed vial < 1 EU/vialfor sizes 1mL -100mLwashed vial < 10 particles when machine drained retains per vial of size > micron<100mL of WFI after 10 min. washed vial < 50ppb drainageTOC residue room free from condensation residual water < production shiftglass breakage < 1% throughout production shiftair used to blow dry vials meets ISO 14644 class 100137©Copyright Globepharm, 2005
PROTOCOLQuality Acceptance Criteria (QAC)Quality Acceptance Criteria are:determined prior to commencement of testingagreed to by all functional groups as being:relevant to the productmeeting all regulatory, quality, + company requirementswithin the theoretical capability of the processapproved, in writing, by appropriate levels of management138©Copyright Globepharm, 2005
QACs: Be Very SpecificSteam System OQQAC: Steam pressure will be at least 25 psig at the use point furthest away from the steam generator (6 steam lines)Steam Line a –on plan drawingsSteam Line c –on isometric drawingSteam Line f –when measured5 weeks to repeat all studies139©Copyright Globepharm, 2005
PROTOCOL sampling + test methodology方案取样＋检测方法sampling methods describe:test methods describe:取样方法描述检测方法描述sample locations取样的位置test equipment to be usednumber and size of samples待用的检测设备取样量和数目calibration of the test equipmentrationales for sample sizes检测设备的校验取样量的基本原则SOP for testing检测SOPsampling loss / recovery potentialstandards to be used所用的标准取样损耗/回收率format of reports and documentation needs报告和文件的格式sampling technique:取样技术training for test techniciansfixed, sequential, continuous固定的，有序的，连续的检验员的培训sample identification and processingdisposal/retention of test samples 样品确认和处理after testingSOP for sampling取样SOP检测后检测样品的处理/留洋training required for sampling technicians取样技术的培训140©Copyright Globepharm, 2005
141©Copyright Globepharm, 2005
PROTOCOL + REPORT FORMAT方案和报告格式PROTOCOL OBJECTIVE + INTRODUCTION方案目的＋介绍QUALITY ACCEPTANCE CRITERIA (QAC)质量接受标准SAMPLING + TESTING METHODOLOGY取样＋检测方法MANAGEMENT REVIEW + APPROVAL管理人员审核＋批准PERFORM TESTING进行检测RECORD RESULTS记录结果ASSESS RESULTS 结果评估CONCLUSIONS结论COLLATE AND ISSUE FINAL REPORT比较和讨论最终报告MANAGEMENT REVIEW + APPROVAL管理人员审核＋批准142©Copyright Globepharm, 2005
PROTOCOL REPORTS方案报告protocol reports include方案报告包括:an abstract and management summary, of the protocol and the report方案报告的摘要和总结key words for data retrieval数据弥补的关键词original protocol with original approval signatures带有原始签名的原方案records of equipment calibration prior to the study研究之前设备校验记录equipment identification, original test plans, raw data and records设备确定，原始检测计划，原始数据和记录supporting analytical data and test results and computations支持性分析数据和检测结论和评估details of deviation reports/change control activity during the study研究阶段偏差报告/变更控制行为的详细资料records of equipment calibration immediately following the study研究之后设备校验现场记录assessment of the data results and comparison to the protocol QACs数据结论和与方案质量接受标准比较结果的评估conclusion, and statement as to whether the protocol is acceptable关于方案是否可被接受的结论和陈述identification and justification of re-validation frequency再验证频率的确定和说明approval signatures by appropriate level of management适宜级别管理人员批准的签名143©Copyright Globepharm, 2005
VALIDATION CONCLUSION验证结论We Have Demonstrated What the Protocol Called For:我们已经展示了如我们方案中所述的结果：We Did Not Demonstrate What the Protocol Called For:我们不能说明如我们方案中所述的结果：144©Copyright Globepharm, 2005
PROTOCOL + REPORT FORMAT方案＋报告格式PROTOCOL OBJECTIVE + INTRODUCTION方案目的＋介绍QUALITY ACCEPTANCE CRITERIA (QAC)质量接受标准SAMPLING + TESTING METHODOLOGY取样＋检测方法MANAGEMENT REVIEW + APPROVAL管理人员的审核＋批准PERFORM TESTING进行检测RECORD RESULTS记录结果ASSESS RESULTS 评估结果CONCLUSIONS结论COLLATE AND ISSUE FINAL REPORT最终报告的比较和讨论MANAGEMENT REVIEW + APPROVAL管理人员的审核＋批准145©Copyright Globepharm, 2005
THE FIVE VALIDATIONS五组验证 METHOD VALIDATION分析方法验证 SYSTEMS VALIDATION计算机系统验证 QUALIFICATION公共设施确认(off line equipment离线设备)4. CLEANING VALIDATION清洁验证5. PROCESS VALIDATION 工艺验证(on line equipment在线设备)VVV146©Copyright Globepharm, 2005
FUTURE-THE SIX VALIDATIONS将来-六组验证 METHOD VALIDATION分析方法验证 SYSTEMS VALIDATION计算机系统验证 QUALIFICATION公共设施确认(off line equipment离线设备)4. CLEANING VALIDATION清洁验证5. PROCESS VALIDATION 工艺验证(on line equipment在线设备6. TRAINING VALIDATION培训验证VVVV147©Copyright Globepharm, 2005
The Training Dilemma培训抉择If I am a great lecturer如果我是一个不错的讲演者If you are a great listener如果你们是不错的听众Then 2 weeks from today:那么从今天起有两周：148©Copyright Globepharm, 2005
Training培训“Read and Understood”Documentation“阅读并理解”文件Supervisor Explains SOP监察员解释SOPFormal Training Program正式培训方案Supervisor Explains SOP监察员解释SOPSupervisor Demonstrated SOP监察员示范SOPWorker Demonstrates Practical Ability in SOP操作人员根据SOP实际示范149©Copyright Globepharm, 2005
150©Copyright Globepharm, 2005
BENEFITS OF VALIDATION验证的益处¾reduced rejects减少退货¾increased productivity¾reduced reworks降低再加工增加生产能力¾reduced sampling + retesting¾faster deviation investigation减少取样和复验更快的进行偏差调查¾reduced utility costs¾faster new process start-up降低公共设施成本加快新工艺的启动¾reduced capital needs¾faster scale-up加速放大降低资金需求¾easier maintenance容易维护¾reduced complaints减少投诉¾easier automation容易自动操作¾INCREASED PROFITABILITY增加收益151©Copyright Globepharm, 2005
THE VALIDATION DEITYBe Warned !警告“validation has, in some circles, assumed the status of a religion with its own initiates, commandments,and arcane language”验证，某种程度上，已经被赋予具有其自身的起始，规则和神秘语言的身份John SharpEditor, UK Guide GMPs(The Orange Guide)152©Copyright Globepharm, 2005
FDA GUIDELINES FOR INSPECTIONSFDA检查的指导原则GUIDE TO INSPECTIONS OF如下检查的指导:Active Pharmaceutical IngredientsPharmaceutical 活性药物成分（原料药）药物QC实验室QC LaboratoriesSterile Drug Substance ManufactureMicrobiological 微生物QC实验室QC Laboratories无菌原料药生产商Validation Dosage Form Drug Manufacturersof Cleaning Processes清洁工艺验证制剂成品药生产商High Purity Process Water高纯水工艺Oral Solid Dosage Forms:口服制剂Foreign Pharmaceutical ManufacturersPre/Post Approval Issues for 杂质医药生产商Development and ValidationGeneral Principles of 研发和验证的预/后批准Process ValidationTopical Drug Products局部用成品药工艺验证的一般原则Oral Solutions and Suspensions口服溶液和悬浮液Guideline for Drug Master FilesLyophilization of Parenterals注射用药的冻干DMF文件方针Cosmetic Product Manufacturers.化妆品生产商Draft Guidelines:起草方针Investigating OOS Test ResultsOOS调查检测结果 Globepharm, 2005
FDA GUIDELINES FOR INSPECTIONSFDA检查的指导原则GUIDE TO INSPECTIONS OF如下检查的指导:Pharmaceutical QC LabsICH-Q7A: API Guideline API指导规范药物QC实验室Sterile Drug Substance ManufactureMicrobiological QC Labs无菌原料药生产商微生物QC实验室Dosage Form Drug ManufacturersValidation of 制剂成品药生产商Cleaning ProcessesOral Solid Dosage Forms:口服制剂清洁工艺验证Pre/Post Approval Issues for High Purity Process WaterDevelopment and Validation高纯水工艺研发和验证的预/后批准Topical Drug Products局部用成品药Oral Solutions and Suspensions口服溶液和悬浮液Lyophilization of Parenterals注射用药的冻干Cosmetic Product Manufacturers.化妆品生产商 Globepharm, 2005
Questions?155©Copyright Globepharm, 2005
FUNDAMENTALS AND ESSENTIALSOF VALIDATIONVALIDATIONMASTERPLANS验证主计划156©Copyright Globepharm, 2005
157©Copyright Globepharm, 2005
验证主计划VALIDATION MASTER PLANdocument, approved by appropriate levels of management, describing the validation work program necessary to be completed in order to consider the system or process validated验证主计划：是由合适的管理人员批准，描述需要完成的验证工作计划以考虑需要验证的系统或生产工艺的文件。note: the validation master plan (VMP) is completed and approved prior to the commencement of validation activities注：验证主计划（VMP）是在验证行为之前完成和批准的158©Copyright Globepharm, 2005
验证主计划VALIDATION MASTER PLANVALIDATION MASTER PLAN验证主计划VALIDATIONVALIDATIONVALIDATIONPROTOCOL “B”PROTOCOL “A”PROTOCOL “C”验证方案“B”验证方案“A”验证方案“C”VALIDATIONVALIDATIONVALIDATIONREPORT “A”REPORT “B”REPORT “C”验证报告“A”验证报告“B”验证报告“C”VALIDATION SUMMARY REPORT验证报告159©Copyright Globepharm, 2005
VALIDATION MASTER PLANThe Globepharm Approach验证主计划Globepharm方法COMPUTER VALIDATION计算机验证ANALYTICAL VALIDATION分析方法验证in-equipment controllers内部设备控制器active assay 活性成分分析（含量测定）out-equipment controllers外部设备控制器impurities assay 杂质分析limit of detection (cleaning)检测限（包括清洁）UTILITIES VALIDATIONPROCESS VALIDATION 工艺验证公用设施验证mixing / blending 混合/混批water systems 水系统filling / compressing 填充/压片room air systems 室内空气系统sterilizing / drying 灭菌/干燥compressed air system 压缩空气系统milling / sizing 磨粉/过筛dust control 尘埃控制inspection / packaging 检查/包装CLEANING VALIDATION 清洁验证sampling tools 取样工具reactor tanks 反应储罐piping systems 管道系统packaging lines 包装线160©Copyright Globepharm, 2005
Generic VMP161©Copyright Globepharm, 2005
VMP-扩展GenenricVMP –Expanded162©Copyright Globepharm, 2005
VMP/清单Generic VMP /as checklist163©Copyright Globepharm, 2005
VMP/公用设施Generic VMP /Utilities164©Copyright Globepharm, 2005
通用VMP/工艺＋清洁验证Generic VMP /Process+CleaningValidation165©Copyright Globepharm, 2005
验证主计划VALIDATION MASTER PLANSYSTEM EQUIPMENT PARAMETER CRITICAL /REFDUEBY系统设备参数关键的/非关键的参照编号完成日期操作者fill linevial washer water pressure水压C12-1-1Oct 12MA填充线盘式洗瓶机water temperature水温C12-1-2Oct 12MAcycle time循环次数C12-1-3Oct 12FTdetergent level清洁剂级别NC12-1-4Oct 12SCoven 烘箱belt speed 传动速率C12-2-1Nov 13 JNtemperature温度C12-2-2Nov 13JNload density负载密度C12-2-3Nov 13JN166©Copyright Globepharm, 2005
VMP进程清单VMP as Progress Checklist167©Copyright Globepharm, 2005
验证途径Validation Pathway设计确认验证主计划DQVMP回顾性再验证确认＋验证qual+val revalidation方案protocolsreview方案的执行日常生产stick to protocolroutinecthe pathimplementationproductionh坚决执行此过程变a确认＋验证确认＋验证更n批准报告gqual+valqual+valeapprovalsreports168©Copyright Globepharm, 2005
验证主计划目录VALIDATION MASTER PLANtable of contentsthe validation master plan may include the following:验证主计划包括以下各方面：Introduction介绍design documentation设计文件facility description设施设备描述support programs支持方案process description工艺描述project schedule项目进度表definition of validation scopevalidation supplies 验证所需定义验证范围validation approach验证的步骤169©Copyright Globepharm, 2005
VMP -Table of Contents [1]VMP-内容[1]Objective目的Product Strategy产品策略Senior Management Approval高管批准Development Reports研发报告Circulation and Issuance分发Technology Transfer技术转移Manufacturing Site生产地点Critical Parameters –Definition关键参数—定义Management Organization组织机构Manufacturing Review生产回顾Company Quality Quality Policies公司质量方针Process Technology工艺技术QA and QC Systems QA和QC体系Route of Synthesis合成路线Documentation and Change Control Validation Strategy验证策略Programs文件体系和变更控制方案Validation Policy + ScopeTraining Program培训计划验证政策和范围Annual Product Review产品质量年度回顾Validation Committee + TeamsNon-Conforming Product Reporting 验证委员会和小组System不合格品报告体系Complaint Investigation Systems投诉调查体系170©Copyright Globepharm, 2005
VMP-内容[2]VMP -Table of Contents [2]Materials 物料Rework Processes返工工艺Raw Materials + Vendor AuditsLaboratory Facilities实验室设施设备物料和供应商审计Equipment --Analytical Packaging and Labeling MaterialsInstruments设备—分析仪器包材和标签Materials Handling物料处理Automated Systems自动化系统Manufacturing Facility 生产设施Validation of Analytical MethodsPlant Description车间描述分析方法验证Scope of Validation Activities验证范围Method Development ReportsValidation Methodology --Manufacturing Unit验证方法学—生产单元方法开发报告Maintenance and Calibration维护和校验Validation Methodology 验证方法学Process Validation工艺验证Reference Standards 标准品Validation Methodology 验证方法学Specifications 质量标准In-Process Controls 中间控制Sampling Plans 取样方案Change Control 变更控制171©Copyright Globepharm, 2005
VMP -Table of Contents [3]VMP-内容[3]Cleaning Validation 清洁验证Documentation文件Establishing Limits 建立限度Definition of Needed Sampling + Test Methods取样＋检SOPs/Specs/Drawings, etc.所需测方法SOPs/标准/绘图的定义Automated/Computerized Systems Documentation drafting and approval Validation自动化/计算机化的系统验证systems文件编制和批准体系Inventory详细清单Document Paper-cide（side？）文件Validation Approach验证方式边框（格式）Training培训Departmental CoordinationScope andEffectiveness 部门间协调Measurement范围和结果评估方式Management of Post-ValidationDelivery MechanismsActivities（培训内容）传达机制Reviews --Annual and Need回顾—年Effectiveness Assessment效果评估度和需要时Change Control变更控制172©Copyright Globepharm, 2005
VMP -Table of Contents [4]VMP-内容[4]VMP Appendices (continued)VMP Appendices VMP附录General Facility Layout 厂区平面图General Flow of:常规流程图Management Organization ChartEquipment (Clean and Used),组织机构图设备（干净的和使用过的）Materials (Raw, In-rocess,Finished)List of SOPs Relevant to VMP物料（原料，中间体，成品）与VMP有关的SOPs列表People人员Route of Syntheses or Process General Equipment LayoutFlow Chart合成路线或工艺流程图总的设备平面图Gantt Chart of Main VMP Activities 主要VMP活动的Gantt图List of Critical Process EquipmentOverall Project Charts:关键工艺设备列表总体项目图表List of Critical Analytical EquipmentPlant Qualification车间确认关键分析设备列表Process Validation工艺验证173©Copyright Globepharm, 2005
VMP –A Brief ThoughtVMP –简论PIC/S:国际医药品检查协约组织Validation Master Plan，Installation And Operational Qualification, 2001主体验证计划，安装和运行确认，2001The VMP should be a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but refer to existing documents such as Policy Documents, SOP's and Validation Protocols/应该是总体的概述性文件，并应简约明了。它不应该重复其他地方提及的信息，但是要涉及到现有文件，如方针策略性文件，SOPs和验证方案/报告The VMP should be agreed by management. VMP应该由管理层批准174©Copyright Globepharm, 2005
RECOMMENDED READING: VMP建议阅读：VMPPIC/S Recommendations On : PIC/S关于如下的建议Validation Master Plan, Installation And Operational Qualification, Non-sterile Process Validation, Cleaning Validation验证主计划，安装和运行确认，非无菌工艺验证，清洁验证 Master Validation Plan 医药工业主体验证计划SyedHaider(176 pages + CD-ROM), St. Lucie PressValidation Standard Operating Procedures验证标准操作规程Syed Haider(576 pages + CD-ROM), St. Lucie Press Validation Master Plan –A Streetwise Guide主体验证计划Trevor Deeks(49 pages), DHI/PDAValidating Automated Manufacturing and Laboratory Applications自动化生产和实验室用软件的验证Guy Wingate (564 pages), CRC PressValidation of Bulk Pharmaceutical Chemicals化学原料药的验证Ira Berry and Dan Harpaz (496 pages), CRC Press175©Copyright Globepharm, 2005
VMP BENEFITSVMP的益处Management understands the true costs of validation管理者明白验证的真实花费Management understands the impact of staff on timing管理者可以及时获知职员的作用Management understands the impact of delays in the project管理者可以明白项目中延误的影响Management agrees to program scope, timing, staffing and costs prior to validation implementation 验证实施前，管理者同意计划范围、设定的时间、人员配置和花费。[hence less daily pressure to complete] 因此会有较少的日工作压力Management makes a commitment to quality --FDA happy管理者制定质量承诺--FDA很欣赏这样做Sound VMPs are only way to recover from an FDA warning letter合理的VMP是从FDA警告信中解脱的唯一出路Faster validations 加速验证[hence savings in time and money] 因此省钱省力176©Copyright Globepharm, 2005
Questions?有疑问吗？177©Copyright Globepharm, 2005
FUNDAMENTALS AND ESSENTIALSOF VALIDATION 验证的基础和要素PROCESSVALIDATION工艺验证178©Copyright Globepharm, 2005
计量METROLOGYWithout Instrumentation没仪器.... You have No Evidence就等于没证据Without Calibration没校验....You Have No Instrumentation就等于没仪器Without Traceability没追溯性.....You Have No Calibration就等于没校验And Without All Three.....You Have Neither Validation Nor Process没有以上三方面……你们既没有验证也没有过程179©Copyright Globepharm, 2005
METROLOGY FUNDAMENTALS计量的基本原则CALIBRATION INTERVALS校验周期MEASUREMENT TRACEABILITY测量的可追溯性CALIBRATION EQUIPMENT ADEQUACY足够的校验设备AUDIT REQUIREMENT审计要求CONTRACTOR CONTROL协约控制RECORDS记录SCHEDULING SYSTEMS进程表LABELING PRACTICES标记规范CALIBRATION PROCEDURES校验规程ENVIRONMENTAL CONTROLS化境控制PERSONNEL TRAINING AND CERTIFICATION人员培训和资质180©Copyright Globepharm, 2005
校验文献CALIBRATION REFERENCENATIONAL CONFERENCE OF STANDARDS LABORATORIES国家标准实验室协会RECOMMENDED PRACTICES No. 6 [RP-6]RECOMMENDED PRACTICES FOR CALIBRATION FOR HEALTHCARE MANUFACTURERS卫生保健器具校验行业规范建议181©Copyright Globepharm, 2005
校准参数CALIBRATABLE PARAMETERSLENGTH 长度TEMPERATUREPRESSURE压力温度WEIGHT重量SOUND声音TIME时间FLOWHUMIDITY湿度LIGHT光VOLUME体积流速AMPS WATTS VOLTS安培瓦特伏特182©Copyright Globepharm, 2005
研发验证DEVELOPMENT VALIDATIONMATERIALS物料identify sensitivity of materials to process确定物料对反应过程的敏感性qualify raw material supplier 物料供应商确认PROCESS工艺过程identify critical process variables确定关键工艺变量identify “edges of failure”确定失败的底线determine interaction of process variables确定工艺变量的相互作用183©Copyright Globepharm, 2005
设备适用性EQUIPMENT SUITABILITY [FDA]“the established capacity of process equipment and ancillary systems to operate consistently within established limits and tolerances”设备实用性：建立使工艺设备和辅助系统持续地在所设定的限度和耐受力范围内运行时所设定的能力。FDA: Proposed cGMP Rules (), May 1996FDA：提议的cGMP规则（），1996年5月184©Copyright Globepharm, 2005
过程的适用性PROCESS SUITABILITY [FDA]“established capacity of the manufacturing process to produce effective + reproducible results consistently”过程的适用性：建立一个生产过程能够持续性产生有效和可重复性结果的能力。FDA: Proposed cGMP Rules (), May 1996FDA：提议的cGMP规则（），1996年5月185©Copyright Globepharm, 2005
生产过程MANUFACTURING PROCESS [FDA]“manufacturing or storage steps in the creation of the finished product from weighing through storing, packaging and labeling of the finisGantthedproduct.生产过程：产生成品的生产和储存步骤：从称量到成品的储存、包装和贴签。Includes, but is not limited to, mixing, granulating, filling, molding, formulating, lyophilizing, tableting, encapsulating, coating, sterilization and filling.”包括，但不限于，混合，制粒，填充，成型，配料，冷冻干燥，压片，封装，包衣，灭菌和填充FDA: Proposed cGMP Rules (), May 1996FDA：提议的cGMP规则（），1996年5月186©Copyright Globepharm, 2005
失败的边缘EDGE OF FAILURE [single edge]INCREASING PARAMETER INTENSITY参数强度逐渐升高187©Copyright Globepharm, 2005
失败的边缘EDGE OF FAILURE [double edge]INCREASING PARAMETER INTENSITY参数强度逐渐升高188©Copyright Globepharm, 2005
PROVEN ACCEPTABLE RANGEbased on ‘edge of failure’基于失败底线，明确的可接受范围P A R INCREASING PARAMETER INTENSITY参数强度逐渐升高189©Copyright Globepharm, 2005
再加工VS返工REWORK vs. REPROCESSINGREPROCESING返工REWORK再加工Introducing a non-Introducing a new conforming intermediate processing stepin order or finished product back to ensure that failed into the process and intermediatesorrepeating step(s) that finished product meets are part of the specificationsvalidated process.将不合引入一个新的工序以确保格中间体或成品返回到已经不合格中间体或成品符合既验证过的工艺当中的工序或定的质量标准。各个步骤进行重新处理。190©Copyright Globepharm, 2005
PROCESS VALIDATIONmixing / blending工艺验证混合purpose: ensure uniformity of particles within a blend目的：确保经过混合使颗粒均一parameters to monitor:monitor by testing:通过以下参数检测监测：监测参数•particle size粒度•equipment design设备设计（规划）•particle size distribution粒度分别•equipment capacity设备容量•bulk density容积密度•batch size批量•content uniformity含量的均一性•mixing time混合时间•flow properties流动性•mixing speed混合速度•[residue on emptying]排空残留191©Copyright Globepharm, 2005
Validation of Powder Blending粉末混合的验证fill levelXXXXX192©Copyright Globepharm, 2005
Validation of Powder Blending粉末混合验证未混合un-mixtimeperfect perfect perfect perfect MixMixMixMix良好混合良好混合良好混合良好混合193©Copyright Globepharm, 2005Standard标准0 deviation偏差
PROCESS VALIDATIONsolids granulation工艺验证固态制粒Purpose目的: enlarge particles to enhance flow and discourage demixing增大颗粒以增强流动性和防止分层parameters to monitor:参数监测monitor by testing:通过检测以下参数监测equipment design设备设计•content uniformity含量均一性impeller blade design 叶片设计•residual moisture残留水分batch size批量impeller speed叶片速度quantity of granulating liquid制粒液态数量liquid feed rate液体添加速度granulation time造粒时间194©Copyright Globepharm, 2005
PROCESS VALIDATIONsolids drying工艺验证固体干燥purpose: solvent removal目的：溶剂去除parameters to monitor参数监测:monitor by testing:通过监测以下参数监测•equipment design设备设计•residual moisture残留水分•bed thickness / load •potency 百分含量干燥床厚度/负载•drying temperature干燥温度•air flow rate空气流速•load/temperature distribution进料/温度分布•inlet/exhaust humidity进/出湿度•drying time干燥时间195©Copyright Globepharm, 2005
RECOMMENDED READING –Process Validation推荐阅读工艺验证Theory and Practice of Industrial PharmacyLachman, Lieberman and Kanig, Lea+Febiger, 1992工业药学原理与规范available from可从此网址获得©Copyright Globepharm, 2005
Process Validation Strategy工艺验证策略Your batch record instructs you to“dry the blend between 50oC –90oC for 3 hours”你的批记录指示你在50℃到90 ℃之间混合干燥3小时For your process validation 3 batches对于你工艺验证的3批what is your process validation strategy?–Do you: 你工艺验证的策略如何？你要：a. run one batch at 50oC, a second at 90oC, and the third somewhere in the middlea.一批在50 ℃进行，一批在90 ℃进行，第三批在中间的某温度进行b. run all three batches at 70oC (the mid-range)b.三批都在70 ℃进行（中间温度）c. run all three at random within the rangec.三批都在温度范围之内，在随机温度下进行197©Copyright Globepharm, 2005
Validation Practices: Industry Survey, 2004验证实践：产业调查2004年197 responses from 4,974 surveyed来自4,974份调查中的197份的响应数据198©Copyright Globepharm, 2005
responses where respondents elaborated on answer回答者就答案进行详细阐述响应情况199©Copyright Globepharm, 2005
WHEN DOES VALIDATION START ?验证从哪开始？FINISHED PHARMACEUTICALS成品EVERY STEP IN PROCESS FROM-STORES-TO-STORES从存贮到存贮，工艺过程中的每一步BIOTECHNOLOGY DERIVED INGREDIENTS [API / BPC]FROM SEED CULTURE TO FINAL PACKAGE生物来源的成分[API/BPC]从菌种培养到终产品包装CHEMICALLY DERIVED ACTIVE [API / BPC]FROM STEP THAT CREATES THE KEY INTERMEDIATE, OR CREATED THE PHARMACOLOGICALLY ACTIVE MOEITY化学来源活性成分[API/BPC ]从生成关键中间体，或者具有生成药理学活性成分的步骤开始200©Copyright Globepharm, 2005
API SYNTHETIC ROUTE API合成路线Level of GMP Increases BThroughout Synthesis合成的整个过程GMP要求逐渐递增CA AA12EEEcrudepuresaltDAPIprocess validationA, B, DCommercial StartStarts工艺验证起始analytical validationC, DPivotal IntermediateStarts分st析ar验ts证起始EKey Intermediate201©Copyright Globepharm, 2005
CLINICAL MANUFACTURING AND GMPs临床行为和GMPClinical Phase临床阶段12 34-post100%Basic GMP Compliance基本符合GMP0%100%Equipment Qualification0%100%Process Validation0%INDNDA202©Copyright Globepharm, 2005
CLINICAL MANUFACTURING AND GMPs临床行为和GMPClinical Phase临床阶段12 3 4-post100%Basic GMP Compliance基本符合GMP0%100%Equipment Qualification设备确认0%100%Process Validation0%INDNDA203©Copyright Globepharm, 2005
CLINICAL MANUFACTURING AND GMPs临床行为和GMPClinical Phase临床阶段12 3 4-post100%Basic GMP Compliance基本符合GMP0%100%Equipment Qualification设备确认0%100%Process Validation工艺验证0%INDNDA204©Copyright Globepharm, 2005
CLINICAL MANUFACTURING AND GMPs临床行为和GMPClinical Phase临床阶段12 3 4-post100%Basic GMP Compliance基本符合GMP0%100%Equipment Qualification设备确认0%100%Process Validation工艺验证0%100%Analytical Validation分析验证NDA0%205©Copyright Globepharm, 2005
Great Process Validation Documents主要的工艺验证文件Canada加拿大–HPB工艺验证：Process Validation: Tablets片剂Process Validation: Capsules胶囊Process Validation: Injectable Products注射剂Process Validation: Form-Fill-SealProcess Validation: Inhalation Drug Products吸入药品206©Copyright Globepharm, 2005
Canada-HPB: Process Validation加拿大-HPB：工艺验证Form-Fill-SealF-F-S Process Outline F-F-S大纲Protocol Development and Control 方案开发和控制Laboratory Considerations 实验室构思Machine Design and Specification 机器设计及规格Equipment Qualification 设备确认Machine Maintenance 机器维护Routine In-Process Control and Monitoring 常规中间控制和监测Aseptic Process Validation –Media Fills 无菌工艺验证-填充Incubation 培养Revalidation 再验证Documentation 文件207©Copyright Globepharm, 2005
Schering-Plough: Validation Issues验证讨论FD-483: Schering-Plough, Kenilworth, January 2001Validation protocols were routinely written and approved after the validation batches had been manufactured验证方案是在验证批次已经生产之后进行书面成文并批准的Established acceptance criteria in validation protocols were notalways met during validation batch manufacturing. Summary reports signed and approved by Validation and QC Management state that the process was considered validated, despite the failure to meet the acceptancecriteria生产的验证批次不能一直符合验证方案内设定的可接受标准。由验证和QC管理人员签字并批准的综合报告陈述验证过程是有效的，而忽视不符合可接受标准的结果。Validation using raw material from a new source was inadequate in that only one batch was manufactured应用新来源原始物料的验证是不充分的，因为只生产了一批Validation of reformulated batch of Claritin Syrupwas inadequate in that only one batch was manufacturedCurrent revalidation protocols contain incorrect acceptance criteria, but were approved by Validation, Manufacturing and the QC departments当前的验证方案含有错误的可接受标准，但是还是被验证，生产和QC部门批准。208©Copyright Globepharm, 2005
Schering-Plough: Validation IssuesFD-483: Schering-Plough, Kenilworth, January 2001In validation of the aerosol line, despite two batches failing validation, the company considered the product validation to have been successful在气雾剂生产线验证过程中，忽视了两批失败的验证，公司还是认为产品验证是成功的ProventilRepeatabsare not validated in that 28% of finished tablet batches were rejected between September 1999 and August 2000 ProventilRepeatabs不是有效的因为成品片剂批次有28％在1999年9月到2000年8月间都被退货Manufacturing and Packing equipment were not all qualified生产和包装用设备并不是都经过确认的The validation department had no written SOPs for performing cleaning validation验证部门没有书面的SOPs以执行清洗验证HVAC systems supporting manufacturing were not qualified支持生产的HVAC系统没有进行确认209©Copyright Globepharm, 2005
FUNDAMENTALS AND ESSENTIALSOF VALIDATION验证的基本原理和要点PRODUCTVALIDATION产品验证210©Copyright Globepharm, 2005
Validation Process验证过程最难清洗的产品清洗SOPHardestCleaning SOPTo CleanProduct回收比例有效的清洁方法Recovery PotentiaValidated l最难清洗的部位Hardest CleaningTo CleanMethodLimit of Equipment建筑绘图包括附属设施Detection/LocationQuantitation“As Built”DrawingsManuals检测/定量限Spare Parts公共设施验证变更控制验证过的产Utilities ValidationChangValidated eSOPs/Training计算机系统验证ConProducttrolSOPs/培训Computer Validation实施工艺验证Calibration验证过的生产工艺Equipment PV RunsValidatedQualification IQ/OQ校验Manufacturing 制剂的开发设备确认IQ/OQProcessFormulationBatch DevelopmentManufacturing批生产记录Records分析方法的开发SOPs/培训验证过的分析方法AnalyticalSOPs/TrainingValidated Analytical MethodDevelopment211©Copyright Globepharm, 2005
IQ Readiness ChecklistGeneral Information: Equipment Log Book General Purchase Order information needed for System Description protocol Plant Tag ID development. Drawings can be Accurate system drawingsred marked but Operating Manuals must reflect actual IdentificationOperational SOPPM SOPCleaning SOPCalibration SOPCritical Instruments with Tag IdFunctional SpecificationControl System SpecificationAlarm DefinitionMotor specificationsOthers212©Copyright Globepharm, 2005
IQ Readiness ChecklistP&IDDrawings -current system or “as-built”drawings for Wiring Diagramsthe equipment/ DiagramsOthersElectrical RequirementsUtility Requirements -definition of utility ranges required Compressed Air RequirementsChilled Water RequirementsSteam RequirementsPotable Water RequirementsVacuum requirementsOthersPassivation (only for new equipment)Certificates -provide copies of certifications needed for Hydrostatic Testthe VesselsPressure Relief ValvesOthers213©Copyright Globepharm, 2005
OQ Readiness ChecklistCritical Instruments selectedInstrument Calibration -critical instruments must be defined, Calibration Certificatescalibrated and tagged; calibration certif Instrumentsicates and calibration Calibration Tags onprogram evidence providedOthersFunctional Requirements/Design System DescriptionSpecificationOperational RequirementsAlarm DefinitionModes of OperationControl LoopsOthers214©Copyright Globepharm, 2005
OQ Readiness ChecklistSOP functionality -SOP's approved, training record, Operational SOPSOP official copy, and signatures from operator and supervisor for functionality agreementMaintenance SOPCleaning SOPCalibration SOPOthers215©Copyright Globepharm, 2005
Computer System QualificationsYellow lined drawings or As builtsWiring Verification -current yellow lined wiring diagrams or “as-built” of the installed versionAnnotated Ladder Logic -hard copy of the current annotated PLC ladder logic with cross of the installed versionControl Screens Specification -hard copy of the current screens report with tag disk and locationBack-up FilesAccess levels and restrictionsSecurity Specification216©Copyright Globepharm, 2005
Cost Validation Effective documentation development role efficienciesin validation adequate people thorough IQ mins+maxsConcentrate on OQ/PQ/ OQ/ extent of qualification and validation efforts based QC lab validation on risk analysiswork plays pivotal role in rapid production start-up217©Copyright Globepharm, 2005
Questions?218©Copyright Globepharm, 2005
FUNDAMENTALS AND ESSENTIALSOF VALIDATIONUTILITIES(Services)VALIDATION公用设施验证219©Copyright Globepharm, 2005
FDA Does not Ignore Utilities FDA并不忽视公用设备P&G Pharmaceuticals Manati, March 2001: FD-483Facilities and Equipment System 1. Failure to have equipment of appropriate design and construction to facilitate operations for its intended use in the manufacture of drug products, in accordance with 21 CFR . For example: The centralized system to deliver compressed air was not adequate to simultaneously supply all areas in the plant where it was needed. In order to have sufficient compressed air pressure for the micronization step for Dantrolene Sodium Active Pharmaceutical Ingredient (API), it was necessary to assure that the compressed air system was not being used in other areas of the plant at the same time that the micronization process was in progress. There were no controls to assure that other areas of the plant did not use the compressed air system during the micronization process and no checks on air pressure being delivered to the micronization system were recorded during the process. 220 ©Copyright Globepharm, 2005
UTILITIES (Services) VALIDATION公用设施验证UTILITY SYSTEM 公用设施DQIQOQPVFire Water System 消防用水系统99Breathing Air System 呼吸系统99Dust Control System 捕尘系统99Compressed Air System 压缩空气系统999Nitrogen Gas System氮气系统999USP Water System (PW/WFI) USP水系统9999Air (HVAC) System空调系统9999221©Copyright Globepharm, 2005
Utilities Validation 公用设备验证Water Systems水系统222©Copyright Globepharm, 2005
VALIDATION: WATER SYSTEMS [IQ]验证：水系统-安装确认installation qualification: 安装确认“as-built”engineering drawings accurate 按照工程设计图建造materials of construction meet specifications 建筑材料符合标准welds documented and inspected (GTAW)记录焊接并检查（亚弧焊）slopes and “dead legs”checked and resolved 倾斜度、死角检查和处理passivation performed 钝化Pharmaceutical WaterEditor: Bill CollentroPublished By: CRC Press223©Copyright Globepharm, 2005
PW Standards 纯化水标准EP-2005IP-4JP-15USP-28Conductivity< μS----< μS -1电导率<μS -2TOC 总有机碳< 500ppb----< 500ppbViable Organisms< 100cfu/mL----< 100 cfu/mL活微生物Endotoxins内毒素--------(EU/mL)Non-Viable --------Particulates非活性微粒224©Copyright Globepharm, 2005
WFI Standards 注射用水EP-2005IP-4JP-15USP-28Conductivity< μS----< μS -1电导率<μS -2TOC 总有机碳< < 10cfu/100mL----< 10 cfu/100mLOrganisms活微生物Endotoxins< < < 内毒素(EU/mL)Non-Viable see table----see tableParticulates非活性微粒225©Copyright Globepharm, 2005
VALIDATION: WATER SYSTEMS [OQ]验证：水系统－运行确认operational qualification: 运行确认ability to deliver specification quality water under varying conditions of：在以下变化条件下供给合乎标准的水的能力flow rate 流速feed quality 供应量demand draw 草图capacity meets DQ requirements 生产能力符合设计要求226©Copyright Globepharm, 2005
Water System OQ + PV水系统运行OQ –Phase 1Microbial –daily sample every POU微生物: 每个使用点每天取样Weeks 1 –4运行确认－第一阶段（1-4周）Chemical –daily sample, loop start/end化学: 水循环出水点和回水点每天取样OQ –Phase 2Microbial –daily sample alternate POU微生物: 每天各使用点轮流取样Weeks 5 -8 运行确认－第二阶段（5-8周）Chemical –daily sample, loop start/end化学: 出水点和回水点每天取样PV Microbial –weekly sample rotating POU微生物: 每周各使用点轮流取样Weeks 9 –52工艺验证（9-52周）Chemical –weekly sample, loop end化学: 回水点每周取样study and trend seasonality impact研究季节性影响趋势227©Copyright Globepharm, 2005
VALIDATION: WATER SYSTEMS [PV]验证：水系统performance qualification: 性能确认extensive monitoring over a 30-60 day period, lesser monitoring thereafter; checking:严密监控30-60天，之后减少监测次数，检查以下项目：every usage point, at least once each week 每个使用点至少每周一次sampling during every working day 每个工作日取样sampling schedule covers worst case operating conditions 取样计划要包含最差的运行状态¾quality acceptance criteria met over entire period在整个验证周期里质量符合可接受标准228©Copyright Globepharm, 2005
Seasonality季节性229©Copyright Globepharm, 2005
Water System OQ + PV水系统OQ –Phase 1Microbial –daily sample every POUWeeks 1 –微生物：每个使用点每天取样4运行确认－第一阶段（1-4周）Chemical –daily sample, loop start/end化学：出水点和回水点每天取样24 hour stoppage ??? 24小时中断？OQ –Phase 2Microbial –daily sample alternate POUWeeks 5 -微生物：每天各使用点轮流取样8 运行确认－第二阶段（5-8周）Chemical –daily sample, loop start/end化学：水循环出水点和回水点每天取样PV Microbial –weekly sample rotating POUWeeks 9 –微生物：每周各使用点轮流取样52性能确认（9-52周）Chemical –weekly sample, loop end化学：水循环回水点每周取样study and trend seasonality impact研究季节性影响趋势230©Copyright Globepharm, 2005
Utilities Validation公用设施验证Compressed Air Systems压缩空气系统231©Copyright Globepharm, 2005
Compressed Air 压缩空气“OIL FREE”–Isn’t无油－是或否__________Black iron, or galvanized, pipe to “close to point-of-use”在接近使用点处使用铸铁或镀锌管道Bacteria retentive (μ) filer细菌截留过滤器(μ)Stainless piping after filter过滤器后－不锈钢管232©Copyright Globepharm, 2005
Compressed Air压缩空气Quality Acceptance Criteria (QAC)可接受标准AT EACH POU: 在每一个使用点particle count 粒子数Viable 活性的non-viable非活性的oil vapormoisture content (dew point)水份（露点）Standards:ISO 8573-1:2001Compressed air -Part 1: Contaminants and purity classesUSP –Medicinal AirPNEUROP (grade 7)233©Copyright Globepharm, 2005
Utilities Validation公用设施验证Air (HVAC) Systems空调系统234©Copyright Globepharm, 2005
ISO 14644 Cleanrooms and Associated Controlled Environments洁净室和控制区域环境235©Copyright Globepharm, 2005
ISO 14644ISO 14644: Cleanroomsand Associated Controlled Environments洁净室和控制区域环境Officially Issued: 正式发布ISO-14644-1 Classification by Airborne ParticlesISO-14644-2 Monitoring for ComplianceISO-14644-4 Design, Construction and Start-upISO-14644-5 Clean room Operations ISO-14644-7 SeparativeDevicesIn Draft Stage: 草案阶段ISO-14644-3 Measurement & TestingISO-14644-6 Terms, Definitions & UnitsISO-14644-8 Molecular Contamination Globepharm, 2005
ISO 14644 Cleanrooms and Associated Controlled Environments洁净室和控制区域环境US -Class 100 EU -Grade AUS-Class 100,000EU -Grade D237©Copyright Globepharm, 2005
Clean Room Qualification [IQ]洁净室确认－安装确认installation qualification –EMPTY ROOM (at rest):安装确认－空房间（静态）HEPA filters cold DOP tested meets ISO 14644Laminar Air Flow 层流HEPA filter air velocity tested 高效过滤器流速90 feet/ Studies 发烟试验Pressure Differentials tested压差∆p > ”(> 13pa)Temperature, Humidity温度、湿度meets Load (static condition)尘埃粒子数（静态）meets ???季节性238©Copyright Globepharm, 2005
WHO HVAC Guidelines (April 2003):Qualification RequirementsRoom Qualification should be carried out under the following scenarios: 房间确认必须在以下几种条件下进行The “as-built”conditionshould relate to carrying out room classification tests on the bare room, without any equipment or personnel.在空态（空房间，无操作人员和设备）的状态下，进行房间洁净等级测试The “at-rest”conditionshould relate to carrying out room classification tests with the normal production equipment in theroom, but without any operators.在静态（有设备、无操作人员）状态下进行的房间洁净等级测试The “operational”conditionshould relate to carrying out room classification tests with the normal production process with equipment operating, and the normal staff present in the room.运行状态：在有设备、有操作人员进行日常生产的状态下进行的房间洁净等级测试239©Copyright Globepharm, 2005
Room Classifications等级划分240©Copyright Globepharm, 2005
Frequency of On-Going HVAC Monitoring空调系统监测频率WHO HVAC Guideline (Apr 2003)241©Copyright Globepharm, 2005
Frequency of On-Going HVAC Monitoring空调系统监测频率WHO HVAC Guideline (Apr 2003)242©Copyright Globepharm, 2005
Clean Room Qualification [OQ]洁净室确认－运行确认operational qualification –TYPICAL USE (Operational)运行确认－典型使用（运行的）Room particulate loading (dynamic condition) 尘埃粒子数（动态）Room recovery potential 回复能力243©Copyright Globepharm, 2005
Real-Time Particulate Monitoring即时粒子数监测244©Copyright Globepharm, 2005
Room Recovery Potential回复能力Recovery Potential (mins)Time (mins)ElectricityFAILURERETURN245©Copyright Globepharm, 2005Pressure differential (Δp)Particle Count
Clean Room Qualification [PQ]洁净室确认-性能确认performance qualification WORST CASE CONDITIONS性能确认－最坏条件Maximum people loading (occupancy) 最大人员负荷（占用率）Maximum temperature, humidity 最大温度、湿度Maximum product loading (production volume) 最大生产能力（最大产出体积）Room recovery potential (?)246©Copyright Globepharm, 2005
Questions?问题247©Copyright Globepharm, 2005
FUNDAMENTALS AND ESSENTIALSOF VALIDATIONCLEANINGVALIDATION清洗验证248©Copyright Globepharm, 2005
HOW CLEAN IS CLEAN怎么样才算清洁的BIOLOGICAL CLEANLINESS 生物学上的清洁bioburden limits 微生物限度endotoxin limits 内毒素限度CHEMICAL CLEANLINESS化学上的清洁product residue limits产品残留限度detergent residue limits清洁剂残留限度solvent residue limits溶剂残留限度PHYSICAL CLEANLINESS物理上的清洁particulate contamination limits微粒污染限度249©Copyright Globepharm, 2005
Clean: Dad’s Definition清洁：爸爸的解释250©Copyright Globepharm, 2005
Clean: Teenager’s Definition清洁：青少年的解释251©Copyright Globepharm, 2005
252©Copyright Globepharm, 2005
CLEANING VALIDATION 清洁验证key considerations –I 关键点1characteristics of residue残留物的确认identity of residue and of degradants残留物和降解物质的确认potency / pharmacology / toxicology 效价/药理学/毒性characteristics of substrate密封件的确认glass / steel / plastic / rubber gaskets玻璃/钢/塑料/橡胶垫圈time between use and cleaning使用和清洁之间的时间immediate / overnight ‘crud’立即进行/放置过夜后进行equipment design设备设计hardest to clean position最难清洗的位置253©Copyright Globepharm, 2005
Blender: Hardest To Clean Location混合机：最难清洁的位置corner?角落tines ?齿轮gasket?垫圈outlet?出口somewhere else?其他别的地方254©Copyright Globepharm, 2005
CLEANING VALIDATION 清洁验证key considerations –II关键点2cleaning medium清洁剂toxicity / effectiveness / residue potential 毒性/效果/潜在残留物composition: if unknown, residues difficult to evaluate构成：如果不知道，很难评价残留物cleaning technique (manual) 清洁技术training effectiveness 培训效果SOP details: SOP细节specific product identified, dismantling method detailed 特殊产品确认，拆卸方法cleaning agents identified, dilutions documented 清洁剂确认，稀释方法cleaning sequences described 清洁顺序‘hardest to clean point’identified 最难清洁点的确认visual inspections, provisions for documentation目视检查，提供记录255©Copyright Globepharm, 2005
CLEANING VALIDATION 清洁验证key considerations –III关键点3cleaning technique (automated -CIP)清洁技术（自动化－在线清洁）“as built”piping diagrams管道图sanitary piping systems消毒管道系统no ball valves没有球阀pipes + valves tagged and identified 管道+阀门连接和标识operators trained 操作人员培训end-point definition终点定义when is it clean? how clean is clean? 什么时候算是清洁？多清洁才算清洁？ (inspector technical guide)256©Copyright Globepharm, 2005
STAIN污点257©Copyright Globepharm, 2005
CLEANING VALIDATION 清洁验证key considerations –IV关键点4sampling technique:取样技术direct surface –swab脏的表面－擦拭法hardest to clean point evaluated最难清洁的地点评估rinse flush淋洗法greater surface coverage覆盖更大的面积inaccessible areas sampled难以到达的部位的取样insolubles not removed and not sampled 不溶性物质（未除去的，未取样的）recovery potential 回收率testing method and method sensitivity检测方法及其灵敏度258©Copyright Globepharm, 2005
Economic Benefits of Cleaning Validation清洗验证所带来的经济学上的好处Solvent Reduction减少溶剂Solvent Switch: Eco-friendly materials溶剂的更换：无环境污染Shorter Cleaning Times缩短清洁时间Increased Equipment Utilization增加了设备利用率Extended Equipment Life延长设备寿命Worker Safety工人的安全Cost-Effectiveness成本259©Copyright Globepharm, 2005
Surface Sampling –Swabs表面取样－擦拭法Disadvantages缺点Advantages 优点Must determine specific surface Direct surface sampling 直接对recovery efficiency and 表面取样variability需测定特定表面的有效回收率和Mechanical abrasion to 变率remove residue 对设备可能存在机械Requires careful handling SOPs 磨损to prevent contamination要求详细Solvent to remove residue用溶的处理SOPs来防止污染剂清除残留Potential for analytical Well defined sampling area规interference from swab material定好的取样面积擦拭物导致的潜在的分析干扰Can see surface to be Manual process requires training操作需要培训sampled可以看见取样表面commonly used with finished pharmaceutical manufacture通常用于成品（制剂？）生产260©Copyright Globepharm, 2005
表面取样－淋洗法Surface Sampling –RinseAdvantages 优点Disadvantages缺点Broad sampling surface, Requires residue to be highly tends to average resultssoluble in solvent要求残留物易溶于溶剂取样面积大，接近于平均结果Need to control surface area Easy access to difficult to exposed to rinse要控制需要淋洗的reach areas易于到达难接触表面表面积Access to large surface Need to control rinse contact areas enhances sensitivity面积time 要控制淋洗的时间更大，增强灵敏度Can over dilute sample if too much solvent used 可能使用太多的溶剂导致样品溶液浓度变稀commonly used in bulk chemical (API) manufacture261©Copyright Globepharm, 2005
清洁验证指南Cleaning Validation GuidelinesCanada-HPBFI-Cleaning Validation GuidelinesTable of Contents:内容 Scope范围 Introduction介绍 Principles原理 Validation of cleaning processes清洁程序验证 Equipment and Personnel设备和人员 Microbiological considerations微生物 Documentation文件 Analytical methods分析方法 Sampling, rinsing, rinse samples and detergents取样，淋洗，淋洗样品和清洁剂 Establishment of limits 限度的确定 Conclusion 结论 References参考 Globepharm, 2005
建立清洁限度-1 Establishing Cleaning Limits -1Product Specific Cleaning Validation for All Products 对指定的产品进行清洁验证Grouping Into Product Families, and Choosing the Worst Case Product 以产品所在家族分类，选择最难清洗的产品Grouping Into Groups of Similar Risk:以类似的风险分类Similar Solubility类似的溶解度Similar Potencies类似的效力Highly Toxic Products 高毒性产品Difficult to Detect Products难于检测的产品Setting Limits for the Maximum Allowable Carryover (MAC)设定最高允许残留（MAC）的限度Different Safety Factors for Different Dosage Forms相对不同剂型采取的不同的安全因子Canada --HPFBI Cleaning Validation Guidelines, 2002 Globepharm, 2005
建立清洁限度-2 Establishing Cleaning Limits –2Maximum Allowable Carryover (MAC)of residue:最高允许残留（MAC）：Most stringent of following:NMT % of normal therapeutic dose of any product to appear in the maximum daily dose of the following product普通剂型的任何产品：不超过最大日剂量的%NMT 10 ppm of any product to appear in any other product出现在其他产品中的任何产品残留：不超过10ppmNo quantity of residue to be visible after cleaning procedures performed清洁后无可见残留物[perform spiking studies to determine visible limit]For certain allergens, penicillins, cephalosporins, or potent steroids and cytotoxics, NMT LOD by best available analytical method[in practice this means using dedicated facilities]对于过敏原、青霉素类、头孢菌素类，或者甾体和细胞毒素，以最好的分析方法检测，不得超过检测限（实际操作时采用专用设备）Canada --HPFBI Cleaning Validation Guidelines, 2002 Globepharm, 2005
目视法清洁Visually CleanEU GMP -Annex 15Most stringent of:Dose calculation 根据剂量计算10ppmVisually clean目视清洁Fourmenand Mullen (USA)Most stringent of:Dose calculation Visually cleanSource: “Visually Clean”, ., Jan 2002265©Copyright Globepharm, 2005
最高允许残留（擦拭法）Maximum Allowable Residue per Swab -MARS MARS =vol. of Batch B * dose A mg. active A 25 of Bdose Bequip areaA --yesterday’s product昨天生产的产品Boday’ poduct 今天生产的产品--safety factor安全因子MDD--max daily dose最大日剂量25 --swab area擦拭面积266©Copyright Globepharm, 2005
计算MAR Calculating Maximum Allowable ResidueAssumptions:假设：All residues evenly dispersed on all surfaces残留均匀分布在所有表面Maximum allowable residue for any contaminant -10ppm最高允许残留Toxicity Level ?毒性水平Limit of Detection ?检测限At least to the toxicity level !Perform cleaning validation study at maximum batch size按最大批量进行清洁验证Assume next batch is minimum batch size for equipment train假设下一批是最小批量Worked Example:实例：Maximum batch size = 252 Kg最大批量=252kg(yesterday’s batch) 昨天的批次10ppm residue = grams total residue in equipment train10ppm残留=总残留物Maximum residue for each piece of equipment in train = MAR= AEQ/ATOTx MARTOTEQ267©Copyright Globepharm, 2005
计算MAR Calculating Maximum Allowable Residue2Shared EquipmentProduct Contact Number of Swab (25cm) 共用设备Surface AreaSamplesSample Area产品接触面积取样数目擦拭面积22Mixing Tank混合容器26,000 cm8200 cm22Stirrer搅拌器500 cm4100 cm22Pump泵750 cm250 cmHoses软管DisposableN/AN/A22Filling Machine5,700 cm10250 cm22TOTAL32,950 cm24600 cmMaximum residue for filling machine(MAR)= A/Ax MAREQEQTOTTOT= 5,700/32,950 x = residue per filling machine swabs= 250/5700 x = = μg268©Copyright Globepharm, 2005
验证：产品矩阵设计Validation: Product MatrixingPRODUCT产品A B C D E F G H I ?Least Soluble 溶解度最z小Most Toxic 毒性最大zMost Viscous 最粘zMost Acid 酸性最强zMost TenaciouszMost Aromatic zDeepest Color 颜色最z深Envelope = Testing of A, B, C, F + G269©Copyright Globepharm, 2005
验证：设备矩阵设计Validation: Equipment MatrixingStep 1 –Create Equipment Usage Database第一步：创建设备使用数据Product 产品ABCFGMixerM1M2M2---M1Dryer干燥机D1D1D1---D2Granulator 制粒机G1G2G1G3G2BlenderB1B2B3B1B2Tablet Press 压片T1T2T3T3T2机270©Copyright Globepharm, 2005
验证：设备矩阵设计Validation: Equipment MatrixingStep 2 –Eliminate dedicated equipment, needs dedicated validationStep 3 –Group SharedEquipment By Operating PrincipleEquipmentPrincipleSizeProductsM1High shear mixer, bottom driven1XA, EM2High shear mixer, side driven1XB, CD1Fluid bed dryer1XA, B, CG1Screen granulator with oscillator1XA, C, EG2Screen granulator with oscillator2XB, EB1Twin shell blender1XA, DB2Twin shell blender2XB, ET2Force feed tablet press1XB, ET3Gravity feed tablet press1XC, D271©Copyright Globepharm, 2005
Validation: Equipment MatrixingStep 2 –Eliminate dedicated equipment, needs dedicated validationStep 3 –Group SharedEquipment By Operating PrincipleEquipmentPrincipleSizeProductsM1High shear mixer, bottom driven1XA, EM2High shear mixer, side driven1XB, CD1Fluid bed dryer1XA, B, CG1Screen granulator with oscillator1XA, C, EG2Screen granulator with oscillator2XB, EB1Twin shell blender1XA, DB2Twin shell blender2XB, ET2Force feed tablet press1XB, ET3Gravity feed tablet press1XC, D272©Copyright Globepharm, 2005
进一步的阅读Further ReadingCleaning ValidationValidated Cleaning 清洁验证Technologies for Pharmaceutical ManufacturingBy: Destin LeBlancBy: Neumann and BismuthPub: CRCPressPublished by: CRC Press273©Copyright Globepharm, 2005
其他清洗验证参考书Other Cleaning Validation , ., and Mullin, Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations, Pharm. Tech., 17(4), 54-60 (1993) -for standard 10 ppm and 1/1000 lowest theoretical dose calculations based on compounds that are , Guide to Inspections of Validation of Cleaning Processes, Rockville, MD, USA, , Destin, Validated Cleaning Technologies for Pharmaceutical Manufacturing, Interpharm Press, Chapter 8 and other relevant sections, pips. 135-149, , ., Validation of Analytical Methods used for Pharmaceutical Cleaning Assessment and Validation, Pharm. Tech., Method Validation Supp. to Pharm. Tech., (1998)Also with respect to allowable residue limits:, ., et al., Setting Health-Based Limits for Contaminants in Pharmaceuticals and Medical Devices, Quality Assurance, Good Practice, Regulation and Law, Academic Press, -180, (1992). Layton, et al., Deriving Allowable Daily Intakes for Systemic Toxicants Lacking Chronic Toxicity Data, Regulatory Toxicology and Pharmacology, 7, pps. 96-112 (1987), ., et al., Regulatory History and Experimental Support of Uncertainty (Safety) Factors, Regulatory Toxicology and Pharmacology, 3, pps. 224-238, (1983). 274©Copyright Globepharm, 2005
问题Questions?275©Copyright Globepharm, 2005
FUNDAMENTALS AND ESSENTIALSOF VALIDATIONCOMPUTERSYSTEMSVALIDATION计算机系统验证276©Copyright Globepharm, 2005
Know Computerese介绍一些计算机术语277©Copyright Globepharm, 2005
一个想法A ThoughtIt is no longer necessary for mankind to scribble on pulverized trees with graphite sticks.…. The electronic age is here !电子时代已经来临278©Copyright Globepharm, 2005
计算机验证COMPUTER VALIDATION ARE YOU APROGRAMMER ?你是一个程序工作者吗？279©Copyright Globepharm, 2005
FDA指南FDA GuidelinesGeneral Principles of Software Validation; Final Guidance for Industry and FDA Staff (Jan 2002) for Industry, FDA Reviewers and Compliance on Off-The-Shelf Software Use in Medical Devices (Sep 1999) for FDA Reviewers and Industry Guidance for the Content of Pre-market Submissions for Software Contained in Medical Devices (May 1998) Globepharm, 2005
软件验证SOFTWARE VALIDATIONwhen and how extensiveWIDELY COMMERCIALLY AVAILABLE:广泛的商业应用：(超过5000人使用正版的软件）DATABASES: Access, Paradox数据库：SPREADSHEETS: Excel, Quattro电子制表软件：LIMS:Beckman, Turbochrom实验室信息管理系统（Laboratory Information Management Systems）：1. Can “assume”that manufacturer has validated system*能否假设制造商已经验证系统？281©Copyright Globepharm, 2005
软件验证SOFTWARE VALIDATIONversions, revisions, releasesCan “assume”that manufacturer has validated system*能否假设制造商已经验证系统？VERSIONSupgrade with new features [create new bugs!]publicly announced --major marketing effort版本：REVISIONSfix bugs, minor product enhancementresponse to mass complaints --damage controlRELEASES/fix bugs, minor product enhancementBUILDSno publicity282©Copyright Globepharm, 2005
软件验证SOFTWARE VALIDATIONwhen and how extensiveWIDELY COMMERCIALLY AVAILABLE: 广泛的商业应用DATABASES: Access, Paradox数据库：SPREADSHEETS: Excel, Quattro 电子制表软件：LIMS:Beckman, Turbochrom实验室信息管理系统（Laboratory Information Management Systems）：1. Can “assume”that manufacturer has validated system*能否假设制造商已经验证系统？ to assure that software works in your situation需要保证软件在你的地方工作 generated templates, macros, applicationprograms, etc. need be to validated本地产生的模版、宏、应用程序等需要验证283©Copyright Globepharm, 2005
软件验证SOFTWARE VALIDATION何时和如何详尽when and how extensiveSMALL USER BASE/ IN-HOUSE DEVELOPED SOFTWARE小规模用户的基础/内部的软件LANGUAGES: PERL, JAVA, C++计算机语言1. Audit software development site审计软件研发地 credentials of project software engineers制定软件工程项目的凭证 references with other healthcare users与其他息息相关的用户一起检查引用 developers work and test to software industryprogramming and testing standards [ISO 9000-3]确保研发者对软件行业程序设计进行工作和测试并测试标准 software validation required完整的软件验证需求284©Copyright Globepharm, 2005
验证的程度：涉及到的等级Degree of Validation: Level of ConcernCATEGORYRISKDESCRIPTION / IMPACT等级[LOC]描述/影响level of concern风险System directly impacts product quality系统直接影响产品质量Critical5关键的 failed system results in OOS productlabel and 错误的系统导致OOS结果OOS failure not detected by other methods/systems其他方法/系统中没有找到不合格System indirectly impacts product quality系统间接影响产品质量Major4较重要的 failed system might result in OOS product错误的系统可能导致OOS结果 failure normally detected by other method用其他方法经常不合格Quality control systems, or systems that indirectly might Mild3impact product quality间接可能影响产品质量的质量控制系统或体系轻微的temperature or …Pre/post market data, information systems, networks, Minor2development tools上市前/上市后的市场数据，信息系统，网络，研发工具较小的285©Copyright Globepharm, 2005
软件的生命周期SOFTWARE LIFECYCLERequirements Phase需求阶段DQUser Requirements用户需求Design Phase设计阶段DQFunctional Specifications功能标准Implementation Phase施行阶段IQTest Phase测试阶段IQInstallation / Checkout安装/检验OQ/PVOperation运行OQ/PVMaintenance / Change Control维护/变更控制286©Copyright Globepharm, 2005
软件的生命周期SOFTWARE LIFECYCLEValidation Plan验证计划everyUser Requirements Specification (URS)用户需求标准stepSupplier Audit供应商审计Supplier Quality Plan供应商质量计划isFunctional (Design) Specification功能设计标准ImportantHardware / Software Design硬件/软件设计每一步都很重要Design Qualification安装确认Programming and Construction程序设计和构造sequenceSupplier Testing供应商测试is vitalInstallation Qualification (IQ)安装确认次序是必须的Operational Qualification (OQ)运行确认Performance Validation (PV)性能验证Validation Report验证报告Ongoing Support进行中的支持287©Copyright Globepharm, 2005
V型计算机验证“V-Model”Computer ValidationCONCEPT &OPERATION &REQUIREMENTS概念和需求MAINTENANCE运行和维护ONGOING APPLICATION SELECTIONLIVE MONITORING & USER REQUIREMENTSSYSTEM MEETS ORIGINAL SELECTIONCHANGE CONTROL适用性选择CRITERIA AND USER REQUIREMENTS用户需求系统符合原始选择标准和用户需求进行中的实时监控和变更控制FUNCTIONAL REQUIREMENTSSYSTEM SPECIFICATIONACCEPTANCEBUSINESS PROCESS MODELSYSTEM PERFORMS INTENDED TTEESSTTININGGTSOPSDSOPSINTEGRATED FUNCTIONS系统可接受测试功能需求系统进行预期的整合功能标准EE商业运作模式SSSYSTEM DESIGN SPECIFICATIONUNIT TESTINGPROGRAM SPECIFICATION IIIPROCESSES & PROGRAMS单元测试系统设计标准PERFORM INTENDEDTI程序标准FUNCTIONS工艺和程序实行预期的功能IGPROGRAM SPECIFICATIONSTRUCTURALNPROGRAMMING STANDARDSNCODE REVIEWCODESOURCE CODE结构代码审核COMPLIES程序标准TO STANDARDSG程序设计标准设代码符合标准源代码测计CONFIGURE / CODE设定/代码试DEVELOPMENT研发288©Copyright Globepharm, 2005
VALIDATION OF COMPUTER SYSTEMS计算机系统验证（产品有效期的软件，MIKE？）CHANGE CONTROL + AUDIT TRAILSSYSTEM DEFINITION系统的定义变更控制+审计跟踪System Components系统的组成MANUALS手册System Documentation系统的文件Standard Operating ProceduresSOPsSYSTEM VALIDATION User/Training/Maintenance ManualsPROTOCOLS系统验证方案用户/培训/维护手册Software Development软件研发MAINTENANCE维护User Responsibilities用户责任System + Data Maintenance系统+数据维护Validation Protocols验证计划Data Storage数据储存Documentation文件SECURITY安全性SYSTEM TESTING系统测试Passwords + Electronic ID密码+电子身份认Testing Types测试类型证System Validation系统验证TRAINING, SUPERVISION, Validation Documentation验证文件PROFICIENCY TESTING, AUDITING培训，监督，熟练测试，审计289©Copyright Globepharm, 2005
系统的定义SYSTEM DEFINITIONSYSTEM COMPONENTS系统的组成SYSTEM COMPONENTSHardware/Software ConcernsPersonnel Factors人员因素硬件/软件涉及到：Training培训hardware/software Certification培训确认compatibility硬件/软件兼容性unique identification唯一的鉴别peripherals interfacing外设的连接access limitations访问限制去机房询physical constraints环境因素问并检查设置权限。maintenance/calibration维护/校验operating instructions操作指南290©Copyright Globepharm, 2005
系统文件SYSTEM DOCUMENTATIONUSER RESPONSIBILITIESVENDOR RESPONSIBILITIES用户责任销售方责任user requirements用户需求operational specifications操作标SOPs（如何管理这个系统，如何维准护，如何变更并保存所有记录）instruction manuals操作手册test databases + descriptions测试数diagrams, flow charts, 据+说明system definitions图表，流程records of operational validation图，系统定义of integrated hardware, software test databases测试数据可外购，+ peripherals完整的硬件软件+外设的运很多公司有这些试数据行验证的记录records of change + maintenance变更和维护记录291©Copyright Globepharm, 2005
系统研发SYSTEM DEVELOPMENTVENDORS TO SUPPLY销售者提供USER TO ASSURE用户保证software developed + validated by specifications, documentation recognized standards and validation for:为以下方面提供标(. ISO 9000-3)软件开发和验证有公准，文件和验证认标准data inputs+outputs数据输入和输出all software versions kept in readable form所有软件版本保存在可读data manipulation数据处理取的状态module-module interaction模块software change follows 与模块之间的交互作用systematic change control软件变更遵peripherals interaction外设的交循系统的变更控制互作用system to be notified of design data storage + maintenance数据储存和维护defects and errors报告系统设计缺陷和误差应锁定这些内容data search + retrieval algorithms数据搜索和检索算法third-party escrow第三方的证书292©Copyright Globepharm, 2005
系统测试SYSTEM TESTINGSOFTWARE TESTING CHALLENGES THE SYSTEM软件测试向系统提出了挑战STRUCTURALexercises all modules + branches of software and 结构上interaction with hardware + peripherals运行所有的模块和所有的软件支线与硬件及外设的交互作用确保运行正常FUNCTIONALdemonstrates system outputs appear to be correct功能上--does not assure operation to requirements or specs证明系统输出看来是正确的——不保证在要求或标准下的运行保证输出正确NORMALdata inputs fall within normal operating range通常输入的数据属于正常操作范围输入正常数据，看输出的结果如何BOUNDARYinput values force system to discern whether input is 上下限valid, or to make a ‘branching’decision输入值迫使系统识别是否输入是正确的，或做一个‘分支’决策INVALIDITYinput values out of normal operating range (.. blank)无效输入超出正常操作范围的值（例如：空白）如何输入非淀数据会咋样WORST CASEstresses system beyond normal specifications最坏条件强制系统超出正常标准如何输入超出正常标准计算机会怎么293样？©Copyright Globepharm, 2005
软件的生命周期：测试阶段SOFTWARE LIFECYCLE: Test PhaseSOFTWARE ERRORS软件错误Syntax 语法Logic逻辑TEST PLAN测试计划Define Expected Output定义预期输出Write Test Cases for All Situations撰写所有情况下的测试方案Challenge the Program挑战程序TEST METHODS测试方法Modular, Integrated, “Black/White”Box 模式化的，综合的，“黑/白”盒294©Copyright Globepharm, 2005
软件测试SOFTWARE TESTINGSYNTAX ERROR:Hubble Telescope语法错误哈勃望远镜LOGIC ERROR:逻辑错误pH < 7pH > 7pH ?295©Copyright Globepharm, 2005
电子表格处理软件的验证Spreadsheet Validation (1)Using spreadsheet to compute mean tablet weight用电子表格处理软件来计算平均片重量296©Copyright Globepharm, 2005
电子表格处理软件的验证Spreadsheet Validation (2)Using spreadsheet to compute mean tablet weight用电子表格处理软件来计算平均片重量Only 9 samples available仅有9个样本可用Result –ERROR!!结果——错误!!297©Copyright Globepharm, 2005
电子表格处理软件的验证Spreadsheet Validation (3)Using spreadsheet to compute mean tablet weight用电子表格处理软件来计算平均片重量Only 9 samples available仅有9个样本可用Which is correctresult ??哪个是正确的结果298©Copyright Globepharm, 2005
电子表格处理软件的验证Spreadsheet Validation (4)All Explained when you see the meta-data:当看到元数据时所有的说明verify/lock formula检验/锁定公式用密码索定print user/date输出用户/数据check changes (vb)检查变更(vb)299©Copyright Globepharm, 2005
系统变更SYSTEM CHANGESdescription of the change变更描述tasks performed to effect the change执行任务来实现变更一种是可预计到的，另一种是预计不到的，是想向之外的person performing the task to effect the change执行任务的人员来实现变更identification of impacted software modules受影响的软件模块的鉴定写方案来验证变更authorization signatures授权签字validation protocols and test cases验证方案和测试方案validation reports验证报告documentation of change and acceptance of change变更和可接受变更的文件300©Copyright Globepharm, 2005
系统规程SYSTEM PROCEDURESSOPs for all operationsUser Manuals用户手册所有操作的SOPstraining manuals培训手册normal events正常事件maintenance manuals维护手册start-up启动document manual文件手册data entry/edit/delete数据输入/修改/删除Password Control密码控制emergency events突发事件periodicity of change变更的周期disaster recovery故障恢复每天总部备Uniqueness唯一性份全部数据两次，机场每两分钟备份一次，存在不同的电脑上ex-staff不包括的人员data archiving数据归档Confidentiality保密性system administration系统管理documentation 文件password control密码控制，密码三个月内必须变更一次，且原来用过和密码必须不再用，有人走过后，须取消，从QA到其他部门后，必须变更权限，如果我共用一个密码，作人没问题，但可能会作牢。301©Copyright Globepharm, 2005
21CFR11–Electronic Records and Signatures302©Copyright Globepharm, 2005
不要混淆Do Not ConfuseComputer Systems Validation计算机系统验证21CFR11 Compliance符合21CFR11一直要到系统验证后才可谈，验证是初步的要求。FDA没有强迫要求保留电子记录，但如果我们决定用电子记录的话，原始记录、数据库、SOP等，就必须符合上述规定。303©Copyright Globepharm, 2005
电子记录+签名ELECTRONIC RECORDS + SIGNATURES“FDA considers electronic records, electronic signatures, and handwritten signatures executed to electronic record to be trustworthy, reliable, and generally equivalent to paper records and handwritten signatures executed on paper …. if they comply with the requirements of these regulations”FDA认为电子记录，电子签名和手写签名使电子记录变得可信，可靠，并通常等价于在纸上进行纸记录和手写签名……如果他们符合那些法规的要求Source: 21CFR11304©Copyright Globepharm, 2005
电子记录ELECTRONIC RECORDSIf you chooseto keep the record electronically, then it must comply with 21CFR11如果你选择保持记录的电子化，那么它必须符合21CFR11Raw Data原始数据Databases数据库Reports报告305©Copyright Globepharm, 2005
21CFR11 –你涉及了吗？21CFR11 –Are You Involved?Question问题NOYESDoes record form part of the predicate(previous) rule?记录由部分断定规则组成吗？Does Systems Capture Raw Data?Does SystemSave Data (Raw or Calculations)?No Welcome21CFR11toIssues21CFR11306©Copyright Globepharm, 2005
断定规则The Predicate Rule21CFR11 applies to any records required by other regulations implemented by FDA (21CFR):21CFR1121CFR11适用于任何根据FDA（21CFR):21CFR11执行的其他法规所要求的记录 arrangements between the clinical investigator and the sponsor在临床研究者和赞助者之间的财政安排 data documentation, protocols, final reports, records of QA inspections, summaries of training and experience, job descriptions, records and reports of maintenance, calibration, and equipment inspection QA审查的原始数据文件，报告，最终报告，记录；培训和经历的摘要；职责描述；维护，校验，设备检查的记录和报告 event reporting, including raw data and correspondence不利的事件报告，包括原始数据和往来信件307©Copyright Globepharm, 2005
断定规则The Predicate Rule21CFR11 applies to any records required by other regulations implemented by FDA (21CFR):21CFR11适用于任何根据FDA（21CFR)执行的其他法规所要求的记录, control, discrepancy and distribution records. Records for components, drug product containers, closures and labeling.生产，控制，偏差和销售记录。合成，药物产品容器，密封，标签的记录 Files投诉文件 of manufacture and distribution of product, records of equipment and supplies sterilization, and necropsy results产品的生产和销售记录，设备和供给灭菌记录 history files, production, control, discrepancy and distribution records. 装置的历史文件，生产，控制，偏差和销售记录308©Copyright Globepharm, 2005
电子记录ELECTRONIC RECORDSData Integrity数据的完整性¾Automatic Generation of Audit Trails审计过程的自动生成¾Backups –Automatic自动备份对改前的数据进行备份¾Uninterrupted Power Sources不中断的动力源使用一个类似UPS的不间断电源。¾要求必须说明改前是什么，改后是什么，显示更改人的姓名及日期。要求在计算机中的数据和人工修改数据同样多的信息。Author Authentication使用者的鉴别(谁创建这些数据）¾Password Access密码访问¾Inactivity Shutdown不活动时关机（1分钟需锁定，解除时需要密码。）309©Copyright Globepharm, 2005
310©Copyright Globepharm, 2005
Questions ?Program + User Passwords程序和用户密码311©Copyright Globepharm, 2005
Great 21CFR11 Information ©Copyright Globepharm, 2005
引用FDA计算机系统的缺陷FDA Citations forComputer System quality unit is unaware of problems质量部门没有意识到这些问题如果有问题的话，是IT的人，而非QA的人。 unknown number of individuals have access to the computer control/monitoring systems, with unknown levels of access, and access performed by outside firms 没有明确可进入计算机系统或对其监控的人员，对进入人员的级别也没有限定，问系统是由外部公司代劳的。未很好地设定权限。整个系统未控制 written procedure in place to describe the controls for computer control/monitoring system remote access 没有适当的书面程序来描述计算机控制/监测系统的远程访问，变更控制很贵，作为销售的上部分，会承诺送货，并进行远程控制，通过电话进行远程控制，其中问题是我们不知道他们作了什么，没办法进行验证，不知道会不会影响其他东西，若有远程访问，必须精确地控制。 master plan fails to take older pieces into account验证主体计划没有将过去的实践记入在内。跟踪记录。 activity tests fail to take into consideration the monitoring devices‘s calibration tolerance报警监测没有考虑到监测设备的可测定的范围，如果压差低，稳定性箱变化也会报警，但很多人忘记对报警器进行校验，很多人没保存记录，也没审核及更正。在稳定性测试中用计算机控制，报警响了，采取降温措施，但若周末发生如何处理，若没记录，相当于没有报警器。Source: Thomas Arista–FDA National Expert –Biotechnology, 2001313©Copyright Globepharm, 2005
FDA计算机系统缺陷的引用FDA Citations forComputer System alarm records are not retained, nor are there documents that alarms were reviewed and followed with necessary corrective actions 系统警报记录没有保留，也没有文件对警告进行审核和跟进必要的整改措施，一些辅助的设施未验证。 alarm checks for computer control monitoring systems for temperature, and relative humidity 没有警报检查温度和相关湿度的计算机控制监测系统 of, or incomplete data to support computer systems validation计算机系统验证数据缺少或不完善。 utilities and equipment not validated or re-qualified following changes or modifications变更或更改之后，辅助设施设备没有进行验证或再确认 system description, ., as built/installation diagrams etc没有系统描述，例如，竣工/安装图表Source: Thomas Arista–FDA National Expert –Biotechnology, 2001314©Copyright Globepharm, 2005
EU计算机系统缺陷的引用EU Citations forComputer System Deficiencies System Configuration, Documentation系统配置，文件Unsatisfying configuration and documentation of systems for the acquisition of critical GMP-relevant parameters.获得关键的与GMP相关的参数的系统配置和文件不令人满意Paperless VideographicRecorders, Hybrid System 无纸化摄像记录，混合系统Unclear distinction between electronic record and paper documentation (operation of hybrid systems), especially with regard to archiving and evaluation.在电子记录和纸张文件（混合系统的运行）之间不清楚的区别，特别是顾及归档和评估Paperless VideographicRecorders, Data Flows无纸化摄像记录，数据流Data integrity endangered by untraceable data flows from the acquisition of a measured value to its recording in a LIMS.数据完整性受不可追溯的数据流的危害，此数据流是从其记录极限获得的一个可测量值。Monitoring System, Validation监测系统，验证Insufficient validation activities in connection with a system for temperature measurement in a cold storage leading to the preliminary rejection of the stored starting materials.不足的验证活动与在冷藏中的温度测量系统有关导致贮存的起始原料被初步拒收Data Loggers, Documentation数据记录器，文件Printouts of data (graphs) based on data collected by data loggers are not precise enough to be used for a GMP-compliant evaluation.打印出的数据（图表）基于收集于数据记录器的数据，但与GMP相关的评估显示此数据记录器精确度不足。315©Copyright Globepharm, 2005
EU计算机系统缺陷的引用EU Citations forComputer System DeficienciesExcel®Used as Evaluation Software, Data Conversion Excel®作为评估软件，数据转换The data generated by a logger were converted into the XLS format and archived without ensuring data integrity. 数据由记录器产生转换成XLS格式且没有确保数据的完整性就归档Room Monitoring System, Validation 房间监测系统，验证The qualification and validation of the room monitoring system was insufficient. Internal calculations executed by the software in use were not comprehensible. 房间监测系统的确认和验证不足。使用的用软件执行的内部计算不易于理解。Room Monitoring System, Projecting and Archiving 房间监测系统，设计和归档Backup of the data acquired by the room monitoring system was not conducted according to the state of the art. A documentation of the alert and system messages could not be presented. 对房间监测系统获得数据的备份没有按照规定的要求进行。不存在报警和系统信息的文件。Room Monitoring System, Access Control Matrix 房间监测系统，访问控制矩阵The configuration of the user settings had considerable safety defects. 用户设置的配置有值得考虑的安全漏洞Data Loggers, Software for Evaluation and Archiving数据记录器，评估软件和归档GMP-relevant setup settings of an evaluation and archiving software for data loggers were either not used or ignored.用于数据台帐评估和存档的软件，有关GMP的安装设置或者没有用到或者被忽视了。316©Copyright Globepharm, 2005
Questions?让IT的人打印一个XLS的后附文件打印出来，生产设备中的控制系统也是计算机，也需经过校验，很多公司未通过FDA的两大原因，一是未执行GMP，二是未进行计算机系统的校验。只的有权限的人才能对数据进行更改。改后计算机会自动作个记录。317©Copyright Globepharm, 2005
FUNDAMENTALS AND ESSENTIALSOF VALIDATIONANALYTICALMETHODVALIDATION分析方法验证318©Copyright Globepharm, 2005
Laboratory BelievabilityCertified Reference Standards 合格的工作标准品Properly Executed Method Transfers 适当的分析方法转移Validated Methodology/System Suitability 验证过的方法学/系统适应性Properly Developed and Robust Methods 经过开发的和有耐用的分析方法性Qualified and Training Laboratory Analysts 有资质的、经过培训的分析人员Accurate Reporting and Data Recording 准确的撰写报告和数据记录Qualified and Calibrated Laboratory Instruments经过确认和校验的仪器319©Copyright Globepharm, 2005
实验室仪器确认Laboratory Instrument QualificationAssemble Qualification TeemYesIs this New Equipment?NoDoes Sufficient Data Exist ToPre-QualificationPermit Retrospective Validation?Determine Extent of QUalificationNoDraft Qualification PlanYesReview Calibration HistoryQualification PlanReview System SuitabilitySystem Scope/DefinitionReview Historical Equipment LogsDefine ResponsibilitiesReview Operator Training RecordsTest Plan: Acceptance CriteriaIQ / OQPQCompile Qualification PackageCompile Qualification SummaryQualification Package Approval320©Copyright Globepharm, 2005
实验室操作LABORATORY OPERATIONSAssay validation 方法验证Standards controls 标准品控制Reagent controls 试剂控制Buffer controls 缓冲液控制Stock solution controls 储备液控制Note book controls 记录控制Laboratory analyst training分析人员培训321©Copyright Globepharm, 2005
METHODS VALIDATION [FDA]“Establishing, through documented evidence, a high degree of assurance that an analytical method will consistently yield results that accurately reflect the quality characteristics of the product tested”分析方法验证：建立一个高水平的保证，保证分析方法能持续得出可准确反应测试样品质量性质的结果。FDA: Proposed cGMP Rules (), May 1996322©Copyright Globepharm, 2005
METHOD VALIDATION [FDA] accuracy, sensitivity, specificity, and reproducibility of test methods used by a manufacturer shall be validated and documented. Such validation shall be accomplished in accordance with 分析方法验证：测试方法的准确性、灵敏度、专属性以及重复性，应该被验证和文件化。这样的验证应按照的要求进行.323©Copyright Globepharm, 2005
ASSAY VALIDATION¾PRECISIONdegree of reproducibility 精密度Repeatability repeatability under same conditions 重复性中间精密度Intermediate Precisionrepeatability under different days/staff重现性Reproducibilityprecision between laboratories¾ACCURACY 准确度agreement expected vs. actual results ¾LIMIT OF DETECTION 检测限lowest detectable level ¾LIMIT OF QUANTITATION 定量限lowest quantifiable level¾SELECTIVITY/SPECIFICITY 选择性/专属性differentiate between analytes¾RANGE 范围range over which assay suitable¾LINEARITY线型response proportionality¾RUGGEDNESS 耐变性assay portability¾ROBUSTNESS 耐用性capacity to withstand small changes324©Copyright Globepharm, 2005
HPLC Assay Validation9Approve Protocol 批准方案Scope / Responsibility / Define SOP + QACs9Determine Method Specificity 定义分析方法专属性Degrade Samples / Collect “Active Peak”/ Screen Detector Systems / Spike Samples9Solution Stability 溶液稳定性Standards and Samples / Reagents and Working Solutions / Concentrated Stock Solutions9Linearity 线型Linearity / Accuracy / Precision / Range / LOD+LOQ / Response ofRelated Analytes9Precision 精密度Injection + Analyst Repeatability / Intermediate Precision / Reproducibility9Evaluation + Final Report 评估＋最后报告325©Copyright Globepharm, 2005
Assay ValidationLinearity 线型> % correlation coefficientRange 范围80-120%Precision 精密度Repeatability可重复性minimum 9 determinations(3 concentration /3 replicates)Robustness耐用性stability of analytical solutionsinfluence of pH on mobile phaseinfluence of mobile phase variationcolumn differences (lots/suppliers)temperature –flow rate326©Copyright Globepharm, 2005
药典方法PharmacopoealMethodsUSPConsider methods validated 分析方法是经过验证过的。Only need to verify that method works in your laboratory with your equipment and your staff你要做的就是确认药典的分析方法在你的仪器上、由你的分析人员操作仍是有效的。Foreign Pharmacopoeias 其他药典方法Need full method validation 需要完全的分析方法验证327©Copyright Globepharm, 2005
分析方法移交Method TransferCompare replicate test results6 –9 –10 –20 –30比较重复的测试结果replicates 取一个样品，作三次检测，从样品配制都需一样，对照检测结果，若RSD小于2%，则转移成功。不同实验室的话，需是我们签字的验证方案。Apply “student”t-test [or other appropriate statistical tool]328©Copyright Globepharm, 2005
LABORATORY PRACTICES [W-L]Certified EquipmentEquipmentQualification 仪器确认Certified MethodsMethod Validation 方法验证Certified AnalystsCompetency Training/Testing能力培训/测试Certified Laboratories329©Copyright Globepharm, 2005
A MATTER OF ________330©Copyright Globepharm, 2005
RECOMMENDED READING –QC LabsAnalytical Chemistry in a GMP EnvironmentMiller and Crowther (488 pages), John WileyValidating Automated Laboratory and Manufacturing ApplicationsGuy Wingate, CRC PressLaboratory Validation –A Practitioners GuideJeanne Moldenhauer, PDA/DHIAvailable from:©Copyright Globepharm, 2005
FDA Reviewer GuidanceValidation of Chromatographic Methods色谱分析方法验证Food and Drug Administration Center for Drug Evaluation and ResearchCommittee of the Chemistry Manufacturing ControlsCoordinating Committee 5600 Fishers LaneRockville MD 20857Ph: 301-594-5700 / Fax: 301-594-0499332©Copyright Globepharm, 2005
Questions?333©Copyright Globepharm, 2005
Globepharm Unashamed Advertising 宣传部In-House Training Courses Offered提供内部培训资料Fundamentals and Essentials Series基本原则和要点:EU-GMPs / US-GMPs / ICH-Q7A GMPs ValidationPharmaceutical Water Systems制药用水系统Good Documentation Practices良好的文件规范Managing the QC Lab in a GMP Compliant MannerQC实验室按照GMP规则管理Effective Quality Assurance Auditing有效的质量保证审计Preparing For, and Passing, an FDA Inspection准备通过FDA检查334©Copyright Globepharm, 2005
Stay In TouchMichael H. AnisfeldGlobepharm Consulting313 Pine StreetDeerfield IL 60015, USAPhone:USA +1+847 914 0922Fax:USA +1+847 914 0988E-mail:manisfeld@:©Copyright Globepharm, 2005
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Fundamentals and Essentials of Validationgood luck !held oglykke!buonafortuna!החלצהב!vielGluck !haze said !buenasuerte!gambate!bonnechance !удачи!337©Copyright Globepharm, 2005
？？？？？？？清洗验证中的10批是制剂还是API？可否30批，如何你验证是好的，就可以。特别是降解产品的检测结果。分析方法验证中，是否有特别的RT的RSD？LN2%。D4Treference standard: only 10mg, how often we have to perform the system suitability test? Buy or prepare the standard against the RS. Every time you run the test, you should do the system suitability test. Officialmethod: verify the method. How to verify? LOD and LOQ is not required for assay, but for the impurity, should -house reference substance: retest date or ??????? Make it fresh. Characterlized. Compressed air: during manufacturing: test the air routinely or?IQ, OQ and PQ finished, every day. Week, month or every year? No idea. Every week 2 months, then once per month, then once per three months, then once a year. For the test frequency, should be built up step by step. For product before milling, we tested every batch, but for air, why? Then you can test every day, it is up to you. Regarding the drier, for the limit of endotoxinduring cleaning validation, cleaned at 40 degree, the result should be undetectable. Regarding purified water system, after a year’s validation, shall we still perform the bacteria limit test? For ever. 338©Copyright Globepharm, 2005
During cleaning validation, used dedicated equipment, in the different step, should we choose a hardest cleaning step to do cleaning validation? If the same type of equipment, yes!Cleaning every 10 batches, between 2 batches, maybe there are materials left on the inner surface, how to do? If during the inspection, the inspector found some material left, yes or no? less than a teaspoon, no question: is there a batch number limit blended into one big batch? From 8 to 16, must be validated. If for some bulk over, maybe more, OK or not?During equipment transfer, what kind of cleaning validation should be performed? If the utilities are the same, SOPs are them same. No need to perform the cleaning validation, but if it intended to use in another product, how to deal with? Have to solvent purity test using GC, suitability test every time? Yes. Every single time you setup the equipment. If I have 2 chamber to do stability test, during temperature map test, if the 2 boxes have different capacity, how many point? Min 9. but. Is there any formulation or? There is a article described it, not a FDA guide. Compound A deproteedto C then add B, we got finished product. No idea about it. We can email to Mike for ©Copyright Globepharm, 2005
During GC, there are a small unknown peak in the bland run, is there any require from the FDA? If the discharge limit is %, and the peak is less than the discharge limit, mobile phase and the dilution is different solvents, maybe a small peakappears in the chromatogram. Such as methanol. If a reactor connect with a filter, could we perform the cleaning validation combined? Yes, if your SOP is the reserve sample, is there any period required difference between starting materials, intermediate and API? Same ©Copyright Globepharm, 2005
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