蒸汽灭菌和冻干工艺的验证及风险分析_翻译

1、会计学1蒸汽灭菌和冻干工艺的验证及风险分析蒸汽灭菌和冻干工艺的验证及风险分析_翻译翻译CONTENT 内容内容 GMP and Validation GMP和验证和验证 Qualification & Validation Lifecycle 确认及验证生命周期确认及验证生命周期 Risk Management 风险管理风险管理 Case studies 案例讨论案例讨论FMEA of Sterilization Process 灭菌工艺灭菌工艺FMEAFMEA of Lyophillization Process 冻干工艺冻干工艺FMEAFTA of Terminal Sterili

2、zed Product 最终灭菌产品故障树分析最终灭菌产品故障树分析 Conclusions 结论结论 GMP及验证及验证 Qualification & Validation lifecycle Risk Management Case studies FMEA of Sterilization Process FMEA of Lyophillization Process FTA of Terminal Sterilized Product Conclusions1972 DEVENPORT INCIDENT (UK)英国德旺波特药难事件英国德旺波特药难事件Infusional s

3、olutions, produced at the Devemport Hospital, caused six patient deceases.在在英国德旺波特医院生产的输液，造成英国德旺波特医院生产的输液，造成6个死亡病例个死亡病例The ROSENHEIM Report found the causes in a not correct sterilization treatment. 在在ROSENHEIM报告中披露，原因是灭菌不完全报告中披露，原因是灭菌不完全Extracted from the ROSENHEIM Report罗森海姆报告有以下内容罗森海姆报告有以下内容The A

4、IR was not properly removed from the chamber没有适当去除空气没有适当去除空气The drain of the chamber was blocked by pieces of glasses排水管被玻璃堵塞排水管被玻璃堵塞The lower section of the load did not reach the sterilization temperature 低部位装载未达到灭菌温度低部位装载未达到灭菌温度The temperature recorder showed this anomaly but people thought it wa

5、s not working properly 温度记录有异常，以为是仪表问题温度记录有异常，以为是仪表问题Sterility tests were carried out only on the upper layers of the load无菌检查只取了上部的样品无菌检查只取了上部的样品Engineering Equipment Implications工程设计工程设计-设备方面设备方面Chapter 3 of EU-GMP (Premises and Equipment) 欧盟欧盟GMP第第3章章 （厂房及设备）（厂房及设备）21 CFR part 211.63, 211.65, 211

6、.67 (Equipment) 联邦法规联邦法规211.63, 211.65, 211.67 （设备）（设备） Annex 11 UE GMP (Computerised systems) 欧盟附录欧盟附录11计算机系统计算机系统 21 CFR part 211.68 (Automatic, mechanical and electronic equipment) （自（自动化、机械及电气设备）动化、机械及电气设备） 21 CFR part 11 (Electronic records Electronic Signatures) 联邦法规联邦法规 21 第第11部分（电子记录部分（电子记录-

7、电子签名）电子签名） GAMP (Good Automated Manufacturing Practice) GAMP= 优良自动化生产规范优良自动化生产规范21 CFR parts 210-211 (211.100, 211.110, 211.213)联邦法规联邦法规210-211 (211.100, 211.110, 211.213)21 CFR part 820 (820.75)联邦法规联邦法规820 (820.75)EU GMP (Cap. 5.21 5.24) 欧盟欧盟-GMP (Cap. 5.21 5.24) EU GMP Annex 15: (Qualification and

8、 Validation)欧盟欧盟-GMP (Cap. 5.21 5.24) 确认与验证确认与验证Compliance Policy Guide Sec. 490.100 (Process Validation Requirements for Drug Products Subject to Pre-Market Approval)达标方针指南达标方针指南 490.100 节节 （药品批准前工艺验证要求）（药品批准前工艺验证要求）EU GMP 5.21: Validation studies should reinforce Good Manufacturing Practice and be

9、 conducted in accordance with defined procedures. Results and conclusions should be recorded.验证试验应强化验证试验应强化GMP并按规程进行。应有记录和结论并按规程进行。应有记录和结论Annex 15 EU GMP Principle: 欧盟欧盟GMP原则原则It is a requirement of GMP that manufacturers identify what validation work is needed to prove control of the critical aspec

10、ts of their particular operations. Significant changes to the facilities, the equipment and the processes, which may affect the quality of the product, should be validated. A risk assessment approach should be used to determine the scope and extent of validation.GMP要求生产企业鉴别需要验证的内容，以证明特殊操作的关键点受控。影响要求

11、生产企业鉴别需要验证的内容，以证明特殊操作的关键点受控。影响产品质量的厂房、设备及工艺的重要变更均应验证。应通过风险评估确定验证产品质量的厂房、设备及工艺的重要变更均应验证。应通过风险评估确定验证的范围。的范围。 What has to be validated? 应验证的内容应验证的内容 A process ? 工艺工艺A product ? 产品产品A piece of equipment ? 设备设备Lets consider the definition of “validation”我们来考虑我们来考虑“验证验证”的定义的定义.Validation is establishing d

12、ocumented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics (FDA Guideline on General Principles of Validation, 1987)_Validation is a defined strategy of inter-related p

13、ractices and procedures which in combination with routine production methods and quality control techniques provides documented assurance that a system is performing repetitively as intended and/or that a product conforms to its pre-determined specifications (PDA TM#1 revised, Glossary)验证是建立文件证据，确保一

14、个特定的工艺肯定能始终如一生产出预定质量特性及质量标准的产品 (FDA 验证总则指南, 1987)_验证是有管理程序与运行操作相关的一种策略，它将常规生产方法和质量控制技术相结合，以文件的形式保证一个系统能良好重复地按预期性能运行，和/或一个产品能符合预期的质量标准(PDA TM#1 revised, Glossary)Common items: 常见项目 - Specify 阐述 - Document 文件 - Verify the effectiveness 检查标准 - Verify the reproducibility 检查重现性The scope of validation is

15、the process or the product 工艺可产品验证的范围The new PDA definition considers validation as a “ongoing process” (maintaining the validated status) FDA新的指南将验证看作一个持续不断的过程（保持经验证的状态）Main concepts 主要概念主要概念 Personnel 人员人员 Equipment 设备设备 Process/Products 工艺工艺/产品产品 Instruments 仪器仪表仪器仪表 Documents and SOP 文件及文件及SOPQu

16、alified, trained 培训、确认资质培训、确认资质To be qualified (IQ, OQ, PQ) 确认确认To be validated 验证验证Suitable, calibration has to be planned and documented 适当，校准有计划适当，校准有计划/文件文件Up-to date, distributed, maintained under control 更新，分发，保持受控更新，分发，保持受控Process 工艺工艺Product 产品产品EquipmentRules and standardsCharacteristics 特性

17、特性Handling 处理处理Stoppering 上胶塞上胶塞Terminally sterilized 最终灭菌最终灭菌Sterilization 灭菌灭菌 ?Lyophillization 冻干冻干?Sterilization method 灭菌方法灭菌方法?设备法规及标准 GMP及验证及验证 Qualification & Validation lifecycle Risk Management Case studies FMEA of Sterilization Process FMEA of Lyophillization Process FTA of Terminal S

18、terilized Product Conclusions确认及验证生命周期Stages of the qualification of a piece of equipment should include DQ, IQ, OQ and PQ.User Requirements SpecificationsFunctionalSpecificationsDesignSpecificationsProject execution InstallationQualificationOperationalQualificationPerformanceQualificationRelated to

19、Related toRelated toDesign QualificationVALIDATION LIFECYCLE一项设备的确认应包括的阶段： DQ, IQ, OQ and PQ.用户需求标准功能标准设计标准项目的实施安装确认运行确认性能确认相关联相关联相关联设计确认设计确认DESIGN QUALIFICATION 设计确认设计确认 The documents of the projects at disposal specify in an exhaustive way the equipment, the systems, and the installations that com

20、pose that project 一个要处理项目详细阐述其设备、系统以及设施的文件一个要处理项目详细阐述其设备、系统以及设施的文件 The documents related to the user requirements specifications, to the basic design (or functional) and to the detail design (or executive) are clearly identified 它是对用户技术要求、基础（或功能）设计以及详细设计相关文它是对用户技术要求、基础（或功能）设计以及详细设计相关文件作详细鉴别件作详细鉴别/审查

21、的文件审查的文件DESIGN QUALIFICATION The project documents are correctly approved by the competent functions upon what established in the quality plan of the project 根据项目所定的质量计划的要求，由主管功能部门批准项目文件根据项目所定的质量计划的要求，由主管功能部门批准项目文件 The functional specs (basic design) and the engineering documents (detail design) of

22、the system under exam are based on the needs of the user (user requirements) 根据用户技术要求，对系统的基础设计及详细设计进行审查根据用户技术要求，对系统的基础设计及详细设计进行审查 The design has been carried out considering a compliance to the cGMPs and eventual applicable guidelines 设计过程中已考虑了设计过程中已考虑了cGMP及相关指南的要求及相关指南的要求“Installation Qualification

23、 is an essential step preceding the Process Validation exercise. It is normally executed by the Engineering group. The installation of equipment, piping, services and instrumentation is undertaken and checked to engineering drawings Piping & Instrument Drawings, (P&I.Ds) and Plant Functional

24、 Specifications developed during the project planning stage. During the project planning stage, Installation Qualification should involve the identification of all system elements, service conduits and gauges and the preparation of a documented record that all installed equipment satisfies the plann

25、ed requirements.”“安装确认是进行工艺验证的重要组成部分。它通常由工程设计组人员完成。相关的设备、管路、公用系统、仪表要按管路及仪表设计图(P&I.Ds)以及项目计划阶段工厂的功能要求核对/审查。在项目的计划阶段，安装确认应对所有系统的组成部分，公用管路、仪表以及文件记录的准备进行鉴别/审查（文件应能够表明所有安装的设备满足计划的要求）。”Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation

26、, Cleaning Validation PI 006-2, 1 July 2004The Rules Governing Medicinal Products in the European Union “Good manufacturing practices” Annex # 15 Final Version Qualification and Validation July 2001“IQ should include, but not limited to, the following:IQ包括，但不局限于以下各项：(a)installation of equipment, pip

27、ing, services and instrumentation checked to current engineering drawing and specifications; 设备、管路，公用管路以及仪表安装的检查符合竣工图及标准(b)collection and collation of supplier operating and working instruction, and maintenance requirements; 收集供货商的运行操作指南及维修要求(c)calibration requirements; 校准文件(d)verification of materi

28、als of construction.” 对建造材料的检查INSTALLATION QUALIFICATION“OQ is an exercise oriented to the engineering function, generally referred to as commissioning. Studies on the critical variables (parameters) of the operation of the equipment or systems will define the critical characteristics for operation

29、of the system or sub-system. All testing equipment should be identified and calibrated before use. Test methods should be authorized, implemented and resulting data collected and evaluated.OQ是试功能，通常指试车。对设备或系统的关键参数（变量）进行试验，确定系统或子系统的关键特性。所有测试仪表均应在使用前校准。试验方法要经批准后实施，收集结果并进行评价。It is important at this sta

30、ge to assure all operational test data conform with pre-determined acceptance criteria for the studies undertaken.” 在此阶段，所有运行试验的数据应符合预定的合格标准。Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation PI 006-2, 1 July 200

31、4OPERATIONAL QUALIFICATION“It is expected that during the Operational Qualification stage the manufacturer should develop draft standard operating procedures (SOPs) for the equipment and services operation, cleaning activities, maintenance requirements and calibration schedules.”在OQ阶段，通常要求生产企业制订SOP草

32、案，包括设备、公用系统、清洁、维修要求及校准计划“The completion of a successful Operational Qualification should allow the finalisation of operating procedures and operator instructions documentation for the equipment. This information should be used as the basis for training of operators in the requirements for satisfacto

33、ry operation of the equipment.”OQ顺利完成应能完成设备的运行规程以及人员操作指南。这些信息应当用作培训员工的基础资料，以满足设备操作的要求。Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation PI 006-2, 1 July 2004OPERATIONAL QUALIFICATION“OQ should include, but not l

34、imited to, the following:OQ包括，但不局限于以下各项：(a)tests that have been developed from knowledge of process, systems and equipment; 根据有关工艺、系统和设备的知识所确定的试验(b)tests to include condition or set of conditions encompassing upper and lower operating limits, sometimes referred to as “worst case” conditions.” 包括确定运行

35、上下限的条件试验，有时称“最差条件”试验The Rules Governing Medicinal Products in the European Union “Good manufacturing practices” Annex # 15 Final Version Qualification and Validation July 2001OPERATIONAL QUALIFICATIONDocumented verification that the system is able to fulfill, in a constant and repetitive way, all th

36、e tasks indicated in the URS.性能确认：有文件及记录确认，系统能始终如一并重复地实现、满足性能确认：有文件及记录确认，系统能始终如一并重复地实现、满足URS中所规定的目标中所规定的目标 Usually they will be designed, to this aim, some challenges for the verification of the process parameters and of the operative conditions, in the established intervals of variability, in compl

37、iance with the data reported in the official records. The conditions limit to the challenge, after the due considerations, can be different from the ones that represent the limit of the process. 为实现这个目标，通常PQ要设计一些试验，根据正式报告中的数据资料，在确定的变量范围以内，来挑战工艺参数及运行条件，经适当考虑后的限度，可与工艺中所列的限度不同。PERFORMANCE QUALIFICATION

38、-性能确认性能确认“PQ should include, but not limited to, the following: PQ包括，但不局限于以下各项：(a)tests, using production material, qualified substitutes or simulated product, that have been developed from knowledge of the process and the facilities, systems or equipment; 根据厂房、系统或设备所积累的工艺知识，采用生产物料，符合要求的替代品或模拟产品进行试验

39、。(b)tests to include a condition or set of conditions encompassing upper and lower operating limits.”要包括上下限运行限度的试验The Rules Governing Medicinal Products in the European Union “Good manufacturing practices” Annex # 15 Final Version Qualification and Validation July 2001PERFORMANCE QUALIFICATION“Docum

40、entation”A report that cross-references the qualification and/or validation protocol should be prepared, summarising the results obtained, commenting on any deviations observed, and drawing the necessary conclusions including recommending changes necessary to correct deficiencies. Any changes to the

41、 plan as defined in the protocol should be documented with appropriate justification.”“文件”应写出有确认/验证方案交叉索引的报告，将获得的结果进行汇总，对观察到的偏差进行说明，图及对图的说明，包括纠正缺陷所需变更的建议。对方案中确定计划的任何变更，应有记录并说明理由。The Rules Governing Medicinal Products in the European Union “Good manufacturing practices” Annex # 15 Final Version Quali

42、fication and Validation July 2001验证和确认小结The Rules Governing Medicinal Products in the European Union “Good manufacturing practices” Annex # 15 Final Version Qualification and Validation July 2001“Documentation”After completion of a satisfactory qualification, a formal release for the next step in qu

43、alification and validation should be made as a written authorization”“文件”在完成一项确认后，正式放行至下一步的确认及验证，应有书面的批准文件。“The following items should be included in the validation report: 验证报告应包括以下内容：(a)A description of the process Batch/Packaging Document, including details of critical steps, 对工艺的阐述包括关键步骤的批/包装文件(

44、b)A detailed summary of results obtained from in-process and final testing, including data from failed tests. When raw data are not included reference should be made to the sources used and where it can be found, 对中间控制及最终检验结果（包括失败试验）的详细总结。如报告中不列原始数据，则应有资料索引，说明资料的存放点。Recommendations on Validation Mas

45、ter Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation PI 006-2, 1 July 2004What should it do? 系统的用处系统的用处 Control and monitor the manufacturing process 控制及监测生产工艺控制及监测生产工艺 Guarantee a safe use of the equipment 保证设备安全使用保证设备安全使用 Comply with applicable

46、standards and rules 符合适用的标准及规定符合适用的标准及规定 Generate a complete and accurate process documentation 获得完整及准确的工艺文件获得完整及准确的工艺文件/记录记录 Integrate with external systems for collecting or processing data 将收集或处理数据的外部系统有机组合将收集或处理数据的外部系统有机组合/集成集成 Exchange information with external systems in general 与外部的通用系统交换数据与外

47、部的通用系统交换数据The criticality of these systems has to be referred to their role in pharmaceutical production必须阐明这些系统在药品生产中的必须阐明这些系统在药品生产中的重要性重要性In 2003 ISPE issued a Good Practice Guide on the validation of PCS 2003年，年，ISPE公布了一个工艺控制系统指南公布了一个工艺控制系统指南 controlling the manufacturing processes and having a d

48、irect impact on the product 控制生产及对产品有直接影响的工艺控制生产及对产品有直接影响的工艺过程过程 processing, transferring or storing process information in electronic format 处理，转换或贮存电子模块的工艺信息处理，转换或贮存电子模块的工艺信息Versione 5 - Drivers 第第5版的动力版的动力优良优良自动化指南自动化指南关注患者安全产品质量及数据完整性实现有效控制保持GxP达标质量源于设计(QbD)质量管理系统持续改进关键质量属性（CQA）改善GxP达标有效性质量管理系统中

49、的生命周期方法可放大符合GxP的方法基于风险质量管理的科学现有文件及知识的使用可靠的供货商关系可配置系统及开发模式Vers 5 Overview 第第5版总览版总览Vers 5 Overview 第第5版总览版总览药品开发药品生产药品上市及分销用户对产品及工艺的理解一质量管理系统中生命周期的方法可放大生命周期活动基于质量风险管理科学影响供货商财政的杠杆供货商（计算机系统及服务）药品开发及服务提供产品及服务保持及支持产品与服务项目阶段变更退役概念项目运行退役保留-搬迁-损坏的可能供货商参与风险管理，设计审查，变更及配置管理，可追溯性，文件管理支持过程计划报告技术要求检查确认配置/编码 GMP及验

50、证及验证 Qualification & Validation lifecycle Risk Management Case studies FMEA of Sterilization Process FMEA of Lyophillization Process FTA of Terminal Sterilized Product Conclusions质量风险管理（ICH Q9）欧洲药品管理局Quality Risk Management 质量风险管理1. Introduction 引言引言2. Scope 范围范围3. Principles of Quality Risk Man

51、agement (QRM) QRM的原则的原则4. General Quality Risk Management Process QRM的一般程序的一般程序5. Risk Management Methodology 质量风险管理方法学质量风险管理方法学6. Integration of QRM into industry & regulatory operations7. Definitions 定义定义 将质量风险管理融入行业及监管工作去将质量风险管理融入行业及监管工作去8. References 参考文献参考文献The Systematic application of qua

52、lity management, policies, procedures and practices to the tasks of assessing, controlling, communicating, and reviewing risk.质量风险管理是.将质量管理、策略、程序及实践系统地应用于风险的评估、控制、沟通和审核的过程ICH Guidance for Industry Q9 Quality Risk ManagementICH 行业指南行业指南- Q9 质量风险管理质量风险管理 This document provides a framework that applied

53、 to of pharmaceutical quality, including development, manufacturing, distribution, inspection and submission/review processes throughout the lifecycle of drug substances and drug products, biological and biotechnological products, and the use of raw materials, solvents, excipients, packaging and lab

54、eling materials.范围本指南提供了一个柜架，它可应用于药品质量的所有方面，包括如原料药、制剂、生物制剂以及生物技术产品整个生命周期内研发、生产、销售，以及现场检查和资料递交/审核过程（包括药品、生物制品和生物技术产品的原料、溶剂、辅料、包装和标签的使用） ICH Q9 primary principles: 二个基本原则1. The of the quality risk should ultimately to the potential harm to the patient. 应根据科学知识对质量风险进行评估，评估应与最终保护患者的目标相关联；2. The of effor

55、t, formality and documentation of the quality risk management process should be with the level of risk. 质量风险管理过程的投入水准、形式和文件，应与风险的级别相适应 质量风险管理的原则质量风险管理的原则风险回顾风险评估风险评估不可接受风险控制风险分析风险降低风险鉴别风险回顾风险接受开始质量风险管理过程风险管理过程的结果/输出信息风 险 沟 通风 险 管 理工具 Define the problem and/or risk question, including pertinent assum

56、ptions, for potential risk identification Assemble background information and/or data on the potential hazard, harm or human health impact relevant to the risk assessment Identify a leader and critical resources Specify a timeline, deliverables, and appropriate level of decision making for the risk

57、management process“Risk assessment” “Consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards”1) RISK INDENTIFICATIONWhat might go wrong?2) RISK ANALYSISWhat is the likelihood (probability) it will go wrong?What are the consequences

58、 (severity)?Is the hazard detectable (detectability)?RISK IDENTIFICATION + RISK ANALYSIS+ RISK EVALUATION “” “由风险识别和风险分析及风险评估构成由风险识别和风险分析及风险评估构成”1)风险识别风险识别哪些可能会出错？2) 风险分析风险分析出问题的概率有多大？有什么后果/严重性？风险可否检察觉/可检测性？风险识别风险识别+风险分析风险分析+风险评估风险评估3) RISK EVALUATION 风险评估Compare the identified and analyzed risk aga

59、inst risk criteria. A qualitative and quantitative process might be used to assign the probability and severity of a risk.将已识别和分析的风险与标准相比。可用定性或定量的方法，来确定某一风险的可能性和严重性。风险识别风险识别+风险分析风险分析+风险评估风险评估High高Medium中Low低QUALITATIVE RISK EVALUATIONRisk reduction + Risk acceptanceIncludes decision making to reduce

60、 and/or accept risks. The purpose of risk control is to reduce the risk to an acceptable level. The amount of effort used for risk control should be proportional to the significance of the risk.Decision makers might use different processes for understanding the optimal level of risk control including benefit-cost analysis.1.Is the