验证主计划模版

Pag. 1 / 48 VALIDATION MASTER PLAN 验证主计划 (China) Co., Ltd. MANUFACTURING PLANT 有限公司工厂 PREPARED BY: QA MANAGER 制定人：QA 经理 CHECKED BY: HEAD OF QA 审核人：质量经理 APPROVED BY: 批准人： VERSION/版本： VALID DATE/生效日期 Pag. 2 / 48 Content/目录目录 1.INTRODUCTION 简介-5 1.1.Validation policy 验证方针 -5 1.2.Aim of the Validation Master Plan (VMP) 验证主计划（VMP）的目的-5 2.LOCATION 位置 -7 3.RESPONSIBILITIES 职责 -7 4.VALIDATION: FLOW SHEETS AND DEFINITIONS 验证：流程和定义-11 4.1.General criteria 一般标准-11 4.2.Validation flow chart 验证流程图-12 4.3.Operative scheme 实施程序-13 5.ACCEPTANCE CRITERIA 接收标准：-17 5.1.General acceptance criteria for qualifications 确认的一般接收标准-17 5.1.1.Design Qualification (DQ) 设计确认（DQ）-17 5.1.2.Installation Qualification (IQ) 安装确认（IQ） -17 5.1.3.Operation Qualification (OQ) 运行确认（OQ） -18 5.1.4.Performance qualification (PQ) 性能资料（PQ）-19 5.2.Specific acceptance criteria for qualifications 确认的专属接收标准 -19 5.3.General acceptance criteria for process validations 工艺验证和一般接收-19 5.4.General acceptance criteria for cleaning validations 清洁验证的一般接收标准-25 5.4.1.Chemical check 化学检查 -25 5.4.2.Microbiological check 微生物检查 -26 6.QUALIFICATIONS AND VALIDATIONS LISTS 确认和验证清单-27 6.1.List of GMP related building and building services qualifications including level of validation GMP 相关的建筑物和厂房服务系统确认清单包括各层水平的验证-27 6.2.List of equipment qualifications including level of validation and critical items 设备确认验证层次的重要项目之清单-28 6.2.1.MANUFACTURING EQUIPMENT 生产设备-28 6.3.List of Quality Control Equipment including the level of qualification 质量控制设备清单-30 6.3.1.Quality Control equipment Chemical Laboratory 质量控制设备-化学试验室-30 6.3.2.Quality Control equipment IPC 质量控制设备-中间过程控制室 -31 6.3.3.Quality Control equipment Microbiological Laboratory 质量控制设备 微生物试验室 -31 6.4.Analytical method validation 分析方法验证-32 6.5.List of products with manufacturing steps 产品清单及生产步骤-33 Pag. 3 / 48 6.6.List of products including level of process validation 拟进行验证的产品清单 -34 6.7.Maintenance of validation 验证维护 -35 7.DOCUMENTATION 文件-36 7.1.Validation protocol 验证方案 -36 7.2.Validation report 验证报告-36 7.3.Deviations 偏差-37 7.4.Document structure for DQ, IQ, OQ, PQ. DQ, IQ, OQ 及 PQ 的文件结构-37 7.5.Documents numbering 文件编号 -39 7.6.Document filing of qualification and validation protocols and reports 确认和验证方案及报告的归档-39 8.STANDARD OPERATING PROCEDURES 标准运作程序-39 9.GLOSSARY 术语 -39 10.GUIDELINES-45 ANNEX 1. ORGANIZATION CHART 附录 1：组织机构图 -46 ANNEX 2: LIST OF ROOMS IN GMP AREA 附录 2：GMP 房间清单 -47 ANNEX 3: Annual validation plan 附录 3：年度验证计划 -50 Pag. 4 / 48 1. INTRODUCTION 简介简介 1.1.Validation policy 验证方针验证方针 Validation is a part of our quality policy. We believe in it as a concept which provides both regulatory compliance and cost benefits. It is the responsibility of the Head of QA to assure that the compliance with this VMP is maintained. Plant Director to assure the resources necessary to achieve the compliance with this guideline shall be provided within the operating budgets of all organizational units. 验证是我们质量方针的组成部份。我们把它看成是既能保证符合法规又能节约成本的一个理念。 质量经理应保证有关工作与该验证主计划的符合性得到适当的维护。工厂总监保证该验证主计 划所必须的资源应该在整个组织范围内作为其运作预算得以提供。 Validation is an important part of the Quality Assurance system of the company and an essential element of Chinese and International GMP standards. This plan defines the nature and extent of testing expected to be done on each system to get documented evidence, for all critical parts of the solids manufacturing site of-. It provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics. 验证是公司质量保证体系的一个重要组成部份，也是中国和国际 GMP 规则的基本要素。该计 划为-固体生产工厂的所有重要部分，确定了在每一个系统中计划进行的测试的内容和 水平，以获得书面的文件记录。证明某一特定的生产程序能持续生产出符合预期规格要求和质 量特性的产品具备了高度保证。 Involved departments are committed to carry out the described programs according to this fixed master plan. 相关部门应根据确定的主计划中说明的程序进行工作。 1.2.Aim of the Validation Master Plan (VMP) 验证主计划（验证主计划（VMP）的目的）的目的 The aim of the VMP is to describe the validation program to be carried out in a structured way according to formally authorized standardized working and administrative procedures. The VMP is a management instrument for planning, implementing and controlling the validation activities. VMP 的目的是描述根据正式授权的、标准化的工作和管理程序，而以一确定的方式来执行的验 证程序。VMP 是计划、实施和控制验证活动的管理工具。 The VMP: VMP 包括： Identifies systems, building, installations, equipment, procedures and processes involved in validation; 说明验证中的系统，建筑，安装，设备，程序和过程； Pag. 5 / 48 Defines required validation activities for each item; 确定每一项目所要求的验证活动； Describes the trials and analytical tests for each part; 描述每一部分的试验和分析测试； Outlines the test procedures and protocols to be followed to accomplish validation; 确定完成验证工作所要依照的测试程序和方案； Defines the acceptance criteria for validation; 确定验证的接收标准； Defines responsibilities for validation; 描述验证项目中的职责； Defines reporting responsibilities and requirements in order to document the work carried out and results obtained; 确定报告的职责和要求，以便书面记录所执行的工作和获得的结果； Determines and manages the required capacity and time schedules for the realization of each validation project. 确定和管理实现每一验证项目所要求的工作量和时间排期。 Furthermore the VMP describes the necessary activities in order to be sure that validated systems continue to conform, including maintenance, revalidation, people training and change control. VMP 进一步描述了保持已验证系统的符合性所必须的活动，包括维护、再验证、人员培训和更 改控制。 The VMP is also an internal and external information system for: VMP 也是下列各项的内部和外部的信息系统： The management, regarding the aim of the validation project including necessary resource 关于验证项目的目的包括必要的资源的管理； The involved departments about the tasks and responsibilities 关于相关部门的任务和职责； The inspectors, to get an overview about the company approach to validation, organization and carrying out the validation activities. 检查员对公司的验证方法、组织和执行验证活动有全方面的认识。 Pag. 6 / 48 2. LOCATION 位置位置 This VMP applies to the solidS manufacturing plant of -, which is located in -. 该 VMP 适用于-的工厂。 The design was made taking into account Chinese and international GMP requirements. The plant is designed to allow implementation of all the solid manufacturing steps. The following manufacturing steps will be performed: weighing, blending, sieving, granulation, tabletting, coating, filling, primary and secondary packaging. 该设计是充分考虑到中国和国际的 GMP 要求而制定。本工厂的设计达到能进行固体制剂全过程的生 产。允许采用下列制造阶段，即称重、混合、过筛、制粒, 压片、包衣、填充、内包装和外包装。 It should be proved that the building, the equipment, the HVAC and all building services of the production site are qualified for the foreseen activities and that the procedures and processes for manufacturing the intended products are validated. 应证明生产厂的所有建筑、设备、HAVC 和厂房服务系统-对于预期的活动是确认合格的，并且将 要生产的产品的程序和工艺都已经过验证。 3. RESPONSIBILITIES 职责职责 The Validation Group has to be appointed and staffed with representatives of all the Departments involved in the validation work, e.g.: 必须组建一个验证小组，且该小组应由所有验证工作相关部门的代表组成，即： PRODUCTION 生产 Quality Assurance (QA) 质量保证 ENGINEERING 工程 PLANT DIRECTOR 厂长 QUALITY MANAGERS OR TECHNOLOGISTS OF CONSTRUCTION AND SUPERVISION COMPANIES OR SUPPLIERS 建筑和监理公司或供应商的质量经理或技术专家 The main responsibilities in validation for each Department are outlined in this VMP. In Annex 1 the relevant Organization Charts of - are reported. 验证工作中各部门的职责应在该 VMP 中加以确定。附录 1 是-公司的组织结构图。 QUALITY ASSURANCE (QA) Committee: 质量保证小组（QA） Pag. 7 / 48 In regard to validations and qualifications, the QA committee is responsible for: 关于验证和确认，质量保证小组应负责： Organizing, coordinating and supervising all validation works and change control procedure. 组织、协调和监管所有验证工作和更改控制程序。 Checking of all S.O.P.s and managing them, according to the relevant procedure. 根据相关程序，检查并管理所有 SOP。 Final approval of S.O.P.s 最终批核 SOP。 Final approval of all the validation and qualification protocols 最终批核所有验证和确认方案（工艺验证，清洁验证，设备确认） Final approval of all validation reports. 最终批核所有验证报告。 Final approval of Annual validation plan,. 最终批核年度验证计划。 Permanent members of the Validation Committee are: 验证小组的固定成员是： Plant manger 厂长 Head of QA 质量经理 Head of Production 生产经理 Quality Assurance 质量保证 Quality Assurance responsibilities include: 质量部门的职责包括： Update VMP. 更新验证主计划； Issuance of cleaning validation protocols and reports. 清洁验证方案和报告的制定； Participating in preparation and issuance of process validation protocols and report, Sampling and testing bulks and finished products during process validations. 参与准备和制定工艺验证方案和报告,在工艺验证过程中，抽样并检验原料及成品； Performing cleaning validations. Pag. 8 / 48 进行清洁验证； Reporting the final results of each validation trial. 报告每次验证试验的最终结果； Reporting any findings that will adversely affect the validation schedule. 报告可能影响验证进度的任何发现； Performing the calibrations and Qualification of testing equipment. 进行检验设备的校验和确认； Performing validation of analytical methods. 进行分析方法验证。 PRODUCTION (PROD.) 生产： Production responsibilities include: 生产部的职责包括 Participating in DQ, IQ, OQ of manufacturing equipment. 参与生产设备的 DQ、IQ、OQ Issuance of PQ protocols and Performing PQ 发行 PQ 草案和执行 PQ Participating issuance of process validation protocols. 参与制定工艺验证方案 Performing process validations, according to a defined protocol. 根据已确定的方案，执行工艺验证 Participating in cleaning validations of manufacturing equipment, according to the relevant procedure. 参与生产设备中清洁验证 Participating in preparing process validation reports. 参与准备工艺验证报告 ENGINEERING (ENGIN.) 工程 Engineering responsibilities include: 工程职责包括： Participating in the set up of qualification protocols (DQ, IQ, OQ) for rooms with GMP functions and GMP related building service installations. 参与制定有关 GMP 房间及 GMP 相关厂房服务系统安装之确认方案（即 DQ、IQ 和 OQ） 。 Participating in performance of qualifications for rooms with GMP functions and GMP related building service installations. Pag. 9 / 48 参与执行有关 GMP 房间及 GMP 相关厂房服务系统安装之确认。 Preparing qualification protocols (DQ, IQ, OQ)for manufacturing equipment. 准备生产设备的确认方案（DQ、IQ 和 OQ） 。 Performing the qualifications of manufacturing equipment. 进行生产设备的确认。 Participating in the preparation of cleaning validation protocols. 参与制定清洁验证方案。 Performing calibrations of manufacturing equipment. 执行生产设备校验。 Reporting the final results of manufacturing equipment qualifications (DQ, IQ, OQ). 报告生产设备确认（DQ、OQ 和 IQ）的最终结果。 QUALITY MANAGERS OR TECHNOLOGISTS OF CONSTRUCTION AND SUPERVISION COMPANIES OR SUPPLIERS 建筑和监理公司或供应商质量经理或技术专家 Set up of qualification protocols (DQ, IQ, OQ) for qualification of rooms with GMP functions and GMP related building service installations. 为有 GMP 房间和相关厂房服务系统安装的建筑和设备资格建立确认方案， （即 DQ、IQ 和 OQ） 。 Issuance of all test instructions which are necessary for performing all qualifications. 制定所有确认工作所必须的测试指南。 Performing and reporting of all tests. 执行并报告所有测试。 Pag. 10 / 48 4.VALIDATION: FLOW SHEETS AND DEFINITIONS 验证：流程和定义验证：流程和定义 4.1.General criteria 一般标准一般标准 Systems are considered critical and must be validated when they are either in direct physical contact with the product or used to measure, monitor, or record a critical parameter. Building service systems, such as heat transfer systems, electrical power, non-process water, are non critical and dont need validation; however, they are handled according to specific procedures. The building services system which effects the monitoring and the control of critical parameters, will be validated. 当系统与产品直接相接触或用于测量、监控或记录重要参数时，被认为是关键部分必须经过验 证。厂房服务系统，比如热转换系统、电力、非工艺用水系统都不是关键部分，也不需要验证； 但无论怎么样，都应根据特定的程序进行处理。然而，在厂房服务系统中能影响监控重要参数 的部分也应进行验证。 Pag. 11 / 48 4.2.Validation flow chart 验证流程图验证流程图 The validation flow is described in the following scheme: 验证流程如下： Validation master plan 验证主计划 Design qualification 设计确认 Installation qualification 安装确认 Operation qualification 运行确认 Performance qualification 性能确认 Process validation 工艺验证 Change control 更改控制 Periodic re-validation 阶段性再验证 Pag. 12 / 48 4.3.Operative scheme 实施程序实施程序 Design specifications describe, in detail, the codes, references and specific requirements of each system in the facility. The requirements of the equipment (equipment specifications, plant functional specifications piping and instrument diagrams) will be fixed by the responsible persons. The DQ of equipment will be realized by checking the existing offer of supplier, the user requirements, the order and the conformation of the order of the supplier. The proof of taken work will be done with check lists which have been created by the validation team in the design phase equipment specification = user requirements, plant functional specifications, piping and instrument diagrams. During the final steps of the design stage, the facilities and equipment necessary for calibration requirements will need to be identified. 设计说明描述了设备中每个系统的编号、参考资料和专项要求。设备的要求（包括设备规格、 工厂功能规格、管道和仪器图）应由相关职责人加以确定。设备的 DQ 应通过检查已有的供应商 报价、用户的要求、订单以及供应商的订单确认来实现。已进行进的工作应通过检查清单来证 明，该检查清单应由验证小组在设计阶段（设备规格 = 用户要求、工厂功能规格、管道和仪器 图）来创建。在设计工作的最后阶段，进行校验工作所必须的设备和设施必须加以确定。 These are 即： Conformation of calibration of calibrating equipment, with reference to the appropriate national standard 参考国家标准，确认校验设备的校验情况。 Calibration of measuring devices utilized in the operational qualification stage, where confirmation from supplier is unavailable 在 OQ 阶段所用的测量设备的校验，即当不可能从供应商处获得校验确认书时。 Calibration of measuring devices related to installed equipment 与安装设备有关的测量设备的校验。 Validation 验证 Qualification buildings/equipment 建筑/设备确认 Validation process/products 工艺/产品验证 Test list or check list 实验或检查表Risk assessment 危险评估 Validation protocol 验 证方案 Implementation 执行 Filled in protocols of 3 batches 三批方案记录 Analytical results of 3 batches 三批分析结果 Validation Report 验证报告 DQIQOQPQ Implementation 执行 DQIQOQPQ Filled in test list or check list 填写实验或检查表 Qualification Report 确认报告 DQ Pag. 13 / 48 Identification of calibration requirements for measuring devices for the future use of the equipment. 对于将来可能使用的测量设备的校验标识。 Calibration is the performance of tests and retests to ensure that measuring instruments used in the manufacturing process or analytical procedure leads to correct measurements within accepted limits. 校验是进行测试和再测试的过程以保证生产或检验过程中所用的测量仪器在规定的限度内能进 行正确的测量 The installation qualification requires a formal and systematic check of all installed equipment with suppliers specification and additional criteria identified by the user as part of the purchase specifications. At the IQ all equipment, gauges and services should have a identifying number and it must be verified that the installed equipment has been installed according to the current version of the pipe the second is a safety factor; and the third is that the cleaning validation program should be robust enough. 出现在另一产品的在最大日剂量中的任何产品不多于最小剂量的 1/1000。有三个 不同的因素 1/1000 的残留值。第一是通常认为药物在其常规处方剂量的 1/10 时 是无效的；第二是安全因素；第三是清洁验证程序足够可靠。 1010 ppm-CRITERIONppm-CRITERION 10PPM10PPM 标准标准 No more than 10 ppm of any product can appear in an other product. The idea of using a maximum allowable parts-per-million level has its roots in the rules that apply to food products. 任何产品出现于另一产品中的浓度不多于 10PPM。采用最大 PPM 浓度的观点来自 食品管理法规。 VISUALLY-CLEANVISUALLY-CLEAN CRITERIONCRITERION 目测检查标准目测检查标准 Pag. 26 / 48 No residue must be visible on the equipment after cleaning procedures have been performed. A certain number of products meets the first two criteria even if residues are visible on the equipment after cleaning. Therefore, if the quantity of residue is enough to be visible, the equipment must be cleaned until no more residues are visible. Appropriate studies showed that the active ingredients (white substances) in most products are visible at approximately 62 g/16 cm2 = 0.388 mg/100cm2. 在进行清洁后，设备外观上无可见的残余物。即使在清洁后设备上有可见的残余物， 即使在清洁后设备上有可见的残余物，一定数量的产品仍能满足前两个标准。因此， 如果残余物的数量多到足够被看见，该设备就应再清洁直到看不到残余物为止。适 当的研究表明在大多数产品中活性成分（白色物质）的可见度大约为 62g/16 cm2 = 0.388 mg/100cm2。 The formulas for calculating the limits are described in the relevant SOP and they take account of: 计算限度的格式在相关的 SOP 中有描述，主要因素： The batch size (units/lot and kg/lot). 批量大小（批数量和每批的重