验证主计划(VMP)--浙江华海药业.doc

验证总计划Validation Master Plan文件编号Protocol Number VMP-001 编写日期Preparation Date 2006.07 编写部门Preparation Department 质量管理部保管部门Storage Department 质量管理部浙江华海药业股份有限公司ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD浙江华海药业股份有限公司ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTDHVAC系统设计确认方案HVAC System Design Protocol文件编号protocol No.：VLDF-06-018编写日期Prep. Date：2006.08页码 Page：2 of 24文件批准 Document Approval下面签字者已阅读了该文件并同意该文件中描述的设施设备验证总计划。此外，签字人还认为，对于所涉及的设施设备，该文件中描述的程序，给出了充分的证据证实华海药业为验证及符合cGMP所付出的努力。The undersigned have read and agree with the Facility Validation Master Plan as outlined in this document. Furthermore, the undersigned agree that the procedures outlined in this plan provide sufficient evidence of HUAHAI PHARMAs dedication to validation and current Good Manufacturing Practices with respect to the facility described by this plan.部门Department姓名及职务Name Title签名与日期SignatureDate职能Role质量管理部Q.A. Dept.批准Approval与cGMP的符合性Compliance with cGMP质量管理部Q.A. Dept.起草文件Finished document中心化验室QC Dept.审核Review正确性和完整性Correctness & Completeness制剂设备部Engineering Dept.审核Review正确性和完整性Correctness & Completeness制剂生产技术部ProductionDept.审核Review正确性和完整性Correctness & Completeness安全环保部EHS Dept.审核Review正确性和完整性Correctness & Completeness项目负责人Project Leader审核Review正确性和完整性Correctness & Completeness浙江华海药业股份有限公司ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD验证总计划Validation Master Plan文件编号Protocol No.：VMP-001编写日期Prep. Date：2006.07页码 Page：53 of 54目 录Contents一. 前言Preface3二. 目的Purpose4三. 定义Definition5四. 范围Scope14五. 验证理念 Validation Philosophy18六. 组织与职责 Organization and Responsibilities20七. 支持程序Support Procedure22八. 工艺验证 Process Validation26九. 返工Rework Procedure28十. 包装验证Packaging Validation28十一. 清洁验证 Cleaning Validation31十二. 分析方法验证Test Method Validation33十三. 设备验证Equipment Qualification34十四. 公用系统Utilities39十七. 验证文件要求Documentation44十八. 变更记载及原因Revision History46一. 前言Preface浙江华海药业股份有限公司始创于1989 年1 月，主要从事原料药及制剂的研发、制造、销售及相关服务活动。制剂大楼于2001 年建成，建筑占地面积1.1 万平方米，建筑面积2.2 万平方米。口服固体制剂车间（包括片剂和硬胶囊剂）位于制剂大楼内。车间建筑面积3500 平方米,其中洁净区面积2000 平方米，按10 万级净化标准设计建造；仓贮面积3500 平方米；公用机房等辅助用房建筑面积3000 平方米。固体制剂车间年设计生产能力片剂10 亿片、胶囊2 亿粒，从造粒到包装整条生产线全套引进国际先进设备，现生产盐酸帕罗西汀片、厄贝沙坦片及抗艾滋病药物奈韦拉平片等5 个产品（7 个包装规格，见附件一）。Zhejiang Huahai Pharmaceutical Co., Ltd., established in January 1989, is devoted to the development, production, distribution and relative services, of API and Preparation. The preparation building area is11,000m2, floor space is 22,000m2 and area was built in 2001. The oral solid finished dosage form workshop (including tablets and hard capsules) is located in the building. The floor space of the workshop is 3,500m2, clean room area is 2,000m2, and it was designed and constructed according to class100, 000. The area of the warehouse is 3,500m2 while the floor space for utility room and auxiliary room is 3,000m2. The annually capacity is: 1 billion tablets, and capsules 200 million. The workshops which house the imported production lines, now produce 5 products including Paroxetine Hydrochloride, Irbesartan Tablets and Nevirapine Tablets used for anti-AIDS (7 packing specifications, see appendix 1). 公司建立了完善的质量管理体系，厂房、设备等硬件设施按照cGMP要求设计和建造，物料、生产过程控制和销售均严格遵循cGMP 要求，确保产品质量。The company has established: a quality assurance system. The facility and equipments were designed and constructed according to cGMPs. The control of material, production and sales also comply with the cGMPs, as well as the companys own product quality assurance policies.厂内主要构成Main section in plant：生产区、生产辅助区、仓储区及厂前区（见华海药业厂区平面布置总图）。OKManufacturing section, support manufacturing area, warehouse and square in front of plant（see Huahai Pharmaceutical General Layout）.该文件至少每年复审一次，验证状态及验证时间表（附录四），每年更新一次。This document will be reviewed annually. Validation and qualification status and time schedules are located in appendix 4. 二. 目的Purpose浙江华海药业有限公司。至此简称华海药业，从事于研发、制造及分销药物制剂。华海药业的初步目标是研发及生产的药物制剂符合或超过美国FDA，中国药监部门及其它国际组织的质量标准。华海坚信对高质量的承诺是其达到第二步目标，成为世界级制药公司并为全球各地提供安全、有效的药物新产品的基础。为实现其目标，华海需要先进的药物制造厂房设施。该厂房设施位于汛桥镇利庄，临海市南部，符合FDA要求，用于临床及正常消费的华海药品的生产。Zhejiang Huahai Pharmaceutical Co., Ltd. Heretofore HUAHAI PHARMA, is dedicated to the development, manufacture and distribution of pharmaceuticals. HUAHAI PHARMAs primary goal is to develop and manufacture its products according to standards that meet or exceed the quality standards required by the United States Food and Drug Administration (FDA), Chinese governmental agencies and other international authorities. HUAHAI PHARMA believes that its commitment to high quality is fundamental to achieving its secondary goal of becoming a world-class pharmaceutical company providing safe and efficacious new pharmaceutical products to the global community. To meet its goals, HUAHAI requires a state-of-the-art pharmaceutical manufacturing facility. The facility, located at Lizhuang Xunqiaozheng , in south of Linhai city will be an FDA compliant facility manufacturing HUAHAI PHARMAs products for clinical and consumer use. 本验证总计划，在此称VMP。该VMP适用于厂房内所有直接或间接影响产品的设备设施，目的是给出额外的可信度：它们是与其生产目的想适应且按预期标准运行。此外，该VMP描述了华海的承诺，将依照cGMP要求、相应的政府及国际标准，对设施、设备、工艺过程进行验证，来实现公司目标。该VMP还有以下目的：This Validation Master Plan, heretofore VMP. The VMP pertains to all direct and indirect impact resources / processes in the facility and is intended to give an additional level of assurance that they are suitable for use and will perform as intended. Furthermore, the VMP describes the commitment by Huahai to perform validation of the necessary facilities, equipment and processes in accordance with current Good Manufacturing Practice (cGMP) requirements, and applicable governmental or international standards, in order to meet its goals. The VMP is specifically intended to provide the following: -使华海药业确定与设施、公用系统及产品相关的法规要求-Enable HUAHAI PHARMA to identify the regulatory requirements associated with the facility, specific utilities and equipment, and manufactured product.-描述并确定华海药业的验证及再验证方法-Describe and define HUAHAI PHARMAs approach to validation and revalidation.三. 定义Definition 可接受标准- 某项测试预定的结果。Acceptance Criteria The predetermined result of a specified test.变更控制- 一个合格系统被评定之前，确定提议变动执行对系统影响的过程。提出的变动应该是在批准在实施之前。Change Control Process by which proposed changes to a qualified system are assessed before implementation to determine impact on the system. Proposed changes should be approved prior to implementation.试运转- 一个有了充分的 计划, 形成文件, 并且处理工程学方法对起动和转交设施, 系统, 和设备给最终用户一个可靠的结果和符合预定设计要求和业主期望的功能环境。Commissioning A well planned, documented, and managed engineering approach to the start-up and turnover of facilities, systems, and equipment to the End-User that results in a safe and functional environment that meets established design requirements and stakeholder expectations.试运转计划- 一个详细说明设施、系统和设备在允许的系统边界能被认可的计划。Commissioning Plan A plan which defines the facilities, systems and equipment that will be commissioned based on the agreed to system boundaries.同步验证- 在销售产品的最初几批地生产中进行验证。Concurrent Validation Validation conducted during the manufacture of initial batches of product for distribution.建筑图纸- 所有系统的2维/3维图纸、安装图、明细表、尺寸、注意事项、证明资料, 等。在项目建筑和完成改造期间这些图纸通常是红线标注。维护, 安全和或GMP 原因建筑图要一直保存。Construction Drawings 2d/3d drawings of all systems, schedules, details, dimensions, notes, references, etc. These drawings are often red-lined during construction and updated at project completion. Construction drawings are kept up to date for maintenance, safety and or GMP reasons.关键部件- 一个部件在系统之内由于操作、接触、数据、控制、警报或故障可能有对产品的质量有直接的影响。Critical Component A component within a system where the operation, contact, data, control, alarm or failure may have a direct impact on the quality of the product.设计影响- 在设计开始实施前，有意用来描述设计结果对系统的影响。Design for Impact Describes the practice of making conscious design decisions with respect to the impact of the system in operation at the beginning of design development.详细设计- 在文件需要提供建筑的标定和相互关系的设计阶段。同系统、设备采购、构筑物、安装和测试同时产生。Detailed Design Design stage when the documents required for construction bidding and contracting, as well as system and equipment purchase, fabrication, installation and testing are produced.直接影响系统- 期望一个系统对产品质量的有直接影响。这些系统被设计并且经常委任根据工程管理质量规范和附加规范, 都属于确认和验证规范必须依存现行药品质量管理规范。Direct Impact System A system that is expected to have a direct impact on product quality. These systems are designed and often commissioned in line with Good Engineering Practice and in addition, are subject to qualification or validation practices necessary for cGMP compliance.工厂验收测试- 检查和测试系统或主要系统组分静态/或者动态测试支持设备确认或系统的运行的和供应商提供的文件证明。Factory Acceptance Tests (FATs) Inspection and static and/or dynamic testing of systems or major system components to support the qualification of equipment or systems conducted and documented at the supplier site.工程质量管理规范(GEP)工程建设方法和标准它被应用在整个项目生命周期过程中以交付适当的低成本的解决方案。Good Engineering Practice (GEP) Established engineering methods and standards that are applied throughout the project lifecycle to deliver appropriate, cost-effective solutions.历史文件一个时间点文档的再现或者是文件的快照。Historical Documents Documents representing a point-in-time, or snapshot. 影响改变变化 给一个系统一个变化，要求重新评估确定这个系统的类型 是否发生改变。Impact Altering Change A change that is made to a system that requires a reassessment be performed to determine if the system type has changed.影响评估- 评估一个系统的 运行, 控制, 报警和故障条件对一个产品质量的影响的过程。Impact Assessment The process of evaluating the impact of the operating, controlling, alarming and failure conditions of a system on the quality of a product. 间接影响系统- 不是预期的对产品质量的直接影响的系统, 但特殊的将对支持 一个直接影响系统 。Indirect Impact System A system that is not expected to have a direct impact on product quality, but typically will support a direct impact system. 检查- 建筑和安装被验证的过程，验证建筑和安装是否和详细设计、指定的建筑标准、材料以及任何相关的法律或同这些领域相关的校准要求相符合。Inspection The process by which the construction and installation is verified as in accordance with the detailed design, specified construction standards and materials and any relevant legal or regulatory demands relating to theses areas.安装确认(IQ) 证明可能影响产品质量的所有设备或系统的方面, 可以提供的规范和安装, 遵守说明书和正确地安装了谈到所有必需的公用设施和空间。Installation Qualification (IQ) The documented verification that all aspects of equipment or systems, that can affect product quality, adhere to approved specifications and installed correctly with respect to all required utilities and space recommendations. 现存文件- 文件维护在整个试运行/或确认期间伴随着设备系统或项目要求被修改或被更新。Living Document Documents maintained throughout the commissioning and/or qualification period as equipment/systems or project requirements are modified or updated.没有影响系统一个系统, 它对产品质量不会有任何直接的和间接的影响。No Impact System A system that will not have any impact, either directly or indirectly, on product quality. 非关键的部件- 系统内一个部件在操作、接触、控制、数据控制、警报或故障对产品的质量将有一个间接的或直接的影响。Non-Critical Component A component within a system where the operation, contact, data control, alarm or failure will have an indirect or no impact on the quality of a product.运行限度- 保证和产品的安全需要符合的极小值并且/或者最大值。Operating Limits The minimum and/or maximum values that will ensure that product and safety requirements are met.运行确认(OQ) 那些能够影响产品质量的所有设备或系统的有证明文件的验证，在整个过程中按 意图运行所有的预期范围或者生产指定参数（高低极限值）。Operational Qualification (OQ) The documented verification that all aspects of equipment or systems, that can affect product quality, operate as intended throughout all anticipated ranges or with-in manufacturer specified parameters (high and low limits). 性能确认(PQ)- 那些能够影响产品质量的所有设备或系统的有证明文件的验证，在特定的运行条件下，按意图完成和预先确定可接受的标准一致。Performance Qualification (PQ) The documented verification that all aspects of equipment or systems, that can affect product quality, perform as intended and meet predetermined acceptance criteria under normal (specific) operating conditions.性能测试- 一个过程，通过它证明相互作用的系统性能和在偏差之内的要求一致证明相互作用的系统产量和交付的必需职责或生产量一致，证明 系统的相互依赖的作用是和指定的一致，并且合适。Performance Testing The process by which the performance of interdependent systems is demonstrated as within the required tolerance, the output of interdependent systems is demonstrated as delivering the required duty or capacity, the interdependent functions of systems are demonstrated to be as specified and appropriate. 管道和仪表流程图(P&IDs)- P&IDs 为公共系统和设备加工描述设计信息, 包括流程、设备配置、过程参量、仪表, 和建筑材料。Piping and Instrumentation Diagrams (P&IDs) P&IDs depict design information for utility systems and process equipment, including process flow, equipment configuration, process parameters, instrumentation, and materials of construction for utility systems and process equipment. 工艺验证- 建立有证明文件的证据, 它提供高度保证一个具体过程将始终如一的生产和它预先确定的规范和质量特征一致的产品。Process Validation Establishing documented evidence, which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specification and quality attributes.前验证- 在使用一个现行质量管理规范生产之前在对设备仪器和辅助系统进行的确认。预确认也进行在一个新产品的销售或者在 一个可能影响到产品特性的生产过程修改下的产品生产前过程确认。Prospective validation - Validation conducted on equipment/instruments and ancillary systems prior to their use in a cGMP capacity. Prospective validation also refers to process validation conducted prior to the distribution of a new product, or product made under a revised manufacturing process, where the revisions may affect the products characteristics. 确认方案一个详细的文件，描述 系统需要考虑的事项、测试计划、接受标准和测试结果确保一个系统安装、运行和性能与预确认规范一致。（例安装确认、运行确认、性能确认方案）。Qualification Protocol A detailed document that describes the system under consideration, the testing plans, the acceptance criteria and test results that ensure that a system is installed, operates and performs in accordance with predetermined specification (i.e. IQ, OQ and PQ protocols).验证总结报告总结一个验证方案实行结果的报告。Qualification Summary Report Report summarizing the results of an executed qualification protocol.质量保证一个团队或者团队的行为对确保设备/系统和药品生产质量管理规范要求一致负责。Quality Assurance (QA) The activity of or group responsible for ensuring that equipment/systems meet GMP requirements.质量控制一个团队或者一个团队的作用对相关同等者的行为负责，和分析测试计划和执行相关联。 Quality Control (QC) Process of or group responsible for coordinating the activities associated with analytical test planning and execution.回顾性验证对已经使用了现行的药品质量管理规范生产后的设备/仪器和辅助系统进行验证。回顾性验证也指对一个已经在销售的产品的基础上积聚的产品进行加工 验证测试和控制数据。Retrospective validation Validation conducted on equipment/instruments and ancillary systems already used in a cGMP capacity. Retrospective validation also refers to process validation conducted for a product already in distribution based upon accumulated production, testing and control data.再验证- 一个先前的验证系统已经被改变或改进的验证 一个系统改变的结果或者一段时间/运行基础上的评估使用重复性验证。Revalidation Validation of a previously validated system that has been changed or modified. Revalidation can be performed as a result of a system change, or a time/performance based assessment.现场验收测试 检查或者系统动态测试或者主要系统的组成部分验证- 建立有文件证明的证据对设备/仪器和辅助系统将依据规定或要求、规范始终如一的运行提供一个高度的保证 。Site Acceptance Testing (SAT) Inspection and/or dynamic testing of the systems or major system components Validation - Establishing documented evidence that provides a high degree of assurance that equipment/instruments and ancillary systems will consistently perform according to stated, or required, specifications.技术说明 清楚明确的定义要求、代号和标准 的文件，在构筑物和建筑物建设、测试要求、接受标准和相关可交付的时候遵守。Specifications Documentation which clearly and explicitly defines the system requirements, codes and standards to be followed during fabrication and construction, test requirements, acceptance criteria and the associated deliverables.标准操作规程确保活动每次以 执行同样方式的书面和被批准的规程。Standard Operating Procedure (SOP) Written and approved procedures to ensure that activities are performed the same way each time.系统- 工程学组分的组织, 有一个被定义的功能(如管道系统, 仪器、设备、设施、计算机硬件、计算机软件, 等.)System An organization of engineering components, which have a defined operational function (i.e. piping, instrumentation, equipment, facilities, computer hardware, computer software, etc).系统界限- 极限被画在系统附近逻辑上定义什么是包括在系统之内什么不包括在系统。System Boundary A limit drawn around a system to logically define what is and what is not included in the system.系统说明- 系统的概述描述它的组分、机能、重要功能和系统界限。System Description General description of a system describing its components, functional capabilities, critical functions and system boundaries.验证总计划(VMP)- 建立一个伞形验证计划为一个完整全部项目的一个高级别文件。Validation Master Plan (VMP) A high level document that establishes an umbrella validation plan for an entire project.验证方案- 一个书面计划陈述验证怎么进行。这包括测试程序/参数和验收标准。参见确认方案。Validation protocol - A written plan stating how the validation will be conducted. This includes test procedures/parameters and acceptance criteria. See also Qualification Protocol.供应商/承包商审计- 供应商的交付一个合格产品/服务的能力的评估。Vendor/Contractor Audit An evaluation of the suppliers ability to deliver a quality product/service.最差状态- 一种情况包含的上部和更低的操作或处理极限和情况, 包括那些在标准操作程序之内, 造成操作或过程故障的最巨大的可能性当与理想的情况比较。这样情况不一定导致操作或过程故障。Worst case - A set of conditions encompassing upper and lower operating or processing limits and circumstances, including those within standard operating procedures, which pose the greatest chance of operation or process failure when compared to ideal conditions. Such conditions do not necessarily induce operation or process failure.四. 范围Scope该计划将，针对直接或间接与cGMP关联的设施、设备、工艺过程，用于并指导实施必要的活动。将包括，但不仅限于，华海药业的制剂楼及相关实验室的设施（结构、空间及公用系统）、工艺公用系统、生产设备、检测仪器、校验程序及检测设备、预维修原则及相应的计算机控制系统。 This protocol will apply to, and guide, requisite activities relating to the validation of all necessary facilities, equipment and processes that are subject to cGMPs and defined as direct or indirect impact resources. This will include, but is not limited to, facilities (structures, spaces and utilities), process utilities, manufacturing and finishing equipment, analytical instrumentation, cali