工艺验证方案模板(89页).doc

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1、-工艺验证方案模板Written by起 草 人Written date起草日期年 月 日Reviewed by审 核 人Reviewed date审核日期年 月 日Approved by批 准 人Approved date批准日期年 月 日Written department起草部门Effective date生效日期年 月 日Issued by:颁发部门： Copy number:拷 贝 号： Change record:Revision number变更记载： Date of approval Effective date修订号 批准日期 生效日期 Change reason and g

2、oal: 变更原因及目的：Distribution department:分发部门:所长办公室 人力资源部 后勤保卫部 物资供应部 工程服务部 生产管理部 质量保证部 销 售 部 仓 储 部 疫苗一室 疫苗二室 疫苗三室 疫苗五室 疫苗六室 生化制品室 细胞因子室 血清制品室 实验动物室 分包装室 培养基室 Verification department (department): 验证科室（部门）： Verifycompletion date: 验证完成日期： Validity: 有 效 期： Index 目录1.Purpose目的52.Scope范围53.Responsibility职责5

3、3.1AAA responsibilities AAA的职责53.2XXX responsibilities XXX的职责64.Regulation and Guidance 法规和指南85.Abbreviations缩略语96.Protocol Description方案说明117.Product And Process Description产品和工艺描述147.1Product specification147.2Drug approval No.147.3Standard Followed:147.4Raw Materials and Adjuvants原辅料情况147.5Proces

4、s description:167.6Process Recipe工艺处方：217.7List of Production Plants生产车间一览267.8List of Production Equipment 生产设备一览297.9Process Flow Diagram 工艺流程图337.10CPP Identification CPP确认347.11Validation Plan验证计划498.Validation prerequisite验证先决条件518.1Personal Identification人员确认518.2Process Documentation Verifica

5、tion 生产文件确认518.3Training Verification 培训确认528.4System and Equipment Instruments Calibration Verification 系统和设备仪表校验确认528.5System and Equipment Instruments Calibration Verification 生产相关验证状态确认538.6Test Instruments Calibration Verification 测试仪器和仪表校验确认538.7Testing Method Validation Verification检验方法验证的确认5

6、48.8Raw Material and Excipient Verification原辅料确认549.Sampling Plan and Evaluation Criteria取样计划及评估标准5610.Sample Coding Method样品编码原则7011.Process Validation Test Execution 工艺验证执行7211.1Liquid Preparation 液体配制7211.2Cell Resurrection and Passage细胞复苏及传代7411.3Harvest liquid test 收获液检测8111.4Clarification Filt

7、ration Efficacy Test 澄清过滤效果检测8311.5UF Concentration 1 Efficacy Test超滤浓缩1效果检测8311.6Ammonium sulfate precipitation efficacy test 硫酸铵沉淀效果检测8511.7Potassium bromide extraction efficacy test 溴化钾提取效果检测8611.8First density gradient centrifugation efficacy test 一次密度梯度离心效果检测8711.9Second density gradient centri

8、fugation efficacy test 二次密度梯度离心效果检测8811.10UF Concentration 2 Efficacy Test 超滤浓缩2效果检测8911.11Chromatography purification product test 层析纯化产物检测9012.Bulk Determination原液检验9213.Process Validation Summarization工艺验证总结9314.PV Report工艺验证报告9414.1Process Validation Report 工艺验证报告9414.2Process Validation Analysi

9、s and Evaluation 工艺验证分析与评价9415.Requirements on Execution Records 执行记录要求9516.Deviation Handling 偏差处理9517.Change Handling 变更处理9518.Test Form测试表96表格 1 缩略语9表格 2原辅料质量标准表11表格 3物料消耗表121表格 4物料消耗表221表格 5所用液体配料表22表格 6生产车间一览表26表格 7主要生产设备一览表29表格 8工艺风险分析表33表格 9工艺时间表49表格 10取样计划表56表格 11样品编码原则70表格 12配液取样检测信息表72表格 1

10、3复苏和传代取样表74表格 14复苏和传代样品编码80表格 15收获液标准82表格 16澄清过滤标准83表格 17超滤浓缩1标准84表格 18硫酸铵沉淀标准85表格 19溴化钾提取标准86表格 20一次密度梯度离心标准87表格 21二次密度梯度离心标准88表格 22超滤浓缩2标准89表格 23纯化产物标准90表格 24原液标准92表格 25测试表列表961. Purpose目的This purpose of this process validation is to provide documented evidence to show that the combination of the

11、personnel, materials, equipment, methods, environmental conditions and the other related utilities XXX Co., LTD (XXX) can ensure the consistent production of products conforming to the enterprise internal standards and the national standards, and the processes are reliable and conforming to the GMP

12、requirements. The process validation and the test results are to be documented based on this validation protocol.本工艺验证用于提供文件化的证据，证明XXX疫苗一室生产XXX原液的人员、材料、设备、方法、环境条件以及其它有关公用设施的组合可以始终如一的生产出符合企业内控标准及国家法定标准的产品，工艺稳定可靠，符合GMP要求，工艺验证的过程和检查的结果将按照该验证方案进行记录。2. Scope范围This protocol is applicable to the process va

13、lidation of XXX produced by the equipment located XXX.本方案适用于XXX原液生产的工艺验证。由于工作细胞库制备的过程并非常规生产过程，因此，不在本次验证中进行考察。The labeling and packaging processes are not within the scope of this document since these processes have been validated per PQ protocol (labeling) and PQ protocol (packaging), and these proc

14、esses have minimal impact on finished product quality. 贴标签和包装也不在此文件范围内，因为这些工艺已经按照PQ方案（贴标签）和PQ方案(包装)验证过，并且这些工艺对产品质量极少有影响。3. Responsibility职责3.1 AAA responsibilities AAA的职责 Compile Protocol方案的编写 Guide Protocol execution, data collection/ Provide test data for review upon request by customer指导方案的实施，数据的

15、收集/在客户要求时提供测试数据供其审核 Final report Review/ Analyze and compile data into the summary report最终报告的审核/对数据进行分析并将其编辑入总结报告之中3.2 XXX responsibilities XXX的职责n Production department 生产部 Review and approve protocol审核并批准验证方案 Assure all the equipment used for validation can be maintained timely保证验证用所有设备均能按SOP进行及时

16、的维护和保养 Assure all the raw materials used for validation can be supplied timely and comply with domestic quality criteria of enterprise保证验证用原辅包装材料能按时到货，并符合企业内控标准n Research and development department 研发部 Provide product registration criteria and review whether recipe and process step described in the

17、protocol is complying with registered criteria提供产品的注册工艺，审核方案中生产处方、工艺与注册资料的一致性 Review and make assurance the compliance of raw material supplier with registered supplier审核原辅料供应商和注册资料的一致性 Review relevant quality criteria including raw material, intermedia and finished product审核原辅料标准、中控质量标准和成品的质量标准n Va

18、ccine one Plant 疫苗一室 Coordination and implementation of this validation protocol协调、实施本验证方案 Training of personnel based on this validation protocol按验证方案对有关人员进行培训 Collection, sorting and reviewing of validation data and drafting of validation reports (including the deviation report, if there are any d

19、eviations)收集、整理和审核验证数据，起草验证报告（如方案执行有偏差，要完成偏差报告）。n Utility support department 工程服务部 Assistance in implementation of this validation protocol协助本验证方案的实施 Calibration of instruments related to this validation protocol and providing relevant calibration certificates and quality certificates负责校验和本验证方案有关的仪器

20、、仪表，出具校验报告并贴合格证 Assure normal operation of the utility system保证公用系统的正常运行 Final report Review 最终报告的审核n Quality control of quality department 质量部质量控制 Determination of test methods used in this validation protocol负责确定本验证方案的检验方法 Validation of the necessary test methods for XXXXX involved in this validat

21、ion protocol负责本验证方案涉及的重组乙型肝炎疫苗（CHO细胞）原液生产的必要的检验方法的验证 The quality inspections on XXXXX Tablet involved in this validation protocol, and presenting full item certificates of analysis and quality inspection reports and records负责本验证方案涉及的重组乙型肝炎疫苗（CHO细胞）原液生产的质量检验，并出具全项检验报告，提供质量检验报告书及检验记录 Providing technic

22、al supports and guidance for tests at each of the process steps负责各工序检验的技术支持和指导 Coordinating the plant in the implementation of this validation protocol协同车间实施本验证方案 Final report Review 最终报告的审核n Quality assurance of quality department 质量部质量保证 Supervision of validation process, review and approval of th

23、is protocol, and ensuring the implementation following this protocol负责验证过程监督，方案的审核与批准，确保按批准的方案执行 Sampling at each process steps during the process validation负责工艺验证中各工序的取样 Coordination among different departments involved in the validation activities负责验证涉及到的各部门之间的协调 Providing equipment validation rep

24、orts related to this validation protocol负责提供和本验证方案有关的设备验证报告 Identification, audit and assessment of suppliers供应商的确认、审计及评价 Assessment and handling of changes and deviations occur during this process validation负责对工艺验证实施过程中出现的变更和偏差的评价和处理 Final report Review 最终报告的审核4. Regulation and Guidance 法规和指南 Eudra

25、Lex Volume 4 EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, November, 2008EudraLex 第四卷 欧盟药品生产质量管理规范指南 医药产品 人用及兽用，2008年11月 Final Version of Annex 15 to the EU Guide to Good Manufacturing Practice : Qualification and Validation , September 2001EudraLex 第四

26、卷 药品生产质量管理规范，附录15 验证与确认，2001年9月 EMEA - Note for guidance on process validation, September 2001 欧洲药品管理局 工艺验证指南，2001年9月 EMEA - Annex II to note for guidance on process validation, January 2005欧洲药品管理局 附录II 工艺验证指南 FDA 21 Code of Federal Regulations, Part 211, current Good Manufacturing Practice for Fini

27、shed Pharmaceuticals, April 2011FDA联邦法典第21篇第211部分，现行药物制剂生产质量管理规范，2011年4月 FDA Process Validation: General Principles and Practices , January 2011FDA工艺验证：一般原则和实践，2011年01月 SFDA Good Manufacturing Practice (2010 Revision), March, 2011SFDA 药品生产质量管理规范（2010年修订），2011年03月 PIC PIC/S Pharmaceutical Inspection

28、Convention, Pharmaceutical Inspection Co-operation Scheme, “Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-sterile Process Validation, Cleaning Validation”, July 2004PIC/S药品监管公约，药品监管合作计划，“有关验证主计划、安装和运行确认、非无菌工艺验证、清洁验证的建议”，2004年7月 A WHO Guide to good manufac

29、turing practice(GMP) requirements , Part 2 Validation , 1997 WHO 关于GMP要求的指南， 第二部分：验证，1997年 Chinese Pharmacopoeia (CP) 2010 Edition 中国药典（CP）2010年版 Process Validation of Protein Manufacturing (Technical Report No. 42 Supplement Vol. 59, No. S-4 September/October 2005 2005 by PDA)蛋白生产的工艺验证（技术报告42，PDA，

30、2005年版）5. Abbreviations缩略语The abbreviations which will be used in this protocol are listed in the following form.在下面的表格中规定了本方案中使用的缩略语。表格 1 缩略语Abbreviations缩略语Definition定义APIActive Pharmaceutical Ingredient (or “Drug Substance”)原料药（或药品物质）CPPCritical Process Parameter关键工艺参数CQACritical Quality attribut

31、e关键质量属性CVCleaning Validation清洗验证IQInstallation Qualification安装确认MFVMedia Fill Validation培养基模拟灌装试验N/ANot applicable不适用OQOperation Qualification运行确认PLCProgrammable Logic Controller可编程逻辑控制器PQPerformance Qualification性能确认PVProcess Validation工艺验证PWPurified Water纯化水QAQuality Assurance质量保证RARisk Assessment

32、风险分析SOPStandard Operation Procedure标准操作程序URSUser Requirement Specification用户使用要求VMPValidation Master Plan验证主计划WFIWater for Injection注射用水6. Protocol Description方案说明n Using this defined process validation shall be performed for the results of the Process Risk Assessment.本方案实施的工艺验证，是基于工艺风险评估结果的。n Using

33、 this defined process validation shall be performed for three consecutive successful runs based on GMP requirements to demonstrate the process control reliability and the repeatability.鉴于XXX的生产已经有近20年历史，本次验证仅是对生产地址发生变更后且主要设备未发生变化的再验证，考虑到本产品生产周期长（总生产周期为158天）的原因，本方案实施的工艺验证将生产1批成功的产品以证明其可靠性。n The deter

34、mination of the intermediate and final product will implement enterprise internal standard but release finished product should be in accordance with criteria of the item “XXX” in Chinese Pharmacopoeia 2010 Edition.n 半成品、成品按企业内控标准检验，成品发放按中国药典2010版三部“XXX ”标准执行Raw material internal standard原辅料内控标准：表格 2

35、原辅料质量标准表Quality Standard Doc.质量控制标准文件Doc. Number文件编号Sodium Chloride (BP) Quality Specification氯化钠（药用级）检验质量标准Sodium Dihydrogen Phosphate (BP) Quality Specification磷酸二氢钠（药用级）检验质量标准Crystal Aluminum Chloride AR Quality Specification 结晶氯化铝AR检验质量标准Glucose (BP) Quality Specification 葡萄糖（药用级）检验质量标准Glutamine

36、 Quality Specification 谷氨酰胺质量标准Potassium Bromide Quality Specification 溴化钾质量标准Disodium Edetate Quality Specification 乙二胺四乙酸二钠质量标准Sodium Hydroxide (BP) Quality Specification 氢氧化钠（药用级）质量标准 Disodium Hydrogen Phosphate (BP) Quality Specification 磷酸氢二钠(药用级)质量标准Merthiolate (BP) Quality Specification 硫柳汞（药

37、用）质量标准Hydrochloric Acid (BP) Quality Specification 盐酸（药用级）检验质量标准Proline (BP) Quality Specification 脯氨酸（药用）质量标准Sodium Bicarbonate (BP) Quality Specification 碳酸氢钠（药用级）检验质量标准DMEM Quality Specification DMEM质量标准Formaldehyde Solution (BP) Quality Specification 甲醛溶液(药用)质量标准Ammonium Sulfate AR Quality Speci

38、fication 硫酸铵AR质量标准 Glycine (BP) Quality Specification 甘氨酸（药用）质量标准Trypsin (BP) Quality Specification 胰蛋白酶(药用)质量标准 New Born Bovine Serum Quality Specification 新生牛血清质量标准Methotrexate氨甲喋呤Dimethyl Sulphoxide二甲基亚砜Semi-product of XXX standard, include the Harvest liquid, the Purification liquid and the Bulk

39、.XXX中间品质量标准，包括细胞收获液、纯化产物、原液（文件号：XXX）Final product of XXX standard XXX成品质量标准：（文件号：XXX）n The validation procedures, items and contents are divided based on the system process steps. The process steps, validation items, sampling methods, testing methods and acceptance criteria are described for each of

40、 the process steps.验证的程序、项目和内容中以系统工序为单位，对各工序中的所涉及的工艺步骤、验证项目、取样方法、检验方法和接受标准进行了规定和描述。n The process recipe of Bulk of XXX (Registration batch No.: for 20g: GUOYAOZHUNZI XXX, and for 10g GUOYAOZHUNZI XXX) is briefly described in this protocol. The contents of the recipe are described and the process flo

41、w diagram is listed. The process procedure is conformed to the registration standard.本方案对XXX原液的工艺处方（注册批号：20g：国药准字 XXX、10g：国药准字 XXX）进行了简介，对处方内容进行描述，并且列出直观化的工艺流程图。工艺规程与注册标准一致。n This protocol is used to specify the purpose and the scope of this validation and the responsibilities of each of the departm

42、ents during the implementation of this validation protocol.本方案旨在指明验证的目的、范围，并规定了该验证方案在实施过程中的各部门的职责。n Summarize and evaluate the entire process validation based on the validation of each of the process steps and record the evaluation results to the report.在各工序验证的基础上，对整个工艺验证进行了总结评价，评价结果记录到验证报告中。7. Prod

43、uct And Process Description产品和工艺描述7.1 Product specification(1) Ampoule, one human dose of 1.0ml, containing 10g of HBsAg (1) 安瓿瓶，每1次人用剂量为1.0ml，含HBsAg 10g；(2) Ampoule, one human dose of 1.0ml, containing 20g of HBsAg (2) 安瓿瓶，每1次人用剂量为1.0ml，含HBsAg 20g；(3) Vial, one human dose of 1.0ml, containing 20g o

44、f HBsAg (3) 西林瓶，每1次人用剂量为1.0ml，含HBsAg 20g；(4) Vial, one human dose of 0.5ml, containing 10g of HBsAg (4) 西林瓶，每1次人用剂量为0.5ml，含HBsAg 10g。7.2 Drug approval No. 20g：GUOYAOZHUNZI S1096004720g：国药准字 S1096004710g：GUOYAOZHUNZI S1096008010g：国药准字 S109600807.3 Standard Followed: Chinese Pharmacopoeia 2010 Edition

45、执行标准：中国药典2010版7.4 Raw Materials and Adjuvants原辅料情况Table 3 Raw Materials and Adjuvants表格 4原辅料信息表Name SpecificationsManufacturerPackaging SpecificationsSodium Chloride BP Tianjin Haiguang Pharmaceutical Industrial Co., Ltd. 1000g/bagDisodium hydrogen phosphate BP Hunan Jiudian Pharmaceutical Co., Ltd. 0.5kg/bottleCrystal Aluminum Chloride AP Beijing Yili Fine Chemical Co., Ltd. 500g/bottleGlucose AP Baitaike Bioltechnology Co., Lt