工艺验证方案模板(87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： 修订号 批准日期 生效日期 Change reason and goal: 变更原因及目的：Distribution department:分发部门:所长办

2、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This purpose of this process validation is to provide documented evidence

3、to show that the combination of the 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

4、 reliable and conforming to the GMP 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 prot

5、ocol is applicable to the process validation 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

6、protocol (packaging), and these processes 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

7、 upon request by customer指导方案的实施，数据的收集/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

8、maintained timely保证验证用所有设备均能按SOP进行及时的维护和保养 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 recip

9、e and process step described in the 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 finish

10、ed product审核原辅料标准、中控质量标准和成品的质量标准n Vaccine 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

11、deviation report, if there are any deviations)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

12、 quality certificates负责校验和本验证方案有关的仪器、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 method

13、s for XXXXX involved in this validation 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

14、验报告，提供质量检验报告书及检验记录 Providing technical 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 validatio

15、n process, review and approval of this 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

16、调 Providing equipment validation reports 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.

17、 Regulation and Guidance 法规和指南 EudraLex 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 Va

18、lidation , September 2001EudraLex 第四卷 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

19、Good Manufacturing Practice for Finished 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

20、PIC PIC/S Pharmaceutical Inspection 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”

21、，2004年7月 A WHO Guide to good manufacturing 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 200

22、5 2005 by PDA)蛋白生产的工艺验证（技术报告42，PDA， 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 Paramet

23、er关键工艺参数CQACritical Quality attribute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QAQu

24、ality Assurance质量保证RARisk Assessment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 Assess

25、ment.本方案实施的工艺验证，是基于工艺风险评估结果的。n Using 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

26、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 determination 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 ma

27、terial internal standard原辅料内控标准：表格 2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 S

28、pecification 葡萄糖（药用级）检验质量标准Glutamine 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Merthiol

29、ate (BP) Quality Specification 硫柳汞（药用）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

30、量标准Ammonium Sulfate AR Quality Specification 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,

31、the Purification liquid and the Bulk.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 acceptanc

32、e criteria are described for each of 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 reci

33、pe are described and the process flow 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 res

34、ponsibilities of each of the departments 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

35、，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. Product 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 h

36、uman dose of 1.0ml, containing 20g of 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

37、: Chinese Pharmacopoeia 2010 Edition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 Hu

38、nan Jiudian Pharmaceutical Co., Ltd. 0.5kg/bottleCrystal Aluminum Chloride AP Beijing Yili Fine Chemical Co., Ltd. 500g/bottleGlucose AP Baitaike Bioltechnology Co., Ltd. (filling)500g/bottleGlutamineusp Gradeinvitrogen corporation (Gibco)1kg /drum Potassium Bromide AP Beijing Yili Fine Chemical Co.

39、, Ltd. 500g/bottleDisodium Edetate AP Sinopharm Chemical Reagent Co., Ltd 250g/bottleSodium Hydroxide AP Beijing Chemical Factory 500g/bottleMono-water disodium hydrogen phosphate BP Hunan Jiudian Pharmaceutical Co., Ltd. 0.5kg/bottleMerthiolate BP (USP/BP/EP)GIHON1kg /drum Hydrochloric acid AP Beij

40、ing Chemical Factory 2500ml/ bottleProline -Shanghai Xiehe Amino Acid Co., Ltd. 500g/bagSodium bicarbonate AP Beijing Chemical Factory 500g/bottleDMEM-Gibco6687g/drum Formaldehyde AP Sinopharm Chemical Reagent Co., Ltd 500ml/ bottleAmmonium sulfate AP Beijing Yili Fine Chemical Co., Ltd. 25kg /drum

41、GlycineAP Sinopharm Chemical Reagent Co., Ltd 100g/ bottle Pancreatin -BD 500g/bottleGibco100g/ bottle Methotrexate99.0%sigma-aldrich（fluka-analytical）100mg/ tube Dimethyl Sulphoxide-SERVA Electrophoresis GmbH1L/ bottle New born bovine serum Top grade Wuhan Sanli Biotechnology Co., Ltd. 1000ml/ bott

42、le-Inner Mongolia Jinyuankang Biotechnology Co., Ltd. 500ml/ bottle原辅料名称规格生产厂家包装规格氯化钠药用级天津海光药业有限公司1000g/袋磷酸氢二钠药用级湖南九典制药有限公司0.5kg/瓶结晶氯化铝分析纯北京益利精细化学品有限公司500g/瓶葡萄糖分析纯宝泰克生物科技公司（分装）500g/瓶谷氨酰胺usp Gradeinvitrogen corporation（Gibco）1kg/桶溴化钾分析纯北京益利精细化学品有限公司500g/瓶乙二胺四乙酸二钠分析纯国药集团化学试剂有限公司250g/瓶氢氧化钠分析纯北京化工厂500g/

43、瓶一水磷酸二氢钠药用级湖南九典制药有限公司0.5kg/瓶硫柳汞药用级（USP/BP/EP）GIHON1Kg/桶盐酸分析纯北京化工厂2500ml/瓶脯氨酸-上海协和氨基酸有限公司500g/袋碳酸氢钠分析纯北京化工厂500g/瓶DMEM-Gibco6687g/桶甲醛分析纯国药集团化学试剂有限公司500ml/瓶硫酸铵分析纯北京益利精细化学品有限公司25kg/桶甘氨酸分析纯国药集团化学试剂有限公司100g/瓶胰酶-BD公司500g/瓶Gibco100g/瓶氨甲喋呤99.0%sigma-aldrich（fluka-analytical）100mg/管二甲基亚砜-SERVA Electrophoresis

44、 GmbH1L/瓶新生牛血清优级武汉三利生物技术有限公司1000ml/瓶-内蒙古金源康生物工程有限公司500ml/瓶7.5 Process description:工艺简述： Process Cycle 工艺周期Table 5 Process Schedule表格 6工艺时间表No.序号Process Steps 工艺步骤Time (Day)时间（天）1Resurrection 复苏12C25 - First square bottle incubation C25-方瓶第一次培养573C26 - second square bottle incubation C26-方瓶第二次培养574C2

45、7 - Kolle flask incubation C27-克氏瓶培养575C28 - First 3L rotary bottle incubation C28-3L转瓶第一次培养576C29 - second 3L rotary bottle incubation C29-3L转瓶第二次培养577C30 - third 3L rotary bottle incubation C30-3L转瓶第三次培养578C31 - first 15L bottle incubation C31-15L瓶第一次培养579C32 - second 15L bottle incubation C32-15L瓶第二次培养571020 consecutive harvest 连续20次收获液40