工艺验证方案模板

1、 Process Validation (PV) Protocol for XXXPage页码Process Validation (PV) Protocol XXX年 月 日年 月 日年 月 日年 月 日Issued by:Changereason修订号批准日期生效日期变更原因及目的：Distribution department:所长办公室 生产管理部 疫 苗 二 室 细胞因子室 人力资源部 质量保证部 疫 苗 三 室 血清制品室 后勤保卫部 销 售 部 疫 苗 五 室 实验动物室 物资供应部 仓 储 部 疫 苗 六 室 分 包 装 室 工程服务部 疫 苗 一 室 生化制品室 培 养 基

2、室 Verification department (department):验证科室（部门）：Verify completion date:验证完成日期：Validity:有 效 期： Process Validation (PV) Protocol for XXXPage页码Index 目录1. Purpose 目的 52. Scope 范围 53. Responsibility 职责 53.13.2AAA responsibilities AAA 的职责 5XXX responsibilities XXX 的职责 64. Regulation and Guidance 法规和指南 85.

3、 Abbreviations 缩略语 96. Protocol Description 方案说明 117. Product And Process Description 产品和工艺描述 147.17.27.37.47.57.6Product specification 14Drug approval No 14Standard Followed: 14Raw Materials and Adjuvants原辅料情况 14Process description: 16Process Recipe 工艺处方： 217.77.87.9List of Production Plants 生产车间一览

4、 26List of Production Equipment 生产设备一览 29Process Flow Diagram 工艺流程图 337.10 CPP Identification CPP 确认 347.11 Validation Plan验证计划 498. Validation prerequisite 验证先决条件 518.18.28.38.48.58.6Personal Identification 人员确认 51Process Documentation Verification 生产文件确认 51Training Verification 培训确认 52System and E

5、quipment Instruments Calibration Verification 系统和设备仪表校验确认. 52System and Equipment Instruments Calibration Verification 生产相关验证状态确认 53Test Instruments Calibration Verification 测试仪器和仪表校验确认 53 Process Validation (PV) Protocol for XXXPage页码8.78.8Testing Method Validation Verification检验方法验证的确认 54Raw Mater

6、ial 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 7211.1 Liquid Preparation 液体配制 7211.2 Cell Resurrection and Passage 细胞复苏及传代 7411.3 Harvest liquid test 收获液检测 8111.4 Clarification

7、Filtration Efficacy Test 澄清过滤效果检测 8311.5 UF Concentration 1 Efficacy Test超滤浓缩 1 效果检测 8311.6 Ammonium sulfate precipitation efficacy test 硫酸铵沉淀效果检测 8411.7 Potassium bromide extraction efficacy test 溴化钾提取效果检测 8511.8 First density gradient centrifugation efficacy test 一次密度梯度离心效果检测 8611.9 Second density

8、 gradient centrifugation efficacy test 二次密度梯度离心效果检测 8711.10 UF Concentration 2 Efficacy Test 超滤浓缩 2 效果检测 8811.11 Chromatography 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 9414.1 Process Validation Report 工艺验证报

9、告 9414.2 Process Validation Analysis 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 1.1表格 3 物料消耗表 1 21 Process Validation (PV) Protocol for XXXPage页码表格 4 物料消耗表 2 21表格 5 所用液

10、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 13 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 81表格 16 澄清过滤标准 83表格 17 超滤浓缩 1 标准 83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

11、 24 原液标准 92表格 25 测试表列表 96 Process Validation (PV) Protocol for XXXPage页码1. Purpose 目的This purpose of this process validation is to provide documented evidence to show that thecombination of the personnel, materials, equipment, methods, environmental conditions and theother related utilities XXX Co.,

12、 LTD (XXX) can ensure the consistent production of productsconforming to the enterprise internal standards and the national standards, and the processesare reliable and conforming to the GMP requirements. The process validation and the test resultsare to be documented based on this validation protoc

13、ol.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 validation of XXX produced by the equipment locatedXXX.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

14、中进行考察。The labeling and packaging processes are not within the scope of this document since theseprocesses have been validated per PQ protocol (labeling) and PQ protocol (packaging), andthese 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，

15、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 bycustomer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

16、析并将其编辑入总结报告之中 Process Validation (PV) Protocol for XXXPage页码3.2 XXX responsibilities XXX 的职责 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 进行及时的维护和保养 Assure all the raw materials used for validatio

17、n can be supplied timely and comply withdomestic 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 Research and development department 研发部 Provide product registration criteria and review whether recipe and process stepdescribed in the protocol is complying with registered criteria提供产品的注册工艺，审

18、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 registeredsupplier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 Vaccine one Plant 疫苗一室 Coordination and implementation of thi

19、s 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 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）。 Utility sup

20、port 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 relevantcalibration certificates and 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 Process Validation (PV) Protocol for XXXPage页码

21、 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 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 validation protocol负责本验证

22、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, andpresenting 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 technical supports and

23、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 Quality assurance of quality department 质量部质量保证 Supervision of validation process, review and approval of this protocol, and e

24、nsuringthe 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 reports related to thi

25、s 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 Process Validation (PV) Protocol for XXXPage页码 Assessment and handling of changes and deviations occur during this processvalidation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. Regulatio

26、n and Guidance 法规和指南 EudraLex Volume 4 EU Guidelines to Good Manufacturing Practice Medicinal Products forHuman 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 : Qualificationand Validation ,

27、 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 Goo

28、d Manufacturing Practice forFinished 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），201

29、1年 03 月 PIC PIC/S Pharmaceutical Inspection Convention, Pharmaceutical Inspection Co-operationScheme, “Recommendations on Validation Master Plan, Installation and OperationalQualification, 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

30、洁验证的建议”，2004 年 7 月 A WHO Guide to good manufacturing practice(GMP) requirements , Part 2 Validation , 1997WHO 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 (PV) Protocol for XXXPage页码Process Validation of Protein Manufacturing (Technical Repor

31、t 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， 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AbbreviationsDefinition缩略语定义Active Pharmaceutical Ingredient (

32、or “Drug Substance”)原料药（或药品物质）APICPPCQACVCritical Process Parameter关键工艺参数Critical Quality attribute关键质量属性Installation Qualification安装确认IQMFVN/AOQPLCPQOperation Qualification运行确认PVRisk Assessment风险分析RA Process Validation (PV) Protocol for XXXPage页码Standard Operation Procedure标准操作程序SOPURSVMPWFIWater f

33、or Injection注射用水 Process Validation (PV) Protocol for XXXPage页码6. Protocol Description 方案说明 Using this defined process validation shall be performed for the results of the Process RiskAssessment.本方案实施的工艺验证，是基于工艺风险评估结果的。 Using this defined process validation shall be performed for three consecutive s

34、uccessfulruns based on GMP requirements to demonstrate the process control reliability and therepeatability.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。 The determination of the intermediate and final product will implement enterpri

35、se internalstandard but release finished product should be in accordance with criteria of the item “XXX”in Chinese Pharmacopoeia 2010 Edition. 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 原辅料质量标准表Sodium Chloride (BP) Quality Specification氯化钠（药用级）检验质量标准Sodium

36、Dihydrogen Phosphate (BP) QualitySpecification磷酸二氢钠（药用级）检验质量标准Crystal Aluminum Chloride AR QualitySpecification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 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

37、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) QualitySpecification磷酸氢二钠(药用级)质量标准Merthiolate (BP) Quality Specification硫柳汞（药用）质量标准 Process Validation (PV) Protocol for XXXPage页码Dimethyl Sulphoxide二甲基亚砜Semi-product of XXX standard, include the Harves

38、t liquid, 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 standardXXX 成品质量标准：（文件号：XXX） The validation procedures, items and contents are divided based on the system processsteps. The process steps, validation items, sampling methods, testing methods anda

39、cceptance 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。 The process recipe of Bulk of XXX (Registration batch No.: for 20g: GUOYAOZHUNZI XXX,and for 10g GUOYAOZHUNZIXXX) is briefly described in this protocol. The contents of the

40、recipe are described and the process flow diagram is listed. The process procedure isconformed 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。 This protocol is used to specify the purpose and the scope of this validation and the

41、responsibilities of each of the departments during the implementation of this validation Process Validation (PV) Protocol for XXXPage页码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。Summarize and evaluate the entire process validation based on the validation of each of theprocess steps and record t

42、he 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。 Process Validation (PV) Protocol for XXXPage页码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,

43、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 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：

44、GUOYAOZHUNZI S1096004720g：国药准字 S1096004710g：GUOYAOZHUNZI S1096008010g：国药准字 S109600807.3 Standard Followed: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 3Raw Materials and Adjuvants表格 4 原辅料信息表PackagingSpecificationsNameManufacturerTianjin Haiguang Pharmac

45、eutical IndustrialCo., Ltd.Sodium Chloride1000g/bagDisodiumhydrogenBPHunan Jiudian Pharmaceutical Co., Ltd.0.5kg/bottlephosphateCrystal AluminumChloride500g/bottle500g/bottle1kg /drum500g/bottle250g/bottleGlucoseBeijing Yili Fine Chemical Co., Ltd.Sinopharm Chemical Reagent Co., LtdDisodium EdetateA

46、P Process Validation (PV) Protocol for XXXPage页码PackagingSpecificationsNameManufacturerSodium HydroxideBeijing Chemical Factory500g/bottle0.5kg/bottleBPHunan Jiudian Pharmaceutical Co., Ltd.BPMerthiolateHydrochloric acidProlineGIHON1kg /drum2500ml/ bottle500g/bag(USP/BP/EP)SodiumbicarbonateDMEMForma

47、ldehydeAmmoniumsulfateGlycinePancreatinMethotrexate-Gibcosigma-aldrich（fluka-analytical）SERVA Electrophoresis GmbHWuhan Sanli Biotechnology Co., Ltd.-Top grade-1000ml/ bottle500ml/ bottleNew born bovineserumInner Mongolia Jinyuankang BiotechnologyCo., Ltd.生产厂家一水磷酸二氢钠硫柳汞盐酸分析纯北京化工厂2500ml/瓶 Process Val

48、idation (PV) Protocol for XXXPage页码生产厂家上海协和氨基酸有限公司北京化工厂Gibco-Gibcosigma-aldrich（fluka-analytical）SERVA Electrophoresis GmbH武汉三利生物技术有限公司内蒙古金源康生物工程有限公司-优级-1000ml/瓶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Time (Day)时间（天）11257C25-方瓶第一次培养C26 - second square

49、bottleincubationC26-方瓶第二次培养C27 - Kolle flask incubationC27-克氏瓶培养575757C28 - First 3L rotary bottleincubationC28-3L 转瓶第一次培养C29 - second 3L rotary bottleincubationC29-3L 转瓶第二次培养C30 - third 3L rotary bottleincubation675757C30-3L 转瓶第三次培养 Process Validation (PV) Protocol for XXXPage页码C31 - first 15L bott

50、le8incubationC31-15L 瓶第一次培养C32 - second 15L bottleincubationC32-15L 瓶第二次培养20 consecutive harvest连续 20 次收获液Filtration for cell residueremoval57957400.50.54511.5一次密度梯度离心Second density gradientcentrifugation161.517181911Chromatography purification层析纯化Bulk solution combination原液合并0.5Preparation of produ

51、ction cells生产用细胞制备Take 1 to 2 tubes of cells from the working cell bank (of a same batch No.), resurrect, mix andinoculate them into a 100ml cell cultivation bottle in a ratio of 1:1. After the cells have grownfull and adhering to the wall to a single layer, perform the 0.25% trypsin digestion andpa

52、ssage. And then inoculate them into a 100ml cell cultivation bottle in a ratio of 1:4. Passageand proliferate following the sequence of 100ml cell cultivation bottle, Kolle flask and therotary bottle. The ratio is determined according to different cell cultivation bottle specifications.Two 100ml cel

53、l cultivation bottles are used for the passage to 1 Kolle flask. One Kolle flask isused for the passage to 1 3L rotary bottle. One 3L rotary bottle is used for the passage to 7 to8 3L rotary bottles. One 3L rotary bottle is used for the passage to 1 15L rotary bottle. One15L rotary bottle is used fo

54、r the passage to 7 to 8 15L rotary bottles. Incubate them while thebottles are kept still or rotated at 361 (the 100ml cell cultivation bottles are kept stillduring incubation and rotary bottles are rotated). The duration of each expansion incubationstep is 5 to 7 days. After proliferated to generat

55、ion No. 32, the change solution is maintained.取工作细胞库细胞 12 支（同一批号），复苏混合后按 1：1 比例接种 100ml 细胞培养瓶，待细胞贴壁长满至单层后，0.25%胰蛋白酶消化传代，按 1：4 比例接种 100ml 细胞培养瓶。按100ml 细胞培养瓶克氏瓶转瓶传代扩增，比例根据不同规格细胞培养瓶而定，2 个 100ml Process Validation (PV) Protocol for XXXPage页码细胞培养瓶传 1 个克氏瓶；1 个克氏瓶传 1 个 3L 转瓶；一个3L 转瓶传 78 个 3L 转瓶；一个3L 转瓶传 1

56、个 15L 转瓶；1 个 15L 转瓶传 78 个 15L 转瓶。置361条件下，采用静止或旋转培养（100ml 细胞培养瓶和克氏瓶采用静止培养，转瓶采用旋转培养法）。每次扩增培养时间为 57 天，传代扩增至 32 代，开始维持换液。 Incubation media 培养液The growth media used for cell passage and proliferation is DMEM solution containing 9% to10% inactivated new born bovine serum with a final concentration of meth

57、otrexate of10-6mol/L and L-glutamine of 2mmol/L. The maintenance solution is DMEM solutioncontaining 3% to 5% inactivated new born bovine serum.细胞传代扩增用生长液为含有 9%10%灭能新生牛血清的 DMEM 液，其中含终浓度为10-6mol/L 氨甲喋呤、2mmol/L L -谷氨酰胺。维持液为含有 3%5%灭能新生牛血清的 DMEM液。 Harvesting 收获After passage to the No. 32 generation and

58、the cells have grown into a compact single layeradhering to the wall (Day 5 to 7), discard the growth liquor, add the maintenance solution,discard the incubation liquor 48 hours later and add the maintenance solution. Replace themaintenance solution every 48 hours thereafter and harvest the incubati

59、on liquor. Measurethe HBsAg content in the harvested supernatant with ELISA (or reverse hemagglutinationmethod), the result shall be above 1.0mg/L (RPHA titer 1:128). At the same time a sterility testshall be performed for the harvested solution of each bottle. The number of harvesting for asame bat

60、ch of production cells shall be 19 to 21 (20 1) and the harvest solution of 1 to 2batches can be combined for purification.传代扩增至 32 代的细胞贴壁长成致密单层后（57 天），弃去生长液，加入维持液，48 小时后弃去培养液，加入维持液。此后，每 48 小时更换一次维持液，并收获培养液。收获的培养上清液采用 ELISA 法(或反向血凝法)检测 HBsAg 含量，应在 1.0mg/L(RPHA 滴度 1：128)以上，同时每瓶细胞培养收获液应进行无菌检查，同一批生产细胞收