工艺验证方案模板样本.doc

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Process Validation (PV) Protocol XXX
XXX工艺验证方案
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 goal:
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) :
Verify completion date:
验证完成日期:
Validity:
有 效 期:

Index 目录

1. Purpose目的 5
2. Scope范围 5
3. Responsibility职责 5
3.1 AAA responsibilities AAA的职责 5
3.2 XXX responsibilities XXX的职责 6
4. Regulation and Guidance 法规和指南 8
5. Abbreviations缩略语 9
6. Protocol Description方案说明 11
7. Product And Process Description产品和工艺描述 14
7.1 Product specification 14
7.2 Drug approval No. 14
7.3 Standard Followed: 14
7.4 Raw Materials and Adjuvants原辅料情况 14
7.5 Process description: 16
7.6 Process Recipe工艺处方: 21
7.7 List of Production Plants生产车间一览 26
7.8 List of Production Equipment 生产设备一览 29
7.9 Process Flow Diagram 工艺流程图 33
7.10 CPP Identification CPP确认 34
7.11 Validation Plan验证计划 49
8. Validation prerequisite验证先决条件 51
8.1 Personal Identification人员确认 51
8.2 Process Documentation Verification 生产文件确认 51
8.3 Training Verification 培训确认 52
8.4 System and Equipment Instruments Calibration Verification 系统和设备仪表校验确认 52
8.5 System and Equipment Instruments Calibration Verification 生产相关验证状态确认 53
8.6 Test Instruments Calibration Verification 测试仪器和仪表校验确认 53
8.7 Testing Method Validation Verification检验方法验证的确认 54
8.8 Raw Material and Excipient Verification原辅料确认 54
9. Sampling Plan and Evaluation Criteria取样计划及评估标准 56
10. Sample Coding Method样品编码原则 70
11. Process Validation Test Execution 工艺验证执行 72
11.1 Liquid Preparation 液体配制 72
11.2 Cell Resurrection and Passage细胞复苏及传代 74
11.3 Harvest liquid test 收获液检测 81
11.4 Clarification Filtration Efficacy Test 澄清过滤效果检测 83
11.5 UF Concentration 1 Efficacy Test超滤浓缩1效果检测 83
11.6 Ammonium sulfate precipitation efficacy test 硫酸铵沉淀效果检测 85
11.7 Potassium bromide extraction efficacy test 溴化钾提取效果检测 86
11.8 First density gradient centrifugation efficacy test 一次密度梯度离心效果检测 87
11.9 Second density gradient centrifugation efficacy test 二次密度梯度离心效果检测 88
11.10 UF Concentration 2 Efficacy Test 超滤浓缩2效果检测 89
11.11 Chromatography purification product test 层析纯化产物检测 90
12. Bulk Determination原液检验 92
13. Process Validation Summarization工艺验证总结 93
14. PV Report工艺验证报告 94
14.1 Process Validation Report 工艺验证报告 94
14.2 Process Validation Analysis and Evaluation 工艺验证分析与评价 94
15. Requirements on Execution Records 执行记录要求 95
16. Deviation Handling 偏差处理 95
17. Change Handling 变更处理 95
18. 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1 21
表格 4物料消耗表2 21
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 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 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 96

1. Purpose目的
This purpose of this process validation is to provide documented evidence 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 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能够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 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 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, 而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
ü Compile Protocol
方案的编写
ü Guide Protocol execution, data collection/ Provide test data for review 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
ü 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
ü Review and approve protocol
审核并批准验证方案
ü 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
ü 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
ü Provide product registration criteria and review whether recipe 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
ü 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
ü 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 Vaccine one Plant 疫苗一室
ü Coordination and implementation of this validation protocol
协调、 实施本验证方案
ü Training of personnel based on this validation protocol
按验证方案对有关人员进行培训
ü 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) 。
n Utility support department 工程服务部
ü Assistance in implementation of this validation protocol
协助本验证方案的实施
ü 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、 仪表, 出具校验报告并贴合格证
ü Assure normal operation of the utility system
保证公用系统的正常运行
ü Final report Review
最终报告的审核
n Quality control of quality department 质量部质量控制
ü Determination of test methods used in this validation protocol
负责确定本验证方案的检验方法
ü Validation of the necessary test methods 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
ü 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
ü 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
ü Coordinating the plant in the implementation of this validation protocol
协同车间实施本验证方案
ü Final report Review
最终报告的审核
n Quality assurance of quality department 质量部质量保证
ü Supervision of validation 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
ü Sampling at each process steps during the process validation
负责工艺验证中各工序的取样
ü 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
ü 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
ü Identification, audit and assessment of suppliers
供应商的确认、 审计及评价
ü 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
ü Final report Review
最终报告的审核
4. Regulation and Guidance 法规和指南
ü EudraLex Volume 4 EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, November,
EudraLex 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, 11月
ü Final Version of Annex 15 to the EU Guide to Good Manufacturing Practice : Qualification and Validation , September
EudraLex 第四卷 药品生产质量管理规范, 附录15 验证与确认, 9月
ü EMEA - Note for guidance on process validation, September
欧洲药品管理局 – 工艺验证指南, 9月
ü EMEA - Annex II to note for guidance on process validation, January
欧洲药品管理局 – 附录II 工艺验证指南
ü FDA 21 Code of Federal Regulations, Part 211, current Good Manufacturing Practice for Finished Pharmaceuticals, April
FDA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, 4月
ü FDA Process Validation: General Principles and Practices , January
FDA工艺验证: 一般原则和实践, 01月
ü SFDA Good Manufacturing Practice ( Revision), March,
SFDA 药品生产质量管理规范( 修订) , 03月
ü 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
PIC/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”, 7月
ü 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
ü Chinese Pharmacopoeia (CP) Edition
中国药典( CP)
ü Process Validation of Protein Manufacturing (Technical Report No. 42 Supplement Vol. 59, No. S-4 September/October © by PDA)
蛋白生产的工艺验证( 技术报告42, PDA, )
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
API
Active Pharmaceutical Ingredient (or ”Drug Substance”)
原料药( 或药品物质)
CPP
Critical Process Parameter
关键工艺参数
CQA
Critical Quality attribute
关键质量属性
CV
Cleaning Validation
清洗验证
IQ
Installation Qualification
安装确认
MFV
Media Fill Validation
培养基模拟灌装试验
N/A
Not applicable
不适用
OQ
Operation Qualification
运行确认
PLC
Programmable Logic Controller
可编程逻辑控制器
PQ
Performance Qualification
性能确认
PV
Process Validation
工艺验证
PW
Purified Water
纯化水
QA
Quality Assurance
质量保证
RA
Risk Assessment
风险分析
SOP
Standard Operation Procedure
标准操作程序
URS
User Requirement Specification
用户使用要求
VMP
Validation Master Plan
验证主计划
WFI
Water 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 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 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 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 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
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 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 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, 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 acceptance 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 20μg: GUOYAOZHUNZI XXX, and for 10μg GUOYAOZHUNZI XXX) is briefly described in this protocol. The contents of the recipe 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: 20μg: 国药准字 XXX、 10μg: 国药准字 XXX) 进行了简介, 对处方内容进行描述, 而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 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, 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 10μg of HBsAg
(1) 安瓿瓶, 每1次人用剂量为1.0ml, 含HBsAg 10μg;
(2) Ampoule, one human dose of 1.0ml, containing 20μg of HBsAg
(2) 安瓿瓶, 每1次人用剂量为1.0ml, 含HBsAg 20μg;
(3) Vial, one human dose of 1.0ml, containing 20μg of HBsAg
(3) 西林瓶, 每1次人用剂量为1.0ml, 含HBsAg 20μg;
(4) Vial, one human dose of 0.5ml, containing 10μg of HBsAg
(4) 西林瓶, 每1次人用剂量为0.5ml, 含HBsAg 10μg。
7.2 Drug approval No.
20μg: GUOYAOZHUNZI S10960047
20μg: 国药准字 S10960047
10μg: GUOYAOZHUNZI S10960080
10μg: 国药准字 S10960080

7.3 Standard Followed:
Chinese Pharmacopoeia Edition
执行标准: 中国药典
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
Specifications
Manufacturer
Packaging Specifications
Sodium Chloride
BP
Tianjin Haiguang Pharmaceutical Industrial Co., Ltd.
1000g/bag
Disodium hydrogen phosphate
BP
Hunan Jiudian Pharmaceutical Co., Ltd.
0.5kg/bottle
Crystal Aluminum C