头孢呋辛酯清洗验证方案wang.doc

NCPC Hebei Huamin Pharmaceutical Co., LTD
华北制药河北华民药业有限责任公司
Doc. No.
文件编号

New Cephalosporins Factory
新头孢工厂
Page
页码
35 of 45
Cefuroxime Axetil Using Equipment Cleaning Validation Protocol
头孢呋辛酯使用设备清洗验证方案

Cefuroxime Axetil Using Equipment
Cleaning Validation Protocol
头孢呋辛酯使用设备
清洗验证方案

Protocol Approval 方案批准

Company/Title
公司/职务
Name
姓名
Signature
签名
Date
日期
Written by
起草
Austar/Validation Engineer
奥星/验证工程师
张映雪

Reviewed by审核
NCPC / NC Process Engineer
华药华民/非无菌原料工艺工程师
周平凡

NCPC/ NC Equipment Engineer
华药华民/非无菌原料设备工程师
杨志云

NCPC/QA Validation Engineer
华药华民/QA验证工程师
王 柳

NCPC/QC QC Manager
华药华民/QC 负责人
王冕

NCPC/QA Manager
华药华民/QA负责人
沈梅

Approved by批准
NCPC/ NC Manager
华药华民/非无菌原料负责人
刘东

NCPC/ Quality Manager
华药华民/质量负责人
刘树林

RESIVION
版本
ISSUED DATE
颁布日期
REASON FOR NEW ISSUE
颁布原因
REV. 00

INITIAL ISSUE首次颁布

Index 目录

1. PURPOSE目的 4
2. SCOPE范围 4
3. RESPONSIBILITY职责 5
4. REGULATION AND GUIDANCE 法规和指南 6
5. ABBREVIATIONS缩略语 7
6. CEFUROXIME AXETIL PROCESS FLOW头孢呋辛酯工艺流程图 8
7. GOOD DOCUMENTATION PRACTICE文件管理规范 9
8. SAMPLING PROCEDURES取样程序 11
8.1 Active pharmaceutical ingredient residues sampling procedures 活性成分残留取样程 序 11
8.1.1 Swab sample 棉签法取样 11
8.2 pH, conductivity sampling procedures酸碱度、电导率取样程序 11
8.2.1 Rinse sample冲淋法取样 11
8.3 Sample coding principle样品编号原则 12
8.4 Sampling principles取样原则 12
9. EQUIPMENT DESCRIPTION设备描述 13
9.1 List of equipment areas in direct contact with the active ingredients与活性成分直接接触设备面积清单 13
9.2 Positions of equipment sampling points设备取样点位置 14
10. ACCEPTANCE CRITERIA 可接受标准 17
10.1 Visual checks目视检查 17
10.2 Active pharmaceutical ingredient residues活性成分残留 17
10.2.1 Principles原理 17
10.2.2 Target Product Selection目标产品选择 17
10.2.3 Minimum daily therapeutic dosage criteria最低日治疗剂量标准 17
10.2.4 10ppm criteria 10ppm标准 18
10.2.5 Comparison of calculation results计算结果对比 19
10.2.6 The calculation of the active ingredient residue per unit area单位面积活性成分 残留的计算 19
10.2.7 Others其它 19
11. VALIDATION DESCRIPTION AND TESTING METHOD DESCRIPTION验证说明及检测方法说明 20
11.1 Validation description验证说明 20
11.2 Testing method description检测方法说明 21
12. TEST LIST测试列表 22
13. PERSONNEL IDENTIFICATION人员确认 23
14. TEST PROCEDURES测试程序 24
14.1 Prerequisites先决条件 24
14.2 SOP and Training Documentation Verification标准操作流程（SOP）和培训文件确认 27
14.3 Calibration of Instruments仪器仪表校验 30
14.4 Verification of visual inspection results目视检查结果的确认 33
14.5 Cotton swab sampling and chemical test results棉签法取样及化学检测结果 37
14.6 Rinsing swab pH, Conductivity and TOC sampling and test results冲淋水酸碱度， 电导率取样及检测结果 45
15. DEVIATION REPORT偏差报告 50

1. Purpose目的
The purpose of this cleaning validation study is to verify and document that the standard cleaning programs for the equipment, systems or facilities in direct contact with the product can ensure that the residual active ingredients and the residues from the former batch of product are within the predefined acceptance criteria, so as to prevent any contaminations (related to the product or the cleaning process) that can cause any adverse effects to the safety or the quality of the products produced the next time, and the selection of product residual limit is also determined at the same time. The set limit shall be practical and testable. The analytical methods used for the detection of residues or contaminants during the cleaning validation shall be validated. The validation results are obtained through the evaluation of the amounts of the residues of the major active ingredients on the equipment surfaces and the pH, the conductivity in the rinse water.
本清洁验证研究的目的是为了确认和记录与产品直接接触的设备、系统或设施的标准清洗程序能够保证活性成分和上一批产品可能的残留物在预先所定义的可接受范围内，以防止出现能够对下一次生产产品的安全性和质量带来不利影响的污染（与产品或清洁工艺相关的），同时对产品残留物限度进行确定。设定的限度应是切合实际和可检查的。清洗验证中检测残留物的分析方法，应该得到验证。验证的结果，通过评估设备表面的主要活性残留物的量和清洗水的酸碱度和电导率而得。
2. Scope范围
This protocol is change production cleaning validation protocol, it mainly contains the equipments and containers below.
本方案为更换品种清洗验证方案，主要涉及以下生产设备及容器：
Ø Dissolution Tank（1）
溶解罐（1台）
Ø Condensation Reactor（1）
缩合反应罐（1台）
Ø Hydrolysis Tank（2）
水解罐（2台）
Ø Hydrolysis Transmission Tank
水解中转罐（1台）
Ø Crystallization Tank（1）
结晶罐（1台）
Ø Finished Product Centrifuge（1）
成品离心机（1台）
Ø Finished Product Dryer（1）
成品干燥单锥（1台）
Ø Vibration Sieve（1）
颗粒机（1台）
Ø Finished Product Mother Liquor Balancing Tank （1）
成品母液平衡罐（1台）
3. Responsibility职责
Austar responsibilities奥星的职责
ü Protocol compilation
方案的编写
NCPC responsibilities华药华民的职责
ü Review and approval of this protocol before execution
执行前审核和批准本方案
ü Supply of all procedures, data, manuals, drawings and documentation necessary for the generation and execution of this protocol and the completion of the final report
提供为方案编写、方案执行和报告编写所需要的所有的规程、数据、手册、图纸和文件
ü Assure all punchlist items and prerequisites for execution are satisfied
保证在执行前所有的未完成项和先决条件得到满足
ü Provide personnel, when necessary, to assist in the operation of utility system
在需要的时候，提供必要的人员协助进行公用系统的运行
ü Protocol execution and data collection
方案的实施，数据的收集
ü Provide personnel, when necessary, to calibrate critical and non-critical measuring, recording, and/or controlling instrumentation
在需要的时候，提供必要的人员进行关键和非关键的测量、记录和控制仪表的校准
ü Define solution for non conformity
针对不一致项，界定解决方法
ü Review and approval of the report after successful execution.形成一个验证小组，并明确每个人的职责

审核和批准报告
4. Regulation and Guidance 法规和指南
Ø (SFDA) Good Manufacturing Practice 1998
(SFDA) GMP 1998版
Ø (SFDA) Good Manufacturing Practice(Draft for comment, Dec 2009)
(SFDA) GMP（2009年12月征求意见稿）
Ø EudraLex - Volume 4 Good Manufacturing Practice (GMP) Guidelines
EudraLex-卷4 GMP指南
Ø China Pharmacopoeia 2010 Edition
中国药典 2010版
Ø (FDA) Guide to Inspections Validation of Cleaning Process （July 1993）
清洗工艺验证检查指南(1993年7月)
Ø Guide to drug manufacture validation 2003
药品生产验证指南2003年版
Ø Part 211: Current Good Manufacturing Practices for Finished Pharmaceuticals
第211部分：现行药品生产质量管理规范
5. Abbreviations缩略语
Abbreviations
缩略语
Definition
定义
IQ
Installation Qualification
安装确认
OQ
Operational Qualification
运行确认
PQ
Performance Qualification
性能确认
GMP
Good Manufacturing Practice
药品生产质量管理规范
SOP
Standard Operation Procedure
标准操作程序
PW
Purified Water
纯化水
CV
Cleaning Validation
清洗验证
6. Cefuroxime Axetil Process Flow头孢呋辛酯工艺流程图
Dissolution
溶解
聚乙烯塑料袋纸板桶
Condensation Reaction
缩合反应
Hydrolyze Reaction
水解反应
Extraction1
萃取
Decoloration
脱色
Filtration
过滤

Crystallization
结晶

Drying
干燥

Filling
分装

Checking
检查

Labelling, Packaging
贴签、包装
Product Centrifugal
成品离心

Extraction2
萃取

7. Good Documentation Practice文件管理规范
Recording pens 记录用笔
- Archive proof ink pens or marker pens shall be used. Blue pens are recommended.
使用不消退的墨水笔和记号笔，推荐使用蓝色笔记录。
Signature 签名
- Only authorized persons can sign on any documents.
被授权的人员才能签署文件。
- Unless otherwise specified, the full name shall be used as the signature
应签全名，除非文件另有规定。
- The signature shall be readable.
签名应该是可辨认的。
- The signatures shall be consistent.
签名应始终一致
Column filling 填写栏目
- All the columns shall be filled.
所有栏目必须填写
- The full text shall be filled if it is the same as that in the field above.
填写内容与上面栏目相同应重新填写
- If there is nothing to be filled in to an individual field, N/A (abbreviation for not applicable) shall be written in this field.
若有单个栏目不需要填入内容，则在空白处填写英文字母“不适用”的简写“N/A”，以表示无此项内容
- If there is nothing to be filled in more than one neighboring fields, such fields shall be crossed with a diagonal line, with “N/A” noted above the line and the signature and the date noted below the line. The signature and the date shall be written along the line on the same side as much as possible.
填写记录时，若有多个栏目不需要填入内容，应用斜线划掉，斜线上方填写“N/A，下方签名和注明日期。签名及日期应尽量沿斜线同侧填写

N/A

签名 日期
Signature date

Correction of mistakes 更改错误
- When any mistakes are to be corrected immediately after the document has been completed, the correct record shall be entered and signed and dated. The original information shall be left clearly readable
文件刚完成，立即更改的
在错误处划线，填入正确的，签名和注明更改日期，确保原先信息仍清晰可识别
For example: January 1, 2010, signature and date
如：2010年01月01日 签字，日期
- When any mistakes are to be corrected afterwards, besides conforming to the above requirements, the reasons for the correction must be noted and the possible influences shall also be assessed and noted
事后更改的，除非立即更改的要求外，还应注明更改的原因，检查和注释可能的影响
Date Recording Format 记录日期
- Four digits shall be used for the indication of the year, two digits for the month and another two for the date.
年用4位数表示，日和月用2位数表示
For example: 2009年09月01日
如：2009年09月01日
Use of Abbreviations 使用缩略语
- An abbreviation shall be noted in brackets immediately after the full name before it can be used in the rest of the document.
在术语全称后的括号内注明缩写，然后才可以使用缩写
Written Words and Names 书面语及名称
- Standard written words and names shall be used.
使用规范的书面语及名称。
- The names shall be consistent all through the document.
文件前后名称要一致
8. Sampling procedures取样程序
8.1 Active pharmaceutical ingredient residues sampling procedures 活性成分残留取样程 序
8.1.1 Swab sample 棉签法取样
Swab the equipment surface after washing with a cotton swab using a 10×10cm2 PTFE frame to help defining the sampling area. During the swabbing process, dip the cotton swab with a small amount of the PW or deionized water and swab horizontally first. Then turn the cotton swab over and swab vertically. Attention shall be paid to follow the same direction during the swabbing process. Do not swab back and forth. All the area defined by the PTFE frame shall be swabbed (please see the following drawing). After the swabbing, put the cotton swab into a volumetric flask with a stopper, dissolve the sample of the PW or deionized and perform the test according to the relevant SOP.
用棉签在清洗后的设备表面进行擦拭，用10×10cm2聚四氟乙烯框作为取样范围，在擦拭过程中用棉签蘸少量去离子水或纯化水首先横向擦拭，然后翻转棉签再纵向擦拭，注意在擦拭时棉签一定沿一个方向擦拭，不可来回擦拭。擦拭过程中要求聚四氟乙烯框范围内都要擦到（见下图）。擦完后棉签放入具塞量筒中用去去离子水或纯化水溶解，按照相应的检测SOP进行测试。

8.2 pH, conductivity sampling procedures酸碱度取样程序、淋洗水化学残留
8.2.1 Rinse sample冲淋法取样
For Dissolution Tank and Condensation Reactor after finishing the normal washing process, rinse it with 100L deionized water, take the rinse solution. Take 10ml the rinse solution and perform the test.
溶解罐和缩合反应罐正常清洗完毕后，再采用100L去离子水反复冲洗，冲洗结束后经物料管道放至下一工序生产设备，并接取淋洗液50ml进行测试。
For Hydrolysis Tank, K Centrifuge, K Centrifuge Reception Tank, Complex salt Ⅰ Crystallization Tank, Complex Salt Ⅰ Centrifuge, Complex salt Ⅰ Dryer, Complex Salt Ⅰ Crystal Conversion Tank, Finished Product Centrifuge, Finished Product Dryer, Vibration Sieve and Condensation Reactor after finishing the normal washing process, rinse it with 100L purified water, take the rinse solution. Take 10ml the rinse solution and perform the test. It should have a separate sample of pH and conductivity test item.
水解罐、K离心机、K离心机接收罐、复盐Ⅰ结晶罐、复盐Ⅰ离心机、复盐Ⅰ干燥双锥、复盐Ⅰ转晶罐、成品离心机、成品干燥单锥、颗粒机、正常清洗完毕后，再采用100L纯化水反复冲洗冲洗结束后经物料管道放至下一工序生产设备，并接取淋洗液1050
ml进行测试。
It should have a separate sample of pH and conductivity test item.
酸碱度和电导率单独取样。
删除
8.3 Sample coding principle样品编号原则
For the chemical swab samples of the equipment. Each of the sampling points of the equipment shall be coded following the sequence of SC1, SC2, SC3, …
对于设备的棉签化学样品，对设备各个取样点进行编排，编号顺序为SC1、SC2、SC3……。
For the chemical swab samples of the equipment. Each of the sampling points of the equipment shall be coded following the sequence of RP1、RP2、RP3, …
对于设备的酸碱度冲淋样品，对设备各个取样点进行编排，编号顺序为RP1、RP2、RP3……。
For the chemical swab samples of the equipment. Each of the sampling points of the equipment shall be coded following the sequence of RD1、RD2、RD3 …
对于设备的电导率化学
冲淋样品，对设备各个取样点进行编排，编号顺序为RD1RC1、RD2RC2、RD3RC3RC1\RC2\RC3
……。
8.4 Sampling principles取样原则
The sample location should select the most difficult cleaning location, when use swab sampling, the component which sample area is not enough should according to the cotton swab area calculating.
取样位置的选择应该选用设备最难清洁的部位，棉签取样时，不足规定取样面积的部件按照棉签擦拭的范围进行计算。
It should have a separate sample of each test item.
每个检测项目单独取样一只。
9. Equipment description设备描述
9.1 List of equipment areas in direct contact with the active ingredients与活性成分直接接触设备面积清单
Equipment Name
设备名称
Contact Area (m2)
接触面积（m2）
Condensation Reactor
缩合反应罐
7.9
Hydrolysis Tank 1
水解罐 1
8.7
Hydrolysis Tank 2
水解罐 2
8.7
Hydrolysis Transmission Tank
水解中转罐
8.5
Crystallization Tank
结晶罐
9.4
Centrifuge
成品离心机
1.7
Finished Product Dryer
成品干燥单锥
8.0
Vibration Sieve
颗粒机
1.8
Total area
面积汇总
54.7

9.2 Positions of equipment sampling points设备取样点位置
第_____次 Page___of___
Equipment
设备
Swab Sample棉签样
Rinse Sample冲淋样
Sampling point
取样点
Chemical sample code
棉签擦拭化学项样品编号
Sampling point
取样点
pH sample code
pH酸碱度
项样品编号
Conductivity sample code
淋洗水化学样品编号
Dissolution Tank
溶解罐
N/A
N/A
Sampling port
取样口
RP1
RC1
Finished Product Dryer
成品干燥单锥
Cone cap
锥盖
SC1
Rinsing sample
冲淋样
RP8
RC2
Stirrer
搅拌
SC2
Granulation machine
颗粒机
Screen stencil
筛网
SC3
Rinsing sample
冲淋样
RP9
RC3
Powder outlet  
出粉口
SC4
Condensation Reactor
缩合反应罐
End plate connection
封头连接处
SC5
Sampling port
取样口
RP2
RC4
Connection between the feeding pipe and the reactor
反应罐罐壁
SC6
Mechanical seal of stirrer shaft
搅拌轴机械密封
SC7
Tank wall
罐壁
SC8
Hydrolysis Tank 1
水解罐 1
Tank wall
罐壁
SC9
Sampling port
取样口
RP3
RC5
Connection between the feeding pipe and the reactor
与反应罐连接的进罐管路处
SC10
Mechanical seal of stirrer shaft
搅拌轴机械密封
SC11
Hydrolysis Tank 2
水解罐 2
Tank wall
罐壁
SC12
Sampling port
取样口
RP4
RC6
Connection between the feeding pipe and the reactor
与反应罐连接的进罐管路处
SC13
Mechanical seal of stirrer shaft
搅拌轴机械密封
SC14
Hydrolysis Transmission Tank
水解中转罐
Tank wall
罐壁
SC15
Sampling port
取样口
RP5
RC7
Connection between the feeding pipe and the reactor
与反应罐连接的进罐管路处
SC16
End plate connection
封头连接处
SC17
Crystallization Tank
结晶罐
Tank wall
罐壁
SC18
Sampling port
取样口
RP6
RC8
Connection between the feeding pipe and the reactor
与反应罐连接的进罐管路处
SC19
Mechanical seal of stirrer shaft
搅拌轴机械密封
SC20
Finished Product Centrifuge
成品离心机
Connection between the feeding pipe and the reactor
与反应罐连接的进罐管路处
SC21
Sampling port
取样口
RP7
RC9
Scraper
刮刀
SC22
Rotary drum
转鼓
SC23

10. Acceptance criteria 可接受标准
10.1 Visual checks目视检查
The SOP for the visual inspection has been established. There shall be no visible product residues on the disassembled equipment or components after cleaning and the equipment shall be kept dry. Lighting shall be used to support the checking.
已经建立目视检查SOP。在清洗后的拆卸设备或部件中，没有肉眼可见的产品残留，设备应该保持干燥。检查过程中，可用灯照辅助检查。
10.2 Active pharmaceutical ingredient residues活性成分残留
10.2.1 Principles原理
When calculating the residue limit for the target residue to be inspected, use the maximum residue limit as the control limit.
在计算残留检测目标