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PID20清洁验证报告（2车间）（第二周期）
PID20 Cleaning Validation Report (Workshop 2) (Second Cycle)

报告编号 Report Number	LHVR-649-C-14.00
执行日期 Execution date	{Eff.Date}
报告依据 The report is based on	LHVP-649-C-05.00
车间名称 Workshop Name	2车间 Workshop 2

浙江瑞博
Zhejiang Ruibo

ZHEJIANG RAYBOW

目录contents
Table of Contents

1. 背景介绍Background 3
Background Introduction Background 3

2. 目的Purpose 3
Purpose

3. 范围Scope 3
Scope 3

4. 描述Description 3
Description 3

4.1 清洗剂Cleaning Agent 3
4.1 Cleaning Agent 3

4.2 清洗概述Cleaning Introduction 3
4.2 Cleaning Overview 3

5. 责任者Person Responsibility 4
5. Person Responsible for Responsibility 4

6. 风险评估Risk Assessment 5
6. Risk Assessment 5

6.1 PID20S生产设备PID20 products need to be cleaned to validate the product equipment 5
6.1 PID20S production equipment PID20 products need to be cleaned to validate the product equipment 5

6.2 风险识别 Risk Identification 8
6.2 Risk Identification 8

6.3 分析流程Analysis Process 8
6.3 Analysis Process 8

6.4 风险分数评估Assessment of Risk Score 9
6.4 Risk Score Assessment

6.5 风险评估Risk Assessment 10
6.5 Risk Assessment 10

6.6 取样设备汇总Sampling Equipment 14
6.6 Sampling Equipment Summary 14

7. 清洗后检查Checking after Cleaning 15
7. Checking after Cleaning 15

7.1 取样流程Sampling Process 15
7.1 Sampling Process 15

7.2 目测检查Visual Inspection 15
7.2 Visual Inspection 15

7.3 化学擦拭取样Chemical Swab Sampling 15
7.3 Chemical Swab Sampling 15

7.4 淋洗液取样Rinse Sampling 17
7.4 Rinse Sampling 17

8. 残留限度确定原则Principle of Residue Limit 18
8. Principle of Residue Limit Determination

8.1 擦拭残留限度确定原则Principle of Swap Residue Limit 19
Principle of Swap Residue Limit 19

8.2 擦拭取样限度Limit of Swab 20
8.2 Swab Sampling Limit Limit of Swab 20

8.3 淋洗取样限度Limit of Rinse 20
8.3 Rinse Sampling Limit Limit of Rinse 20

8.4 允许残留限度汇总Residue Limit Summary 20
8.4 Residue Limit Summary 20

9. 残留测定方法Testing Procedure of Chemical Residual 21
9. Testing Procedure of Chemical Residual 21

9.1 PID20残留测定方法Testing Procedure of PID20 21
9.1 PID20 Residue Testing Method Testing Procedure of PID20 21

9.2 清洗检测方法适用性评估Assessment of Test Method 24
9.2 Applicability Assessment of Cleaning Test Methods Assessment of Test Method 24

10. 设备空置时间和清洗有效期考察Study of DHT and CHT 24
Study of DHT and CHT 24

10.1 设备空置时间考察Study of DHT 24
10.1 Study of DHT 24 Equipment Idle Time

10.2 清洗有效期考察Study of CHT 25
10.2 Cleaning Validity Period Study of CHT 25

10.3 连续生产周期考察Study of Continuous Production Period 25
10.3 Study of Continuous Production Period 25

11. 确认操作和测定结果Results 25
Confirm operation and measurement results Results 25

12. 变更/偏差Change /Deviation 27
12. Change /Deviation 27

12.1 变更Change 27
12.1 Change 27

12.2 偏差Deviation 27
12.2 Deviation 27

13. 总结SUMMARY 27
13. Summary SUMMARY 27

14. 相关文件Relevant Document 27
Relevant Document 27

15. 附件AnnexPID20 ICH M7报告 28
15. Annex PID20 ICH M7 Report 28

1. 背景介绍
Background Introduction

浙江瑞博制药有限公司2车间025生产区域设备用于PID20产品的生产。生产结束后，设备按照制定的清洗操作规程进行清洗，为了防止产品之间的交叉污染验证清洗的有效性，需要在清洗完成之后进行清洗验证。
The equipment in the production area 025 of Workshop 2 at Zhejiang Ruibo Pharmaceutical Co., Ltd. is used for the production of PID20 products. After production, the equipment is cleaned according to the established cleaning procedures. To verify the effectiveness of cleaning and prevent cross-contamination between products, cleaning validation is required after the cleaning process is completed.

2. 目的
2. Purpose

通过本次清洗验证，旨在证明：在生产完成PID20相关生产设备在生产一定时间后或更换为其它产品生产之前，采用清洗SOP制定的清洗方法，对生产中接触到PID20的设备和管道进行彻底清洁，保证在其它产品生产中，不会因设备清洗不完全，造成PID20污染到其它产品的风险，达到预防交叉污染的目的。
Through this cleaning validation, the aim is to demonstrate that after the production of PID20-related equipment has been completed for a certain period or before switching to the production of other products, the cleaning method specified in the cleaning SOP is used to thoroughly clean the equipment and pipelines that have come into contact with PID20 during production. This ensures that in the production of other products, there is no risk of PID20 contaminating other products due to incomplete equipment cleaning, thereby achieving the purpose of preventing cross-contamination.

3. 范围
3. Scope

本报告适用于2车间PID20生产之后的产品生产设备、容器和工具等的清洗验证。
This report is applicable to the cleaning validation of production equipment, containers, and tools used after the production of PID20 in Workshop 2.

4. 描述
4. Description

4.1 清洗剂
4.1 Detergent

产品溶解度如下：
Product solubility is as follows:

产品名称 Product Name	清洗溶剂 Cleaning solvent	溶解度 Solubility
PID20	甲醇 Methanol	易溶（＞100 g/100 mL， 25 ℃） Soluble (＞100 g/100 mL, 25 ℃)
PID20		乙醇 Ethanol	易溶（＞100 g/100 mL， 25 ℃） Soluble (＞100 g/100 mL, 25 ℃)

小结：由上表可知，目标检测物，PID20可溶于甲醇，且甲醇价格低于乙醇，因此溶剂清洗可选择甲醇作为清洗溶剂。
Summary: From the table above, it can be seen that the target detection substance, PID20, is soluble in methanol, and the price of methanol is lower than that of ethanol. Therefore, methanol can be chosen as the cleaning solvent.

4.2 清洗概述
4.2 Cleaning Overview

详见PID20清洗规程（2车间） LHPC-649-02。.
Refer to PID20 Cleaning Procedure (Workshop 2) LHPC-649-02.

5. 责任者
5. Responsible Party

姓名 Name	职务 Position	验证实施分工 Verification Implementation Division of Labor
向玉婷 Xiang Yuting	QA	编制清洁验证方案和报告，负责收集检测数据 Develop cleaning validation protocols and reports, responsible for collecting testing data
金增波 Jin Zengbo	生产车间主任 Production Workshop Supervisor	负责生产设备清洁方法的建立，组织车间职工进行设备清洗，并对清洁现场进行管理。 Responsible for establishing cleaning methods for production equipment, organizing workshop staff to clean the equipment, and managing the cleaning site.
肖庭波 Xiao Tingbo	QC经理 QC Manager	审核验证清洁方案和报告，组织样品的接收和测定 Review and verify cleaning protocols and reports, organize the reception and determination of samples
胡小兰 Hu Xiaolan	QA经理 QA Manager	审核验证清洁方案和报告 Review and verify cleaning plans and reports
易根龙 Yi Genlong	质量负责人 Quality Manager	批准验证清洁方案和报告 Approve validation cleaning plan and report

6. 风险评估
6. Risk Assessment

6.1 PID20生产设备
6.1 PID20 Production Equipment

设备编号 Equipment number	设备名称 Device name	规格型号 Specifications and Models	材质 Material	设备内表面积 Internal surface area of the equipment	主要接触物料 Mainly in contact with materials	用途 Purpose	清洗评估 Cleaning Evaluation
R02-402	反应罐 Reaction vessel	8000 L	搪玻璃 Enameled glass	27.6	硫酸二甲酯、PID20、三乙胺、甲苯、生活饮用水、碳酸氢钠、氯化钠 Dimethyl sulfate, PID20, triethylamine, toluene, domestic drinking water, sodium bicarbonate, sodium chloride	配料、分层 Ingredients, Layering	1）碳酸氢钠、氯化钠溶于水，通过大量水冲洗能有效去除残留；故不作为目标物进行考察。 1) Sodium bicarbonate and sodium chloride dissolve in water, and residues can be effectively removed by rinsing with a large amount of water; therefore, they are not considered as target substances for investigation. 2）三乙胺、甲苯与甲醇互溶，通过大量水冲洗、甲醇回流清洗后能够有效去除，故不作为目标考察物； 2) Triethylamine, toluene, and methanol are mutually soluble and can be effectively removed through extensive water rinsing and methanol reflux cleaning, thus they are not considered as target analytes; 3）硫酸二甲酯容易水解成硫酸和甲醇，通过大量水冲洗、烘干能有效去除残留；故不作为目标物进行考察； 3) Dimethyl sulfate is easily hydrolyzed into sulfuric acid and methanol, and residual amounts can be effectively removed by thorough rinsing with water and drying; therefore, it is not considered as a target for investigation; 4）PID20作为最后的产物，在该设备的残留风险是最大的，故本设备选择PID20作为清洁验证考察物。 PID20, as the final product, poses the greatest residual risk in this equipment, hence it has been selected as the cleaning validation test article for this device.
R02-403	反应罐 Reaction vessel	5000 L	搪玻璃 Enameled glass	21.1	硫酸二甲酯、PID20、三乙胺、甲苯、生活饮用水、碳酸氢钠、氯化钠 Dimethyl sulfate, PID20, triethylamine, toluene, domestic drinking water, sodium bicarbonate, sodium chloride	分层 stratification
R02-404	反应罐 Reaction vessel	8000 L	304	27.6	PID20 、生活饮用水 PID20, Drinking Water	接收料液 Receive feed liquid	PID20作为最后的产物，在该设备的残留风险是最大的，但PID20工序与PID50工序共用反应罐(R02-404)，且反应罐(R02-404)在PID20工序中主要用于接收PID20，反应罐(R02-404)在PID50工序中为主反应釜，用于PID20、PID40反应，故在PID20工序不对反应罐(R02-404)进行清洗，在PID50工序进行清洗并取样检测。 PID20, as the final product, has the highest residual risk in this device. However, the PID20 process shares the reaction vessel (R02-404) with the PID50 process. The reaction vessel (R02-404) is mainly used to receive PID20 in the PID20 process and serves as the main reactor in the PID50 process for the reactions of PID20 and PID40. Therefore, the reaction vessel (R02-404) is not cleaned during the PID20 process but is cleaned and sampled for testing during the PID50 process.
R02-408	反应罐 Reaction vessel	3000 L	衬四氟 PTFE-lined	15.4	L-焦谷氨酸甲酯（PID10）、硫酸二甲酯、PID20 L-Pyroglutamic acid methyl ester (PID10), dimethyl sulfate, PID20	反应 reaction	1）PID10作为PID20的原料，在反应过程中通过中控控制原料PID10残留；通过产后清洗可以认为原料的残留极其微量，故不作为目标物进行考察。 1) PID10, as the raw material for PID20, is controlled for residual content during the reaction process through central control; post-production cleaning ensures that the residual amount of the raw material is extremely minimal, thus it is not considered as a target for investigation. 2）三乙胺、甲苯溶于甲醇，通过大量水冲洗、吹干能有效去除残留；故不作为目标物进行考察； 2) Triethylamine and toluene dissolved in methanol can be effectively removed by washing with a large amount of water and drying; therefore, they are not considered as target substances for investigation 3）硫酸二甲酯下容易水解成硫酸和甲醇，通过大量水冲洗后烘干能有效去除残留；故不作为目标物进行考察； 3) Dimethyl sulfate is easily hydrolyzed into sulfuric acid and methanol, and effective removal of residues can be achieved by rinsing with a large amount of water followed by drying; therefore, it is not considered as a target for investigation; 4）PID20作为最后的产物，在该设备的残留风险是最大的，故本设备选择PID20作为清洁验证考察物 4) PID20, as the final product, poses the greatest residual risk in this equipment, hence PID20 is selected as the subject for cleaning validation in this device
R02-409	反应罐 Reaction vessel	3000 L	搪玻璃 Enameled glass	15.4	硫酸二甲酯、PID20、三乙胺、甲苯 Dimethyl sulfate, PID20, triethylamine, toluene	蒸馏 Distillation
R02-407	反应罐 Reaction vessel	2000 L	搪玻璃 Enameled glass	12.6	生活饮用水、碳酸氢钠、氯化钠 Drinking water, sodium bicarbonate, sodium chloride	配料 Ingredients	碳酸氢钠、氯化钠溶于水，通过大量水冲洗后烘干能有效去除残留；故不作为目标物进行考察。 Sodium bicarbonate and sodium chloride dissolve in water, and effective removal of residues can be achieved by rinsing with a large amount of water followed by drying; therefore, they are not considered as target substances for investigation.
V02-346	接收罐 Receiving tank	6000 L	304	20.96	甲苯 Toluene Toluene	接收馏分 Receive distillate	甲苯溶于甲醇，通过大量水冲洗、吹干能有效去除残留；故不作为目标物进行考察； Toluene is soluble in methanol, and residual amounts can be effectively removed by rinsing with a large amount of water and drying; therefore, it is not considered as a target for investigation
V02-408	接收罐 Receiving tank	1000 L	304	7.8	PID20	接收料液 Receive feed liquid	PID20作为最后的产物，在该设备的残留风险是最大的，故本设备选择PID20作为清洁验证考察物。 PID20, as the final product, has the highest residual risk in this equipment, therefore PID20 is selected as the subject for cleaning validation in this device.
V02-417	储罐 Storage tank	1000 L	搪玻璃 Enameled glass	7.8	硫酸二甲酯 Dimethyl sulfate	滴加 Add drop by drop	1）硫酸二甲酯容易水解成硫酸和甲醇，通过大量水冲洗后烘干能有效去除残留；故不作为目标物进行考察。 1) Dimethyl sulfate is easily hydrolyzed into sulfuric acid and methanol, and effective removal of residues can be achieved by rinsing with a large amount of water followed by drying; therefore, it is not considered as a target for investigation. 2）碳酸氢钠、氯化钠溶于水，通过大量水冲洗、吹干能有效去除残留；故不作为目标物进行考察。 2) Sodium bicarbonate and sodium chloride dissolve in water, and residual substances can be effectively removed by rinsing with a large amount of water and drying; therefore, they are not considered as target substances for investigation.
X02-422	手套箱 Glove box	1200700850	304	5.23	氯化钠、碳酸氢钠 Sodium chloride, sodium bicarbonate	投料 Feeding

6.2 风险识别
6.2 Risk Identification

多产品共线生产中产生危害的原因主要从人、机、物、法、环几个角度来分析，参照下面鱼骨图进行风险识别：
The causes of hazards in multi-product co-line production are mainly analyzed from the perspectives of people, machines, materials, methods, and environment. Refer to the fishbone diagram below for risk identification:

6.3 分析流程Analysis Process
6.3 Analysis Process

A. 确定研究对象：即PID20产品清洗工序的可能的残留物及检测项目。
A. Identify the research subject: possible residues and detection items in the cleaning process of PID20 product.

B. 采用头脑风暴、经验、数据、鱼骨图等列出可能失败的偏差及影响。
B. Use brainstorming, experience, data, fishbone diagrams, etc., to list potential failure deviations and their impacts.

C. 设计评估（打分）：严重性、发生可能性、可发现能力。
C. Design Evaluation (Scoring): Severity, Likelihood of Occurrence, Detectability.

等级 Level	严重性 Severity	风险发生可能性 Risk occurrence possibility	风险的可发现能力 Risk discoverability
等级 Level		发生质量风险后对产品安全性的影响程度 The extent of impact on product safety after a quality risk occurs	发生偏差或缺陷等风险的可能性 The possibility of risks such as deviations or defects	风险发生及有发生趋势时发现的可能性 Possibility of detecting when risks occur or have a tendency to occur
高	清洗前产品的残留对下一批产品的安全性有严重影响，必须严格控制才能保证下一批产品的质量。 Residues from the previous product have a significant impact on the safety of the next batch, and strict control is necessary to ensure the quality of the subsequent product..	物料在溶剂中不溶或者设备很难清洗，很容易造成上一批产品的残留。 The material is insoluble in the solvent or the equipment is difficult to clean, which can easily lead to residue from the previous batch of products.	物料有残留时不能通过目测或者丝光毛巾擦拭发现。 Residual material cannot be detected by visual inspection or wiping with a mercerized towel.
中	清洗前产品的残留对下一批产品的安全性可能有影响，不严格控制可能会影响下一批产品的质量。 Residues from the product before cleaning may affect the safety of the next batch, and lack of strict control could impact the quality of the next batch.	经过清洗后物料有可能会还有残留。. After cleaning, there may still be residues in the material.	物料有残留时比较难以发现 Residual materials are relatively difficult to detect
低	清洗前产品的残留对下一批产品的安全性影响很小或者没有影响。 The residue of the product before cleaning has little or no impact on the safety of the next batch of products.	物料在溶剂中极易溶解，设备很容易清洗干净，物料残留风险极低。 The material is very soluble in the solvent, the equipment is easy to clean, and the risk of material residue is extremely low.	清洗后一目了然，很容易通过目测发现是否还有物料残留。 After cleaning, it is clear at a glance and easy to visually detect whether any material residue remains.

算出风险指数：RPN=严重性×发生可能性×可发现能力
Calculate the risk index: RPN=Severity × Probability of Occurrence × Detectability

制订行动计划来降低风险，再评估该风险是否可以接受。
Develop an action plan to reduce the risk, then reassess whether the risk is acceptable.

6.4 风险分数评估
6.4 Risk Score Assessment

评估方法：对于总风险分数(RPN)的估计，需要计算风险优先权分数。O栏是评估潜在失败的发生的可能性。 C栏是评估潜在的故障的后果严重程度。D栏是风险发生及有发生趋势时发现的可能性，通过风险值制订行动计划来降低风险。
Evaluation method: To estimate the overall risk score (RPN), it is necessary to calculate the risk priority number. Column O assesses the likelihood of potential failure occurrence. Column C evaluates the severity of the consequences of potential failures. Column D assesses the likelihood of detecting the risk when it occurs or has a tendency to occur, and an action plan is developed to reduce the risk based on the risk value.

C		O		D		Risk priority number (Total risk figure)		是否可接受 Is it acceptable?
严重性 Severity		发生可能性 Probability of occurrence		可发现能力 Discoverability		RPN(总分数 RPN (Total Score))
Points	Explanation	Points	Explanation	Points	Explanation	Points	Explanation
1	低	1	w低 w low	1	低	1-4	次要的 Secondary	目检 Visual inspection
2	中	2	中	2	中	6-9	主要的 main	目检+擦拭取样或者淋洗液取样 Visual inspection + wiping sampling or rinse sampling
3	高	3	高	3	高	12-27	关键的 crucial	需采取措施（如改变清洗方法），降低风险 Measures need to be taken (such as changing cleaning methods) to reduce risks

备注：本文中“目检”是指目视检查+丝光毛巾擦拭。
Note: In this article, "visual inspection" refers to visual examination + wiping with a mercerized towel.

6.5 风险评估
6.5 Risk Assessment

6.5.1 PID20设备风险评估
6.5.1 PID20 Equipment Risk Assessment

设备/部件 Equipment/Components			风险评估 Risk Assessment							确认采取的措施 Confirm the measures taken
编号 Serial number	设备 Equipment	部件名称 Part Name	清洗方法 Cleaning method	可能发生的偏差及其影响 Possible deviations and their impacts	O 失败风险的可能性 The possibility of failure risk	C 严重 Severe	D 可发现能力 Discoverability	RPN	风险等级 Risk Level	确认采取的措施 Confirm the measures taken
	反应罐 Reaction vessel	人孔口内侧（搅拌轴顶端附近） Inside the manhole (near the top of the mixing shaft)	1）水冲洗； 1) Rinse with water; 2）溶剂回流清洗； 2) Solvent reflux cleaning; 3）水冲洗； 3) Water rinse; 4）特殊部位拆洗； 4) Special parts disassembly and cleaning; 5）水冲洗； 5) Water rinse; 6）沥干、烘干或吹干设备。 Draining, drying, or blow-drying equipment.	清洗溶剂不容易浸泡到，可能导致残留。 Cleaning solvent is not easy to soak in, which may lead to residue.	2	3	1	6	主要的 main	1）目视检查 Visual inspection 2）擦拭取样测PID20残留 2) Wipe sampling to measure PID20 residue
					内壁 Inner wall		设备内壁光滑无死角，容易被清洗干净。但内壁面积大，残留多。 The inner wall of the equipment is smooth and free of dead angles, making it easy to clean thoroughly. However, the large surface area of the inner wall results in more residue.	2	3	1	6	主要的 main	1）目视检查 Visual inspection 2）淋洗取样测PID20残留 2) Rinse sampling to measure PID20 residue
					搅拌轴 Stirring shaft 搅拌桨 Stirring paddle		搅拌轴与搅拌桨连接处不易清洗干净，可能导致残留。 The connection between the stirring shaft and the stirring paddle is difficult to clean thoroughly, which may lead to residue.	2	3	1	6	主要的 main	很难进行擦拭取样，但可通过目视检查+溶剂淋洗取样测PID20残留来考察 It is difficult to perform wipe sampling, but visual inspection + solvent rinse sampling to measure PID20 residues can be used for evaluation
					出料口 Discharge port （阀门附近） (Near the valve)		出料口阀门附近存在转角不易清洁，可能导致残留。 There is a corner near the discharge valve that is difficult to clean, which may lead to residue.	2	3	1	6	主要的 main	1）目视检查 Visual inspection 2）淋洗取样测PID20残留 2) Rinse sampling to measure PID20 residue
					真空口、放空口等管口处 Vacuum port, vent port, and other pipe openings		清洗过程中会将相关管口阀门拆除清洗 During the cleaning process, the relevant pipe port valves will be removed for cleaning	1	3	1	3	次要的 Secondary	目视检查 Visual inspection
	反应罐 Reaction vessel R02-407	人孔口内侧（搅拌轴顶端附近） Inside the manhole (near the top of the mixing shaft)	1）水冲洗； 1) Rinse with water; 2）沥干、烘干或吹干设备。 2) Drain, dry, or blow-dry equipment.	设备在生产工序中不接触PID20，仅接触碳酸氢钠、氯化钠，碳酸氢钠、氯化钠易溶于水容易去除，风险低 The equipment does not come into contact with PID20 during the production process, only with sodium bicarbonate and sodium chloride, which are easily soluble in water and easy to remove, presenting a low risk	1	2	1	2	次要的 Secondary	目视检查 Visual inspection
						内壁 Inner wall			1	2	1	2	次要的 Secondary	目视检查 Visual inspection.
						搅拌轴 Stirring shaft 搅拌桨 Stirring paddle			1	2	1	2	次要的 Secondary	目视检查 Visual inspection
						出料口 Discharge port （阀门附近） (Near the valve)			1	2	1	2	次要的 Secondary	目视检查 Visual inspection
						真空口、放空口等管口处 Vacuum port, vent port, and other pipe openings			1	2	1	2	次要的 Secondary	目视检查 Visual inspection
	接收罐 Receiving tank V02-408	内壁 Inner wall	水循环； Water cycle; 2）溶剂循环； 2) Solvent circulation; 3）水循环； 3) Water cycle; 4）特殊部位拆洗； 4) Special parts disassembly and cleaning; 5）水循环 5) Water Cycle 6）沥干或吹干、复位。 6) Drain or blow dry, then reset.	储罐结构比较简单，易于清洗，接触PID20物料，需进行淋洗取样测PID20。 The tank structure is relatively simple and easy to clean. Since it comes into contact with PID20 material, it requires rinsing and sampling to measure PID20.	2	3	1	6	主要的 main	1）目视检查 Visual inspection 2）淋洗取样测PID20残留 2) Rinse sampling to measure PID20 residue
	接收罐 Receiving tank V02-346	内壁 Inner wall	1）水循环； 1) Water cycle; 2）溶剂循环； 2) Solvent circulation; 3）水循环； 3) Water cycle; 4）特殊部位拆洗； 4) Special parts disassembly and cleaning; 5）水循环 5) Water Cycle 6）沥干或吹干、复位。 6) Drain or blow dry, then reset.	储罐结构比较简单，易于清洗，甲苯溶于甲醇，通过大量水冲洗、吹干能有效去除残留； The tank structure is relatively simple and easy to clean. Toluene is soluble in methanol, and residual substances can be effectively removed by extensive water rinsing and drying	1	3	1	3	次要的 Secondary	目视检查 Visual inspection
	储罐 Storage tank V02-417	内壁 Inner wall	水循环； Water cycle; 2）溶剂浸泡； 2) Solvent soaking; 3）特殊部位拆洗 3) Special parts disassembly and cleaning 4）水循环； 4) Water cycle; 5）沥干或吹干设备。 5) Drain or blow-dry equipment.	储罐未接触产品，结构简单，易于清洗，且仅接触硫酸二甲酯，硫酸二甲酯容易水解，易于清除。 The tank does not come into contact with the product, has a simple structure, is easy to clean, and only contacts dimethyl sulfate, which is easily hydrolyzed and simple to remove.	1	3	1	3	次要的 Secondary	目视检查. Visual inspection.
	手套箱 Glove box X02-422	内壁 Inner wall	水冲洗； Water rinse; 2）溶剂擦洗 2) Solvent scrubbing 3）水冲洗； 3) Water rinse; 4）沥干或吹干。 Drain or blow dry.	手套箱内外表面平滑易清洗，采用溶剂擦洗和水洗以及拆洗方式进行清洗就可以达到生产要求，目视检查无残留物即可。 The inner and outer surfaces of the glove box are smooth and easy to clean. Solvent wiping, water washing, and disassembly cleaning methods can meet production requirements. Visual inspection should confirm no residue is left.	1	2	1	2	次要的 Secondary	目视检查 Visual inspection
												手套 gloves
												投料口 Feed inlet

PID20产品生产结束之后或更换其他产品之前要进行清洗，清洗结束之后需对所有设备进行目视检查，目视检查合格再对生产接触到产品的设备进行化学残留检测。
After the production of PID20 product is completed or before switching to other products, cleaning must be performed. After cleaning, a visual inspection of all equipment is required. If the visual inspection is passed, a chemical residue test must be conducted on the equipment that comes into contact with the product during production.

PID20使用甲醇清洗，清洗之后会用大量水冲洗除去溶剂，并对设备进行烘干、沥干或吹干，不需要进行溶剂残留的检测。
PID20 uses methanol for cleaning, followed by a thorough rinse with water to remove the solvent. The equipment is then dried, drained, or blown dry, and no solvent residue testing is required.

6.6 取样设备汇总
6.6 Summary of Sampling Equipment

PID20工序 PID20 process							备注 Remarks
编号 Serial number	设备名称 Device name	材质 Material	规格型号 Specifications and Models	设备内表面积 Internal surface area of the equipment （包括管路、工具）(m² (including pipelines, tools) (m ² )	擦拭取样 Wipe sampling	淋洗取样 Rinse sampling	备注 Remarks
R02-402	反应罐 Reaction vessel	搪玻璃 Enameled glass	8000 L	27.6	√	√	考察PID20 Inspect PID20
R02-403	反应罐 Reaction vessel	搪玻璃 Enameled glass	5000 L	21.1	√	√
R02-404	反应罐 Reaction vessel	304	8000 L	27.6	×	×
R02-407	反应罐 Reaction vessel	搪玻璃 Enameled glass	2000 L	12.6	×	×
R02-408	反应罐 Reaction vessel	衬四氟 PTFE-lined	3000 L	15.4	√	√
R02-409	反应罐 Reaction vessel	搪玻璃 Enameled glass	3000 L	15.4	√	√
V02-346	接收罐 Receiving tank	304	6000 L	20.96	×	×
V02-408	接收罐 Receiving tank	304	1000 L	7.8	×	√
V02-417	储罐 Storage tank	搪玻璃 Enameled glass	1000 L	7.8	×	×
X02-422	手套箱 Glove box	304	1200700850	5.23	×	×
管道及软管 Pipes and hoses		衬四氟 PTFE-lined	N/A	4.88	×	√
PID20接触设备总内表面积 Total internal surface area of PID20 contact equipment				92.18

说明：
Instructions:

1）“√”表示属于本清洁验证方案中的取样计划，“×”表示不属于本清洁验证方案中的取样计划。
1) "√" indicates that it is part of the sampling plan in this cleaning validation protocol, "×" indicates that it is not part of the sampling plan in this cleaning validation protocol.

2）PID20与PID50共用反应罐（R02-404），且反应罐（R02-404）在PID20工序中主要用于接收PID20，反应罐（R02-404）在PID50工序中为主反应釜，用于PID20、PID40反应，故在PID20工序不对反应罐（R02-404）进行清洗，在PID50工序进行清洗并取样检测。
PID20 and PID50 share the reaction tank (R02-404), and the reaction tank (R02-404) is mainly used to receive PID20 in the PID20 process. In the PID50 process, the reaction tank (R02-404) serves as the main reactor for the reaction of PID20 and PID40. Therefore, the reaction tank (R02-404) is not cleaned in the PID20 process, but is cleaned and sampled for testing in the PID50 process.

7. 清洗后检查
7. Post-cleaning inspection

7.1 取样流程
7.1 Sampling Process

生产停止
Production stopped

↓

设备空置
Equipment idle

↓

按照清洗SOP清洗
Clean according to the cleaning SOP

↓

目检
Visual Inspection

↓

化学擦拭取样
Chemical Wipe Sampling

↓

溶剂淋洗取样（检测化学残留）
Solvent rinse sampling (detecting chemical residues)

↓

水冲洗（除去淋洗溶剂）
Water rinse (to remove the rinse solvent)

备注：本流程中“目检”是指目视检查+丝光毛巾擦拭。
Note: In this process, "visual inspection" refers to visual examination + wiping with a mercerized towel.

7.2 目测检查
7.2 Visual Inspection

1）目测检查
Visual inspection

内外清洁干燥，无可见物料。
Clean and dry inside and out, with no visible material.

2）丝光毛巾擦拭检查
2) Inspect with a mercerized towel

丝光毛巾上无物料痕迹。
No material traces on the mercerized towel.

7.3 化学擦拭取样
7.3 Chemical Wipe Sampling

7.3.1 擦拭方法Swab Method
7.3.1 Swab Method

7.3.1.1 规则平面
7.3.1.1 Regular Plane

如取样位置为规则平整的表面，并大于擦拭取样面积（10 cm×10 cm）。则QA用棉签醮取少量清洗溶剂，在设备或容器选取100 cm²（长10 cm的正方形）内表面。手持棉签将棉签头的一面平整的压在设备表面上，按下图1擦拭方式平稳而缓慢地擦拭取样表面，擦拭力度以控制棉签头一面始终接触设备表面而棉签略微弯曲为宜，如图3。棉签向前擦拭移动的同时将其从一边移动到另一边，擦拭过程应覆盖整个选定的取样面积（10 cm×10 cm）。翻转棉签，让棉签另一面按照上述方法擦拭一遍。
If the sampling location is a regular and flat surface and larger than the swabbing sampling area (10 cm × 10 cm), the QA should use a cotton swab dipped in a small amount of cleaning solvent to swab a 100 cm² (10 cm × 10 cm square) inner surface of the equipment or container. Hold the cotton swab and press one side of the swab head flat against the equipment surface. Swab the sampling surface smoothly and slowly as shown in Figure 1, with the force controlled so that one side of the swab head remains in contact with the equipment surface while the swab is slightly bent, as shown in Figure 3. While moving the swab forward, also move it from one side to the other, ensuring the entire selected sampling area (10 cm × 10 cm) is covered. Flip the swab and repeat the process with the other side using the same method.

第一根棉签擦拭完成，取第二根棉签以图2擦拭方向（擦拭方向与图1垂直）按照上述方法擦拭。
The first cotton swab wipe is completed. Take the second cotton swab and wipe in the direction shown in Figure 2 (the wiping direction is perpendicular to Figure 1) following the method described above.

一个取样点擦拭结束，将2根采样后棉签装入玻璃试管或玻璃瓶中，密塞，贴上注明有设备编号、取样点编号和日期的标签，供测试分析擦拭取样棉签中目标残留物的残留量。
After completing the swabbing of a sampling point, place the two used swabs into a glass test tube or glass bottle, seal it tightly, and attach a label indicating the equipment number, sampling point number, and date for testing and analysis of the target residue on the swabs.

图1 擦拭取样方式一图2 擦拭取样方式二图3 棉签擦拭示意图
Figure 1 Wiping Sampling Method One Figure 2 Wiping Sampling Method Two Figure 3 Schematic Diagram of Cotton Swab Wiping

7.3.1.2 不规则平面
7.3.1.2 Irregular Plane

取样点的取样位置为不规则平面，则擦拭时只需要保证最终擦拭面积总和等于100 cm²即可（例如擦拭面积可以是5 cm×20 cm、4 cm×25 cm或6 cm×6 cm+8 cm×8 cm等。擦拭方案仍然用2个棉签按照图1~2分别擦拭后将采样的棉签装入玻璃试管或玻璃瓶中，密塞，贴上注明有设备编号、取样点编号和日期的标签，供测试分析擦拭取样棉签中目标物的残留量。
The sampling location at the sampling point is an irregular plane, so during wiping, it is only necessary to ensure that the total wiping area equals 100 cm² (for example, the wiping area could be 5 cm × 20 cm, 4 cm × 25 cm, or 6 cm × 6 cm + 8 cm × 8 cm, etc.). The wiping procedure still involves using two cotton swipes as shown in Figures 1~2, then placing the sampled cotton swipes into a glass test tube or glass bottle, sealing it tightly, and attaching a label with the equipment number, sampling point number, and date for testing and analyzing the residual amount of the target substance in the sampled cotton swipes.

7.3.2 回收率评估
7.3.2 Recovery Rate Assessment

1）PID20生产过程中物料直接接触的设备表面种类包括：搪玻璃、不锈钢、衬四氟。聚四氟乙烯（垫圈）、硅橡胶（垫圈），应综合考虑上述材质的擦拭回收率和淋洗回收率。
1) The types of equipment surfaces in direct contact with materials during the PID20 production process include: glass-lined, stainless steel, and PTFE-lined. Polytetrafluoroethylene (gaskets) and silicone rubber (gaskets) should be considered comprehensively for their wipe recovery rate and rinse recovery rate.

a. 垫圈（硅橡胶）处于管道连接之间，在淋洗液取样时，淋洗液已经通过管道包括垫圈，最终检测淋洗液中的残留。对于垫圈，我们实际上进行的是淋洗液取样而非擦拭取样；
a. The gasket (silicone rubber) is located between the pipe connections. During the eluent sampling, the eluent has passed through the pipe including the gasket, and finally, the residue in the eluent is detected. For the gasket, we actually perform eluent sampling rather than swab sampling.

b. 垫圈（聚四氟乙烯）紧固在管道法兰连接之间，不易进行擦拭取样。且垫圈接触面很小，不具备较大接触面以方便进行擦拭回收率的操作条件；
b. The gasket (polytetrafluoroethylene) is tightly secured between the pipe flange connections, making it difficult to perform wipe sampling. Additionally, the contact surface of the gasket is very small, lacking a larger contact area to facilitate the conditions for wipe recovery rate operations.

c. 因此将对PID20进行搪玻璃、衬四氟的擦拭回收率试验以及搪玻璃、不锈钢、衬四氟的淋洗回收率试验；
Therefore, the wiping recovery rate test for PID20 with glass-lined and PTFE-lined surfaces, as well as the rinse recovery rate test for glass-lined, stainless steel, and PTFE-lined surfaces, will be conducted.

综上：
In summary:

目标物 Target object	需做擦拭回收率的材质 Materials requiring wipe recovery rate	需做淋洗回收率试验的材质 Materials requiring leaching recovery rate testing
PID20	搪玻璃、衬四氟 Glass-lined, PTFE-lined	搪玻璃、不锈钢、衬四氟 Enameled glass, stainless steel, PTFE-lined

7.3.3 PID20设备擦拭取样点清单
7.33 PID20 Equipment Wipe Sampling Point List

设备名称 Device name	材质 Material	擦拭取样位置 Wipe the sampling location	取样点编号 Sampling point number	检测项目 Inspection item
反应罐 Reaction vessel （R02-402） (R02-402)	搪玻璃 Enameled glass	人孔口内侧（搅拌轴顶端附近） Inside the manhole (near the top of the mixing shaft)	R02-402-X₁	PID20
反应罐 Reaction vessel （R02-403） (R02-403)	搪玻璃 Enameled glass	人孔口内侧（搅拌轴顶端附近） Inside the manhole (near the top of the mixing shaft)	R02-403-X₁
反应罐 Reaction vessel （R02-408） (R02-408)	衬四氟 PTFE-lined	人孔口内侧（搅拌轴顶端附近） Inside the manhole (near the top of the mixing shaft)	R02-408-X₁
反应罐 Reaction vessel （R02-409） (R02-409)	搪玻璃 Enameled glass	人孔口内侧（搅拌轴顶端附近） Inside the manhole (near the top of the mixing shaft)	R02-409-X₁

7.4 淋洗液取样g
Wash solution sampling g

7.4.1 PID20取样流程
7.4.1 PID20 Sampling Process

PID20淋洗线路：
PID20 Rinse Circuit

淋洗线路：
Rinse circuit:

向反应罐(R02-408)加入甲醇800±20 L，开启搅拌并升温至回流，回流搅拌1~2小时，回流结束；将反应罐(R02-408)内的清洗液全部转移至反应罐(R02-402)；
Add 800±20 L of methanol to the reaction vessel (R02408), start stirring and heat to reflux, stir under reflux for 1~2 hours, end the reflux; transfer all the cleaning solution from the reaction vessel (R02408) to the reaction vessel (R02402)

开启反应罐(R02-402)搅拌并升温至回流，回流搅拌1~2小时，回流结束；将反应罐(R02-402)内的清洗液全部转移至反应罐(R02-403)；
Start the stirring of the reaction vessel (R02402) and heat to reflux, stir under reflux for 1~2 hours, then end the reflux; transfer all the cleaning solution from the reaction vessel (R02402) to the reaction vessel (R02403)

开启反应罐(R02-403)搅拌并升温至回流，回流搅拌1~2小时，回流结束，将反应罐(R02-403)内全部的清洗液转移至反应罐(R02-402)；
Start the stirring of the reactor (R02403) and heat it to reflux. Stir under reflux for 1~2 hours. After the reflux ends, transfer all the cleaning solution in the reactor (R02403) to the reactor (R02402)

通过反应罐(R02-402)将全部清洗液转移至反应罐(R02-409)；
Transfer all the cleaning liquid to the reaction tank (R02409) via the reaction tank (R02402)

开启反应罐(R02-409)搅拌并升温至回流，回流搅拌1~2小时，回流结束；将反应罐(R02-409)的全部清洗液转移至接收罐(V02-408)；
Start the reaction vessel (R02409), stir and heat to reflux, reflux and stir for 1~2 hours, end the reflux; transfer all the cleaning solution from the reaction vessel (R02409) to the receiving tank V02-408;

开启接收罐(V02-408)的泵，开始循环30~40分钟，循环结束；
Start the pump for receiving tank V02-408, begin circulation for 30~40 minutes, and end the circulation

QA用玻璃取样瓶采集100 mL淋洗液，瓶上注明有设备编号V02-408–Y和日期的标签，供测试分析淋洗液PID20；
Use a glass sampling bottle labeled with the equipment number V02-408-Y and the date to collect 100 mL of rinse solution for PID20 test analysis

取样结束，剩余清洗液至三废处理。上述溶剂淋洗取样结束后，采用高压水枪冲洗冲洗各个设备顶部、内壁和底部及管道约10-20分钟，直到设备和管道冲洗干净；
Sampling completed, remaining cleaning solution to be disposed of as waste. After the solvent rinse sampling is finished, use a high-pressure water gun to rinse the tops, inner walls, bottoms, and pipelines of each equipment for about 10-20 minutes until the equipment and pipelines are thoroughly cleaned.

上述设备冲洗结束后；烘干、沥干或吹干上述设备。
After the above equipment is rinsed, dry, drain, or blow dry the equipment.

注：1）淋洗液通过管道转移时，需用真空或泵将清洗液打到下一清洗设备，管道出口端的阀门适当调小，以保证清洗液在通过管道时有一定的压力并延长清洗液在管道内的清洗时间。
Note: 1) When transferring the rinsing solution through the pipeline, use a vacuum or pump to send the cleaning solution to the next cleaning equipment. Adjust the valve at the outlet end of the pipeline appropriately to ensure that the cleaning solution has a certain pressure when passing through the pipeline and to extend the cleaning time of the solution within the pipeline.

2）在取样前应确认玻璃取样瓶是否清洁，并用淋洗样润洗取样瓶。

7.4.2 淋洗取样点汇总
7.4.2 Summary of Leaching Sampling Points

设备名称 Device name	材质 Material	设备编号 Equipment number	取样量﹙ml﹚ Sampling volume (ml)	取样点编号 Sampling point number.	淋洗剂 Rinsing agent	检测项目 Inspection item
接收罐 Receiving tank	304	V02-408	约100 Approximately 100	V02-408–Y	甲醇 Methanol	PID20

8. 残留限度确定原则
8. Principles for Determining Residue Limits

对本产品的药品毒性数据或健康数据进行分析制定产品清洗残留限度
Analyze the drug toxicity data or health data of this product to establish the cleaning residue limits for the product:

序号
Serial number

分析内容
Analyze content

分析结果
Analysis results

已知的基因毒性化合物或极有可能是人类致癌物（如DNA烷化细胞抑制剂）
Known genotoxic compounds or substances that are highly likely to be human carcinogens (such as DNA alkylating cytostatic agents)

无警示结构，或虽有警示结构但有充分的数据证明无致突变性或者致癌性。
No warning structure, or although there is a warning structure, there is sufficient data to prove no mutagenicity or carcinogenicity.

PID20的毒理数据如下：
The toxicological data of PID20 is as follows:

ADE可接受暴露水平 ADE Acceptable Exposure Level	N/A
PDE允许日暴露水平 PDE allows daily exposure level	N/A
TDD最低日治疗剂量 TDD minimum daily therapeutic dose	N/A
LD50半数致死量 LD50 median lethal dose	N/A
LD致死剂量 LD lethal dose	N/A
TCC毒理学关注阈值TCC TCC Toxicology Concern Threshold TCC	N/A
最大日剂量（MDD） Maximum Daily Dose (MDD)	N/A
临床健康受试者安全剂量 Clinical healthy subject safety dose	N/A
用药途径 Route of administration	N/A
OEL值 OEL value	N/A
其他数据 Other data	N/A

低剂量可产生生殖或发育作用的化合物，临床日制剂量<10 mg/天。
Compounds that can produce reproductive or developmental effects at low doses, with a clinical daily dose of <10 mg/day.

否

低剂量可能产生严重靶器官毒性或其严重不良反应的物质，临床日制剂量<10mg/天。
Substances that may cause severe target organ toxicity or serious adverse reactions at low doses, with a clinical daily dose of <10mg/day.

否

具有高效药理作用的物质，推荐日剂量<1mg//天。
Substances with highly efficient pharmacological effects, recommended daily dose <1mg/day.

否

具有高度潜在致敏性的物质（如青霉素，头孢类，培南类）
Substances with high potential for allergenicity (such as penicillin, cephalosporins, carbapenems)

否

具有细胞毒性的物质
Substances with cytotoxic properties

否

OEB-4或OEB-5产品OEB-4 or OEB-5 products
OEB-4 or OEB-5 products

否

经过以上评估，PID20判定为普通药品活性物质API中间体。
After the above evaluation, PID20 is determined to be an intermediate of the active pharmaceutical ingredient (API) of a common drug.

假定所有表面上残留分布是均匀的，根据计算算出上一产品到下一产品的最大允许残留限度MACO值，从而计算出单位表面积残留限度目标值。
Assuming that the residual distribution on all surfaces is uniform, the maximum allowable carryover limit (MACO) from the previous product to the next product is calculated, thereby determining the target residual limit per unit surface area.

8.1 擦拭残留限度确定原则
8.1 Principles for Determining Residue Limits for Wiping

PID20 产品合成路线：
PID20 Product Synthesis Route:

8.1.1 PID20 MACO值
8.1.1 PID20 MACO value

根据APIC指南（APIC GUIDANCE ON ASPECTS OF CLEANING VALIDATION OF IN ACTIVE PHARMACEUTICAL INGREDIENT PLANTS），一般产品中MAXCONC设置为5-500 ppm,在API MAXCONC设置为100 ppm，为了从严控制，将PID20更换产品后允许残留量以100 ppm计算，现2车间共线产品中最小批量约28 kg，为CME粗品，按28 kg计，代入计算：
According to the APIC Guidance on Aspects of Cleaning Validation of Active Pharmaceutical Ingredient Plants, the MAXCONC for general products is set at 5-500 ppm, and for APIs, it is set at 100 ppm. To enforce stricter control, the allowable residue after product change for PID20 is calculated at 100 ppm. Currently, the minimum batch size of co-manufactured products in Workshop 2 is approximately 28 kg, which is the CME crude product. Using 28 kg for calculation:

MACO=MAXCONC×MBS=100 ppm×28 kg=2.8 g

综上所述，选择最大允许残留限度MACO：2.8 g进行擦拭限度和淋洗限度计算。
In summary, the maximum allowable carryover limit (MACO) of 2.8 g was selected for the calculation of wipe and rinse limits.

8.2 擦拭取样限度
8.2 Wipe Sampling Limits

8.2.1 PID20 擦拭取样限度
8.2.1 PID20 Wipe Sampling Limit

PID20生产接触物料的主体设备总内表面积为92.18 m²，假定残留物平均分配到上述设备中，（擦拭面积以10 cm×10 cm区域）即可得到设备清洗后PID20允许擦拭残留限度：
The total internal surface area of the main equipment in contact with materials for PID20 production is 92.18 m². Assuming the residue is evenly distributed across the equipment, (with a wiping area of 10 cm × 10 cm) the allowable residue limit for PID20 after equipment cleaning can be determined.

$擦拭限度 = \frac{MACO(mg)}{设备总表面积} = \frac{2.8 × 1000 mg}{92.18 × 100 × 100 {cm}^{}} = 0.304 \frac{mg}{100 {cm}^{}}$

将PID20的擦拭取样浓度限量定为0.304 mg/100 cm²。
Set the wipe sampling concentration limit for PID20 to 0.304 mg/100 cm².

8.3 淋洗取样限度
8.3 Rinse Sampling Limit

淋洗线路：
Rinse circuit:

淋洗取样所用淋洗液体积为800 L，可得淋洗液残留限度：
The volume of the eluent used for elution sampling is 800 L, and the residual limit of the eluent can be obtained as:

$浓度限量= \frac{MACO（mg）}{淋洗溶剂体积} = \frac{2.8 ×1000 mg}{800 ×1000 mL} = 0.0035 mg/ mL$

因此，淋洗线路的淋洗液限度定为：0.0035 mg/mL.
Therefore, the limit of the eluent in the elution line is set at: 0.0035 mg/mL.

8.4 允许残留限度汇总Residue Limit Summary
8.4 Residue Limit Summary

擦拭取样限度汇总 Wipe Sampling Limit Summary
设备名称 Device name	材质 Material	擦拭取样位置 Wipe the sampling location	取样点编号 Sampling point number	检测项目 Inspection item	限度 Limit
反应罐 Reaction vessel （R02-402） (R02-402)	搪玻璃 Enameled glass	人孔口内侧（搅拌轴顶端附近） Inside the manhole (near the top of the mixing shaft)	R02-402-X₁	PID20	0.304 mg/100 cm²
反应罐 Reaction vessel （R02-403） (R02-403)	搪玻璃 Enameled glass	人孔口内侧（搅拌轴顶端附近） Inside the manhole (near the top of the mixing shaft)	R02-403-X₁
反应罐 Reaction vessel （R02-408） (R02-408)	衬四氟 PTFE-lined	人孔口内侧（搅拌轴顶端附近） Inside the manhole (near the top of the mixing shaft)	R02-408-X₁
反应罐 Reaction vessel （R02-409） (R02-409)	搪玻璃 Enameled glass	人孔口内侧（搅拌轴顶端附近） Inside the manhole (near the top of the mixing shaft)	R02-409-X₁

PID20淋洗取样限度汇总
PID20 Rinse Sampling Limit Summary

设备名称
Device name

设备编号
Equipment number

取样量﹙mL﹚
Sampling volume (mL)

取样点编号
Sampling point number.

淋洗剂
Rinsing agent

检测项目
Inspection item

限度
Limit

接收罐
Receiving tank

V02-408

100 mL

V02-408-Y

甲醇
Methanol

Mathanol
Methanol

PID20

0.0035 mg/mL

9. 残留测定方法T
9. Residual Determination Method T

9.1 PID20残留测定方法
9.1 PID20 Residue Determination Method

9.1.1 PID20擦拭回收率试验
9.1.1 PID20 Wipe Recovery Test

回收率试验方案及结果详见《LHVP-649-A-10 PID20清洗检测方法(HPLC)验证方案》和《LHVR-649-A-10 PID20清洗检测方法(HPLC)验证报告》。
The recovery rate test plan and results are detailed in the "LHVP-649-A-10 PID20 Cleaning Detection Method (HPLC) Validation Plan" and the "LHVR-649-A-10 PID20 Cleaning Detection Method (HPLC) Validation Report."

9.1.2 PID20残留测定方法
9.1.2 PID20 Residue Determination Method

稀释剂：甲醇：水（1：1,V/V）
Diluent: Methanol: Water (1:1, V/V)

空白溶液：稀释剂
Blank solution: diluent

对照品储备溶液：精密称取PID20对照品约35 mg，置于100.0mL容量瓶中，用甲醇振摇溶解并稀释至刻度，摇匀（浓度约0.35mg/mL）。
Reference stock solution: Accurately weigh approximately 35 mg of PID20 reference standard, place it in a 100.0 mL volumetric flask, dissolve and dilute to the mark with methanol, and mix well (concentration approximately 0.35 mg/mL).

对照品溶液：精密移取1.0mL对照储备溶液，置于100.0 mL容量瓶中，用稀释剂稀释至刻度，摇匀（PID20浓度约3.5 μg/mL）。
Reference solution: Precisely transfer 1.0 mL of the reference stock solution into a 100.0 mL volumetric flask, dilute to the mark with the diluent, and mix well (PID20 concentration approximately 35 μg/mL).

灵敏度溶液：精密移取3.0 mL对照品溶液，置于10.0 mL容量瓶中，用稀释剂稀释至刻度，摇匀（PID20浓度约1.05 μg/mL）。
Sensitivity solution: Precisely transfer 3.0 mL of the reference solution into a 10.0 mL volumetric flask, dilute to the mark with the diluent, and mix well (PID20 concentration approximately 1.05 μg/mL).

清洗溶剂：工业甲醇
Cleaning solvent: Industrial methanol

擦拭棉签空白溶液：精密吸取10 mL稀释剂于装有棉签的玻璃试管或玻璃瓶中，浸泡5分钟，摇匀。
Blank solution for swab wiping: Precisely draw 10 mL of diluent into a glass test tube or glass bottle containing the swab, soak for 5 minutes, and shake well.

擦拭棉签样品：精密吸取10 mL稀释剂于装有取样棉签的玻璃试管或玻璃瓶中，浸泡5分钟，摇匀。
Sample swab: Precisely pipette 10 mL of diluent into a glass test tube or glass bottle containing the sampling swab, soak for 5 minutes, and shake well.

淋洗空白样品：取淋洗用溶剂（工业甲醇）
Rinse blank sample: Take the solvent for rinsing (industrial methanol)

淋洗样品：精密移取5 mL淋洗液，置于10.0 mL容量瓶中，用水稀释到刻度，摇匀。
Rinse sample: Precisely transfer 5 mL of the rinse solution into a 10.0 mL volumetric flask, dilute to the mark with water, and mix well.

2）色谱系统
2) Chromatographic system

色谱仪：Agilent 1260或类似仪器
Chromatograph: Agilent 1260 or similar instrument

色谱柱：Waters Xbridge C18, 4.6 mm×150 mm , 3.5 µm,或类似色谱柱
Column: Waters Xbridge C18, 4.6 mm×150 mm, 3.5 µm, or similar column

柱温：30 ℃
Column Temperature: 30 ℃

样品室温度：5 ℃
Sample room temperature: 5 ℃

流动相A：10mM磷酸二氢钾水溶液
Mobile phase A: 10mM potassium dihydrogen phosphate aqueous solution

例如：精密称取1.36g磷酸二氢钾于1000 mL纯化水中，混匀，0.45μm膜过滤，超声脱气。
For example: Accurately weigh 1.36g of potassium dihydrogen phosphate into 1000 mL of purified water, mix well, filter through a 0.45μm membrane, and degas by ultrasonication.

流动相B：乙腈
Mobile phase B: Acetonitrile

梯度：
Gradient:

时间 (min) Time (min)	流动相A (%, V/V) Mobile phase A (%, V/V)	流动相B (%, V/V) Mobile phase B (%, V/V)
0	90	10
2	90	10
7	55	45
12	20	80
15	20	80
15.1	90	10
20	90	10

流速：1.0 mL/min
Flow rate: 1.0 mL/min

运行时间：20 min
Running time: 20 min

检测器波长：UV 210 nm
Detector wavelength: UV 210 nm

进样量：50 μL
Sample volume: 50 μL

洗针试剂：甲醇
Needle Washing Reagent: Methanol

数据采集：Agilent OpenLAB CDS2软件或其它类似软件的计算机
Data acquisition: Computer with Agilent OpenLAB CDS2 software or other similar software

保留时间Retention time:：
Retention time:

物质名称 Substance Name	保留时间RT（min）约 Retention time RT (min) approximately
PID20	6.2

3）系统适应性试验
3) System Adaptability Test

进样空白溶液，检查基线是否干扰，重复进样空白溶液直至系统稳定，且在主峰保留时间处无显著干扰，如有干扰，干扰峰应不大于灵敏度溶液中主峰峰面积的30%；
Inject the blank solution to check for baseline interference. Repeat the injection of the blank solution until the system stabilizes and there is no significant interference at the retention time of the main peak. If there is interference, the interference peak should not exceed 30% of the peak area of the main peak in the sensitivity solution

进样灵敏度溶液，要求PID20峰的信噪比不得小于10。
The sensitivity solution for injection requires that the signal-to-noise ratio of the PID20 peak should not be less than 10.

进样对照品溶液3针，记录色谱图，要求：3针对照品溶液中PID20峰面积的RSD不得大于10%。
Inject the reference solution three times, record the chromatogram, with the requirement: the RSD of the PID20 peak area in the three injections of the reference solution should not exceed 10%.

进样空白溶液1针，记录色谱图，系统应无残留。
Inject one blank solution and record the chromatogram. The system should show no residue.

4）测定measure
Measurement

系统适应性试验通过之后，开始分析测定：
After the system adaptability test is passed, the analysis and measurement begin:

1）进样棉签空白溶液1针，记录色谱图，要求棉签空白溶液对主峰无干扰；
1) Inject one sample of the swab blank solution, record the chromatogram, and ensure that the swab blank solution does not interfere with the main peak

2）进样淋洗空白溶液1针，记录色谱图，要求淋洗空白溶液对主峰无干扰；
2) Inject and rinse the blank solution once, record the chromatogram, ensuring that the rinse blank solution does not interfere with the main peak;

3）进样供试溶液1针，记录色谱图；
3) Inject the test solution once and record the chromatogram

4）继续进样其他批次的供试品溶液；
4) Continue to inject the test solution from other batches;

按下表顺序进样
Inject samples in the order of the table below

溶液名称 Solution Name	份	针次 Number of doses
空白溶液 Blank solution	1	1或多针 One or more needles
灵敏度溶液 Sensitivity solution	1	1
对照品溶液 Reference solution	1	3
空白溶液 Blank solution	1	1
棉签空白溶液 Cotton swab blank solution	1	1
淋洗空白溶液 Rinsing blank solution	1	1
供试品溶液X Test solution X	1	1
供试品溶液Y Test solution Y	1	1
供试品溶液Z Test solution Z	1	1
…	…	…

5）结果计算
5) Result Calculation

擦拭棉签中PID20浓度按下式计算：
The concentration of PID20 in the swab is calculated by the following formula:

$PID20擦拭残留量（ mg/100 {cm}^{} ）= \frac{A_{}}{A_{}} × \frac{W_{}}{100} × \frac{1}{100} × \frac{10}{R_{}}$ $PID20 （ mg/100 {cm}^{} ）= \frac{A_{}}{A_{}} × \frac{W_{}}{100} × \frac{1}{100} × \frac{10}{R_{}}$

式中：A_S——供试溶液中PID20的峰面积；A_R——对照溶液中PID20的峰面积；
In the formula: A _S —— the peak area of PID20 in the test solution; A _R —— the peak area of PID20 in the reference solution;

W_R——PID20对照品称量，mg； $R_{}$ ——擦拭回收率，以50%带入计算；
W _R ——Reference substance weighing, mg; $R_{}$ ——Wipe recovery rate, calculated at 50%;

淋洗液中PID20浓度按下式计算：
The concentration of PID20 in the leaching solution is calculated by the following formula:

$PID20淋洗残留量（ mg/ml ） = \frac{A_{}}{A_{}} × \frac{W_{}}{100} × \frac{1}{100} × \frac{1}{R_{}} ×2$

$PID20 （ mg/ml ） = \frac{A_{}}{A_{}} × \frac{W_{}}{100} × \frac{1}{100} × \frac{1}{R_{}} ×2$

W_R——PID20对照品称量，mg； $R_{}$ ——淋洗回收率，以50%带入计算；
W _R ——Reference substance weighing, mg; $R_{}$ ——Elution recovery rate, calculated based on 50%;

9.2 清洗检测方法适用性评估
9.2 Evaluation of the Applicability of Cleaning and Testing Methods

残留物质 Residual substances	残留限度 Residual Limit	LOQ	结论 Conclusion
PID20	擦拭限度：0.304 mg/100cm² Wipe limit: 0.304 mg/100cm ²	LOQ值为1.05 μg/mL The LOQ value is 1.05 μg/mL	检测方法适用 Applicable detection methods
PID20		LOQ值为1.05 μg/mL The LOQ value is 1.05 μg/mL	检测方法适用 Applicable detection methods	淋洗限度：0.0035 mg/mL Washing limit: 0.0035 mg/mL

10. 设备空置时间和清洗有效期考察
10. Investigation of equipment idle time and cleaning validity period.

10.1 设备空置时间考察
10.1 Equipment Idle Time Investigation

设备名称 Device name	设备编号 Equipment number	第二周期（DHT） The second cycle (DHT)
反应罐 Reaction vessel	R02-402	1天17小时 1 day 17 hours
反应罐 Reaction vessel	R02-403	3天16小时 3 days and 16 hours
反应罐 Reaction vessel	R02-407	4天9小时 4 days and 9 hours
反应罐 Reaction vessel	R02-408	4天1小时 4 days and 1 hour
反应罐 Reaction vessel	R02-409	0天2小时 0 days 2 hours
接收罐 Receiving tank	V02-417	5天0小时 5 days 0 hours
接收罐 Receiving tank	V02-408	0天4小时 0 days 4 hours
母液罐 Mother liquor tank	V02-346	1天19小时 1 day 19 hours
手套箱 Glove box	X02-422	4天8小时 4 days and 8 hours

备注：上述为清洗第二周期的DHT考察，后续将会进行第三个周期的DHT考察，待三个周期的DHT考察结束后会制定PID20的DHT。
Note: The above is the DHT examination for the second cycle of cleaning. The DHT examination for the third cycle will be conducted subsequently. After the DHT examinations for the three cycles are completed, the DHT for PID20 will be formulated.

10.2 清洗有效期考察
10.2 Cleaning Validity Period Investigation

根据LHV06-01<清洗验证管理>规定：在化学合成车间，设备没有微生物要求可以参考如下操作进行CHT考察，设备在清洗之后密闭保存，设备清洗之后干燥保存，清洗有效期可根据生产实际情况制定。设备空置期间应保证所有阀门关闭、人孔口关闭，使设备/系统保持密闭，下次使用之前对设备进行目视检查，检查设备内部或垫圈、法兰、底阀等零部件有无异物、锈迹、发霉等情况。如果合格则可以使用，若不合格则对设备进行0级清洗，并检查通过之后方可使用。
According to the LHV06-01 regulation: In the chemical synthesis workshop, for equipment without microbial requirements, the following operations can be referenced for CHT evaluation. The equipment should be sealed and stored after cleaning, and dried after cleaning. The cleaning validity period can be established based on actual production conditions. During the idle period of the equipment, all valves and manholes should be closed to keep the equipment/system sealed. Before the next use, a visual inspection of the equipment should be conducted to check for foreign objects, rust, mold, etc., inside the equipment or on components such as gaskets, flanges, and bottom valves. If qualified, it can be used; if not, the equipment should undergo a Level 0 cleaning and can only be used after passing the inspection.

PID20在合成区生产，使用的设备没有微生物要求，设备清洗之后干燥保存，并且重新投入生产时会进行清洗评估，风险较低，暂不对其清洗有效期进行考察。
PID20 is produced in the synthesis area, and the equipment used has no microbial requirements. After cleaning, the equipment is dried and stored. A cleaning evaluation is conducted when it is put back into production, and the risk is low. Therefore, the cleaning validity period is not currently being investigated.

10.3 连续生产周期考察
10.3 Continuous Production Cycle Investigation

根据LHE-649-01《2车间(025生产区)防交叉污染 (新增PID20和PID50)》及LHV06-01《清洁验证管理》评估，本次定单生产周期短，不对连续生产清洗周期进行考察。
Based on the evaluation of LHE-649-01 "Prevention of Cross-Contamination in Workshop 2 (Production Area 025) (Addition of PID20 and PID50)" and LHV06-01 "Cleaning Validation Management," the production cycle for this order is short, and the continuous production cleaning cycle will not be examined.

11. 确认操作和测定结果
11. Confirm operation and measurement results

第二周期：目视检查和丝光毛巾擦拭结果均合格，详见PID20清洗验证化学残留取样记录，记录控制号：CON-20241110-0009-2，PID20产后清洗记录详见LHPC-649-02-R03.01《PID20清洗记录（2级）》，记录编号：3649-1001-241101；
Second cycle: Both visual inspection and mercerized towel wiping results are qualified. For details, refer to the PID20 cleaning validation chemical residue sampling record, control number: CON-20241110-0009-2. The PID20 post-production cleaning record can be found in LHPC-649-02-R03.01 "PID20 Cleaning Record (Level 2)", record number: 3649-1001-241101;

擦拭结果和淋洗结果均合格，详见PID20清洗验证检测结果COA，COA贴在PID20清洗验证化学残留取样记录，记录控制号：CON-20241110-0009-2
The wiping and rinsing results are both qualified. For details, please refer to the PID20 cleaning validation test results COA, which is attached to the PID20 cleaning validation chemical residue sampling record. Record control number: CON-20241110-0009-2

设备名称 Device name	材质 Material	接受标准 Acceptance criteria	检查结果 Inspection results		是否合格 Whether it is qualified
设备名称 Device name	材质 Material	接受标准 Acceptance criteria			是否合格 Whether it is qualified		目视检测 Visual inspection	丝光毛巾擦拭检查 Silk towel wipe inspection
反应罐 Reaction vessel （R02-402） (R02-402)	搪玻璃 Enameled glass	1）目测检查：内外清洁，无可见物料 Visual inspection: Clean inside and out, no visible material 2）丝光毛巾擦拭检查：丝光毛巾上无物料痕迹 2) Inspection with mercerized towel: No material traces on the mercerized towel	内外清洁，无可见物料 Clean inside and outside, with no visible material	丝光毛巾上无物料痕迹 No material traces on the mercerized towel	是 □否 No
反应罐 Reaction vessel （R02-403） (R02-403)	搪玻璃 Enameled glass			内外清洁，无可见物料 Clean inside and outside, with no visible material	丝光毛巾上无物料痕迹 No material traces on the mercerized towel	是 □否 No
反应罐 Reaction vessel （R02-407） (R02-407)	搪玻璃 Enameled glass			内外清洁，无可见物料 Clean inside and outside, with no visible material	丝光毛巾上无物料痕迹 No material traces on the mercerized towel	是 □否 No
反应罐 Reaction vessel （R02-408） (R02-408)	衬四氟 PTFE-lined			内外清洁，无可见物料 Clean inside and outside, with no visible material	丝光毛巾上无物料痕迹 No material traces on the mercerized towel	是 □否 No
反应罐 Reaction vessel （R02-409） (R02-409)	搪玻璃 Enameled glass			内外清洁，无可见物料 Clean inside and outside, with no visible material	丝光毛巾上无物料痕迹 No material traces on the mercerized towel	是 □否 No
接收罐 Receiving tank Receiver （V02-346） (V02-346)	304			内外清洁，无可见物料 Clean inside and outside, with no visible material	丝光毛巾上无物料痕迹 No material traces on the mercerized towel	是 □否 No
接收罐 Receiving tank （V02-408） (V02-408)	304			内外清洁，无可见物料 Clean inside and outside, with no visible material	丝光毛巾上无物料痕迹 No material traces on the mercerized towel	是 □否 No
储罐 Storage tank （V02-417） (V02-417)	搪玻璃 Enameled glass			内外清洁，无可见物料 Clean inside and outside, with no visible material	丝光毛巾上无物料痕迹 No material traces on the mercerized towel	是 □否 No
手套箱 Glove box （X02-422） (X02-422)	304			内外清洁，无可见物料 Clean inside and outside, with no visible material	丝光毛巾上无物料痕迹 No material traces on the mercerized towel	是 □否 No

设备名称 Device name	材质 Material	擦拭取样位置 Wipe the sampling location	取样点编号 Sampling point number	检测 Detection 项目 Project	限度 Limit	擦拭样品 Wipe the sample 检测结果(mg/100cm² Test result (mg/100cm ² )	是否合格 Whether it is qualified
反应罐 Reaction vessel （R02-402） (R02-402)	搪玻璃 Enameled glass	人孔口内侧 Inside the manhole opening （搅拌轴顶端附近） (Near the top of the stirring shaft)	R02-402-X₁	PID20	0.304 mg/100 cm²	ND	是 □否 No
反应罐 Reaction vessel （R02-403） (R02-403)	搪玻璃 Enameled glass	人孔口内侧 Inside the manhole opening （搅拌轴顶端附近） (Near the top of the stirring shaft)	R02-403-X₁					ND	是 □否 No
反应罐 Reaction vessel （R02-408） (R02-408)	衬四氟 PTFE-lined	人孔口内侧 Inside the manhole opening （搅拌轴顶端附近） (Near the top of the stirring shaft)	R02-408-X₁					ND	是 □否 No
反应罐 Reaction vessel （R02-409） (R02-409)	搪玻璃 Enameled glass	人孔口内侧 Inside the manhole opening （搅拌轴顶端附近） (Near the top of the stirring shaft)	R02-409-X₁					ND	是 □否 No

设备名称
Device name

设备编号
Equipment number

取样量﹙mL﹚
Sampling volume (mL)

取样点编号
Sampling point number.

淋洗剂
Rinsing agent

检测项目
Inspection item

限度
Limit

淋洗样品
Rinsing the sample

检测结果（mg/mL）
Test result (mg/mL)

是否合格
Whether it is qualified

接收罐
Receiving tank

V02-408

100 mL

V02-408-Y

甲醇
Methanol

PID20

0.0035 mg/mL

是Yes
Yes

□否No
□No

12. 变更/偏差
12. Change Deviation

12.1 变更
12.1 Change

在清洗验证过程中，未发生变更。
No changes occurred during the cleaning validation process.

12.2 偏差
12.2 Deviation

在清洗验证过程中，未发生偏差。
No deviations occurred during the cleaning validation process.

13. 总结
13. Summary

本次清洁验证相关的生产信息如下：
The production information related to this cleaning validation is as follows:

本次清洁验证PID20生产批号为：CN241001、CN241002、CN241101。
The cleaning validation PID20 production batch numbers are: CN241001, CN241002, CN241101.

本次清洗时间轴如下： 2024.10.15（生产开始）——2024.10.29（生产结束）。连续生产14天，共生产3批PID20。2024.11.03~2024.11.10(开始清洗时间~结束清洗时间)——2024.11.10~2024.11.12（化学残留取样时间）。
The cleaning timeline is as follows: 2024.10.15 (start of production) – 2024.10.29 (end of production). Continuous production for 14 days, producing 3 batches of PID20. 2024.11.03~2024.11.10 (start of cleaning time ~ end of cleaning time) – 2024.11.10~2024.11.12 (chemical residue sampling time).

结论：生产结束后，对设备进行了擦拭、淋洗取样前，对PID20工序使用设备进行了目视检查和丝光毛巾检查，目视检查结果均为“内外清洁，无可见物料”，丝光毛巾擦拭检查结果均为“丝光毛巾上无物料痕迹”。PID20清洁验证擦拭检测结果均为ND，均符合擦拭限度（PID20≤0.304 mg/100cm²）要求，淋洗结果均为ND，符合淋洗限度（PID20≤0.0035 mg/mL）要求。
Conclusion: After production, the equipment was wiped and rinsed. Before sampling, a visual inspection and a mercerized towel inspection were conducted on the equipment used in the PID20 process. The visual inspection results showed "clean inside and outside, no visible material," and the mercerized towel inspection results showed "no material traces on the mercerized towel." The PID20 cleaning verification wipe test results were all ND, meeting the wipe limit (PID20≤0.304 mg/100cm ² ) requirements. The rinse results were all ND, meeting the rinse limit (PID20≤0.0035 mg/mL) requirements.

综上所述，PID20第二周期清洁验证是成功的。
In summary, the PID20 second cycle cleaning verification was successful.

14. 相关文件
14. Relevant Documents

文件名称 File name	记录编号 Record Number
PID20清洗验证化学残留取样记录 PID20 Cleaning Validation Chemical Residue Sampling Record	CON-20241110-0009-2
PID20清洗验证中期审核单 PID20 Cleaning Validation Mid-Term Review Form	CON-20241115-0431-3
PID20清洗检测方法(HPLC)验证报告 PID20 Cleaning Detection Method (HPLC) Validation Report	LHVP-649-A-10

15. 附件PID20 ICH M7报告
15. Attachment PID20 ICH M7 Report