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[原料药] APIC 201405原料药厂清洁验证指南:9.0清洁验证方案(中英文)

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APIC 201405原料药厂清洁验证指南:9.0清洁验证方案(中英文)  

9.0 Cleaning Validation Protocol 清洁验证方案



PREPARED BY (DEPT.):  DATE:
起草人(部门):                                日期:            
REVIEWED BY (DEPT.):  DATE:
审核人(部门):                                日期:            
APPROVED BY (DEPT.):  DATE:
批准人(部门):                                日期:            
APPROVED BY (DEPT.):  DATE:
批准人(部门):                                日期:            
APPROVED BY (DEPT.):  DATE:
批准人(部门):                                日期:            
TITLE方案标题:
PROTOCOL NO:
方案编号:                    
PROTOCOL ISSUE DATE:
方案签发日期:                        
CLEANING SOP REFERENCE AND ISSUE NO:
清洁SOP索引号和发放号:                    

TABLE OF CONTENTS 目录
9.1 Background
背景
9.2 Purpose
目的
9.3 Scope
范围
9.4 Responsibility
职责
9.5 Sampling procedure
取样程序
9.6 Testing procedure
检测方法
9.7 Acceptance criteria
可接受标准
9.8 Deviations
偏差
9.9 Revalidation
再验证
9.1 Background 背景
Equipment X is routinely cleaned after product Y (or group of products*) according to procedure XXX......
设备X在产品Y(或产品组)生产结束后,根据程序XXX进行常规清洁……
*If group of products describe rational for choosing this grouping strategy.
*如果产品组说明了选择该分组策略的理由。
Describe: Equipment
Cleaning method
Cleaning agents.
描述:设备、清洁方法、清洁剂
9.2 Purpose 目的
The purpose of this study is to demonstrate that remaining product residues previous in a piece of equipment are always within the established acceptance criteria if the equipment is cleaned by a defined cleaning method.
本研究的目的是证明如果根据制订的清洁程序进行清洁,上一产品在一个设备中的残留物总能保持在所制订的可接受标准以内。
9.3 Scope 范围
A visual test and a chemical evaluation of the equipment will be performed after a clean to demonstrate that product residue(s) (active ingredient, intermediates and / or excipients) and cleaning agent residues (exclude solvents used in process) have been removed to levels within the acceptance criteria.
在清洁完成后,对设备进行目视检查和化学评估,证明产品残留物(活性成分、中间体和/或辅料)和清洁剂残留(除工艺所用的溶剂外)已被清除至可接受标准以内。
The equipment cleanliness will be proven by testing and evaluation of samples in accordance with this protocol fromZ* consecutive cleans. (*Z: Generally three consecutive cleans are acceptable, however, companies should determine the number adequate for their operation.)
根据本方案,实施Z次连续清洁,通过对样品的检测和评估证明设备的清洁度(*Z:一般三次连续清洁是可以接受的,但是,公司应针对自己的操作决定清洁验证的轮次)。
At least a visual revision of the working areas will performed to minimize the risk of cross contamination that results from e.g. contamination on the surface of the process room.
对工作区域至少要进行目视检查,以将,如工艺房间表面污染带来的,交叉污染风险降至最小。
In order for the cleaning procedure to be deemed valid all data generated during the study should be within the acceptance criteria detailed in section 9.7 of this protocol.
为证明本清洁程序有效,所有在研究过程中产生的数据均应符合本方案9.7部分描述的可接受标准。
A report will be written assessing the data generated and thus determining the validity of the cleaning process.
应起草一份报告,评估所产生的数据,决定清洁工艺的有效性。
The equipment should not be used to process another product until clearance indicating that the equipment is adequately clean has been received from the validation department in accordance with process transfer SOP AAA (or detail whatever system is in-place to ensure that equipment is not used).
根据工艺转移SOP AAA(或在此详述已有系统的要求,以保证设备不会被误用)从验证部门接收到设备经过充分清洁的证明后,方可将该设备用于另一产品的生产。
9.4 Responsibility 职责
The responsibility for completion of this study lies as follows (for example):
完成本研究的责任列明如下(举例):
Scheduling: Manufacturing, QA, QC and Engineering.
Cleaning of equipment: Manufacturing
Removal of samples: QA
Testing of samples: QC
Review of data and approval of study: Validation / Manufacturing / QC
计划:生产部、QAQC和工程部
设备清洁:生产部
取样:QA
样品测试:QC
研究数据审核和批准:验证部、生产部、QC
9.5 Sampling Procedure 取样程序
Remove swab and rinse samples from the equipment as detailed in section 8.3 of this guidance document.
按本指南文件8.3部分描述从设备中取擦拭样和淋洗样。
SWAB SAMPLES: 擦拭样
See attached equipment sampling diagram (It is important to show clearly where the sampling locations are). Definition of sampling locations should be based on a Risk Assessment.
参见所附设备取样示意图(要清楚显示取样位置)。应根据风险评估来确定取样位置。
Swab samples should be removed according to swabbing procedure SOP BBB (or if there is no SOP in place describe in the text the validated sampling technique for the QA sampler).
擦拭样应根据SOP BBB擦拭程序进行取样(或如果没有SOP,则在验证取样技术中进行描述,以指导QA取样人员)。
The swab sampling locations are as follows:
擦拭取样位置如下:
Product residue samples: list of sample locations and no of swabs to be removed.
产品残留样:取样位置清单,应取擦拭样的数量
Cleaning agent samples: list of sample locations and no of swabs to be removed.
清洁剂样品:取样位置清单,应取擦拭样的数量
Samples should be removed from the locations on the equipment deemed to be ‘worst case’ i.e. most difficult to clean locations and therefore where product is most likely to reside if cleaning has not been adequate. It is important that these locations have been determined scientifically and can be rationalised if necessary.
样品应取自设备中“最差情况”的位置,即最难清洁位置,如果设备清洁不充分的话,产品最可能残留在这些地方。重要的是必要时,已经科学合理地对这些位置进行了确认。
RINSE SAMPLES: 淋洗样
Rinse samples should be removed according to procedure SOP CCC (or if there is no SOP in place describe the sampling technique for the QA sampler).
淋洗样要根据程序SOP CCC(或如果没有该SOP,则在此为QA取样人员描述取样技巧)取样。
The volume of liquid used to rinse the equipment should be detailed. (volume must be shown to be sufficient to cover all product contact surfaces of the equipment). The volumes of the rinse samples should also be stipulated in the protocol.
用于淋洗设备的液体体积要详细描述(体积必须足以覆盖所有与设备表面接触的产品)。淋洗样品的体积也应该在方案中说明。
MICROBIOLOGICAL TESTING 微生物检测
See attached equipment sampling diagram (It is important to show clearly where the sampling locations are)
参见所附的设备取样示意图(要清洁显示从哪些位置取样)。
Microbiological test samples should be removed according to procedure SOP DDD (or if there is no SOP in place describe the sampling technique for the QA sampler).
微生物检测样品应根据程序SOP DDD(或如果没有该SOP,则在此为QA取样人员描述取样技巧)取样。
The microbiological testing locations are as follows:
微生物检测位置如下:
List of sample locations and no of microbiological tests samples to be removed
样品位置清洁,要取的微生物检测样品数量
All sampling details (swab, rinse and microbiological) should be referenced in Table Samples should then be sent to the QC department for analysis. Any relevant sample transfer conditions should be noted.
所有的样品详细情况(擦拭、淋洗和微生物)应在样品表中进行索引,然后送QA部门进行检测。要注意所有有关样品的送样条件。
9.6 Testing procedure 检验方法
Rinse samples should be tested for: 淋洗样应检测
—       Product residues in accordance with analytical protocol
—       根据检验方案检测产品残留
—       Cleaning agent residues in accordance with analytical protocol
—       根据分析方案检测清洁剂残留
Swab samples should be tested for: 擦拭样要检测
—       Product residues in accordance with analytical protocol
—       根据检验方案检测产品残留
—       Cleaning agent residues in accordance with analytical protocol
—       根据分析方案检测清洁剂残留
Microbiological test samples should be tested for: 微生物试样要检测
Total germ number
总菌数
Note the limits of quantitation and detection as well as the % recovery for the tests being performed.
注意要验证检测方法的检测限和定量限及回收率。
The analytical protocol should include a calculation to convert the amount of residue detected in the sample to 100% (i.e. if the analytical validation results indicate that only 50% of spiked active / cleaning agent is recovered using the swabbing / rinse method of choice, the amount of active cleaning agent recovered per sample should be multiplied by 2 to bring result to 100%).
检测方案要包括将样品中残留结果进行折算至100%的方法(即,如果方法验证结果显示采用擦拭/淋洗方法时加入的活性成份/清洁剂只有50%被回收,则样品中活性物质/清洁剂测得结果要乘以2使回收率达到100%)。
All data generated should be attached to this study and returned to the Validation department where calculations and adherence to acceptance criteria is determined.
所有生成的数据要附入本研究,交回验证部门,由验证部门计算并与可接受标准进行比较。
9.7 Acceptance criteria 可接受标准
? The Visual cleanliness of the equipment must be checked and verified after cleaning according to the procedure xxx:必须目视检查设备清洁度,在清洁后根据程序XXX进行确认。
Equipment is visually clean: Signed (manufacturing): _______ Date: _______
设备经目视检查清洁:签名(生产部)              日期:        
Verified (QA): ______ Date: _______
审核(QA       日期         
The swab / rinse sample acceptance criteria for product and cleaning agent residues as well as the microbiological test acceptance criteria should be detailed along with a rational for the figures quoted.
擦拭/淋洗样品中产品和清洁剂残留物的可接受标准与微生物检查的可接受标准应与引用数值的理由一起进行详细描述。
(Unlike product residues, it is expected that no (or for ultra sensitive analytical test methods - very low), detergent levels remain after cleaning. Detergents are not part of the manufacturing process and are only added to facilitate cleaning. Thus they should be easily removed. Otherwise a different detergent should be selected.)
(与产品残留不同,清洁剂在清洁后应没有残留(或特别灵敏的分析方法----非常低)。清洁剂不是生产工艺的一部分,只是在清洁时加入设备中的物质,因此应该易于清除,否则要重新选择清洁剂。)
Reference: Please see chapter 4 of this guidance document for examples of calculating acceptance criteria.
参考:请参见本指南的第4章,其中有计算可接受标准的例子。
In addition a sample calculation detailing how the residual levels of active ingredient / cleaning agent for the entire equipment are computed should be given.
另外,要给出一个计算的样例,详细写出如何计算整个设备中的活性成分/清洁剂的残留水平。
POINTS TO CONSIDER: 要考虑的问题
Surface area calculations should be performed, verified and kept on file for all equipment evaluated (photos may be incorporated into the protocol to ensure samples are taken from the correct position).
要对所有设备表面积进行计算、验算并保存在文件中(可以将照片放入方案中,以保证从正确的位置取样)。
When the worst case result recorded is less than the limit of quantitation but greater than the limit of detection for the test method, the value denoting the limit of quantitation should be used to perform the calculations.
如果所记录的最差情况结果低于检测方法的定量限,但大于检测限,则应将定量限值作为样品结果用于计算。
When the worst case result recorded is less than the limit of detection for the test being performed the value denoting the limit of detection should be used to perform the calculations.
如果所记录的最差情况结果低于测试方法的检测限,则应将检测限值作为样品结果用于计算。
Dirty Hold Times and Clean Hold Times
清洁前保存时长和清洁后保存时长
The period and when appropriate, conditions of storage of equipment before cleaning, commonly referred to as The Dirty Hold Time (DHT) and the time between cleaning and equipment reuse, prior to additional cleaning, commonly referred to as The Clean Hold Time (CHT), should form part of the validation of cleaning procedures. This is to provide confidence that routine cleaning and storage of equipment does not allow potential for build up of degradation products that may not be removed by the standard cleaning procedure and does not allow potential for microbial contamination of equipment and to ensure that these potential risks are properly assessed and controlled.
清洁前设备可以放置的时长,适当时包括放置的条件,一般称为清洁前保存时长(DHT),以及设备在清洁后再次使用前,进行重新清洁之前,一般称为清洁后保存时长(CHT),应该作为清洁程序验证的一部分。该验证证明对设备的常规清洁和存放不会使得标准清洁程序未能清除的降解产物增加,以保证这些潜在风险经过了适当的评估和控制。

TABLE 1: SAMPLE REFERENCE TABLE
Sample
To be tested for
Area swabbed
Total surface area (cm2)
Sample ref.
Signed/date
Swab sample
Active
xxx
Swab sample
Cleaning agent
Xxx
Swab sample
Active
Xxx
Swab sample
Cleaning agent
Xxx
Swab sample
Active
Xxx
Swab sample
Cleaning agent
Xxx
Swab sample
Active
Xxx
Swab sample
Cleaning agent
Xxx
Swab sample
Active
Xxx
Swab sample
Cleaning agent
Xxx
Sample
To be tested for
Sample volume
Total volume of rinse
Sample ref.
Signed/date
Rinse sample
Active
Xxx
Rinse sample
Cleaning agent
xxx
Sample
To be tested for
Sample ref.
Signed/date
Swab sample
Microbial contamination
Swab sample
Microbial contamination
1:样品对照表
样品
测试项目
擦拭面积
总面积 (cm2)
样品编号
签名/日期
擦拭样品
活性成分
xxx
擦拭样品
清洁剂
Xxx
擦拭样品
活性成分
Xxx
擦拭样品
清洁剂
Xxx
擦拭样品
活性成分
Xxx
擦拭样品
清洁剂
Xxx
擦拭样品
活性成分
Xxx
擦拭样品
清洁剂
Xxx
擦拭样品
活性成分
Xxx
擦拭样品
清洁剂
Xxx
样品
测试项目
样品体积
Total volume of rinse
样品编号
签名/日期
淋洗样品
Active
Xxx
淋洗样品
Cleaning agent
xxx
样品
测试项目
样品编号
签名/日期
擦拭样品
微生物
擦拭样品
微生物
9.8 Deviations 偏差
Please indicate whether deviations occurred during the completion of this Validation Protocol and give details especially with regard to impact on the effectiveness of the cleaning validation and with regard to corrective and preventive actions.
在此说明在完成此验证方案的过程中是否有偏差发生,特别要详细说明偏差对清洁验证效果的影响,以及相应的纠正预防措施。
9.9 Revalidation 再验证
Define the Revalidation strategy for cleaning processes
确定清洁工艺的再验证策略。
Signed: __________________ Verified: _________________
签名:                  确认:                  


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药徒
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赞!谢谢!
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辛苦了,谢谢分享。
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