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3、过滤器完整性测试原理及在线完整性测试-密理博110428 [兼容模式]

Filter Integrity Test and SIP g y 过滤器完整性测试原理及在线完整性测试

Content 讲座目录
Why we do integrity test for sterile filter? 为什么要对除菌滤器进行完整性测试? Method for IT?完整性测试的方法有哪些? Why bubble p y point could replace bacterial retention test? p 为什么可以用起泡点的方法代替细菌挑战试验? When should we do IT? 什么时候进行完整性检测? Bubble point theory.起泡点测试原理是什么? Diffusion test theory.扩散流测试原理是什么? Automatic integrity tester自动完整性测试仪

What is filter integrity? 什么是滤膜完整性?
Integral membrane 完整滤膜 Contaminant 比膜孔大的污染物 Non-integral membrane 非完整滤膜 Contaminant比膜孔大的污染物
No contaminant in downstream 下游没有污染物
Contaminant in downstream
下游污染

Why Integrity Test? 为什么做完整性测试?
Common Sense 通常理解 Filtration is often the most critical step in an operation 过滤通常是操作的关键步骤 Confirmation of manufacturers specifications 确认制造规格 Detecting leaks due to o-rings, gaskets, seals 检测O形环,垫圈,密封垫的泄漏 Assuring the correct pore size filter A i th t i filt 确认正确的过滤孔经 Assuring integrity before sterilization 确认灭菌前完整性 Assuring integrity after steaming or autoclaving 确认蒸汽和消毒锅灭菌后完整性 Business Practice 商业惯例 Government Guidelines & Regulations法规要求 Part of corporate standard operating procedure公司标准 操作规程 Auditing requirement审计需要

Regulations about integrity test 法规中对完整性测试的规定
FDA Guideline指南 (2003) Whatever filter or combination of filters is used, validation should include microbiological challenges to simulate worst-case production conditions…” conditions 对于由一个或多个滤器组成的过滤系统,对它 的验证都应该包括在最差条件下进行的微生物挑 战试验。

Regulations about integrity test 法规中对完整性测试的规定
Revision of annex 1 to EC Guide to GMP for sterile medicinal products (1997) 欧盟对于无菌药品GMP指南的附件一(1997版) “The integrity of the sterilized filter should be verified before use and should The be confirmed immediately after use by an appropriate method such as a bubble point, diffusive flow or pressure hold test” 除菌过滤膜应该在使用前及使用后立即采取合适的方法确认其完整性,可以采用 除菌过滤膜应该在使用前及使用后立即采取合适的方法确认其完整性 可以采用 泡点,扩散流或压力保持的方法. FDA Guideline on Sterile Drug Products Produced by Aseptic Processing (2004) FDA关于无菌工艺生产的无菌药品的指南(2004版) Integrity testing of the filter(s) can be performed prior to processing, and should be routinely performed post-use. It is important that integrity testing be conducted after filtration to detect any filter leaks or perforations that might have occurred during the filtration. 完整性测试可以在过滤工艺前进行,并应当在过滤以后进行日常测试。过滤后 通过完整性测试检测过滤过程中可能出现的泄露或破损是非常重要的。 PDA Technical Report # 26 PDA技术报告26版 It “It generally is regarded as a cGMP requirement that filters or filter systems routinely be integrity tested both prior to and after use.” 现行的GMP要求过滤器及过滤系统在使用前及使用后均需要进行完整性测试

Where & When Do We Integrity Test? 何时和何处做完整性测试?
WHEN TO DO IT? 什么时候做? Before sterilization 灭菌前 Before use 使用前 After use 使用后 DETECTS WHAT? 检查什么? Faulty housings 外壳的问题 Out-of-the box failures 包装以外的问题 Sterilization induced failures 灭菌的影响 Stress induced failures 压力的影响

What Are The Integrity Testing Choices? 完整性测试的选择? 金标准
Type 分类 T Test T t name 测试名称 Tester T t 测试实施者
Manufacturer and M f t d Destructive Bacterial retention test customer do validation 破坏性 制造商以及客户进行验证 细菌挑战测试 时进行 NonNon Bubble point diffusion Manufacturer release point, and customer on site 制 destructive test 造商出厂时及使用者现场 非破坏性 起泡点测试,扩散测试 进行 g y q y g Regulatory & quality organizations need data from both to assure reliable and predictable filter performance法规和质量管 理需要数据确保可靠和预知过滤器性能

Destructive vs. Non-destructive Testing 破坏性和非破坏性测试
There must be a correlation between a destructive and a nondestructive integrity test
破坏性和非破坏性测试两者必须有 关联 Regulatory requirement 法规需要 FDA Aseptic Guidelines FDA无菌指南 Validation justification for the use of a test 测试应用的验证理由

Integrity Testing Correlations 完整性测试关联
# of Samples
Specification Retentive NonRetentive
2
4
6
8
10 12 14 16 18 20 22 24
26
Bubble point can have a direct correlation 起泡点有直接的关联
Diffusion & other tests can have an "go - no go correlation go go" 扩散和其它测试有”通过,不通过”关连

What Non-Destructive Integrity Tests are Available? 何种非破坏性测试合适? Capillary Capillar based tests
基于毛细管测试
Bubble Point起泡点 HydroCorr 挤水法 Corrtest水压法
P1 Air
s q f
P2 d Water
Diffusive based tests 基于扩散测试
Diffusion扩散 Forward Flow前向流 Pressure hold / decay压力保持/ 衰减

Bubble Point Introduction 起泡点介绍
Bubble point is the pressure at which gas di l displaces liquid from the largest set li id f th l t t of filter pores and flows rapidly through the filter 起泡点是气体从湿润的最大膜孔挤出液体快 速流出时的压力 Bubble point indicates the magnitude of the f th forces holding liquid in the filter h ldi li id i th filt structure 起泡点显示过滤结构内保持液体的力的大小 The oldest non-destructive integrity test g y 最传统的非破坏性测试
Air
Pact < PBpt
Membrane
Pact > PBpt

Bubble point test 泡点测试
Integral 完整膜 Non-Integral 非完整膜 Fully wetting 完全润湿的膜 Pressure less than bubble point上游压力 小于泡点值 No mass gas fluid observed 没有大量气 流出现 Pressure less than bubble point上游 压力小于泡 点值
Largest Pore
mass gas fluid observed
破损出现的大孔 保持力低,导致低 于泡点即被吹干 出现气流

Bubble Point Test Applicability 起泡点测试适用性 Useful for qualified manual testing of filters less than approximately 2000 cm^2 (~2 sq.ft.) 手动测试通常适用于过滤器面积小于2000平方厘米 Useful for automatic integrity testers for filters with gas flow rates of up to 100 ml/min or limit of the automatic testers qualifications 自动完整性测试仪适用于气体流速超过100毫升/分钟或自 动测试仪的限定

Bubble Point Equation 起泡点方程
The bubble point is expressed as:泡点可表达为
4 . k . γ . cos
P1 BP = ----------------Air d where 这里 k = shape correction factor 形状校正因子 = surface tension 表面张力 = contact angle 接触角 d = pore diameter 孔径
σ θ
P2 d Water

Effect on bubble point test 泡点的影响因素
Depends on capillary f D d ill forces; 依赖毛细管力 membrane material surface material, tension, contact angle, effective diameter, 膜材料,表面张力,接触角,有效孔径 起泡点说明(包括SOP)应当包括 filter type过滤器类型 wetting liquid湿润液体 Temperature温度 minimum pressure最小压力

Contact angle 接触角的影响
Solid / liquid interaction 固/液相互作用
Changing the wetting fluid changes the bubble point 改变湿润液体会改变起泡点
Applies to
different wetting fluid不同的湿润液体 different surface chemistries不同的表面化学性 pre-use vs. post-use comparison使用前和使用后比较
Must know the effects of the changes, perform flushing or conduct product bubble p point q qualification 必须知道变化的影响,进行冲洗或用产 品泡点确认

Examples of the Effect of Contact Angle and Surface Tension on Bubble Point Values 接触角和表面张力对起泡点值的影响实例
Two sterilizing grade filters with identical bacterial retention claims and performance have the following minimum bubble point specifications: 两种无菌过滤膜用同一细菌截留有下列最小的起泡点规格: Durapore? PVDF CVGL >= 50 psig Charged Durapore? PVDF CCGL >= 40 psig A sterilizing grade filter has is the following minimum bubble point specifications: 一种无菌过滤膜有下列最小的起泡点规格: Water >= 50 psig 70/30 IPA >= 18.5 psig p g Higher bubble point test values do not mean better filters 高起泡点值并不是意味好的过滤膜 Check the filter manufacturer's validation guide for the destructive / nonmanufacturer s destructive integrity test correlation, integrity testing technique and bacterial challenge method 检查过滤膜制造商对破坏性 非破坏性完整性测试关连的验证文本,完整性测试技 检查过滤膜制造商对破坏性/非破坏性完整性测试关连的验证文本,完整性测试技 术和细菌挑战理论 膜没有洗干净可能影响到接触角而导致完整性测试失败

Diffusion Testing Introduction 扩散流测试介绍
Gas dissolves in liquid held in the pores of a fully wetted membrane filter.气体溶解在完全 湿润的滤器膜孔内的液体中
A pressure differential will p give a different gas concentration across the 膜压差造成跨膜气体浓度差
上游 压缩 气体 P1 扩散流 P1 > P2
下游气体 P2 Z
filter.
Results in gas flow through the liquid dissolved in the filter pores 结果 pores.结果 使膜孔溶解的气体流出