Integrity Testing Theory
完整性测试理论完整性测试理论
过滤/完整性测试培训课程
内容提要
为什么要对除菌滤器进行完整性测试?
完整性测试的方法有哪些?
为什么可以用起泡点的方法代替细菌挑战试验?
什么时候进行完整性检测?
起泡点测试原理是什么?
扩散流测试原理是什么?扩散流测试原理是什么?
自动完整性测试仪
什么是滤膜完整性?
完整滤膜 非完整滤膜完整滤膜
比膜孔大的污染物
非完整滤膜
比膜孔大的污染物
下游污染下游没有污染物 下游污染下游没有污染物
Why Integrity Test?
为什么做完整性测试?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 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 Assuring the correct pore size filter
确认正确的过滤孔径
Assuring integrity before sterilization
确认灭菌前完整性 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
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操作规程Part of corporate standard operating procedure公司标准操作规程
Auditing requirement审计需要
法规中对完整性测试的规定
FDA Guideline指南 (2003)FDA Guideline指南 (2003)
– Whatever filter or combination of filters is used, validation
should include microbiological challenges to simulate worst-s ou d c ude c ob o og ca c a e ges to s u ate o st
case production 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。
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 (199 版)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 be confirmed immediately after use by an appropriate
method such as a bubble point, diffusive flow or pressure hold test”p , p
– 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 (1987)
FDA对于无菌操作生产的无菌药品的要求(1987版)FDA对于无菌操作生产的无菌药品的要求(1987版)
– “Normally, integrity testing of the filter is performed after the filter unit is
assembled and sterilized prior to use.”
– 完整性测试通常在过滤器安装,灭菌后使用前进行完 性 试 常在 安 , 菌后使 前 行
PDA Technical Report # 26
PDA技术
报告
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26版
– “It generally is regarded as a cGMP requirement that filters or filter systems
routinely be integrity tested both prior to and after use ”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?
何时和何地做完整性测试?何时和何地做完整性测试?
WHEN TO DO IT? DETECTS WHAT?WHEN TO DO IT?
什么时候做?
Before sterilization
DETECTS WHAT?
检查什么?
Before sterilization
灭菌前 Faulty housings
外壳的问题
Before use
使用前 Out-of-the box failures包装以外的问题
After use
使用后
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?完整性测试的选择?
分类 测试名称 测试实施者金标准分类 测试名称 测试实施者
制造商以及客户进行验证时破坏性 细菌挑战测试 制造商以及客户进行验证时进行
非破坏性 起泡点测试,扩散测试 制造商出厂时及使用者现场进行
Regulatory & quality organizations need data from
both to assure reliable and predictable filterboth 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破坏性和非破坏性测试
There must be a correlation
between a destructive and a be wee a des uc ve a d a
non-destructive 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 法规需要
z FDA Aseptic Guidelines
z FDA无菌指南
V lid ti j tifi ti f th Validation justification for the
use of a test
测试应用的验证理由测试应用的验证理由
Integrity Testing Correlations
完整性测试关联完整性测试关联
Specification
# of
Retentive
Non-
R t tiSamples Retentive
B bbl i t h di t
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
扩散和其它测试有”通过,不通过”关起泡点有直接的关联 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?何种非破坏性测试合适?
Capillary based tests
基于毛细管测试基于毛细管测试
Bubble Point起泡点
HydroCorr 挤水法
P1
P2
Air Water
d
s
q fy
Corrtest水压法
Diff i b d t t
Waterq f
Diffusive based tests
基于扩散测试
Diff i 扩散 Diffusion扩散
Forward Flow前向流
Pressure hold / decay压力保持/y压力保持/
衰减
Bubble Point Introduction
起泡点介绍
Bubble point is the pressure at which gas
起泡点介绍
Bubble point is the pressure at which gas
displaces liquid from the largest set 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
Air Pact < PBpt
forces holding liquid in the filter structure
起泡点显示过滤结构内保持液体的力的大小
Th ld t d t ti i t it t t
Membrane
The oldest non-destructive integrity test
最传统的非破坏性测试 Pact > PBpt
泡点测试
完整膜 非完整膜完整膜 非完整膜
完全润湿的膜
上游压力 没有大量气 上游压力
破损出现的大
孔保持力低,导
Largest
Pore
上游压力
小于泡点
值
没有大量气
流出现
上游压力
小于
泡点值
孔保持力低,导
致低于泡点即
被吹干出现气
流流
Bubble Point Equation
起泡点等式起泡点等式
The bubble point is expressed
泡点可表达为as:泡点可表达为
4 . k . γ . cos θ
BP = P1 P2σBP = -----------------
d
where 这里
P1
Air
Water
d
σ
θ
k = shape correction factor
形状校正因子
= surface tension 表面张力γ = surface tension 表面张力
θ = contact angle 接触角
d = pore diameter 孔径p 孔径
泡点的影响因素
Depends on capillary forces;Depends on capillary forces;
依赖毛细管力
membrane material, surface tension, , ,
contact angle, effective diameter,
膜
材料
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,表面张力,接触角,有效孔径
起泡点说明(包括SOP)应当包
括括
filter type过滤器类型
wetting liquid湿润液体 wetting liquid湿润液体
Temperature温度
minimum pressure最小压力
接触角的影响
Solid / liquid interactionSolid / liquid interaction
固/液相互作用
Changing the wetting fluid
h h b bbl ichanges the bubble point
改变湿润液体会改变起泡点
Applies to
不同的湿润液体 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 pre-use vs. post-use
comparison使用前和使用后比较
Must know the effects
f th h fof the changes, perform
flushing or conduct product bubble
point qualificationpoint 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:
两种无菌过滤膜有同样的细菌截留率,有下列最小的起泡点规格:
Durapore® PVDF CVGL >= 50 psig– Durapore® PVDF CVGL >= 50 psig
– Charged Durapore® PVDF CCGL >= 40 psig
A sterilizing grade filter has is the following minimum bubble point specifications:
种无菌过滤膜有下列最小的起泡点规格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
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 / non-
destructive integrity test correlation integrity testing technique and bacterialdestructive 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
术和细菌挑战理论
Bubble Point Test Applicability
起泡点测试适用性起泡点测试适用性
Useful for qualified manual testing of filters less than
approximately 2000 cm^2 ( 2 sq ft )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 testersrates 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
实验室-小面积起泡点测试实
Flush with water冲洗 Apply air pressure加压
Increase presssure until bubblesIncrease presssure until bubbles
are seen downstream
增加压力直到起泡点在下游出现
试验安排---手工起泡点测试
0 22 PVDF Millidi k 亲水滤芯起0.22um PVDF Millidisk 亲水滤芯起
泡点测试
Diffusion Testing Introduction
扩散流测试介绍扩散流测试介绍
下游气体
上游
缩 Gas dissolves in liquid
held in the pores of a fully wetted
b filt 气体溶解在完全
下游气体
P2
压缩
气体
P1membrane filter.气体溶解在完全
湿润的滤器膜孔内的液体中
A pressure differential will
P1
扩散流 Z
A pressure differential will
give a different gas
concentration across the
P1 > P2
filter.膜压差造成跨膜气体浓度差
Results in gas flow
through the liquid
dissolved in the filter pores.结果
使膜孔溶解的气体流出使膜孔溶解的气体流出
扩散流测试
完整膜 非完整膜完整膜 非完整膜
完全润湿的膜
上游压力 下游气流小 上游压力
破损出现的大
孔会扩散更多
Largest
Pore
上游压力
80%泡点
值
下游气流小
于规定值
上游压力
80%
泡点值
孔会扩散更多
气体使得下游
气流大于规定
值值
Diffusion Testing Equation
扩散测试方程扩散测试方程
Upstream PressurizedUpstream Pressurized
Regulated compressed gas
K . (P1 - P2) . A . ρ
Diffusion = -------------------------
L
where:
K = Diffusivity / Solubility
扩散因子coefficient扩散因子
P1, P2 = Pressure difference across
the system系统两边的压力
ρ M b it 膜开孔率ρ = Membrane porosity膜开孔率
L = Effective path length有效膜孔长度
A = Membrane area膜面积 Gas flow rate measured
downstreamdownstream
Diffusion Test 扩散测试
At pressures below the bubbleAt pressures below the bubble
point, diffusion always occurs在
低于起泡点压力 扩散发生低于起泡点压力,扩散发生
Diffusion testing does not
indicate pore size扩散测试不显indicate pore size扩散测试不显
示膜孔径
At 2 8 bar (40 psig) a 0 22 and At 2.8 bar (40 psig), a 0.22 and
0.1 um rated filters will have the
“same” diffusional flowrates在在
2.8Bar,0.22和0.1um空径膜具有相
同的扩散速率
A Reason for Diffusion Testing
什么情况下采用扩散测试什么情况下采用扩散测试
Bubble Point detection becomes
harder as membrane area
increases
随着膜面积增加起泡点检测变
得困难得困难
Need as much information about
the filter as possible
Gas
Flow
1m 2
需要尽可能多关于膜的信息
Use diffusion testing in
combination with bubble Diff ti l P
0.1m 2
combination with bubble
point testing使用起泡点与
扩散测试相结合
Differential Pressure
Diffusion Test Applicability
扩散测试适用性扩散测试适用性
For filters with gas flowrate of >100 ml/minFor filters with gas flowrate of >100 ml/min
过滤器扩散流速大于100ml/min
high surface area filters大表面积过滤器 high surface area filters大表面积过滤器
thin membranes薄的膜
organic solvent wetted filters有机溶剂湿润的过滤器
Diffusional flow specifications (and the S.O.P.) should
include;扩散速率说明(包括SOP)应当包括
过滤器类型 filter type过滤器类型
wetting liquid湿润液体
test gas测试气体 test gas测试气体
Temperature温度
maximum acceptable flow rate最大接受流速
Factors Affecting Diffusion Tests
扩散测试的影响因素扩散测试的影响因素
W i 湿润度Wetting湿润度
Lower or inconsistent film thickness increases diffusion
低的和不均匀的薄厚会增加扩散 低的和不均匀的薄厚会增加扩散
Fluid流体
Organic solvents have high diffusion flowratesO ga c so ve ts ave g d us o ow ates
有机溶剂有较高的扩散流速
Gas气体
Carbon dioxide has higher gas flow than air or nitrogen
二氧化碳比空气或氮气有较高的扩散流速
T t 温度Temperature温度
80% higher flowrate at 60 degrees
在60摄氏度流速高80%
Poor Venting Proper Venting
在60摄氏度流速高80%
Example of Changed Diffusional Flow举例
Polypropylene cartridge tested with nitrogen at 18.8 psig (1.3 bar )
聚丙烯过滤器用氮气(18.8psig)测试聚丙烯过滤器用氮气(18.8psig)测试
– Acetone <390 ml/min
– IPA <120 ml/min
MESSAGE:
Changing solvents changes diffusional flowChanging solvents changes diffusional flow
Pure organic solvents have high diffusional flow
改变溶剂可改变扩散流速,纯溶剂有较高的流速改变溶剂可改变扩散流速,纯溶剂有较高的流速
– Can mask bubble points
– 可能与起泡点相混
Example of Changed Diffusional Flow举例
Hydrophilic filter is tested with both nitrogen and compressed air at
2.8 bar (40psi)( p )
– Nitrogen < 8 ml/min
Compressed air < 10 ml/min– Compressed air < 10 ml/min
MESSAGE:
Changing the test gas can give a false diffusional flowrate改变测试气
体可以给错误的扩散流速体可以给错误的扩散流速
Example of Changed Diffusional Flow举例
What is the maximum diffusional flow for a 5x30" pleated cartridge filter
system?y
– 10" element < 13.3 ml/min
30" element < 39 9 ml/min– 30" element < 39.9 ml/min
– 5x30" elements < 199.5 ml/min
MESSAGE:
For the same device diffusion is directly proportional to surface area相同For the same device, diffusion is directly proportional to surface area相同
的过滤器,扩散与膜面积成正比
“Diffusion Testing” Summary
扩散测试
总结
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扩散测试总结
Diffusion testing measures gas flow扩散测试测量气体流速
At bubble point gas flows rapidly through the largest pore(s)At bubble point, gas flows rapidly through the largest pore(s)
在起泡点,气体则快速通过最大的孔
Downstream gas flow (or upstream pressure loss) can comeDownstream gas flow (or upstream pressure loss) can come
from both diffusion through the wetted pores PLUS the gas
flow through the “dry” pores which have reached their bubbleflow through the dry pores which have reached their bubble
point
下游气流(或上游压力损失)可以由扩散流和达到起泡点下游气流(或上游压力损失)可以由扩散流和达到起泡点
时流出“干”孔的气流两者引起
Manual Test 手动测试
How to Measure Gas Flow
怎样测量气体流量怎样测量气体流量
Other Integrity Testing Terms
其它完整性测试其它完整性测试
Forward Flow前向流Forward Flow前向流
Marketing term for diffusional flow.
只是扩散的不同说法
P D 压力衰减Pressure Decay压力衰减
Measures the maximum loss of upstream gas pressure with time (typically 10
minutes) on the upstream side of a filter.) p
在过滤器上游测试10分钟上游气体压力的最大损失
Needs a sensitive and accurate pressure measuring device
需要敏感和精确的压力测试装置
Is dependent on upstream volume
与上游体积相关
Can be converted to a "diffusional" flow rate using an equationg q
能够使用算式换算成扩散流速
Useful as a "go" or "no-go" test for gross testing only
仅适合做一些粗的是或不是的测试仅适合做 些粗的是或不是的测试
Overview of Temperature Effects
温度的影响温度的影响
Manual bubble point手动起泡点
Minor effect dependent mainly on surface Minor effect dependent mainly on surface
tension表面张力有小影响
Approximately 15% change from 20 - 60 ºC
从20-60摄氏度15%的改变
As temperature rises, bubble point falls温
度升高,起泡点降低
Manual diffusion test手动扩散测试
Mi ff t l t t t l Minor effect on manual test at normal
ambient range dependent on gas solubility
and diffusivity与气体溶解度和扩散率相关
Approximately 80% change from 20 - 60 ºC Approximately 80% change from 20 - 60 C
从20-60摄氏度80%的改变
As temperature rises, diffusional flow rate
rises温度升高,扩散流速增加度升高 扩散 增加
Automatic test自动测试
Major effect with temperature change
during the test on diffusional
flowrate主要影响测试时的扩散流速
Summary 总结
Bubble point and Diffusion (or “Forward flow”) are BOTH valid Bubble point and Diffusion (or Forward flow ) are BOTH valid
integrity tests as per regulatory agencies.
起泡点 扩散流(或前向流)是符合法规的完整性测试方法起泡点, 扩散流(或前向流)是符合法规的完整性测试方法
The choice of an integrity test depends on the testing equipment, the
filter manufacturer, the company‘s philosophy and the testing environmentp y p p y g
完整性测试的选择倚赖测试装置,过滤器制造商,公司体系和测试环
境
B bbl i t id di t l ti t b t i l t ti th Bubble point provides a direct correlation to bacterial retention, the
critical performance characteristic
起泡点提供与细菌截留的直接关联,重要的性能特性起泡点提供与细菌截留的直接关联,重要的性能特性
Diffusion testing provides a sensitive way to determine integrity for
larger area filters扩散测试提供一个敏感方法来测试大面积过滤器