7自动完整性测试仪

Automated Integrity Testers 自动完整性测试仪 What you will learn 你可以了解 • Why people use automatic integrity testers 为何用户会选用自动完整性测试仪 • How to determine gas flow rate from pressure decay measurements 如何从压力衰减测试中知道气体的流速 • How automatic testers measure bubble point and diffusion 自动测试仪如何测量泡点及扩散 • The impact of temperature on pressure decay measurements 温度对压力衰减测试的影响 • How to fully interpret the printed results from an automatic integrity test 如何从一完整性测试中去完全解释打印出的结果 Why Do People Use Automatic Testers 为何用户会选用自动测试仪 • Ability to perform test without risk to downstream sterility 可以在排除下游无菌状态受到影响的情况下操作 – Post SIP testing – 可以在蒸气灭菌后操作 • Hard copy printout 有打印文本 • Eliminate operator subjectivity 排除操作人员的主观因素 • Validatable 可验证的 Post SIP Integrity Testing 灭菌后完整性测试 • Revision of annex 1 to EC Guide to GMP for sterile medicinal products (1997) • 欧盟对于无菌药品GMP的要求的附件一(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” – 除菌过滤膜应该在使用前及使用后立即采取合适的办法去验证及确认其 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) – “Normally, integrity testing of the filter is performed after the filter unit is assembled and sterilized prior to use.” – 完整性测试通常是在过滤器安装后进行,然后在使用前需要灭菌 • PDA Technical Report # 26 • PDA技术报告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.” – 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 Automated Integrity Testing 自动完整性测试 • A. During integrity testing gas molecules leave the system due to diffusion or bulk flow • 在完整性测试中,气体流失的原因 是扩散及穿孔后的流失 • B. Fewer gas molecules upstream results in lower pressure. • 压力越低,上游气体流失越少 • C. All else being constant, the change in pressure can be used to determine the gas flow rate • 在其它参数保持稳定的状况下,压 力的改变可以去测得气体的流速 Ideal Gas Law 理想气体定律 • PV = nRT – Where其中: • P = pressure 压力 • V = volume 体积 • n = number of gas molecules气体分子数 • R = gas constant 气体常数 • T = temperature温度 • Key Point - The pressure in a closed system is directly related to the number of gas molecules in the system. • 关键点:在密闭系统内,压力直接与气体的分子数有关 Relating Pressure Decay to Gas Flow Rate 压力衰减与气体流速的关系 Gas flow rate calculation 气体流速计算 Where其中 N = Gas flow rate 气体流速 ΔP = Pressure decay压力衰减 ttest = time (min)时间 Patm = atmospheric pressure大气压 Vu = housing volume (cc)外壳体积 atmtest u Pt VPN × ×Δ= Pressure Drop Conversion for Gas Flow 压力衰减转化至气体流量 Diffusion rate x Time x 14.7 psi Pressure Decay = Upstream Volume Example: Maximum Allowable Pressure Drop for 1 10" CVGL Durapore cartridge a 1 X 10" housing 例: 在1根10英寸外壳中,1根10英寸CVGL滤芯允许的最大压降 13.3 cc/min. x 1 min. X 14.7 2000 cc's 0.1 psi = How Automatic Testers Determine Integrity 完整性测试仪如何工作 • Dependent on upstream volume • 依据上游体积 • Dependent on gas flow curve properties of the filter • 依据过滤器的气体流量曲线 – Diffusion is gas flow measurement at a single pressure – 扩散是在单一压力下测量的气体流 – Bubble point is a determined by measuring gas flow multiple times at increasing pressures – 泡点是在不断加压的情况下多次测量气体流的情况下而得的. Upstream Volume Measurement 上游体积的测量 P1V1 = P2V2 – Internal tank is V1 – 内部储罐是V1 – P1 is measured – P1是测量而得 – Valve between internal tank and housing opens – 在内部储罐及外壳之间 的阀门是开的 – P2 is measured – P2是测量而得 – V2 is calculated – V2是计算而得 XDCR Tank Test Filter Gas Flow Curve 气体流速曲线 „ Diffusion and Bubble point together make up a "gas flow curve“ „ 扩散及泡点共同组成了一个”气体流速曲线” Î If flow is due to diffusion, it will increase linearly vs. delta P Î如果流速是由扩散而造成,流速与压降成正比 Î If flow is a combination of diffusion and bulk flow, it will increase exponentially vs. delta P Î如果流速由扩散流及穿孔流共同组成,流速与压差成指数关系 gas flow delta P diffusive flow B. Pt. Gas Flow Curve – Diffusion 气体流速曲线—扩散 • During diffusion, gas flow will increase linearly vs. delta P • 在扩散中,气体流速与压降成正比 – Therefore, the gas flow curve based on diffusive flow can be determined from the specification. – 因此,基于扩散流的气体流速曲线可从公式得到 gas flow delta P Specified Test Pressure Specified Maximum Diffusion Rate Automated Test Procedure – Diffusion 自动测试步骤---扩散 P r e s s u r e 压 力 Time时间 Empty Upstream 排空上游System Size 测试系统 体积 Stabilize 稳定 Diffusion Test 扩散测试 atmtest u Pt VPN × ×Δ= Where其中: N = Diffusion rate扩散流 ΔP = Pressure decay压力衰减 ttest = time (min)时间 Patm = atmospheric pressure 大气压 Vu = housing volume (cc) 外壳体积 Gas Flow Curve = “Enhanced Bubble Point“ 气体流速曲线=增强起泡点 • Measure gas flow at increasing delta P intervals • 在增加压力的间隔下测试流速 • Plot results • 用点来 表 关于同志近三年现实表现材料材料类招标技术评分表图表与交易pdf视力表打印pdf用图表说话 pdf 示结果 • Look for point where gas flow increases greater than expected based on linear extrapolation • 当气体流速增加大于线性推断的数值时,泡点也就找到了 gas flow delta P diffusive flow B. Pt. Automated Test Procedure 自动测试步骤 P r e s s u r e 压 力 Time 时间 Empty Upstream 空的上游 体积 System Size 系统计算 Stabilize 稳定 Diffusion Test 扩散测试 Bubble Point Test 起泡点 Interpreting the Gas Flow Curve 解释气体流速曲线 • Method used by Exacta • Exacta使用的方法 – Two Tangent Method – 两线相切的方法 • Determine the slope of diffusive flow curve • 得到扩散流曲线的斜率 • Determine the slope of bulk flow curve • 得到穿破流曲线的斜率 • Bubble point is pressure where the two curves intersect • 泡点就是两线相交时的压力值gas flow delta P Bubble Point Which Test To Use? 使用了何种测试 • Depends on device size and detection method 依靠的设备尺寸及测试方法 – Manual Bubble Point Test – 手动泡点测试 • Less than 2 ft2 devices • 膜面积小于2平方英尺 – Manual Diffusion test – 手动扩散测试 • Any device greater than 2 ft2 • 大于2平方英尺的所有膜 – Automated Testing – 自动测试 • Bubble point up to about 70 ft2 - (dependent on transducer sensitivity and manufacturers qualification)面积可至70平方英尺(取决于传感器的灵 敏度及生产商的条件) • Diffusion on any size device扩散可在任何尺寸的设备上使用 Effect of Temperature on Bubble Point 温度对起泡点的影响 • Effect of temperature on surface tension • 温度影响表面张力 • Very little effect near ambient temperatures • 在室温附近影响不大 • Watch out at elevated temperatures such as with hot WFI • 在升高温度时,特别是使用 热的注射用水时需要小心 80 60 40 20 0 1006020 Temp. (º C) (d yn es /c m ) Effect of Temperature on Diffusion 温度对扩散的影响 • As Temperature increases, Diffusivity increases • 温度上升,扩散率增加 – Specified test temperature is 23 C.指定测试温度23度 – Less than 10% variation in normal ambient range – 在室温范围内,一般小于10%的变化 Effe c t o f T e m p e ra tu re o n D i ffu sio n a l F lo w ra te 0 .8 1 .0 1 .2 1 .4 1 .6 1 .8 2 .0 2 .2 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0 5 5 6 0 6 5 7 0 T e m p e r a tu r e (C ) C o r r e c t i o n F a c t o r ( R e l a t i v e t o 2 3 C ) Effect of Temperature on Automated Testing 温度对自动测试的影响 • Temperature CHANGES during a pressure decay test will have MAJOR impact on test results. • 在压力衰减测试中,温度变化对结果的影响是非常大的. Î Ideal Gas Law - PV = nRT理想气体定律 z As Temperature increases Pressure increases z 温度上升时压力上升 z As Temperature decreases Pressure decreases 温度下降时压力下降 • If the temperature changes even 1oC. during the test, the pressure change WILL NOT be solely due to gas flow • 在测试中,温度变化1度,压力的变化不仅仅归于气体流失 Î Additional pressure loss or pressure gain are test error Î 额外的压力损失及增加使测试错误 Temperature Effects 温度影响 • Heating the housing加热外壳 – Increases the upstream gas pressure增加上游的气体压力 – Negates diffusional flow through the membrane – 穿过膜的是负的扩散流 – Can potentially cause a false pass潜在的会导致错误的成功 • Cooling the housing冷却外壳 – Decreases the upstream gas pressure降低上游的气体压力 – Adds to the measured pressure decay会增加测量到的压力衰减 – Can potentially cause a false failure会导致错误的失败 Temperature Changes 温度变化 • Temperature changes can be due to: • 温度变化是由以下因素引起 – Inadequate stabilization after steaming – 灭菌后,冷却时间不够 – Touching the housing – 碰到了外壳 – Heating the automated tester – 加热了自动完整性测试仪 – Environmental changes during testing – 在测试中,环境温度变化 – Expansion and contraction – 膨胀及压缩 Interpreting the Printout 解释打印的结果 • Important to look at the whole printout, not just the words “PASSED” or FAILED” • 流览整个打印报告是非常重要的,而非仅看”通过”或”失败” • Check for:核实 – Changes is gas flow rate气体流速的改变 • Temperature changes during the test测试中温度的变化 – Very low gas flow rates气体流速非常低 • Increasing temperature温度的提高 • Improperly closed valves不正确的关闭阀门 – Marginally high gas flow rates非常高的气体流速 • Leaks泄露 – Product specifications产品的规格 • Does the test program match the type of filter?测试程序是否能适用于 此种滤芯? • Correct volume?体积是否正确? Automatic Tester Troubleshooting 自动测试仪故障检查 • Checking for leaks泄漏检查 – Run a concurrent test by measuring the gas flow on the filter outlet at the same time the instrument controls and measures upstream pressure. – 在测量上游压力时,同时测量过滤膜下游的气体 流速 Summary总结 • Main advantage of automatic integrity testers is ability to easily test sterilized systems • 自动完整性测试仪的优点是能够容易的测试无菌系统 • Upstream pressure decay measurements are related to actual downstream gas flow • 上游压力衰减与下游气体的流速相关 • Automated integrity test systems are VERY sensitive to temperature changes • 自动完整性测试仪对于温度的变化非常敏感 • Interpreting the test result is more than just looking for “PASSED” or “FAILED” • 看结果时不应只看”通过”或”失败” Automated Integrity Testers�自动完整性测试仪 What you will learn�你可以了解 Why Do People Use Automatic Testers�为何用户会选用自动测试仪 Post SIP Integrity Testing�灭菌后完整性测试 Automated Integrity Testing�自动完整性测试 Ideal Gas Law�理想气体定律 Relating Pressure Decay to Gas Flow Rate�压力衰减与气体流速的关系 Pressure Drop Conversion for Gas Flow �压力衰减转化至气体流量 How Automatic Testers Determine Integrity�完整性测试仪如何工作 Upstream Volume Measurement�上游体积的测量 Gas Flow Curve�气体流速曲线 Gas Flow Curve – Diffusion�气体流速曲线—扩散 Automated Test Procedure – Diffusion�自动测试步骤---扩散 Gas Flow Curve = “Enhanced Bubble Point“�气体流速曲线=增强起泡点 Automated Test Procedure�自动测试步骤 Interpreting the Gas Flow Curve�解释气体流速曲线 Which Test To Use? �使用了何种测试 Effect of Temperature on Bubble Point�温度对起泡点的影响 Effect of Temperature on Diffusion�温度对扩散的影响 Effect of Temperature on Automated Testing�温度对自动测试的影响 Temperature Effects �温度影响 Temperature Changes�温度变化 Interpreting the Printout�解释打印的结果 Automatic Tester Troubleshooting�自动测试仪故障检查 Summary总结