1、MILLIPORE過濾/完整性測試培訓課程Integrity Testing Theory完整性測試理論MILLIPORE內容提要為什么要對除菌濾器進行完整性測試?完整性測試的方法有哪些？為什么可以用起泡點的方法代替細菌挑戰試驗?什么時候進行完整性檢測? 起泡點測試原理是什么？ 擴散流測試原理是什么？自動完整性測試儀MILLIPORE完整濾膜非完整濾膜MILLIPOREMILLIPORE比膜孔大的污染物比膜孔大的污染物o ° o ° °O 匸 C ° O00%°o°o o ° ° o ° oMILLIPO

2、REMILLIPORE下游沒有污染物MILLIPOREWhy Integrity Test?MILLIPORE為存么做完墓性測試？Common Sense通常理解 Filti'ation is often tlie most critical step in an operation過濾通常是操作的關鍵步驟 Confinnation of manufacturers specifications確認制造規格 Detecting leaks due to o-nngs, gaskets, seals檢測0形環，墊圈，密封墊的泄漏 Assiumg tlie coiTect pore siz

3、e filter確認正確的過濾孔徑 Assuring integrity before sterilization確認滅菌前完整性 Assiumg integrity after steammg or autoclavmg確認蒸汽和消毒鍋滅菌后完整性Bus mess Practice 商業慣例 Government Guideluies & Regulations法規要求 Part of coiporate staiidaid operatuig piocedure公 司 標準操作規程Auditing Tequirement審彳十需要MILLIPOREGuidance for Indu

4、strySterile Drug ProductsProduced by Aseptic Processing Current Good Manufacturing Practice'爐mF /'FI< Ar ifSF皿 O出.Wk ET法規中對完整性測試的規定FDA Guideline指南(2003)一 Whatever filter or combination of filters is used, validation should include microbiological challenges to simulate worstcase productio

5、n conditions”對于由一個或多個濾器組成的過泯 系統,對它的驗證都應該包括在最差條件下進行的微生物挑戰 試驗。MILLIPOREI、IK pmrin of Ikaltte 4inl llv«4n Srrkc% nl ！ 1衍成< <Mer 仏I ndb i< l>l R>< cure2d小Rccv“h“Tll Ri<lllkc ttcxukiltir%l<*H Srplcno»<r ilKMPli4riii»c<tttiil ( S、ll%MILUPORE法規中對完整性測試的規定Revision

6、 of annex 1 to EC Guide to GMP for sterile medicinal products (1997) 歐盟對于無菌藥品GMP指南的附件一 (1997版)一 “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 test55-

7、除菌過濾膜應該在使川前及使用后立即采取合適的方法確認其完整性，可以采用 泡點,擴散流或壓力保持的方法.FDA Guideline on Sterile Drug Products Produced by Aseptic Processing (1987) FDA對于無菌操作生產的無菌藥品的要求(1987版)一 “Normally, integrity testing of the filter is performed after the filter unit is assembled and sterilized prior to use.”-完整性測試通常在過濾器安裝，滅菌后使用前進行P

8、DA Technical Report # 26PDA技術報告26版一 “It generally is regarded as a cGMP requirement that filters or filter systems routinely be integrity tested both prior to and after use.55-現行的GMP要求過濾器及過濾系統在使用前及使用后均需要進行完整性測試Where & When Do We Integrity Test? 何時和何地做完整性測試？WHEN TO DO IT?什么時候做？DETECTS WHAT? 檢查什么？

9、Before sterilization滅菌前Faulty housings 外殼島問題Before use使用前Out-of-the box failures 包裝以外的問題After use使用后Sterilization induced failures滅菌的影響Stress induced failures壓力的影響What Are The Integrity Testing Choices? 完整性測試的選擇？ 分類測試名標準測試實施者破壞性細菌挑戰測徐制造商以及客戶進行驗證時 進行非破壞性起泡點測試，擴散測試制造商出廠時及使用者現場 進行Regulatory & quali

10、ty organizations need data from both to assure reliable and predictable filter performance法規和質量管理需要數據確保可靠和預知 過濾器性能MILLIPOREDestructive vs. Non-destructive Testing 破壞性和非破壞性測試There must be a correlation between a destructive and a non-destructive integrity test 破壞性和非破壞性測試兩鳥必須有 關聯 Regulatory requiremen

11、t法規需要 FDA Aseptic Guidelines FDA無菌指南 Validation justification for the use of a test測試應用的驗證理由Integrity Testing Correlations 完整性測試關聯MILLIPOREMILLIPORE3m<> NOE弓OC Oo-JUJCDomwBUBBLE POINT (in psi)MILLIPOREMILLIPOREBubble point can have a direct correlation起泡點有直接的關聯Diffusion & other tests can h

12、ave an ngo no gon correlation擴散和其它測試有汀通過，不通過汀關 連MILLIPOREWhat Nou-Destructive Integrity Tests are AvailablM1 LL|PORE 何種非破壞性測試合適？®Capillary based tests 基于毛監管測試 Bubble Point起泡點 HydroCorr 擠水法 Corrtest水壓法Diffusive based tests基于擴散測試 Difiusion 擴散 Forward Flow前向流 Pressure hold / decay壓力保持/ 衰減Bubble Po

13、int Introduction 起泡點介紹MembraneBubble point is the pressure at which gas displaces liquid fi om tlie largest set of filter pores and flows rapidly tlnough the filter 起泡點是氣體從濕潤的最大膜孔擠出液體快 速流出時的壓力Bubble point indicates tlie magnitude of tlie forces holding liquid in the filter stmctiue 起泡點顯示過濾結構內保持液體的力的

14、大小The oldest non-destmctive integrity test 最傳統的非破壞性測試MILLIPORE泡點測試全潤濕的膜閩沒有大量氣 流出現Lareest破損出現的大 孔保持力低，導 致低于泡點即 被吹干出現氣 流上游壓力 小于 泡點值非完整膜MILLIPOREBubble Point Equation 起泡點等式UlThe bubble point is expressedas:泡點可表達為4 . k . y. cos 9BP=dwhere這里k = shape correction factor 形狀校正因子y = surface tension 表面張力0 = co

15、ntact angle 接觸角d = pore diameter 孑0徑泡點的影響因素Depends on capillary forces; 依賴毛細管力 membrane material, surface tension, contact angle, effective diameter,膜材料，表面張力,接觸角，有效孔召起泡點說明（包括SOP）應當包 括 filter type過濾器類型 wetting liquid濕潤液體 TemperatuTe 溫度minimum pressuw最小壓力MILLIPORE接觸角的影響Solid / liquid interaction固/液相互作

16、用 Changing the wetting fluid changes the bubble point改變濕潤液體會改變起泡點Applies to different wetting fluid不同的濕潤液體 different swfacechemistries不同的表面化學性 pre-use vs. post-use comparison使用前和使用后比較Must know the effectsMore Hvd<O0hMicenrttCosine0出of the changes, performflushing or conduct product bubble point q

17、ualification必須知道變化的影響，進行沖洗或用 產品泡點確認Conkcl- Ancle (degrees!Effect of Contact Ang e on i1fsO.R75 30 85 SOExamples of the Effect of Contact Angle and Surface Tension也jjpore Bubble Point Values接觸角和表面張力對起泡點值的影響實例Two sterilizing grade filters with identical bacterial retention claims and performanee have

18、the following minimum bubble point specifications:兩種無菌過龜膜有同樣的細菌截菌率，有下列最小的起泡點規格：-Durapore® PVDF CVGL>= 50 psigbubble point specifications:50 psig18.5 psig-Charged Durapore® PVDF CCGL >= 40 psigA sterilizing grade filter has is the following minimum 一種無菌過蒲膜有下列最小的起泡點規格：-Water>=-70/30

19、 IPA>=nt test values do not mean better filters 意味好的過濾膜Higher b 哥起泡點-Check the filter manufacturer's validation guide for the destructive / nondestructive integrity test correlation, integrity testing technique and bacterial challenge method完整性測試關連的驗證文本，完整性測試技-楂查垃薩月竟初造商 術和細菌挑戰理論MILLIPOREBubbl

20、e Point Test Applicability 起泡點測試適用性Useful for qualified manual testing of filters less than approximately 2000 cmA2 （2 sq.ft）手動測試通常適用于過濾器面積小于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自動完整性測試儀適用于氣

21、體流速超過100毫升/分鐘或自 動測試儀的限定實驗室-小面積起泡點測試MILLIPOREMILLIPOREFlush with water沖洗Apply air pressure加壓MILLIPOREIncrease presssure until bubbles are seen down stream增加壓力直到起泡點在下游出現試驗安排-手工起泡點測試S60.22um PVDF Millidisk 親水濾芯起 泡點測試Diffusion Testing IntroductionMILLIPORE擴散流測試介紹下游氣體P2 Gas dissolves in liquidheld in the

22、 pores of a fully wetted membrane filter'氣體溶解在完全 濕潤的濾器膜孔內的液體中 A pressure differential will give a different gas concentration across thefilter.膜壓差造成跨膜氣體濃度差上游 壓縮' 氣體Pl 擴散流(u-dv-uz £sso_u.SeoGas PressurePl > P2 Results in gas flow through the liquid dissolved in the filter pores.結果 使膜孔

23、溶解的氣體流出MILLIPORE擴散流測試上游壓力80%泡點 值下游氣流小 于頂定值非完整破損出現的大 孔會擴散更多 氣體使得下游 氣流大于規定 值上游壓力80%泡點值MILLIPOREDiffusion Testing Equation 擴散測試方程Regulated compressed gasK.(P1 -P2).A.pDiffusio n =Upstream Pressurizedwhere:K = Diffiisivity / Solubility coefficient擴散因子Pl, P2 = Pressiue differenceacrossthe system系統兩邊的壓力p

24、= Membrane porosity開孑b率L = Effective path length有效膜孔長度A = Membrane area 面積i is % iA<<<<< 卜Gas flow rate measured dow nstreamMILLIPOREDiffusion Test 擴散測試At pressures below the bubble point, diffusion always occurs在 低于起泡點壓力，擴嵌發生Diffusion testing does not indicate pore size擴散測試不顯i 示膜孔徑1

25、At 2.8 bar (40 psig), a 0.22 and0.1 um rated filters will have the usameJ, diffusional flowrates在2.8Bar,0.22和0.1 um空徑膜具有相同的擴散速率MILLIPOREGas FlowA Reason for Diffusion Testing 什么情況下采用擴散測試Bubble Point detection becomes harder as membrane area increases隨著膜面積增加起泡點檢測變 得困難Need as much information about th

26、e filter as possible需要盡可能多關于膜的信息 Use diffusion testing in combination with bubble point testing使用起泡點與 擴散測試相結合Diffusion Test Applicability擴散測試適用性For filters with gas flowrate of >100 ml/min 過濾器擴散流速大于lOOml/min high surface area filters大表面積過濾器 thin membranes薄的膜 organic solvent wetted filters有機溶劑濕潤的過

27、濾器Diffusional flow specifications （and the S.O.PJ should include;擴散速率說明（包括SOP）應當包括 filter type過濾器類型 wetting liquid濕潤液體 test gas測試氣體 Temperature 溫度 maximum acceptable flow Tate最大接受 流速Factors Affecting Diffusion Tests 擴散測試的影響因素Vetting濕潤度 Lower or inconsistent film thickness increases diffusion Q低的和不均勻

28、的薄厚會增加擴散JlFluid 流體 Organic solvents have high diffusion flowratesII w I有機溶劑有較高的擴散流速"Gas氣體 Carbon dioxide has higher gas flow than air or nitrogen二氧化碳比空氣或氮氣有較高的擴散流速| ."emperatu re 溫度Proper VentingPoor Venting 80% higher flowrate at 60 degrees 在6 0攝氏度流速咼80%MILLIPOREExample of Changed Diffusi

29、onal Flow舉例psig (1.3 bar)Polypropylene cartridge tested with nitrogen at 18. 聚丙烯過濾器用氮氣(188psig)測試-Acetone<390 ml/min-I PA<120 ml/minMESSAGE:Changing solvents changes diffusional flow Pure organic solvents have high diffusional flow 改變溶劑可改變擴散流速,純溶劑有較高的流速-Can mask bubble points-可能與起泡點相混Example o

30、f Changed Diffusional Flow舉例Hydrophilic filter is tested with both nitrogen and compressed air at 2.8 bar (40psi)-Nitrogen< 8 ml/min-Compressed air < 10 ml/minMESSAGE:Changing the test gas can give a false diffusional flowrate改變測試氣 體可以給錯誤的擴散流速MILLIPOREWhat is the maximum system?-10n element-30

31、” element-5x30" elementsExample of Changed Diffusional Flow舉例diffusional flow for a 5x30” pleated cartridge filter<13.3 ml/minv 39.9 ml/minv 199.5 ml/minMESSAGE:For the same device, diffusion is directly proportional to surface area扌目同 的過濾器，擴散與膜面積成正比MILLIPORE“Diffusion Testing” Summary 擴散測試總

32、結Diffusion testing measwres gas flow擴散測試測量氣體流速 At bubble point, gas flows rapidly through the largest pore(s) 在起泡點，氣體則快速通過最大的孔Downstream gas flow (or upstream pressure loss) can come from both diffusion through the wetted pores PLUS the gas flow through the "dr/ pores which have reached their b

33、ubble point下游氣流(或上游壓力損失)可以由擴散流和達到起泡點 時流出“干”孔的氣流兩者引起Manual Test手動測試Diffusion / Bubble Point ProcedureHydrophilic 0 2 micron filterTime (minutes)(一sd)Enssai:How to Measure Gns30WZ-EszmGasOther Integrity Testing Terms 其它完整性測試Forward Flow前 向流 Marketing term for diffusional flow. 只是擴散的不同說法亠Pressure Decay

34、壓力衰減 Measures the maximum loss of upstream gas pressure with time (typically 10 minutes) on the upstream side of a filter.-在過濾器上游測試10分鐘上游氣體壓力的最大損失 Needs a sensitive and accurate pressure measuring device-需要敏感和精確的壓力測試裝置 Is dependent on upstream volume-與上游體積相關 Can be converted to a "diffusional&q

35、uot; flow rate using an equation能夠使用算式換算成擴散流速 Useful as a "gon or"no-go" test for gross testing only-僅適合做一些粗的是或不是的測試Overview of Temperature EffectsMILLIPORE溫度的影響Manual bubble point于動起泡點 Minor effect dependent mainly on surface tension表面張另有小影響 Approximately 15% change from 20 - 60 QC 從20