5、過(guò)濾工藝驗(yàn)證-頓昕

1、Filtration process review過(guò)濾工藝審核頓 昕 密理博公司市場(chǎng)部驗(yàn)證經(jīng)理Bill_dunmillipore Areas reviewed in process review 涉及內(nèi)容Operator training過(guò)濾操作者培訓(xùn)Filtration equipment assembly and use 過(guò)濾設(shè)備的管理Documentation文件建立與管理Control of filter devices 過(guò)濾器管理Process control and environmental Monitoring過(guò)濾過(guò)程控制與環(huán)境監(jiān)控包括人員和物料Sterilization of

2、 filters 過(guò)濾芯及過(guò)濾安裝的滅菌Water systems filtration水純化及其中過(guò)濾系統(tǒng)管理Validation of filters過(guò)濾器驗(yàn)證Agenda提綱Risk assessment in Filtration Process 過(guò)濾工藝中的風(fēng)險(xiǎn)分析Filter application and Qualification 過(guò)濾器的運(yùn)用與確認(rèn)Filter Integrity testing 過(guò)濾器完好性測(cè)試Filtration process Validation 過(guò)濾工藝驗(yàn)證Filtration process review 過(guò)濾工藝審核藥害事件與滅菌平安性滅菌工藝選

3、擇的決策樹(shù) 產(chǎn)品能否可以121濕熱滅菌15分鐘 產(chǎn)品能否可以濕熱滅菌F08分鐘，到達(dá)SAL106產(chǎn)品處方能否可以經(jīng)過(guò)微生物滯留過(guò)濾器過(guò)濾四運(yùn)用無(wú)菌組分配制和灌封一運(yùn)用高壓滅菌鍋12115分鐘三無(wú)菌過(guò)濾和無(wú)菌加工結(jié)合運(yùn)用否是否是否是二運(yùn)用濕熱滅菌F08分鐘不同滅菌工藝的無(wú)菌保證才干過(guò)度殺滅法Fo1210-6熱穩(wěn)定性好的產(chǎn)品以殺滅微生物作為實(shí)現(xiàn)無(wú)菌的手段殘存概率法Fo810-6熱穩(wěn)定性一般產(chǎn)品工藝過(guò)程將防止產(chǎn)品被耐熱菌污染放在首位,而不是僅依賴(lài)最終滅菌去消除污染 流通蒸汽法不計(jì)算Fo0.1%熱不穩(wěn)定產(chǎn)品以無(wú)菌生產(chǎn)工藝（除菌過(guò)濾）為基礎(chǔ)，加熱是除菌過(guò)濾的補(bǔ)充手段除菌過(guò)濾法LRV70.1%不能加熱的產(chǎn)

4、品LRV=log reduction value 過(guò)濾對(duì)數(shù)下降值,一般上游為107下游為1，則LRV=7除菌過(guò)濾的風(fēng)險(xiǎn)過(guò)濾前料液的生物負(fù)荷過(guò)濾器的選擇風(fēng)險(xiǎn)與驗(yàn)證困難過(guò)濾工藝的操作與控制過(guò)濾系統(tǒng)的設(shè)計(jì)與滅菌驗(yàn)證Processdesign過(guò)濾設(shè)計(jì)FilterSterilisation過(guò)濾器的滅菌TesterIQ OQ檢測(cè)儀的安裝運(yùn)轉(zhuǎn)確認(rèn)Bioburden Sterility 生物負(fù)荷的降低Bacteriaretention細(xì)菌截留Physical characteristic物理性質(zhì)Adsorption吸附性Productspecific產(chǎn)品完好性測(cè)試,規(guī)范及 方法FilterintegrityT

5、est過(guò)濾器的完好性檢測(cè)Compatibility兼容性Filterintegrity testoperator certification濾器操作者資歷證書(shū)滅菌過(guò)程設(shè)計(jì),規(guī)范操作程序的培訓(xùn)Steritest school無(wú)菌培訓(xùn)取樣設(shè)備IQ OQ微生物方法驗(yàn)證airsurfacesfluids滅菌過(guò)程設(shè)計(jì),規(guī)范操作程序的制定,滅菌驗(yàn)證Filterabilitystudies過(guò)濾線(xiàn)的設(shè)計(jì)Engineering施工,RegulatoryCompliance法規(guī)Sterility Assurance無(wú)菌保證生物負(fù)荷確實(shí)認(rèn)預(yù)過(guò)濾Extractables析出物TrainingEducation培訓(xùn)Fi

6、lterperformance過(guò)濾器性能AgendaRisk analysis in Filtration Process 過(guò)濾工藝中的風(fēng)險(xiǎn)分析Filter application and Qualification 過(guò)濾器的運(yùn)用與確認(rèn)Filter Integrity testing 過(guò)濾器完好性測(cè)試Filtration process Validation 過(guò)濾工藝驗(yàn)證Filtration process review除菌過(guò)濾 在無(wú)菌藥品消費(fèi)中的運(yùn)用消毒劑滅菌設(shè)備干熱滅菌水預(yù)處置純蒸汽發(fā)生器高風(fēng)險(xiǎn)操作區(qū)域混合灌裝其他VHP,EO發(fā)生器緊縮空氣無(wú)菌檢測(cè)清洗設(shè)備蒸汽滅菌最終滅菌凍干機(jī)認(rèn)識(shí)我們運(yùn)用

7、的過(guò)濾器認(rèn)識(shí)我們運(yùn)用的過(guò)濾器認(rèn)識(shí)我們運(yùn)用的過(guò)濾器過(guò)濾器確認(rèn)根據(jù)過(guò)濾對(duì)象根據(jù)親水或疏水根據(jù)過(guò)濾階段根據(jù)孔徑 根據(jù)材質(zhì) 選擇過(guò)濾器方式選擇過(guò)濾面積 0.22m123451 根據(jù)過(guò)濾對(duì)象 objective of filtration反 滲 透超 濾微 濾粒 子 過(guò) 濾常見(jiàn)2 根據(jù)親水或疏水 Hydrophilic and Hydrophobic材 質(zhì)纖維素資料(NC)尼龍(Nylon)親水聚偏二氟乙烯(PVDF)聚謎砜PES)聚丙烯PP)應(yīng) 用 水, 緩沖液，培育基，藥液選擇過(guò)濾方式2 根據(jù)親水或疏水 Hydrophilic and Hydrophobic3 根據(jù)過(guò)濾階段 Filtration s

8、tage培育基預(yù)過(guò)濾及除菌過(guò)濾廓清過(guò)濾除菌過(guò)濾預(yù)過(guò)濾大/小容量注射劑 LVP and SVP預(yù)過(guò)濾 : Milligard (CWSS) 最終過(guò)濾 : 最終過(guò)濾 Durapore HL (0.45 m) 或(0.22 m)預(yù)過(guò)濾除菌過(guò)濾API原料藥氣 體 除 菌澄 清 過(guò) 濾預(yù) 過(guò) 濾有機(jī)溶劑萃取發(fā) 酵除 熱 源結(jié) 晶切向流濃縮種子培育除 菌 過(guò) 濾預(yù) 過(guò) 濾預(yù) 過(guò) 濾混 和層 析/活性碳/溶劑沉淀孔徑逐漸減小的過(guò)濾系列在過(guò)濾系列開(kāi)場(chǎng)是最大的過(guò)濾容量在過(guò)濾系列終端是最大的過(guò)濾截留率 澄 清 預(yù) 濾 除 菌根據(jù)過(guò)濾階段 Filtration stage能夠有纖維零落截留率小于95%厚度(3-30

9、毫米),通常有吸附較大的承污才干例如-玻璃纖維,線(xiàn)繞式,壓板式壓力承載范圍根據(jù)過(guò)濾階段 Filtration stage: clarification可以給出公稱(chēng)空徑，均勻較薄(小于1毫米),較小吸附給出顆粒減少的比例(95-99.9%)例如-纖維素酯涂纖維或聚酯片多空聚合物鑄造而成，可以控制孔徑，均勻的多，可以預(yù)測(cè)截留情況根據(jù)過(guò)濾階段 Filtration stage: prefiltration堅(jiān)強(qiáng)，硬不易碎，更薄曲折的通道65%-75%開(kāi)孔率大小排除顆粒截流與流速和壓力無(wú)關(guān)無(wú)菌過(guò)濾器必需具有大于99.99999%截流0.22um的意義根據(jù)過(guò)濾階段 Filtration stage: St

10、erilizing filtration除菌過(guò)濾舉例：PVDF過(guò)濾膜1 單層：極低吸附2 高開(kāi)孔濾：高流速3 耐受多次蒸汽滅菌4 單獨(dú)包裝雙層膜的問(wèn)題制造工藝消費(fèi)環(huán)境(Class 100.000十萬(wàn)級(jí)環(huán)境)(Class 10.000) 最終裝配,檢測(cè)及包裝完好性檢測(cè)100%完好性檢測(cè)消費(fèi)技術(shù)與控制全自動(dòng)無(wú)縫結(jié)合溫差實(shí)驗(yàn)及細(xì)菌挑戰(zhàn)Durapore ManufacturingQuality Control Release Tests 過(guò)濾器的質(zhì)量保證4 根據(jù)孔徑廓清過(guò)濾深層過(guò)濾膜0.1um,0.3um,0.5um,1.0um,3.0um,10um,25um,50um,100um,預(yù)過(guò)濾外表過(guò)濾膜0

11、.2um,0.2+0.5um, 0.5+1.2um,除菌過(guò)濾絕對(duì)過(guò)濾膜0.1um,0.22um,0.45um,5 根據(jù)過(guò)濾膜材質(zhì)親水膜材質(zhì)：纖維素資料(NC)尼龍(Nylon)親水聚偏二氟乙烯(PVDF)聚謎砜PES)聚丙烯PP)疏水膜材質(zhì)：聚丙烯PP)疏水聚偏二氟乙烯(PVDF)聚四氟乙烯PTFE)6 根據(jù)濾器構(gòu)造搜集10分鐘內(nèi)，特定壓力下過(guò)濾數(shù)據(jù)Cumulative volume (V) 累積體積Time (t) 時(shí)間7 根據(jù)過(guò)濾面積過(guò)濾器確認(rèn)根據(jù)過(guò)濾對(duì)象根據(jù)親水或疏水根據(jù)過(guò)濾階段根據(jù)孔徑 根據(jù)材質(zhì) 根據(jù)過(guò)濾器方式根據(jù)過(guò)濾面積 0.22m12345AgendaRisk analysis i

12、n Filtration Process 過(guò)濾工藝中的風(fēng)險(xiǎn)分析Filter application and Qualification 過(guò)濾器的運(yùn)用與確認(rèn)Filter Integrity testing 過(guò)濾器完好性測(cè)試Filtration process Validation 過(guò)濾工藝驗(yàn)證Filtration process review Integrity Testing Theory完好性測(cè)試實(shí)際 講座目錄為什么要對(duì)除菌濾器進(jìn)展完好性測(cè)試？完好性測(cè)試的方法有哪些？為什么可以用起泡點(diǎn)的方法替代細(xì)菌挑戰(zhàn)實(shí)驗(yàn)？什么時(shí)候進(jìn)展完好性檢測(cè)？起泡點(diǎn)測(cè)試原理是什么？分散流測(cè)試原理是什么？自動(dòng)完好性測(cè)試儀

13、為什么要進(jìn)展完好性測(cè)試?除菌工藝需求：濾器性能過(guò)濾線(xiàn)的設(shè)計(jì)與濾器滅菌完好性測(cè)試規(guī)范確實(shí)定法規(guī)要求及貿(mào)易需求出口認(rèn)證FDA，COS, EDMF)SDA檢查法規(guī)中認(rèn)可的兩類(lèi)完好性測(cè)試方法分類(lèi)測(cè)試名稱(chēng)測(cè)試實(shí)施者破壞性細(xì)菌挑戰(zhàn)測(cè)試制造商非破壞性起泡點(diǎn)測(cè)試，擴(kuò)散測(cè)試制造商及使用者什么可以用起泡點(diǎn)來(lái)替代挑戰(zhàn)實(shí)驗(yàn)？破壞性和非破壞性測(cè)試兩者必需建立關(guān)聯(lián)應(yīng)該在什么時(shí)候做完好性測(cè)試?滅菌前？滅菌后，過(guò)濾前運(yùn)用前？過(guò)濾后？什么時(shí)候檢測(cè)完好性？ FDA對(duì)無(wú)菌過(guò)濾工藝的指南 “Normally, integrity testing of the filter is performed prior to processi

14、ng, after the filter apparatus has already been assembled and sterilized. 正常情況下, 濾器應(yīng)在過(guò)濾前，即組裝好后，且滅菌后執(zhí)行完好性檢測(cè). “It is important that the integrity testing be conducted after filtration to detect any filter leaks or perforations that might have occurred during the filtration.非常重要的是:在過(guò)濾后對(duì)濾器進(jìn)展完好性檢測(cè),從而查看濾器

15、能否走漏和膜已破損. 什么時(shí)候檢測(cè)完好性？(續(xù))PDA Technical Report n 26 PDA技術(shù)報(bào)告26號(hào)“. It generally is regarded as a cGMP requirement that filters or filter systems routinely be integrity tested both prior to and after use.“ 普通以為過(guò)濾前后的常規(guī)性完好性檢測(cè)是現(xiàn)行GMP的要求.EU GMP“The integrity of the sterilised filter should be verified before

16、use and should be confirmed immediately after use by an appropriate method such as bubble point, diffusive flow or pressure hold test.對(duì)于已滅菌的濾器的完好性檢測(cè)應(yīng)該在運(yùn)用前和運(yùn)用后立刻執(zhí)行,例如泡點(diǎn),分散流及壓力堅(jiān)持實(shí)驗(yàn).應(yīng)該在什么時(shí)候做完好性測(cè)試? 起泡點(diǎn)是氣體從潮濕的最大膜孔快速流出的壓力起泡點(diǎn)顯示過(guò)濾構(gòu)造內(nèi)堅(jiān)持液體的力的大小最傳統(tǒng)的非破壞性測(cè)試起泡點(diǎn)測(cè)試原理壓力P2空氣Waterd起泡點(diǎn)等式起泡點(diǎn)可表達(dá)為: 4 . k . . cos BP = - d

17、這里k =外形校正因子 = 外表張力 = 接觸角d = 孔徑P1P2AirWaterd起泡點(diǎn)合格規(guī)范不同孔徑規(guī)范不同CVVL PVDF 0.1um 23攝氏度 水 =70psi不同材質(zhì)規(guī)范不同CCGL 帶正電荷PVDF 0.22um 23攝氏度 水 =39psi不同潤(rùn)濕液體不同CVGL PVDF 0.22um 23攝氏度 水 =50psi 70/30 IPA=18.5 psi測(cè)試起泡點(diǎn)的方法 沖洗 加壓添加壓力直到延續(xù)起泡在下游出現(xiàn)分散流檢測(cè)原理施 加 壓 力P0PLALP1P2AirWaterd分散流測(cè)試方法上 游 壓 力緊縮空氣下游監(jiān)測(cè)氣流速度HydroCorr TestResistanc

18、e to water intrusion水浸入法測(cè)試02.6bar02.6barP atmP atm02.6bar02.6bar01020Time (min.)Install dry cartridge裝上干的濾芯Fill upstream w/ water在上游充溢水a(chǎn)pply pressureand hold加壓并堅(jiān)持Measure pressureDecay丈量壓力衰減Pressure causes pleats to compact - resulting in apparent water flow壓力導(dǎo)致折疊式濾膜進(jìn)一步緊縮景象是有一定的水流完好性測(cè)試失敗處置措施交換過(guò)濾柱并且退回

19、膜去分析再潮濕過(guò)濾器，運(yùn)用兩倍于初次潮濕壓或沖洗量或浸泡時(shí)間或者運(yùn)用高壓差在過(guò)濾器兩邊再測(cè)試過(guò)濾器能否經(jīng)過(guò)測(cè)試完好性測(cè)試評(píng)價(jià)能否改動(dòng)否是運(yùn)用前能否邊緣失敗是否他能否重裝過(guò)濾柱用規(guī)范程序重裝和沖洗過(guò)濾器記錄價(jià)值和程序能否再測(cè)試是否運(yùn)用后測(cè)試在運(yùn)用前還是運(yùn)用后能否邊緣失敗沖洗過(guò)濾器，運(yùn)用兩倍沖洗量或者浸泡時(shí)間再測(cè)試過(guò)濾器能否經(jīng)過(guò)測(cè)試沖洗過(guò)濾器，運(yùn)用兩倍于初次潮濕壓或者運(yùn)用高壓在過(guò)濾器兩邊記錄價(jià)值和程序完好性測(cè)試評(píng)價(jià)能否接近規(guī)范值70/30異丙醇潤(rùn)濕，檢測(cè)是否是否否是AgendaRisk analysis in Filtration Process 過(guò)濾工藝中的風(fēng)險(xiǎn)分析Filter applicat

20、ion and Qualification 過(guò)濾器的運(yùn)用與確認(rèn)Filter Integrity testing 過(guò)濾器完好性測(cè)試Filtration process Validation 過(guò)濾工藝驗(yàn)證Filtration process review過(guò)濾驗(yàn)證總結(jié)法規(guī)部門(mén)的要求過(guò)濾器驗(yàn)證流程為什么運(yùn)用者要對(duì)過(guò)濾器進(jìn)展驗(yàn)證？過(guò)濾器驗(yàn)證包括那些工程？再驗(yàn)證周期及條件US GMP 21 CFR Parts 210 & 211 美國(guó)GMPAppropriate written proceduresshall be established and followed. Such procedures sha

21、ll include validation of any sterilization process必需建立和跟進(jìn)相應(yīng)的證明性文件.,，這些文件中包括一切的除菌工藝的驗(yàn)證文件EU GMP Annex 1 Sterile Medicinal Products 歐盟GMP 無(wú)菌藥品附錄All sterilization processes should be validated一切除菌工藝必需進(jìn)展驗(yàn)證Filter Validation is Required Worldwide by GMP世界各國(guó)法規(guī)要求進(jìn)展過(guò)濾器驗(yàn)證Filter Validation is Required Worldwide

22、 by GMP世界各國(guó)法規(guī)要求進(jìn)展過(guò)濾器驗(yàn)證續(xù)Australian TGA GMP 澳大利亞 TGA GMPFiltration processes used as the sterilizing step for products should be validated出于除菌目的過(guò)濾工藝應(yīng)該驗(yàn)證Health Canada GMP 加拿大GMPDocumented evidence is available establishing validation and validity of each sterilization process每步除菌工藝必需求有驗(yàn)證其有效性的證明性文件Filte

23、r Validation in Regulatory and Industry Guidelines 法規(guī)及行業(yè)指南對(duì)過(guò)濾驗(yàn)證的要求FDA Aseptic Processing Guidelines (1987 & 2004, ) FDA無(wú)菌工藝指南Correlate filter performance with filter integrity testing Include microbiological challenges to simulate worst case production conditions 與過(guò)濾器完好性相關(guān)的性能測(cè)試應(yīng)包括：模擬消費(fèi)條件，在最苛刻

24、消費(fèi)環(huán)境下進(jìn)展微生物挑戰(zhàn)實(shí)驗(yàn)。PDA Technical Report 26 (1998, )“Early, careful screening of potential filter types and configuration can result in fewer technical and regulatory problems, fewer delays, more efficient product processing, and greater sterility assurance 更早地，更細(xì)致地選用過(guò)濾器的規(guī)格和類(lèi)型可減少技術(shù)和法規(guī)方面的問(wèn)題，防止延誤，更有

25、效的消費(fèi)，更好的無(wú)菌保證Filter Validation in Regulatory and Industry Guidelines 法規(guī)及行業(yè)指南對(duì)過(guò)濾驗(yàn)證的要求續(xù)ISO/DIS 13408-2 Aseptic Processing (2003, iso.ch) ISO/DIS 無(wú)菌工藝Filter Pre-selection shall take into account chemical and physical characteristics of the filter, as established by the filter manufacturer.Bacterial rete

26、ntion performance of filters shall be validated in a fluid-specific manner or for fluid groups under worst case conditions in production. 選擇過(guò)濾器前向消費(fèi)商確認(rèn)，仔細(xì)思索過(guò)濾器的物理，化學(xué)性能。細(xì)菌截留性能驗(yàn)證：需求在消費(fèi)過(guò)程中能夠遇到的最差的條件下進(jìn)展，運(yùn)用產(chǎn)品或模擬液進(jìn)展驗(yàn)證。Other Sources of Guidance其它相關(guān)指南FDA 483 and warning letters FDA 483FOIShow regulatory tren

27、d法規(guī)開(kāi)展方向Site Lack of Validation for缺陷常發(fā)生在：Filter Compatibility with product過(guò)濾器與產(chǎn)品間的兼容性Filter Extractables過(guò)濾器的析出物Actual Filtration Process Conditions used實(shí)踐過(guò)濾操作條件Filter Integrity Testing Methods/Fluids過(guò)濾器完好性測(cè)試方法測(cè)試流體Equivalency of alternate filters過(guò)濾器的一致性過(guò)濾器驗(yàn)證流程Protocol方案VMP驗(yàn)證總體方案AccessQuestionnaire調(diào)查表

28、Report報(bào)告ValidationMaster file 驗(yàn)證總文件除菌過(guò)濾器驗(yàn)證流程定義工藝條件及流程確定操作條件,指定驗(yàn)證方案完好性檢測(cè)方法析出物，兼容性，吸附微生物挑戰(zhàn)實(shí)驗(yàn)，毒性壓力，流速，溫度驗(yàn)證指南產(chǎn)品運(yùn)用闡明最差條件Validation Guide 驗(yàn)證指南過(guò)濾器驗(yàn)證工程Biological生物性能Microbial Retention微生物截留Customized to客戶(hù)定制Flow Rate流速Throughput產(chǎn)量Process temperature操作溫度Pressure壓力System Size系統(tǒng)尺寸大小Physical物理性能Integrity完好性Produ

29、ct/water BP ratio產(chǎn)品水起泡點(diǎn)Diffusion ratio分散流Binding吸附 Chemical化學(xué)性能CompatibilityExtractables兼容性析出物Compatibility Testing兼容性測(cè)試化學(xué)兼容性驗(yàn)證ABCABC酸和堿汽油LNR乙酸 (5%)RRR甘油RRR硼酸RRR己烷L(zhǎng)NR濃鹽酸RRR雙氧水(3%)RRR氫氟酸RNN異丁醇RRR濃硝酸NNN異丙酸乙酯RNR濃硫酸NNR異丙醇RRR氨水 (6N)NRR煤油LNR濃氫氧化鈉NRR甲醇RRR溶劑二氯甲烷L(zhǎng)NR丙酮NNR甲乙酮LNRA-Durapore CVGL濾柱B-硅膠O形圈C-不銹鋼過(guò)濾器

30、外殼化學(xué)兼容性Filter/Product Compatibility Testing過(guò)濾器與產(chǎn)品兼容性測(cè)試Is the filter membrane compatible with the drug product?濾膜與產(chǎn)品兼容嗎？Static soak in actual drug product for process time 將濾膜浸泡在料液中。浸泡時(shí)間不短于消費(fèi)時(shí)間Inspect for visible changes 察看有無(wú)可見(jiàn)的變化Evaluate for physical change in檢測(cè)物理性能的變化：Water Flow Rate水流速M(fèi)embrane Wei

31、ght濾膜分量Product Bubble Point產(chǎn)品起泡點(diǎn)Extractables Evaluation析出物評(píng)價(jià)Filter Extractables Evaluation過(guò)濾器析出物評(píng)價(jià)Filter Extractables evaluation is mentioned in both PDA Technical Reports 15 and 26.在注射劑管理委員會(huì)的15及26號(hào)報(bào)告中描畫(huà)了過(guò)濾器析出物評(píng)價(jià)方法。Knowledge of Extractables level is important in relation to:了解析出物程度有利于：Filter flush v

32、olume determination決議過(guò)濾器預(yù)先沖洗體積Small volume applications-where dilution of extractables is minimal決議過(guò)濾器能否用于小體積過(guò)濾無(wú)法沖淡和稀釋析出物Direct filling-where extractables levels are highest in first vials filled直接灌裝這時(shí)第一瓶的析出物含量最高Filter Extractables Evaluation過(guò)濾器析出物評(píng)價(jià)續(xù)2 methods to consider:思索運(yùn)用兩種方法：Determination of E

33、xtractables in Actual Drug 在實(shí)踐藥物中的析出物Use Model Solvent Stream Approach用溶劑來(lái)模擬，檢測(cè)析出物析出物檢測(cè)濾器析出物驗(yàn)證: NVR, TOC, HPLC, FTIRWater controlDrug productWater extractIntegrity testing完好性測(cè)試產(chǎn)品起泡點(diǎn)測(cè)試原理及必要性:方法:勝利規(guī)范CV5%案例:Binding Studies吸附研討Why Binding Studies?為什么對(duì)吸附進(jìn)展研討A filter should neither add nor remove any ingr

34、edients from a fluid.一個(gè)濾器既不應(yīng)該對(duì)流體添加成分，也不應(yīng)減少流體中的成分。Durapore is a low-binding membrane. Druapore是低吸附膜。However, preservatives and proteins still may bind in small quantities.然而，防腐劑和蛋白仍會(huì)有少部分損失Why Binding Studies?為什么對(duì)吸附進(jìn)展研討續(xù)When the concentration of an ingredient is critical, it is important to understand

35、 how filtration my affect concentration in the final product. 當(dāng)流體中的成分濃度很關(guān)鍵時(shí)，了解濾器對(duì)產(chǎn)品的吸附程度就顯得非常重要了。Microbial Retention Testing 微生物截留實(shí)驗(yàn)What is a Sterilizing-Grade Filter? 什么是除菌級(jí)過(guò)濾器？Defined by ASTM F838-83 (1993) 給出定義A filter which, when challenged with the bacterium Brevundimonas diminuta, at a minimum

36、 concentration of 107 cfu per cm2 of filter surface area, will produce a sterile effluent. 除菌級(jí)過(guò)濾器是指符合以下規(guī)范的過(guò)濾器：用每平方厘米107CFu的缺陷性假單胞菌進(jìn)展挑戰(zhàn)這一濾器，下游液體無(wú)菌。Basic Schematic of a Filter Retention Test Direct Inoculation直接培育的細(xì)菌截留實(shí)驗(yàn)程序Actual drug productinoculated with B. diminuta在藥品中參與缺陷性假單孢菌Sterilizing-Grade Tes

37、t Filter 除菌級(jí)過(guò)濾器(47 mm Durapore0.22 m disc)MicrobialAssay Filter集菌濾器(47 mm MEC)Plate MEC47 mm discon TSAIncubate 7 days, Inspect for Growth培育7天，察看有無(wú)菌生長(zhǎng)Waste再驗(yàn)證周期及條件再驗(yàn)證周期及條件：1 process parameters工藝參數(shù)： A pressure 壓力 B flow rate流速 C temperature溫度 D others其他2 過(guò)濾器： A materials材質(zhì) B type型號(hào) C filtration area面

38、積過(guò)濾驗(yàn)證總結(jié)法規(guī)部門(mén)的要求過(guò)濾器驗(yàn)證流程為什么運(yùn)用者要對(duì)過(guò)濾器進(jìn)展驗(yàn)證？過(guò)濾器驗(yàn)證包括那些工程？再驗(yàn)證周期及條件Processdesign過(guò)濾設(shè)計(jì)FilterSterilisation過(guò)濾器的滅菌TesterIQ OQ檢測(cè)儀的安裝運(yùn)轉(zhuǎn)確認(rèn)Bioburden Sterility 生物負(fù)荷的降低Bacteriaretention細(xì)菌截留Physical characteristic物理性質(zhì)Adsorption吸附性Productspecific產(chǎn)品完好性測(cè)試,規(guī)范及 方法FilterintegrityTest過(guò)濾器的完好性檢測(cè)Compatibility兼容性Filterintegrity tes

39、toperator certification濾器操作者資歷證書(shū)滅菌過(guò)程設(shè)計(jì),規(guī)范操作程序的培訓(xùn)Steritest school無(wú)菌培訓(xùn)微生物方法驗(yàn)證airsurfacesfluids滅菌過(guò)程設(shè)計(jì),規(guī)范操作程序的制定,滅菌驗(yàn)證Filterabilitystudies過(guò)濾線(xiàn)的設(shè)計(jì)Engineering施工,RegulatoryCompliance法規(guī)Sterility Assurance無(wú)菌保證生物負(fù)荷確實(shí)認(rèn)預(yù)過(guò)濾Extractables析出物TrainingEducation培訓(xùn)Filterperformance過(guò)濾器性能AgendaRisk analysis in Filtration Pr

40、ocess 過(guò)濾工藝中的風(fēng)險(xiǎn)分析Filter application and Qualification 過(guò)濾器的運(yùn)用與確認(rèn)Filter Integrity testing 過(guò)濾器完好性測(cè)試Filtration process Validation 過(guò)濾工藝驗(yàn)證Filtration process reviewCheck list 檢查清單 Operator training過(guò)濾操作者培訓(xùn)Have operators been trained in filter use sterilization, integrity testing ?能否對(duì)過(guò)濾器的運(yùn)用者進(jìn)展了過(guò)濾器滅菌，完好性監(jiān)測(cè)的培訓(xùn)？

41、Is this training documented ?這些培訓(xùn)有相關(guān)記錄嗎？Is this training adequate for the functions required ?這些培訓(xùn)足夠嗎？Examples of observations察看到的例子：Operator training is not documented對(duì)操作者的培訓(xùn)沒(méi)有記錄Operators not formally trained in integrity test操作者不熟習(xí)完好性的檢測(cè)Control of filter devices 過(guò)濾設(shè)備的管理Is filter inspected on arriv

42、al ?過(guò)濾器到貨后能否經(jīng)過(guò)檢查？Is filter stored to prevent mix ups / contamination ?過(guò)濾器的儲(chǔ)存能否有防止發(fā)生混淆的措施？Is filter Certificate of Quality filed ; where ?過(guò)濾器能否有質(zhì)量證書(shū)？放在哪里？Are old / obsolete filters in use ?能否一些淘汰的廢棄的過(guò)濾器仍在運(yùn)用？Examples of observations例子Filters not inspected and therefore an incorrect filter is issued to

43、 manufacturing應(yīng)為沒(méi)有對(duì)過(guò)濾器進(jìn)展檢查呵斥過(guò)濾器被錯(cuò)誤的發(fā)放到消費(fèi)線(xiàn) Very old / obsolete filters issued to manufacturing非常老舊的過(guò)濾器被發(fā)放到了消費(fèi)線(xiàn)。Documentation setup and management文件建立與管理Do procedures conform to GMP ?制定的規(guī)程能否符合GMP的要求？Are procedures up to date and correct ? 指定的規(guī)程是最新的和正確的嗎？Are procedures followed ? 這些規(guī)程能否被遵照?qǐng)?zhí)行？Are proced

44、ures / reports readily accessible ?這些規(guī)程或報(bào)告能否容易被拿到？Examples of observations例子Different versions of the same procedure 發(fā)現(xiàn)了同一文件的不同版本Procedures never updated with new filters / integrity test criteria規(guī)程中的過(guò)濾器型號(hào)和完好性測(cè)試規(guī)范沒(méi)有被更新Process control and Environmental monitoring工藝控制和環(huán)境監(jiān)測(cè)Are critical parameters monit

45、ored (differential pressures / temperatures / times) and controlled ? 關(guān)鍵的參數(shù)能否被監(jiān)測(cè)？壓差/溫度/時(shí)間)?Is critical equipment calibrated ?關(guān)鍵的設(shè)備能否被計(jì)量和校驗(yàn)？Is integrity testing performed correctly ?完好性測(cè)試能否被正確的執(zhí)行？Are critical areas monitored adequately ?關(guān)鍵的地點(diǎn)能否有足夠的檢測(cè)？Process control and Environmental monitoring工藝控制和環(huán)境監(jiān)測(cè)續(xù)Examples of observations例子Filter specifications being exceeded過(guò)濾器的運(yùn)用規(guī)范被超越Incorrect / inadequate integrity test methods 完好性測(cè)試方法不正確和不充分Lack of traceability for results 缺乏對(duì)結(jié)果的跟蹤Sterilization of filters 過(guò)