【正文】 產(chǎn)品使用說明 最差條件Validation Guide 驗證 指南過濾器驗證項目Biological生物性能– Microbial Retention微生物截留? Customized to客戶定制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完整性? Product/water BP ratio產(chǎn)品／水起泡點? Diffusion ratio擴散流– Binding吸附 Chemical化學(xué)性能w Compatibilityw Extractables兼容性＼析出物Compatibility Testing兼容性測試化學(xué)兼容性驗證A B C A B C酸和堿 汽油 L N R乙酸 (5%) R R R 甘油 R R R硼酸 R R R 己烷 L N R濃鹽酸 R R R 雙氧水 (3%) R R R氫氟酸 R N N 異丁醇 R R R濃硝酸 N N N 異丙酸乙酯 R N R濃硫酸 N N R 異丙醇 R R R氨水 (6N) N R R 煤油 L N R濃氫氧化鈉 N R R 甲醇 R R R溶劑 二氯甲烷 L N R丙酮 N N R 甲乙酮 L N RADurapore CVGL濾 柱B硅膠 O形圈C不 銹鋼過濾 器外殼ＣＶＧＬ化學(xué)兼容性Filter/Product Compatibility Testing過濾器與產(chǎn)品兼容性測試Is the filter membrane patible 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。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，更細致地選用過濾器的規(guī)格和類型可減少技術(shù)和法規(guī)方面的問題，避免延誤，更有效的生產(chǎn)，更好的無菌保障．Filter Validation in Regulatory and Industry Guidelines 法規(guī)及行業(yè)指南對過濾驗證的要求（續(xù)）ISO/DIS 134082 Aseptic Processing (2022, ) ISO/DIS 無菌工藝– Filter Preselection shall take into account chemical and physical characteristics of the filter, as established by the filter manufacturer.– Bacterial retention performance of filters shall be validated in a fluidspecific manner or for fluid groups under worst case conditions in production. 選擇過濾器前向生產(chǎn)商確認，仔細考慮過濾器的物理，化學(xué)性能。 211 美國 GMP? Appropriate written procedures…shall be established and followed. Such procedures shall include validation of any sterilization process　必須建立和跟進相應(yīng)的證明性文件 …., ，這些文件中包括所有的除菌工藝的驗證文件．EU GMP Annex 1 Sterile Medicinal Products 歐盟GMP 無菌藥品附錄? All sterilization processes should be validated　所有除菌工藝必須進行驗證Filter Validation is Required Worldwide by GMP世界各國ＧＭＰ法規(guī)要求進行過濾器驗證Filter Validation is Required Worldwide by GMP世界各國ＧＭＰ法規(guī)要求進行過濾器驗證（續(xù)）Australian TGA GMP 澳大利亞 TGA GMP? Filtration processes used as the sterilizing step for products should be validated　出于除菌目的過濾工藝應(yīng)該驗證Health Canada GMP 加拿大 GMP? Documented evidence is available establishing validation and validity of each sterilization process　每步除菌工藝必須要有驗證其有效性的證明性文件Filter Validation in Regulatory and Industry Guidelines 法規(guī)及行業(yè)指南對過濾驗證的要求FDA Aseptic Processing Guidelines (1987 amp。 26 PDA技術(shù)報告 26號“... It generally is regarded as a cGMP requirement that filters or filter systems routinely be integrity tested both prior to and after use.“ 一般認為 過濾前后 的常規(guī)性完整性檢測是現(xiàn)行 GMP的要求 .EU GMP“The integrity of the sterilised filter should be verified before use and should be confirmed immediately after use by an appropriate method such as bubble point, diffusive flow or pressure hold test.”對于已滅菌的濾器的完整性檢測應(yīng)該在 使用前和使用后立即執(zhí)行 ,例如泡點 ,擴散流及壓力保持試驗 .應(yīng)該在什么時候做完整性測試 ? ?起泡點是氣體從濕潤的最大膜孔快速流出的壓力?起泡點顯示過濾結(jié)構(gòu)內(nèi)保持液體的力的大小?最傳統(tǒng)的非破壞性測試起泡點測試原理壓力 P2空氣 Water d??起泡點等式起泡點可表達為 : 4 . k . ? . cos ?BP = d 這里k =形狀校正因子? = 表面張力? = 接觸角d = 孔徑P1 P2AirWaterd??起泡點合格標(biāo)準(zhǔn)? 不同孔徑標(biāo)準(zhǔn)不同– CVVL PVDF 23攝氏度 水 =70psi? 不同材質(zhì)標(biāo)準(zhǔn)不同– CCGL 帶正電荷 PVDF 23攝氏度 水 =39psi? 不同潤濕液體不同– CVGL PVDF 23攝氏度 水 =50psi 70/30 IPA= psi測試起泡點的方法 沖洗 加壓增加壓力直到連續(xù)起泡在下游出現(xiàn)擴散流檢測原理施 加 壓 力P0PLALP1 P2Air Water d??擴散流測試方法上 游 壓 力壓縮空氣下游監(jiān)測氣流速度HydroCorr TestRes