培育基模擬灌裝【根本概念】灌裝試驗實際證技術(shù)。無菌于設(shè)備、容器裝有培育基的產(chǎn)中產(chǎn)品被污染的概率。【法規(guī)】GMP無菌附錄第四十七條無菌生產(chǎn)工藝的驗證應(yīng)當包括培育基模擬灌裝試驗。基。應(yīng)當盡產(chǎn)中可能消滅的各種干預(yù)和最差條件。3化系統(tǒng)、設(shè)備、灌裝試驗通常應(yīng)當依據(jù)生產(chǎn)工藝每班次半年進展1次，每次至少一批。灌裝的數(shù)量應(yīng)要求:5000500010000121000012(四)發(fā)生任何微生物污染時，均應(yīng)當進展調(diào)查。EUGMPAnnex1ManufactureofSterileMedicinalProductsValidationofasepticprocessingshouldincludeaprocesssimulationtestusinganutrientmedium(mediafill).Selectionofthenutrientmediumshouldbemadebasedondosageformoftheproductandselectivity,clarity,concentrationandsuitabilityforsterilisationofthenutrientmedium.Theprocesssimulationtestshouldimitateascloselyaspossibletheroutineasepticmanufacturingprocessandincludeallthecriticalsubsequentmanufacturingsteps.Itshouldalsotakeintoaccountvariousinterventionsknowntooccurduringnormalproductionaswellasworst-casesituations.ProcesssimulationtestsshouldbeperformedasinitialvalidationwiththreeconsecutivesatisfactorysimulationtestspershiftandrepeatedatdefinedintervalsandafteranysignificantmodificationtotheHVAC-system,equipment,processandnumberofshifts.Normallyprocesssimulationtestsshouldberepeatedtwiceayearpershiftandprocess.Thenumberofcontainersusedformediafillsshouldbesufficienttoenableavalidevaluation.Forsmallbatches,thenumberofcontainersformediafillsshouldatleastequalthesizeoftheproductbatch.Thetargetshouldbezerogrowthandthefollowingshouldapply:Whenfillingfewerthan5000units,nocontaminatedunitsshouldbedetected.Whenfilling5,000to10,000units:One(1)contaminatedunitshouldresultinaninvestigation,includingconsiderationofarepeatmediafill;Two(2)contaminatedunitsareconsideredcauseforrevalidation,followinginvestigation.Whenfillingmorethan10,000units:One(1)contaminatedunitshouldresultinaninvestigation;Two(2)contaminatedunitsareconsideredcauseforrevalidation,followinginvestigation.【實施指導(dǎo)】培育基模擬灌裝的試驗方法程有差異，這產(chǎn)品類型包/乳膏劑/乳劑/凝膠/無菌滴眼GMP12.1無菌工藝模擬試驗方法培育基模擬灌裝的實施整個無菌工藝基灌裝應(yīng)在與慮生產(chǎn)時可規(guī)生產(chǎn)可能遇培育基的選擇和處理;培育基灌裝試驗頻率;導(dǎo)致操作失誤灌裝批次量生產(chǎn)線的運行速度及設(shè)置動(例如設(shè)備環(huán)境監(jiān)測方案和取樣操作關(guān)鍵區(qū)域內(nèi)最多可以容納的總?cè)藬?shù)及人員可能的活動容器的密封系統(tǒng)(如規(guī)格/大小、類型、對設(shè)備的兼容性)灌裝過程中的稱重微生物污染水平測試[4]GMP12.2無菌工藝模擬試驗的實施培育基模擬灌裝的結(jié)果解讀不管是否符的風險。對于超出標準的結(jié)果，應(yīng)當在調(diào)查清楚緣由后再次進展培育基灌裝。培育基灌裝試驗結(jié)果被認作無效的狀況是及其罕見的。更不能直接將失敗的培育時也應(yīng)同樣處理。參考藥品GMP12.3無菌工藝模擬試驗結(jié)果解讀【實例分析】培育基模擬灌裝的批次量確定換班更衣灌裝時間5000050003000-10000多一個批次在兩個班次內(nèi)完成。可以考慮的模擬灌裝批次是10000瓶，灌裝時間持GMP12.2無菌工藝模擬試驗的實施培育基模擬灌裝結(jié)果的污染調(diào)查括如下項:生產(chǎn)環(huán)境監(jiān)測數(shù)據(jù)(粒子、浮游菌、沉降碟等)對人員的監(jiān)測結(jié)果高效過濾器的完整性檢測數(shù)據(jù)層流臺性能數(shù)據(jù)(氣流流速、壓差記錄等)人員培訓(xùn)狀況，操作資質(zhì)和力氣干擾模擬的執(zhí)行狀況無菌室生產(chǎn)用具和其他相關(guān)物品的儲存狀況清潔消毒流程的執(zhí)行狀況設(shè)備儀器的校驗結(jié)果生產(chǎn)過程發(fā)生的偏差培育基的培育爭論生產(chǎn)線和培育基的歷史數(shù)據(jù)分析GMP指南無菌制劑12.3無菌工藝模擬試驗結(jié)果解讀PDAPDAtechnicalreportNO.22Processsimulationtestingforasepticallyfilledproducts,1996PDAtechnicalreportNO.28ProcesssimulationtestingforSterileBulkPharmaceuticalchemicals,2023PDAtechnicalreportNO.36CurrentPracticesintheValidationofAsepticProcessing,2023【參考資料】GMP