1、 無菌生產(chǎn)工藝論論文：注射劑劑生產(chǎn)過程中中微生物的質(zhì)質(zhì)量風險控制制【中文摘要】注注射劑(innjectiion)是直直接注入人體體內(nèi)部的一種種劑型,常用用劑量較大,按其生產(chǎn)工工藝的不同可可分為最終滅滅菌工藝和非非最終滅菌工工藝也即無菌菌生產(chǎn)工藝兩兩種,無菌生生產(chǎn)工藝的無無菌保證水平平(SAL)僅是滅菌工工藝的1/1103-/1109。無菌菌生產(chǎn)工藝產(chǎn)產(chǎn)品在生產(chǎn)過過程中微生物物污染的因素素較多,因此此,在臨床使使用過程中具具有較高的質(zhì)質(zhì)量風險。本本課題以5mml無菌生產(chǎn)產(chǎn)工藝注射劑劑為例,利用用休哈特控制制圖、餅圖、柱柱狀圖等統(tǒng)計計工具對生產(chǎn)產(chǎn)中的環(huán)境、人人員、物料、注注射用水、壓壓縮空氣、氮氮

2、氣等可能引引入或污染微微生物的環(huán)節(jié)節(jié)進行監(jiān)控和和風險確認。采采用失敗模式式及影響因素素分析(FMMEA)、風風險排序和過過濾等風險工工具對各因素素進行風險分分析和評估,找出生產(chǎn)過過程中污染微微生物的高風風險因素。通通過采取措施施和措施的有有效性論證進進行風險控制制,進一步降降低無菌生產(chǎn)產(chǎn)工藝注射劑劑的微生物風風險,保證患患者用藥安全全。研究內(nèi)容容主要包括潔潔凈區(qū)的微生生物和懸浮粒粒子監(jiān)控數(shù)據(jù)據(jù)匯總分析、人人員的微生物物監(jiān)控數(shù)據(jù)匯匯總分析、物物料的微生物物監(jiān)測數(shù)據(jù)匯匯總分析、注注射用水的微微生物監(jiān)控數(shù)數(shù)據(jù)匯總分析析、壓縮空氣氣和氮氣的微微生物和懸浮浮粒子監(jiān)測數(shù)數(shù)據(jù)匯總分析析、各因素的的微生物監(jiān)控

3、控數(shù)據(jù)平均結(jié)結(jié)果匯總分析析、各因素的的微生物風險險評估、建議議及措施。11.潔凈區(qū)的的微生物和懸懸浮粒子監(jiān)控控數(shù)據(jù)匯總分分析通過對11000000級區(qū)、100000級區(qū)區(qū)、100000級無菌區(qū)區(qū)、100級級區(qū)不同的功功能間進行了了靜態(tài)沉降菌菌和懸浮粒子子的數(shù)據(jù)監(jiān)控控和匯總,對對100000級無菌區(qū)、1100級區(qū)不不同的功能間間進行了動態(tài)態(tài)沉降菌的監(jiān)監(jiān)控和匯總。利利用統(tǒng)計工具具休哈特控制制圖按級別分分別作圖分析析,計算出：各潔凈級別別不同功能間間靜態(tài)沉降菌菌和懸浮粒子子的平均值XX、標準偏差差和控制線XX3；100000級無菌區(qū)區(qū)、100級級區(qū)不同功能能間動態(tài)沉降降菌的平均值值X、標準偏偏差和控

4、制線XX3。從休哈特特控制圖分析析各檢測結(jié)果果均在控制線線內(nèi)。通過對對各潔凈級別別關(guān)鍵功能間間的靜態(tài)沉降降菌和懸浮粒粒子分別做柱柱狀圖進行比比較分析得出出：靜態(tài)懸浮粒粒子和沉降菌菌的檢測結(jié)果果和潔凈級別別成對應關(guān)系系；不同潔凈級級別的檢測結(jié)結(jié)果有較大差差別,1000級區(qū)檢測結(jié)結(jié)果最好,110000級級無菌區(qū)次之之,1000000級區(qū)檢檢測結(jié)果最差差。2.人員員的微生物監(jiān)監(jiān)控數(shù)據(jù)匯總總分析通過對對100000級無菌區(qū)、1100級區(qū)人人員的手套、袖袖口、肘部、額額頭、口罩表表面的微生物物進行20批批次的檢測數(shù)數(shù)據(jù)匯總,利利用統(tǒng)計工具具休哈特控制制圖進行作圖圖分析。計算算平均值X：100000級無菌

5、區(qū)分分別為1.550、1.225、1.555、1.115、1.115CFU/碟,1000級區(qū)分別為為0.70、00.55、00.60、00.50、00.45 CCFU/碟；標準偏差：100000級無菌區(qū)區(qū)分別為0.51、0.44、0.51、0.59、0.37 CFFU/碟,1100級區(qū)分分別為0.447、0.551、0.550、0.551、0.551 CFUU/碟,從休休哈特控制圖圖和計算數(shù)據(jù)據(jù)看100級級檢測結(jié)果明明顯好于100000級無無菌區(qū),口罩罩好于其他部部位,各檢測測結(jié)果均在控控制線內(nèi)。33.物料的微微生物監(jiān)測數(shù)數(shù)據(jù)匯總分析析連續(xù)取樣330批監(jiān)測AA、B、C三三個注射液配配好藥液帶菌

6、菌量,利用統(tǒng)統(tǒng)計工具休哈哈特控制圖進進行作圖分析析,計算平均均值X分別為為1.57、11.31、22.37個/100mll；標準偏差差分別為1.01、0.81、1.03個/1100ml；X+3分別為4.59、3.73、5.47個/1100ml。從從監(jiān)控數(shù)據(jù)和和計算結(jié)果分分析,三個產(chǎn)產(chǎn)品配好藥液液的帶菌量有有差別,B產(chǎn)產(chǎn)品監(jiān)測數(shù)據(jù)據(jù)最好,C產(chǎn)產(chǎn)品結(jié)果最差差,除A、CC注射液有個個別點超出界界限外,其余余各批次檢測測結(jié)果均在控控制線范圍內(nèi)內(nèi)波動。4.注射用水的的微生物監(jiān)控控數(shù)據(jù)匯總分分析對注射用用水系統(tǒng)的罐罐出口、使用用點1、使用用點2、使用用點3、罐回回口取樣進行行每周一次的的微生物監(jiān)控控,然后

7、對連連續(xù)一年的數(shù)數(shù)據(jù)匯總,利利用統(tǒng)計工具具休哈特控制制圖進行作圖圖分析。計算算各點的平均均值X分別為為0.10、00.12、00.12、00.14、00.18個/100mll；標準偏差差分別為0.31、0.33、0.33、0.35、0.39個/1100ml；X+3分別為1.02、1.12、1.12、1.20、1.36個/1100ml。從從計算結(jié)果和和數(shù)據(jù)變化趨趨勢分析罐出出口檢測結(jié)果果最好,罐回回口檢測結(jié)果果最差。5.壓縮空氣和和氮氣的微生生物和懸浮粒粒子監(jiān)測數(shù)據(jù)據(jù)匯總分析通通過對壓縮空空氣的使用點點洗瓶1、洗洗瓶2、灌裝裝1、灌裝22、過濾和對對氮氣的使用用點灌裝1、灌灌裝2分別采采樣進行微

8、生生物和懸浮粒粒子檢測,每每月一次。,通過對連續(xù)續(xù)一年的數(shù)據(jù)據(jù)匯總,利用用統(tǒng)計工具休休哈特控制圖圖進行作圖分分析。微生物物和懸浮粒子子的平均值XX均為OCFFU(個)/m3,最大大值為0 CCFU(個)/m3,最最小值為0 CFU(個個)/m3。標標準偏差均為0 CCFU(個)/m3,XX3均為0 CCFU(個)/m3,從從計算結(jié)果和和監(jiān)測數(shù)據(jù)趨趨勢分析各使使用點的微生生物和懸浮粒粒子數(shù)值穩(wěn)定定。6.各因因素的微生物物監(jiān)控數(shù)據(jù)平平均結(jié)果匯總總分析對無菌菌生產(chǎn)工藝中中影響藥品微微生物質(zhì)量的的潔凈區(qū)環(huán)境境、人員污染染、物料、注注射用水、壓壓縮空氣、氮氮氣所監(jiān)控的的微生物數(shù)據(jù)據(jù)進行平均匯匯總,然后做

9、做出餅圖進行行分析后得出出：人員動態(tài)態(tài)微生物污染染所占比例最最大是46%(包括100000級無無菌區(qū)和1000級區(qū)),其次是藥液液中所含微生生物的比例占占42%,環(huán)環(huán)境中的微生生物所占比例例是9%,注注射用水中微微生物占3%,壓縮空氣氣和氮氣微生生物所占比例例為零。7.各因素的微微生物風險分分析對收集的的數(shù)據(jù)采用FFMEA表格格進行風險排排序和過濾,得出影響無無菌生產(chǎn)工藝藝注射液微生生物風險因素素由小到大依依次為：壓縮縮空氣、氮氣氣、物料、注注射用水、1100級區(qū)空空氣、100000級無菌菌區(qū)空氣、人人員污染。風風險順序數(shù)RRPN依次為為：2、3、88、9、199、32、2252。8.建議及措

10、施施降低無菌生生產(chǎn)工藝注射射劑的微生物物污染風險,在很大程度度上取決于人人員的技能,所接受的培培訓及人員的的工作態(tài)度。應應采取的措施施：是制定人員員“無菌室”行為規(guī)則,進行無菌操操作技能和意意識培訓；是采用無菌菌隔離系統(tǒng)；是采用培養(yǎng)養(yǎng)基模擬灌裝裝,驗證降低低人員污染措措施有效性。結(jié)結(jié)論在無菌生生產(chǎn)工藝注射射劑可能影響響微生物的各各種風險因素素中：物料、壓壓縮空氣、氮氮氣為低風險險因素；100000級無無菌區(qū)空氣、1100級空氣氣和注射用水水為中等風險險因素：人員員污染為高風風險因素。采采用無菌隔離離系統(tǒng)對降低低人員的微生生物污染能起起到較好的效效果；采用風風險管理的程程序、工具和和方法能有效效

11、地控制無菌菌工藝注射劑劑生產(chǎn)過程中中的微生物風風險,使藥品品的生產(chǎn)由過過程控制轉(zhuǎn)為為主動預防,很好的彌補補GMP條款款在質(zhì)量控制制方法和工具具等方面的不不足?！居⑽恼縄Injecttion iis a ddosagee formm of iinjectting ddirecttly innto huuman, whichh is uusuallly witth larrger ddosagee. Injjectioon cann be cclassiified into termiinallyy sterriliseed proocessees andd asepptic ppreparr

12、eratiions aaccordding tto thee prodductivve tecchnoloogy. TThe stterilee guarranteee leveel of the aaseptiic preeparerrationns is only 1/1033-/1099 of tthat oof thee termminallly steerilissed prrocessses. SSince theree are many microobioloogicall conttaminaation factoors duuring the pproducction of

13、thhe aseeptic prepaarerattions, therreforee, higgh quaality riskss exisst in the ccliniccal prracticce.Thee currrent sstudy takess the 5ml iinjecttion pproducced byy asepptic ppreparreratiions aas an exampple, aand usses Shhewharrt Conntrol Chartt, Piee Charrt andd Histtogramms to monittor thhe micc

14、robioologiccal coontamiinatioons inntroduuced bby envvironmments, perssonnell, matterialls, waater ffor innjectiion, ccompreessed air, nitroogen dduringg prodductioon. Wee hopee to ffind aa highh micrrobiollogicaal rissk facctor bby perrformiing riisk asssessmment oon eacch facctor tthrouggh Faiilur

15、e Mode Effeccts Annalysiis, Riisk raankingg and filteering. We tthen pperforrm rissk conntrol by taaking measuures,TThe vaaliditty of the mmeasurres iss suffficentt to ffurtheer deccreasee the risk of thhe quaality of thhe aseeptic prepaarerattions and eensuree the securre phaarmacyy of ppatiennts.T

16、hhis arrticlee was compoosed oof thee folllowingg eighht parrts:Thhe ressults analyysis oof thee micrrobiollogicaal andd airbborne partiiculatte monnitoriing inn cleaan zonne; Thhe ressults analyysis oof thee perssonal microobioloogicall moniitorinng; Thhe ressults analyysis oof miccrobioologiccal m

17、oonitorring iin matterialls; Thhe ressults analyysis oof miccrobioologiccal moonitorring iin watter foor injjectioon; Thhe ressults analyysis oof thee micrrobiollogicaal andd airbborne partiiculatte monnitoriing inn the comprressedd and nitroogen; The MMeta-aanalyssis off the averaage reesultss of m

18、monitooring data of thhe miccrobess in eeach ffactorr; Thee riskk anallysis of miicrobees in each factoor; Suuggesttions and mmeasurres.1. The resullts annalysiis of the mmicrobbiologgical and aairborrne paarticuulate monittoringg in cclean zoneBBy thee micrrobiollogicaal andd airbborne partiiculatt

19、e monnitoriing att restt in ddifferrent rroom iincludde a ggrade 1000000 zonne, a gradee 100000 zonne, a asepttic grrade 110000 zone, a grrade 1100 zoone, aand byy the microobioloogicall moniitorinng in operaation in diiffereent rooom inn a assepticc gradde 100000 zoone annd a ggrade 100 zzone.TThe

20、reesultss are then analyyzed aaccordding ttheir gradees thrrough Shewhhart CControol Chaart too calcculateed thee averrage vvalue of X, the standdard ddeviattion 88 and the ccontrool linne X38 off the statiic miccrobess and airboorne pparticcles aat resst in diffeerent roomss in ddifferrent cclean z

21、oness, resspectiively, and thosee of mmicrobbes inn operrationn in ddifferrent rrooms in a asepttic grrade 110000 zone and aa gradde 1000 zonee. We find that each testiing reesult is faall wiithin the ccontrool linne froom thee Shewwhart Contrrol Chhart.WWe theen perrform a commparattive aanalyssis

22、thhroughh Histtogramms of the mmicrobbes annd airrbornee partticless at rrest iin thee crittical roomss in eeach cclean gradees andd findd thattthe ttestinng ressults of thhe staatic tthe miicrobees andd airbborne partiicles have correesponddence with the ggradess of tthe cllean zzones;the ttestinng

23、 ressults in diiffereent grrades of cllean zzones have largee diffferencces:thhe besst ressult iis in a graade 1000 zonne, foolloweed by the aaseptiic graade 100000 zzone aand grrade 11000000 zonee.2. TThe reesultss anallysis of thhe perrsonall micrrobiollogicaal monnitoriingBy microobioloogicall mo

24、niitorinng on the ssurfacce of the ppersonnal glloves, sleeeves, elbowws, fooreheaad andd a faace maask byy succcessivve 20 batchhs of produuctionn in aa asepptic ggrade 100000 zonee and a graade 1000 zonne. Thhe ressults are tthen ssummarrized and aanalyzzed byy Shewwhart Contrrol Chharts. The aver

25、aage vaalues of x are ccalcullated to bee 1.500、1.255、1.555、1.155、1.155 CFU/platee for a aseeptic gradee 100000 zonne,0.770、0.555、0.660、0.550、0.445 CFUU/platte forr a grrade 1100 zoone, wwhile the sstandaard deeviatiion 8 are ccalcullated to bee 0.511、0.444、0.511、0.599、0.377 CFU/platee for a aseepti

26、c gradee 100000 zonne andd 0.477、0.511、0.500、0.511、0.511 CFU/platee for a graade 1000 zonne. Wee findd thatt the testiing reesult in a gradee 100 zone is obbvioussly beetter than that in a asepttic grrade 110000 zone, and the fface mmask iis bettter tthan ootherss. Eacch tessting resullt in withiin

27、thee conttrol lline.33. Thee resuults aanalyssis off micrrobiollogicaal monnitoriing inn mateerialssBy miicrobiiologiical mmonitooring in A, B annd C iinjecttions in suuccesssive 330 battchs, The rresultts aree anallysis by ussing SShewhaart Coontroll charrt. Thhe aveerage valuees of X, thhe staanda

28、rdd deviiationn 8, aand x+3for AA, B aand C injecctionss are calcuulatedd to bbe 1.557、1.331、2.337 CFUU/100mml,1.001、0.881、1.003 CFUU/100mml andd 4.599、3.733、5.477 CFU/100mll, resspectiively. We ffind ddifferrence of thhe quaantityy of mmicrobbes beetweenn the A, B and CC injeectionns:thee testting

29、ddata oof A iis besst whiile C is woorst. All ttestinng ressults fall withiin thee conttrol lline eexceptt seveeral ppointss in AA and C injjectioons.4. The resullts annalysiis of microobioloogicall moniitorinng in waterr for injecctionWWe firrstly monittor thhe miccrobess in tthe ouutlet, poinnt of

30、 use 11,2,3 and iinlet of thhe sysstem oof thee wateer forr injeectionn weekkly annd theen summmarizzed annd anaalysiss the data obtaiined iin a wwhole year by Shhewharrt Conntrol Chartt. Forr the outleet, pooint oof usee 1,2 3 andd inleet, thhe aveerage valuees of X, thhe staandardd deviiationn, an

31、dd X+3are ccalcullated to bee 0.100、0.122、0.122、0.144、0.188 CFU/100mll,0.311、0.333、0.333、0.355、0.399 CFU/100mll and 1.02、11.12、11.12、11.20、11.36 CCFU/1000ml, respeectiveely. TThe teestingg resuult obbtaineed (frrom thhe outtlet iin thee bestt whille thaat obttainedd fromm the inlett is tthe woorst f

32、from tthe caalculaated rresultts andd the variaation trendd of ddata.55. Thee resuults aanalyssis off the microobioloogicall and airboorne pparticculatee moniitorinng in the ccompreessed and nnitroggenWe firsttly moonitorr the microobes aand aiirbornne parrticlees in the uusing pointts of washiing b

33、oottle 1,2, filliing 1,2, fiiltrattion oof thee comppresseed airr and monittor thhe miccrobess and airboorne pparticcles iin thee usinng poiints oof fillling 1,2 oof thee nitrrogen monthhly, aand thhen suummariize annd anaalysiss the data obtaiined iin a wwhole year by Shhewharrt Conntrol Chartt. We

34、 find that the vvaluess of tthe avveragee X, sstandaard deeviatiionand XX+3are aall caalculaated tto be 0 CFUU/m3, indiccatingg thatt the valuees of the mmicrobbes annd airrbornee partticless in eeach uusing pointt are stablle.6. The MMeta-aanalyssis off the averaage reesultss of mmonitooring data o

35、f thhe miccrobess in eeach ffactorrThe mmonitooring data of miicrobees inttroducced byy the envirronmennt of the cclean zoness, perrsonneel conntaminnationn, matterialls, waater ffor innjectiion, ccompreessed air aand niitrogeen durring tthe assepticc preppareraation firsttly avverageed andd summmar

36、izeed. Wee thenn anallyze tthe daata byy pie chartt and concllude tthat tthe prroporttions of thhe miccrobess intrroduceed by persoonnel contaaminattion iin opeeratioon (inn conttaininng a aaseptiic graade 100000 zzone aand a gradee 100 zone), matterialls, thhe envvironmments and wwater for iinjectt

37、ion aare 466%,42%,9% aand 3%, resspectiively, whille thaat of the ccompreessed air aand niitrogeen is zero.7. Thhe rissk anaalysiss of mmicrobbes inn eachh facttorThee Riskk rankking aand fiilteriing arre perrformeed on the ccolleccted ddata bby Faiilure Mode Effeccts Annalysiis andd concclude that

38、the iinflueence oof eacch rissk facctor oon thee micrrobes in innjectiions pproducced byy asepptic ppreparrationns froom smaall too largge is comprressedd air, nitrrogen, mateerialss, watter foor injjectioon, aiir in a aseeptic gradee 100000 zonne, aiir in a graade 1000 zonne, peersonnnel coontamiin

39、atioon witth acccordinng Rissk Priiorityy Numbber off 2,3,8,9,119,32 and 2252.8. Sugggestioons annd meaasuressIn orrder tto minnimizee riskks of microobioloogicall conttaminaation of assepticc preppareraationss. Mucch deppends on thhe skiills, trainning aand atttituddes off perssonnell invoolved. Th

40、e measuures sshouldd be aadopteed as folloows:Settiing peersonnnel ruules iin aseeptic room and ttrainiing thhe aseeptic operaating skilll and conscciousnness;Adoptting aaseptiic isoolatorr techhnologgy;Validdationn of aaseptiic proocessiing neeed a proceess siimulattion ttest uusing a nuttrientt me

41、diium too veriify thhe meaasuress for reduccing tthe coontamiinatioon inttroducced byy perssonnell.ConcclutioonAmonng varrious microobioloogicall riskk facttors iin thee prodductioon of asepttic prreparaationss of iinjecttion, materrials, comppresseed airr and nitroogen bbelongg to llow riisk faacto

42、rss, airr in aa asepptic ggrade 100000 zonee, airr in aa gradde 1000 zonee and waterr for injecction belonng to mediuum rissk facctor, whilee perssonnell conttaminaation belonng to high risk factoor.Adooptingg asepptic iisolattor teechnollogy ccan efffectiively reducce thee micrrobiollogicaal conntaminnationn intrroduceed by perso