注射剂生产过程中微生物的质量风险控制

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《销售经理学院》56套讲座+14350份资料《销售人员培训学院》72套讲座+4879份资料政无菌耳生产凳工艺清论文究：注催射剂悠生产弊过程牙中微欢生物灰的质由量风耀险控杨制【中文摘要】刑注射早剂(孩in捡je杆ct蒜io蜓n)图是直船接注鼻入人全体内蛾部的央一种辞剂型诚,常灰用剂响量较午大,罩按其么生产老工艺管的不便同可餐分为始最终蝶灭菌些工艺筒和非荣最终扶灭菌贫工艺疗也即绘无菌窄生产崖工艺勺两种疼,无脖菌生明产工阿艺的旨无菌悉保证攀水平剩(S鲁AL育)仅驻是灭细菌工洋艺的湾1/排10番3-拔/1唐09予。无粪菌生丢产工讲艺产际品在逗生产价过程餐中微仪生物做污染望的因鞭素较床多,度因此现,在震临床薯使用血过程墓中具阶有较浩高的并质量弹风险涛。本血课题凑以5神ml怨无菌确生产语工艺鼻注射圾剂为龟例,割利用次休哈厅特控躺制图特、饼腾图、赤柱状鬼图等馋统计缠工具惨对生咸产中糟的环压境、凝人员慧、物垃料、彼注射特用水趣、压栗缩空虽气、坚氮气塘等可母能引喝入或迅污染铺微生案物的蛛环节露进行点监控奸和风糕险确泥认。贷采用伯失败况模式肯及影揉响因链素分逼析(百FM弦EA秩)、超风险熟排序箩和过些滤等冲风险逗工具冠对各剂因素抵进行别风险吩分析桑和评泛估,呈找出稿生产袍过程夫中污沉染微镇生物茄的高购风险芦因素瞎。通巴过采苹取措扣施和摘措施赚的有巾效性邻论证窝进行猫风险遭控制早,进咐一步维降低献无菌蛮生产醋工艺婶注射茄剂的渴微生始物风熄险,点保证阔患者斧用药许安全迎。研棋究内平容主颂要包榆括洁卖净区隆的微朽生物象和悬确浮粒齐子监机控数斩据汇跟总分杜析、惯人员守的微偿生物叙监控谈数据驻汇总豆分析某、物句料的榨微生禽物监能测数圾据汇明总分掀析、隔注射狭用水吹的微低生物喘监控还数据王汇总车分析革、压屈缩空筛气和敞氮气籍的微驳生物蜘和悬雹浮粒桂子监亿测数蝴据汇惠总分俯析、表各因述素的留微生荣物监北控数王据平甩均结悄果汇纽总分塔析、埋各因弊素的脚微生处物风兰险评魔估、裹建议舅及措字施。恒1.鹅洁净贝区的谦微生忌物和舅悬浮驴粒子临监控论数据捡汇总灰分析赵通过检对1床00泥00撒0级租区、员10设00职0级始区、绑10寒00峡0级妥无菌台区、捧10纷0级落区不对同的指功能偶间进草行了涂静态未沉降屯菌和低悬浮樱粒子锤的数料据监款控和革汇总浴,对保10景00中0级职无菌晌区、手10蜂0级抢区不拴同的涛功能杰间进谣行了哭动态窝沉降诊菌的喷监控关和汇洗总。旧利用酿统计疏工具龙休哈辣特控胃制图念按级罪别分某别作腔图分道析,萍计算谣出：不各洁角净级价别不掩同功植能间示静态迟沉降扯菌和胁悬浮爽粒子箭的平疯均值海X、魄标准气偏差缩δ虽和控叨制线森X逝±怎3紫δ得；1傲00衣00荷级无冬菌区糟、1筋00限级区壶不同决功能僵间动阻态沉余降菌键的平诱均值者X、乳标准耻偏差婶δ艺和控输制线凉X容±钉3饺δ捡。从侦休哈梢特控照制图券分析么各检浸测结吗果均良在控迁制线蛇内。才通过后对各竞洁净以级别歼关键何功能画间的舰静态搂沉降合菌和待悬浮怖粒子效分别昆做柱钥状图最进行杜比较效分析叫得出跟：姜①羊静态液悬浮断粒子风和沉为降菌培的检遭测结销果和竟洁净眨级别插成对初应关池系；绢②睛不同侄洁净翼级别读的检影测结疮果有汤较大毒差别伶,1抹00屈级区惭检测络结果抽最好焦,1饲00倦00示级无草菌区数次之描,1牛00已00凤0级誉区检抄测结墓果最筐差。坛2.驾人员循的微愤生物周监控歌数据锋汇总积分析舱通过佣对1帆00择00建级无楼菌区棵、1随00立级区蝶人员溪的手惹套、倾袖口撤、肘滚部、破额头有、口挽罩表较面的理微生瞧物进笋行2算0批穴次的絮检测铅数据局汇总介,利灭用统送计工距具休厘哈特匆控制珍图进刺行作阁图分润析。株计算眨平均饮值X敏：1才00课00普级无拐菌区晚分别建为1贸.5哑0、粮1.罗25匆、1所.5福5、勿1.摩15棉、1链.1境5C廉FU划/碟皇,1绩00博级区硬分别坊为0哪.7长0、要0.货55钢、0段.6陶0、赠0.桥50水、0框.4崭5撇CF绩U/追碟；挠标准神偏差湾δ补：1段00授00晋级无畏菌区喘分别滤为0劣.5目1、团0.吧44张、0升.5吹1、室0.杠59鸦、0蜘.3震7乡CF馅U/悄碟,逐10击0级贴区分叛别为超0.授47聪、0蹦.5什1、兔0.帽50蛙、0乡.5其1、茫0.橡51僵C怜FU府/碟孝,从丢休哈返特控什制图术和计络算数肯据看庙10蓬0级寄检测穿结果焰明显到好于浆10责00猴0级死无菌洞区,持口罩攻好于社其他岩部位杨,各怖检测牢结果例均在晃控制晕线内熔。3仪.物坟料的轻微生棕物监秆测数钓据汇餐总分衫析连观续取叉样3德0批擦监测糖A、纷B、花C三荡个注排射液壮配好闸药液倦带菌余量,冠利用杂统计艰工具如休哈搭特控格制图朽进行教作图助分析代,计类算平杯均值依X分肌别为辨1.壤57蚀、1叛.3贝1、熔2.仔37捷个/眯10雾0m宗l；双标准播偏差岩δ犯分别洽为1厘.0芒1、熔0.奉81你、1妇.0厘3个层/1意00卷ml撇；X狭+3愁δ盒分别温为4闸.5仍9、体3.栗73费、5抓.4疼7个首/1垒00莫ml锄。从供监控酱数据俭和计宴算结蹈果分升析,迅三个朽产品筛配好呼药液盗的带话菌量参有差捕别,误B产凑品监血测数统据最段好,剧C产钩品结占果最绵差,蔑除A船、C竭注射券液有穷个别案点超状出界钟限外陵,其毫余各萄批次堤检测久结果比均在办控制膝线范河围内闭波动侄。4喝.注柴射用现水的搭微生设物监臂控数裙据汇错总分模析对尸注射杜用水纽系统侮的罐至出口慎、使洪用点偏1、飘使用挣点2的、使泉用点笔3、踩罐回勾口取州样进躬行每结周一兔次的积微生甲物监挨控,脸然后鞠对连螺续一扮年的袍数据挖汇总挑,利舅用统隙计工谅具休血哈特触控制拾图进欲行作遭图分责析。择计算闹各点阅的平至均值窃X分而别为全0.咏10习、0位.1绵2、坛0.叶12惰、0怨.1父4、短0.柱18踪个/杆10筒0m临l；阻标准壮偏差禁δ竿分别荷为0冠.3楚1、恋0.坟33筋、0府.3匙3、废0.誉35悄、0微.3午9个教/1贡00喉ml探；X燕+3躬δ努分别爸为1姑.0扯2、太1.迷12诸、1觉.1环2、习1.领20阻、1际.3匹6个荷/1奥00受ml伙。从啦计算杨结果肢和数亮据变厘化趋役势分脖析罐右出口杯检测圾结果修最好袄,罐渣回口异检测缺结果思最差腿。5卡.压刻缩空僚气和支氮气卧的微胡生物妈和悬摔浮粒舟子监请测数胶据汇馅总分把析通任过对闯压缩骑空气高的使锯用点莫洗瓶兰1、阴洗瓶柱2、就灌装此1、方灌装碰2、式过滤兽和对苍氮气州的使鱼用点端灌装日1、我灌装断2分土别采吐样进跑行微配生物筛和悬钩浮粒笛子检颗测,瓜每月碌一次耳。,观通过时对连步续一搅年的习数据核汇总冠,利急用统同计工堡具休卷哈特厉控制猾图进膀行作含图分黄析。胳微生禾物和弹悬浮促粒子摊的平姑均值炊X均届为O染CF浴U(临个)扫/m笋3,态最大言值为劳0扯CF蛾U(喊个)朋/m织3,勤最小卵值为吃0绍CF腾U(排个)吐/m孤3。堵标准荡偏差孔δ滴均为宁0劝CF阶U(抵个)号/m大3,三X胳±弱3狸δ灾均为痒0雕CF浅U(羡个)箭/m痛3,寄从计床算结赢果和麦监测量数据菜趋势汽分析甲各使晋用点献的微姑生物止和悬印浮粒全子数撞值稳欢定。汁6.井各因多素的还微生尺物监摩控数传据平惑均结较果汇芬总分屋析对绘无菌苍生产弓工艺宿中影永响药刘品微音生物隙质量郑的洁你净区仇环境耳、人丽员污玻染、舍物料月、注伤射用惑水、报压缩滥空气妄、氮鼓气所稼监控攀的微伍生物漏数据至进行到平均鸭汇总理,然吧后做听出饼裳图进魄行分斜析后威得出胳：人天员动址态微何生物壤污染轮所占喘比例血最大册是4交6%边(包爬括1沾00顽00游级无牛菌区谦和1吗00虹级区灶),著其次羞是药欺液中抱所含毒微生度物的孙比例欢占4限2%划,环妖境中肯的微傲生物硬所占笔比例嚼是9腔%,节注射勿用水害中微邪生物浙占3疲%,瘦压缩身空气挨和氮碰气微喇生物键所占验比例胁为零花。7疗.各恨因素员的微旷生物马风险毛分析抬对收从集的川数据赛采用傲FM章EA召表格欣进行踪风险岛排序帜和过偿滤,笼得出李影响货无菌弹生产鲁工艺漫注射腰液微喷生物帖风险塔因素统由小约到大当依次助为：跳压缩话空气猜、氮搂气、书物料磨、注笛射用举水、阿10孤0级房区空躺气、配10烂00猪0级途无菌奔区空线气、士人员厅污染裳。风近险顺粉序数乞RP奉N依纸次为声：2盗、3耻、8留、9削、1陕9、谨32法、2余52裙。8大.建改议及眯措施贩降低渔无菌脊生产促工艺天注射堪剂的夹微生吩物污孕染风洒险,赛在很放大程中度上脑取决月于人烦员的尖技能你,所痒接受轧的培趁训及奔人员威的工庄作态幅度。挥应采闯取的闪措施割：羞①伶是制盏定人淋员耐“留无菌灭室载”油行为缠规则剪,进胁行无归菌操栽作技阳能和谜意识奏培训酸；铅②口是采旷用无摧菌隔头离系捏统；父③爷是采籍用培御养基弄模拟障灌装馒,验盆证降首低人抬员污推染措够施有梯效性渴。结霉论在连无菌订生产痰工艺为注射制剂可妙能影吉响微熔生物雨的各冶种风贪险因唱素中爬：物黄料、胳压缩合空气抬、氮糠气为身低风挨险因话素；睬10再00厚0级研无菌饮区空分气、狭10已0级撇空气思和注迈射用吐水为君中等即风险座因素性：人步员污令染为渡高风息险因配素。督采用槽无菌剥隔离刮系统寿对降姨低人牛员的奇微生轿物污进染能滋起到凝较好别的效恰果；萄采用劲风险评管理威的程此序、渐工具类和方找法能杏有效斗地控归制无核菌工园艺注课射剂急生产蜘过程阴中的包微生勇物风恳险,泼使药释品的揪生产弹由过竟程控忙制转告为主突动预圾防,铜很好那的弥志补G稠MP客条款阻在质管量控自制方灾法和精工具决等方作面的忘不足搅。【英文摘要】Injectionisadosageformofinjectingdirectlyintohuman,whichisusuallywithlargerdosage.Injectioncanbeclassifiedintoterminallysterilisedprocessesandasepticpreparerationsaccordingtotheproductivetechnology.Thesterileguaranteeleveloftheasepticpreparerationsisonly1/103-/109ofthatoftheterminallysterilisedprocesses.Sincetherearemanymicrobiologicalcontaminationfactorsduringtheproductionoftheasepticpreparerations,therefore,highqualityrisksexistintheclinicalpractice.Thecurrentstudytakesthe5mlinjectionproducedbyasepticpreparerationsasanexample,andusesShewhartControlChart,PieChartandHistogramstomonitorthemicrobiologicalcontaminationsintroducedbyenvironments,personnel,materials,waterforinjection,compressedair,nitrogenduringproduction.WehopetofindahighmicrobiologicalriskfactorbyperformingriskassessmentoneachfactorthroughFailureModeEffectsAnalysis,Riskrankingandfiltering.Wethenperformriskcontrolbytakingmeasures,Thevalidityofthemeasuresissufficenttofurtherdecreasetheriskofthequalityoftheasepticpreparerationsandensurethesecurepharmacyofpatients.Thisarticlewascomposedofthefollowingeightparts:Theresultsanalysisofthemicrobiologicalandairborneparticulatemonitoringincleanzone;Theresultsanalysisofthepersonalmicrobiologicalmonitoring;Theresultsanalysisofmicrobiologicalmonitoringinmaterials;Theresultsanalysisofmicrobiologicalmonitoringinwaterforinjection;Theresultsanalysisofthemicrobiologicalandairborneparticulatemonitoringinthecompressedandnitrogen;TheMeta-analysisoftheaverageresultsofmonitoringdataofthemicrobesineachfactor;Theriskanalysisofmicrobesineachfactor;Suggestionsandmeasures.1.TheresultsanalysisofthemicrobiologicalandairborneparticulatemonitoringincleanzoneBythemicrobiologicalandairborneparticulatemonitoringatrestindifferentroomincludeagrade100000zone,agrade10000zone,aasepticgrade10000zone,agrade100zone,andbythemicrobiologicalmonitoringinoperationindifferentroominaasepticgrade10000zoneandagrade100zone.TheresultsarethenanalyzedaccordingtheirgradesthroughShewhartControlCharttocalculatedtheaveragevalueofX,thestandarddeviation8andthecontrollineX±38ofthestaticmicrobesandairborneparticlesatrestindifferentroomsindifferentcleanzones,respectively,andthoseofmicrobesinoperationindifferentroomsinaasepticgrade10000zoneandagrade100zone.WefindthateachtestingresultisfallwithinthecontrollinefromtheShewhartControlChart.WethenperformacomparativeanalysisthroughHistogramsofthemicrobesandairborneparticlesatrestinthecriticalroomsineachcleangradesandfindthat①thetestingresultsofthestaticthemicrobesandairborneparticleshavecorrespondencewiththegradesofthecleanzones;②thetestingresultsindifferentgradesofcleanzoneshavelargedifferences:thebestresultisinagrade100zone,followedbytheasepticgrade10000zoneandgrade100000zone.2.TheresultsanalysisofthepersonalmicrobiologicalmonitoringBymicrobiologicalmonitoringonthesurfaceofthepersonalgloves,sleeves,elbows,foreheadandafacemaskbysuccessive20batchsofproductioninaasepticgrade10000zoneandagrade100zone.TheresultsarethensummarizedandanalyzedbyShewhartControlCharts.Theaveragevaluesofxarecalculatedtobe1.50、1.25、1.55、1.15、1.15CFU/plateforaasepticgrade10000zone,0.70、0.55、0.60、0.50、0.45CFU/plateforagrade100zone,whilethestandarddeviation8arecalculatedtobe0.51、0.44、0.51、0.59、0.37CFU/plateforaasepticgrade10000zoneand0.47、0.51、0.50、0.51、0.51CFU/plateforagrade100zone.Wefindthatthetestingresultinagrade100zoneisobviouslybetterthanthatinaasepticgrade10000zone,andthefacemaskisbetterthanothers.Eachtestingresultinwithinthecontrolline.3.TheresultsanalysisofmicrobiologicalmonitoringinmaterialsBymicrobiologicalmonitoringinA,BandCinjectionsinsuccessive30batchs,TheresultsareanalysisbyusingShewhartControlchart.TheaveragevaluesofX,thestandarddeviation8,andx+3δforA,BandCinjectionsarecalculatedtobe1.57、1.31、2.37CFU/100ml,1.01、0.81、1.03CFU/100mland4.59、3.73、5.47CFU/100ml,respectively.WefinddifferenceofthequantityofmicrobesbetweentheA,BandCinjections:thetestingdataofAisbestwhileCisworst.AlltestingresultsfallwithinthecontrollineexceptseveralpointsinAandCinjections.4.TheresultsanalysisofmicrobiologicalmonitoringinwaterforinjectionWefirstlymonitorthemicrobesintheoutlet,pointofuse1,2,3andinletofthesystemofthewaterforinjectionweeklyandthensummarizedandanalysisthedataobtainedinawholeyearbyShewhartControlChart.Fortheoutlet,pointofuse1,23andinlet,theaveragevaluesofX,thestandarddeviationδ,andX+3δarecalculatedtobe0.10、0.12、0.12、0.14、0.18CFU/100ml,0.31、0.33、0.33、0.35、0.39CFU/100mland1.02、1.12、1.12、1.20、1.36CFU/100ml,respectively.Thetestingresultobtained(fromtheoutletinthebestwhilethatobtainedfromtheinletistheworstfromthecalculatedresultsandthevariationtrendofdata.5.TheresultsanalysisofthemicrobiologicalandairborneparticulatemonitoringinthecompressedandnitrogenWefirstlymonitorthemicrobesandairborneparticlesintheusingpointsofwashingbottle1,2,filling1,2,filtrationofthecompressedairandmonitorthemicrobesandairborneparticlesintheusingpointsoffilling1,2ofthenitrogenmonthly,andthensummarizeandanalysisthedataobtainedinawholeyearbyShewhartControlChart.WefindthatthevaluesoftheaverageX,standarddeviationδandX+3δareallcalculatedtobe0CFU/m3,indicatingthatthevaluesofthemicrobesandairborneparticlesineachusingpointarestable.6.TheMeta-analysisoftheaverageresultsofmonitoringdataofthemicrobesineachfactorThemonitoringdataofmicrobesintroducedbytheenvironmentofthecleanzones,personnelcontamination,materials,waterforinjection,compressedairandnitrogenduringtheasepticpreparerationfirstlyaveragedandsummarized.Wethenanalyzethedatabypiechartandconcludethattheproportionsofthemicrobesintroducedbypersonnelcontaminationinoperation(incontainingaasepticgrade10000zoneandagrade100zone),materials,theenvironmentsandwaterforinjectionare46%,42%,9%and3%,respectively,whilethatofthecompressedairandnitrogeniszero.7.TheriskanalysisofmicrobesineachfactorTheRiskrankingandfilteringareperformedonthecollecteddatabyFailureModeEffectsAnalysisandconcludethattheinfluenceofeachriskfactoronthemicrobesininjectionsproducedbyasepticpreparationsfromsmalltolargeiscompressedair,nitrogen,materials,waterforinjection,airinaasepticgrade10000zone,airinagrade100zone,personnelcontaminationwithaccordingRiskPriorityNumberof2,3,8,9,19,32and252.8.SuggestionsandmeasuresInordertominimizerisksofmicrobiologicalcontaminationofasepticpreparerations.Muchdependsontheskills,trainingandattitudesofpersonnelinvolved.Themeasuresshouldbeadoptedasfollows:①Settingpersonnelrulesinasepticroomandtrainingtheasepticoperatingskillandconsciousness;②Adoptingasepticisolatortechnology;③Validationofasepticprocessingneedaprocesssimulationtestusinganutrientmediumtoverifythemeasuresforreducingthecontaminationintroducedbypersonnel.ConclutionAmongvariousmicrobiologicalriskfactorsintheproductionofasepticpreparationsofinjection,materials,compressedairandnitrogenbelongtolowriskfactors,airinaasepticgrade10000zone,airinagrade100zoneandwaterforinjectionbelongtomediumriskfactor,whilepersonnelcontaminationbelongtohighriskfactor.Adoptingasepticisolatortechnologycaneffectivelyreducethemicrobiologicalcontaminationintroducedbypersonnel.Itiseffectiveincontrolingmicrobiologicalriskbymakinguseofriskmanagementprocessandtoolsa