药品生产质量管理规范附录(2010年修订)中英文对照.docx
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《药品生产质量管理规范(2010年修订)》《GoodManufacturingPractice(2010revision)》
Annex1toAnnex5TechnicalReviewedbyISPE
MichaelLee,ZhaoChunhua
ZhaoYunxia,HeGuoling,JiYiyun
InitialTranslationfromNNEPharmaplan
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ChineseGMPrevisedin2010
附录1:
Annex1:
无菌药品
SterileMedicinalProducts
目录
TableofContents
第一章范围.....................................................................................................4
Chapter1Scope...............................................................................................4
第二章原则.....................................................................................................4
Chapter2Principle............................................................................................4
第三章洁净度级别及监测...............................................................................5
Chapter3Cleanlinessclassificationandmonitoring........................................5
第四章隔离操作技术....................................................................................15
Chapter4Isolatortechnology.........................................................................15
第五章吹灌封技术........................................................................................16
Chapter5Blow/fill/sealtechnology.................................................................16
第六章人员...................................................................................................17
Chapter6Personnel.......................................................................................17
第七章厂房..........................................................................................……..19
Chapter7Premises.........................................................................................19
第八章设备...................................................................................................21
Chapter8Equipment......................................................................................21
第九章消毒...................................................................................................23
Chapter9Sanitation........................................................................................23
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第十章生产管理............................................................................................24
Chapter10Processing....................................................................................24
第十一章灭菌工艺........................................................................................29
Chapter11Sterilisation...................................................................................29
第十二章灭菌方法........................................................................................31
Chapter12Sterilisationmethod......................................................................31
第十三章无菌药品的最终处理......................................................................37
Chapter13Finishingofsterileproducts..........................................................37
第十四章质量控制........................................................................................38
Chapter14Qualitycontrol..............................................................................38
第十五章术语...............................................................................................39
Chapter15Glossary.......................................................................................39
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第一条
第一章范围
Chapter1Scope
无菌药品是指法定药品标准中列有无菌检查项目的制剂和原料药,
包括无菌制剂和无菌原料药。
Article1Thesterilemedicinalproducts,includingsteriledrugproductsand
drugsubstances,refertothedrugproductanddrugsubstanceswhicharesubjecttosterilitytestitemsasrequiredinthestatutorydrugspecifications
第二条
产过程。
本附录适用于无菌制剂生产全过程以及无菌原料药的灭菌和无菌生
Article2Thisannexappliestothewholemanufactureprocessforsterile
drugproducts,andtotheprocessofsterilisationandsterileproductionforsteriledrugsubstances.
第二章原则
Chapter2Principle
第三条
无菌药品的生产须满足其质量和预定用途的要求,应当最大限度降
低微生物、各种微粒和热原的污染。
生产人员的技能、所接受的培训及其工作态度是达到上述目标的关键因素,无菌药品的生产必须严格按照精心设计并经验证的方法及规程进行,产品的无菌或其它质量特性绝不能只依赖于任何形式的最终处理或成品检验(包括无菌检查)。
Article3Themanufactureofsterileproductsshouldmeettherequirementsofqualityandtheintendeduse.Itshouldminimizerisksofmicrobiologicalcontamination,andofparticulateandpyrogencontamination.Theskill,trainingandattitudesofthepersonnelinvolvedarecriticalfactors.Themanufactureof
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sterileproductsmuststrictlyfollowtheestablishedandvalidatedmethodsofpreparationandprocedure.Thesterilityorotherqualitycharacteristicsofproductscannotonlyrelyonanyformofterminalprocessorfinishedproducttest(includingsterilitytest).
第四条无菌药品按生产工艺可分为两类:
采用最终灭菌工艺的为最终灭菌产品;部分或全部工序采用无菌生产工艺的为非最终灭菌产品。
Article4Sterilemedicinalproducts,accordingtothemanufacturingprocess,canbedividedintotwocategories:
Termininallysterilisedproducts,wheretheproductsareterminallysterilised;andnon-terminallysterilisedproducts,wherethemanufactureprocessesarepartiallyorcompletelyaseptic.
第五条
无菌药品生产的人员、设备和物料应通过气锁间进入洁净区,采用
机械连续传输物料的,应当用正压气流保护并监测压差。
Article5Themanufactureofsterileproductsshouldbecarriedoutincleanareasentrytowhichshallbethroughairlocksforpersonneland/orforequipmentandmaterials.Ifequipmentisusedtoachievecontinuoustransferofmaterials,positivepressureairflowshallbeusedtoprotectmaterialsandpressuredifferenceshallbemonitored.
第六条
物料准备、产品配制和灌装或分装等操作必须在洁净区内分区域
(室)进行。
Article6Thevariousoperationsofcomponentpreparation,productpreparationandfillingshouldbecarriedoutinseparateareaswithinthecleanarea.
第七条应当根据产品特性、工艺和设备等因素,确定无菌药品生产用洁净区的级别。
每一步生产操作的环境都应当达到适当的动态洁净度标准,尽可能降低产品或所处理的物料被微粒或微生物污染的风险。
Article7Cleanareasforthemanufactureofsterileproductsareclassifiedaccordingtothepropertiesofproducts,thecharacteristicsofprocessandequipmentused.Eachstepofmanufacturingoperationrequiresanappropriateenvironmentalcleanlinesslevelintheoperationalstateinordertominimisetherisksofparticulateormicrobialcontaminationoftheproductormaterialsbeinghandled.
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(3)
(1)
第八条
第三章洁净度级别及监测
Chapter3CleanlinessClassificationandItsMonitoring
洁净区的设计必须符合相应的洁净度要求,包括达到“静态”和“动态”
的标准。
Article8Thedesignofeachcleanroomorsuiteofcleanroomsshallmeettherequirementsofcorrespondingcleanlinessclassification,ofwhich“inoperation”and“atrest”statesshallbedefined.
第九条无菌药品生产所需的洁净区可分为以下4个级别:
A级:
高风险操作区,如灌装区、放置胶塞桶和与无菌制剂直接接触的敞口包装容器的区域及无菌装配或连接操作的区域,应当用单向流操作台(罩)维持该区的环境状态。
单向流系统在其工作区域必须均匀送风,风速为0.36-0.54m/s(指导值)。
应当有数据证明单向流的状态并经过验证。
在密闭的隔离操作器或手套箱内,可使用较低的风速。
B级:
指无菌配制和灌装等高风险操作A级洁净区所处的背景区域。
C级和D级:
指无菌药品生产过程中重要程度较低操作步骤的洁净区。
以上各级别空气悬浮粒子的标准规定如下表:
洁净度级别
悬浮粒子最大允许数/立方米
静态
动态
≥0.5μm
≥5.0μm
(2)
≥0.5μm
≥5.0μm
A级
3520
20
3520
20
B级
3520
29
352000
2900
C级
352000
2900
3520000
29000
D级
3520000
29000
不作规定
不作规定
Article9Forthemanufactureofsterilemedicinalproducts4gradescanbedistinguished.
GradeA:
Thelocalzoneforhighriskoperations,e.g.fillingzone,stopperbowls,open
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containersthatareindirectcontactwithsterilepreparations,makingasepticconnections.Normallysuchconditionsareprovidedbyauni-directionalairflowworkstation.uni-directionalairflowsystemsshouldprovideahomogeneousairspeedinarangeof0.36–0.54m/s(guidancevalue)attheworkingpositioninopencleanroomapplications.Uni-directionalstatemustbevalidated,anddatamustbeavailabletoprovethevalidationstatus.
Alowervelocitiesmaybeusedinclosedisolatorsandgloveboxes.
GradeB:
Forasepticpreparationandfilling,thisisthebackgroundenvironmentforthegradeAzone.
GradeCandD:
Cleanareasforcarryingoutlesscriticaloperationstagesinthemanufactureofsterileproducts.
Themaximumpermittedairborneparticleconcentrationforeachgradeisgiveninthefollowingtable.
Grade
Maximumpermittednumberofparticlespermequaltoor
greaterthanthetabulatedsize
Atrest
Inoperation(3)
≥0.5μm
≥5.0μm
(2)
≥0.5μm
≥5.0μm
A
(1)
3520
20
3520
20
B
3520
29
352000
2900
C
352000
2900
3520000
29000
D
3520000
29000
Notdefined
Notdefined
B:
(1)为确认A级洁净区的级别,每个采样点的采样量不得少于1立方米。
A级洁净区空气悬浮粒子的级别为ISO4.8,以≥5.0μm的悬浮粒子为限度标准。
B级洁净区(静态)的空气悬浮粒子的级别为ISO5,同时包括表中两种粒径的悬浮粒子。
对于C级洁净区(静态和动态)而言,空气悬浮粒子的级别分别为ISO7和ISO8。
对于D级洁净区(静态)空气悬浮粒子的级别为ISO8。
测试方法可参照ISO14644-1。
(2)在确认级别时,应当使用采样管较短的便携式尘埃粒子计数器,避免≥5.0μm悬浮粒子在远程采样系统的长采样管中沉降。
在单向流系统中,应当采用等动力学的取样头。
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(3)动态测试可在常规操作、培养基模拟灌装过程中进行,证明达到动态的洁净度级别,但培养基模拟灌装试验要求在“最差状况”下进行动态测试。
Note:
(1)TodeterminethecleanlinesslevelforGradeAzones,aminimumsamplevolumeof1mshouldbetakenpersamplelocation.ForGradeAtheairborneparticleclassificationfollowsISO4.8dictatedbythelimitforparticles≥5.0μm.ForGradeB(atrest)theairborneparticleclassificationfollowsISO5,containingbothparticlesizeslistedintheabovetable.ForGradeC(atrest&inoperation)theairborneparticleclassificationfollowsISO7andISO8respectively.ForGradeD(atrest)theairborneparticleclassificationfollowsISO8.Formeasuringprocedure,refertoISO14644-1.
(2)Portableparticlecounterswithashortlengthofsampletubingshouldbeusedfor
classificationpurposesbecauseoftherelativelyhigherrateofprecipitationofparticles
≥5.0μminremotesamplingsystemswithlonglengthsoftubing.Isokineticsampl