欧盟对灭菌技术的要求课件

,Click to edit Master title style,Click to edit Master text styles,Second Level,Third Level,Fourth Level,Fifth Level,欧盟对灭菌技术的要求,Sterilisation Technology EU Regulatory Experiences,the,compliance,group,Stan ONeill,CPAPE 2011,年会,Agenda,内容,Background,背景,Typical Process description,典型工艺的描述,Virtual inspection typical issues,我们来作一次虚拟的检查,看常见的问题,Miscellaneous,其它,Background,背景,Experience in industry in,Reg,Affairs and QA(as QP)prior to IMB,在进爱尔兰药品管理局前，有制药、法规与,QA(QP),的经验,10 Years IMB,experience in most technologies,EMEA IWG,and training.,爱尔兰药品管理局,10,年，有多种技术、,EMEA IWG,以及培训方面的经验,Now a“virtual inspector”,现在是“事实上的检查员”,So lets do a“virtual inspection”,好，我们来,做当一回“检查员”,But lets talk about the solutions/strategies/positions;not just the problems.,我们先来讨论,战略位置,/,策略,/,解决方案，而不只是讨论问题,Typical process,典型工艺,Raw material sampling,原料取样,Materials dispensed,物料配制,Raw materials mixed,原料混合,Bulk product filtered,已过滤的药液,Product filled,已灌装产品,Bulk product stored,药液储存,Units sealed,密封产品,Units,stoppered,已加塞产品,Units inspected,已检查品,Quality control,质量控制,Sealed units terminally sterilised,密封产品最终灭菌,Colour coding system,彩色编码系统,Processing steps,操作步骤,Aseptic,无菌操作,Terminally,Sterilized,最终灭菌,Problem,问题,Solution,解决方案,Ancillary steps,辅助步骤,Processing steps,Aseptic,Terminally Sterilized,Problem,Solution,Ancillary steps,Raw material sampling,Identity testing of each container of API and,excipients,Validated NIR acceptable on each container with MA identity test on composite,Classification and garbing for sampling area,Grade C(equivalent activity to compounding).No outdoor clothing.,Materials dispensed,Classification and garbing for dispensing area,Grade C(equivalent activity to compounding).No outdoor clothing.,Sampling&identification,加工步骤,无菌操作,最终灭菌,问题,解决方案,辅助操作,原料取样,对每个容器的原料药与辅料进行鉴别实验,可用经验证的近红外，在生产现场对组份作每个容器的鉴别试验,取样区级别与着装,C,级区,(,与配制活动同级,),，不穿室外衣服,物料称量,配料区级别与着装,C,级区,(,与配制活动同级,),，不穿室外衣服,原料鉴别,Processing steps,Aseptic,Terminally,Sterilised,Problem,Solution,Ancillary steps,Raw materials mixed,Bulk product filtered,Weeping seal between clean and non-clean side of mixing shaft,Understanding the system,ensuring weeping fluid is WFI.,Pre-use,post sterilization integrity test,The test should be performed,as confirmed by the EMEA.Numerous technical solutions are possible.,T and P not independent of control systems,Consider introduction of independent monitoring system.At a minimum,a pressure gauge periodically checked.,Sterilization of equipment using SIP,T&P monitoring,原料混合,过滤的半成品,搅拌轴清洁和不清洁间的密封要淋洗,搞清楚系统，保证用注射用水淋洗,使用前，灭菌后，作完整性测试,正如,EMEA,确认的那样，应进行测试，可采用多种技术方案,温度与压力不独立于控制系统,考虑引入独立的监测系统，至少定期检查压力表,使用在线灭菌的灭菌设备,加工步骤,无菌,最终灭菌,问题,解决方案,辅助步骤,搅拌密封清洁、过滤器、监测系统,Bulk product stored,Holding time exceeded,Often a mis-undestanding that there is an absolute limit.Longer times can be validated,(taking into account MA filing).,Processing steps,Aseptic,Terminally,Sterilised,Problem,Solution,Ancillary steps,Holding time,半成品储存,存放时间超标,经常出现误解，认为限度是绝对的。时间长一些可经过验证,(,考虑上市场许可的要求,),加工步骤,无菌操作,最终灭菌,问题,解决方案,辅助步骤,存放时间,Processing steps,Aseptic,Terminally Sterilized,Problem,Solution,Ancillary steps,Product filled,Autoclave validation for porous loads,Use of air detectors in autoclaves,use of HTM 2010 validation criteria,use of 5 pulses to meet equilibration time criteria,Aseptic processing,Sterilization of ancillary supplies e.g.pens,paper,Where steam sterilization not possible,consider gamma irradiation,Sterilization of components by ethylene oxide-torturous path,Vent plastic bags with a,tyvex,strip,Operator,behaviour,Practise,observation of set up and observation of garbing in a non-familiar environment(e.g.Board.Room)where suitable facilities not available.,Tunnel validation,lack of objective criteria,Consider use of objective criteria such as F,H,Vent plastic bags,产品灌装,多孔装载蒸汽灭菌的验证,在灭菌柜采用空气探测器，采用,HTM 2010,标准，用,5,个脉冲使平衡时间达到标准,无菌工艺,辅助材料，如笔，纸的灭菌,在不可能蒸汽灭菌时，考虑,射线辐照灭菌,部件用环氧乙烷灭菌,-“,折磨,人的路径,塑料袋口用,tyvex,条,操作人员的,行为,在无合适设备时，在不熟悉的环境,(,如会议室,),中，安排调试和着装，观察,人员的行为,隧道灭菌器验证无客观标准,考虑使用客观标准如,F,H,加工步骤,无菌操作,最终灭菌,问题,解决方案,辅助步骤,纸笔灭菌及人员行为,Units,stoppered,Freeze drying;pressure not monitored during,sterilisation,of chamber,Design independent pressure monitoring into,sterilisation,cycle.,Freeze drying;no system to assess for shelf coolant leakage,potentially entering units,Use pressure hold test to check shelf integrity.May necessitate,vapour,pressure calculations for coolant.,2nd choice-declare,chember,to be,sanitised,rather than,sterilised,2nd choice-check coolant levels in between batches,Sterilisation,of stoppers using stopper processor,Considered to be SIP rather than autoclaving,so lower sterility assurance,Design taking account of some aspects of autoclaves and autoclave validation criteria.,Processing steps,Aseptic,Terminally Sterilized,Problem,Solution,Ancillary steps,pressure not monitored,已加塞瓶,/,单元,冻干：冻干腔室,/,箱灭菌过程中没监测压力,在灭菌程序设计中,增加独立的压力监测,冻干：无系统来评估冷媒的泄露,有可能进入瓶,/,单元中,使用压力保持试验对系统检漏，有必要计算冷媒的蒸汽压,第,2,种办法,-,声明腔室是消毒处理的，不是灭菌的,第,2,种办法,-,在批与批之间检查冷媒的水平,用塞处理机,灭菌胶塞,考虑在线灭菌而不是高压灭菌,由此降低了无菌保证水平,设计中考虑蒸汽灭菌的相关因素及蒸汽灭菌程序验证的标准,加工步骤,无菌操作,最终灭菌,问题,解