湿热灭菌的介绍参数放行 PPT课件.ppt

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1、Baxter Confidential1Parametric Release of Moist Heat Sterilized Products at Baxter百特湿热灭菌产品的参数放行百特湿热灭菌产品的参数放行Mike SadowskiDirector,Sterile Manufacturing Support无菌生产技术支持总监Round Lake,Illinois USABaxter Confidential2Introduction介绍介绍This presentation will be limited to parametric release as it relates to

2、 Baxter moist heat sterilization processes本次演讲仅限于百特湿热灭菌生产产品的参数放行Baxter Confidential3Parametric Release-General Definition参数放行参数放行-基本定义基本定义Sterile release of product based on the achievement of validated process parameters 产品无菌放行应基于所有经过验证的工艺参数符合要求Baxters position:Parametric release is the“natural end

3、”to a properly validated process 百特观点：参数放行是生产过程经过验证的“自然结果”Not dependent on results of sterility test 不依靠无菌检查的结果Baxter Confidential4Baxters US Implementation History百特在美国实施参数放行的历史百特在美国实施参数放行的历史First parametric release submission in the United States in 1981.Delay in approval due to conflict within th

4、e agency.1981年第一次在美国申请参数放行，由于管理机构(FDA)内部意见不统一而被推迟审批Approval granted for LVPs&SVPs in January,1985,prior to issuance of formal guidance to the industry.1985.1获得FDA批准对大小容量输液实行参数放行。此时FDA尚无正式工业指南The Initial Submission Served as the Model for Future Requirements百特的首次申请所递交的材料被FDA视为将来要求的模式FDA Compliance Po

5、licy Guide 7132a.13 issued in 1987.1987年，FDA颁布了参数放行政策指南7132a.13Baxter Confidential5All moist heat sterilized US products produced at the North Cove,NC,Jayuya,PR and Cleveland,MS facilities are released parametrically.在North Cove,NC,Jayuya,PR and Cleveland,MS facilities工厂生产的湿热灭菌的美国产品才用参数放行。All new pr

6、oducts in the United States,for the above facilities,are submitted for parametric release.以上工厂生产的所有美国新产品将递交申请参数放行。Baxters US Implementation History百特在美国实施参数放行的历史百特在美国实施参数放行的历史Baxter Confidential6Current Baxter Parametric Release Locations目前百特实施参数放行的地区Australia 澳大利亚Brazil 巴西Canada*加拿大Chile 智利China*中国

7、Columbia 哥伦比亚Germany 德国*Manf.Locations:US and Canada *生产地址：美国和加拿大*In Combination w/Sterility Test*与无菌检验结合实施Ireland以色列Mexico墨西哥Spain西班牙Singapore新加坡United Kingdom 英国(Thetford)United States美国Baxter Confidential7Sterility Test vs.Parametric Release无菌检验无菌检验 vs.参数放行参数放行Baxter Confidential8Limitations of S

8、terility Test无菌检查的局限性无菌检查的局限性An inadequate process monitor不充分的生产过程监测10 to 20 product units per batch每批仅抽取10-20个样品Successful tests for sterility tells us little about the Sterility Assurance Level(SAL)of units in the batch样品检测合格不能完全代表同批其它产品的无菌水平(SAL)Baxter Confidential9Statistically Limited统计学局限统计学局限

9、Detection Sensitivity(n=20 samples)检验灵敏度检验灵敏度Microorganism Concentration微生物污染Probability of One Sterility Test Positive无菌检查阳性概率1.01.00.10.880.010.180.0010.0210-61.9 X 10-5Limitations of Sterility Test无菌检查的局限性无菌检查的局限性Baxter Confidential10Sterility Testing is Prone to Inaccurate Results无菌检查易获得不精确的结果Fa

10、lse Positive Rate is High 假阳性率高Complexity of test sample 检测样品复杂Number of manipulations required需要多次处理Number/experience of“Testers”检验人员的经验/人员差异Environmental factors环境因素Unnecessary product rejection 不必要的产品报废Limitations of Sterility Test无菌检查的局限性无菌检查的局限性Baxter Confidential11Sterility Test is Costly to P

11、erform执行无菌检查耗费成本Multiple product samples from each load 每个灭菌柜次取样Test environment validation maintenance 测试环境验证及保养Specially trained personnel 特殊培训操作人员Labor Cost 人工成本Media and equipment preparation 准备培养基和设备High product inventories required 产品库存量大14 Day Sterility Test“Hold”14天无菌检验等待期Product Cost 产品成本Li

12、mitations of Sterility Test无菌检查的局限性无菌检查的局限性Baxter Confidential12Moist Heat Sterilization Process湿热灭菌工艺的特点Non-toxic无毒Less Expensive经济Universally Recognized普遍认可Broad Spectrum Lethality广谱杀菌能力（molds霉菌，yeasts酵母，bacteria细菌/spores孢子，viruses病毒）Oldest,Safest,Most Dependable Process最古老，最安全，最可靠的工艺Easily Contro

13、lled and Validated易于控制和验证Preferred by Most Regulatory Bodies被多数法规机构推荐使用Why the Moist Heat Sterilization Process?为什么采用湿热灭菌工艺？为什么采用湿热灭菌工艺？Baxter Confidential13“Natural”Candidate for Parametric Release参数放行是“自然”结果Minimal Key Parameters 至少关键灭菌参数Temperature:115 125oC温度温度：105135oCExposure Time:12-120 minut

14、es 暴露时间暴露时间：5200minutesPressure:-Saturated Steam Pressure 121oC=30 PSIA/15 PSIG 压力压力：121oC的饱和蒸汽压=30PSIA/15 PSIGWhy the Moist Heat Sterilization Process?为什么采用湿热灭菌工艺？为什么采用湿热灭菌工艺？Baxter Confidential14Parametric Release Requirements US参数放行要求参数放行要求 美国美国FDA Compliance Policy Guide 7132a.13,issued in 1987F

15、DA 法规7132a.13,1987年出版US Pharmacopoeia 31 美国药典31版AAMI TIR 13:Principles of Industrial Moist Heat SterilizationAAMI 技术指引：工业湿热灭菌原理ISO 11134:Sterilization of healthcare products Requirements for validation and routine control Industrial moist heat sterilizationISO 11134:医疗产品的灭菌 验证及日常控制要求-工业湿热灭菌PDA Techn

16、ical Report No.30(1999)PDA 技术报告No 30(1999)Baxter Confidential15FDA Compliance Policy Guide 7132a.13FDA 政策法规指南政策法规指南 7132a.13Parametric Release:参数放行定义A sterility release procedure based upon effective control of a validated sterilization process cycle in lieu of release based upon end-product sterili

17、ty testing.All parameters within the procedure must be met before the lot is released.参数放行：为一种替代对最终产品作无菌检查的无菌放行系统。它基于对一个经过验证的灭菌生产过程进行有效的控制。一批产品放行前，系统中规定的所有参数必须符合规定。Baxter Confidential16FDA CPG 7132a.13 RequirementsFDA CPG 7132a.13要求要求Cycle Validation灭菌循环验证Container/Closure Integrity Validated容器或封口完整

18、性验证Bio-burden Testing 微生物负载检测Chemical or Biological indicators in each individual Sterilizer Truck(carrier or pallet).每一灭菌车(货架或托盘)放化学或生物指示剂Biological Indicator(BI)Documentation文件化管理生物指示剂Baxter Confidential17US Pharmacopoeia 31美国药典美国药典 31版版USP:Terminally Sterilized Pharmaceutical ProductParametric Re

19、leaseUSP：最终灭菌药品：最终灭菌药品 参数放行参数放行Mode of sterilization well understood灭菌过程被充分理解Critical physical processing parameters defined定义关键过程物理参数Lethality of the cycle validated microbiologically 验证灭菌循环的微生物致死性10-6 SAL required要求10-6 SAL（无菌保证）FDA approval required得到FDA批准Baxter Confidential18AAMI TIR 13Where rel

20、iable process measurement and control can be documented for the entire manufacturing process,and correlated with sterility assurance,terminally sterilized items can be considered for release in accordance with delivered process parameters 当可靠的过程测量和控制可以用来记录整个生产过程及与其相关的无菌保证，那么最终灭菌产品可以按生产过程参数进行放行。Compl

21、iance with ANSI/AAMI/ISO 11134 in its entirety allows for parametric release符合ANSI/AAMI/ISO 11134的要求，可以允许执行参数放行。AAMI(Association for the Advancement of Medical Instrumentation)Baxter Confidential19ISO 11134Title:Sterilization of healthcare productsRequirements for validation and routine controlIndus

22、trial moist heat sterilization标题：医疗产品的灭菌标题：医疗产品的灭菌 验证及日常控制要求验证及日常控制要求-工业湿热灭菌工业湿热灭菌Note:ISO 11134 has been replaced by ISO 17665(fully effective end of 2009)注意：ISO11134将被ISO17665（2009年底生效）(for medical devices)General considerations,including personnel training and packaging总要求，包括人员培训和包装Equipment设备Pro

23、cess development 工艺开发Process validation过程验证Routine sterilization常规灭菌Baxter Confidential20ISO 111348.5 Release of sterilized products灭菌产品的放行灭菌产品的放行Process parameters monitored during routine sterilization shall be within the validated limits日常生产过程中监控的生产参数应该在验证限度内。A system to differentiate between pro

24、cessed and unprocessed items shall be used应该建立区分加工过产品及未加工过产品的系统。Only authorized persons shall release products after sterilization只有授权人才可以放行灭菌后产品。A.8.5 Release of sterilized products灭菌产品的放行“finished product testing or biological indicator testing might be required by some regulatory authorities.”“某些

25、国家法规可能要求最终产品测试或微生物指示剂测试。”Baxter Confidential21PDA Technical Report No.30(1999)PDA 技术报告技术报告No 30(1999)Applies only to products with 10-6 SAL 仅适用于10-6 无菌保证的产品Critical Parameters must be met to achieve release关键参数满足要求后，才能进行放行Demonstrate that entire load exposed to sterilization process证明整个装载都经过灭菌过程Proc

26、edures in place to document qualification,processing,and release requirements.有程序记录验证、生产过程和放行要求Note:This document is currently under revision in final review and expected to be issued in Q3,2009.注意：该文件正在做最终复核，预计2009年第三季度发布。Baxter Confidential22Baxter Compliance百特执行要求百特执行要求Product Design Control产品设计控

27、制Sterilization Equipment灭菌设备Sterilization Process Validation灭菌工艺验证Physical Lethality(Combination Studies)物理性细菌致死性（联合实验）Microbiological Lethality微生物致死性Container/Closure Integrity容器或封口完整性Sterile/Non-sterile Segregation灭菌/非灭菌的隔离Risk Assessment/Failure Mode and Effects Analysis(FMEA)风险分析/失败模式及效应分析(FMEA)

28、Baxter Confidential23Product Design Control产品设计控制产品设计控制Formal product design and validation procedures正式产品设计和验证过程Bill of Materials产品物流清单Incoming inspection and sampling of raw materials and components原料和组件的进厂取样检验Evaluation of change procedures变更流程的评估Baxter Confidential24Sterilization Equipment灭菌设备灭菌

29、设备Equipment configuration control设备配置控制Hardware and Software硬件和软件Robust recirculating water system设计可靠的水循环系统以防非无菌水进入灭菌后的系统Redundant instrumentation 多种检测仪器Routine calibration 常规校验Routine maintenance常规维护保养IQ/OQ validation安装/运行验证Baxter Confidential25Validated and controlled software programs软件程序需经验证并受控

30、Control system monitors and ensures delivery of critical parameters and compares results with redundant instrumentation控制系统监测并确保关键参数的实现，并与多种检测结果比较Sterilization Equipment灭菌设备灭菌设备Baxter Confidential26Sterilization Process Validation灭菌过程验证灭菌过程验证Combination penetration/distribution studies to validate m

31、inimum and maximum product requirements are met联合热穿透及热分布研究，以验证最小和最大产品符合规定Fractional validation to ensure sufficient lethality in solution and closure system用分段验证确保对溶液和密封的包装系统有足够的杀灭能力Routine requalification of process 工艺常规再验证Closure integrity validated 密封完整性验证Specified loading patterns 特定装载方式验证Baxter

32、 Confidential27Sterility Assurance Level无菌保证水平无菌保证水平Most medical devices and drug/pharmaceutical products require a 10-6 SAL大多数医疗器械和药品/医药产品需要10-6 无菌保证There cannot be more than one non-sterile unit in every 1,000,000 processed每一百万产品中不能存在多于一个非无菌产品Most sterilization processes far exceed this probabilit

33、y湿热灭菌过程可以远高于这个可能性。Baxter Confidential28Bioburden Testing生物负荷检测生物负荷检测Conducted on each batch of pre-sterilized(non sterile)drug product 每批产品应在灭菌前检测微生物负载Quantity and resistance of spore forming organisms found must be monitored and compared to that of the organism used to validate the cycle对新发现的孢子进行耐热

34、研究并与验证所用的微生物比较Baxter Confidential29In-Process Bioburden Testing Results生产过程生物负荷测试结果生产过程生物负荷测试结果Performed for over 20 years since Parametric Release approved自从参数放行被批准后，执行了自从参数放行被批准后，执行了20年年Total Counts show low levels of organisms总菌数显示了低水平的微生物Rarely detect spores几乎没有监测到孢子Spore resistance significantl

35、y less than BI used to validate the process孢子的热抗性远低于用于过程验证的生物指示剂（BI）Due to history of demonstrated control,FDA has approved Parametric Release for Baxter without holding for bio-burden results根据历史数据证实过程受控制，FDA批准百特的参数放行且无需等待生物负荷结果。Baxter Confidential30BI Documentation生物指示剂文件管理生物指示剂文件管理Each Moist Heat

36、 BI Lot(In-House)每批湿热用的BI批号Organisms name微生物名称Source来源D-valueD值Spore concentration孢子浓度Expiration date 有效期Storage conditions贮存条件Baxter Confidential31Container/Closure Integrity包装容器及封口的完整性包装容器及封口的完整性Robust Design产品设计Validated to demonstrate microbial barrier effectiveness for in-process and post-proce

37、ss over the products shelf life验证产品在生产过程中及生产后有效期内均可防止被污染Validation should include physical or microbial ingress tests验证应包括物理或微生物侵入实验“Worst Case”heat history processing历史“最差”加热过程Must utilize representative units from typical production必须使用正常生产的产品Baxter Confidential32Sterile/Non-sterile Segregation灭菌灭

38、菌/未灭菌产品隔离未灭菌产品隔离Physical Barriers物理隔断物理隔断Load reconciliation count to ensure the quantity of product entering the sterilizer equals the quantity exiting sterilization area装载平衡 数量计算以确保进入灭菌器的产品数量等于到达已灭菌区域产品数量Sterilizer product truck design prevents loss of a unit-sidescreens or tray design产品灭菌车设计防止产品丢

39、失 侧窗或者板设计Chemical indicators on every product truck demonstrate exposure to a sterilization cycle化学指示剂放置在每个灭菌车 证明产品曾经暴露于灭菌循环Baxter Confidential33Chemical or Biological Indicators(BIs)化学或生物指示剂（化学或生物指示剂（BI）Must be included in each truck,tray or pallet of each sterilizer load每个灭菌循环内每载车必须放置化学或生物指示剂Time

40、and/or temperature response characteristics and stability of the indicator are documented记录指示剂对时间及温度的反应特性和稳定性Minimum degradation values or color change(e.g.autoclave tape)required for each sterilization cycle are established建立每个灭菌循环的最小降解值Chemical indicators cannot be used to evaluate cycle microbiol

41、ogical lethality化学指示剂不能用于评估灭菌循环的杀灭能力BIs are typically not used for routine release of moist heat sterilized pharmaceutical products生物指示剂通常不用在湿热灭菌产品的日常放行Chemical indicators are a visual aid used to demonstrate that product has been exposed to a sterilization process化学指示剂只是帮助目视管理证明产品曾经暴露于灭菌循环Baxter Co

42、nfidential34Risk Assessment/FMEA风险评估风险评估/FMEAPerformed for each sterilization process to ensure risk of undetected failures is eliminated针对每个灭菌过程进行评估，确保未发现的失败已被消除。Evaluates probability of a failure,risk associated with that failure,and the detectability of that failure.评估失败的可能性、相关风险及失败的可检测性。Baxter C

43、onfidential35Upcoming Documents即将被批准的文件即将被批准的文件US FDA Guidance for Industry Submission of Documentation in Applications for Parametric Release of Human and Veterinary Drug Products Terminally Sterilized by Moist Heat Processes美国FDA指引-工业申请文件，用于申请最终湿热灭菌的人用药和兽用药参数放行PDA has provided industry commentsFDA

44、已经批准工业注释Compliance Policy Guide also expected to be updated 符合性指导政策也需要被更新PDA TR 30(Parametric Release)参数放行Draft routed for comments by FDA 07/08.FDA 在2007年08月起草征询意见Being led by Mike Sadowski of Baxter Sterility Assurance.百特无菌保证部门Mike 领导Baxter Confidential36Update on China Parametric Release Experience中国在参数放行上的经验Baxter Confidential37Summary:总结总结Baxter is a global sterilization leader that has been successfully using Parametric Release for moist heat sterilized solution products for over 20 years.百特是全球灭菌工艺的领先者，已经在湿热灭菌的输液产品百特是全球灭菌工艺的领先者，已经在湿热灭菌的输液产品上成功实施了超过上成功实施了超过20年的参数放行。年的参数放行。