上海一家企业参数放行理念课件

,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,上海一家企业参数放行理念,*,参数放行,Parametric Release,参数放行,Parametric Release,上海一家企业参数放行理念,Parametric Release,参数放行,Introduction,简介,Why Parametric Release?,为何实行参数放行？,Parametric Release Requirements,参数放行的法规要求,Baxters Implementation History,百特实施参数放行的历史,The process in China,中国的进展,上海一家企业参数放行理念,Introduction,简介,Parametric release is defined as a sterility release procedure based upon effective control, monitoring, and documentation of a validated sterilization process cycle in lieu of release based upon end-product sterility testing. (FDA7132a.13),参数放行为一种可替代用无菌试验放行最终产品的无菌放行程序。参数放行必须在对经过验证的灭菌循环进行有效控制、监测及文件化管理的基础上实施。,上海一家企业参数放行理念,Introduction,简介,Can only be applied to products terminally sterilized in their final containers；Include steam heat, dry heat and Gamma ray sterilization etc.,参数放行仅适用于在最后的包装容器中进行最终灭菌的产品；包括湿热、干热及辐射灭菌等；,This presentation will be limited to parametric release as it relates to moist heat sterilization processes.,本处提及的参数放行仅限于湿热灭菌工艺,上海一家企业参数放行理念,Why Parametric Release?,为何实行参数放行,（,General Definition,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过程参数达到要求,Baxters position: Parametric release is the “natural end” to a properly validated process,百特观点：参数放行是工艺过程经过验证的“自然结果”,Not dependent on results of sterility test,不依靠无菌检验的结果,上海一家企业参数放行理念,Why Parametric Release?,为何实行参数放行？,(,Limitations of Sterility Test,无菌检查的局限性）,An inadequate process monitor,一种不充分的过程监测,Statistically limited,统计学局限,Difficult to perform,操作困难,Prone to achieve inaccurate results,易导致不准确的结果,Costly,消耗成本,上海一家企业参数放行理念,Why Parametric Release?,为何实行参数放行？,(Limitations of Sterility Test,无菌检查的局限性),Inadequate Process Monitor,不充分的过程监测,10,to 20 product units per batch,每批仅抽取10-20个样品,Successful tests of these tells us little about the level of sterilization in other 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,上海一家企业参数放行理念,Statistically Limited,统计学的局限,Detection Sensitivity(n=20 samples),检测灵敏度,微生物平均污染量/每件,无菌试验阳性概率,无菌试验通过概率,1.0,1.0,0,0.1,0.88,12%,0.01,0.18,82%,0.001,0.02,98.1%,10,-6,2.0,X 10,-5,100% (99.9998%),Why Parametric Release?,为何实行参数放行？,(Limitations of Sterility Test,无菌检查的局限性),上海一家企业参数放行理念,Sterility Testing is Prone to Inaccurate Results,无菌检查易获得不精确的结果,False positive rate high as 2%,假阳性率高至2%,Complexity of test sample,检测过程复杂,Number of manipulations required,需要大量的人力,Number/experience of “Testers”,依赖检测人员的数量和经验,Environmental factors,受环境因素影响,Unnecessary product rejection,不必要的产品报废,Why Parametric Release?,为何实行参数放行？,(,Limitations of Sterility Test,无菌检查的局限性),上海一家企业参数放行理念,Sterility Test is Costly,无菌检查消耗成本,Multiple product samples from each load,每灭菌锅取样量大,Clean room validation maintenance,无菌室需验证及保养,Specially trained personnel,需特殊培训操作人员,Media and equipment preparation,需准备培养基和设备,High product inventories required,产品库存量大,Why Parametric Release?,为何实行参数放行？,(,Limitations of Sterility Test,无菌检查的局限性),上海一家企业参数放行理念,Why Parametric Release?,为何实行参数放行？,（,Process,生产过程）,Moist Heat Sterilization Process,湿热灭菌工艺的特点,Non-toxic,无毒,Less Expensive,低耗费,Universally Recognized,国际普遍认可,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 Controlled and Validated,易于控制和验证,Preferred by Most Regulatory Bodies,被多数法规部门推荐使用,上海一家企业参数放行理念,Why Parametric Release?,为何实行参数放行？,（Moist Heat Sterilization,湿热灭菌）,“,Natural” Candidate for Parametric Release,参数放行是“自然”选择,Minimal Key Parameters,至少应有的关键参数,Temperature,温度：,105135,o,C,Exposure Time,暴露时间：,5200,minutes,Pressure,:,Saturated Steam Pressure 121,o,C,= 30,PSIA/15 PSIG,压力：,121,o,C,的饱和蒸汽压 = 30,PSIA/15 PSIG,上海一家企业参数放行理念,Why Parametric Release？,为何参数放行？,Baxter is convinced:,Parametric release is the only way to demonstrate required sterility assurance levels for terminally sterilized products,百特深信：,参数放行是唯一可以保证最终灭菌产品所要求的无菌保证水平的方法,上海一家企业参数放行理念,Parametric Release Requirements,参数放行的要求,上海一家企业参数放行理念,Regions,国家和地区,United States,美国,Europe,欧洲,ICH,国际药品协调会,ISO11134 ISO,国际标准,Japan,日本,China,中国,上海一家企业参数放行理念,FDA Guidance 7132a.13 FDA,政策法规指南,7132,a.13,Parametric 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 sterility,testing. All parameters within the procedure must,be met before the lot is released.,基于对一个经过验证的灭菌循环过程进行有效的控制，参数放行可定义为一种替代对最终产品作无菌检验的无菌放行程序。一批产品放行前，程序中规定的所有参数必须符合要求。,上海一家企业参数放行理念,FDA 7132a.13 Requirements FDA,法规,7132,a.13,Cycle Validation,灭菌循环验证,Container/Closure integrity validated.,容器或封口完整性验证,Bioburden testing,微生物负荷检测,Chemical or biological indicators in each individual sterilizer truck (carrier or pallet).,每一灭菌车(载物或托盘)有化学或生物指示剂,Biological Indicator (BI) documentation.,生物指示剂的文件化管理,上海一家企业参数放行理念,Cycle Validation,灭菌循环验证,6,SLR,细菌减少6对数值,Heat penetration and distribution studies for each load configuration.,对每种装载方式的热穿透及热分布进行验证,Identification and monitoring of all critical cycle parameters.,确定灭菌循环的所有关键参数并进行监控,上海一家企业参数放行理念,Container/Closure Integrity,容器及封口的完整性,Validate to prevent in-process and post-process contamination over the products shelf life.,验证产品在生产中及生产后的有效期内均可防止被污染,Validation should include chemical or microbial ingress tests.,验证应包括化学或细菌侵入实验,Must utilize units from typical production.,必须使用正常生产的产品,上海一家企业参数放行理念,Bioburden Testing,生物负荷,Conducted on each batch of pre-sterilized (non sterile) drug,product.,每批产品应在未灭菌前检测微生物负荷,Resistance of spore forming organisms found must be compared to that of the organism used to validate the cycle.,对新发现的孢子进行耐热研究并与验证所用的微生物做对比,上海一家企业参数放行理念,Chemical or Biological Indicators (BIs),化学/生物指示剂,Must be included in each truck or pallet of each sterilizer load.,每锅内每载车必须放置化学或生物指示剂,Time/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 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 lethality.,化学指示剂不能用于评估灭菌循环的杀灭能力,上海一家企业参数放行理念,BI Documentation,生物指示剂的文件化管理,Each BI lot.,每批,BI,批号,Organisms name,微生物名称,Source,来源,D-value,D,值,Spore concentration,孢子浓度,Expiration date,有效期,Storage conditions.,贮存条件,上海一家企业参数放行理念,Europe,欧洲,CPMP/QWP/3015: Note for Guidance on Parametric Release,欧洲药品专卖局参数放行指南,Annex 17, EU Guide to GMP,欧洲,GMP,指南，附录17,European Pharmacopoeia (EP), 4,rd,edition.,欧洲药典第4版,上海一家企业参数放行理念,欧洲药品专卖局参数放行指南,（,CPMP/QWP/3015）,This document outlines the requirements for applications that propose parametric release.,该文件规定了实行参数放行的要求,Requirements similar to FDA with the additional requirement to perform a risk assessment for the release of non-sterile product.,上述要求与,FDA,关于“放行非无菌产品需进行风险评估”的附加要求相同,Adopted, effective September 2001.,已经被采用，2001年9月生效,上海一家企业参数放行理念,Annex 17, EU Guide to GMP,欧洲,GMP,指南，附录17,Parametric Release,: A system of release that gives the assurance that the product is of the intended quality based on information collected during the manufacturing process and on the compliance with the specific GMP requirements related to Parametric Release.,参数放行,：是一种放行系统，它可以确保产品质量符合生产过程中收集的数据，并符合与参数放行相关的具体,GMP,要求。,上海一家企业参数放行理念,Annex 17, EU Guide to GMP,欧洲,GMP,指南，附录17,Guide for inspectorate to use at facility for Parametric Release applications or routine inspections.,检查员用于申请参数放行或常规检查的检查指南,Stresses robustness of overall SA system.,强调可靠性强的全面无菌保证系统,Requires Good to Excellent evaluation.,要求评估从良好到优秀,Examines history of GMP compliance at the facility.,检查工厂,GMP,符合性的历史,上海一家企业参数放行理念,EP 4,rd,edition,欧洲药典第4版,Section 5.1.1: parametric release may be carried out subject to approval of the competent authority.,第,5.1.1,节:,实行参数放行需要经过法规机构批准,Requires 15 F,0,unless product degradation results, in which case an SAL of 6 must be demonstrated.,除非产品会降解否则要求,F,0,值达到15，此时才能证明无菌保证水平(,SAL),达到10,-6,上海一家企业参数放行理念,ICH Q6a,国际药品协调会条款,Q6a,Section 2.6:,第,2.6,节,Parametric release can be used as an alternative to routine release testing when approved by regulatory authority.,当被法规机构批准后，参数放行可以代替常规检验放行,Chemical or physical indicator may be included in the program.,本过程亦可采用化学或物理指示剂,Process must be validated and revalidated.,生产过程必须经过验证和再验证,上海一家企业参数放行理念,ISO 11134 ISO,国际标准,General considerations, including personnel training and packaging.,总要求，包括人员培训和包装,Equipment,设备,Process development,工艺开发,Process validation,工艺验证,Routine sterilization,常规灭菌,上海一家企业参数放行理念,ISO 11134 ISO,国际标准,8.5,Release of sterilized products,灭菌产品的放行,Process parameters monitored during routine sterilization shall be within the validated limits.,于常规灭菌过程中测量的参数必须符合验证时的限度,A system to differentiate between processed and unprocessed items shall be used.,必须有区分已灭菌和未灭菌产品的系统,Only authorized persons shall release products after sterilization.,只有经过授权的人员才能放行灭菌后的产品,上海一家企业参数放行理念,Japan JP XIII, supplement 2,日本药局方13版，第二增补本,Parametric release is a method that can be applied,参数放行法可以应用于：,Sterilization system is clearly defined,清楚地规定了灭菌系统,important control points are clearly specified,清楚地明确了重要的控制点,sterilization system process can be validated by microbiological methods using appropriate biological indicators.,灭菌工艺过程应能用生物指示剂法进行验证,上海一家企业参数放行理念,China,中国,Chinese Pharmacopoeia(2000) & GMP(1998) does not currently recognize Parametric Release.,中国药典2000版及,GMP1998,版目前尚未认可参数放行,上海一家企业参数放行理念,Baxters Implementation History,百特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 the agency.,1981年第一次在美国申请参数放行，由于当时管理机构内部意见不统一而被推迟,Approval granted for LVPs and SVPs in January, 1985, prior to issuance of formal guidance to the industry. Baxters release method served as the model for future requirements.,1985.1,首次获得,FDA,批准,对大小容量输液实行参数放行，此,时,FDA,尚未发布正式工业指南，因此百特的放行标准被,FDA,视为今后的标准模式,FDA Compliance Policy Guide 7132a.13 issued in 1987.,1987,年，,FDA,正式颁布了法规政策指南,7132,a.13,上海一家企业参数放行理念,Baxters Implementation History,百特实施参数放行的历史,Since then, all moist heat sterilized products in the United States are released parametrically. Over 2 million IV containers per day.,自1985年，百特在美国所有用湿热灭菌的产品均采用参数放行。百特每天生产约200多万袋输液药品,All new products in the United States are submitted for parametric release.,所有在美国上市的新产品均申请参数放行,上海一家企业参数放行理念,Current Parametric Release Locations,目前已批准实行参数放行的国家,Australia,澳大利亚,Brazil,巴西,Canada,加拿大,Chile,智利,Columbia,哥伦比亚,Germany,德国,Netherlands,荷兰,Mexico,墨西哥,Spain,西班牙,Singapore,新加坡,United Kingdom,英国,United States,美国,上海一家企业参数放行理念,Future Locations,正在申报的国家,Turkey,土耳其,Japan,日本,France,法国,Italy,意大利,China,中国,上海一家企业参数放行理念,SDA,参数放行项目领导小组成员:,安全监管司，药品生产监督处,药品注册司，化学药品处,SDA,药品认证管理中心,中国药品生物制品检定所,国家药典委员会,上海一家企业参数放行理念,Parametric Release GMP,参数放行标准高于,GMP,Parametric release is a commitment of the entire company to maintain GMP compliance at a high level across the entire operation; it is not just reserved to the sterility assurance process,参数放行是全公司在整体运作中各环节上高水平执行,GMP,的承诺；它不仅限于对灭菌过程的保证。,上海一家企业参数放行理念,