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1、参数放行参数放行 Parametric Release参数放行参数放行Parametric Release参数放行参数放行 Parametric ReleaseParametric Release 参数放行nIntroduction 简介nWhy Parametric Release? n为何实行参数放行？nParametric Release Requirements n参数放行的法规要求nBaxters Implementation History n百特实施参数放行的历史nThe process in China n中国的进展参数放行参数放行 Parametric ReleaseIntr
2、oduction 简介nParametric 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)n 参数放行为一种可替代用无菌实验放行最终产品的无菌放行程序。参数放行必需在对经过验证的灭菌循环
3、进展有效控制、监测及文件化管理的根底上实施。参数放行参数放行 Parametric ReleaseIntroduction 简介nCan only be applied to products terminally sterilized in their final containers；Include steam heat, dry heat and Gamma ray sterilization etc.n 参数放行仅适用于在最后的包装容器中进展最终灭菌的产品；包括湿热、干热及辐射灭菌等；nThis presentation will be limited to parametric re
4、lease as it relates to moist heat sterilization processes.n 本处提及的参数放行仅限于湿热灭菌工艺参数放行参数放行 Parametric ReleaseWhy Parametric Release? 为何实行参数放行 General Definition 根本定义nSterile release of product based on the achievement of validated process parameters n产品无菌放行应基于一切经过验证的过程参数到达要求nBaxters position: Parametric
5、 release is the “natural end to a properly validated process n百特观念：参数放行是工艺过程经过验证的“自然结果nNot dependent on results of sterility test n不依托无菌检验的结果参数放行参数放行 Parametric ReleaseWhy Parametric Release? 为何实行参数放行？ ( Limitations of Sterility Test 无菌检查的局限性nAn inadequate process monitor n一种不充分的过程监测nStatistically l
6、imited 统计学局限nDifficult to perform 操作困难nProne to achieve inaccurate results 易导致不准确的结果nCostly 耗费本钱参数放行参数放行 Parametric ReleaseWhy Parametric Release? 为何实行参数放行？ (Limitations of Sterility Test 无菌检查的局限性)nInadequate Process Monitor 不充分的过程监测n10 to 20 product units per batch n每批仅抽取10-20个样品nSuccessful tests o
7、f 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程度参数放行参数放行 Parametric ReleasenStatistically Limited 统计学的局限nDetection Sensitivity(n=20 samples) 检测灵敏度微生物平均污染量微生物平均污染量/每每件件无菌实验阳性概率无菌实验阳性概率无菌实验经过概率无菌实验经过概率1.01.000.10.8812%0.010.1882%0.0010.0298.1
8、%10-62.0 X 10-5100% (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)参数放行参数放行 Parametric ReleasenSterility Testing is Prone to Inaccurate Results 无菌检查易获得不准确的结果nFalse positive rate high as 2% 假阳性率高至2%nComplexity of test sample 检测过程复杂nNumber of manipulations required
9、 需求大量的人力nNumber/experience of “Testers 依赖检测人员的数量和阅历nEnvironmental factors 受环境要素影响nUnnecessary product rejection 不用要的产品报废Why Parametric Release? 为何实行参数放行？ (Limitations of Sterility Test 无菌检查的局限性)参数放行参数放行 Parametric ReleasenSterility Test is Costly 无菌检查耗费本钱nMultiple product samples from each load 每灭菌锅
10、取样量大nClean room validation maintenance n无菌室需验证及保养nSpecially trained personnel n需特殊培训操作人员nMedia and equipment preparation n需预备培育基和设备nHigh product inventories required n产品库存量大n Why Parametric Release? 为何实行参数放行？ (Limitations of Sterility Test 无菌检查的局限性)参数放行参数放行 Parametric ReleaseWhy Parametric Release?
11、为何实行参数放行？Process 消费过程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 广谱杀菌才干(molds 霉菌, yeasts 酵母, bacteria 细菌/spores 孢子, viruses 病毒)Oldest, Safest, Most Dependable Process 最古老，最平安，最可靠的工艺Easily Controlled and Validated 易于控制
12、和验证Preferred by Most Regulatory Bodies 被多数法规部门引荐运用参数放行参数放行 Parametric ReleaseWhy Parametric Release? 为何实行参数放行？ Moist Heat Sterilization 湿热灭菌n“Natural Candidate for Parametric Release n参数放行是“自然选择nMinimal Key Parameters 至少应有的关键参数nTemperature 温度：105oCnExposure Time 暴露时间：5200 minutesnPressure: Saturated
13、 Steam Pressure 121oC = 30 PSIA/15 PSIG n压力：121oC的饱和蒸汽压 = 30 PSIA/15 PSIG参数放行参数放行 Parametric ReleaseWhy Parametric Release？为何参数放行？nBaxter is convinced:nParametric release is the only way to demonstrate required sterility assurance levels for terminally sterilized productsn百特坚信：n 参数放行是独一可以保证最终灭菌产品所要求
14、的无菌保证程度的方法参数放行参数放行 Parametric ReleaseParametric Release Requirements参数放行的要求参数放行的要求参数放行参数放行 Parametric ReleaseRegions 国家和地域nUnited States 美国nEurope 欧洲nICH 国际药品协调会nISO11134 ISO国际规范nJapan 日本nChina 中国参数放行参数放行 Parametric ReleaseFDA Guidance 7132a.13 FDA 政策法规指南 7132a.13Parametric Release: 参数放行定义A sterilit
15、y 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展有效的控制，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，程序中规定的一切参数
16、必需符合要求。参数放行参数放行 Parametric Release FDA 7132a.13 Requirements FDA 法规 7132a.13nCycle Validation 灭菌循环验证nContainer/Closure integrity validated. 容器或封口完好性验证nBioburden testing 微生物负荷检测nChemical or biological indicators in each individual sterilizer truck (carrier or pallet). n每一灭菌车(载物或托盘)有化学或生物指示剂nBiologica
17、l Indicator (BI) documentation. 生物指示剂的文件化管理参数放行参数放行 Parametric ReleaseCycle Validation 灭菌循环验证n6 SLR 细菌减少6对数值nHeat penetration and distribution studies for each load configuration. n对每种装载方式的热穿透及热分布进展验证nIdentification and monitoring of all critical cycle parameters. n确定灭菌循环的一切关键参数并进展监控参数放行参数放行 Paramet
18、ric Release Container/Closure Integrity 容器及封口的完好性nValidate to prevent in-process and post-process contamination over the products shelf life. 验证产品在消费中及消费后的有效期内均可防止被污染nValidation should include chemical or microbial ingress tests. 验证应包括化学或细菌侵入实验nMust utilize units from typical production. n必需运用正常消费的产
19、品参数放行参数放行 Parametric ReleaseBioburden Testing 生物负荷nConducted on each batch of pre-sterilized (non sterile) drug product. n每批产品应在未灭菌前检测微生物负荷nResistance of spore forming organisms found must be compared to that of the organism used to validate the cycle. 对新发现的孢子进展耐热研讨并与验证所用的微生物做对比参数放行参数放行 Parametric R
20、elease Chemical or Biological Indicators (BIs) 化学/生物指示剂nMust be included in each truck or pallet of each sterilizer load. n每锅内每载车必需放置化学或生物指示剂 n Time/temperature response characteristics and stability of the indicator are documented. n记录指示剂对时间及温度的反响特性和稳定性nMinimum degradation values for each steriliza
21、tion cycle are established. n建立每个灭菌循环的最小降解值nChemical indicators cannot be used to evaluate cycle lethality. n化学指示剂不能用于评价灭菌循环的杀灭才干参数放行参数放行 Parametric Release BI Documentation 生物指示剂的文件化管理nEach BI lot.每批BI批号nOrganisms name微生物称号nSource来源nD-valueD值nSpore concentration 孢子浓度nExpiration date有效期nStorage cond
22、itions.储存条件参数放行参数放行 Parametric ReleaseEurope 欧洲欧洲nCPMP/QWP/3015: Note for Guidance on Parametric Release n欧洲药品专卖局参数放行指南nAnnex 17, EU Guide to GMP n欧洲GMP指南，附录17nEuropean Pharmacopoeia (EP), 4rd edition. n欧洲药典第4版参数放行参数放行 Parametric Release欧洲药品专卖局参数放行指南欧洲药品专卖局参数放行指南CPMP/QWP/3015 nThis document outlines
23、 the requirements for applications that propose parametric release. n该文件规定了实行参数放行的要求nRequirements 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展风险评价的附加要求一样nAdopted, effective September 2001. n曾经被采用，2001年9月生效参数
24、放行参数放行 Parametric ReleaseAnnex 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
25、 to Parametric Release. 参数放行：是一种放行系统，它可以确保产质量量符合消费过程中搜集的数据，并符合与参数放行相关的详细GMP要求。参数放行参数放行 Parametric ReleaseAnnex 17, EU Guide to GMP欧洲GMP指南，附录17nGuide for inspectorate to use at facility for Parametric Release applications or routine inspections. n检查员用于恳求参数放行或常规检查的检查指南nStresses robustness of overall S
26、A system. n强调可靠性强的全面无菌保证系统nRequires Good to Excellent evaluation. n要求评价从良好到优秀nExamines history of GMP compliance at the facility. n检查工厂GMP符合性的历史参数放行参数放行 Parametric ReleaseEP 4rd edition 欧洲药典第欧洲药典第4版版nSection 5.1.1: parametric release may be carried out subject to approval of the competent authority.
27、 n第5.1.1 节: 实行参数放行需求经过法规机构同意nRequires 15 F0 unless product degradation results, in which case an SAL of 6 must be demonstrated. n除非产品会降解否那么要求F0值到达15，此时才干证明无菌保证程度(SAL)到达10-6参数放行参数放行 Parametric ReleaseICH Q6a 国际药品协调会条款Q6aSection 2.6: 第2.6 节Parametric release can be used as an alternative to routine re
28、lease testing when approved by regulatory authority. 当被法规机构同意后，参数放行可以替代常规检验放行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. 消费过程必需经过验证和再验证参数放行参数放行 Parametric ReleaseISO 11134 ISO国际规范nGeneral considerations, including personnel
29、 training and packaging. n总要求，包括人员培训和包装nEquipment 设备nProcess development 工艺开发nProcess validation 工艺验证nRoutine sterilization 常规灭菌参数放行参数放行 Parametric ReleaseISO 11134 ISO国际规范8.5Release of sterilized products 灭菌产品的放行Process parameters monitored during routine sterilization shall be within the validated
30、 limits. 于常规灭菌过程中丈量的参数必需符合验证时的限制A system to differentiate between processed and unprocessed items shall be used. 必需有区分已灭菌和未灭菌产品的系统Only authorized persons shall release products after sterilization. 只需经过授权的人员才干放行灭菌后的产品参数放行参数放行 Parametric ReleaseJapan JP XIII, supplement 2日本药局方13版，第二增补本Parametric rele
31、ase is a method that can be applied 参数放行法可以运用于：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展验证参数放行参数放行 P
32、arametric ReleaseChina 中国中国nChinese Pharmacopoeia(2000) & GMP(1998) does not currently recognize Parametric Release.n 中国药典2000版及GMP1998版目前尚未认可参数放行参数放行参数放行 Parametric ReleaseBaxters Implementation History百特实施参数放行的历史nFirst parametric release submission in the United States in 1981. Delay in approval d
33、ue to conflict within the agency. n1981年第一次在美国恳求参数放行，由于当时管理机构内部意见不一致而被推迟nApproval 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. n1985.1初次获得FDA同意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
34、行规范被FDA视为今后的规范方式nFDA Compliance Policy Guide 7132a.13 issued in 1987. n1987年，FDA正式公布了法规政策指南7132a.13参数放行参数放行 Parametric ReleaseBaxters Implementation History百特实施参数放行的历史nSince then, all moist heat sterilized products in the United States are released parametrically. Over 2 million IV containers per da
35、y. 自1985年，百特在美国一切用湿热灭菌的产品均采用参数放行。百特每天消费约200多万袋输液药品nAll new products in the United States are submitted for parametric release. 一切在美国上市的新产品均恳求参数放行参数放行参数放行 Parametric ReleaseCurrent Parametric Release Locations目前已同意实行参数放行的国家nAustralia 澳大利亚nBrazil 巴西nCanada 加拿大nChile 智利nColumbia 哥伦比亚nGermany 德国nNetherl
36、ands 荷兰nMexico 墨西哥nSpain 西班牙nSingapore 新加坡nUnited Kingdom 英国 nUnited States 美国参数放行参数放行 Parametric ReleaseFuture Locations 正在申报的国家nTurkey 土耳其nJapan 日本nFrance 法国nItaly 意大利nChina 中国参数放行参数放行 Parametric ReleaseSDA参数放行工程指点小组成员参数放行工程指点小组成员:n平安监管司，药品消费监视处n药品注册司，化学药品处nSDA药品认证管理中心n中国药品生物制品检定所n国家药典委员会参数放行参数放行 Parametric ReleaseParametric Release GMP 参数放行规范高于GMPnParametric 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 n参数放行是全公司在整体运作中各环节上高程度执行GMP的承诺；它不仅限于对灭菌过程的保证。
