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Ⅱ本文主要思考和讨论的内容是尝试将质量源于设计（QualitybyDesign，QbD）这一理念和原则运用于一个全新的医疗器械产品研发的项目全程设计、跟踪、指导和管理，以期获得将QbD落实于医疗器械研发的一些初步方法和成功或失败两方面的一些基本经验，以及为今后进一步探索如何将QbD指导原则同医疗器械新产品研发相结合建立一个初步的研究实例和方法学案例。相较于制药企业，国内的医疗器械（包括诊断试剂）企业对GMP理念和原则的接受和推广得更晚，因而更需要有既符合科学实践原则又具有实际指导意义的新理念和新方法来指导医疗器械产品（包括诊断试剂产品）的研发、生产和市场销售的各个阶段。而POCT（PointofCareTesting），国内目前通常译作即时检验或现场检验，作为医疗器械产品中的一个特殊领域，近年来在国外，尤其是欧美市场取得了长足的发展，但国内自上世纪九十年代中期开始引进和推广血糖仪产品及妊娠和尿试纸检测等少数几个产品外，并无更多的产品推出，而临床和实际又有较广泛的应用和需要。本项目团队根据这一个情况，经过广泛的调研和认真的评估，提出了开发总胆固醇（TotalCholesterol，TC）POCT产品的计划和构想，并依据同期在北大IPEM学习所获得的QbD相关知识、方法和经验，创新地尝试在项目启动初期即将正在国内外制药领域推广应用的QbD的方法和原则运用于实际的产品研发全过程中。关键词：质量源于设计医疗器械研发即时检验总胆固醇检测仪ⅢTitle：AcaseoftheapplicationofQbDrulesintheresearchanddevelopmentofmedicaldevice----theanalysisofprojectmanagementoftheinstanttotalcholesterolkitABSTRACTInthispaper，theprincipleofQbD(QualitybyDesign)conceptwasdiscussedandappliedinthewholeresearchprocessofanewmedicaldevice(MD),includingthedesignprocess,projecttracking,guidanceandmanagement.ItwasexpectedtoacquiresomefundamentalmethodandbasicexperienceofbothsuccessandfailurefromtheMDresearch,andalsotryingtoestablishaninitialresearchexampleandamethodologycasetodiscoverhowtocombinetheQbDrulewiththedevelopmentofMDproductinthefuture.Comparetothepharmaceuticalindustry,theGMPprinciplewasmuchlaterintroducedandacceptedtothemedicaldeviceindustry(includingthediagnosticreagentindustry)inChina.Soitismorenecessarytobringnewideasandnewmethodswhicharebothscientific,reasonableandpracticaltoinstructthedevelopmentofanewmedicaldeviceproductasanintegratedprocess，fromresearchtomanufacturingandtomarketingofthefinalproduct.POCTasashortformofPointofCareTestingisaspecialareaofMDproducts,whichhasmadesignificantprogressesontheU.S.andEuropeanmarketinrecentdecades.ButinChina,thepopularproductsthathasbeenintroducedasaPOCTproductincludeonlyafewsuchlikeglucometer，pregnanttestkitandurinetestkit,whilePOCTproductsareactuallymorewidelyandnecessarilydemandedandrequiredforbothhealthcareandclinicalpurposes.Accordingtosuchsituation,theteamhaslaunchedacomprehensivedevelopmentplanofTotalCholesterol（TC）productsbasedonextensivestudyandcarefulevaluation.Theknowledge,principleandexperienceofQbDlearnedinPekingUniversitywereinnovativelyintroducedintheresearchprocessattheverybeginning.ⅣInthispaper,themethodandprincipleofQbDwasapproachedintheresearchanddevelopmentofaninstanttotalcholesteroltestkit.Themajortasksofthisprojectincludethefollowings:Keywords：QualitybyDesign,ResearchandDevelopment,MedicalDeviceandDiagnosticReagents,PointofCareTesting,TotalCholesterolTestKitⅤ目录第一章序言·····························11.1研究背景·····························11.1.1QbD及其在制药行业中的应用·················11.1.2医疗器械和POCT·······················51.1.3层析式胆固醇自测仪的研究背景················81.2研究内容·····························81.3研究意义·····························101.4本论文的研究方法·························10第二章层析式总胆固醇自测仪的设计·················112.1检测原理设计···························112.1.1总胆固醇定量分析方法概述··················112.1.2定量分析方法选择······················132.2仪器设计·····························142.2.1仪器原理设计························142.2.2检测系统设计························142.2.3检测系统选材························16第三章层析式总胆固醇自测仪的开发·················223.1总胆固醇的酶法模拟检测······················223.1.1过氧化氢的测定·······················223.1.2胆固醇的测定························253.1.3猪血清中总胆固醇的测定···················283.1.4人血清中总胆固醇的测定···················333.2总胆固醇的快速层析检测······················373.2.1反应系统的定型·······················373.2.2仪器结构的定型·······················423.2.3过氧化氢的测定·······················443.2.4质控血清中总胆固醇的测定··················463.2.5人血清中总胆固醇的测定···················47Ⅴ第四章稳定性研究·························504.1稳定性研究方案··························504.1.1稳定性研究目的·······················504.1.2稳定性的基本内容······················504.1.3有效期限的确定·······················524.1.4稳定性研究项目的设置····················534.2稳定性研究结果·························544.2.1显色试纸的稳定性结果····················544.2.2反应控制纸的稳定性结果···················544.2.3HRP溶液的稳定性结果····················56第五章临床试验··························615.1临床试验方案···························615.1.1目的和项目内容·······················615.1.2总体设计··························615.1.3临床评价标准························625.1.4临床试验持续时间及其确定理由················645.1.5每病种临床试验例数及其确定理由···············645.1.6选择对象范围、选择对象数量及选择理由············645.1.7副作用预测及应当采取的措施·················655.1.8临床性能的评价方法和统计处理方法··············655.2临床试验结果···························665.2.1回收试验结果························665.2.2对比试验结果························665.2.3批内精密度·························74第六章结论与展望·························766.1结论·······························766.2案例说明·····························766.2.1工艺设计的透彻理解·····················766.2.2实验设计和验证·······················786.2.3设计空间的建立·······················80Ⅴ6.3展望·······························82参考文献·······························83后记·································861第一章序言1.1研究背景1.1.1QbD及其在制药行业中的应用1.1.1.1QbD概念的起源QbD是质量源于设计（QualitybyDesign）的简称，美国知名质量管理学者JosephM.Juran首先提出这个概念，他在多篇著作中阐述了他的观念，其中最著名的当数JuranonQualitybyDesign[1]。Juran认为质量应该能被设计出来，大多数的质量危机和问题与最初的设计有关。QbD原则已被用于提高各个工业的产品和