2022年医学专题—报批美国FDA仿制药研发与相关问题探讨-Final.ppt

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1、开发报批美国开发报批美国FDA的仿制的仿制(fngzh)药与相关问题探讨药与相关问题探讨上海复星普适医药上海复星普适医药(yyo)(yyo)科技有限公司科技有限公司何平何平第一页，共四十一页。内容提要内容提要(ni rn t yo)(ni rn t yo)开发仿制药的重要性和机遇 开发仿制药的挑战申报仿制药的分类仿制药研发团队仿制药的研发过程QbD在制剂开发中怎么体现研发(高难(o nn)o nn)仿制药的一些体会：案例研究第二页，共四十一页。开发(kif)(kif)仿制药的重要性 新药与仿制新药与仿制(fngzh)(fngzh)药药-NDA-NDA andand ANDAANDA开发仿制药与

2、我国药物研发的海外战略开发仿制药与我国药物研发的海外战略药物制剂药物制剂目标目标(mbio)主流市场主流市场第三页，共四十一页。开发(kif)(kif)仿制药的挑战性 开发仿制药更具挑战性药物制剂 专利专利 仿制药的竞争仿制药的竞争(jngzhng)(jngzhng)仿制药厂之间的竞争仿制药厂之间的竞争由品牌药转成仿制药由品牌药转成仿制药第四页，共四十一页。仿制(fngzh)(fngzh)药竞争的方式HOW TO COMPETE Cost-IR ProductRaw Materials ProcessProcess Finished ProductFinished ProductTechnol

3、ogy-Modified Release Products第五页，共四十一页。申报(仿制(fngzh)(fngzh)新药的分类规范市场规范市场(FDA)1。P-I2。P-II3。P-III4。P-IV(1(1stst to file)to file)中国中国(zhn u)(zhn u)市场市场（sFDA）1 1类类2类类类类3 3类类4 4类类5类类类类6类类第六页，共四十一页。仿制(fngzh)药研发团队CONCEPT-1 BUILD UP A TEAMINFORMATIONFORMULATIONPRODUCTREGULATORYANALYTICALBIO-PHARMACEUTICALPRO

4、JECTLEGEL第七页，共四十一页。DRUG DELIVERY SYSTEMS FOR ORAL SOLID FORMULATIONS-MR MATRIX SYSTEMSMATRIX SYSTEMS RESERVIOR SYSTEMSRESERVIOR SYSTEMS OSMOTICAL PUMP SYSTEMSOSMOTICAL PUMP SYSTEMS COMBO-SYSTEMSCOMBO-SYSTEMS缓控释给药的技术(jsh)(jsh)平台和给药系统CONCEPT-2 BUILD UP A SYSTEM第八页，共四十一页。Product Development Roadmap仿制仿制

5、(fngzh)药的药的研发过程研发过程第九页，共四十一页。Quality Acceptably low risk of failing to achieve the desired clinical attributes Pharmaceutical Quality=f drug substance,excipients,manufacturing.QbD Product and process performance characteristicsscientifically designed to meet specific objectives,not merely empiricall

6、y derived from performance of test batchesWhat is QbD(Quality by Design)?QbDQbD在制剂在制剂(zhj)(zhj)开发中怎么体现？开发中怎么体现？第十页，共四十一页。What is QbD?QbDQbD在制剂开发在制剂开发(kif)(kif)中怎么体现？中怎么体现？Pharmaceutical Quality by Design(QbD)QbD means designing and developing formulations and manufacturing processes to ensure predef

7、ined product qualityUnderstanding and controlling formulation and Understanding and controlling formulation and manufacturing process variables affecting the quality of manufacturing process variables affecting the quality of a drug producta drug product第十一页，共四十一页。Essential elements of QbD Definitio

8、n of the quality target product profileHigh level quality aspects of the product:purity,drug release(dissolution/disintegration time),pharmacokinetic profile,etc.Critical quality attributes(CQAs)for drug product Characteristics of DP which have impact on desired profile Conscious attempt to study an

9、d control Critical Process Parameters(CPPs)Identification of material properties and process parameters which haveeffect on product CQAs Design Space:The multidimensional combination and interaction ofinput variables and process parameters that have been demonstrated to provide assurance of quality

10、Identification of a control strategy for critical process parametersWhat is QbD?QbDQbD在制剂开发中怎么在制剂开发中怎么(zn me)(zn me)体现？体现？第十二页，共四十一页。Raw MaterialsEquipmentEnvironmentOperatorsVariable Inputsx“Locked”Process=Variable QualityHow Did We Work in the PastWhat is QbD?QbDQbD在制剂在制剂(zhj)(zhj)开发中怎么体现？开发中怎么体现？

11、第十三页，共四十一页。Raw MaterialsEquipmentEnvironmentOperatorsUnderstood Variable InputsxUnderstood and Controlled Process=Predefined QualityFlexible Process Design SpaceHow Can We Work in the FutureWhat is QbD?QbDQbD在制剂开发在制剂开发(kif)(kif)中怎么体现？中怎么体现？第十四页，共四十一页。What is QbD?QbDQbD在制剂开发中怎么在制剂开发中怎么(zn me)(zn me)体

12、现？体现？Raw MaterialsWet GranulationFluid Bed DryingBlendingCompressionProduct第十五页，共四十一页。Drug SubstanceExcipientsSourceAssayImpurities LODPS What is QbD?QbDQbD在制剂开发在制剂开发(kif)(kif)中怎么体现？中怎么体现？Raw MaterialsWet GranulationFluid Bed DryingBlendingCompression第十六页，共四十一页。WaterBinderTempSpray RateSpeedTimeP.SW

13、hat is QbD?QbDQbD在制剂开发在制剂开发(kif)(kif)中怎么体现？中怎么体现？Raw MaterialsWet GranulationFluid Bed DryingBlendingCompression第十七页，共四十一页。What is QbD?QbDQbD在制剂在制剂(zhj)(zhj)开发中怎么体现？开发中怎么体现？Raw MaterialsWet GranulationFluid Bed DryingBlendingCompressionAir FlowTempRHShock CycleP.S.第十八页，共四十一页。What is QbD?QbDQbD在制剂开发中

14、怎么在制剂开发中怎么(zn me)(zn me)体现？体现？Raw MaterialsWet GranulationFluid Bed DryingBlendingCompressionFill VolumeRotation SpeedEnd Point(Time)Blend UniformityDensitiesAngle of Repose第十九页，共四十一页。What is QbD?QbDQbD在制剂开发中怎么在制剂开发中怎么(zn me)(zn me)体现？体现？Raw MaterialsWet GranulationFluid Bed DryingBlendingCompressio

15、nFeed FrameToolingPunch Penetration DepthCompression ForcePress SpeedFeeder Speed 第二十页，共四十一页。Quality Assessment under QbRQuestion-based Review(QbR)is a general framework for a science and risk-based assessment of product qualityQbR contains the important scientific and regulatory review questions to

16、 Comprehensively assess critical formulation and Comprehensively assess critical formulation and manufacturing process variablesmanufacturing process variables Set regulatory specifications relevant to qualitySet regulatory specifications relevant to quality Determine the level of risk associated wi

17、th the Determine the level of risk associated with the manufacture and design of the productmanufacture and design of the product第二十一页，共四十一页。Examples of QbD questions under QbR Control of Drug Substance What is the drug substance specification?Does it include all the critical drug substance attribut

18、es that affect the manufacturing and quality of the drug product?(2 pages)Drug Product What attributes should the drug product possess?(1.5 pages)How were the excipients and their grades selected?How was the final formulation optimized?Manufacturing Process How are the manufacturing steps(unit opera

19、tions)related to the drug product quality?How were the critical process parameters identified,monitored,and/or controlled?Pharmaceutical Development Manufacture Container Closure System第二十二页，共四十一页。AspectsTraditionalQbDPharmaceuticaldevelopmentEmpirical;univariateexperimentsSystematic;multivariateexp

20、erimentsManufacturingprocessFixed;validation on 3 initialfull-scale batches;focus on reproducibilityAdjustable within design space;continuous verification;focus on control strategyProcess controlIn-process testing for go/nogo;offline analysis w/slow responsePAT utilized for feedback&feed forward,rea

21、l timeProductspecificationPrimary means of qualitycontrol;based on batch dataPart of the overall qualitycontrol strategy;based ondesired product performanceControlstrategyMainly by intermediate andend product testingRisk-based;controls shiftedupstream;real-time releaseLifecyclemanagementReactive to

22、problems&OOS;post-approvalContinuous improvementenabled within design spaceQbDQbD小结小结(xi(xioji)oji)-SUMMARY-SUMMARY第二十三页，共四十一页。研发研发(高难高难(o nn)o nn)仿制药的一些体仿制药的一些体会会第二十四页，共四十一页。案例(n l)(n l)研究-1CASE STUDY 1-IR TabletsVery Low Water Solubility(Very Low Water Solubility(低水溶性低水溶性)Very Low PotencyVery Low

23、Potency (低剂量低剂量)Micronized API usedMicronized API used (微粉化原料药微粉化原料药)Wet Granulation ProcessWet Granulation Process (湿法制湿法制(fzh)(fzh)粒粒)第二十五页，共四十一页。Dissolution Profile-体外溶出曲线体外溶出曲线(qxin)第二十六页，共四十一页。生物等效生物等效(dn xio)(BE)结果结果AUC0-tAUC0-infCmaxFastRatio108.01%108.12%86.26%90%Geometric C.I.103.49%to 112.

24、73%103.64%to 112.79%75.28%to 98.84%FedRatio111.21%112.48%85.24%90%Geometric C.I.104.40%to 118.47%105.78%to 119.60%73.47%to 98.90%Summary of in vivo study results of Test Formulation vs.RLD第二十七页，共四十一页。原因原因(yunyn)调查调查第二十八页，共四十一页。案例(n l)(n l)研究-2CASE STUDY 2-ER CAPSULESNo Patent(无专利(zhunl)(zhunl)Coated

25、 Pellets(包衣微丸)1st Bio Study Failed Fast:CloseFast:CloseFed(Compared with Fast):Brand:BA Reduced Brand:BA Reduced Tested:BA Increased Tested:BA Increased第二十九页，共四十一页。TEAM WORKMore Information CollectedAnalytical Support Identify the Process Used Identify the Process Used Provide the Info for Functiona

26、l CoatingOne more Pilot and One Full Bio-Passed第三十页，共四十一页。案例(n l)(n l)研究-3CASE STUDY 3-ER CAPSULESBrand Product Micro-Tablets in CapsulesMicro-Tablets in Capsules 95%of API existed in Finished Product95%of API existed in Finished ProductSystem and Process Patented第三十一页，共四十一页。UNIQUE SYSTEM-CREATIVE D

27、ESIGNCompressed Granules in CapsulesRequirement Same Dissolution BehaviorSame Dissolution BehaviorUniformUniform Yield Acceptable Yield Acceptable 第三十二页，共四十一页。SYSTEM COMPARISON 第三十三页，共四十一页。PILOT BIO-STUDYPRODUCT P DATA(Log Transformed Data,Fast,n-12)Ratio of Geometric Means x 10090%CI of Log Transfo

28、rmed DataCV(%)Test A vs ReferenceAUC10690.4;12322.0Cmax10480.1;13436.4Test B vs ReferenceAUC133114;15522.0Cmax129100;16736.4第三十四页，共四十一页。PILOT BIO-STUDYPRODUCT P DATA(Log Transformed Data,FED,n-11)Ratio of Geometric Means x 10090%CI of Log Transformed DataCV(%)Test A vs ReferenceAUC96.175.4;12332.7Cm

29、ax10983.5;14135.3Test B vs ReferenceAUC92.472.5;11832.7Cmax10983.7;14135.3第三十五页，共四十一页。PIVOTAL BIO-STUDYPRODUCT P DATA(Log Transformed Data)Ratio of Geometric Means x 10090%CI of Log Transformed DataCV(%)FASTAUC10293;11133,9Cmax10594.5;11638.8FEDAUC98.891.6;10726.4Cmax99.689.2;11138.4第三十六页，共四十一页。案例案例

30、(n l)研究研究-4CASE STUDY 4-ER CAPSULESAPI is Water Soluble.Prototype formulation was proposed based on in vitro dissolution(OGD method).第三十七页，共四十一页。PILOT BIO-STUDYPRODUCT DATA(Log Transformed Data)AUC0-tAUC0-infCmaxT-1Ratio111.21%112.48%140%90%Geometric C.I.104.40%to 118.47%105.78%to 119.60%133.7%to 14

31、7.0%T-2Ratio117.5%117.2%135.9%90%Geometric C.I.113.2%to 122.2%112.4%to 122.1%129.5%to 142.4%第三十八页，共四十一页。Further Investigation第三十九页，共四十一页。谢谢(xi xie)(xi xie)!139-1866-第四十页，共四十一页。内容(nirng)总结开发报批美国FDA的仿制药与相关问题(wnt)探讨。新药与仿制药-NDA and ANDA。仿制药竞争的方式HOW TO COMPETE。End Point(Time)。Coated Pellets(包衣微丸)。Fed(Compared with Fast):。Tested:BA Increased。UNIQUE SYSTEM-CREATIVE DESIGN。Same Dissolution Behavior第四十一页，共四十一页。