1、开发报批美国开发报批美国FDA的仿制药的仿制药与相关问题探讨与相关问题探讨药物制剂药物制剂目标主流市场目标主流市场仿制药研发团队CONCEPT-1 BUILD UP A TEAMINFORMATIONFORMULATIONPRODUCTREGULATORYANALYTICALBIO-PHARMACEUTICALPROJECTLEGELProduct Development Roadmap仿制药的仿制药的研发过程研发过程 Quality Acceptably low risk of failing to achieve the desired clinical attributes Pharma
2、ceutical Quality=f drug substance,excipients,manufacturing.QbD Product and process performance characteristicsscientifically designed to meet specific objectives,not merely empirically derived from performance of test batchesWhat is QbD(?QbDQbD在制剂开发中怎么体现？在制剂开发中怎么体现？What is QbD?QbDQbD在制剂开发中怎么体现？在制剂开发
3、中怎么体现？Essential elements of QbD Definition 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 desi
4、red profile Conscious attempt to study and 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 demo
5、nstrated to provide assurance of quality Identification of a control strategy for critical process parametersWhat is QbD?QbDQbD在制剂开发中怎么体现？在制剂开发中怎么体现？Raw MaterialsEquipmentEnvironmentOperatorsVariable Inputs x“Locked”Process=Variable QualityHow Did We Work in the PastWhat is QbD?QbDQbD在制剂开发中怎么体现？在制剂开
6、发中怎么体现？Raw MaterialsEquipmentEnvironmentOperatorsUnderstood Variable InputsxUnderstood and Controlled Process=Predefined QualityFlexible Process Design SpaceHow Can We Work in the FutureWhat is QbD?QbDQbD在制剂开发中怎么体现？在制剂开发中怎么体现？What is QbD?QbDQbD在制剂开发中怎么体现？在制剂开发中怎么体现？Raw MaterialsWet GranulationFluid
7、Bed DryingBlendingCompressionProductDrug SubstanceExcipientsSourceAssayImpurities LODPS What is QbD?QbDQbD在制剂开发中怎么体现？在制剂开发中怎么体现？Raw MaterialsWet GranulationFluid Bed DryingBlendingCompressionWaterBinderTempSpray RateSpeedTimeP.SWhat is QbD?QbDQbD在制剂开发中怎么体现？在制剂开发中怎么体现？Raw MaterialsWet GranulationFlui
8、d Bed DryingBlendingCompressionWhat is QbD?QbDQbD在制剂开发中怎么体现？在制剂开发中怎么体现？Raw MaterialsWet GranulationFluid Bed DryingBlendingCompressionAir FlowTempRHShock CycleP.S.What is QbD?QbDQbD在制剂开发中怎么体现？在制剂开发中怎么体现？Raw MaterialsWet GranulationFluid Bed DryingBlendingCompressionFill VolumeRotation SpeedEnd Point
9、(Time)Blend UniformityDensitiesAngle of ReposeWhat is QbD?QbDQbD在制剂开发中怎么体现？在制剂开发中怎么体现？Raw MaterialsWet GranulationFluid Bed DryingBlendingCompressionFeed FrameToolingPunch Penetration DepthCompression ForcePress SpeedFeeder Speed Examples of QbD questions under QbR Control of Drug Substance What is
10、the drug substance specification?Does it include all the critical drug substance attributes 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 fin
11、al formulation optimized?Manufacturing Process How are the manufacturing steps(unit operations)related to the drug product quality?How were the critical process parameters identified,monitored,and/or controlled?Pharmaceutical Development Manufacture Container Closure SystemAspectsTraditionalQbDPharm
12、aceuticaldevelopmentEmpirical;univariateexperimentsSystematic;multivariateexperimentsManufacturingprocessFixed;validation on 3 initialfull-scale batches;focus on reproducibilityAdjustable within design space;continuous verification;focus on control strategyProcess controlIn-process testing for go/no
13、go;offline analysis w/slow responsePAT utilized for feedback&feed forward,real timeProductspecificationPrimary means of qualitycontrol;based on batch dataPart of the overall qualitycontrol strategy;based ondesired product performanceControlstrategyMainly by intermediate andend product testingRisk-ba
14、sed;controls shiftedupstream;real-time releaseLifecyclemanagementReactive to problems&OOS;post-approvalContinuous improvementenabled within design spaceQbDQbD小结小结-SUMMARY-SUMMARY研发研发(高难高难)仿制药的一些体仿制药的一些体会会Dissolution Profile-体外溶出曲线体外溶出曲线生物等效生物等效(BE)结果结果AUC0-tAUC0-infCmaxFastRatio108.01%108.12%86.26%9
15、0%Geometric C.I.103.49%to 112.73%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原因调查原因调查PRODUCT P DATA(Log Transformed Data,Fast,n-12)Ratio of Geometric Means x 1
16、0090%CI of Log Transformed DataCV(%)Test A vs ReferenceAUC10690.4;12322.0Cmax10480.1;13436.4Test B vs ReferenceAUC133114;15522.0Cmax129100;16736.4PRODUCT 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;12332.7Cmax109
17、83.5;14135.3Test B vs ReferenceAUC92.472.5;11832.7Cmax10983.7;14135.3PRODUCT 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案例研究案例研究-402040608010004812162024Amount dissolved(
18、%)Time(Hrs)Dissolution Profile for xxxx ER Formulation,USP Apparatus II,Water,50 RPM RefT-1T-2API is Water Soluble.Prototype formulation was proposed based on in vitro dissolution(OGD method).PRODUCT 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 147.0%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%Further Investigation02040608010012004812162024Amount dissolved(%)Time(Hrs)Simulated Dissolution for xxxx ER Formulation,RefT-2
