医学专题—报批美国FDA仿制药研发与相关问题探讨-Final课件

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第一页，共四十一页。第二页，共四十一页。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。第四页，共四十一页。第五页，共四十一页。第六页，共四十一页。仿制(fngzh)药研发团队CONCEPT-1 BUILD UP A TEAMINFORMATIONFORMULATIONPRODUCTREGULATORYANALYTICALBIO-PHARMACEUTICALPROJECTLEGEL第七页，共四十一页。第八页，共四十一页。Product Development Roadmap仿制仿制(

2、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 empir

3、ically derived from performance of test batchesWhat 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？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？第十一页，共四十一页。Essential elements of QbD Definition of the quality target product profileHigh level quality aspects of the product: purity, drug

4、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 and control Critical Process Parameters (CPPs) Identification of material properties and

5、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 Identification of a control strategy for critical process parametersWhat is QbD?QbDQ

6、bD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？第十三页，共四十一页。Raw MaterialsEquipmentEnvironmentOperatorsUnderstood Variable InputsxUnd

7、erstood 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)体现？体现？Raw MaterialsWet GranulationFluid Bed DryingBlendingCompressionProduct第十五页，共四十

8、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.SWhat 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

9、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在制剂开发中怎么在制剂开发中怎么(zn me)(zn me)体现？体现？Raw MaterialsWet GranulationFluid Bed DryingBlendingC

10、ompressionFill 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 DryingBlendingCompressionFeed FrameToolingPunch Penetration DepthCompression ForcePress SpeedFeeder Speed

11、第二十页，共四十一页。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 attributes that affect the manufacturing and quality of the drug product? (2 pages) Drug Product What attributes should the d

12、rug 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 operations) related to the drug product quality? How were the critical process parameters identified, monitored, an

13、d/or controlled? Pharmaceutical Development Manufacture Container Closure System第二十二页，共四十一页。AspectsTraditionalQbDPharmaceuticaldevelopmentEmpirical; univariateexperimentsSystematic; multivariateexperimentsManufacturingprocessFixed; validation on 3 initialfull-scale batches; focus on reproducibilityA

14、djustable 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, real timeProductspecificationPrimary means of qualitycontrol; based on batch dataPart of the overall

15、 qualitycontrol strategy; based ondesired product performanceControlstrategyMainly by intermediate andend product testingRisk-based; controls shiftedupstream; real-time releaseLifecyclemanagementReactive to problems &OOS; post-approvalContinuous improvementenabled within design spaceQbDQbD小结小结(xioji

16、)(xioji)-SUMMARY-SUMMARY第二十三页，共四十一页。研发研发( (高难高难(o nn)(o nn) )仿制药的一些仿制药的一些体会体会第二十四页，共四十一页。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 112.73%103.64% to 112.79%75.28% to 98.84%FedRatio

17、111.21%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。第二十九页，共四十一页。第三十页，共四十一页。第三十一页，共四十一页。第三十二页，共四十一页。第三十三页，共四十一页。PRODUCT P DATA (Log Transformed Data, Fast, n-12)Rat

18、io of Geometric Means x 10090% CI of Log Transformed 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。PRODUCT P DATA (Log Transformed Data, FED, n-11)Ratio of Geometric Means x 10090% CI of Log Transformed DataCV

19、(%)Test A vs ReferenceAUC96.175.4; 12332.7Cmax10983.5; 14135.3Test B vs ReferenceAUC92.472.5; 11832.7Cmax10983.7; 14135.3第三十五页，共四十一页。PRODUCT 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(n l)研究研究-4API is Water Soluble. Prototy