(精品)报批美国FDA仿制药研发与相关问题探讨-何平.ppt

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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上海复星普适医药科技有限公司上海复星普适医药科技有限公司上海复星普适医药科技有限公司上海复星普适医药科技有限公司何平何平何平何平内容提要内容提要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)仿制药的一些体会：案例研究开发仿制药的重要性 新药与仿制药新药与仿制药-NDA-NDA andand ANDAANDA开发仿制药与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主流市场目标主流市场开发仿制药的挑战性 开发仿制药

2、更具挑战性药物制剂药物制剂专利专利 仿制药的竞争仿制药的竞争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仿制药竞争的方式HOW TO COMPETE Cost-IR ProductRaw MaterialsRaw MaterialsProcessProcessFinished ProductFinished ProductTechnology-Modified Release Products申报(仿制)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)中国市场（中国市场（sFDA）

3、1 1类类类类2 2类类类类3 3类类类类4 4类类类类5 5类类类类6 6类类类类仿制药研发团队CONCEPT-1 BUILD UP A TEAMINFORMATIONFORMULATIONPRODUCTREGULATORYANALYTICALBIO-PHARMACEUTICALPROJECTLEGELDRUG DELIVERY SYSTEMS FOR ORAL SOLID FORMULATIONS-MRMATRIX SYSTEMSMATRIX SYSTEMSRESERVIOR SYSTEMSRESERVIOR SYSTEMSOSMOTICAL PUMP SYSTEMSOSMOTICAL P

4、UMP SYSTEMSCOMBO-SYSTEMSCOMBO-SYSTEMS缓控释给药的技术平台和给药系统CONCEPT-2 BUILD UP A SYSTEMProduct 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 Pharmaceutical Quality=f drug substance,excipients,manufacturing.QbD Product and process perfor

5、mance characteristicsscientifically designed to meet specific objectives,not merely empirically derived from performance of test batchesWhat is QbD(Quality by Design)?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？Pharmaceutical Quality by Design(QbD)QbD means designing and deve

6、loping QbD means designing and developing formulations and manufacturing processes to formulations and manufacturing processes to ensure predefined product qualityensure predefined product qualityUnderstanding and controlling formulation and Understanding and controlling formulation and manufacturin

7、g process variables affecting the manufacturing process variables affecting the quality of a drug productquality of a drug productEssential elements of QbD Definition of the quality target product profileHigh level quality aspects of the product:purity,drug release(dissolution/disintegration time),p

8、harmacokinetic 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 process parameters which haveeffect on product CQA

9、s 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?QbDQbD在制剂开发中怎么体现？在制剂开发中怎么体现？Raw MaterialsEquipmentEnvir

10、onmentOperatorsVariable 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？在制剂开发中怎么体现？Raw MaterialsEquipmentEnvironmentOperatorsUnderstood Variable InputsxUnderstood and Controlled Process=Predefined QualityFlexible Process Design SpaceHow Can We Work in

11、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 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 DryingBlen

12、dingCompressionWaterBinderTempSpray 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 GranulationFluid 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?Q

13、bDQbD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(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 Pene

14、tration DepthCompression ForcePress SpeedFeeder Speed Quality Assessment under QbRQuestion-based Review(QbR)is a general Question-based Review(QbR)is a general framework for a science and risk-based framework for a science and risk-based assessment of product qualityassessment of product qualityQbR

15、contains the important scientific and QbR contains the important scientific and regulatory review questions toregulatory review questions to Comprehensively assess critical formulation and Comprehensively assess critical formulation and manufacturing process variablesmanufacturing process variables

16、Set regulatory specifications relevant to qualitySet regulatory specifications relevant to quality Determine the level of risk associated with the Determine the level of risk associated with the manufacture and design of the productmanufacture and design of the productExamples of QbD questions under

17、 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 drug product possess?(1.5 pages)How were the excipients an

18、d 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,and/or controlled?Pharmaceutical Development Manufacture Container C

19、losure SystemAspectsTraditionalQbDPharmaceuticaldevelopmentEmpirical;univariateexperimentsSystematic;multivariateexperimentsManufacturingprocessFixed;validation on 3 initialfull-scale batches;focus on reproducibilityAdjustable within design space;continuous verification;focus on control strategyProc

20、ess 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 qualitycontrol strategy;based ondesired product performanceControlstrategyMainly by int

21、ermediate andend product testingRisk-based;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)仿制药的一些体会仿制药的一些体会案例研究-1CASE STUDY 1-IR TabletsVery Low Water Solubility(Ve

22、ry Low Water Solubility(低水溶性低水溶性)Very Low PotencyVery Low 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 (湿法制粒湿法制粒)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%90%Geometric C.I.103.

23、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原因调查原因调查案例研究-2CASE STUDY 2-ER CAPSULESNo Patent(无专利)Coated Pellets(包衣微丸)1st Bio Study FailedFast:Close

24、Fast:CloseFedFed(Compared with Fast)(Compared with Fast):Brand:BA Reduced Brand:BA Reduced Tested:BA Increased Tested:BA IncreasedTEAM WORKMore Information CollectedAnalytical SupportIdentify the Process Used Identify the Process Used Provide the Info for Functional CoatingProvide the Info for Funct

25、ional CoatingOne more Pilot and One Full Bio-Passed案例研究-3CASE STUDY 3-ER CAPSULESBrand ProductMicro-Tablets in CapsulesMicro-Tablets in Capsules95%of API existed in Finished Product95%of API existed in Finished ProductSystem and Process PatentedSystem and Process PatentedUNIQUE SYSTEM-CREATIVE DESIG

26、NCompressed Granules in CapsulesRequirementRequirementSame Dissolution BehaviorSame Dissolution BehaviorUniformUniformYield Acceptable Yield Acceptable SYSTEM COMPARISON PILOT BIO-STUDYPRODUCT P DATA(Log Transformed Data,Fast,n-12)Ratio of Geometric Means x 10090%CI of Log Transformed DataCV(%)Test

27、A vs ReferenceAUC10690.4;12322.0Cmax10480.1;13436.4Test B vs ReferenceAUC133114;15522.0Cmax129100;16736.4PILOT 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;12332.7Cmax10983.5;14135.3Test B vs Refe

28、renceAUC92.472.5;11832.7Cmax10983.7;14135.3PIVOTAL 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案例研究案例研究-4CASE STUDY 4-ER CAPSULESTime(Hrs)Amount dissolved

29、(%)04812162024100806040200Dissolution 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).PILOT BIO-STUDYPRODUCT DATA(Log Transformed Data)AUC0-tAUC0-infCmaxT-1Ratio111.21%112.48%140%

30、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 InvestigationTime(Hrs)Amount dissolved(%)04812162024120100806040200Simulated Dissolution for xxxx ER Formulation,RefT-2谢谢!139-1866-7400139-1866-