报批美国FDA仿制药研发与相关问题探讨-Final.ppt

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,开发报批美国,FDA,的仿制药与相关问题探讨,上海复星普适医药科技有限公司,何平,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,-NDA,and,ANDA,开发仿制药与我国药物研发的海外战略,药物制剂,目标主流市场,开发仿制药的挑战性,开发仿制药更具挑战性,药物制剂,专利,仿制药的竞争,仿制药厂之间的竞争,由品牌药转成仿制药,仿制药竞争的方式,HOW TO COMPETE,Cost,-IR Product,Raw Materials,Process,Finished Product,Technology,-Modified Release Products,申报,(,仿制,),新药的分类,规范市场,(FDA),1,。,P-I,2,。,P-II,3,。,P-III,4,。,P-IV,(1,st,to file),中国市场（,sFDA,）,1,类,2,类,3,类,4,类,5,类,6,类,仿制药研发团队,CONCEPT-1 BUILD UP A TEAM,INFORMATION,FORMULATION,PRODUCT,REGULATORY,ANALYTICAL,BIO-PHARMACEUTICAL,PROJECT,LEGEL,DRUG DELIVERY SYSTEMS FOR ORAL SOLID FORMULATIONS-MR,MATRIX SYSTEMS,RESERVIOR SYSTEMS,OSMOTICAL PUMP SYSTEMS,COMBO-SYSTEMS,缓控释给药的技术平台和给药系统,CONCEPT-2 BUILD UP A SYSTEM,P,roduct,D,evelopment,R,oadmap,仿制药的,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 performance characteristics,scientifically designed to meet specific objectives,not merely,empirically derived from performance of test batches,What is Q,bD,(,Quality by Design),?,QbD,在制剂开发中怎么体现？,What is Q,bD,?,QbD,在制剂开发中怎么体现？,Pharmaceutical Quality by Design(QbD),QbD means designing and developing formulations and manufacturing processes to ensure predefined product quality,Understanding and controlling formulation and manufacturing process variables affecting the quality of a drug product,Essential elements of QbD,Definition of the quality target product profile,High 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 and control,Critical Process Parameters(CPPs),Identification of,material properties and process parameters which have,effect on product CQAs,Design Space,:The multidimensional combination and interaction of,input variables and process parameters that have been demonstrated to provide assurance of quality,Identification of a control strategy for critical process parameters,What is Q,bD,?,QbD,在制剂开发中怎么体现？,Raw Materials,Equipment,Environment,Operators,Variable,Inputs,x,“Locked”Process,=,Variable Quality,How Did We Work in the Past,What is Q,bD,?,QbD,在制剂开发中怎么体现？,Raw Materials,Equipment,Environment,Operators,Understood Variable Inputs,x,Understood and Controlled Process,=,Predefined Quality,Flexible Process Design Space,How Can We Work in the Future,What is Q,bD,?,QbD,在制剂开发中怎么体现？,What is Q,bD,?,QbD,在制剂开发中怎么体现？,Raw Materials,Wet Granulation,Fluid Bed Drying,Blending,Compression,Product,Drug Substance,Excipients,Source,Assay,Impurities,LOD,PS,What is Q,bD,?,QbD,在制剂开发中怎么体现？,Raw Materials,Wet Granulation,Fluid Bed Drying,Blending,Compression,Water,Binder,Temp,Spray Rate,Speed,Time,P.S,What is Q,bD,?,QbD,在制剂开发中怎么体现？,Raw Materials,Wet Granulation,Fluid Bed Drying,Blending,Compression,What is Q,bD,?,QbD,在制剂开发中怎么体现？,Raw Materials,Wet Granulation,Fluid Bed Drying,Blending,Compression,Air Flow,Temp,RH,Shock Cycle,P.S.,What is Q,bD,?,QbD,在制剂开发中怎么体现？,Raw Materials,Wet Granulation,Fluid Bed Drying,Blending,Compression,Fill Volume,Rotation Speed,End Point,(Time),Blend Uniformity,Densities,Angle of Repose,What is Q,bD,?,QbD,在制剂开发中怎么体现？,Raw Materials,Wet Granulation,Fluid Bed Drying,Blending,Compression,Feed Frame,Tooling,Punch Penetration Depth,Compression,Force,Press Speed,Feeder Speed,Quality Assessment under QbR,Question-based Review(QbR)is a general framework for a science and risk-based assessment of product quality,QbR contains the important scientific and regulatory review questions to,Comprehensively assess critical formulation and manufacturing process variables,Set regulatory specifications relevant to quality,Determine the level of risk associated with the manufacture and design of the product,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 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 operations)related to the drug product quality,?,How were the critical process parameters identified,monitored,and/or controlled?,Pharmaceutical Development,Manufacture,Container Closure System,Aspects,Traditional,QbD,Pharmaceutical,development,Empirical;univariate,experiments,Systematic;multivariate,experiments,Manufacturing,process,Fixed;validation on 3 initial,full-scale batches;,focus on reproducibility,Adjustable within,design,space,;continuous verification;,focus on control strategy,Process control,In-process testing for go/nogo;offline analysis w/slow response,PAT utilized for feedback&,feed forward,real time,Product,specification,Primary means of quality,control;based on batch data,Part of the overall quality,control strategy;based on,desired product performance,Control,strategy,Mainly by intermediate and,end product testing,Risk-based;controls shifted,upstream;real-time release,Lifecycle,management,Reactive to problems&,OOS;post-approval,Continuous improvement,enabled within design space,QbD,小结,-SUMMARY,研发,(,高难,),仿制药的一些体会,案例研究,-1,CASE,STUDY,1-,IR,Tablets,Very Low Water Solubility(,低水溶性,),Very Low Potency,(,低剂量,),Micronized API used,(,微粉化原料药,),Wet Granulation Process,(,湿法制粒,),Dissolution,Profile-,体外溶出曲线,生物等效,(BE),结果,AUC0-t,AUC0-inf,Cmax,Fast,Ratio,108.01%,108.12%,86.26%,90%Geometric C.I.,103.49%to 112.73%,103.64%to 112.79%,75.28%,to 98.84%,Fed,Ratio,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,原因调查,案例研究,-2,CASE,STUDY,2,-ER CAPSULES,No Patent,(,无专利,),Coated Pellets,(,包衣微丸,),1,st,Bio Study Failed,Fast:Close,Fed,(Compared with Fast),:,Brand:BA Reduced,Tested:BA Increased,TEAM WORK,More Information Collected,Analytical Support,Identify the Process Used,Provide the Info for Functional Coating,One more Pilot and One Full Bio-Passed,案例研究,-3,CASE,STUDY,3,-ER CAPSULES,Brand Product,Micro-Tablets in Capsules,95%of API existed in Finished Product,System and Process Patented,UNIQUE SYSTEM-CREATIVE DESIGN,Compressed Granules in Capsules,Requirement,Same Dissolution Behavior,Uniform,Yield Acceptable,SYSTEM COMPARISON,PILOT BIO-STUDY,PRODUCT P DATA(Log Transformed Data,Fast,n-12),Ratio of Geometric Means x 100,90%CI of Log Transformed Data,CV(%),Test A vs Reference,AUC,106,90.4;123,22.0,Cmax,104,80.1;134,36.4,Test B vs Reference,AUC,133,114;155,22.0,Cmax,129,100;167,36.4,PILOT BIO-STUDY,PRODUCT P DATA(Log Transformed Data,FED,n-11),Ratio of Geometric Means x 100,90%CI of Log Transformed Data,CV(%),Test A vs Reference,AUC,96.1,75.4;123,32.7,Cmax,109,83.5;141,35.3,Test B vs Reference,AUC,92.4,72.5;118,32.7,Cmax,109,83.7;141,35.3,PIVOTAL BIO-STUDY,PRODUCT P DATA(,Log Transformed Data),Ratio of Geometric Means x 100,90%CI of Log Transformed Data,CV(%),FAST,AUC,102,93;111,33,9,Cmax,105,94.5;116,38.8,FED,AUC,98.8,91.6;107,26.4,Cmax,99.6,89.2;111,38.4,案例研究,-4,CASE,STUDY,4,-ER CAPSULES,API is Water Soluble.Prototype formulation was proposed based on in vitro dissolution(OGD method).,PILOT BIO-STUDY,PRODUCT DATA(Log Transformed Data),AUC0-t,AUC0-inf,Cmax,T-1,Ratio,111.21%,112.48%,140%,90%Geometric C.I.,104.40%to 118.47%,105.78%to 119.60%,133.7%,to,147.0%,T-2,Ratio,117.5%,117.2%,135.9%,90%Geometric C.I.,113.2%,to,122.2%,112.4%,to,122.1%,129.5%,to,142.4%,Further Investigation,谢谢!,139-1866-7400,paxhp,