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1、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 ProductRaw MaterialsProcessFinished Pro
2、ductTechnology-Modified Release Products,申报(仿制)新药的分类,规范市场(FDA)1。P-I2。P-II3。P-III4。P-IV (1st 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,REGULATORY,DRUG DELIVERY SYSTEMS FOR ORAL SOLID FORMULATIONS-MRMATRIX SYSTEMSRESERVIOR SYSTEMSOSMOTICAL PUMP SYSTEMSCOMBO-SYSTEMS,缓控释给药的技术平台和给药
3、系统CONCEPT-2 BUILD UP A SYSTEM,Product Development Roadmap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 characteristicsscientifically designed to meet
4、 specific objectives, not merely empirically derived from performance of test batches,What is QbD (Quality by Design )?QbD在制剂开发中怎么体现？,What is QbD?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 pro
5、duct qualityUnderstanding and controlling formulation and manufacturing process variables affecting the quality of a drug product,Essential elements of QbD Definition of the quality target product profileHigh level quality aspects of the product: purity, drug release (dissolution/disintegration time
6、), 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 haveeffect on p
7、roduct 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 parameters,What is QbD?QbD在制剂开发中怎么体现？,Raw Materials,Equipment,Envi
8、ronment,Operators,Variable Inputs,x,“Locked” Process,=,Variable Quality,How Did We Work in the Past,What is QbD?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 Wo
9、rk in the Future,What is QbD?QbD在制剂开发中怎么体现？,What is QbD?QbD在制剂开发中怎么体现？,Raw Materials,Wet Granulation,Fluid Bed Drying,Blending,Compression,Product,Drug Substance,Excipients,SourceAssayImpurities LODPS ,What is QbD?QbD在制剂开发中怎么体现？,WaterBinderTempSpray RateSpeedTimeP.S,What is QbD?QbD在制剂开发中怎么体现？,What i
10、s QbD?QbD在制剂开发中怎么体现？,Air FlowTempRHShock CycleP.S.,What is QbD?QbD在制剂开发中怎么体现？,Fill VolumeRotation SpeedEnd Point (Time)Blend UniformityDensitiesAngle of Repose,What is QbD?QbD在制剂开发中怎么体现？,Feed FrameToolingPunch Penetration DepthCompression ForcePress SpeedFeeder Speed ,Quality Assessment under QbR,Qu
11、estion-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 toComprehensively assess critical formulation and manufacturing process variablesSet regulatory specifications relevant to
12、qualityDetermine 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
13、 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 quali
14、ty? How were the critical process parameters identified, monitored, and/or controlled? Pharmaceutical Development Manufacture Container Closure System,QbD小结-SUMMARY,研发(高难)仿制药的一些体会,案例研究-1CASE 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 Gran
15、ulation Process (湿法制粒),Dissolution Profile-体外溶出曲线,生物等效(BE)结果,Summary of in vivo study results of Test Formulation vs. RLD,原因调查,案例研究-2CASE STUDY 2-ER CAPSULES,No Patent (无专利)Coated Pellets (包衣微丸)1st Bio Study FailedFast: CloseFed(Compared with Fast): Brand: BA Reduced Tested: BA Increased,TEAM WORK,M
16、ore Information CollectedAnalytical SupportIdentify the Process Used Provide the Info for Functional CoatingOne more Pilot and One Full Bio-Passed,案例研究-3CASE STUDY 3 - ER CAPSULES,Brand ProductMicro-Tablets in Capsules95% of API existed in Finished ProductSystem and Process Patented,UNIQUE SYSTEM-CR
17、EATIVE DESIGN,Compressed Granules in CapsulesRequirementSame Dissolution BehaviorUniformYield Acceptable,SYSTEM COMPARISON,PILOT BIO-STUDY,PRODUCT P DATA (Log Transformed Data, Fast, n-12),PILOT BIO-STUDY,PRODUCT P DATA (Log Transformed Data, FED, n-11),PIVOTAL BIO-STUDY,PRODUCT P DATA (Log Transformed Data),案例研究-4CASE 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),Further Investigation,谢谢!,139-1866-,
