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1、Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,,,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,,*,,優(yōu)秀精品課件文檔資料,優(yōu)秀精品課件文檔資料,開發(fā)報批美國,FDA,的仿制藥與相關(guān)問題探討,,,,,,上海復(fù)星普適醫(yī)藥科技

2、有限公司,何平,開發(fā)報批美國FDA的仿制藥與相關(guān)問題探討上海復(fù)星普適醫(yī)藥科技,內(nèi)容提要,開發(fā)仿制藥的重要性和機遇,開發(fā)仿制藥的挑戰(zhàn),申報仿制藥的分類,仿制藥研發(fā)團隊,仿制藥的研發(fā)過程,QbD,在制劑開發(fā)中怎么體現(xiàn),研發(fā),(,高難,),仿制藥的一些體會,：,案例研究,內(nèi)容提要開發(fā)仿制藥的重要性和機遇,開發(fā)仿制藥的重要性,新藥與仿制藥,-NDA,,and,,ANDA,開發(fā)仿制藥與我國藥物研發(fā)的海外戰(zhàn)略,,,,,,,,藥物制劑,目標主流市場,開發(fā)仿制藥的重要性 新藥與仿制藥-NDA and ANDA藥,開發(fā)仿制藥的挑戰(zhàn)性,開發(fā)仿制藥更具挑戰(zhàn)性,藥物制劑,專利,仿制藥的競爭,仿制藥廠之間的競爭,由品牌

3、藥轉(zhuǎn)成仿制藥,,,開發(fā)仿制藥的挑戰(zhàn)性 開發(fā)仿制藥更具挑戰(zhàn)性,仿制藥競爭的方式,HOW TO COMPETE,Cost,-IR Product,Raw Materials,Process,Finished Product,Technology,-Modified Release Products,仿制藥競爭的方式HOW TO COMPETE Cost-I,申報,(,仿制,),新藥的分類,規(guī)范市場,(FDA),1,。,P-I,2,。,P-II,3,。,P-III,4,。,P-IV,(1,st,to file),中國市場（,sFDA,）,1,類,2,類,3,類,4,類,5,類,6,類,,申報(仿制

4、)新藥的分類規(guī)范市場(FDA)中國市場（sFDA）,仿制藥研發(fā)團隊,,CONCEPT-1 BUILD UP A TEAM,,INFORMATION,,FORMULATION,,PRODUCT,,REGULATORY,,ANALYTICAL,,BIO-PHARMACEUTICAL,,,,,,,PROJECT,,LEGEL,仿制藥研發(fā)團隊CONCEPT-1 BUILD UP A,DRUG DELIVERY SYSTEMS FOR ORAL SOLID FORMULATIONS-MR,MATRIX SYSTEMS,RESERVIOR SYSTEMS,OSMOTICAL PUMP SYSTEMS

5、,COMBO-SYSTEMS,緩控釋給藥的技術(shù)平臺和給藥系統(tǒng),CONCEPT-2 BUILD UP A SYSTEM,DRUG DELIVERY SYSTEMS FOR ORAL,Product Development Roadmap,仿制藥的,研發(fā)過程,Product Development Roadmap,?,Quality,–,Acceptably low risk of failing to achieve the desired clinical,,attributes,,?,Pharmaceutical Quality,= f {drug substance, excipient

6、s, 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,在制劑開發(fā)中怎么體現(xiàn)？,? QualityWhat is QbD (Quality,What is QbD?,QbD,在制

7、劑開發(fā)中怎么體現(xiàn)？,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,,What is QbD?Pharmac

8、eutical Qua,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,? Charact

9、eristics 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 i

10、nteraction 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 QbD?,QbD,在制劑開發(fā)中怎么體現(xiàn)？,Essential elements of QbDWhat,Raw Materials,Equipment,Environment,Operators,Va

11、riable,,Inputs,x,“Locked” Process,=,Variable Quality,How Did We Work in the Past,What is QbD?,QbD,在制劑開發(fā)中怎么體現(xiàn)？,Raw MaterialsEquipmentEnvironm,Raw Materials,Equipment,Environment,Operators,Understood Variable Inputs,x,Understood and Controlled Process,=,Predefined Quality,Flexible Process Design Space

12、,How Can We Work in the Future,What is QbD?,QbD,在制劑開發(fā)中怎么體現(xiàn)？,Raw MaterialsEquipmentEnvironm,What is QbD?,QbD,在制劑開發(fā)中怎么體現(xiàn)？,,,,,,Raw Materials,Wet Granulation,Fluid Bed Drying,Blending,Compression,Product,What is QbD?Raw MaterialsWet G,,Drug Substance,,Excipients,Source,Assay,Impurities,… …,LOD,PS,,… …,

13、,,What is QbD?,QbD,在制劑開發(fā)中怎么體現(xiàn)？,,,,,,Raw Materials,Wet Granulation,Fluid Bed Drying,Blending,Compression,SourceWhat is QbD?Raw Material,Water,Binder,Temp,Spray Rate,Speed,Time,P.S,,What is QbD?,QbD,在制劑開發(fā)中怎么體現(xiàn)？,,,,,,Raw Materials,Wet Granulation,Fluid Bed Drying,Blending,Compression,WaterWhat is QbD?R

14、aw Materials,What is QbD?,QbD,在制劑開發(fā)中怎么體現(xiàn)？,,,,,,Raw Materials,Wet Granulation,Fluid Bed Drying,Blending,Compression,Air Flow,Temp,RH,Shock Cycle,P.S.,,What is QbD?Raw MaterialsWet G,What is QbD?,QbD,在制劑開發(fā)中怎么體現(xiàn)？,,,,,,Raw Materials,Wet Granulation,Fluid Bed Drying,Blending,Compression,Fill Volume,Rotat

15、ion Speed,End Point,(Time),Blend Uniformity,Densities,Angle of Repose,,What is QbD?Raw MaterialsWet G,What is QbD?,QbD,在制劑開發(fā)中怎么體現(xiàn)？,,,,,,Raw Materials,Wet Granulation,Fluid Bed Drying,Blending,Compression,Feed Frame,Tooling,Punch Penetration Depth,Compression,,Force,Press Speed,Feeder Speed,… …,,What

16、 is QbD?Raw MaterialsWet G,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

17、 process variables,Set regulatory specifications relevant to quality,Determine the level of risk associated with the manufacture and design of the product,Quality Assessment under QbRQu,Examples of QbD questions under QbR,,? Control of Drug Substance,–,What is the drug substance specification? Does

18、 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 optimize

19、d?,? 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,Examples of QbD questions un

20、de,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 st

21、rategy,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,C

22、ontrol,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,小結(jié),-SUMMARY,AspectsTraditionalQbDPharmaceu,研發(fā),(,高難,),仿制藥的一些體會,

23、研發(fā)(高難)仿制藥的一些體會,案例研究,-1CASE STUDY,,1-,IR Tablets,,Very Low Water Solubility (,低水溶性,),Very Low Potency,,(,低劑量,),Micronized API used,,(,微粉化原料藥,),Wet Granulation Process,,(,濕法制粒,),案例研究-1CASE STUDY 1-IR Tablets,Dissolution,,Profile-,體外溶出曲線,Dissolution Profile-體外溶出曲線,生物等效,(BE),結(jié)果,,AUC0-t,AUC0-inf,Cmax,F

24、ast,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,,生物等效(BE)結(jié)果AUC0-tAUC0-in

25、fCmaxFa,原因調(diào)查,原因調(diào)查,案例研究,-2,CASE,STUDY,2-ER CAPSULES,No Patent,,(,無專利,),Coated Pellets,,(,包衣微丸,),1,st,Bio Study Failed,Fast: Close,Fed(Compared with Fast):,Brand: BA Reduced,Tested: BA Increased,案例研究-2CASE STUDY 2-ER CAPSULE,TEAM WORK,More Information Collected,Analytical Support,Identify the Proce

26、ss Used,Provide the Info for Functional Coating,One more Pilot and One Full Bio---Passed,,TEAM WORKMore Information Coll,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,案例研究-3CASE STUDY 3 - ER CAPSU,UNIQUE

27、 SYSTEM-CREATIVE DESIGN,Compressed Granules in Capsules,Requirement,Same Dissolution Behavior,Uniform,Yield Acceptable,UNIQUE SYSTEM-CREATIVE DESIGNC,SYSTEM COMPARISON,SYSTEM COMPARISON,PILOT BIO-STUDY,PRODUCT P DATA (Log Transformed Data, Fast, n-12),,Ratio of Geometric Means x 100,90% CI of Log Tr

28、ansformed 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-STUDYPRODUCT P DATA,PILOT BIO-STUDY,PRODUCT P DATA (Log Transformed Data, FED, n-11),,Ratio of Geometric Means x 100,90% CI of Log Trans

29、formed 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,PILOT BIO-STUDYPRODUCT P DATA,PIVOTAL BIO-STUDY,PRODUCT P DATA (,Log Transformed Data),,Ratio of Geometric Means x 100,90% CI of Log Transforme

30、d 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,PIVOTAL BIO-STUDYPRODUCT P DAT,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).,案例研究-4API is Wa

31、ter Soluble. P,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%,PILOT BIO-STUDYPRODUCT DATA (L,Further Investigation,Further Investigation,謝謝,!,139-1866-7400,paxhp@,謝謝!139-1866-7400,