FDA藥品批準程序簡介ppt課件

1、FDA Drug Approval ProcessFDA藥品同意程序from Chemistry Manufacturing Controls Perspective化學消費控制(CMC)展望上海寶鉅.New Drug Development Process新藥的研發(fā)過程1. Research & Development (研討和開發(fā)2. Pre-clinical Studies 藥理毒理研討3.Investigational New Drug (IND) Phase I, II, III Clinical Trials 臨床實驗4.New Drug Application (NDA) 新藥懇

2、求5.Post-marketing 新藥同意后的市場調查跟蹤 Post-approval changes 同意后的消費工藝變卦.New Drug Development Process新藥研發(fā)程序.New Drug Development Process新藥研發(fā)程序新化學體有機合成天然產品臨床前研討理化特性生物活性預制劑研討型新藥懇求臨床實驗 I, II, III階段新藥懇求FDA審核同意前檢查FDA操作市場調查跟蹤IV階段臨床研討副作用報告產品缺陷報告產品線擴展同意后CMC變卦研討：長期動物毒性研討產品劑型研發(fā)消費和控制包裝和標簽設計.懇求人(藥品研發(fā)者)新藥懇求NDA醫(yī)學化學藥學生物制藥學

3、數(shù)據統(tǒng)計微生物學CDER審核不立檔處置,發(fā)回絕信立檔處置該懇求嗎否是.Generic Drug Development Process非專利藥開發(fā)過程1. API Process Development 原料藥消費工藝開發(fā)2.Dosage Form Development 制劑的研發(fā)3.Bioequivalent Study 生物等效性實驗4.ANDA Review 非專利藥的審批- DS & DP manufacturing sites CGMP inspection DS和DP消費現(xiàn)場CGMP檢查5.Post-approval Changes 同意后的消費工藝變卦.Drug Applica

4、tion 藥品懇求NDA (IND) 新藥Chemistry, Manufacturing, & Controls (CMC) 化學性，消費和控制CMCAnimal Studies 動物實驗Bioavailability 生物有效性Clinical Studies 臨床實驗 ANDA 非專利藥Chemistry, Manufacturing, & Controls (CMC) 化學性，消費和控制CMCBioequivalence 生物等效性.Bioavailability (BA) 生物有效性21 CFR 320.1(a) Defined as “the rate and extent to

5、which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.“指“從醫(yī)藥產品中吸收到的，且能在作用位置產生有效作用的活性成分或其部分活性成分的比率和范圍.Bioequivalence (BE) 生物等效性21 CFR 320.1(e) Defined as “the absence of a significant difference in the rate and extent to which the act

6、ive ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. 指“活性成分。在經適當設計的研討中，在類似條件下，當 給藥的摩爾劑量一樣時，在藥品的對應作用位置,其被利用的比率和范圍沒

7、有明顯差別.Generic Drug 非專利藥Definition 非專利藥的定義A generic drug is identical, or bioequivalent to a brand name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use非專利藥在藥劑方式、平安性、強度、給藥途徑、質量、性能特征和運用用途上與專利藥一樣或者生物等效性一樣。.Generic Drug Requirement非專利藥

8、要求To gain FDA approval, a generic drug must: 要獲得FDA的同意，非專利藥必需：Contain the same active ingredients as the innovator drug (inactive ingredients may vary) 包括和新藥一樣的活性成分非活性成分可以有所不同Be identical in strength, dosage form, and route of administration 強度、劑型、和給藥途徑一樣Have the same use indications 運用方法一樣Be bioequ

9、ivalent 具有生物等效性Meet the same batch requirements for identity, strength, purity, and quality 符合同批藥品在標識、強度、純度和質量上的要求Be manufactured under the same strict standards of FDAs good manufacturing practice regulations required for innovator products 消費規(guī)范與FDA的GMP對于新藥的嚴厲規(guī)范一樣.Type of ANDA 非專利藥懇求的分類No.Type of A

10、pplication申請類型Requirement要求1Paragraph I CertificationI類證書無專利存在2Paragraph II CertificationII類證書專利已過期3Paragraph III CertificationIII類證書專利沒過期4Paragraph IV CertificationIV類證書向專利挑戰(zhàn).2002 年全球藥品銷售分析國家或地域銷售US$)銷售% 年增長北美203.6 51 12 %歐洲(EU)90.6 22 8歐洲其他 11.3 3 9日本46.912 1亞洲,非洲，澳洲31.6 8 11(日本除外拉丁美洲 16.54 -10總數(shù)

11、400 Billion100 % +8%Source: IMS原料藥的年銷售額估計約在 US$30-35 Billion (300-350億美圓).2003-2004 年全球藥品銷售分析國家或地域銷售US$)全球市場 年增長U.S. (美國)228.7 46.1% 10%Japan (日本) 55.411.1 3Germany (德國) 27.8 5.6 6France (法國) 26.4 5.3 7U.K. (英國) 18.4 3.7 11Italy (意大利) 17.9 3.6 6Spain (西班牙) 12.8 2.6 11Canada (加拿大) 10.5 2.1 1China (中國

12、) 6.6 1.3 19Mexico (墨西哥) 6.3 1.3 11 Top 10 (總數(shù))410 Billion 82.6 % 9%Source: IMS, for the 12 months ending June 2004原料藥的年銷售額估計約在 US$40 Billion (400億美圓).Worldwide Pharmaceutical Market by Sectors ($ Billions)世界藥品市場分類單位：十億美圓 20002001200220032021 增長*Ethical 317.1363.4401.0437.6677.8 9.1處方藥Generic 24.0 2

13、7.030.537.064.0 11.6非專利藥OTC 70.573.878.582.0101.0 4.3 Biophar-22.126.331.036.558.69.0Maceutical生物藥Total433.7490.5541.0593.1901.48.7Source: IMS *Estimated from 2003 to 2021.Top 10 Therapies10大類藥物Therapeutic Sale toShare of AnnualClassesJune 2004Global SaleChange藥物 截至2004年 全球銷售 年度分類 6月的銷售額 份額 變化Choles

14、terol & triglyceride膽固醇和甘油三酸酯藥物 28.1 5.6% 13%Antiulcerants抗?jié)兯?24.9 5.0 5Antidepressant抗抑郁藥 20.2 4.1 7 Antipsychotics安定藥 13.2 2.6 9Antirheumatic nonsteroidals非類固醇類抗風濕藥 13.1 2.6 3Erythropoietins紅細胞生成素 11.0 2.215Antiepileptics抗癲癇藥 10.4 2.121Oral antidiabetics口服糖尿病藥 9.6 1.912Cephalosporins頭孢菌素 8.5 1.7

15、2 Top 10 Therapy 150.3 Billion30.2% 10%10大藥物 1503億美圓Source: IMS, for the 12 months ending June 2004 來源：IMS，以2004年六月截至第12個月計.Top 10 Products (2003-2004)10大藥品20032004Brand Name MarketerSales Annual(Generic Name)($ Billion)Change品名非專利藥名 消費商 銷售額十億美圓 年度變化Liptor (Atorvastatin)輝瑞11.013%Zocor (Simvastatin)默

16、克 6.0 -9Zyprexa (Olanzepine)禮來 4.9 5Norvasc (Amlodipine)輝瑞 4.7 6 Plavix (Clopidogrel)賽諾非安萬特 4.337BMSNexium (Esomeprazole)AstraZeneca 4.337Advair (Salmeterol葛蘭素史克 4.230 fluticasone)Procrit (Erythropoietin)強生 4.1 0Prevacid (Lansoprazole)Takeda/Abbott 3.9 3Zoloft (Sertraline)輝瑞 3.612 Top 10 Products 10

17、大產品 $51.0 13%Source: IMS, for the 12 months ending June 2004 來源：IMS,截至2004年6月的12個月的數(shù)據.Drugs off U.S. Patent by 2007截至2007年美國專利到期的藥品Drug NameMarketerSales Off Patent藥品稱號 消費商 銷售額 專利到期日Diflucan (Fluoconazole)Pfizer輝瑞1.2 Billion 12億2004Neurontin (Gabapentin)Pfizer輝瑞2.7 Prevacid (Lansoprazole)Takeda3.9 2

18、005Zoloft (Sertraline HCl)Pfizer輝瑞3.1 Zocor (Simvastatin)Merck默克6.0Norvasc (Amlodipine)Pfizer輝瑞4.3 2006Paxil (Paroxetine)GSK 葛蘭素史克3.3Pravachol (Pravastatin)BMS2.8Resperdal (Risperidone)Janssen楊森2.0 2007Fosamax (Alendronate)Merck默克1.9 Zyrec (Certirizine)Pfizer輝瑞1.3 .Chemistry, Manufacturing and Contr

19、ols (CMC)化學性、消費和控制CMCCMC 的內容包括兩大部分：I.Drug Substance 原料藥部分a.As Part of CMC Section in an Applicationor Reference to a Drug Master File (DMF) 懇求或參考DMF時作為CMC的一部分b.CGMP Compliance of a Manufacturing Facility 消費車間符合CGMP規(guī)范II.Drug Product 制劑部分a.Part of CMC Section 作為CMC的一部分b.CGMP Compliance of a Manufactur

20、ing Facility 消費車間符合CGMP規(guī)范.Drug Master File (DMF) 藥物主文件DMFTYPES OF DRUG MASTER FILES 藥物主文件的分類Type I Manufacturing Site, Facilities, Operating Procedures, and Personnel I類 消費現(xiàn)場、設備、操作程序和人員Type IIDrug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product II類 藥品原

21、料、藥品原料中間體和配制過程中運用的資料，或者藥品Type III Packaging MaterialIII類 包裝資料Type IV Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation IV類 賦形劑、著色劑、香料、香精、或配制過程中運用的資料Type VFDA Accepted Reference InformationV類 FDA認可的參考信息.Drug Master File (DMF)藥物主文件DMF在 FDA 注冊 DMF 的有利之處維護原料藥消費的工藝技術和商業(yè)有利于原料藥消費商

22、尋覓多方面的客戶表示原料藥消費商已具有 CGMP 預備邁出了開發(fā)美國原料藥市場的第一步.CGMP Inspection ProcessCGMP檢查程序.CGMP Inspection ProcessCGMP檢查程序NDA/ANDA懇求CMC審核其他審核規(guī)那么符合辦公室地域辦公室.CGMP Regulation & Guideline有關 CGMP 的文件 A.Code of Federal Regulations 21.210 and 21.211 有關制劑消費的CGMPB.ICH Q7A Good Manufacturing Practice Guidance for Active Phar

23、maceutical Ingredients (August 2001)有關原料藥消費的 CGMP.System Based Current Good Manufacturing Practice (CGMP) 基于CGMP的系統(tǒng)Quality System 質量管理系統(tǒng)Material System 原資料系統(tǒng)Facilities and Equipment System消費設備和設備系統(tǒng)Production System 消費系統(tǒng))Packaging and Labeling System 包裝和標志系統(tǒng)Laboratory Control System 實驗室控制系統(tǒng).DMF Prepa

24、rationDMF文件的預備I.Conventional Format 傳統(tǒng)方式- Accepted by FDA 被FDA所認可II.The CTD-Format (Module 3) CTD方式模板3- Accepted,Not Required by FDA FDA認可，但沒有要求- Accepted by EU 歐盟認可.Drug Substance (API)原料藥APIStarting Material原資料- Define starting materials and their specifications 確定原資料及其規(guī)格Process Control and Critical Parameters 工藝控制和關鍵參數(shù) - Identifying critical process parameters 識別關鍵工