【正文】 僅靠最后的測試來提高，而是來源于產(chǎn)品的精心設計和生產(chǎn)過程的合理控制，并在良好的 cGMP條件下生產(chǎn)。 70 QBR: Drug Substance 71 QBR: Drug Product 72 QBR: Drug Substance 73 QBR: Drug Product 74 QBR: Drug Product 75 QBR: Process Development Report 76 QBR: Process Development Report 77 QBR: Process Development Report QbD 質(zhì)量源于設計 ? Quality by Design is a scientific approach where systematic study of product development is undertaken based up on predefined objectives with emphasis on product and process understanding and process control based on sound science and quality risk management 78 QbD 質(zhì)量源于設計 早期的理念是“藥品質(zhì)量是通過檢驗來控制的”，后來過渡到“藥品質(zhì)量是通過生產(chǎn)過程控制來實現(xiàn)的”，進而又發(fā)展到“藥品質(zhì)量是通過良好的設計來達到的”。 2) 幫助制藥企業(yè)了解仿制藥評審部門的評審標準和程序。如果在 3O個月內(nèi)，法庭判定原研藥專利無效或侵權不存在， FDA可立即批準仿制藥申請。而專利的所有者可以在收到該通知的 45天內(nèi)提出專利侵權的訴訟。 ? 對于 4), 法院決定是否侵犯專利。s good manufacturing practice regulations required for innovator products 53 仿制藥申報程序 54 55 Simplified Application 21 CFR ? Do Not Prove Safe and Effective ? Prove Bioequivalent to the Reference Listed Drug 21 CFR Part 320 ? Bioequivalence based on ? Cmax ? AUC (area under the timeconcentration curve) ANDA 申報 56 ? Need a Reference “Listed Drug” 21 CFR ? Same Active Ingredients ? Same Route of Administration ? Same Dosage Form ? Same Strength ? Same Indication/Conditions for Use ? Some Changes Allowed – Suitability Petition ? (Patents go to marketing, not approvability) ANDA 申報 57 1984年的 Hatch— Waxman法案提出了四種可 能狀態(tài)聲明： 1)： 專利尚未申請 2)： 專利已經(jīng)過期 3)： 專利將會過期 4)： 專利無效或不存在侵權 ? 對于 1）和 2）兩種情形，只要其它部分符合條件，該 ANDA可馬上被批準。 4000 Supplements ? FDA receives ~800 Originals, ~1600 DMFs annually ? Impacts all of CDER – Review – Inspection – Petitions – Medical/clinical consults – Post‐ marketing safety GDUFA Status ? Second attempt to negotiate。 meets pendial or other applicable standards of strength, quality, purity, and identity. ? Bioavailability The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and bees available at the site of action. ? Bioequivalence Two pharmaceutical equivalent drug products are bioequivalent if after drug administration, the bioavailabilities (rate and extent of drug availability) provide similar effects with respect to efficacy and safety. FDA 仿制藥相關定義 36 ? Bioequivalence is established if the in vivo bioavailability of a test drug product (usually the generic product) does not differ significantly (., statistically insignificant) in the product?s rate and extent of drug absorption from that of the reference listed drug (usually the brand name product) when administered at the same molar dose of the active moiety under similar experimental conditions, either single dose or multiple dose. FDA 仿制藥相關定義 37 ? The RLD is the reference drug product upon which an applicant relies when seeking approval of an abbreviated new drug application (ANDA). ? The RLD is generally the brandname drug that has a full new drug application (NDA). ? FDA designates a single reference listed drug as the standard to which all generic versions must be shown to be bioequivalent. ? FDA hopes to avoid possible significant variations among generic drugs and their brand name counterpart. Such variations could result if generic drugs were pared to different reference listed drugs. FDA仿制藥指導 38 FDA仿制藥指導 39 FDA仿制藥指導 40 FDA仿制藥指導 41 FDA仿制藥指導 42 43 Bioequivalence Example 6 12 18 24 30 36 42 48 0 1 2 3 4 5 6 7 8 Test/Generic Reference/Brand T/R (%) 80% 125% 44