質(zhì)量源于設計QbDExample演示文稿

1、The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.TM質(zhì)量源于設計質(zhì)量源于設計(QbD)淺析淺析The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.概概 述述藥品質(zhì)量源于設計(QbD)簡介為什么FD

2、A推出QbD?FDA推行QbD的策略QbD實施過程總結(jié)附：FDA 展示 QbD實施案例The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.藥品質(zhì)量源于設計簡介藥品質(zhì)量源于設計簡介工業(yè)最早引入“質(zhì)量源于設計”質(zhì)量源于設計的相關理念最早出現(xiàn)在20世紀70年代Toyota為提高汽車質(zhì)量提出，并經(jīng)過在通信，航空等領域的發(fā)展逐漸形成。醫(yī)藥工業(yè)沒有引入QbD的原因醫(yī)藥工業(yè)自動化程度，生產(chǎn)效率雙低；藥品與其他工

3、業(yè)產(chǎn)品的區(qū)別，沒有明確指標化的產(chǎn)品定義（這就是為什么需要臨床，因為說不準，判斷不了的不得已而為之） 產(chǎn)品質(zhì)量是由質(zhì)量檢驗或者生產(chǎn)來保證的：非常高的缺陷率，2到3個sigma 產(chǎn)品一次成功率在85%-95%，準時出貨率在60%-80%這個范圍； .The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.FDAFDA推出推出QbDQbD時機時機_ _質(zhì)量系統(tǒng)的描述趨于完善質(zhì)量系統(tǒng)的描述趨于完善ICH Q8

4、 (R2) 制藥產(chǎn)業(yè)發(fā)展 一個綜合性的醫(yī)藥發(fā)展方式應當包含對工藝過程和產(chǎn)品的理解，并確定變化產(chǎn)生的原因。引起產(chǎn)品質(zhì)量變化的原因應當被查明，對其進行研究，接著進行控制措施。/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073507.pdfICH Q9 質(zhì)量風險管理對過程和產(chǎn)品的理解應當與質(zhì)量風險管理（請見ICH Q9）相結(jié)合。通過過程控制可以用適宜的方式補償變化（例如原料）帶來的影響，從而得到一致的產(chǎn)品質(zhì)量。/downloads/dru

5、gs/guidancecomplianceregulatoryinformation/guidances/ucm073511.pdf ICH Q10 制藥質(zhì)量系統(tǒng) 基于 ISO 概念的有效制藥質(zhì)量體系的綜合模型，包括現(xiàn)行的GMP 法規(guī)，并補充了ICH Q8“藥物研發(fā)”和 ICH Q9 “質(zhì)量風險管理”。ICH Q10 這一制藥質(zhì)量體系模型可以應用于產(chǎn)品生命周期之各個階段。/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073517.pdf4The information conta

6、ined in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.FDAFDA推出推出QbDQbD時機時機_ _質(zhì)量系統(tǒng)的描述趨于完善質(zhì)量系統(tǒng)的描述趨于完善ICH Q8，Q9，Q10：問題和回答/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm210822.pdfICH Q IWG： Q8, Q9 ,Q10 /./dru

7、gs/advisorycommitteeforpharmaceuticalscienceandclinicalpharmacology/ucm179003.pdfPost-approval changes /downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070582.pdfProcess Validation: General Principles and Practices. /downloads/drugs/./guidances/

8、ucm070336.pdf5The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.FDAFDA推出推出QbDQbD時機時機原研/仿制藥品召回數(shù)量大增。控制政府預算，降低醫(yī)療總支出（1725% GDP），Generic 作為解決方案之一，但是質(zhì)量以及穩(wěn)定性受到原研廠家的指責，民眾缺乏信心，反而有先入為主的客觀現(xiàn)實存在；政府需要改變這一現(xiàn)狀?；A醫(yī)療領域未能發(fā)現(xiàn)新的靶點，小分子藥物開發(fā)乏力，作為監(jiān)管層的

9、FDA意識到整個行業(yè)都需要提升內(nèi)力，特別是在醫(yī)藥工業(yè)的低谷期。The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.FDA 推行推行QbD的策略的策略n 監(jiān)管層的利益n 工藝遷移的問題n 簡化而有效的監(jiān)管n 消除輿論的抨擊n政府的利益n 減少預算n 贏得投票n民眾的利益n 可靠的治療藥物n 更低的治療支出，無/非醫(yī)療保險類的疾病n 原研制藥商的利益n 獲得工藝優(yōu)化和變更的機會n 生產(chǎn)效益的提高n 專

10、利藥高定價n 質(zhì)量保證 產(chǎn)品質(zhì)量 召回的損失n 仿制藥商的利益n 信任投票n 獲得工藝變更的機會n 生產(chǎn)效益的提高n 質(zhì)量保證 /me better 的機會n 上游供應商的利益n 公平競爭的機會n 內(nèi)在質(zhì)量的控制n 質(zhì)量標準的制定n 保險公司的利益n 業(yè)務增長n 控制藥價（Harvoni PK ViekiraPak）The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.QbD實施實施QbDQTPPC

11、QACPPDesign spaceControl strategyThe information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.產(chǎn)品設計及理解產(chǎn)品設計和理解的關鍵要素原料藥的物理，化學和生物學特性輔料類型和規(guī)格的確定和選擇，以及對輔料內(nèi)在變異性的理解處方的優(yōu)化及原料和輔料的CMAs的鑒定 The information contained in this presentation is proprietar

12、y to Colorcon and may not be used or disseminated inappropriately.工藝設計及基本理解工藝設計及基本理解的步驟找出所有可能對工藝性能造成影響的物料屬性和工藝參數(shù)用科學知識和經(jīng)驗積累的風險評估來確定高風險屬性和/或參數(shù)確定這些現(xiàn)在高風險屬性和參數(shù)的水平或范圍設計和進行試驗，適時采用實驗設計（DOE)對實驗數(shù)據(jù)進行分析來確定物料屬性和工藝參數(shù)是否關鍵，若實驗中物料屬性和工藝參數(shù)的變化會顯著影響到產(chǎn)品質(zhì)量，那么該物料屬性和工藝參數(shù)是關鍵物料屬性和工藝參數(shù)建立控制策略。為關鍵物料屬性和工藝參數(shù)制定可接受的范圍，而對于非關鍵的屬性和參數(shù)，其

13、接受范圍就是研究范圍。當涉及的工藝參數(shù)或者物料屬性多與一個時，這些定義的可接受范圍被稱作設計空間The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.Design space設計空間設計空間Adapted from GE Liu Jing Product Support Manager The information contained in this presentation is proprie

14、tary to Colorcon and may not be used or disseminated inappropriately.Design space整個案例中都沒有提到Design space, 但卻是制藥廠商最想得到的，Design space的數(shù)據(jù)需要從實驗中得到，理論推導的只是一部分或是需要驗證的，那么從投入和回報的關系來說，如果希望得到商業(yè)生產(chǎn)批量的Design space 就必須開展該批量的DOE實驗以及其他必要的驗證工作；中試的design space?可以分析數(shù)據(jù)得到一部分；有什么辦法？Post- Approval changes申請現(xiàn)場檢查之前可以只提交驗證方案，

15、無需生產(chǎn)驗證，但是批準后必須要做的The information contained in this presentation is proprietary to Colorcon, Inc. and may not be used or disseminated inappropriately.The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.控制策略控制策略 Control strategy

16、ICH Q8(R2) 將控制策略定義為源于對現(xiàn)有產(chǎn)品和工藝的理解、確保工藝性能和產(chǎn)品質(zhì)量的一套有計劃控制手段，這些手段包括與原料藥和藥品物料及組分、設施與設備操作條件、過程控制、成品質(zhì)量標準有關的參數(shù)和屬性，以及檢測與控制相關的方法和檢測與控制的頻率。The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.工藝能力和持續(xù)改進工藝能力是測量在統(tǒng)計控制狀態(tài)下，一個穩(wěn)定的生產(chǎn)工藝中的固有比哪一型和已建立的驗

17、收標準之間的關系；工藝能力指數(shù)：Cp和Cpk；指標：Pp和Ppk；持續(xù)改進確定具體問題和項目目標測量當前生產(chǎn)工藝的關鍵環(huán)節(jié)，并收集相關的數(shù)據(jù)；分析數(shù)據(jù)，調(diào)查和合適出現(xiàn)問題的因果關系，確定關系，確保所有因素均已考慮在內(nèi)，找出缺陷的根本原因；以使用諸如實驗設計等技術的數(shù)據(jù)分析為依據(jù)，改善或者優(yōu)化目前的工藝，創(chuàng)建未來的新的工藝監(jiān)控新的生產(chǎn)工藝，確保來自目標的所有偏差都在導致缺陷錢得以糾正。The information contained in this presentation is proprietary to Colorcon and may not be used or disseminat

18、ed inappropriately.總結(jié)總結(jié)API的理化性質(zhì)影響并決定了處方和工藝可能的選擇以及檢測方法專屬性推動行業(yè)發(fā)展，用發(fā)展來解決問題問題產(chǎn)品在供應商之間的區(qū)別沒有比較原研和仿制藥QbD的不同在于QTPP的設定控制策略是基于目前工藝和產(chǎn)品知識確保質(zhì)量的綜合概述，控制策略可根據(jù)產(chǎn)品生命周期中獲得的額外知識進一步改進，但是, 必須遵循Postapproval Changes (SUPAC) guidance，Process validationThe information contained in this presentation is proprietary to Colorcon

19、and may not be used or disseminated inappropriately.TM質(zhì)量源于設計質(zhì)量源于設計(QbD) IR ExampleThe information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.QbD Example Flow PathThe information contained in this presentation is proprietary to Colorc

20、on and may not be used or disseminated inappropriately.QbD Example簡介簡介 質(zhì)量風險評估，經(jīng)驗 預先的產(chǎn)品知識和臨床數(shù)據(jù)，API性質(zhì)/臨床指標QTPP目標產(chǎn)品質(zhì)量概況 預先的工藝知識 對產(chǎn)品的理解，風險分析和DOE實驗CQA 關鍵質(zhì)量屬性CPP 關鍵工藝參數(shù) 預先的產(chǎn)品和工藝知識 風險分析和DOEDesign Space 設計空間Control Strategy 控制策略 質(zhì)量風險評估 DOE設計仿制20mg Acetriptan 干法制粒The information contained in this presentatio

21、n is proprietary to Colorcon and may not be used or disseminated inappropriately.案例中的案例中的QTPP制定制定(ANDA)臨床藥代動力學藥物釋放理化特性配方組成The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.QTPPThe information contained in this presentation i

22、s proprietary to Colorcon and may not be used or disseminated inappropriately.CQAs含量 標示含量的100%w/w，含量變化會影響安全性和有效性，工藝變量可能會影響藥品含量，因此對于含量的評測貫穿于產(chǎn)品和工藝開發(fā)的全過程。含量 均勻度 符合USP計量單位均勻度，含量均勻度變化會影響安全性和有效性，處方和工藝的變量會對均勻度造成影響，因此，在處方和工藝的開發(fā)過程中都應對此CQA進行評價。溶出度 溶出度不低于80%，溶出度不符合標準將可能影響藥品的生物利用度，處方和工藝變量均影響溶出曲線，因此，在處方和工藝開發(fā)的整個過

23、程中都需要進行研究。降解 產(chǎn)物 標準略，降解產(chǎn)物影響安全性，特定已知雜質(zhì)，單雜和總雜都必須設定閾值，處方和工藝變量都會影響降解產(chǎn)物，因此，在處方和工藝開發(fā)的整個過程都應進行評估。根據(jù)產(chǎn)品QTPP，配方開發(fā)者經(jīng)驗和對該產(chǎn)品的了解，確定產(chǎn)品的CQAsThe information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.處方開發(fā)處方開發(fā)I-原輔料屬性的初始評估原輔料屬性的初始評估The information conta

24、ined in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.處方開發(fā)處方開發(fā)I- 處方選擇處方選擇The information contained in this presentation is proprietary to Colorcon, Inc. and may not be used or disseminated inappropriately.The information contained in this presentati

25、on is proprietary to Colorcon and may not be used or disseminated inappropriately.處方開發(fā)處方開發(fā)IThe information contained in this presentation is proprietary to Colorcon, Inc. and may not be used or disseminated inappropriately.The information contained in this presentation is proprietary to Colorcon and

26、 may not be used or disseminated inappropriately.處方開發(fā)處方開發(fā)IIThe information contained in this presentation is proprietary to Colorcon, Inc. and may not be used or disseminated inappropriately.The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated

27、 inappropriately.處方開發(fā)處方開發(fā)IIThe information contained in this presentation is proprietary to Colorcon, Inc. and may not be used or disseminated inappropriately.The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.處方開發(fā)結(jié)論和處方開發(fā)結(jié)論和C

28、QAs重新評估重新評估The information contained in this presentation is proprietary to Colorcon, Inc. and may not be used or disseminated inappropriately.The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.工藝開發(fā)工藝開發(fā)IThe information contai

29、ned in this presentation is proprietary to Colorcon, Inc. and may not be used or disseminated inappropriately.The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.工藝開發(fā)工藝開發(fā)IIThe information contained in this presentation is prop

30、rietary to Colorcon, Inc. and may not be used or disseminated inappropriately.The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.工藝開發(fā)工藝開發(fā)III_制粒前預混制粒前預混The information contained in this presentation is proprietary to Colorcon,

31、 Inc. and may not be used or disseminated inappropriately.The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.工藝開發(fā)工藝開發(fā)IIIThe information contained in this presentation is proprietary to Colorcon, Inc. and may not be used or di

32、sseminated inappropriately.The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.工藝開發(fā)工藝開發(fā)IIIThe information contained in this presentation is proprietary to Colorcon, Inc. and may not be used or disseminated inappropriately.The

33、information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.工藝開發(fā)工藝開發(fā)IVThe information contained in this presentation is proprietary to Colorcon, Inc. and may not be used or disseminated inappropriately.The information contained in this pr

34、esentation is proprietary to Colorcon and may not be used or disseminated inappropriately.工藝開發(fā)工藝開發(fā)IVThe information contained in this presentation is proprietary to Colorcon, Inc. and may not be used or disseminated inappropriately.The information contained in this presentation is proprietary to Col

35、orcon and may not be used or disseminated inappropriately.工藝開發(fā)工藝開發(fā)IVThe information contained in this presentation is proprietary to Colorcon, Inc. and may not be used or disseminated inappropriately.The information contained in this presentation is proprietary to Colorcon and may not be used or dis

36、seminated inappropriately.工藝開發(fā)小結(jié)工藝開發(fā)小結(jié)The information contained in this presentation is proprietary to Colorcon, Inc. and may not be used or disseminated inappropriately.The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.工藝開發(fā)

37、工藝開發(fā)V_總混總混The information contained in this presentation is proprietary to Colorcon, Inc. and may not be used or disseminated inappropriately.The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.工藝開發(fā)工藝開發(fā)v_總混總混The information co

38、ntained in this presentation is proprietary to Colorcon, Inc. and may not be used or disseminated inappropriately.The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.工藝開發(fā)工藝開發(fā)VI_壓片壓片The information contained in this presentatio

39、n is proprietary to Colorcon, Inc. and may not be used or disseminated inappropriately.The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.工藝開發(fā)工藝開發(fā)VI_壓片壓片The information contained in this presentation is proprietary to Colorco

40、n and may not be used or disseminated inappropriately.工藝開發(fā)工藝開發(fā)VI_壓片壓片The information contained in this presentation is proprietary to Colorcon, Inc. and may not be used or disseminated inappropriately.The information contained in this presentation is proprietary to Colorcon and may not be used or di

41、sseminated inappropriately.工藝開發(fā)工藝開發(fā)_總結(jié)總結(jié)The information contained in this presentation is proprietary to Colorcon, Inc. and may not be used or disseminated inappropriately.The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.Sc

42、ale upThe information contained in this presentation is proprietary to Colorcon, Inc. and may not be used or disseminated inappropriately.The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.Scale upThe information contained in

43、 this presentation is proprietary to Colorcon, Inc. and may not be used or disseminated inappropriately.The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.工藝開發(fā)再評估工藝開發(fā)再評估The information contained in this presentation is propri

44、etary to Colorcon, Inc. and may not be used or disseminated inappropriately.The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.CPPs根據(jù)CQAs和產(chǎn)品知識，按照工藝過程分布展開羅列并評估所有工藝參數(shù)，其中對被視作CPPs的參數(shù)，通過DOE實驗論證，論證后重新評估CQAs，直至風險降低到最低等級，從而通過控制CPPs得到需要的QTPP.當輸入物料的實際變化能顯著影響產(chǎn)出物料的屬性時，則該物料或工藝就是關鍵的The information contained in this pre