药物制程开发庄哲仁.ppt
藥物製程開發,莊哲仁10/25/2002,Estimated Global Markets Year 2000,MARKET SECTORSSIZE(Billion USD)Pharmaceuticals400(North America 41.8%;EU 24.8%;Japan 11.3%;SE Asia&China 5%)Biotech Products12.5Herbs(Dietary Supplement+Drugs)20(US 20%),Estimated Global Markets Year 2000(Continued),MARKET SECTORSSIZE(Billion USD)Diagnostics23(US 37.3%;EU 35.5%;Japan 19.2%;ROW 8%)Medical Devices157(US 42%;EU 27%;Japan 14%;China 1.5%)Bio/Pharm Information Technology 134,Estimated Global Markets Year 2000(Continued),MARKET SECTORSSIZE(Billion USD)Life Science R&D Spending72(Pharmaceuticals R&D 35%)Chemicals for Life Science R&D8,新藥開發上市流程,藥物,藥物是一集合多樣專業以團隊方式研發創造,並經動物實驗及人體臨床試驗,證明安全性與有效性,以取得政府衛生單位核准上市的化學或生化產品.藥物使用在人體或動物大多不是以純粹有效成分(Active Pharmaceutical Ingredients,“API”)方式應用,而是以含有非有效成分的賦型劑(Excipients)之配方劑型(Formulated Products)方式應用.,藥物劑型及有效藥物成分,藥物劑型大致可分為固體劑型(例如錠劑或粉劑),液體劑型(例如針劑,液劑,或軟膏),及特殊藥物傳遞劑型(例如噴劑,貼劑,或植入劑).有效藥物成分(Active Pharmaceutical Ingredients)的來源大致來自於化學合成,生物科技,或天然物萃取.,新藥及學名藥,藥品依專利情況又可分為新藥(New Drugs)及專利過期的學名藥(Generic Drugs).新藥上市需要經過嚴格的前臨床(Pre-clinical Studies)及醫學臨床(Clinical Studies)研究證明安全與有效以取得政府衛生單位核准,一個新藥由新化學物質(New Chemical Entity,NCE)的發現程序到核准上市大約平均發費15年及3億美元,但是一個新藥卻往往可創造年出2至10億美元的年銷售額.,台灣藥物研發現況,台灣藥物研發在配方劑型(Formulated Products)方面,尤其在學名藥(Generic Drugs)已經具備相當的實力,在化學合成製造原料藥方面也有不錯的基礎,但在生物科技,前臨床(Pre-clinical Studies),醫學臨床(Clinical Studies),以及取得外國政府衛生單位核准的能力尚屬薄弱.,藥品製造cGMP,不論有效藥物成分或配方劑型都必須以符合藥品cGMP(現行優良製造程序,Current Good Manufacturing Practice)規範方式來製造,而其製程幾乎全為化工程序.,藥物製程開發,製程開發為產業的基礎,製藥工業也不例外.藥物製程源自於實驗室Process Chemistry 或Biochemistry Development,而藥物製程的確定則重視產程放大(Process Scale-up),產程最佳化(Process Optimization)及製程確效(Process Validation).化學或生化人員初期發展出來的製造方法(Synthesis Method)通常是實驗室規模的,製程開發人員承接其方法來改進(Process Improvement),放大(Scale-up)及確效(Validation),以期發展出適合大型生產用途的產程.,ASSEMBLE PROCESSVALIDATION TEAM,DEVELOP PROCESS VALIDATION MASTER PLAN,PROCESS CHEMISTRY DEVELOPMENT,PROCESS DEVELOPMENT,PLANT SCALE DEMO PROCESS VALIDATION,LITERATURE SEARCH(and MARKET ANALYSIS),ASSEMBLE PROCESSDEVELOPMENT TEAM,FEASIBILITY STUDIES:SYNTHESIS ALTERNATIVES,PATENT ISSUES,EQUIPMENT AVAILABILITY,SAFETY CONCERNS,ENVIRONMENTAL ISSUES,PROCESS CHEMISTRY REVIEW&REPETITION STUDIES,INITIAL PROCESS PROPOSAL&EXECTIVE DECISION,LAB PROCESS DEVELOPMENT,LAB SACLE-UP,KILO LAB STUDIES,PROCESS OPTIMIZATION,IMPURITY IDENTIFICATION,CHEMISTRY&HAZOP REVIEWS,FREEZING OF SYNTHESIS ROUTE,BIO BATCH PRODUCTION,PROCESS CHEMISTRY REPORT；PREPARATION FOR IND FILING,PROCESS IMPROVEMENT,SOLVENT SLECTION,REACTION ENGINEERING,PROCESS INTEGRATION and OPTIMIZATION,PILOT PLANT TESTING,FINAL PROCESS REVIEW HAZOP REVIEW,EXHIBIT LOT PRODUCTION PROCESS PRE-VALIDATION IMPURITY PROFILE DETERMINATION,PROCESS DEVELOPMENT REPORT；PREPARATION OF C.M.C.SECTION(NDA FILING OR FOR DRUG MASTER FILE),EQUIPMENT&FACILITY IQ/OQ&SYSTEM PQ,WATER AND SOLVENT TEST RUNS,PLANT PROCESS PREVIEW&HOZOP REVIEW,PROCESS DEMO,PROCESS VALIDATION,IMPURITY PROFILE DETERMINATION,TECHNOLOGY TRANSFER PACKAGE,FDA INSPECTION,圖1 原料藥製程開發與規模放大流程 TZ Chaung,Note:IQ:Installation QualificationOQ:Operation QualificationPQ:Performance Qualification,ASSEMBLE START UPTEAM,DEVELOP VALIDATION MASTER PLAN&PROTOCOL,DEVELOPMENT PHASE,DESIGN/CONSTRUCTION,START-UP,TECHNOLOGY TRANSFER OF CHEMICAL SYNTHESIS FROM CHEMICAL RESEARCH,ASSEMBLE PROJECT TEAM(CPE,CE,QC/QA,SAFETY),ASSEMBLE A JOINT PROCESS DEVELOPMENT TEAM(CPE,BCPE,QC/QA,SAFETY,CHEMICAL OPERATIONS)APPOINT PROCESS TEAM COORDINATORS,PROCESS FLOW DIAGRAM REVIEW&PRELIMINARY DESIGN,INITIAL PROCESS REVIEW,LAB PROCESS DEVELOPMENT,MINI PILOT STUDY,PILOT PLANT STUDY,FINAL PROCESS REVIEW&HAZOP REVIEW,EXHIBIT LOT PRODUCTION,TECHNOLOGY TRANSFER PACKAGE COMPILATION,VENDER SELECTION&PLANT LAYOUT,INITIAL DESIGN REVIEW,DETAILED DESIGN,HAZOP REVIEW,PLANT CONSTRUCTION,EQUIPMENT PROCUREMENT&INSTALLATION,EQUIPMENT&FACILITY IQ/OQ&SYSTEM PQ,WATER AND SOLVENT TEST RUN,PLANT PROCESS PREVIEW&HOZOP REVIEW,PLANT PROCESS START UP&VALIDATION,FDA Pre NDA APPROVAL INSPECTION,COMPLETION OF TECHNOLOGY TRANSFER TO PRODUCTION WITH CONTINUOUS PLANT SUPPORT,FINAL DESIGN,SAFETY INSPECTION,圖2 原料藥生產製程開發流程 TZ Chaung,藥物製程開發程序,(1)製程分析,資料查詢,基本分析方法建立(2)製程驗證,建立Step-by-Step的In-Process-Control(IPC)分析方法.(3)初步可行性及經濟評估.(4)尋找最適於大量生產的溶媒(Solvent Selection).(5)尋找最適的反應條件(溫度,壓力,攪拌方式與程度).,藥物製程開發程序(Continued),(6)尋找最適的添加次序(Regular or Reverse Addition)及方式(液面或液下).(7)尋找最適但最經濟等級的溶劑及反應物,注意產品純度.(8)尋找最適但最經濟的可替代的反應物,注意反應程度,速率,與產品純度.(9)製程整合(Process Integration)及產程最佳化(Process Optimization)(10)產程安全性評估(Hazardous Operation Review或HAZOP).,藥物製程開發程序(Continued),(11)製程放大(Scale-up),試驗工廠(Kilo-Lab and Pilot Plant)探討.(12)製程總檢討及大型產程安全性評估(HAZOP).(13)試驗工廠(Kilo-Lab and Pilot Plant)驗證及連續三次成功試製.(14)探討產程操作極限(Parametric Studies),建立初步製程確效(Pilot Scale Process Validation)(15)建立初步的產品純度及不純物分析(Impurity Profile).,藥物製程開發程序(Continued),(16)建立產品穩定性試驗程序(Stability Test Program)並開始做加速穩定性試驗(Accelerated Stability Tests).(17)撰寫製程驗證報告(Preliminary Process Validation Report),技術移轉報告(Technology Transfer Package).(18)準備大量試製或建廠,並撰寫工廠標準操作程序(Standard Operation Procedures,或S.O.P).,Drug Master File(DMF),原料藥的行銷,一般而言,必需在FDA登記Drug Master File(DMF),其重要內容包括製造公司及組織圖的介紹,生產與品管品保流程(CMC,Chemistry,Manufacturing,and Control),產品穩定性實驗,產品規格,及產品不純物分析(Impurity Profile).CMC Section(Chemistry,Manufacturing,and Control)是Drug Master File或新藥申請(NDA Filing)的主體,其內容是由製程開發,製程驗證,品質管制及保證過程簡化而來的.製程開發人員在這部份可做重要的貢獻.,cGMP的執行,cGMP的執行由藥廠的品質部門與生產部門共同規劃,藥廠的品質部門(Quality Unit)分為品質控制(QC,quality control)與品質保證(QA,quality assurance)兩大單位,品質控制成員以分析化學人員為主;品質保證成員以化工人員為主.品質部門的權職必須獨立於生產部門之外.,cGMP執行,cGMP執行與品質保證應由硬體與軟體同時規劃,在硬體方面首重製造環境與製程的清潔以及藥物交叉污染的防止.廠區設備管路易清潔性,製程用水空氣與蒸汽的清潔與無菌,廢棄物及廢水的收集處理,潔淨室以及人流物流空氣流的順暢與隔離,抗生素賀爾蒙有毒藥物與生物產品的管制與隔離等等,為設計cGMP藥廠的基本原則.,cGMP管理,cGMP軟體首重管理程序的建立,重要程序及製程都要有標準操作程序(SOP,standard operation procedure)的訂定,以及修改程序權限的控制(Change Control).沒有經過修改程序權限控制程序核准不可用來生產正式產品.製造過程,清潔過程,倉儲管理,與QC均需有完整而詳細的記錄,重要的操作程序大都需有重複檢視簽名(Double Checking)的程序以達可追溯的目的.任何製程及產品之異常均需做異常報告(Deviation Report)及開會檢討,並提出確實改善方案.與製造有關的員工必需經常接受cGMP,工安,環保,與SOP訓練.,製程驗證及清潔驗證,製程驗證及清潔驗證為近來cGMP檢查及FDA Inspection的重點,其程序相當繁雜費時,而且必需具備充分的專業知識.規劃製程驗證及清潔驗證程序首先需提出驗證計劃(Validation Master Plan and Validation Protocol),其內容主要包括製程介紹,驗證目的,驗證範圍,驗證邏輯,檢驗方法,及驗證方法.製程驗證過程中必需有Step-by-Step 的IPC(In-Process Control)來確認每個步驟均達到要求規格.一般而言,經過驗證成功後未來實際生產製程很多IPC即可省略.一般製程及清潔程序往往要求經過至少連續三次大型生產規模的成功驗證.,PURCHASING QC APPROVAL ACCEPTANCE SPECIFICATIONS,STARTING MATERIAL,IN SITU TESTING,INTERMEDIATE-1,INTERMEDIATE-2,IN SITU TESTING,LESS INTENSIVEINTER MEDIATE TESTS(C 1),OUT SOURCING QC APPROVAL(ACCEPTANCE PECIFICATIONS)AND MAJOR INTERMEDIATE TESTS(C 2),IPC 1MINOR IN PROCESS TESTING,LESS INTENSIVEINTERMEDIATE TESTS(C-1),IPC 2MAJOR IN PROCESS TESTING,MAJORINTERMEDIATE TESTS(C 2),IPC 1 MINOR IN PROCESS TESTING,INTERMEDIATE-4,KEY INTERMEDIATE,MAJOR INTERMEDIATE TESTS(C 2),PENULTIMATE,IPC 1MINOR IN PROCESS TESTING,QC APPROVAL REQULATORY SPECIFICATIONS,FINAL API,PIVOTAL INTERMEDIATES-3,圖3 QC CONTROLS IN A MULTIPLE STEP API PROCESS,製程技術移轉,製程技術移轉(TECHNOLOGY TRANSFER)為藥廠製程開發人員經常接觸到的重要任務之一.技術移轉包括移轉與接受,技術語言的使用以簡易能相互共通為目的,報告內容以詳盡有條理為原則,切忌報喜不報憂,應盡所知詳述製程開發期間失敗經驗及可能的製程操作極限.製程技術移轉文件(Technology Transfer Package)為未來工廠操作標準程序(S.O.P.,Standard Operation Procedures),清潔程序驗證(Cleaning Validation),及製程驗證(Process Validation)的基礎,也是日後申請藥品登記在技術說明部份(CMC Section:Chemistry,Manufacturing,and Control)文件的根據.,蛋白質學名藥?,美國FDA仍然不接受蛋白質學名藥之申請；台灣CDE則仍以美國FDA精神為準則。蛋白質藥物之IMPURITY PROFILE隨生產及純化方法不同而異。蛋白質藥物難以完全純化。美國FDA目前要求所有蛋白質藥物做全面性臨床。中國大陸可接受蛋白質學名藥之申請。,
