-固體制劑仿制藥研發(fā)流程

1、Generic Drug Product Development Stages仿制藥發(fā)展階段(Oral Solid Dosage Forms, Tablets)（口服固體制劑，片劑）StageChemistry, Manufacturing & Controls inOral Solid Dosage Form Development 口服固體制劑發(fā)展中的化學(xué)特性，生產(chǎn)和 控制CGMP Complianceto MeetRegulatory Requirements 滿足法規(guī)要求的CGMP規(guī)范1Drug Packaging Insert Study to obtain basic inform

2、ation about RLD, such as 通過對對照藥物的包材以內(nèi)成分的分析， 獲取有關(guān)該對照藥物的基本信息1 Components in the formulation 處方 成份2 BE information生物等效性信息3 Etc.其它2Reverse Engineering Study, including evaluation of three different lots of RLD for:根據(jù)前述研究釆用倒推法研究制劑工藝， 包括對參批不同批次對照藥物的評估1 Potency/purity 效價/純度2 Impurity profile (relatedSystem

3、 based CGMP auditing on manufacturing facility: Quality System Materials System Facilities and EquipmentSystem Production Systemsubstances)3雜質(zhì)分布曲線圖(相關(guān)物質(zhì))1 Content uniformity 含量均勻度5 Weight variation 重量差異6 Dissolution profile 溶出曲線7 Disintegration time 崩解時間8 Hardness and Friability 硬度和脆碎 度 Packaging an

4、d LabelingSystem Laboratory Control System 對生產(chǎn)設(shè)施進行基于系統(tǒng)的CGMP 審計 質(zhì)量系統(tǒng) 物料系統(tǒng) 設(shè)施設(shè)備系統(tǒng) 生產(chǎn)系統(tǒng) 包裝和標(biāo)簽系統(tǒng) 實驗室控制系統(tǒng)3Pre-formulation Studies處方前研究1 Analytical method development 分析 方法發(fā)展(Develop adequate analytical methods for API)針對原料藥發(fā)展合適的分析方法2 Acquiring API and related impurityreference standards (USP or other sou

5、rces)獲得原料藥和相關(guān)朵質(zhì)參考標(biāo)準(zhǔn)(美國藥典或其他來源)3 API characterization and qualification, including chemical and physical properties studies, such as solubility, density, particle size distribution, polymorphism (any attributes1 Qualification of API and excipients suppliers, including auditing and full testing on thr

6、ee different lots原料藥和輔料供應(yīng)商的資格認 證，包括審計和對三種不同批次進 行的全面測試。2 Establish acceptance criteria for API and excipients and corresponding analytical methods建立可接受的 原料藥及輔料標(biāo)準(zhǔn)和相應(yīng)的分析方 法3 validation or verification of these analytical methods 這 些分析方法的驗證和確認。1 Preparation of pre-relevant to the formulation） 原料藥的特性和認證，

7、包括理化特征研 究，如：溶出度，密度，顆粒粒徑分布， 多態(tài)現(xiàn)象（任何與處方相關(guān)的屬性） 4 Excipients specifications （acceptance criteria and testing methods to meet USP/NF standards）, and excipients characterization and qualification, including compatibility studies with API.輔料的技術(shù)規(guī)范（符合USP和NF標(biāo)準(zhǔn)的 可接受標(biāo)準(zhǔn)和測試方法）輔料特性認證， 包括與原料藥的相容性研究formulation study

8、 report or summary from CGMP perspective 從現(xiàn)行GMP的角度，準(zhǔn)備處方前研 究報告或概括總結(jié)Formulation Development1) Properly document study處方開發(fā)results and preparation of1 Formulation selection (components andDP formulation developmentcomposition) based on RLD formulation andreport or summary to supportin-house study.處方篩選（組

9、成成份）以對照the formulation for further4藥物配方和室內(nèi)研究為基礎(chǔ)）development2 Define initial process (platform) for1）正確記錄研究結(jié)果并寫下關(guān)preparation of prototype generic drug于藥品制劑開發(fā)制備的報告或總product （DP）,闡述制備仿制藥的原型產(chǎn)品結(jié)，以便支持對配方更進一步的（DP）的初始過程（平臺）開發(fā)。3 Define the initial specifications for2) Preparation of properDP, including logo

10、and number artworkanalytical method validationpreparation on the surface of the drug product闡述藥品的初始規(guī)范，包括藥品表面上的標(biāo) 識，數(shù)字或圖形的安排。1 Produce one (or more) small research and development DP batch and test the product according to finished product specifications, including the evaluation of DP impurity profil

11、e and perform dissolution profile study compared with the RLD product.主產(chǎn)一小批經(jīng)研究開發(fā)的藥 品，并根據(jù)制成品規(guī)范對其進行測試，這包括 藥品雜質(zhì)分布評估，和對照藥物進行比對，進 行溶出曲線研究。5 Place the DP on accelerated stabilitystudy (up to 3 months) to evaluate the stability of the formulation developed對 藥品進行加速穩(wěn)定性實驗(最多3個月)來評 估所研制配方的穩(wěn)定性。6 Analytical meth

12、od validation or verification, including forced degradation studies on DP to demonstrate that the analytical method used is stabi.1 ity-indicating分析方法驗證和確認， 包括通過藥品的強制降解研究，來表明所使用 的分析方法能指示穩(wěn)定性。7 Selection of container closure system (CCS), including component resin,or verification protocol and final re

13、ports準(zhǔn)備正確的分析方法驗證方案和 最終報告3) Vendor qualification, including full testing on the first three lots of CCS 供應(yīng)商資格認證，包括容器密封 系統(tǒng)前三批次的測試Note:CCS which has been used inFDA approved drugs is highly recommended注意：強烈推薦在FDA審批過程 中應(yīng)用CCS即包裝容器及密封管 理系統(tǒng)。specification, test methods, supplier* s DMF.容器密封系統(tǒng)（CCS）的挑選，包括樹脂組份

14、， 規(guī)范，測試方法，供應(yīng)商的DMF號等Process Understanding,characterization and Optimization（Scale-up）工藝?yán)斫猓匦约皟?yōu)化（放大）1) Document justification on1) Identification of the criticalcritical parameterparameter(s) in each unit operationidentifiedtion and their in-and implement in-process controlprocess control ranges,range

15、s, such as核對每個單元操作的關(guān)鍵確定關(guān)鍵參數(shù)及其在線控制范圍的參數(shù)，落實過程控制范圍，例如確認的證明文件1 Blend content uniformity (BCU) issue2) Preparation of product and(Is the blending time critical? Whatprocess development report or5is the sampling plan and samplingsummary to support the criticalmethod to monitor BCU? What are theparameters

16、identified and theiranalytical method and acceptancein-process control ranges usedcriteria for BCU? Etc.for pilot batch and commercial2有關(guān)混合含量的均勻度的問題（混合時間batch manufacture.是否關(guān)鍵？監(jiān)督混合含量均勻度的采樣計劃制備產(chǎn)品和工藝研發(fā)報告或總結(jié)，和采樣方法是什么？混合含量均勻度的分析用于支持在中試和商業(yè)化生產(chǎn)規(guī)模方法和可接受標(biāo)準(zhǔn)是什么？等等）中的生產(chǎn)中的關(guān)鍵參數(shù)及其控制范3 LOD in dry process （time,temp

17、erature, etc.）干法工藝的最低檢測限（時間，溫度，等）圍的確定1 Weight variation control in tablet compression壓片的重量差異控制5 Etc.等2) Several development batches in varies batch sizes may be produced for research and development purpose Adequate experimentai data should be collected to support any critical parameters identified

18、and in-process control ranges used in scale-up process可以生產(chǎn)一些不同產(chǎn)量規(guī)模的產(chǎn)品來用于研 發(fā)。為支持任何經(jīng)確認的關(guān)鍵參數(shù)和在線控 制范圍，需要搜集足夠的實驗數(shù)據(jù)。1 The final DP specificstions should be established.需建立藥品技術(shù)規(guī)范。1) validation Master Plan (VMP) for the specified product should be prepared at this stage It should be served as a uroad mapM t

19、o startQualification and validation works related to the product 特定產(chǎn)品的驗證主計劃必須在這個 階段準(zhǔn)備。它將被用做開始進行與 產(chǎn)品相關(guān)認證和驗證工作的路線 圖。61) Engineering or Demonstration Batch1) Following work should beManufacture匸程批或驗證批的生產(chǎn)1 Preparation of batch record (BR) for Engineering or demonstration batch manufacture X程或驗證批次生產(chǎn)的批記錄

20、準(zhǔn)備2 Reviewing drafted BR and ensuring the critical parameter(s) are adequately identified and the in- process control ranges are properly implemented.審查起草的批記錄并且確保正 確執(zhí)行了經(jīng)過驗證的關(guān)鍵參數(shù)及其在線控制 范圍。3 A comprehensive sampling plan should be considered to collect more data at this scale.在此規(guī)模下，需要考慮制定一 個綜合釆樣計劃來收集更

21、多的數(shù)據(jù)。1 The batch size should be at least 100,000 tablets or 10% of proposed commercial batch size.必須批量生產(chǎn)的 片劑至少為100, 000片或者為市售批量的 百分之十。5 It is highly recommended that engineering or demonstration batch be produced by using commercial manufacturing equipmentcompleted according VMP before demonstration

22、 batch or pilot batch preparation:以下工作必須在驗證批或中試批生 產(chǎn)前，根據(jù)驗證主計劃來完成1 Qualification of related facilities and systems (such as, HVAC, waster system, etc)相 關(guān)設(shè)備和系統(tǒng)(如：空調(diào)系統(tǒng)，水 系統(tǒng)的驗證)2 Qual辻ication ( DQ, IQ, OQ and PQ) of the equipment used in manufacturing of the DP 在生產(chǎn)中需要用到的設(shè)備的驗證(設(shè)計確認、安裝確認、運行確認 和性能確認)3 Prepa

23、ration of equipment cleaning validation protocol 設(shè)備清潔驗證方案的準(zhǔn)備1 Analytical methods validation or verification分析方法的驗證強烈建議使用將來會用到的商業(yè)化規(guī)模的生 產(chǎn)設(shè)備來生產(chǎn)工程或驗證批的產(chǎn)品。6 The final DP release tests should meet established specifications 最終 的藥物發(fā)放檢測需要符合已建立的技術(shù)規(guī) 范。This engineering or demonstration batch manufacture could

24、be optional depending upon the research and development study performed and related manufacturing experience a firm has匸程或驗證批的生產(chǎn)是可選擇的，可以根據(jù) 所進行的研發(fā)研究和公司的相關(guān)生產(chǎn)經(jīng)驗來 決定。71) BE Pilot Study to gain information on bio-equivalent of in- house product生物等效性的中試規(guī)模研 究，以獲取內(nèi)部使用產(chǎn)品的生物等效信息1 Using the samples from engine

25、ering or demonstration batch 使用工程或驗 證批的樣品23-5 persons compared with RLD 3至5個人的生物等效性數(shù)據(jù)和對照藥 物的數(shù)據(jù)的對比This is also an option這也是可選項8Bio-batch or Submission BatchPreparation of final DPPreparation生物批或申報批的準(zhǔn)備1) Manufacturing a bio-batch or submission batch under CGMP controls 按照CGMP規(guī)范生產(chǎn)生物批或申報批1 Executed batc

26、h record should include yield in each unit operation, final DP units manufactured and packaged, as well as batch reconciliation data and draft labe1.2所執(zhí)行的批記錄應(yīng)當(dāng)包括每個單元操作 的收益，最終藥品單元的生產(chǎn)和包裝，批 流程數(shù)據(jù)和標(biāo)簽草案等信息2) Bio-batch release testing and issue COA生物批的發(fā)放檢測和成品出廠 合格證書的發(fā)行1 Dissolution profile (12 units and5 t

27、ime points) compared with RLD batch.溶出曲線和對照藥物進行對比(12 個單元和5個治療點)2 Tested according established specification根據(jù)已建立的規(guī)范進行檢 測3) Est ablish stability proto col 建立 穩(wěn)定性方案 Testing time points (0, 1, 2, 3 M for accelerated and 0, 3 6. 9. 12. 18. 24 development report (or combination of pre-formulat ion, formu

28、lation and process development summaries) 最終藥品開發(fā)報告的準(zhǔn)備(或處方前研 究，處方研究和工藝開發(fā)總結(jié)的綜 合。)Note:This report will be served as the basis for preparation of Quality Overall Summary (QOS, 2. 3 in CTD- formdt) and Pharmaceutical Development Section (3.2.P2 in CTD-format) in ANDA submission 備注： 該報告是ANDA申報中藥物研發(fā)部分和 質(zhì)量

29、概述部分所需要的基本組成部分。for long-term conditions)測試時間點 (0, 1, 2, 3月為加速測試，0, 3. 6. 9. 12. 18. 24為長期條件下的穩(wěn)定 性測試) Intermediate condition if necessary如果需要，也需進行中間條件 測試 Stability test attributes (Appearance, purity, related substances, dissolution, etc.)穩(wěn)定性 測試屬性(外觀，純度，相關(guān)物質(zhì)，溶 解，等等)4) Perform DP stability study as appropriate (at least 3 months under accelerated condition) for submission purpose 為達到提交的 LI 的，需要執(zhí)行合適的藥品穩(wěn)定性測試(至 少在加速條件下進行3個月)91)BE Study生物等效性研究 Using bio-batch or submission batch samples to compare wit