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仿制藥發(fā)展階段

 

01、口服固體制劑發(fā)展中的化學(xué)特性，生產(chǎn)和控制

 

Drug Packaging Insert Study to obtain basic information 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

 

02、口服固體制劑發(fā)展中的化學(xué)特性，生產(chǎn)和控制

 

ReverseEngineeringincSludtuingdeyva, luation  of three different lots of RLD for:

根據(jù)前述研究采用倒推法研究制劑工藝，包括對叁批不同批次對照藥物的評估

① Potency/purity 效價 /純度

② Impurity profile (related substances)

③ 雜質(zhì)分布曲線圖（相關(guān)物質(zhì)）

④ 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

 

滿足法規(guī)要求的CGMP規(guī)范

 

System based CGMP auditing on manufacturing facility:

① Quality System

② Materials System

③ Facilities and Equipment System

④ Production System

⑤ Packaging and Labeling System

⑥ Laboratory Control System

對生產(chǎn)設(shè)施進(jìn)行基于系統(tǒng)的 CGMP 審計

① 質(zhì)量系統(tǒng)

② 物料系統(tǒng)

③ 設(shè)施設(shè)備系統(tǒng)

④ 生產(chǎn)系統(tǒng)

⑤ 包裝和標(biāo)簽系統(tǒng)

⑥ 實驗室控制系統(tǒng)

 

03、口服固體制劑發(fā)展中的化學(xué)特性，生產(chǎn)和控制

 

Pre-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 impurity reference standards (USP or other sources) 獲得原料藥和相關(guān)雜質(zhì)參考標(biāo)準(zhǔn)（美國藥典或其他來源）

③API characterization and qualification, including chemical and physical properties studies, such as solubility, density, particle size distribution, polymorphism (any attributes

relevant to the formulation)

原料藥的特性和認(rèn)證，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(rèn)證，包括與原料藥的相容性研究

 

滿足法規(guī)要求的CGMP規(guī)范

 

① Qualification of API and excipients suppliers, including auditing and full testing on three  different lots 

原料藥和輔料供應(yīng)商的資格認(rèn)證，包括審計和對三種不同批次進(jìn)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(rèn)

④ Preparation of pre-formulation study 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)

 

04、口服固體制劑發(fā)展中的化學(xué)特性，生產(chǎn)和控制

 

3 Formulation Development

處方開發(fā)

① Formulation selection (components and composition) based on RLD formulation and

in-house study. 處方篩選（組成成份）以對照藥物配方和室內(nèi)研究為基礎(chǔ)）

② Define initial process (platform) for

preparation of prototype generic drug product (DP),  闡述制備仿制藥的原型產(chǎn)品（ DP ）的初始過程（平臺）

③ Define the initial specifications for DP, including logo and number artwork preparation 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。

④ 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 profile and perform dissolution profile study

compared with the RLD product. 

生產(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(jìn)行測試，這包括藥品雜質(zhì)分布評估，和對照藥物進(jìn)行比對，進(jìn)行溶出曲線研究

⑤ Place the DP on accelerated stability study (up to 3 months) to evaluate the stability of the formulation developed. 

對藥品進(jìn)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 method validation or verification,

including forced degradation studies on DP to demonstrate that the analytical method used

is stability-indicating 

分析方法驗證和確認(rèn)，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, specification, test methods, supplier ’s DMF.

容器密封系統(tǒng)（CCS）的挑選，包括樹脂組份，規(guī)范，測試方法，供應(yīng)商的DMF號等

 

滿足法規(guī)要求的CGMP規(guī)范

 

1）Properly document study results and preparation of DP formulation development report or summary to support the formulation for further development.

正確記錄研究結(jié)果并寫下關(guān)于藥品制劑開發(fā)制備的報告或總結(jié)，以便支持對配方更進(jìn)一步的開發(fā)。

2） Preparation of proper analytical method validation or verification protocol and final reports

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(rèn)證，包括容器密封系統(tǒng)前三批次的測試

 

Note:

CCS which has been used in FDA 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)。

 

05、口服固體制劑發(fā)展中的化學(xué)特性，生產(chǎn)和控制

 

Process Understanding, characterization and

Optimization (Scale-up) 

工藝?yán)斫?，特性及?yōu)化（ 放大 ）

1） Identification of the critical parameter(s) in each unit operation and implement in-process

control ranges , such as 

核對每個單元操作的關(guān)鍵參數(shù)，落實過程控制范圍，例如

① Blend content uniformity (BCU) issue (Is the blending time critical? What is the sampling plan and sampling method to monitor BCU? What are the analytical method and acceptance criteria for BCU? Etc.

② 有關(guān)混合含量的均勻度的問題（混合時間是否

關(guān)鍵？監(jiān)督混合含量均勻度的采樣計劃和采樣方法是什么？混合含量均勻度的分析方法和可接受標(biāo)準(zhǔn)是什么？等等）

③ LOD in dry process (time, temperature, etc.)

干法工藝的最低檢測限（時間，溫度，等）

④ 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 experimental data should be collected to support any critical parameters identified 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(rèn)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 specifications should be established. 

需建立藥品技術(shù)規(guī)范。

 

滿足法規(guī)要求的CGMP規(guī)范

 

1）Document justification on critical parameter identification and their in-process control ranges,

確定關(guān)鍵參數(shù)及其在線控制范圍的確認(rèn)的證明文件

2）Preparation of product and process development report or summary to support the critical parameters identified and their in-process control ranges used for pilot batch and commercial batch manufacture..

制備產(chǎn)品和工藝研發(fā)報告或總結(jié)，用于支持在中試和商業(yè)化生產(chǎn)規(guī)模中的生產(chǎn)中的關(guān)鍵參數(shù)及其控制范圍的確定

 

06、口服固體制劑發(fā)展中的化學(xué)特性，生產(chǎn)和控制

 

1） Engineering or Demonstration Batch Manufacture

工程批或驗證批的生產(chǎn)

① Preparation of batch record (BR) for  Engineering or demonstration  batch  manufacture  

工程或驗證批次生產(chǎn)的批記錄準(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采樣計劃來收集更

多的數(shù)據(jù)。

④ 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 equipment.

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 be optional depending upon the research and development study performed and related manufacturing experience a firm has.

工程或驗證批的生產(chǎn)是可選擇的，可以根據(jù)所進(jìn)行的研發(fā)

研究和公司的相關(guān)生產(chǎn)經(jīng)驗來決定。

 

滿足法規(guī)要求的CGMP規(guī)范

 

1） Validation Master Plan (VMP) for the specified product should be prepared at this stage. It should be served as a “ road map ”

to start qualification 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(jìn)行與產(chǎn)品相關(guān)認(rèn)證和驗證工作的路線 圖。

2） Following work should be completed according VMP before demonstration 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 Qualification ( 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(rèn)、安裝確 認(rèn)、運行確認(rèn)和性能確認(rèn)）

③ Preparation of equipment cleaning validation protocol

設(shè)備清潔驗證方案的準(zhǔn)備

④ Analytical methods validation or verification

分析方法的驗證

 

07、口服固體制劑發(fā)展中的化學(xué)特性，生產(chǎn)和控制

 

1） 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 engineering or

demonstration batch 使用工程或驗證批的樣品

② 3 –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

 

08、口服固體制劑發(fā)展中的化學(xué)特性，生產(chǎn)和控制

 

Bio-batch or Submission Batch Preparation

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 batch record should include yield in each unit operation, final DP units manufactured and packaged, as well as batch reconciliation data and draft label.

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 and 5 time

points) compared with RLD batch.  溶出曲線和對照藥物進(jìn)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(jìn)行檢測

3） Establish stability protocol 

建立穩(wěn)定性方案

① Testing time points (0,1,2,3M for accelerated

and 0,3.6.9.12.18.24 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）

② Intermediate condition if necessary 

如果需要， 也需進(jìn)行中間條件測試

③ 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(dá)到提交的目的，需要執(zhí)行 合適的藥品穩(wěn)定性測（至少在加速條件下進(jìn)行 3個月）

 

滿足法規(guī)要求的CGMP規(guī)范

 

Preparation of final DP development report (or combination of pre- formulation, formulation 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-format) and Pharmaceutical Development Section (3.2.P.2 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)量概述部分所需要的基本組成部分。

 

09、口服固體制劑發(fā)展中的化學(xué)特性，生產(chǎn)和控制

 

1） BE Study 生物等效性研究

① Using bio-batch or submission batch samples to compare with RLD 

使用生物批或申報批樣本同對照藥物作比較

② 24 to36 patients, cross over studies.

24 至 36 個病人，交叉研究

 

滿足法規(guī)要求的CGMP規(guī)范

 

1） BE study should be conducted in a clinical laboratory which is in compliance with FDA GLP requirements.

生物等效性研究必須在臨床實驗室里實行，這與 FDA 的GLP 要求相一致

 

10、口服固體制劑發(fā)展中的化學(xué)特性，生產(chǎn)和控制

 

1） Preparation of ANDA package for submission  ANDA 申請?zhí)峤晃募臏?zhǔn)備

① CTD-format should be used for preparation of an ANDA

以 CTD  格式來準(zhǔn)備 ANDA 申請

 

11、口服固體制劑發(fā)展中的化學(xué)特性，生產(chǎn)和控制

 

Preparation for Pre-approval Inspection (PAI)

迎接批準(zhǔn)前檢查的準(zhǔn)備工作

 

滿足法規(guī)要求的CGMP規(guī)范

 

1） Preparation PAI from CGMP perspective by evaluating GMP systems on site.

通過在現(xiàn)場對 GMP 系統(tǒng)的評價，從 CGMP 規(guī)范的角度完成批準(zhǔn)前檢查的準(zhǔn)備工作。

2） Preparation of process validation (PV) protocol, and may start or complete process validation by producing three consecutive conforming batches at commercial scale) and preparation validation report

工藝驗證方案的準(zhǔn)備，通過按照商業(yè)生產(chǎn)規(guī)模進(jìn)行的連續(xù)三批驗證批的生產(chǎn)來開始或完成工藝驗證，并準(zhǔn)備驗證報告。

Note:

PV is not required to be completed for ANDA approval. However, validation protocol should be in place at the time of pre-approval inspection (PAI)

備注：并不需要在 ANDA 批準(zhǔn)前完成工藝驗證。但驗證方案必須在批準(zhǔn)前檢查時已經(jīng)完成。