固体制剂仿制药研发流程(共7页).doc

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1、精选优质文档-倾情为你奉上Generic Drug Product Development Stages仿制药发展阶段(Oral Solid Dosage Forms, Tablets)（口服固体制剂，片剂）StageChemistry, Manufacturing & Controlsin Oral Solid Dosage Form Development 口服固体制剂发展中的化学特性，生产和控制CGMP Complianceto Meet Regulatory Requirements满足法规要求的CGMP规范1Drug Packaging Insert Study to obtain

2、basic information about RLD, such as通过对对照药物的包材以内成分的分析，获取有关该对照药物的基本信息 Components in the formulation处方成份 BE information生物等效性信息 Etc.其它2Reverse Engineering Study, including evaluation of three different lots of RLD for:根据前述研究采用倒推法研究制剂工艺，包括对叁批不同批次对照药物的评估 Potency/purity 效价/纯度 Impurity profile (related sub

3、stances) 杂质分布曲线图（相关物质） Content uniformity 含量均匀度 Weight variation 重量差异 Dissolution profile 溶出曲线 Disintegration time 崩解时间 Hardness and Friability 硬度和脆碎度 System based CGMP auditing on manufacturing facility: Quality System Materials System Facilities and Equipment System Production System Packaging and

4、 Labeling System Laboratory Control System对生产设施进行基于系统的CGMP审计 质量系统 物料系统 设施设备系统 生产系统 包装和标签系统 实验室控制系统 3Pre-formulation Studies处方前研究 Analytical method development分析方法发展(Develop adequate analytical methods for API)针对原料药发展合适的分析方法 Acquiring API and related impurity reference standards (USP or other sources

5、)获得原料药和相关杂质参考标准（美国药典或其他来源） API characterization and qualification, including chemical and physical properties studies, such as solubility, density, particle size distribution, polymorphism (any attributes relevant to the formulation) 原料药的特性和认证，包括理化特征研究，如：溶出度，密度，颗粒粒径分布，多态现象（任何与处方相关的属性） Excipients spe

6、cifications (acceptance criteria and testing methods to meet USP/NF standards), and excipients characterization and qualification, including compatibility studies with API.辅料的技术规范（符合USP和NF标准的可接受标准和测试方法）辅料特性认证，包括与原料药的相容性研究 Qualification of API and excipients suppliers, including auditing and full tes

7、ting on three different lots原料药和辅料供应商的资格认证，包括审计和对三种不同批次进行的全面测试。 Establish acceptance criteria for API and excipients and corresponding analytical methods建立可接受的原料药及辅料标准和相应的分析方法 Validation or verification of these analytical methods 这些分析方法的验证和确认。 Preparation of pre-formulation study report or summary

8、from CGMP perspective从现行GMP的角度，准备处方前研究报告或概括总结4Formulation Development处方开发 Formulation selection (components and composition) based on RLD formulation and in-house study.处方筛选（组成成份）以对照药物配方和室内研究为基础） Define initial process (platform) for preparation of prototype generic drug product (DP), 阐述制备仿制药的原型产品（D

9、P）的初始过程（平台） Define the initial specifications for DP, including logo and number artwork preparation on the surface of the drug product.阐述药品的初始规范，包括药品表面上的标识，数字或图形的安排。 Produce one (or more) small research and development DP batch and test the product according to finished product specifications, inclu

10、ding the evaluation of DP impurity profile and perform dissolution profile study compared with the RLD product.生产一小批经研究开发的药品，并根据制成品规范对其进行测试，这包括药品杂质分布评估，和对照药物进行比对，进行溶出曲线研究。 Place the DP on accelerated stability study (up to 3 months) to evaluate the stability of the formulation developed.对药品进行加速稳定性实验

11、（最多3个月）来评估所研制配方的稳定性。 Analytical method validation or verification, including forced degradation studies on DP to demonstrate that the analytical method used is stability-indicating分析方法验证和确认，包括通过药品的强制降解研究，来表明所使用的分析方法能指示稳定性。 Selection of container closure system (CCS), including component resin, speci

12、fication, test methods, suppliers DMF.容器密封系统（CCS）的挑选，包括树脂组份，规范，测试方法，供应商的DMF号等1）Properly document study results and preparation of DP formulation development report or summary to support the formulation for further development.1）正确记录研究结果并写下关于药品制剂开发制备的报告或总结，以便支持对配方更进一步的开发。2）Preparation of proper analy

13、tical method validation or verification protocol and final reports准备正确的分析方法验证方案和最终报告3）Vendor qualification, including full testing on the first three lots of CCS.供应商资格认证，包括容器密封系统前三批次的测试Note:CCS which has been used in FDA approved drugs is highly recommended注意：强烈推荐在FDA审批过程中应用CCS即包装容器及密封管理系统。5Process

14、Understanding, characterization and Optimization (Scale-up)工艺理解，特性及优化（放大）1） Identification of the critical parameter(s) in each unit operation and implement in-process control ranges, such as核对每个单元操作的关键参数，落实过程控制范围，例如 Blend content uniformity (BCU) issue (Is the blending time critical? What is the sa

15、mpling plan and sampling method to monitor BCU? What are the analytical method and acceptance criteria for BCU? Etc. 有关混合含量的均匀度的问题（混合时间是否关键？监督混合含量均匀度的采样计划和采样方法是什么？混合含量均匀度的分析方法和可接受标准是什么？等等） LOD in dry process (time, temperature, etc.)干法工艺的最低检测限（时间，温度，等） Weight variation control in tablet compression压

16、片的重量差异控制 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.可以生产一些不同产量规模的产品来用于研发。为支持任何经确认的

17、关键参数和在线控制范围，需要搜集足够的实验数据。 The final DP specifications should be established.需建立药品技术规范。1）Document justification on critical parameter identification and their in-process control ranges,确定关键参数及其在线控制范围的确认的证明文件2）Preparation of product and process development report or summary to support the critical para

18、meters identified and their in-process control ranges used for pilot batch and commercial batch manufacture.制备产品和工艺研发报告或总结，用于支持在中试和商业化生产规模中的生产中的关键参数及其控制范围的确定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 qualifi

19、cation and validation works related to the product.特定产品的验证主计划必须在这个阶段准备。它将被用做开始进行与产品相关认证和验证工作的路线图。61）Engineering or Demonstration Batch Manufacture工程批或验证批的生产 Preparation of batch record (BR) for Engineering or demonstration batch manufacture工程或验证批次生产的批记录准备 Reviewing drafted BR and ensuring the critic

20、al parameter(s) are adequately identified and the in-process control ranges are properly implemented.审查起草的批记录并且确保正确执行了经过验证的关键参数及其在线控制范围。 A comprehensive sampling plan should be considered to collect more data at this scale.在此规模下，需要考虑制定一个综合采样计划来收集更多的数据。 The batch size should be at least 100,000 table

21、ts or 10% of proposed commercial batch size. 必须批量生产的片剂至少为100，000片或者为市售批量的百分之十。 It is highly recommended that engineering or demonstration batch be produced by using commercial manufacturing equipment. 强烈建议使用将来会用到的商业化规模的生产设备来生产工程或验证批的产品。 The final DP release tests should meet established specificatio

22、ns. 最终的药物发放检测需要符合已建立的技术规范。This engineering or demonstration batch manufacture could be optional depending upon the research and development study performed and related manufacturing experience a firm has.工程或验证批的生产是可选择的，可以根据所进行的研发研究和公司的相关生产经验来决定。1）Following work should be completed according VMP befo

23、re demonstration batch or pilot batch preparation:以下工作必须在验证批或中试批生产前，根据验证主计划来完成 Qualification of related facilities and systems (such as, HVAC, waster system, etc)相关设备和系统（如：空调系统，水系统的验证） Qualification ( DQ, IQ, OQ and PQ) of the equipment used in manufacturing of the DP 在生产中需要用到的设备的 验证（设计确认、安装确认、运行确认和

24、性能确认） Preparation of equipment cleaning validation protocol设备清洁验证方案的准备 Analytical methods validation or verification分析方法的验证71）BE Pilot Study to gain information on bio-equivalent of in-house product生物等效性的中试规模研究，以获取内部使用产品的生物等效信息 Using the samples from engineering or demonstration batch使用工程或验证批的样品 3 5

25、 persons compared with RLD3至5个人 的生物等效性数据和对照药物的数据的对比This is also an option这也是可选项8Bio-batch or Submission Batch Preparation生物批或申报批的准备1） Manufacturing a bio-batch or submission batch under CGMP controls 按照CGMP规范生产生物批或申报批 Executed batch record should include yield in each unit operation, final DP units

26、manufactured and packaged, as well as batch reconciliation data and draft label. 所执行的批记录应当包括每个单元操作的收益，最终药品单元的生产和包装，批流程数据和标签草案等信息2）Bio-batch release testing and issue COA生物批的发放检测和成品出厂合格证书的发行 Dissolution profile (12 units and 5 time points) compared with RLD batch.溶出曲线和对照药物进行对比（12个单元和5个治疗点） Tested acc

27、ording established specification根据已建立的规范进行检测3）Establish stability protocol 建立稳定性方案 Testing time points (0,1,2,3 M for accelerated and 0,3.6.9.12.18.24 for long-term conditions)测试时间点（0，1，2，3月为加速测试，0,3.6.9.12.18.24 为长期条件下的稳定性测试） Intermediate condition if necessary 如果需要，也需进行中间条件测试 Stability test attrib

28、utes (Appearance, purity, related substances, dissolution, etc.)稳定性测试属性（外观，纯度，相关物质，溶解，等等）4） Perform DP stability study as appropriate (at least 3 months under accelerated condition) for submission purpose为达到提交的目的，需要执行合适的药品稳定性测试（至少在加速条件下进行3个月）Preparation of final DP development report (or combination

29、 of pre-formulation, formulation and process development summaries)最终药品开发报告的准备（或处方前研究，处方研究和工艺开发总结的综合。）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备注：

30、该报告是ANDA申报中药物研发部分和质量概述部分所需要的基本组成部分。91）BE Study 生物等效性研究 Using bio-batch or submission batch samples to compare with RLD使用生物批或申报批样本同对照药物作比较 24 to 36 patients, cross over studies.24至36个病人，交叉研究1）BE study should be conducted in a clinical laboratory which is in compliance with FDA GLP requirements.生物等效性研

31、究必须在临床实验室里实行，这与FDA的GLP 要求相一致101）Preparation of ANDA package for submission ANDA申请提交文件的准备 CTD-format should be used for preparation of an ANDA 以CTD格式来准备ANDA申请11Preparation for Pre-approval Inspection (PAI)迎接批准前检查的准备工作1）Preparation PAI from CGMP perspective by evaluating GMP systems on site.通过在现场对GMP系

32、统的评价，从CGMP规范的角度完成批准前检查的准备工作。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工艺验证方案的准备，通过按照商业生产规模进行的连续三批验证批的生产来开始或完成工艺验证，并准备验证报告。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)备注：并不需要在ANDA批准前完成工艺验证。但验证方案必须在批准前检查时已经完成。Version of May 6, 2008专心-专注-专业