分享 | 固体制剂仿制药研发流程

处方前研究

① 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

② Acquiring API and related impurity reference standards (USP or other sources) 获得原料药和相关杂质参考标准（美国药典或其他来源）

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）

④ Excipients specifications (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

处方开发 Formulation Development

① 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）

② Define initial process (platform) for preparation of prototype generic drug product (DP),  阐述制备仿制药的原型产品（ DP ）的初始过程（平台）

③ 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。

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

⑤ 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（最多 3 个月）来评估所研制配方的稳定性。

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。

⑦ Selection of container closure system (CCS), including component resin, specification, test methods, supplier ’s 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 

② Preparation of proper analytical 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。

Process 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：

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.）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）

② LOD in dry process (time, temperature, etc.) 干法工艺的最低检测限（时间，温度，等）

③ Weight variation control in  tablet  compression 压片的重量差异控制

④ 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关键参数和在线控制范围， 需要搜集足够的实验数据。

① The final DP specifications should be established. 需建立药品技术规范。

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 qualification 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。

1） BE study should be conducted in a clinical laboratory which is in compliance with FDA GLP requirements.  生物等效性研究必须在临床实验室里实行，这与 FDA 的GLP 要求相一致

1） Preparation of ANDA package for submission  ANDA 申请提交文件的准备

① CTD-format should be used for preparation of an ANDA  以 CTD  格式来准备 ANDA 申请