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1、I摘 要研究背景：随着药品管理法规的要求不断加强，所有欧盟成员国的制药企业都必须要遵守对进口原料药的法规，目前没有取得CEP证书或未获得EDMF批准的原料药将很难进入欧盟市场。申请CEP认证，是生产商能主动采取的化学原料药进入欧洲市场的方式之一。EDQM CEP申报文件采用 “两轮”评审的原则，对申报文件的质量提出了要求，其重点在于对所申报生产工艺的科学理解。制药工业界指南ICH Q11 正式发布，明确了对ICH M4Q CTD 文件中原料药相关的开发和制造方面包括杂质降低的步骤设计，在申报文件中引入了QbD的理念。研究内容：结合 CEP 认证工作实践，分析 QbD 的理念在药品注册文件中的体
2、现。研究方法：本文通过搜集、归纳分析 EDQM 颁布的三年 CEP 申报文件首次评审十大典型缺陷，总结分析典型缺陷发生的原因，从中明确 CEP 申报文件中引入了QbD 的理念。运用列举法以盐酸曲马多 CEP 申报为例分析 QbD 理念在注册申报文件中应用：识别原料中可能存在的杂质来源及去除方法；运用风险管理工具进行风险识别，确定申报产品的关键质量属性。研究结果：在 CEP 申报文件中对生产工艺的科学理解体现了 QbD 的理念，这些都反应在 CEP 申报文件中。CEP 申报文件的申报质量取决于对产品工艺的理解程度。研究结论：CEP 申报文件即通用技术文件（CTD）的设计中引入了 QbD 的理念，
3、只有在对申报产品的工艺有了科学、充分的认识后才能在申报文件中体现出来，才能有的放矢，提交充分的支持性材料来证明产品的质量可控，以满足评审专家的评审要求，顺利通过评审。关键词：原料药；质量源于设计；CEP 文件评审IIStudy on Implementation of Quality by Design in API Registration Study Based on Tramadol HCl CEP ApplicationBackground: With the tightening of pharmaceutical regulations, all the pharmaceutica
4、l companies in EU should follow the regulations for imported APIs used in their finished drug products. Without CEP or approval from EDMF, importing API to the EU markets can be very difficult.CEP application is one of the routines that API manufacturer can actively take to enter into EU markets. ED
5、QM adopts “Two cycle review” policy for the CEP application dossier, which focus on the scientific understanding of the submitted manufacturing process. ICH Q11 guideline has clarified impurity reduction steps in the process development and manufacturing of API, the first time of the concept of “Qua
6、lity by Design” used in the registration application documents.Content: This paper is based on the practices to analysis the reflection of QbD concept in the CEP application dossier.Method: In this paper, the author collected and summarized the “Top ten deficiencies” published in EDQM website from 2
7、006 to 2011, analyzed the reasons that lead to the deficiencies, and emphasized the importance of QbD concept in the CEP submission dossier. In the paper, the author took an example of Tramadol HCl CEP application, which received the deficiencies from EDQM. Based on the deficiencies adopted the QbD
8、concept in understanding the process and controls, to identify the sources of impurities and establish methods of removing those impurities. Risk analysis tool were also used in the evaluation of the risks and the critical product attributes.Result: The demonstration of scientifically understanding
9、of the process reflects the concept of QbD, which in turn will be reflected in the CEP application dossiers. The quality of the CEP application dossier is depends on the understanding of process.Conclusion: QbD concept should be build into CEP application. Only after manufacturer fully understand th
10、e product process and the science behind it, then the quality dossier of CEP can be prepared in satisfactory supported with relevant information showing IIIassurance that the quality product is under control. Only if all the information reviewers looking for are readily available in the CEP dossiers
11、, review process can be made easier and pass successfully. Keywords: API (Active Pharmaceutical Ingredient), Quality by Design, CEP Dossier ReviewI目录第一章 序言 .31.1 质量源于设计背景介绍 .31.2 注册申报文件的质量反应药物研发过程中 QBD 的运用程度 .4第二章 CEP 认证基本信息介绍 .82.1 CEP 认证基本介绍 .82.1.1 CEP 认证程序 .82.1.2 CEP 申报文件简介 .102.2 CEP 申报文件典型缺陷分析及法规要求 .132.2.1 化学原料药 CEP 申报典型缺陷分析 .142.2.2 化学原料药 CEP 申报杂质控制方面的法规要求 .18第三章 . 通过盐酸曲马多 CEP 申报文件分析 QBD 在注册中的应用 .243.1 盐酸曲马多 CEP 申报文件相关信息 .243.1.1 盐酸曲马多基本信息 .243.1.2 盐酸曲马多工艺概述 .243.1.3 盐酸曲马多 CEP 首次评审结果相关信息 .263.2 从 CEP 首次评审缺陷分析 QBD 理念在注册文件中的应用 .
