API混合物和CEP程序：要考虑哪些？

API mixtures and CEP Procedure: What should be considered?

API混合物和CEP程序：要考虑哪些？

In some cases, it is necessary to produce APIs not in pure form, but as a mixture. Among others, easier manageability or API stability can be a reason for that. Chlorhexidine digluconate in aqueous solution, a clavulanate potassium auxiliary mixture or simvastatin blended with an antioxidant are typical examples. In April 2016, the QWP of the EMA published a Q and A document entitled "Quality Working Party questions and answers on API mix" (EMA/CHMP/CVMP/QWP/152772/2016) on this issue. It clarifies how these API mixes are to be handled in an ASMF or CEP procedure during an authorisation. We had reported about this in our news "Quality Documentation of API mix in the Marketing Authorisation Procedure".

有些时候，API需要采用混合方式生产。原因有可能是为了易于管理，或者是因为API的稳定性。水溶液中的葡萄糖酸氯己定、克拉维酸钾混合物以及辛伐他汀与抗氧剂混合是典型的例子。2016年4月，EMA的QWP发布了一份关于此问题的题为“API混合物的QWP问答”（EMA/CHMP/CVMP/QWP/152772/2016）的文件。其中澄清了这些API混合在ASMF或CEP程序中要如何处理。我们已经在我们的新闻中进行了报道。

In December 2016, the EDQM published a "Public Document" called "API-Mix (or mixtures) and CEPs" (PA/PH/CEP (16) 70). This document describes the procedure of applying for a CEP for API mixtures.

2016年12月，EDMQ发布了一份公开文件，题为“API混合物和CEP”（PA/PH/CEP (16) 70）。该文件描述了API混合物的CEP适用程序。

An application for a CEP for an API mix must contain at least the following information:

一个API混合物的CEP申报必须包括至少以下信息：

• Information on the mixing process, on qualitative/quantitative composition and on the control strategy
• 混合工艺的信息，关于组分的定性/定量信息以及控制策略
• Supporting data on the choice and amount of the excipient, unless already covered by the pharmacopoeial monograph itself
• 辅料品种和数量选择的支持性数据，已经在药典各论中覆盖者除外
• Supporting data on the choice and amount of the excipient, if these are allowed according to the monograph but not defined in any more detail ("...a suitable antioxidant may be added ..."). must be observed. Additional data (stability data e.g.) are required for changes in the content of the antioxidant and in the impurity profile of the mix. The EMA guideline provisions "Excipients in the dossier for application for marketing authorisation of a medicinal product" (EMEA/CHMP/QWP/396951/2006)
• 辅料品种和数量选择的支持性数据，如果根据各论是允许加入，但并没有任何细节规定（“……可以添加适当的抗氧剂……”）。如果在混合物的杂质概况或抗氧剂的数量上有变化，则需要提供额外数据（例如稳定性数据）。EMA指南条款“药品上市批准申报资料中的辅料”（EMEA/CHMP/QWP/396951/2006）
  

A CEP for an API mix contains the following information (unless already contained in the pharmacopoeial monograph):

API混合物的CEP包括有以下信息（已经包括在药典各论中的除外）：

• designation of the excipient(s) used and their amount
• 所用辅料的用途及其数量
• in case of antioxidant, a validated test method for its control (as an annex to the CEP)
• 如果使用了抗氧剂，对其进行控制所用经过验证的检验方法（作为CEP的附件）
• information on the labelling of the mixture, if the monograph contains a paragraph on labeling
• 如果各论中包括有关于标签的段落，则需要有混合物标签信息
  

As of 1 December 2016, a CEP is generally granted for an API mix if the excipient used is listed in the "Definition" paragraph of the pharmacopoeia. If the mixture does not comply with the monograph regarding qualitative and/or quantitative composition, the application for a CEP will be refused.

自2016年12月1日起，如果所用辅料已经列在药典的“定义”段落中，通常会为该API混合物颁发CEP。如果混合物不符合各论中定性和/或定量组分的要求，则该CEP申报会被拒绝。

来源：julia