PA/PH/CEP (16) 70 原料药混合物和CEP（中英）

Certification of Substances Department

FML/CB

PUBLIC DOCUMENT

(LEVEL 1)

Englishonly/Anglaisseulement

PA/PH/CEP (16) 70

Strasbourg, December 2016

  Certification of suitability to the Monographs of the European Pharmacopoeia

  API-Mix (or mixtures) and CEPs

原料药混合物和CEP

Address: 7 Allée Kastner, CS 30026  F-67081 Strasbourg (France) Tel: +33 (0) 3 88 41 30 30 – Fax: +33 (0) 3 88 41 27 71 - e-mail: cep@edqm.euInternet: http://www.edqm.eu

1.    Introduction 概述

This document describes the approach to betaken regarding applications for CEPs for API-mix, which are mixtures of drug substances (API-active pharmaceuticalingredient) with excipients, following the publication in April 2016 of Questions and Answers (Q&A) on this subject bythe Quality Working Party of the European Medicines Agency (EMA): http://www.ema.europa.eu/ema/ind ... eneral_content_0015 24.jsp&mid.

本文描述了原料药混合物申报方法。原料药混合物是原料药（API-活性药物成分）与辅料的混合物，符合EMA的质量工作组于2016年4月发布的问答（Q&A）中的定义。

These Q&A provide information on how to deal with API-mix, and to identify situations where it will be acceptable to usethe ASMF/CEP procedures and perform manufacture under EU GMP Part II (except for the manufacturing steps such assterilisation activities and the steps after sterilisation where EU GMP Part I is mandatory).

这些问答提供了如何对待原料药混合物的信息，以及如何识别出什么情况下使用ASMF/CEP程序，按EU GMP第II部分进行生产（诸如灭菌活动和灭菌之后的生产步骤除外，这些步骤是需要实施EU GMP第I部分的）是可以接受的。

Typical situations for API-mix are the addition of an antioxidant to a drug substance, or the introduction of a drugsubstance into a matrix. Drug substances in solution are also considered as API-mixes.

原料药混合物的一般情况是向原料药中添加抗氧化剂，或者是将一种原料药加入到一种基质中。原料药放在溶液中也被认为是原料药混合物。

The Q&A also clarify that where there is an existing Ph. Eur. monograph for an API-mix, a CEP can be granted.Examples are potassium clavulanate diluted (where the potassium clavulanate is mixed with an excipient), simvastatin(where there is a statement under Definition that “A suitable antioxidant may be added”) and chlorhexidinedigluconate solution where the active substance is present in aqueous solution.

问答还澄清了如果原料药混合物已有欧洲药典各论，则可以颁发CEP。这样的例子有稀释克拉维酸钾（克拉维酸钾与一种辅料混合）、辛伐他汀（在定义项中有一个声明说“可以加入适当的抗氧化剂”）和葡萄糖酸氯己定溶液（原料药在水溶液中）。

Additionally the Q&A make clear that a statement in Ph. Eur. monograph, such as "A suitable antioxidant may beadded", is considered sufficient and acceptable per se as a justification for the use of an API-mix. However, additionaljustification on the choice and level of antioxidant needs to be provided, and a control test is required for the antioxidantin the API-mix.

此外，问答还对欧洲药典各论中的声明进行了澄清，如“可以加入适当的抗氧化剂”，就足以作为使用原料药混合物的论证。当然，还是需要提交关于抗氧剂选择和数量，以及原料药混合物中抗氧剂所需的控制测试的论证，

2.    Acceptance of applications for CEPs CEP申报的接受标准

From 1 December 2016, where there is a Ph. Eur. monograph which covers an API-mix, a CEP application can beaccepted.

自2016年12月1日起，只要欧洲药典中的原料药混合物，都可以接受申报CEP。

Where the Ph. Eur. monograph describes the excipients which may be used (generally in the Definition section), themonograph requirements should be complied with in the CEP application. If the API-Mix does not meet therequirements of the monograph with regards the qualitative and/or quantitative composition, the CEP application will notbe accepted.

如果欧洲药典各论中描述了可能使用的辅料（通常是在定义部分），则在CEP申报中应符合各论要求。如果原料药混合物不符合各论中关于组份定量和/或定性的要求，则CEP申报就不会被接受。

3.    Assessment of CEP applications for API-mix 原料药混合物CEP申报评估

The CEP dossier should contain all relevant information on the mixing process, qualitative and quantitative compositionof the mixture and on the control strategy.

CEP文档应包括所有混合工艺相关信息、混合物组份定量和定性信息以及控制策略信息。

DAta supporting the choice and the amount of the excipient(s) should be provided, unless they are covered by the Ph.Eur. monograph and this also applies to the quality and amounts of antioxidants where these are allowed by themonograph but not identified (i.e. .. a suitable antioxidant may be added...). The guideline on “Excipients in thedossier for application for marketing authorisation of a medicinal product” (EMEA/CHMP/QWP/396951/2006) isapplicable; therefore the CEP application should include data to support the changes to the content of the antioxidant and the API-mix impurity profile at release and after storage (i.e. stability data).

应提交支持辅料选择和数量的数据，欧洲药典各论中已包括者除外。这同样适用于各论中允许加入抗氧剂但没有说明时（即，可以加入适当的抗氧剂……），对抗氧剂的质量和数量的数据。《药品上市许可申报文件中的辅料指南》（EMEA/CHMP/QWP/396951/2006）指南在此也适用，因此CEP申报应包括支持抗氧剂含量变更、原料药混合物在放行时和存贮后杂质概况的数据（即稳定性数据）。

A re-test period for the API-mix can be accepted, if justified. If appropriate, the stability data should include details ofthe levels of the additives such as antioxidants during the programme.

如果有论证，也可以接受原料药混合物的复验期。适当时，稳定性数据应包括计划中添加剂的添加数量的详细情况，例如抗氧剂。

4.    Information included on a CEP for API-mix 原料药混合物的CEP上所包括的信息

If there is a labelling section in the Ph. Eur. monograph, this is reflected on the CEP. The presence of an antioxidantis generally highlighted in the subtitle for the substance on the CEP.

如果在欧洲药典各论里有标签部分，则应在CEP里反映出来。如有抗氧剂，通常在CEP的物质子标题中突出显示。

The following information is mentioned on the CEP for an API-mix, unless it is already included in the Ph. Eur monograph:

除已包括在欧洲药典各论中的预混剂以外，原料药混合物的CEP上要列出以下信息：

-       The name of any excipient used

-       所用的辅料名称

-       The amount (range) of any excipient used

-       所用的全部辅料的数量（范围）

-       For the control of antioxidants, an appropriately validated control method is annexed to the CEP

-       抗氧剂控制所用的经过适当验证的控制方法要附入CEP