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Guidelines

of 19 March 2015

on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for

excipients of medicinal products for human use

人用药所用辅料的 GMP 水平确定用正式风险评估指南

(Text with EEA relevance)

(2015/C 95/02)

Introduction 概述

These guidelines are based on the fifth paragraph of Article 47 of Directive 2001/83/EC (1).
这些指南是基于指令 2001/83/EC(1)第 47 条款第 5 段落的。

According to the second paragraph of Article 46(f) of Directive 2001/83/EC, the manufacturing authorisation
holder is required to ensure that the excipients are suitable for use in medicinal products by ascertaining what
the appropriate good manufacturing practice (GMP) is. The appropriate GMP for excipients of medicinal
products for human use shall be ascertained on the basis of a formalised risk assessment in accordance with
these guidelines. The risk assessment shall take into account requirements under other appropriate quality
systems as well as the source and intended use of the excipients and previous instances of quality defects. The
manufacturing authorisation holder shall ensure that the appropriate GMP ascertained is applied. The
manufacturing authorisation holder shall document the measures taken.
根据指令 2001/83/EC(1)第 46(f)条款第 2 段，生产许可持有人应保证辅料适用于其在药品中的用途，确认怎样
的 GMP 是适当的。人药用辅料适当的 GMP 应根据这些指南，基于正式的风险评估进行确定。风险评估应考
虑在其它适当质量体系下的要求，以及辅料来源和辅料用途，和之前的质量缺陷情况。生产许可持有人应保
证所确定的适当的 GMP 是适用的。生产许可持有人应记录所采取的措施。

The excipient risk assessment/risk management procedure should be incorporated in the pharmaceutical quality
system of the manufacturing authorisation holder.
辅料风险评估/风险管理程序应结合在生产许可持有人的药品质量体系中。

Manufacturing authorisation holders should have the risk assessment/management documentation for
appropriate GMP for excipients available on site for review by GMP inspectors. Consideration should be given to
sharing relevant information from the risk assessment with the excipient manufacturer to facilitate continuous
improvement.

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生产许可持有人应有针对辅料所用的适当的 GMP 要求的风险评估/管理文件记录，并能提供能 GMP 审核人员

审核。应考虑与辅料生产商共享风险评估所产生的相关信息，以促进持续改进。

A risk assessment as set out in these guidelines should be carried out for excipients for authorised medicinal
products for human use by 21 March 2016.
自 2016 年 3 月 21 日起，人用上市药品用的辅料应实施这些指南中要求的风险评估。

CHAPTER 1 — SCOPE
第 1 章---范围

These guidelines apply to the risk assessment for ascertaining the appropriate GMP for excipients for medicinal
products for human use. According to Article 1(3b) of Directive 2001/83/EC, an excipient is any constituent of a
medicinal product other than the active substance and the packaging material.
这些指南适用于风险评估，来评价应用适当的 GMP 于人用药所用辅料管理。根据指令 2001/83/EC 的第 1(3b)
条款，一种辅料是药品中除活性物质和包装材料外任意的组成部分。

These guidelines do not cover substances added to stabilise active substances that cannot exist on their own.
这些指南不涵盖添加入药品中用于那些不能单独存在，而需要在活性物质中添加稳定剂来使活性物质稳定的
成份。

CHAPTER 2 — DETERMINATION OF APPROPRIATE GMP BASED ON TYPE AND USE OF EXCIPIENT

第 2 章---基于辅料类型和用途的适当的 GMP 决策

In EudraLex Volume 4, Guidelines for Good Manufacturing Practice, Medicinal Products for Human and
Veterinary Use, Part III: GMP related documents, ICH guideline Q9 on Quality Risk Management (ICH Q9),
principles and examples of tools for quality risk management that can be applied to different aspects of
pharmaceutical quality, including excipients, can be found.
在欧盟药品法卷 4，人用和兽用药品 GMP 指南，第 3 部分，GMP 相关文件，ICH 指南 Q9 质量风险管理中，
可以找到能应用于药品质量，包括辅料，不同方面的质量风险管理的原则和工具实例。

These quality risk management principles should be used to assess the risks presented to the quality, safety and
function of each excipient and to classify the excipient in question, e.g. as low risk, medium risk or high risk.
Quality risk management tools such as those listed in EudraLex Volume 4, Part III, ICH Q9 (e.g. hazard analysis
and critical control points — HACCP) should be used for this purpose.
这些质量风险管理原则应用于评估每种辅料所呈现的质量、安全和功能方面的风险

For each excipient from each manufacturer used, the manufacturing authorisation holder should identify the
risks presented to the quality, safety and function of each excipient from its source — be that animal, mineral,

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vegetable, synthetic, etc. — through to its incorporation in the finished pharmaceutical dose form. Areas for
consideration should include, but are not limited to:
来自于每个生产商的每种辅料，生产许可持有人应从其来源---动物、矿物、植物、合成等-----识别每种辅料的
质量、安全和功能风险，通过其结合于制剂成品的方式。要考虑的内容应包括但不仅限于：
o transmissible spongiform encephalopathy;
o TSE 风险
o potential for viral contamination;
o 病毒污染的可能性
o potential for microbiological or endotoxin/pyrogen contamination;
o 微生物或内毒素/热原污染可能性
o potential, in general, for any impurity originating from the raw materials, e.g. aflatoxins or pesticides, or
generated as part of the process and carried over, e.g. residual solvents and catalysts;
o 原料中产生的任何杂质存在的可能性，例如，黄曲霉素或杀虫剂，或作为工艺一部分产生和带入的杂质，
例如，残留溶剂和催化剂
o sterility assurance for excipients claimed to be sterile;
o 声明无菌的辅料的无菌保证
o potential for any impurities carried over from other processes, in absence of dedicated equipment and/or
facilities;
o 非专用设备和/或设施中其它工艺带入任何杂质的可能性
o environmental control and storage/transportation conditions including cold chain management, if
appropriate;
o 环境控制和存贮运输条件，适当时包括冷链管理
o supply chain complexity;
o 供应链复杂程度
o stability of excipient;
o 辅料稳定性
o packaging integrity evidence.
o 包装完整性证据

Additionally, with respect to the use and function of each excipient, the manufacturing authorisation holder
should consider:
另外，关于每种辅料的使用和功能，生产许可持有人应考虑：
o the pharmaceutical form and use of the medicinal product containing the excipient;
o 含有辅料的药品剂型和药品的用途
o the function of the excipient in the formulation, e.g. lubricant in a tablet product or preservative material in
a liquid formulation, etc.;
o 辅料在制剂中的功能，例如，片剂产品中的润滑剂或液体制剂中的防腐剂等
o the proportion of the excipient in the medicinal product composition;

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o 辅料在药品成分中的所占比例
o daily patient intake of the excipient;
o 患者日摄入辅料量
o any known quality defects/fraudulent adulterations, both globally and at a local company level related to
the excipient;
o 全球范围或当地公司范围与辅料有关的所有已知的质量缺陷/造假情况
o whether the excipient is a composite;
o 辅料是否是一种组分
o known or potential impact on the critical quality attributes of the medicinal product;
o 对药品关键质量属性的已知或潜在的影响
o other factors as identified or known to be relevant to assuring patient safety.
o 识别的或已知的与保证患者安全相关的其它因素

Having established and documented the risk profile of the excipient, the manufacturing authorisation holder
should establish and document the elements of EudraLex Volume 4 that he believes are needed to be in place in
order to control and maintain the quality of the excipient, e.g. Annex 1 or/and Annex 2; Part II: Basic
Requirements for Active Substances used as Starting Materials.
在建立和记录辅料的风险概况之后，生产许可持有人应建立和记录欧盟药品法第 4 卷的要素，这些要素应是
公司认为其为控制和维护辅料质量所必须的，例如附录 1 和/或附录 2，第 2 部分用作起始物料的活性物质的基
本要求。

These elements will vary depending on the source, the supply chain and the subsequent use of the excipient,
but as a minimum the following high level GMP elements should be considered by the manufacturing
authorisation holder:
这些要素会根据辅料的来源、供应链和随后的使用而不同，但生产许可持有人最少应考虑以下水平的 GMP 要
素：
o establishment and implementation of an effective pharmaceutical quality system;
o 建立和实施有效的药品质量体系
o sufficient competent and appropriately qualified personnel;
o 具备充足的具备适当资质的人员
o defined job descriptions for managerial and supervisory staff responsible for manufacturing and quality
activities;
o 对生产和质量活动定义管理人员和主管员工的岗位职责
o training programmes for all staff involved in manufacturing and quality activities;
o 所有涉及生产和质量活动的员工的培训程序
o training programmes related to health, hygiene and clothing as identified as necessary to the intended
operations;
o 健康、卫生和更衣有关的培训程序，必要时应识别适用于其既定操作

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o provision and maintenance of premises and equipment appropriate to the intended operations;
o 设施和设备的结构和维护适合于其既定操作
o documentation system(s) covering all processes and specifications for the various manufacturing and
quality operations;
o 文件记录体系覆盖所有不同生产和质量操作的加工和质量标准
o systems for coding and identifying starting materials, intermediates and excipients to allow full traceability;
o 起始物料、中间体和辅料的编码和识别系统可以进行全程追踪
o qualification program of suppliers;
o 供应商确认程序
o system for quality control of the excipient and a responsible person independent from production to
release the batches;
o 有系统对辅料进行质量控制，有一个责任人独立于生产以外来放行批次
o retention of records for incoming materials and excipients and retention of samples of excipients for the
periods required by EudraLex Volume 4, Part II;
o 进厂物料和辅料记录应保存，辅料留样时间应符合欧洲药品法第 4 卷第二部分 y 要求
o systems to ensure that any activity contracted out is subject to a written contract;
o 系统保证所有外包活动都有书面合同
o maintenance of an effective system whereby complaints are reviewed and excipients may be recalled;
o 有效系统的维护，客诉进行审核，辅料可能被召回
o change management and deviation management system;
o 变更管理和偏差管理系统
o self-inspection program;
o 自检程序
o environmental control and storage conditions.
o 环境控制和存贮条件

CHAPTER 3 — DETERMINATION OF EXCIPIENT MANUFACTURER’S RISK PROFILE

第 3 章---确定辅料生产的风险概况

After determination of the appropriate GMP, a gap analysis of the required GMP against the activities and
capabilities of the excipient manufacturer should be performed.
在确定了适当的 GMP 后，应针对辅料生产商的活动和能力进行所要求的 GMP 的差距分析。

Data/evidence to support the gap analysis should be obtained through audit or from information received from
the excipient manufacturer.
用以支持差距分析的数据/证据应通过审计获得，或从辅料生产商处收到的信息获得。

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Certification of quality systems and/or GMP held by the excipient manufacturer and the standards against which
these have been granted should be considered as such certification may fulfil the requirements.
质量体系的证书和/或辅料生产商持有的 GMP 证书，和颁发证书所依据的标准应进行考虑，因为该认证可能满
足这些要求。

Any gaps identified between the required GMP and the activities and capabilities of the excipient manufacturer
should be documented. Furthermore, the manufacturing authorisation holder should perform a further risk
assessment to determine the risk profile, e.g. low risk, medium risk or high risk, for that excipient manufacturer.
EudraLex Volume 4, Part III, ICH Q9 should be used for that purpose. Quality risk management tools such as
those listed there — HACCP etc. — should be used for this.
所识别出的 GMP 要求和辅料生产商的活动与能力之间的差距应进行记录。另外，生产许可持有人应实施进一
步风险评估，以决定该辅料生产商的风险概况，例如，低风险、中等风险或高风险。欧盟药品法第 4 卷，第 3
部分，ICHQ9 应用于此目的。质量风险管理工具，例如列于其中的那些----HACCP 等-----应用于此。

The manufacturing authorisation holder should have a series of strategies ranging from acceptance through
control to unacceptable for the different risk profiles and based on these a control strategy, e.g. audit,
document retrieval and testing, should be established.
生产许可持有人应制订有一系列的策略，对不同风险概况从可接受到控制到不可接受。基于这些，应建立一
种控制策略，例如，审计，文件恢复和检测。

CHAPTER 4 — CONFIRMATION OF APPLICATION OF APPROPRIATE GMP

第 4 章----适当 GMP 的申请确认

Once the appropriate GMP for the excipient and the risk profile of the excipient manufacturer have been
defined, ongoing risk review should be performed through mechanisms such as:
一旦定义了该辅料适用的 GMP，以及辅料生产商的风险概况，后续应通过一定机制进行持续风险评估，如：
o number of defects connected to batches of excipient received;
o 与收到的辅料批次相卷边的缺陷的数量
o type/severity of such defects;
o 这些缺陷的类型和严重程度
o monitoring and trend analysis of excipient quality;
o 辅料质量监控和趋势分析
o loss of relevant quality system and/or GMP certification by excipient manufacturer;
o 相关质量体系的缺失和/或辅料生产商持有的 GMP 证书
o observation of trends in drug product quality attributes; this will depend on the nature and role of
excipient;
o 药品质量属性的趋势观察，这些将取决于辅料的属性和作用
o observed organisational, procedural or technical/process changes at the excipient manufacturer;

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o 观察到的辅料生产商的组织性的、程序性的或技术性的/工艺变更
o audit/re-audit of excipient manufacturer;
o 对辅料生产商进行审计/复审
o questionnaires.
o 问卷

Based on the outcome of the risk review, the established control strategy should be reviewed and revised if
needed.
基于风险审核的结果，应对已建立的控制策略进行审核，并在必要时进行修订。

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