人用药所用辅料的GMP水平确定用正式风险评估指南

人用药所用辅料的GMP水平确定用正式风险评估指南Guidelinesof 19 March 2015on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for humanuse(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.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 riskmanagement 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 thoselisted 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, 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：•transmissible spongiform encephalopathy;TSE风险•potential for viral contamination;病毒污染的可能性•potential for microbiological or endotoxin/pyrogen contamination;微生物或内毒素/热原污染可能性•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;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•sterility assurance for excipients claimed to be sterile;声明无菌的辅料的无菌保证•potential for any impurities carried over from other processes, in absence of dedicated equipment and/or facilities;非专用设备和/或设施中其它工艺带入任何杂质的可能性•environmental control and storage/transportation conditions including cold chain management, if appropriate;环境控制和存贮运输条件，适当时包括冷链管理•supply chain complexity;供应链复杂程度•stability of excipient;辅料稳定性•packaging integrity evidence.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：•the pharmaceutical form and use of the medicinal product containing the excipient;含有辅料的药品剂型和药品的用途•the function of the excipient in the formulation, e.g. lubricant in a tablet product or preservative material in a liquid formulation, etc.;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•the proportion of the excipient in the medicinal product composition;辅料在药品成分中的所占比例•daily patient intake of the excipient;患者日摄入辅料量•any known quality defects/fraudulent adulterations, both globally and at a local company level related to the excipient;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•whether the excipient is a composite;辅料是否是一种组分•known or potential impact on the critical quality attributes of the medicinal product;对药品关键质量属性的已知或潜在的影响•other factors as identified or known to be relevant to assuring patient safety.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 ActiveSubstances 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。