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1、Impurities In New Drug Substances新原料药中的杂质INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USEICH Harmonised Tripartite GuidelineImpurities In New Drug SubstancesQ3A(R2)Current Step 4 versiondated 25 October 2006This Guideline has been
2、developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA.Q3A(R2)Document
3、 HistoryFirst CodificationHistoryDateNew CodificationNovember 2005Q3Approval by the Steering Committee under Step 2 and release for public consultation.15March 1994Q3AQ3AApproval by the Steering Committee under Step 4 and recommendation for adoption to the three ICH regulatory bodies.Q3 was renamed
4、Q3A.30March 1995Q3AQ3A(R)Approval by the Steering Committee of the first Revision under Step 2 and release for public consultation.7October 1999Q3A(R1)Q3A(R)Approval by the Steering Committee of the first Revision under Step 4 and recommendation for adoption to the three ICH regulatory bodies.6 Febr
5、uary 2002Q3A(R1)Current Step 4 versionQ3A(R2)Approval by the Steering Committee of the revision of the Attachment 2 directly under Step 4 without further public consultation.25 October 2006Q3A(R2)Impurities In New Drug SubstancesICH Harmonised Tripartite GuidelineHaving reached Step 4 of the ICH Pro
6、cess at the ICH Steering Committee meeting on 7 February 2002, this guideline is recommended for adoption to the three regulatory parties to ICH.Attachment 2 has been revised on 25 October 2006.TABLE OF CONTENTS1.PREAMBLE12.CLASSIFICATION OF IMPURITIES13.RATIONALE FOR THE REPORTING AND CONTROL OF IM
7、PURITIES23.1Organic Impurities23.2Inorganic Impurities43.3Solvents44.ANALYTICAL PROCEDURES45.REPORTING IMPURITY CONTENT OF BATCHES56.LISTING OF IMPURITIES IN SPECIFICATIONS67.QUALIFICATION OF IMPURITIES88.GLOSSARY9ATTACHMENT 113ATTACHMENT 214ATTACHMENT 315Impurities In New Drug Substances新原料药中的杂质1.P
8、REAMBLE 序言This document is intended to provide guidance for registration applications on the content and qualification of impurities in new drug substances produced by chemical syntheses and not previously registered in a region or member state. It is not intended to apply to new drug substances use
9、d during the clinical research stage of development. The following types of drug substances are not covered in this guideline: biological/biotechnological, peptide, oligonucleotide, radiopharmaceutical, fermentation product and semi-synthetic products derived therefrom, herbal products, and crude pr
10、oducts of animal or plant origin. 本文件旨在为化学合成的新原料药（这些新原料药尚未在任何地区或成员国注册）在注册申请时，对其杂质的含量和界定的申报提供指导。本报导原则不适用于临床研究期间所用的新原料药。本文件不涵盖生物生物制品、肽、寡聚核苷酸。放射性药物、发酵和半合成产品、草药以及来源于动、植物的粗制品。Impurities in new drug substances are addressed from two perspectives: 新原料药中的杂质分两个方面阐述：Chemistry Aspects include classification an
11、d identification of impurities, report generation, listing of impurities in specifications, and a brief discussion of analytical procedures; and化学方面：包括对杂质的分类和鉴定、杂质生成、规范中杂质的检查项目以及对分析方法的简要讨论。Safety Aspects include specific guidance for qualifying those impurities that were not present, or were present
12、 at substantially lower levels, in batches of a new drug substance used in safety and clinical studies. 安全性方面：对用于安全性研究和临床研究的新原料药批次中不存在或含量很低的那些杂质的界定的指南。2.CLASSIFICATION OF IMPURITIES 杂质的分类Impurities can be classified into the following categories: 杂质可分为下列类型: Organic impurities (process- and drug-rela
13、ted) 有机杂质（与工艺和药物有关的） Inorganic impurities 无机杂质 Residual solvents 残留溶剂Organic impurities can arise during the manufacturing process and/or storage of the new drug substance. They can be identified or unidentified, volatile or non-volatile, and include:有机杂质可能会在新原料药的生产过程和（或）储存期间有所增加。这些杂质可能是已确定的或者是未确定的、
14、挥发性的或者非挥发性的。它包括： Starting materials 起始物 By-products 副产物 Intermediates中间体 Degradation products降解产物 Reagents, ligands and catalysts试剂、配位体、催化剂Inorganic impurities can result from the manufacturing process. They are normally known and identified and include:无机杂质可能来源于生产过程，它们一般是已知的和确定的。包括： Reagents, ligan
15、ds and catalysts 试剂、配位体、催化剂 Heavy metals or other residual metals 重金属或其他残留金属 Inorganic salts 无机盐 Other materials (e.g., filter aids, charcoal) 其他物质（例如：过滤介质、活性炭等）Solvents are inorganic or organic liquids used as vehicles for the preparation of solutions or suspensions in the synthesis of a new drug substance. Since these are generally of known toxicity, the selection of appropriate controls is easily accomplished (see ICH Guideline Q3C on Residual Solvents).溶剂是在新原料药合成过程中用于制备溶液或混悬液的有机或无机液体，由于它们
