人用药品注册技术要求国际协调会
ICH H ARMONISED G UIDELINE
ICH 协调指导原则
杂质：残留溶剂的指导原则 Q3C(R6)
最终版本
2016年 10 月 20日
本指导原则由相应的ICH 专家工作组制定，并根据ICH 进程已提交给管理当局征询意见。在ICH 进程的第四阶段，最后的草案被推荐给欧盟、日本、美国、加拿大和瑞士的管理机构采纳。
Q3C（R6）文件历史
母指导原则：杂质：残留溶剂的指导原则
对母指导原则所含THF的PDE信息的修订
修订母指导原则所含NMP的PDE信息
母指导原则：杂质：残留溶剂的指导原则
对母指导原则所含异丙基苯的PDE信息的修订
修订母指导原则所含甲基异丁基酮的PDE
信息，并纳入三乙胺的PDE
乙二醇PDE修正
I MPURITIES: G UIDELINE FOR R ESIDUAL S OLVENTS
杂质：残留溶剂的指导原则
TABLE OF CONTENTS目录
PART I:IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS (4)
第一部分：杂质：残留溶剂的指导原则 (4)
1.INTRODUCTION引言 (4)
2.SCOPE OF THE GUIDELINE 指导原则的适用范围 (5)
3.GENERAL PRINCIPLES通则 (6)
3.1Classification of Residual Solvents by Risk Asssment基于风险评估的残留溶剂的分类 (6)
3.2 Methods for Establishing Exposure Limits 建立暴露限度的方法 (6)
3.3 Options for Describing Limits of Class 2 Solvents 2 类溶剂限度的表示方法 (7)
3.4 Analytical Procedures分析方法 (9)
3.5 Reporting levels of residual solvents残留溶剂的报告水平 (9)
4.LIMITS OF RESIDUAL SOLVENTS 残留溶剂的限度 (10)
4.1 Solvents to Be Avoided应避免的溶剂 (10)
4.2 Solvents to Be Limited应限制的溶剂 (10)
4.3 Solvents with Low Toxic Potential低潜在毒性的溶剂 (12)
4.4 Solvents for which No Adequate Toxicological Data was Found 没有足够毒理学数据的溶剂 (13)
GLOSSARY术语 (14)
APPENDIX 1. LIST OF SOLVENTS INCLUDED IN THE GUIDELINE附录 1：指导原则中包括的溶剂列
表 (15)
APPENDIX 2. ADDITIONAL BACKGROUND附录 2：其他背景 (18)
APPENDIX 3. METHODS FOR ESTABLISHING EXPOSURE LIMITS附录 3：建立暴露限度的方法 (19)
PART II:IMPURITIES: RESIDUAL SOLVENTS (MAINTENANCE)PDE FOR TETRAHYDROFURAN第二部分：杂质：残留溶剂（修订）四氢呋喃的 PDE (23)
PART III:IMPURITIES : RESIDUAL SOLVENTS (MAINTENANCE) PDE FOR N-METHYLPYRROLIDONE (NMP) 第三部分：杂质：残留溶剂（修订）N-甲基吡咯烷酮（NMP）的 PDE25 PART IV:IMPURITIES : RESIDUAL SOLVENTS (MAINTENANCE) PDE FOR CUMENEICH Harmonid Tripartite Guideline第四部分：杂质：残留溶剂（修订）异丙基苯的 PDE (27)
PART V:IMPURITIES : RESIDUAL SOLVENTS (MAINTENANCE)PDE FOR TRIETHYLAMINE AND PDE OF METHYLISOBUTYLKETONE第五部分：杂质：残留溶剂（修订）三乙胺的 PDE 和甲基异丁
基酮的 PDE (31)
PART I:IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS
第一部分：杂质：残留溶剂的指导原则
Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 17 July 1997, this Guideline is recommended for adoption to the three regulatory parties to ICH
在 1997 年 7 月 17 日的 ICH 指导委员会会议上进入 ICH 进程第四阶段，
并建议 ICH 的三方监管机构采纳该指导原则
1.INTRODUCTION引言
The objective of this guideline is to recommend acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. The guideline recommends u of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents.
本指导原则旨在建议为保证患者安全而应规定的药物中残留溶剂的可接受量。本指导原则建议使用低毒的溶剂，并阐述了一些残留溶剂在毒理学上的可接受水平。
Residual solvents in pharmaceuticals are defined here as organic volatile chemicals that are ud or produced in the manufacture of drug substances or excipients, or in the preparation of drug products. The solvents are not completely removed by practical manufacturing techniques. Appropriate lection of the solvent for the synthesis of drug substance may enhance the yield, or determine characteristics such as crystal form, purity, and solubility. Therefore, the solvent may sometimes be a critical parameter in the synthetic process. This guideline does not address solvents deliberately ud as excipients nor does it address solvates. However, the content of solvents in such products should be evaluated and justified.药物中的残留溶剂在此定义为在原料药或辅料的生产中以及制剂制备过程中使用或产生的有机挥发性化合物。这些溶剂在实际生产技术中不能完全除去。
选择适当的溶剂合成原料药可提高收率或决定药物的性质，如晶型、纯度和溶解度。因此，溶剂有时可能是合成工艺的关键因素。本指导原则并不针对特意用作辅料的溶剂，也不针对溶剂化物。然而这些制剂中的溶剂也应进行评价，并论证其合理性。
Since there is no therapeutic benefit from residual solvents, all residual solvents should be removed to the extent possible to meet product specifications, good manufacturing practices, or other quality-bad requirements. Drug products should contain no higher levels of residual solvents than can be supported by safety data. Some solvents that are known to cau unacceptable toxicities (Class 1, Table 1) should be avoided in the production of drug substances, excipients, or drug products unless their u can be strongly justified in a risk-benefit asssment. Some solvents associated with less vere toxicity (Class 2, Table 2) should be limited in order to protect patients from potential adver effects. Ideally, less toxic solvents (Class 3,Table 3) should be ud where practical. The complete list of solvents included in this guideline is given in Appendix 1.
由于残留溶剂没有治疗益处，故应尽可能除去所有残留溶剂，以符合制剂质量标准、生产质量管理规范（GMP）或其他质量要求。制剂的残留溶剂量不应高于安全性数据可支持的水平。除非在风险-收益评估中强有力地论证了使用这些溶剂的合理性，否则在生产原料药、辅料或制剂时，应避免一些已知会引起不可接受的毒性的溶剂（1 类，表1）。对于一些毒性较不严重的溶剂（2 类，表
2），应进行限制，以防止患者出现潜在的不良反应。如切合实际，应尽可能使用低毒溶剂（3 类，表 3）。附录 1 中列出了本指导原则涵盖的全部溶剂。
The lists are not exhaustive and other solvents can be ud and later added to the lists. Recommended limits of Class 1 and 2 solvents or classification of solvents may change as new safety data becomes available. Supporting safety data in a marketing application for a new drug product containing a new solvent may be bad on concepts in this guideline or the concept of qualification of impurities as expresd in the guideline for drug substance (Q3A, Impurities in New Drug Substances) or drug product (Q3B, Impurities in New Drug Products), or all three guidelines.
表中所列溶剂并非详尽无遗，可使用其他溶剂并在日后补充到该列表中。第1、2 类溶剂的建议限度或溶剂分类可能会在得到新的安全性数据时变更。含有新溶剂的新制剂其上市申请的支持性安全性数据应符合本指导原则或原料药指导原则（Q3A，新原料药中的杂质）或制剂指导原则（Q3B，新药制剂中的杂质）中所述的杂质控制原则，或者同时符合上述三者。
2.SCOPE OF THE GUIDELINE 指导原则的适用范围
Residual solvents in drug substances, excipients, and in drug products are within the scope of this guideline. Therefore, testing should be performed for residual solvents when production or purificatio
n process are known to result in the prence of such solvents. It is only necessary to test for solvents that are ud or produced in the manufacture or purification of drug substances, excipients, or drug product. Although manufacturers may choo to test the drug product, a cumulative method may be ud to calculate the residual solvent levels in the drug product from the levels in the ingredients ud to produce the drug product. If the calculation results in a level equal to or below that recommended in this guideline, no testing of the drug product for residual solvents need be considered. If, however, the calculated level is above the recommended level, the drug product should be tested to ascertain whether the formulation process has reduced the relevant solvent level to within the acceptable amount. Drug product should also be tested if a solvent is ud during its manufacture.
本指导原则的范围包括原料药、辅料和制剂中所含的残留溶剂。因此，当已知生产或纯化工艺中会出现这些溶剂时，应进行残留溶剂检查。且仅有必要对原料药、辅料或制剂的生产或纯化中使用或产生的溶剂进行检查。生产商可选择检验制剂，也可根据制剂生产所用的各成分的残留溶剂水平，累积计算出制剂中残留溶剂整体水平。如果算出的结果等于或低于本指导原则建议的水平，则不需考虑对制剂进行该残留溶剂检查。但如果计算结果高于建议水平，则应对制剂进行检验，以确定制剂工艺是否将有关溶剂的量降至可接受水平。如果制剂生产中用到某种溶剂，也应对制剂进行检验。
This guideline does not apply to potential new drug substances, excipients, or drug products ud during the clinical rearch stages of development, nor does it apply to existing marketed drug products.
本指导原则不适用于临床研究开发阶段所使用新原料药、辅料和制剂，也不适用于已上市的制剂。
The guideline applies to all dosage forms and routes of administration. Higher levels of residual solvents may be acceptable in certain cas such as short term (30 days or less) or topical application. Justification for the levels should be made on a ca by ca basis.
