EMA残留溶剂指南附录.pdf
EP残留溶剂中文版
Identification and control residual solvents(残留溶剂的鉴定与控制)The test procedures described in this general method may be used:基本方法中描述的步骤可能用至：1）活性中间体（原料药），赋形剂和医药产品中的第一类、第二类不明溶剂的鉴定。
2）活性中间体（原料药），赋形剂和医药产品中的第一类、第二类溶剂的限度检测。
3）第二类溶剂大于1000ppm（0.1%）时的定量或第三类溶剂的定量。
第一、二、三类残留溶剂详见5.43种溶剂用于样品制备和顶空进样条件选择。
2种色谱体系体系A更合适而体系B常用于定性分析。
样品制备过程取决于被检测物的溶解性和一定程度上的残溶的控制。
下列残留溶剂不宜用顶空进样检测：2-乙氧基乙醇（2-ethoxyethanol）、2-甲氧基乙醇（2-methoxyethanol）、乙二醇(ethylene glycol)、甲基吡咯烷酮（NMP）(N-methylpyrrolidone)、环丁砜(sulfolane)当一种方法用于定量控制某种物质里的残留溶剂，必须对它进行验证。
方法、步骤（PROCEDURE）静态顶空气相色谱法检测（2.2.28）样品制备1.水溶性的物质残留溶剂控制样品溶液（1）将0.200g待测物溶解于水(water R)并稀释至20.0ml。
样品制备2. 非水溶性物质残留溶剂控制。
样品溶液（2）将0.200g待测物溶解于DMF（二甲基甲酰胺）并稀释至20.0ml。
样品制备 3 用于当确定或怀疑待测物质里含有N,N-二甲基乙酰胺N,N-二甲基甲酰胺中的一种或两种时的残留溶剂的控制。
样品溶液（3）将0.200g待测物溶解于DMI（1,3-二甲基-2-咪唑啉酮）并稀释至20.0ml。
如以上所列样品制备方法均不适合，制备样品溶液使用的其它溶剂和静态顶空须验证。
溶剂溶液溶剂溶液（a）1.0ml第一类残留溶剂溶液（CRS）加入9ml二甲亚砜，并用水(water R)稀释到100.0ml，用水稀释上述溶液1.0ml到100.0ml。
EMA关于API中基因毒性、金属杂质和残留溶剂的标准（中英文对照）
EMA关于API中基因毒性、金属杂质和残留溶剂的标准（中英文对照）EMA关于API中基因毒性,金属杂质和残留溶剂的标准1.What is a reasonable policy forsetting specifications for potentially genotoxic impurities which aretheoreti cal or actual impurities in a drug substance manufacturing process?HJune20121.什么是设定潜在基因毒性杂质（原料药生产工艺中理论或实际的杂质）标准的基本原则？人用药品，2012年6月Different possible scenarios can beidentified and the applicable policies to be applied for each of them arede scribed below:不同的可能情况可被划分，并且不同的适用原则对应于下面描述的各个情况：Example1–A potential genotoxicimpurity举例1—潜在基因毒性杂质The definition for a potentialgenotoxic impurity is derived from the definition for'potential impurity':animp urity that theoretically can arise during manufacture or storage.It may ormay not actually appear in the(new) drug substance(ICH Q3A,glossary).潜在基因毒性杂质的定义起源于“潜在杂质”的定义：理论上可能在生产中或贮藏中出现的杂质，它可能会或不会实际存在于（新）原料药中（ICH Q3A，术语）。
美国对残留溶剂的要求指南文件
Guidance for Industry Residual Solvents in Drug Products Marketed in theUnited StatesU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)November 2009CMCGuidance for Industry Residual Solvents in Drug Products Marketed in theUnited StatesAdditional copies are available from:Office of CommunicationDivision of Drug InformationCenter for Drug Evaluation and ResearchFood and Drug Administration10903 New Hampshire AvenueBldg. 51, rm. 2201Silver Spring, MD 20993-0002(Tel) 301-796-3400/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)November 2009CMCTABLE OF CONTENTSI.INTRODUCTION (1)II.BACKGROUND/POLICY (2)III.RECOMMENDATIONS (2)pendial Drug Products Approved Under an NDA or ANDA (2)pendial Drug Products Not Approved Under an NDA or ANDA (3)C.Non-compendial NDA or ANDA Drug Products (3)Guidance for Industry1Residual Solvents in Drug Products Marketed in the United States This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.I. INTRODUCTIONThis guidance is intended to assist manufacturers in responding to the issuance of the United States Pharmacopeia (USP) requirement2 for the control of residual solvents in drug products marketed in the United States. Specifically, this guidance makes recommendations on the following:1. How new drug application (NDA) and abbreviated new drug application (ANDA)applicants for noncompendial drug products should limit residual solvents as described in the International Conference on Harmonisation (ICH) guidance for industry Q3CImpurities: Residual Solvents (Q3C). This guidance contains recommendations onsolvent classification and permitted daily exposure.32. How manufacturers of compendial drug products that are not marketed under anapproved NDA or ANDA can comply with USP General Chapter <467> “ResidualSolvents” and the Federal Food, Drug, and Cosmetic Act (the Act).3. How holders of NDAs or ANDAs for compendial drug products should report changes inchemistry, manufacturing, and controls specifications to FDA to comply with GeneralChapter <467> and 21 CFR 314.70.For recommendations on solvent classification and permitted daily exposure, please refer to the ICH Q3C.FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are1 This guidance has been prepared by the Office of Pharmaceutical Science in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.2 USP; General Chapter <467> “Residual Solvents.”3 The levels in ICH Q3C and General Chapter <467> should also be considered for products that are not subject to an NDA or ANDA (e.g., over-the-counter monograph products).cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.II. BACKGROUNDOn July 1, 2008, the USP implemented a requirement for the control of residual solvents in drug products marketed in the United States. The requirement, General Chapter <467> “Residual Solvents,” replaced General Chapter <467> “Organic Volatile Impurities.” The effective date of this change was July 1, 2008.III. RECOMMENDATIONSFDA makes the following recommendations concerning implementation of the USP requirement General Chapter <467> “Residual Solvents.”A. Compendial Drug Products Approved Under an NDA or ANDA1.Beginning July 1, 2008, U.S. marketed drug products with an official USPmonograph were required to meet the requirements for control of residual solvents asdescribed in General Chapter <467>.4General Chapter <467> requires control of residual solvents in finished drug products. Although manufacturers may choose to test the drug product, General Chapter <467> also provides options for evaluating the active pharmaceutical ingredient and excipient components of the finished drug product for residual solvents. FDA can accept residual solvent test data on components from tests performed by the drug product manufacturer or the manufacturer may provide test data or, if applicable, appropriate statements obtained from properly qualified suppliers as described in 21 CFR 211.84(d)(2). For example, reports of analysis can be accepted from a properly qualified5 supplier of a drug product component and will be used by the drug product manufacturer to determine whether the finished drug product complies with the General Chapter <467> defined limits. If the test limits are met for the drug product components, finished product testing is unnecessary.2.FDA will accept the use of appropriate analytical procedures other than thoseincluded in General Chapter <467>.The USP General Notices section on “Tests and Assays – Residual Solvents” references the use of “suitable methods” other than the specific analytical methods included in General Chapter<467>. FDA will accept the use of such other analytical procedures as referenced in 21 CFR 314.50(d) provided that all such procedures are properly described and validated and their4 The Federal Food, Drug, and Cosmetic Act, section 501(b) (21 U.S.C. 351).5 As part of ongoing supplier management, a drug product manufacturer is expected to monitor a supplier to assure that the component it produces continues to be of consistent quality and laboratory results reported on the COA remain reliable.suitability verified under actual conditions of use as described in the current good manufacturing practices (CGMPs) regulations at 21 CFR 211.165(e) and 211.194(a)(2).For compendial drug products approved under an NDA or ANDA, changes made to the specifications in the approved application regarding General Chapter <467> should be in accordance with applicable regulations described in 21 CFR 314.70 and the recommendations in the guidance for industry on Changes to an Approved NDA or ANDA.Generally, an annual report, if needed, can be used to report changes such as adding a test to a finished product specification or adding an alternative analytical procedure to a specification to comply with the USP. The annual report must contain the information described in 21 CFR 314.70(d)(3). As described in 21 CFR parts 210 and 211, detailed data and information related to control of residual solvents and compliance with General Chapter <467> should be documented and kept available at the manufacturing site for the Agency to review upon request during an inspection.The annual report should be submitted in accordance with applicable regulations described in 21 CFR 314.70 and the recommendations in the guidance for industry on Changes to an Approved NDA or ANDA.3.Applicants can submit an amendment to their pending NDA or ANDA to documentany changes made to implement General Chapter <467> if the drug products are thesubject of an official USP monograph and the applicants have already submittedNDAs or ANDAs to the Agency for approval.The amendment should be submitted as soon as possible. Similarly, this same information should be included in all new NDAs and ANDAs submitted for compendial drug products.pendial Drug Products Not Approved Under an NDA or ANDAMarketed compendial drug products not approved under an NDA or ANDA (e.g., over-the-counter (OTC) drug products marketed under an FDA OTC monograph) are also subject to the provisions of the Act, General Chapter <467>, and CGMP documentation requirements described in 21 CFR parts 210 and 211. Manufacturers can use appropriate analytical procedures other than those in General Chapter <467> provided they properly describe and validate their procedures and verify their suitability under actual conditions of use as described in 21 CFR 211.165(e) and 211.194(a)(2).C.Non-compendial NDA or ANDA Drug ProductsGeneral Chapter <467> does not apply to noncompendial drug products. However, FDA recommends that NDA and ANDA applicants for noncompendial drug products limit residual solvents as described in guidance for industry Q3C Impurities: Residual Solvents. Applicants who have not included limits for residual solvents in their NDA or ANDA, as described in 21 CFR 314.50(d), should amend their pending applications as soon as possible.。
原料药残留溶剂试验的要求及常见问题分析-2011.4-北京周立春.pdf
举例：头孢泊肟酯
残留溶剂 照残留溶剂测定法（附录Ⅷ P）测定。 甲醇、乙腈、丙酮、二氯甲烷、异丙醇、丁酮、乙酸乙 酯、四氢呋喃、乙酸丁酯、1,2-二氯乙烷、乙酸异丙酯、 苯、四氯化碳、环己烷、二氧六环、甲基异丁基酮、吡 啶、甲苯 色谱条件与系统适用性试验 略 内标溶液的制备 取正丙醇适量，用二甲基亚砜稀释制成 每1ml中约含200μg的溶液，作为内标溶液。
顶空进样：
原理：将含有挥发性组分的样品 置于密闭系统中，在一定温 度下使样品中的挥发性组分 在气-液或气-固两相甚至气液-固三相中的分配达到平衡， 然后取凝聚相上端的气体送 入气相色谱仪进行分析 优点：干净。样品中不挥发组分 不影响GC分析。减轻污染。 要求：样品至少在顶空条件下溶 解。
K
1 p i
0 i
p0i为纯溶质的蒸气 压 γi为组分的活度系 数
顶空条件的选择
顶空温度：残留溶剂的沸点较高，顶空温度也应 相应提高；但应兼顾供试品的热分解特性，尽量 避免供试品产生的挥发性热分解产物对测定的干 扰。 顶空平衡时间：一般为30～45分钟，以保证供试 品溶液的气-液两相有足够的时间达到平衡。顶 空时间通常不宜过长，如超过60分钟，可能引起 顶空瓶的气密性变差，导致定量准确性的降低。 传输管温度：对于有传输管的顶空进样器，传输 管温度应适当，通常设定在110℃～120℃。 对照品溶液与供试品溶液必须使用相同的顶空条 件。
原料药残留溶剂试 验的要求及常见问 题分析
周立春 2011.4
主要内容
1. 2. 3. 4.
前言 2010版药典中残留溶剂的相关内容 残留溶剂的方法学研究 残留溶剂测定的常见问题
前 言
1) 2) 3)
残留溶剂定义 残留溶剂的分类 药物中残留溶剂的特点
ich残留溶剂限度表
ICHQ3C将残留溶剂分为四类：
1.1类为应避免使用，包括已知的人体致癌物，或者有较大致癌嫌疑，以及环
境危害物，1类溶剂采用浓度限度（ppm）来控制。
2.2类为应限制使用，包括非遗传毒性致癌物质，可能引起神经中毒或畸变等
不可逆毒性的溶剂，可能具有严重但可逆的毒性的溶剂，2类溶剂一般采用PDE（每日允许暴露量）（mg/天）或浓度限度（ppm）控制。
3.3类为低潜在毒性的溶剂，无须制定基于健康的暴露程度，应该由GMP或其
它基于质量的要求进行限度。
4.4类为未知毒性，没有足够毒性资料，使用较少的溶剂，如果使用该类溶剂
需论证合理性。
此外，某些特定的化合物在特定条件下可能被归为更具体的类别。
因此，建议在制定具体的残留溶剂限度时，结合化合物性质和用途，参考最新版残留溶剂指导原则和指导原则附录。
残留溶剂的指导原则
杂质：残留溶剂的指导原则1．介绍本指导原则旨在介绍药物中残留溶剂在保证人体安全条件下的可接受量，指导原则建议使用低毒的溶剂，提出了一些残留溶剂毒理学上的可接受水平。
药物中的残留溶剂在此定义为在原料药或赋形剂的生产中，以及在制剂制备过程中产生或使用的有机挥发性化合物，它们在工艺中不能完全除尽。
在合成原料药中选择适当的溶剂可提高产量或决定药物的性质，如结晶型。
纯度和溶解度。
因此．有时溶剂是合成中非常关键的因素。
本指导原则所指的溶剂不是谨慎地用作赋形剂的溶剂，也不是溶剂化物，然而在这些制剂中的溶剂含量也应进行测定，并作出合理的判断。
出于残留溶剂没有疗效，故所有残留溶剂均应尽可能．去，以符合产品规范、GMP或其他基本的质量要求。
制剂所含残留溶剂的水平不能高于安全值，已知一些溶剂可导致不接受的毒性（第一类，表1），除非被证明特别合理，在原药、赋形剂及制剂生产中应避免使用。
一些溶剂毒性不太大（第二类，表2）应限制使用，以防止病人潜在的不良反应。
使用低毒溶剂（第三类，表3）较为理想。
附录1中列出了指导原则中的全部溶剂。
表中所列溶剂并非详尽无遗，其他可能使用的溶剂有待日后补充列人。
第一、二类溶剂的建议限度或溶剂的分类会随着。
新的安全性资料的获得而调整。
含有新溶剂的新药制剂、其上市申请的安全性资料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）或新药制剂（Q3B新药制剂中的杂质）中所述的杂质控制原则，或者符合上述三者。
2. 指导原则的范围指导原则范围包括原料药、赋形剂或制剂中所含残留溶剂．因此，当生产或纯化过程中会出现这些溶剂时。
应进行残留溶剂的检验。
也只有在上述情况下，才有必要作溶剂的检查。
虽然生产商可以选择性地测定制剂，但也可以从制剂中各成分的残留溶液水平来累积计算制剂中的残留溶剂。
如果计算结果等于或低于本原则的建议水平，该制剂可考虑不检查残留溶剂，但如果计算结果高于建议水平则应进行检测，以确定制剂制备过程中是否降低了有关溶剂的量以达到可接受水平。
2005 药典残留溶剂测定法
附录ⅧP 残留溶剂测定法药物中的残留溶剂系指在原料药或辅料的生产中，以及在制剂制备过程中使用的，但在工艺过程中未能完全去除的有机溶剂。
药物中常见的残留溶剂及限度见附表1，除另有规定外，第一、第二、第三类溶剂的残留量应符合表中的规定；对其他溶剂，应根据生产工艺的特点，制定相应的限度，使其符合产品规范、GMP或其他基本的质量要求。
本法照气相色谱法（附录ⅤE）测定。
色谱柱1．毛细管柱除另有规定外，极性相近的同类色谱柱之间可以互代使用。
（1）非极性色谱柱固定液为100％的二甲基聚硅氧烷的毛细管柱。
（2）极性色谱柱固定液为聚乙二醇（PEG-20M）的毛细管柱。
（3）中极性色谱柱固定液为（35%）二苯基-（65%）甲基聚硅氧烷，（50%）二苯基-（50%）二甲基聚硅氧烷，（35%）二苯基-（65%）二甲基亚芳基聚硅氧烷，（14%）氰丙基苯基-（86%）二甲基聚硅氧烷，（6%）氰丙基苯基-（94%）二甲基聚硅氧烷的毛细管柱。
（4）弱极性色谱柱固定液为（5%）苯基-（95%）甲基聚硅氧烷，（5%）二苯基-（95%）二甲基亚芳基硅氧烷共聚物的毛细管柱。
2．填充柱以直径为0.25～0.18mm的乙二烯苯-乙基乙烯苯型高分子多孔小球或其他适宜的填料作为固定相。
系统适用性试验（1）用待测物的色谱峰计算，毛细管色谱柱的理论板数均应大于5000；填充柱法的理论板数应大于1000。
（2）色谱图中，待测物色谱峰与其相邻的色谱峰的分离度应大于1.5；（3）以内标法测定时，对照品溶液连续进样5次，所得待测物与内标物峰面积之比的相对标准偏差（RSD）应不大于5％；若以外标法测定，所得待测物峰面积的相对标准偏差（RSD）应不大于10％。
供试品溶液的制备1．顶空进样除另有规定外，精密称取供试品0.1～1g；通常以水为溶剂；对于非水溶性药物，可采用N，N－二甲基甲酰胺、二甲基亚砜或其他适宜溶剂；根据供试品和待测溶剂的溶解度，选择适宜的溶剂且应不干扰待测溶剂的测定。
欧盟规定农药最大残留限量指标
0.1
0.002 琥珀酸脱氢酶(Isofetamid)
0.01
0.01 甜菜宁(Phenmedipham)
0.01
0.01 甜菜安(Desmedipham)
0.01
0.05 甲咪唑烟酸(Imazapic)
0.01
0.02 甲基二磺隆(Mesosulfuron-Methyl)
0.01
0.01 甲基嘧啶磷(Pirimiphos-methyl) 0.02 甲基对硫磷(Parathion-methyl) 0.01 甲基毒死蜱(Chlorpyrifos-methyl)
0.01
2,4-滴丙酸(Dichlorprop)
0.02 氟咯草酮(Flurochloridone)
0.1
2,4-滴和 2,4-滴钠盐(2,4-D and 2,4-D Na)
0.05 氟喹唑(Fluquinconazole (F))
0.05
2,4,5-涕及其各种盐类和酯类(2, 4, 5-T and its salts and 0.01 氟嘧菌酯(Fluoxastrobin)
0.02 氯氨吡啶酸(Aminopyralid)
0.01
丙硫菌唑(Prothioconazole)
氯氰菊酯和高效氯氰菊酯(Cypermethrin and
0.01
0.5
beta-cypermethrin)
丙苯磺隆(Propoxycarbazone)
0.02 氯炔灵(Chlorbufam (F))
0.01
T/SNX 6-2020
附录A （规范性附录） 欧盟规定农药最大残留限量指标
欧盟规定农药最大残留限量指标A.1。
表 A.1 欧盟规定农药最大残留限量指标
EMA残留溶剂指南附录
Annexes to:CPMP/ICH/283/95 Impurities: Guideline for residual solvents&CVMP/VICH/502/99 Guideline on impurities: residual SolventsEMA关于残留溶剂指南CPMP/ICH/283/95 杂质-残留溶剂指南和CVMP/VICH/502/99 杂质指南-残留溶剂的附录Annex I: specifications for class 1 and class 2 residual solvents in active Substances附录I：API中I类和II类残留溶剂质量标准Annex II: residues of solvents used in the manufacture of finished products附录II：制剂生产中使用溶剂的残留Discussion at Quality Working Party 质量工作组讨论会议January 2003 to June 2004 2003.01~2004.06Adoption by CVMP CVMP 采纳July 2004 2004.07Adoption by CHMP CHMP 采纳July 2004 2004.07Date for coming into operation 生效时间January 2005 2005.01Rev. 01 Adoption by Quality Working Party 质量工作组采纳的01版本22 November 20122012.11.22Rev. 01 Adoption by CVMP CVMP采纳的01版本7 February 2013 2013.02.07Rev. 01 Adoption by CHMP CHMP采纳的01版本11 February 2013 2013.02.11Rev. 01 Date for coming into operation 01版本生效1 March 2013 2013.03.01Introduction前言The two (V)ICH residual solvents guidelines, ICH Q3C Impurities: Guideline for residual solvents (CPMP/ICH/283/95) and VICH GL18 Guideline on impurities: residual solvents in new veterinary medicinal products, active substances and excipients (CVMP/VICH/502/99), have been in operation for several years, since March 1998 and June 2001 respectively.虽然ICH颁布的ICH Q3C 杂质: 残留溶剂指导原则 (CPMP/ICH/283/95) 和VICH GL18 杂质指导原则：兽用药、API和辅料(CVMP/VICH/502/99)中的残留溶剂这两个关于残留溶剂的指南分别从1998.03和2001.06就开始被采纳应用。
中国药典分析检测技术指南 溶剂残留
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残留溶剂指导原则ICHQ3CR5
August 2011EMA/CHMP/ICH/82260/2006ICH guideline Q3C (R5) on impurities: guideline for residual solventsStep 5Part I (Parent guideline)Transmission to CHMP November 1996 Adoption by CHMP for release for consultation November 1996 End of consultation (deadline for comments) May 1997 Final adoption by CHMP September 1997 Date for coming into effect March 1998 Part II and part III (PDE for Tetrahydrofuran and N-Methylpyrrolidone)Transmission to CHMP July 2000 Adoption by CHMP for release for consultation July 2000 End of consultation (deadline for comments) September 2000 Final adoption by CHMP September 2002 Corrigendum to calculation formula for NMP November 2002 Transmission to CHMP March 2003February 2009 Update of table 2, table 3 and appendix 1 to reflect therevision of the PDEs for N-Methylpyrrolidone andTetrahydrofuran Q3C(R4)Part IV (PDE for cumene)Transmission to CHMP June 2010 Adoption by CHMP for release for consultation June 20107 Westferry Circus ● Canary Wharf ● London E14 4HB ● United KingdomEnd of consultation (deadline for comments) September 2010 Final adoption by CHMP March 2011 Date for coming into effect August 2011Q3C (R5) on impurities: guideline for residual solventsTable of contentsPart I (4)Impurities: Residual solvents - Parent guideline (4)1. Introduction (4)2. Scope of the guideline (4)3. General principles (5)3.1. Classification of residual solvents by risk assessment (5)3.2. Methods for establishing exposure limits (5)3.3. Options for describing limits of class 2 solvents (6)3.4. Analytical procedures (7)3.5. Reporting levels of residual solvents (7)4. Limits of residual solvents (8)4.1. Solvents to be avoided (8)4.2. Solvents to be limited (8)4.3. Solvents with low toxic potential (9)4.4. Solvents for which no adequate toxicological data was found (10)Glossary (11)Appendix 1: List of solvents included in the guideline (12)Appendix 2: Additional background (16)Appendix 3: Methods for establishing exposure limits (17)PART II: (20)PDE for Tetrahydrofuran (20)PART III: (22)PDE for N-Methylpyrrolidone (NMP) (22)PART IV (24)PDE for cumene (24)Part IImpurities: Residual solvents - Parent guideline1. IntroductionThe objective of this guideline is to recommend acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. The guideline recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents. Residual solvents in pharmaceuticals are defined here as organic volatile chemicals that are used 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 selection 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 used as excipients nor does it address solvates. However, the content of solvents in such products should be evaluated and justified.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-based requirements. Drug products should contain no higher levels of residual solvents than can be supported by safety data. Some solvents that are known to cause unacceptable toxicities (Class 1, Table 1) should be avoided in the production of drug substances, excipients, or drug products unless their use can be strongly justified in a risk-benefit assessment. Some solvents associated with less severe toxicity (Class 2, Table 2) should be limited in order to protect patients from potential adverse effects. Ideally, less toxic solvents (Class 3, Table 3) should be used where practical. The complete list of solvents included in this guideline is given in Appendix 1.The lists are not exhaustive and other solvents can be used 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 based on concepts in this guideline or the concept of qualification of impurities as expressed 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.2. Scope of the guidelineResidual 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 purification processes are known to result in the presence of such solvents. It is only necessary to test for solvents that are used or produced in the manufacture or purification of drug substances, excipients, or drug product. Although manufacturers may choose to test the drug product, a cumulative method may be used to calculate the residual solvent levels in the drug product from the levels in the ingredients used 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 therelevant solvent level to within the acceptable amount. Drug product should also be tested if a solvent is used during its manufacture.This guideline does not apply to potential new drug substances, excipients, or drug products used during the clinical research stages of development, nor does it apply to existing marketed drug products.The guideline applies to all dosage forms and routes of administration. Higher levels of residual solvents may be acceptable in certain cases such as short term (30 days or less) or topical application. Justification for these levels should be made on a case by case basis.See Appendix 2 for additional background information related to residual solvents.3. General principles3.1. Classification of residual solvents by risk assessmentThe term "tolerable daily intake" (TDI) is used by the International Program on Chemical Safety (IPCS) to describe exposure limits of toxic chemicals and "acceptable daily intake" (ADI) is used by the World Health Organization (WHO) and other national and international health authorities and institutes. The new term "permitted daily exposure" (PDE) is defined in the present guideline as a pharmaceutically acceptable intake of residual solvents to avoid confusion of differing values for ADI's of the same substance.Residual solvents assessed in this guideline are listed in Appendix 1 by common names and structures. They were evaluated for their possible risk to human health and placed into one of three classes as follows:Class 1 solvents: Solvents to be avoidedKnown human carcinogens, strongly suspected human carcinogens, and environmental hazards. Class 2 solvents: Solvents to be limitedNon-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity.Solvents suspected of other significant but reversible toxicities.Class 3 solvents: Solvents with low toxic potentialSolvents with low toxic potential to man; no health-based exposure limit is needed. Class 3 solvents have PDEs of 50 mg or more per day.3.2. Methods for establishing exposure limitsThe method used to establish permitted daily exposures for residual solvents is presented in Appendix 3. Summaries of the toxicity data that were used to establish limits are published in Pharmeuropa, Vol. 9, No. 1, Supplement, April 1997.3.3. Options for describing limits of class 2 solventsTwo options are available when setting limits for Class 2 solvents.Option 1: The concentration limits in ppm stated in Table 2 can be used. They were calculated using equation (1) below by assuming a product mass of 10 g administered daily. Concentration (ppm) = 1000 x PDE(1)Here, PDE is given in terms of mg/day and dose is given in g/day.These limits are considered acceptable for all substances, excipients, or products. Therefore this option may be applied if the daily dose is not known or fixed. If all excipients and drug substances in a formulation meet the limits given in Option 1, then these components may be used in any proportion. No further calculation is necessary provided the daily dose does not exceed 10 g. Products that are administered in doses greater than 10 g per day should be considered under Option 2.Option 2: It is not considered necessary for each component of the drug product to comply with the limits given in Option 1. The PDE in terms of mg/day as stated in Table 2 can be used with the known maximum daily dose and equation (1) above to determine the concentration of residual solvent allowed in drug product. Such limits are considered acceptable provided that it has been demonstrated that the residual solvent has been reduced to the practical minimum. The limits should be realistic in relation to analytical precision, manufacturing capability, reasonable variation in the manufacturing process, and the limits should reflect contemporary manufacturing standards. Option 2 may be applied by adding the amounts of a residual solvent present in each of the components of the drug product. The sum of the amounts of solvent per day should be less than that given by the PDE.Consider an example of the use of Option 1 and Option 2 applied to acetonitrile in a drug product. The permitted daily exposure to acetonitrile is 4.1 mg per day; thus, the Option 1 limit is 410 ppm. The maximum administered daily mass of a drug product is 5.0 g, and the drug product contains two excipients. The composition of the drug product and the calculated maximum content of residual acetonitrile are given in the following table.Acetonitrile content Daily exposure Component Amount informulationDrug substance 0.3 g 800 ppm 0.24 mgExcipient 1 0.9 g 400 ppm 0.36 mgExcipient 2 3.8 g 800 ppm 3.04 mgDrug Product 5.0 g 728 ppm 3.64 mgExcipient 1 meets the Option 1 limit, but the drug substance, excipient 2, and drug product do not meet the Option 1 limit. Nevertheless, the product meets the Option 2 limit of 4.1 mg per day and thus conforms to the recommendations in this guideline.Consider another example using acetonitrile as residual solvent. The maximum administered daily mass of a drug product is 5.0 g, and the drug product contains two excipients. The composition of the drug product and the calculated maximum content of residual acetonitrile is given in the following table.Acetonitrile content Daily exposure Component Amount informulationDrug substance 0.3 g 800 ppm 0.24 mgExcipient 1 0.9 g 2000 ppm 1.80 mgExcipient 2 3.8 g 800 ppm 3.04 mgDrug Product 5.0 g 1016 ppm 5.08 mgIn this example, the product meets neither the Option 1 nor the Option 2 limit according to this summation. The manufacturer could test the drug product to determine if the formulation process reduced the level of acetonitrile. If the level of acetonitrile was not reduced during formulation to the allowed limit, then the manufacturer of the drug product should take other steps to reduce the amount of acetonitrile in the drug product. If all of these steps fail to reduce the level of residual solvent, in exceptional cases the manufacturer could provide a summary of efforts made to reduce the solvent level to meet the guideline value, and provide a risk-benefit analysis to support allowing the product to be utilised with residual solvent at a higher level.3.4. Analytical proceduresResidual solvents are typically determined using chromatographic techniques such as gas chromatography. Any harmonised procedures for determining levels of residual solvents as described in the pharmacopoeias should be used, if feasible. Otherwise, manufacturers would be free to select the most appropriate validated analytical procedure for a particular application. If only Class 3 solvents are present, a non-specific method such as loss on drying may be used. Validation of methods for residual solvents should conform to ICH guidelines Text on Validation of Analytical Procedures and Extension of the ICH Text on Validation of Analytical Procedures.3.5. Reporting levels of residual solventsManufacturers of pharmaceutical products need certain information about the content of residual solvents in excipients or drug substances in order to meet the criteria of this guideline. The following statements are given as acceptable examples of the information that could be provided from a supplier of excipients or drug substances to a pharmaceutical manufacturer. The supplier might choose one of the following as appropriate:Only Class 3 solvents are likely to be present. Loss on drying is less than 0.5%.Only Class 2 solvents X, Y, ... are likely to be present. All are below the Option 1 limit. (Here the supplier would name the Class 2 solvents represented by X, Y, ...)Only Class 2 solvents X, Y, ... and Class 3 solvents are likely to be present. Residual Class 2 solvents are below the Option 1 limit and residual Class 3 solvents are below 0.5%.If Class 1 solvents are likely to be present, they should be identified and quantified."Likely to be present" refers to the solvent used in the final manufacturing step and to solvents that are used in earlier manufacturing steps and not removed consistently by a validated process.If solvents of Class 2 or Class 3 are present at greater than their Option 1 limits or 0.5%, respectively, they should be identified and quantified.4. Limits of residual solvents4.1. Solvents to be avoidedSolvents in Class 1 should not be employed in the manufacture of drug substances, excipients, and drug products because of their unacceptable toxicity or their deleterious environmental effect. However, if their use is unavoidable in order to produce a drug product with a significant therapeutic advance, then their levels should be restricted as shown in Table 1, unless otherwise justified. 1,1,1-Trichloroethane is included in Table 1 because it is an environmental hazard. The stated limit of 1500 ppm is based on a review of the safety data.TABLE 1. Class 1 solvents in pharmaceutical products (solvents that should be avoided).Solvent Concentration limitConcern(ppm)Benzene 2 CarcinogenCarbon tetrachloride 4 Toxic and environmental hazard1,2-Dichloroethane 5 Toxic1,1-Dichloroethene 8 Toxic1,1,1-Trichloroethane 1500 Environmental hazard4.2. Solvents to be limitedSolvents in Table 2 should be limited in pharmaceutical products because of their inherent toxicity. PDEs are given to the nearest 0.1 mg/day, and concentrations are given to the nearest 10 ppm. The stated values do not reflect the necessary analytical precision of determination. Precision should be determined as part of the validation of the method.TABLE 2. Class 2 solvents in pharmaceutical products.Solvent PDE (mg/day) Concentration limit(ppm)Acetonitrile 4.1 410Chlorobenzene 3.6 360Chloroform 0.6 60Cyclohexane 38.8 38801,2-Dichloroethene 18.7 1870Dichloromethane 6.0 6001,2-Dimethoxyethane 1.0 100N,N-Dimethylacetamide 10.9 1090N,N-Dimethylformamide 8.8 8801,4-Dioxane 3.8 3802-Ethoxyethanol 1.6 160Ethyleneglycol 6.2 620Formamide 2.2 220Hexane 2.9 290Methanol 30.0 30002-Methoxyethanol 0.5 50Methylbutyl ketone 0.5 50Methylcyclohexane 11.8 1180N-Methylpyrrolidone1 5.3 530Nitromethane 0.5 50Pyridine 2.0 200Sulfolane 1.6 160Tetrahydrofuran27.2 720Tetralin 1.0 100Toluene 8.9 8901,1,2-Trichloroethene 0.8 80Xylene* 21.7 2170*usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene4.3. Solvents with low toxic potentialSolvents in Class 3 (shown in Table 3) may be regarded as less toxic and of lower risk to human health. Class 3 includes no solvent known as a human health hazard at levels normally accepted in pharmaceuticals. However, there are no long-term toxicity or carcinogenicity studies for many of the solvents in Class 3. Available data indicate that they are less toxic in acute or short-term studies and negative in genotoxicity studies. It is considered that amounts of these residual solvents of 50 mg per day or less (corresponding to 5000 ppm or 0.5% under Option 1) would be acceptable without justification. Higher amounts may also be acceptable provided they are realistic in relation to manufacturing capability and good manufacturing practice.Table 3: Class 3 solvents which should be limited by GMP or other quality-based requirements. Acetic acid HeptaneAcetone Isobutyl acetateAnisole Isopropyl acetate1 The information included for N-Methylpyrrolidone reflects that included in the Revision of PDE Information for NMP which reached Step 4 in September 2002 (two mistyping corrections made in October 2002), and was incorporated into the core guideline in November 2005. See Part III (pages 20-21).2 The information included for Tetrahydrofuran reflects that included in the Revision of PDE Information for THF which reached Step 4 in September 2002, and was incorporated into the core guideline in November 2005. See Part II (pages 18-19).1-Butanol Methyl acetate2-Butanol 3-Methyl-1-butanolButyl acetate Methylethyl ketonetert-Butylmethyl ether Methylisobutyl ketoneCumene 2-Methyl-1-propanolDimethyl sulfoxide PentaneEthanol 1-PentanolEthyl acetate 1-PropanolEthyl ether 2-PropanolEthyl formate Propyl acetateFormic acid4.4. Solvents for which no adequate toxicological data was foundThe following solvents (Table 4) may also be of interest to manufacturers of excipients, drug substances, or drug products. However, no adequate toxicological data on which to base a PDE was found. Manufacturers should supply justification for residual levels of these solvents in pharmaceutical products.Table 4 Solvents for which no adequate toxicological data was found.1,1-Diethoxypropane Methylisopropyl ketone1,1-Dimethoxymethane Methyltetrahydrofuran2,2-Dimethoxypropane Petroleum etherIsooctane Trichloroacetic acidIsopropyl ether Trifluoroacetic acidGlossaryGenotoxic Carcinogens:Carcinogens which produce cancer by affecting genes or chromosomes.LOEL:Abbreviation for lowest-observed effect level.Lowest-Observed Effect Level:The lowest dose of substance in a study or group of studies that produces biologically significant increases in frequency or severity of any effects in the exposed humans or animals.Modifying Factor:A factor determined by professional judgment of a toxicologist and applied to bioassay data to relate that data safely to humans.Neurotoxicity:The ability of a substance to cause adverse effects on the nervous system.NOEL:Abbreviation for no-observed-effect level.No-Observed-Effect Level:The highest dose of substance at which there are no biologically significant increases in frequency or severity of any effects in the exposed humans or animals.PDE:Abbreviation for permitted daily exposure.Permitted Daily Exposure:The maximum acceptable intake per day of residual solvent in pharmaceutical products. Reversible Toxicity:The occurrence of harmful effects that are caused by a substance and which disappear after exposure to the substance ends.Strongly Suspected Human Carcinogen:A substance for which there is no epidemiological evidence of carcinogenesis but there are positive genotoxicity data and clear evidence of carcinogenesis in rodents.Teratogenicity:The occurrence of structural malformations in a developing fetus when a substance is administered during pregnancy.Appendix 1: List of solvents included in the guideline Solvent Other Names Structure Class Acetic acid Ethanoic acid CH3COOH Class 3Acetone 2-PropanoneCH3COCH3 Class 3Propan-2-oneAcetonitrile CH3CN Class 2Anisole Methoxybenzene OCHClass 33Benzene Benzol Class 11-Butanol n-Butyl alcoholCH3(CH2)3OH Class 3Butan-1-olCH3CH2CH(OH)CH3 Class 3 2-Butanol sec-Butyl alcoholButan-2-olButyl acetate Acetic acid butyl ester CH3COO(CH2)3CH3 Class 3tert-Butylmethyl ether 2-Methoxy-2-methyl- propane (CH3)3COCH3 Class 3Carbon tetrachloride Tetrachloromethane CCl4 Class 1Chlorobenzene Cl Class 2Chloroform Trichloromethane CHCl3 Class 2Cumene IsopropylbenzeneCH(CH3)2Class 3(1-Methyl)ethylbenzeneCyclohexane Hexamethylene Class 2CH2ClCH2Cl Class 1 1,2-Dichloroethane sym-DichloroethaneEthylene dichlorideEthylene chloride1,1-Dichloroethene 1,1-DichloroethyleneH2C=CCl2 Class 1Vinylidene chloride1,2-Dichloroethene 1,2-DichloroethyleneClHC=CHCl Class 2Acetylene dichlorideDichloromethane Methylene chloride CH2Cl2 Class 2H3COCH2CH2OCH3 Class 2 1,2-Dimethoxyethane Ethyleneglycol dimethyl etherMonoglymeDimethyl CellosolveN,N-Dimethylacetamide DMA CH3CON(CH3)2 Class 2 N,N-Dimethylformamide DMF HCON(CH3)2 Class 2(CH3)2SO Class 3 Dimethyl sulfoxide MethylsulfinylmethaneMethyl sulfoxideDMSO1,4-Dioxane p-DioxaneO O Class 2[1,4]DioxaneEthanol Ethyl alcohol CH3CH2OH Class 3 2-Ethoxyethanol Cellosolve CH3CH2OCH2CH2OH Class 2 Ethyl acetate Acetic acid ethyl ester CH3COOCH2CH3 Class 3HOCH2CH2OH Class 2 Ethyleneglycol 1,2-Dihydroxyethane1,2-EthanediolCH3CH2OCH2CH3 Class 3 Ethyl ether Diethyl etherEthoxyethane1,1’-OxybisethaneEthyl formate Formic acid ethyl ester HCOOCH2CH3 Class 3 Formamide Methanamide HCONH2 Class 2 Formic acid HCOOH Class 3 Heptane n-Heptane CH3(CH2)5CH3 Class 3Hexane n-Hexane CH3(CH2)4CH3 Class 2Isobutyl acetate Acetic acid isobutyl ester CH3COOCH2CH(CH3)2 Class 3 Isopropyl acetate Acetic acid isopropyl ester CH3COOCH(CH3)2 Class 3 Methanol Methyl alcohol CH3OH Class 2 2-Methoxyethanol Methyl Cellosolve CH3OCH2CH2OH Class 2 Methyl acetate Acetic acid methyl ester CH3COOCH3 Class 33-Methyl-1-butanol Isoamyl alcoholIsopentyl alcohol3-Methylbutan-1-ol(CH3)2CHCH2CH2OH Class 3Methylbutyl ketone 2-HexanoneHexan-2-oneCH3(CH2)3COCH3 Class 2Methylcyclohexane Cyclohexylmethane CH3Class 2 Methylethyl ketone 2-ButanoneMEKButan-2-oneCH3CH2COCH3 Class 3Methylisobutyl ketone 4-Methylpentan-2-one4-Methyl-2-pentanoneMIBKCH3COCH2CH(CH3)2 Class 32-Methyl-1-propanol Isobutyl alcohol2-Methylpropan-1-ol(CH3)2CHCH2OH Class 3 N-Methylpyrrolidone 1-Methylpyrrolidin-2-one1-Methyl-2-pyrrolidinone NCH3OClass 2Nitromethane CH3NO2 Class 2 Pentane n-Pentane CH3(CH2)3CH3 Class 3 1-Pentanol Amyl alcohol CH3(CH2)3CH2OH Class 3Pentan-1-olPentyl alcohol1-Propanol Propan-1-olPropyl alcoholCH3CH2CH2OH Class 32-Propanol Propan-2-olIsopropyl alcohol(CH3)2CHOH Class 3 Propyl acetate Acetic acid propyl ester CH3COOCH2CH2CH3 Class 3PyridineNClass 2Sulfolane Tetrahydrothiophene 1,1-dioxideSO OClass 2Tetrahydrofuran1Tetramethylene oxideOxacyclopentane OClass 2Tetralin 1,2,3,4-Tetrahydro-naphthalene Class 2Toluene Methylbenzene CH3Class 2 1,1,1-Trichloroethane Methylchloroform CH3CCl3 Class 1 1,1,2-Trichloroethene Trichloroethene HClC=CCl2 Class 2Xylene* DimethybenzeneXylolCH3CH3Class 2*usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene1 The information included for Tetrahydrofuran reflects that included in the Revision of PDE Information for THF which reached Step 4 in September 2002, and was incorporated into the core guideline in November 2005. See Part II (pages 18-19).Appendix 2: Additional backgroundA2.1 Environmental Regulation of Organic Volatile SolventsSeveral of the residual solvents frequently used in the production of pharmaceuticals are listed as toxic chemicals in Environmental Health Criteria (EHC) monographs and the Integrated Risk Information System (IRIS). The objectives of such groups as the International Programme on Chemical Safety (IPCS), the United States Environmental Protection Agency (USEPA), and the United States Food and Drug Administration (USFDA) include the determination of acceptable exposure levels. The goal is protection of human health and maintenance of environmental integrity against the possible deleterious effects of chemicals resulting from long-term environmental exposure. The methods involved in the estimation of maximum safe exposure limits are usually based on long-term studies. When long-term study data are unavailable, shorter term study data can be used with modification of the approach such as use of larger safety factors. The approach described therein relates primarily to long-term or life-time exposure of the general population in the ambient environment, i.e. ambient air, food, drinking water and other media.A2.2 Residual Solvents in PharmaceuticalsExposure limits in this guideline are established by referring to methodologies and toxicity data described in EHC and IRIS monographs. However, some specific assumptions about residual solvents to be used in the synthesis and formulation of pharmaceutical products should be taken into account in establishing exposure limits. They are:1) Patients (not the general population) use pharmaceuticals to treat their diseases or forprophylaxis to prevent infection or disease.2) The assumption of life-time patient exposure is not necessary for most pharmaceuticalproducts but may be appropriate as a working hypothesis to reduce risk to human health.3) Residual solvents are unavoidable components in pharmaceutical production and will oftenbe a part of drug products.4) Residual solvents should not exceed recommended levels except in exceptionalcircumstances.5) Data from toxicological studies that are used to determine acceptable levels for residualsolvents should have been generated using appropriate protocols such as those describedfor example by OECD, EPA, and the FDA Red Book.Appendix 3: Methods for establishing exposure limitsThe Gaylor-Kodell method of risk assessment (Gaylor, D. W. and Kodell, R. L.: Linear Interpolation algorithm for low dose assessment of toxic substance. J Environ. Pathology, 4, 305, 1980) is appropriate for Class 1 carcinogenic solvents. Only in cases where reliable carcinogenicity data are available should extrapolation by the use of mathematical models be applied to setting exposure limits. Exposure limits for Class 1 solvents could be determined with the use of a large safety factor (i.e., 10,000to 100,000) with respect to the no-observed-effect level (NOEL). Detection and quantitation of these solvents should be by state-of-the-art analytical techniques.Acceptable exposure levels in this guideline for Class 2 solvents were established by calculation of PDE values according to the procedures for setting exposure limits in pharmaceuticals (Pharmacopeial Forum, Nov-Dec 1989), and the method adopted by IPCS for Assessing Human Health Risk of Chemicals (Environmental Health Criteria 170, WHO, 1994). These methods are similar to those used by the USEPA (IRIS) and the USFDA (Red Book) and others. The method is outlined here to give a better understanding of the origin of the PDE values. It is not necessary to perform these calculations in order to use the PDE values tabulated in Section 4 of this document. PDE is derived from the no-observed-effect level (NOEL), or the lowest-observed effect level (LOEL) in the most relevant animal study as follows:PDE =NOEL x Weight Adjustment(1)F1 x F2 x F3 x F4 x F5The PDE is derived preferably from a NOEL. If no NOEL is obtained, the LOEL may be used. Modifying factors proposed here, for relating the data to humans, are the same kind of "uncertainty factors" used in Environmental Health Criteria (Environmental Health Criteria 170, World Health Organization, Geneva, 1994), and "modifying factors" or "safety factors" in Pharmacopeial Forum. The assumption of 100% systemic exposure is used in all calculations regardless of route of administration.The modifying factors are as follows:F1 = A factor to account for extrapolation between speciesF1 = 5 for extrapolation from rats to humansF1 = 12 for extrapolation from mice to humansF1 = 2 for extrapolation from dogs to humansF1 = 2.5 for extrapolation from rabbits to humansF1 = 3 for extrapolation from monkeys to humansF1 = 10 for extrapolation from other animals to humans。
EP有机残留(精校版本)
5.4.残留溶剂控制活性物质，赋形剂和医药产品中溶剂残留量国际协调会议对人类使用的脑出血药品注册方面的技术要求，已通过溶剂残留量的规定。
规定溶剂可留在活性物质，药用辅料及加工后的产品中的残留量。
这一标准，全文转载如下，不包括现有的销售的产品。
欧洲药典是一部所载各项标准对现有的活性物质，赋形剂和医药产品（不论它们是否是问题）都适用的一本专著药典。
本章节内容是对所有物质和产品可能残留的溶剂进行的检验。
适用的限定量应遵守下面的规定，在特定的专著中一般不提及检测溶剂残留量，因为溶剂生产可能从一个制造商转移到另一个。
这一章适用于经过专著统计的药品物质，（ 2034年前使用）。
主管机关应告知在生产过程中适用的溶剂。
符合欧洲药典的证书材料上面也应注明此信息。
如果只使用第三类溶剂，其残留溶剂可以用干燥失重方法检测，但是具体到某个品种的残留溶剂测试方法，这还要取决于产品本身的特性。
如果这三溶剂的使用量高于规定的限额0.5%，则必须对溶剂进行一个特定的测定。
当使用第1类溶剂残留或第2类溶剂残留量（或第3类溶剂残留量超过了0.5%），在可能的情况下，药典（ 2.4.24 ）中所描述的方法是适用的，否则必须进行适当的验证。
当定量测定溶剂残留时，必须考虑测量物质的含量，否则用干品进行测量。
杂质：溶剂残留指南（ CPMP/ICH/283/95 ）1、导言2、标准范围3、总则3.1通过风险评估进行溶剂残留的分类3.2建立接触限值的方法3.3第2类溶剂描述极限的选择3.4分析方法3.5残留溶剂的呈报水平4.溶剂残留限量4.1需避免的溶剂4.2需限量的溶剂4.3低毒性溶剂4.4被发现没有足够毒物学资料的溶剂专业词汇汇编附录1、总则中包括的溶剂清单附录2、附加的背景2.1有机挥发性溶剂的环境管理2.2药品的溶剂残留量附录3、建立接触极限的方法1、导言这个标准的目标是提出保证病人安全的最大药品溶剂残留量，该标准建议溶剂的使用量应在毒性较低的水平，并且一些溶剂的残留量应在毒物学可接受的范围内。
EMA关于 API 中基因毒性、金属杂质和残留溶剂的标准(中英文对照)
EMA关于API中基因毒性,金属杂质和残留溶剂的标准1.What is a reasonable policy forsetting specifications for potentially genotoxic impurities which aretheoreti cal or actual impurities in a drug substance manufacturing process?HJune20121.什么是设定潜在基因毒性杂质（原料药生产工艺中理论或实际的杂质）标准的基本原则？人用药品，2012年6月Different possible scenarios can beidentified and the applicable policies to be applied for each of them arede scribed below:不同的可能情况可被划分，并且不同的适用原则对应于下面描述的各个情况：Example1–A potential genotoxicimpurity举例1—潜在基因毒性杂质The definition for a potentialgenotoxic impurity is derived from the definition for'potential impurity':animp urity that theoretically can arise during manufacture or storage.It may ormay not actually appear in the(new) drug substance(ICH Q3A,glossary).潜在基因毒性杂质的定义起源于“潜在杂质”的定义：理论上可能在生产中或贮藏中出现的杂质，它可能会或不会实际存在于（新）原料药中（ICH Q3A，术语）。
溶剂残留限度
1.0
0.01
1,1-二乙氧基丙烷
四氢呋喃
7.2
0.072
1,1-二甲氧基甲烷
甲苯
8.9
0.089
2,2-二甲氧基丙烷
1,1,2-三氯乙烯
0.8
0.008
异辛烷
二甲苯①
21.7
0.217
异丙醚
甲基异丙基酮
甲基四氢呋喃
石油醚
三氯乙酸
三氟乙酸
①通常含有60％间二甲苯，14％对二甲苯，9％邻二甲苯和17％乙苯
异丁醇
50.0
0.5
甲基丁基酮
0.5
0.005
正戊烷
50.0
0.5
甲基环己烷
11.8
0.118
正戊醇
50.0
0.5
N-甲基吡咯烷酮
5.3
0.053
正丙醇
50.0
0.5
硝基甲烷
0.5
0.005
异丙醇
50.0
0.5
吡啶
2.0
0.02
乙酸丙酯
50.0
0.5
四氢噻吩
1.6
0.016
第四类溶剂（尚无足够毒理学资料）
50.0
0.5
1,2-二氯乙烯
18.7
0.187
乙酸乙酯
50.0
0.5
二氯甲烷
6.0
0.06
****
50.0
0.5
1,2-二甲氧基乙烷
1.0
0.01
甲酸乙酯
50.0
0.5
N,N-二甲氧基乙酰胺
10.9
0.109
甲酸
50.0
0.5
N,N-二甲氧基甲酰胺
ICH残留溶剂指南(中文翻译)
5．4 残留溶剂在活性物质、赋形剂和药品中残留溶剂的级别限度International Conference on Technical Requirements for Registration of Pharmaceuticals for Human Use （ICH）已采用了关于残留溶剂的杂质指南，它规定了生产后允许残留在活性物质、赋形剂和药品中溶剂的含量限度。
本指南（文本复制见下文）不包括已上市的产品。
然而欧洲药典应用了存在的活性物质、赋形剂和药品指南中同样的原理，无论它们是否药典专论主题。
所有物质和产品都需要测定可能存在于物质或产品中的残留溶剂的含量。
如果异类溶剂的使用已被证明其合理性也已授权，那么它会在各个专论的测试部分受限定。
通常，药典专论不包括单一二类溶剂的测试限度，因为该类溶剂随生产商的不同变化很大。
因而生产工艺中使用该类溶剂时应通知主管当局。
这个通知也应随用于证明欧洲药典的实用型的档案一同提交，并在证明中提及。
当生产工艺中只使用了三类溶剂，可应用干燥失重测试，该测试应在单一专论中叙述。
如果三类溶剂的限度大于0.5%，并已经证明合理性和授权，那么还要求有该溶剂的指定的检测方法。
在这种情况下，限度在单一专论中给出，因为定义指的是无水和无溶剂的物质。
在所有情况下，应巴使用的溶剂通知主管当局。
至于二类溶剂，该通知已在适用性证明中提及。
当使用了一类残留溶剂或二类残留溶剂（或三类残留溶剂超过0.5%），应尽可能使用在一般方法（2.4.24）中叙述的方法学。
否则应使用经适当验证的方法。
杂质：残留溶剂指南CPMP/ICH/283/95）1. 引言2. 指南的范围3. 一般原则3.1. 危险评估对溶剂的分类3.2. 规定暴露限度的方法3.3. 二类溶剂的限度叙述的选择3.4. 分析规程3.5. 残留溶剂的报告水平4. 残留溶剂的限度4.1. 避免使用的溶剂4.2. 规定限度的溶剂4.3. 低毒性潜能的溶剂4.4. 未发现充分毒性数据的溶剂词汇表附录1. 溶剂列表包括指南附录2. 附加背景资料附录2.1: 有机挥发性溶剂的环境规程附录2.2: 药物中的残留溶剂附录3. 规定暴露限度的方法1. 引言⋯⋯（原文不清楚）。
各国溶剂残留限量
usp[467]有机挥发性杂质残留溶剂限度Ⅰ级残留溶剂：不得残留已知人体实验致癌物质；强烈疑似人体实验致癌物质；环境危害物质Ⅱ级残留溶剂：应在限度内动物实验非生殖毒性（遗传）；动物实验致癌物质或其它可能的非可逆致病因子；产生毒性如神经毒性或致畸性；其它疑似重大但可逆毒性Ⅲ级残留溶剂：低潜在毒性溶剂对人体存在低毒性溶剂；无人体摄入量规定（注：Ⅲ级残留溶剂PDEs上限为≥50mg/天）表1 Ⅰ级残留溶剂溶剂浓度限度（ppm）不良反应苯 2 致癌物四氯化碳 4 中毒和外周脑组织损害1，2-二氯乙烷 5 中毒1，1-二氯乙烷8 中毒1，1，1-三氯乙烷1500 环境危害Ⅱ级残留溶剂表2 Ⅱ级残留溶剂溶剂PDE（mg/天）浓度限度（ppm）乙腈 4.1 410氯苯 3.6 360氯仿0.6 60环己烷38.8 38801，2-二氯乙烯18.7 18701，2-二甲氧乙烷 1.0 100N，N-二甲基乙酰胺10.9 1090N，N-二甲基甲酰胺8.8 8801，4-二氧六环 3.8 3802-乙氧基乙醇 1.6 160乙二醇 6.2 620甲酰胺 2.2 220己烷 2.9 290甲醇30.0 30002-甲氧基乙醇0.5 50甲基丁基（甲）酮2-己酮0.5 50甲基环己烷11.8 1180二氯甲烷 6.0 600N-甲基吡咯烷酮 5.3 530硝酸甲烷0.5 50吡啶 2.0 200环丁砜 1.6 160四氢呋喃7.2 7201，2，3，4-四氢化萘 1.0 100甲苯8.9 890三氯乙烯0.8 80二甲苯* 21.7 2170 *通常含有60%间-二甲苯，14%对-二甲苯，9%邻-二甲苯和17%乙苯Ⅲ级残留溶剂表3 Ⅲ级残留溶剂（GMP或其它原料药、赋形剂和药物制剂质量标准规定）醋酸庚烷丙酮乙酸异丁酯苯甲醚乙酸异丙酯正丁醇乙酸甲酯2-丁醇3-甲基-1-丁醇乙酸丁酯甲基乙基酮叔丁基甲基醚甲基异丁基酮异丙基苯2-甲基-1-丙醇二甲基亚砜戊烷乙醇1-戊醇乙酸乙酯1-丙醇乙醚2-丙醇甲酸乙酯乙酸丙酯甲酸表4 其它残留溶剂（缺乏足够的毒物学方面的资料）1，1-二乙氧基丙烷甲基异丙基酮1，1-二甲氧基甲烷甲基四氢呋喃2，2-二甲氧基丙烷溶剂己烷异辛烷三氯醋酸异丙醚三氟醋酸除另有规定外，样品中残留的有机挥发性杂质不得超过下表中规定限度：有机挥发性杂质限度（μg/g）氯仿601，4-二氧杂环己烷380二氯甲烷600三氯乙烷80附录1 本章节所述残留溶剂表溶剂别名化学结构式级别醋酸乙酸CH3COOH Ⅲ级丙酮2-丙酮，丙醛-2-CH3COCH3 Ⅲ级酮乙腈CH3CN Ⅱ级苯甲醚甲氧基苯Ⅲ级苯安息油Ⅰ级CH3(CH2)3OH Ⅲ级1-丁醇正丁醇,丁基-1-醇CH3CH2CH(OH)CH3 Ⅲ级2-丁醇2-丁基醇,丁基-2-醇醋酸丁酯醋酸丁基醚CH3COO(CH2)3CH3 Ⅲ级(CH3)3COCH3 Ⅲ级叔丁基甲基醚2-甲氧基-2-甲基丙烷四氯化碳四氯甲烷CCl4 Ⅰ级氯苯Ⅱ级氯仿三氯甲烷CHCl3 Ⅱ级Ⅲ级枯烯异丙基苯,(1-甲基乙基)苯环己烷Ⅱ级1,2-二氯乙烷均二氯乙烷CH2ClCH2Cl Ⅰ级1,1-二氯乙烷1,1-二氯乙烯H2C=CCl2 Ⅰ级1,2-二氯乙烷1,2-二氯乙烯ClHC=CHCl Ⅱ级二甲基溶纤剂H3COCH2CH2OCH3 Ⅱ级1,2-二甲氧基乙烷DMA CH3CON(CH3)2 Ⅱ级N,N-二甲基乙酰胺N,N-二甲基甲酰DMF HCON(CH3)2 Ⅱ级胺二甲亚砜DMSO (CH3)2SO Ⅲ级Ⅱ级1,4-二氧杂环己烷乙醇CH3CH2OH Ⅲ级2-乙氧基乙醇溶纤剂CH3CH2OCH2CH2OH Ⅱ级醋酸乙酯CH3COOCH2CH3 Ⅲ级乙二醇1,2-二羟基乙烷HOCH2CH2OH Ⅱ级乙醚二乙基醚CH3CH2OCH2CH3 Ⅲ级甲酸乙酯HCOOCH2CH3 Ⅲ级甲酰胺HCONH2 Ⅱ级甲酸HCOOH Ⅲ级庚烷正庚烷CH3(CH2)5CH3 Ⅲ级己烷正己烷CH3(CH2)4CH3 Ⅱ级醋酸异丁酯CH3COOCH2CH(CH3)2 Ⅲ级醋酸异丙酯CH3COOCH(CH3)2 Ⅲ级甲醇CH3OH Ⅱ级2-甲氧基乙醇甲基溶纤剂CH3OCH2CH2OH Ⅱ级醋酸甲酯CH3COOCH3 Ⅲ级3-甲基-1-丁醇异戊基醇(CH3)2CHCH2CH2OH Ⅲ级甲基丁基(甲)酮2-己酮CH3(CH2)3COCH3 Ⅱ级甲基环己烷Ⅱ级二氯甲烷CH2Cl2 Ⅱ级甲基乙基(甲)酮2-丁酮CH3CH2COCH3 Ⅲ级MIBK CH3COCH2CH(CH3)2 Ⅲ级甲基异丁基(甲)酮2-甲基-1-丙醇异丁基醇(CH3)2CHCH2OH Ⅲ级Ⅱ级N-甲基吡咯烷酮1-甲基-2-吡咯烷酮硝基甲烷CH3NO2 Ⅱ级戊烷正戊烷CH3(CH2)3CH3 Ⅲ级1-戊醇CH3CH2CH2OH Ⅲ级2-戊醇(CH3)2CHOH Ⅲ级醋酸丙酯CH3COOCH2CH2CH3 Ⅲ级吡啶Ⅱ级环丁砜四氢噻吩1,1-二Ⅱ级氧化物四氢呋喃环氧戊烷Ⅱ级Ⅱ级1,2,3,4-四氢化萘甲苯Ⅱ级1,1,1-三氯乙烷甲基氯仿CH3CCl3 Ⅰ级三氯乙烯1,1,2-三氯乙烯HClC=CCl2 Ⅱ级二甲苯* Ⅱ级*通常含有60%间-二甲苯，14%对-二甲苯，9%邻-二甲苯和17%乙苯ep残留溶剂表一.第一类残留溶剂溶剂极限浓度（ppm）涉及苯 2 致癌物质四氯化碳 4 有毒、对环境有害的1，2-二氯乙烷 5 有毒1，1-二氯乙烷8 有毒1，1，1-三氯乙烷1500 环境表二第二类残留溶剂溶剂PDE（mg/天）浓度极限（ppm）乙腈 4.1 410氯苯 3.6 360氯仿0.6 60环己烷38.8 3380 1，2-二氯乙烷18.7 18701，2-二甲氧基乙烷 1.0 100N,N-二甲基乙酰胺10.9 1090N,N-二甲基甲酰胺8.8 8801，4-二氧杂环己烷 3.8 380 2-乙氧基乙醇 1.6 160 乙二醇 6.2 620甲酰胺 2.2 220己烷 2.9 290甲醇30.0 3000 2-甲氧基乙醇0.5 50甲基丁基酮0.5 50甲基环己烷11.8 1180二氯甲烷 6.0 600 N-甲基吡咯烷酮 5.3 530 硝基甲烷0.5 50 吡啶 2.0 200环丁砜 1.6 160四氢呋喃7.2 720四氢化奈 1.0 100 甲苯8.9 890 三氯乙烯0.8 80二甲苯* 21.7 2170*通常含有60%间二甲苯，14%对二甲苯，9%邻二甲苯，和17%乙苯表三第三类残留溶剂（在药品、辅料、药物制剂中受到GMP或其它质量要求的限制）乙酸庚烷丙酮乙酸异丁酯苯甲醚乙酸异丙酯1-丁醇乙酸甲酯2-丁醇3-甲基-1-丁醇乙酸丁酯甲乙酮叔-丁基甲基醚甲异丁酮异丙基苯2-甲基-1-丙醇二甲基亚砜戊烷乙醇1-戊醇乙酸乙酯1-丙醇乙醚2-丙醇甲酸乙酯乙酸丙酯甲酸表四其它残留溶剂（没有充分毒物学数据）1，1-二乙氧基丙烷甲异丁酮1，1-二甲氧基甲烷甲基四氢呋喃2，2-二甲氧基丙烷溶剂已烷异辛烷三氯乙酸异丙醚三氟乙酸附录1 标准中所列的溶剂清单溶剂别名结构分类乙酸醋酸CH3COOH 第三类丙酮2-丙酮CH3COCH3第三类乙腈CH3CN 第二类苯甲醚 茴香醚第三类苯 安息油第一类1-丁醇 丁-1-醇 CH 3（CH 2）3OH 第三类 2-丁醇 丁-2-醇 CH 3CH 2CH(OH)CH 3 第三类 乙酸丁酯 醋酸丁酯CH 3CO （CH 2）3CH 3 第三类 叔丁基甲醚 2-甲氧基-2-甲基 (CH 3)3COCH 3 第三类 四氯化碳 四氯甲烷 CCl 4第一类 氯苯第二类氯仿CHCl 3第二类 异丙基苯异丙苯（1-甲基乙基）苯第三类环己烷环己胺1，2-二氯乙烷 二氯化乙烯 CH 2ClCH 2Cl 第一类 1，1-二氯乙烷 偏二氯乙烯 H 2C=CCl 2 第一类 二氯乙烯 二氯乙炔 ClHC=CHCl 第二类 二氯甲烷亚甲基氯 CH 2Cl 21，2-乙二醇二甲醚 H 3COCH 2CH 2OCH 3 第二类 NN-二甲基乙酰胺 DMA CH 3CON(CH 3)2 第二类 NN-二甲基甲酰胺 DMF HCON(CH 3)2 第二类 二甲基亚砜 DMSOHCON(CH 3)2第三类 1,4-二氧六环（1，4）二恶烷第二类 乙醇CH 3CH 2OH 第三类 二乙氧基乙醇 溶纤剂 CH 3CH 2OCH 2CH 2OH 乙酸乙酯醋酸乙酯CH 3COOCH 2CH 3第三类乙二醇 1，2-乙二醇 HOCH 2CH 2OH 第二类 乙醚 二乙醚 CH 3CH 2OCH 2CH 3 第三类 甲酸乙酯 HCOOCH 2CH 3 第三类 甲酰胺 HCONH 2 第二类 甲酸 HCONH 2 第三类 庚烷 n -庚烷 CH 3（CH 2）4CH 3 第三类 正己烷 n -正己烷 CH 3（CH 2）4CH 3 第二类 乙酸异丁酯 醋酸异丁酯 CH 3COOCH 2CH(CH 3)2 第三类 乙酸异丙酯 醋酸异丙酯 CH 3COOCH(CH 3)2 第三类 甲醇 CH 3OH 二甲醚CH 3OCH 2CH 2OH 第二类 乙酸甲酯 醋酸甲酯 CH 3COOCH 3 第三类 异戊醇 3-甲基-1-丁醇 (CH 3)2CHCH 2CH 2OH 第三类 甲丁酮 2-己酮 CH 3（CH 2）3COCH 3第二类 甲基环己烷环己基甲烷第二类丁酮 2-丁酮 MEK CH 3CH 2COCH 3 第三类 丙酮醛MIBK CH 3COCH 2CH(CH 3)2 第三类 2-甲基-1-丙醇 异丁醇 (CH 3)2CHCH 2OH第三类 N-甲基吡咯烷酮第二类硝基甲烷 CH 3NO 2第二类 戊烷 n -戊烷 CH 3（CH 2）3CH 3 第三类 正戊醇 戊乙醇 CH 3（CH 2）3CH 2OH 第三类 丙醇 丙-1-醇 CH 3CH 2CH 2OH 第三类 2-丙醇 丙-2-醇 (CH 3)2CHOH 第三类 丙基乙酸 丙基醋酸 CH 3COOCH 2CH 2CH 3第三类 吡啶第二类环丁砜 四亚甲基亚砜第二类四氢呋喃氧杂环戊烷第二类四氢萘1，2，3，4-四氢萘第二类 甲苯第二类 1，1，1-三氯乙烷 CH 3CCl 3 第一类 1，1，2-三氯乙烯 HClC=CCl 2第二类 二甲苯*第二类 *通常含有60%间二甲苯，14%对二甲苯，9%邻二甲苯，和17%乙苯限度标准一览表：cp 限度标准一览表：。
EMEA关于金属催化剂或金属试剂残留量限度规定的指导
EMEA关于金属催化剂或金属试剂残留量限度规定的指导2008年2月21日EMEA/CHMP颁布了金属催化剂或金属试剂残留量限度规定的指导文件（GUIDELINE ON THE SPECIFICATION LIMITS FOR RESIDUES OF METAL CATALYSTS OR METAL REAGENTS），并将于2008年9月1日在欧盟正式实施。
该指导文件从1998年6月开始起草，历经多次咨询、讨论，最后定稿。
目前国内对药物中金属残留量的控制限度还缺乏明确的技术要求。
本文对EMEA指导文件进行简要介绍，通过对14种金属的分类、分析方法和控制限度的了解，希望对药物质量控制和技术评价有所帮助。
一、该指导文件的结构框架该指导文件包括背景介绍、定义和范围、法规基础、正文、名词、参考文献、附录等七个部分。
其中正文中包括了重金属分类、暴露量限度、浓度限度的设定、分析方法、批结果和检测频率、金属残留报告水平等6个方面。
该文件有三个附录。
附录1是允许日接触量（PDE）设定的考虑因素，附录2是14种金属的单论，包括各金属简介、食物摄取情况、不同给药途径和周期的毒性数据、PDE评估结论，附录3是PDE和浓度限度的计算举例。
二、该指导文件的目的、定义和应用范围在原辅料合成中可能用到金属催化剂或金属试剂，如铂、钯、锌、铁、铬等，这些金属可能原料药中残留，它们可能以最初形式存在，也可能由于后续化学过程以其他形式存在。
原辅料中残留的金属会进一步带入到制剂中。
这些残留的金属通常不具有治疗作用，基于安全性和质控的需要进行严格控制。
该指导文件的目的是为原辅料和制剂中残留的金属催化剂或金属试剂推荐最大可接受浓度限度。
该指导原则适用于新批准和已上市的制剂，EMEA为已上市制剂设定了5年的执行过渡期。
指导文件不适用于正处于临床研究阶段的新原料药和辅料，他们可以设定更高的可接受的金属残留限度。
该指导文件不适用于原辅料中应有的金属成分（如用作成盐离子对的金属），也不适用于制剂中应有的含金属辅料（如制剂中的铁氧化物颜料）。
各国溶剂残留限量
USP[467]有机挥发性杂质残留溶剂限度Ⅰ级需避免的溶剂已知人体实验致癌物质；强烈疑似人体实验致癌物质；环境危害物质Ⅱ级需被限制的溶剂动物实验非生殖毒性（遗传）；动物实验致癌物质或其它可能的非可逆致病因子；产生毒性如神经毒性或致畸性；其它疑似重大但可逆毒性Ⅲ级具有低潜在毒性溶剂对人体存在低毒性溶剂；无人体摄入量规定（注：Ⅲ级残留溶剂PDEs上限为≥50mg/天）表1 Ⅰ级残留溶剂溶剂浓度限度（ppm）不良反应苯 2 致癌物四氯化碳 4 中毒和外周脑组织损害1，2-二氯乙烷 5 中毒1，1-二氯乙烷8 中毒1，1，1-三氯乙烷1500 环境危害Ⅱ级残留溶剂表2 Ⅱ级残留溶剂溶剂PDE（mg/天）浓度限度（ppm）乙腈Acetonitrile 4.1 410氯苯Chlorobenzene 3.6 360氯仿Chloroform0.6 60环己烷Cyclohexane38.8 38801，2-二氯乙烯1,2-Dichloroethene18.7 18701，2-二甲氧乙烷 1.0 100N，N-二甲基乙酰胺N,N-Dimethylacetamide10.9 1090N，N-二甲基甲酰胺N,N-Dimethylformamide8.8 8801，4-二氧六环1,4-Dioxane3.8 3802-乙氧基乙醇 1.6 160乙二醇Ethylene glycol 6.2 620甲酰胺Formamide 2.2 220己烷Hexane 2.9 290甲醇Methanol30.0 30002-甲氧基乙醇0.5 50甲基丁基（甲）酮0.5 502-己酮甲基环己烷11.8 1180二氯甲烷 6.0 600N-甲基吡咯烷酮 5.3 530硝酸甲烷0.5 50吡啶 2.0 200环丁砜 1.6 160四氢呋喃7.2 7201，2，3，4-四氢化萘 1.0 100甲苯8.9 890三氯乙烯0.8 80二甲苯* 21.7 2170 *通常含有60%间-二甲苯，14%对-二甲苯，9%邻-二甲苯和17%乙苯Ⅲ级残留溶剂表3 Ⅲ级残留溶剂（GMP或其它原料药、赋形剂和药物制剂质量标准规定）醋酸Acetic acid 庚烷Heptane丙酮Acetone 乙酸异丁酯苯甲醚乙酸异丙酯正丁醇乙酸甲酯2-丁醇3-甲基-1-丁醇乙酸丁酯甲基乙基酮叔丁基甲基醚甲基异丁基酮异丙基苯2-甲基-1-丙醇二甲基亚砜戊烷乙醇1-戊醇乙酸乙酯1-丙醇乙醚2-丙醇甲酸乙酯乙酸丙酯甲酸表4 其它残留溶剂（缺乏足够的毒物学方面的资料）1，1-二乙氧基丙烷甲基异丙基酮1，1-二甲氧基甲烷甲基四氢呋喃2，2-二甲氧基丙烷溶剂己烷异辛烷三氯醋酸异丙醚三氟醋酸除另有规定外，样品中残留的有机挥发性杂质不得超过下表中规定限度：有机挥发性杂质限度（μg/g）氯仿601，4-二氧杂环己烷380二氯甲烷600三氯乙烷80附录1 本章节所述残留溶剂表溶剂别名化学结构式级别醋酸乙酸CH3COOH Ⅲ级CH3COCH3 Ⅲ级丙酮2-丙酮，丙醛-2-酮乙腈CH3CN Ⅱ级苯甲醚甲氧基苯Ⅲ级苯安息油Ⅰ级1-丁醇正丁醇,丁基-1-CH3(CH2)3OH Ⅲ级醇CH3CH2CH(OH)CH3 Ⅲ级2-丁醇2-丁基醇,丁基-2-醇醋酸丁酯醋酸丁基醚CH3COO(CH2)3CH3 Ⅲ级叔丁基甲基醚2-甲氧基-2-甲基(CH3)3COCH3 Ⅲ级丙烷四氯化碳四氯甲烷CCl4 Ⅰ级氯苯Ⅱ级氯仿三氯甲烷CHCl3 Ⅱ级枯烯异丙基苯,(1-甲Ⅲ级基乙基)苯环己烷Ⅱ级1,2-二氯乙烷均二氯乙烷CH2ClCH2Cl Ⅰ级1,1-二氯乙烷1,1-二氯乙烯H2C=CCl2 Ⅰ级1,2-二氯乙烷1,2-二氯乙烯ClHC=CHCl Ⅱ级1,2-二甲氧基乙二甲基溶纤剂H3COCH2CH2OCH3 Ⅱ级烷DMA CH3CON(CH3)2 Ⅱ级N,N-二甲基乙酰胺N,N-二甲基甲酰DMF HCON(CH3)2 Ⅱ级胺二甲亚砜DMSO (CH3)2SO Ⅲ级Ⅱ级1,4-二氧杂环己烷乙醇CH3CH2OH Ⅲ级2-乙氧基乙醇溶纤剂CH3CH2OCH2CH2OH Ⅱ级醋酸乙酯CH3COOCH2CH3 Ⅲ级乙二醇1,2-二羟基乙烷HOCH2CH2OH Ⅱ级乙醚二乙基醚CH3CH2OCH2CH3 Ⅲ级甲酸乙酯HCOOCH2CH3 Ⅲ级甲酰胺HCONH2 Ⅱ级甲酸HCOOH Ⅲ级庚烷正庚烷CH3(CH2)5CH3 Ⅲ级己烷正己烷CH3(CH2)4CH3 Ⅱ级醋酸异丁酯CH3COOCH2CH(CH3)2 Ⅲ级醋酸异丙酯CH3COOCH(CH3)2 Ⅲ级甲醇CH3OH Ⅱ级2-甲氧基乙醇甲基溶纤剂CH3OCH2CH2OH Ⅱ级醋酸甲酯CH3COOCH3 Ⅲ级3-甲基-1-丁醇异戊基醇(CH3)2CHCH2CH2OH Ⅲ级甲基丁基(甲)酮2-己酮CH3(CH2)3COCH3 Ⅱ级甲基环己烷Ⅱ级二氯甲烷CH2Cl2 Ⅱ级甲基乙基(甲)酮2-丁酮CH3CH2COCH3 Ⅲ级甲基异丁基(甲)MIBK CH3COCH2CH(CH3)2 Ⅲ级酮2-甲基-1-丙醇异丁基醇(CH3)2CHCH2OH Ⅲ级Ⅱ级N-甲基吡咯烷酮1-甲基-2-吡咯烷酮硝基甲烷CH3NO2 Ⅱ级戊烷正戊烷CH3(CH2)3CH3 Ⅲ级1-戊醇CH3CH2CH2OH Ⅲ级2-戊醇(CH3)2CHOH Ⅲ级醋酸丙酯CH3COOCH2CH2CH3 Ⅲ级吡啶Ⅱ级Ⅱ级环丁砜四氢噻吩1,1-二氧化物四氢呋喃环氧戊烷Ⅱ级Ⅱ级1,2,3,4-四氢化萘甲苯Ⅱ级1,1,1-三氯乙烷甲基氯仿CH3CCl3 Ⅰ级三氯乙烯1,1,2-三氯乙烯HClC=CCl2 Ⅱ级二甲苯* Ⅱ级*通常含有60%间-二甲苯，14%对-二甲苯，9%邻-二甲苯和17%乙苯EP残留溶剂表一.第一类残留溶剂溶剂极限浓度（ppm）涉及苯 2 致癌物质四氯化碳 4 有毒、对环境有害的1，2-二氯乙烷 5 有毒1，1-二氯乙烷8 有毒1，1，1-三氯乙烷1500 环境表二第二类残留溶剂溶剂PDE（mg/天）浓度极限（ppm）乙腈 4.1 410氯苯 3.6 360氯仿0.6 60环己烷38.8 3380 1，2-二氯乙烷18.7 18701，2-二甲氧基乙烷 1.0 100N,N-二甲基乙酰胺10.9 1090N,N-二甲基甲酰胺8.8 8801，4-二氧杂环己烷 3.8 380 2-乙氧基乙醇 1.6 160 乙二醇 6.2 620甲酰胺 2.2 220己烷 2.9 290甲醇30.0 3000 2-甲氧基乙醇0.5 50甲基丁基酮0.5 50甲基环己烷11.8 1180二氯甲烷 6.0 600 N-甲基吡咯烷酮 5.3 530硝基甲烷0.5 50 吡啶 2.0 200环丁砜 1.6 160四氢呋喃7.2 720四氢化奈 1.0 100 甲苯8.9 890 三氯乙烯0.8 80二甲苯* 21.7 2170 *通常含有60%间二甲苯，14%对二甲苯，9%邻二甲苯，和17%乙苯表三第三类残留溶剂（在药品、辅料、药物制剂中受到GMP或其它质量要求的限制）乙酸庚烷丙酮乙酸异丁酯苯甲醚乙酸异丙酯1-丁醇乙酸甲酯2-丁醇3-甲基-1-丁醇乙酸丁酯甲乙酮叔-丁基甲基醚甲异丁酮异丙基苯2-甲基-1-丙醇二甲基亚砜戊烷乙醇1-戊醇乙酸乙酯1-丙醇乙醚2-丙醇甲酸乙酯乙酸丙酯甲酸表四其它残留溶剂（没有充分毒物学数据）1，1-二乙氧基丙烷甲异丁酮1，1-二甲氧基甲烷甲基四氢呋喃2，2-二甲氧基丙烷溶剂已烷异辛烷三氯乙酸异丙醚三氟乙酸附录1 标准中所列的溶剂清单溶剂别名结构分类乙酸醋酸CH3COOH 第三类丙酮2-丙酮CH3COCH3第三类乙腈CH3CN 第二类苯甲醚茴香醚第三类苯安息油第一类1-丁醇丁-1-醇CH3（CH2）3OH 第三类2-丁醇丁-2-醇CH3CH2CH(OH)CH3第三类乙酸丁酯醋酸丁酯CH3CO（CH2）3CH3第三类叔丁基甲醚2-甲氧基-2-甲基(CH3)3COCH3第三类四氯化碳四氯甲烷CCl4第一类氯苯第二类氯仿CHCl3第二类异丙基苯异丙苯（1-甲基乙基）苯第三类环己烷环己胺1，2-二氯乙烷二氯化乙烯CH2ClCH2Cl 第一类1，1-二氯乙烷偏二氯乙烯H2C=CCl2第一类二氯乙烯二氯乙炔ClHC=CHCl 第二类二氯甲烷亚甲基氯CH2Cl21，2-乙二醇二甲醚H3COCH2CH2OCH3第二类NN-二甲基乙酰胺DMA CH3CON(CH3)2第二类NN-二甲基甲酰胺DMF HCON(CH3)2第二类二甲基亚砜DMSO HCON(CH3)2第三类1,4-二氧六环（1，4）二恶烷第二类乙醇CH3CH2OH 第三类二乙氧基乙醇溶纤剂CH3CH2OCH2CH2OH乙酸乙酯醋酸乙酯CH3COOCH2CH3第三类乙二醇1，2-乙二醇HOCH2CH2OH 第二类乙醚二乙醚CH3CH2OCH2CH3第三类甲酸乙酯HCOOCH2CH3第三类甲酰胺HCONH2第二类甲酸HCONH2第三类庚烷n-庚烷CH3（CH2）4CH3第三类正己烷n -正己烷CH3（CH2）4CH3第二类乙酸异丁酯醋酸异丁酯CH3COOCH2CH(CH3)2第三类乙酸异丙酯醋酸异丙酯CH3COOCH(CH3)2第三类甲醇CH3OH二甲醚CH3OCH2CH2OH 第二类乙酸甲酯醋酸甲酯CH3COOCH3第三类异戊醇3-甲基-1-丁醇(CH3)2CHCH2CH2OH 第三类甲丁酮2-己酮CH3（CH2）3COCH3第二类甲基环己烷环己基甲烷第二类丁酮2-丁酮 MEK CH3CH2COCH3第三类丙酮醛MIBK CH3COCH2CH(CH3)2第三类2-甲基-1-丙醇异丁醇(CH3)2CHCH2OH 第三类N-甲基吡咯烷酮第二类硝基甲烷CH3NO2第二类戊烷n-戊烷CH3（CH2）3CH3第三类正戊醇戊乙醇CH3（CH2）3CH2OH 第三类丙醇丙-1-醇CH3CH2CH2OH 第三类2-丙醇丙-2-醇(CH3)2CHOH 第三类丙基乙酸丙基醋酸CH3COOCH2CH2CH3第三类吡啶第二类环丁砜四亚甲基亚砜第二类四氢呋喃氧杂环戊烷第二类四氢萘1，2，3，4-四氢萘第二类甲苯第二类1，1，1-三氯乙烷CH3CCl3第一类1，1，2-三氯乙烯HClC=CCl2第二类二甲苯* 第二类*通常含有60%间二甲苯，14%对二甲苯，9%邻二甲苯，和17%乙苯限度标准一览表：药物中常见残留溶剂及其限度溶剂名称PDE值 (mg/天）限度（％）溶剂名称PDE值 (mg/天）限度（％）第一类溶剂（应该避免使用）第三类溶剂（GMP或其他质量要求限制使用）苯0.0 0.0002 醋酸50.0 0.5 四氯化碳0.0 0.0004 丙酮50.0 0.5 1, 2-二氯乙烷0.1 0.0005 甲氧基苯50.0 0.5CP限度标准一览表：。
EMEA关于金属催化剂或金属试剂残留量限度规定的指导文件简介
EMEA关于金属催化剂或金属试剂残留量限度规定的指导文件简介2008年2月21日EMEA/CHMP颁布了金属催化剂或金属试剂残留量限度规定的指导文件（GUIDELINE ON THE SPECIFICATION LIMITS FOR RESIDUES OF METAL CATALYSTS OR METAL REAGENTS），并将于2008年9月1日在欧盟正式实施。
该指导文件从1998年6月开始起草，历经多次咨询、讨论，最后定稿。
目前国内对药物中金属残留量的控制限度还缺乏明确的技术要求。
本文对EMEA指导文件进行简要介绍，通过对14种金属的分类、分析方法和控制限度的了解，希望对药物质量控制和技术评价有所帮助。
一、该指导文件的结构框架该指导文件包括背景介绍、定义和范围、法规基础、正文、名词、参考文献、附录等七个部分。
其中正文中包括了重金属分类、暴露量限度、浓度限度的设定、分析方法、批结果和检测频率、金属残留报告水平等6个方面。
该文件有三个附录。
附录1是允许日接触量（PDE）设定的考虑因素，附录2是14种金属的单论，包括各金属简介、食物摄取情况、不同给药途径和周期的毒性数据、PDE评估结论，附录3是PDE和浓度限度的计算举例。
二、该指导文件的目的、定义和应用范围在原辅料合成中可能用到金属催化剂或金属试剂，如铂、钯、锌、铁、铬等，这些金属可能原料药中残留，它们可能以最初形式存在，也可能由于后续化学过程以其他形式存在。
原辅料中残留的金属会进一步带入到制剂中。
这些残留的金属通常不具有治疗作用，基于安全性和质控的需要进行严格控制。
该指导文件的目的是为原辅料和制剂中残留的金属催化剂或金属试剂推荐最大可接受浓度限度。
该指导原则适用于新批准和已上市的制剂，EMEA为已上市制剂设定了5年的执行过渡期。
指导文件不适用于正处于临床研究阶段的新原料药和辅料，他们可以设定更高的可接受的金属残留限度。
该指导文件不适用于原辅料中应有的金属成分（如用作成盐离子对的金属），也不适用于制剂中应有的含金属辅料（如制剂中的铁氧化物颜料）。
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Annexes to:CPMP/ICH/283/95 Impurities: Guideline for residual solvents&CVMP/VICH/502/99 Guideline on impurities: residual SolventsEMA关于残留溶剂指南CPMP/ICH/283/95 杂质-残留溶剂指南和CVMP/VICH/502/99 杂质指南-残留溶剂的附录Annex I: specifications for class 1 and class 2 residual solvents in active Substances附录I：API中I类和II类残留溶剂质量标准Annex II: residues of solvents used in the manufacture of finished products附录II：制剂生产中使用溶剂的残留Discussion at Quality Working Party 质量工作组讨论会议January 2003 to June 2004 2003.01~2004.06Adoption by CVMP CVMP 采纳July 2004 2004.07Adoption by CHMP CHMP 采纳July 2004 2004.07Date for coming into operation 生效时间January 2005 2005.01Rev. 01 Adoption by Quality Working Party 质量工作组采纳的01版本22 November 20122012.11.22Rev. 01 Adoption by CVMP CVMP采纳的01版本7 February 2013 2013.02.07Rev. 01 Adoption by CHMP CHMP采纳的01版本11 February 2013 2013.02.11Rev. 01 Date for coming into operation 01版本生效1 March 2013 2013.03.01Introduction前言The two (V)ICH residual solvents guidelines, ICH Q3C Impurities: Guideline for residual solvents (CPMP/ICH/283/95) and VICH GL18 Guideline on impurities: residual solvents in new veterinary medicinal products, active substances and excipients (CVMP/VICH/502/99), have been in operation for several years, since March 1998 and June 2001 respectively.虽然ICH颁布的ICH Q3C 杂质: 残留溶剂指导原则 (CPMP/ICH/283/95) 和VICH GL18 杂质指导原则：兽用药、API和辅料(CVMP/VICH/502/99)中的残留溶剂这两个关于残留溶剂的指南分别从1998.03和2001.06就开始被采纳应用。
However, it has become evident that further clarification was required regarding the specifications for Class 1 and class 2 residual solvents in active substances.但是从应用的实际情况来看，EMA觉得需要对API中I类和II类残留溶剂质量标准的问题进行澄清。
A clear interpretation of the issues regarding residues of solvents used in the manufacture of finished medicinal products, both human and veterinary, was also required.EMA同时也认为需要对人用药和兽用药生产中的溶剂残留问题进行清楚的解释和说明。
Annex I: Specifications for class 1 and class 2 residual solvents in active substances附录I：API中I类和II类残留溶剂质量标准Specifications for class 1 solventsI类溶剂质量标准In both the ICH and VICH guidelines on impurities: residual solvents it is stated that “solvents in class 1 should not be employed in the manufacture of drug/active substances, excipients, and drug/veterinary medicinal products because of their unacceptable toxicity or their deleterious environmental effect. However, if their use is unavoidable in order to produce a drug/veterinary medicinal product with a significant therapeutic advance, then their levels should be restricted as shown…….., unless otherwise justified”.因为I类溶剂的巨大的毒性或者对环境的危害性的原因，因此在ICH和VICH关于杂质-残留溶剂的指南中已经明确说明了在制剂/API、药用辅料和人用药/兽用药生产中不应该使用I类溶剂；但如果在生产一种具有显著疗效的人用药/兽用药时而不得不使用到I类溶剂的时候，那么除非有其他的解释，否则就应该将相应的I 类溶剂残留水平控制在指南中规定的限度……。
The justification for using a class 1 solvent as a solvent in a manufacturing process may be based on the current scientific and technical knowledge and the step in which this solvent is involved. For example, use of that class 1 solvent is unavoidable for the specific chemical reaction, or the desired purity profile can only be obtained by using that class 1 solvent. If a class 1 solvent is involved in a very early step of the manufacturing process and if the absence of this solvent is shown in a suitable intermediate, such an approach may be acceptable (for example, friedel crafts chemical reaction).（生产商）可以根据现阶段的科学技术以及I类溶剂在实际生产中使用的步骤来对工艺中采用I类溶剂的情况进行解释和说明。
比如说某个化学反应必须要使用1类溶剂，或使用I类溶剂来获得所需的纯度。
如果只是在生产中较早的工艺步骤中使用到I类溶剂，而且这个溶剂可以在某个中间体之前被除尽的话，在这种情况下在工艺中使用I类溶剂是可以接受的（例如傅-克反应）。
The maximum acceptable limit, in a suitable intermediate or in the final active substance, for a class 1solvent, whether it is used as a solvent, a starting material, is present as a by-product, or it is present in a solvent, should comply with the limits prescribed in the relevant aforementioned ICH/VICH guideline on impurities: residual solvents, unless otherwise justified (for example, by the benefit-risk ratio).除非有其他特别的合理解释（比如说效益风险比的考虑），否则不论是作为溶剂、起始原料、反应副产物还是其他溶剂携带的I类溶剂在中间体还是API中控制的限度都必须符合前面提到的ICH/VICH指南中对于残留溶剂规定的限度。
In all cases, the content of class 1 solvents in the final active substance should comply with the requirements of the relevant aforementioned Guideline, if tested.任何存在I类溶剂测试的情况下API中I类溶剂的残留量都必须符合前面提到的指南中相应的要求。
A class 1 solvents used as starting materials作为起始物料使用的I类溶剂Certain class 1 solvents, such as benzene and 1,2-dichloroethane, can be used as starting materials.Indeed, the use of benzene as a starting material is unavoidable when benzene is a structural part of the active substance.某些特定的I类溶剂，如苯和1,2-二氯乙烷是可能被用作起始物料的。