EMA残留溶剂指南附录.pdf

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）。

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.。

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。

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。

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。

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。

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