ICH Q C R 残留溶剂 培训
ICH常用有机溶剂分类及残留限度
ICH常用有机溶剂分类及残留限度国际药品管理机构ICH（International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use）在药品的质量控制方面，制定了一系列规定。
其中，ICH Q3C Guideline for Residual Solvents是针对制药过程中可能存在的残留有机溶剂进行限制和规定的。
该指南中将有机溶剂分为三类：类1、类2和类3。
本文将详细介绍ICH常用的有机溶剂分类及其残留限度。
类1有机溶剂类1有机溶剂是指在制药工业中使用频率最高、风险最低的有机溶剂。
这类有机溶剂在制药过程中的使用应该越少越好，但即使在非常规制造情况下，其残留量也应该受到限制。
以下是ICH对类1有机溶剂的限制：有机溶剂残留限度（mg/每日剂量单位）苯 2甲苯50二氯甲烷601,2-二氯乙烷 41,1,1-三氯乙烷0.61,1-二氯乙烷 61,1,2-三氯乙烷 11,1,2,2-四氯乙烷0.62-氯乙酸乙酯2002-乙醇5000甲醇3000丙酮300乙酸丁酯300乙酸乙酯900甲醛30N,N-二甲基甲酰胺390乙酸乙酰胺600乙醇5000类2有机溶剂类2有机溶剂与类1有机溶剂相比，使用的风险略高一些。
类2有机溶剂的使用应该尽量避免，但如果使用，其残留也应该受到限制。
以下是ICH对类2有机溶剂的限制：有机溶剂残留限度（mg/每日剂量单位）丁酮0.81-丁醇802-丁醇50叔丁醇600溴丁烷 3正丁烷3000甲苯500乙苯420乙醇3000乙酸异丙酯500乙腈20二甲苯150二甲醚3000二氯乙烷 5甲酸甲酯 3甲酸乙酯300甘油正丁醚690甘油乙二醇正丁醚690甘油乙醚/环已醚840马来酸酐30甲酸300三氯乙烯 4类3有机溶剂类3有机溶剂的使用量和风险都比类1和类2更高。
这类有机溶剂在制药过程中必须严格控制，在常规制药过程中尽可能避免使用。
ichq3c溶剂残留指导原则
ichq3c溶剂残留指导原则？
答：ICH Q3C是国际药品注册协调委员会（International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use，简称ICH）发布的一系列指导原则之一。
ICH Q3C溶剂残留指导原则旨在提供关于制药产品中有机溶剂残留限量的建议和指导。
这些指导原则主要适用于药品开发和注册过程中的有
机溶剂残留问题，并帮助制药行业确保药品制造过程中使用的有机溶剂不对人体产生不良影响。
ICH Q3C溶剂残留指导原则分为三个部分：
1.ICH Q3C（R6）：这个文档提供了关于食品和药品制品中有机溶剂残留限量的概述和指南。
它包含了各种有机溶剂的分类、评估方法和安全性评价。
2.ICH Q3C（R8）：这个文档是对Q3C（R6）的更新版本，添加了关于新的有机溶剂的信息，包括氯仿和四氢呋喃等。
3.ICH Q3C（R7）：这个文档是对Q3C（R6）的进一步更新版本，修订了关于有机溶剂分类和限量的一些内容。
根据ICH Q3C溶剂残留指导原则，制药企业需要进行有机溶剂残留评估，并确保其产品中的有机溶剂残留量在国际上接受的安全水平范围内。
这有助于确保药品的质量、安全性和有效性。
请注意，具体的有机溶剂残留限量要求可能因地区和国家而异，制药企业在制定和执行相关政策时应考虑当地法规和准则。
ICH_Q3a培训PPT概述
杂质报告
• 保留从研制开始到模拟上市的所有批次的分析记录，包括 图谱。 • 记录应包括：
a. b. c. d. e. f. g.
批号与批量 生产日期 生产地点 生产工艺 单个杂质的含量与总杂质含量 批次的用途 分析方法的参考文献
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杂质限度
• 在新原料药中将要检测的杂质应根据模拟上市 生产的批次 所发现的杂质来选择。并有列入和不列入的理由。 • 列人新原料药规 范中所需检测的杂质称为特定杂质。特定 杂质可能是已确定的。也可 能是未确定的。
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杂质报告
• 汇总于临床、安全性研究、稳定性试验的新原料药所有批 次 产品的分析结果以及用于模拟上市产品的分析结果。 • 报告这些批次的新原料药中的每个已确定或未确定的杂质 量及 杂质总量，使用表格形式更佳、各杂质均应以编号或 以合适的参数〔例 如：保留时间〕表示。
• 对于那些存在的，但其含量低于定量限度的杂 质。可以不 必报告；
ICH Q3a
新原料药中的杂质
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范围
适用于化学合成的新原料药（未在成员国注册）。
不适用于草药及来源于动植物的粗制品。
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研究方向
化学方面：包括对杂质的分类和界定、杂质产生的报告、建 立规范以及对分析方法的简要讨论。 安全性方面：某些杂质，他们在用于安全性研究和临床研究 的新药批次中不存在和（或）实际水平高于那 些批次，对这 些杂质的界定进行专门指导。杂 质的阈值应确定，低于阈值 的，则不需要界定。
产生于生产过程，一般是已知的和确定的
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残留溶剂
• 生产过程中，使用的，通常是已知的，包括毒性，容易控 制。
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本文不包括
（1）外源性污染物（不应该存在于 新原料药中，可以用 GMP 来控制）； （2）多晶型（一种新原料药的 固态性质）； （3）对映体杂质。
ICH杂质残留溶剂的指导原则QCR
ICH杂质残留溶剂的指导原则QCRICH杂质残留溶剂的指导原则QCR（Quality Control Residual Solvents）是国际药品监管机构-国际药品注册、技术和质量控制委员会（ICH）发布的一项指南，用于规范药品制造过程中的溶剂残留物的质量控制。
溶剂残留物是指在药品生产过程中添加的溶剂，但在制剂中未完全蒸发或被移除的溶剂。
导言溶剂在药品生产过程中广泛应用，包括分离、提取、结晶和纯化等步骤。
然而，溶剂中的残留物可能对人体产生毒性或对药品质量产生影响。
因此，在药品开发和生产过程中，需要对残留溶剂进行必要的质量控制。
溶剂分类ICHQCR指导原则将溶剂分为类1、类2A和类2B三类。
类1溶剂是无毒、无致畸、无致癌和生殖毒性的溶剂，如水、乙醇、甘油等。
这些溶剂的使用一般没有限制。
类2A溶剂是有潜在毒性或限制使用的溶剂，但在限定剂量下不会对人体产生危害。
这类溶剂的最大可容许残留量取决于药物用量、剂型和给药途径。
一些常见的类2A溶剂包括氯仿、氯化甲烷、二氯甲烷等。
类2B溶剂是有潜在毒性，并且在制剂中的残留量应尽量减少的溶剂。
这类溶剂的最大可容许残留量取决于药物用量和给药途径。
一些常见的类2B溶剂包括苯、乙酸乙酯、二甲基甲醚等。
质量控制要求ICHQCR指导原则确定了三种质量控制要求来管理溶剂残留物。
1. 可容许残留量（Permitted Daily Exposure, PDE）：PDE是指人体每日接触该溶剂残留量的最大可容许量。
它可以通过毒理学评估和毒性数据来确定。
对于类1溶剂，PDE通常设置为无限大。
对于类2A和类2B 溶剂，PDE被用来确定最大可容许残留量。
2.可容许残留量限度：可容许残留量限度是指药品中残留溶剂的最大可容许浓度。
它根据预期剂量、给药途径和药物性质等因素来确定。
通过使用PDE和剂量预设的数学公式，可以计算出每种溶剂的可容许残留量限度。
3.分析方法：为了确保溶剂残留物的质量控制，需要使用适当的分析方法进行检测和分析。
有机溶剂残留量的测定培训课件
5000
▪ 乙酸异丙酯 Isopropyl acetate
5000
▪ 乙酸甲酯 Methyl acetate 5000
▪ 3－甲基－1－丁醇 3-Methyl-1-butanol
▪ 丁酮 Methylethyl ketone
5000
▪ 甲基异丁基酮 Methylidobutyl ketone 5000
合成化学发展水平
判断使用 是否合理
合理 不合理
严格控制残留量 替代研究
临床研究前 临床研究期间
产品上市后
有机溶剂残留量的测定
13
确定何种溶剂需进行研究的原则
▪ 意义和目的
保障临床用药安全，控制产品质量
▪ 与其他方面研究工作密不可分
进一步验证工艺控制的合理性 为确定合理可行的质量标准提供数据支持
▪ 思考的出发点
▪ 1，2－二氯乙烯 1,2-Dichloroethene
1870
▪ 二氯甲烷 Dichloromethane 600
▪ 1，2－二甲氧基乙烷 1,2-Dimethoxyethane 100
有机溶剂残留量的测定
22
第二类溶剂（应该限制使用）
▪ N,N-二甲氧基乙酰胺N,N-Dimethylacetamide 1090
顶空进样法 直接进样法 ▪ HPLC法：例如测定吡啶 ▪ 离子色谱法：测定N-甲基吡咯烷酮 ▪ 气质联用
有机溶剂残留量的测定
28
有机溶剂残留量测定方法分类
▪ 1.直接进样法 适用范围：沸点高溶剂或受热不易分解样品。 优点：简便、无需专用设备，绝对进样量大。 缺点：污染进样口及柱子，溶剂峰响应大，样
▪ N,N-二甲氧基甲酰胺N,N-Dimethylformamide 880
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。
ICH_Q3c_杂质：残余溶剂的指导原则（中文版）纯净版
ICH_Q3c_杂质：残余溶剂的指导原则（中文版）纯净版杂质：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。
第 1 页共 18 页杂质：残留溶剂的指导原则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。
残留溶剂培训讲义USP467
• 2类混合A标准溶液：移取1.0ml2类标准贮备液A到合适的顶空瓶中，加
5.0ml水，密封，加盖 。 • 2类混合B标准溶液：移取5.0ml2类标准贮备液B到合适的顶空瓶中，加
1.0ml水，密封，加盖。
• 供试贮备液——精密称取供试品约250mg到25-ml容量瓶，用水溶解并稀 释到刻度，摇匀。
• 供试液——移取5.0ml供试贮备液到适宜的顶空瓶中，加入1.0ml水，
加盖密封，摇匀。 • 一类系统适应性溶液 ——移取1.0ml一类标准贮备液到合适的顶空瓶 中，加入5.0ml供试贮备液，加盖密封，摇匀。
气相色谱系统（见色谱法<621>）
• 色谱柱：0.32-mm × 30-m的弹性石英色谱柱，液膜厚1.8-µ m的 G43，或0.53-mm × 30-m的多孔性色谱柱，液膜厚3.0-µ m 的G43 • 载气：氮气（或氦气）线速度约为35cm/s • 分流比为1：5 （为了优化灵敏度，可适当调节） • 柱温：先在40℃维持20分钟，再以10℃/min的升温速率升至240，并 维持20分钟 • 进样口温度： 140℃ • FID检测器温℃：250℃
和在临床研究阶段研发的制剂，也不适用于已存
在的市售制剂。
残留溶剂按风险评估的分类 “ 每日允许接触量”（PDE）用于定义药物中可接
受的有机溶剂的最大摄入量。应采用多种灵敏度高、 选择性好、线形范围宽的检测器 按对人类健康的潜在危险分为如下三类 一类
应该避免使用
公认的对人体有致癌作用
非常可疑为对人体有致癌作用 对环境有危害作用
二类
应该限制使用 对动物无遗传毒性，但可能存在其他不可逆的毒性， 如神经毒性、致畸性。 非常可疑存在其他潜在的严重的可逆毒性。
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PDE（Permitted Daily Exposure）
每日允许暴露量 指药物中残留溶剂每日可接受的最大摄入量
• 认为这些限度适用于所有原料药、辅料和制剂。 •因此，若日摄入总量未知或未定，可采用这种方法。 •若处方中的所有辅料及原料药都符合限度，则这些组分可按任意比例使用。 •只要日摄入总量不超过 10g，就无须进一步计算。
• 对人体低潜在毒性的溶剂，无须制定基于健康的暴露限度。3类溶剂的PDE为每天50mg或 50mg以上
LIMITS 残留溶剂的限度
• ICH Q3C（R6）与《中国药典》（2015年）的对比
Ⅰ类溶剂限度
ICH Q3C（R6）与ChP 2015 四部 0861 中的Ⅰ类溶剂，种类与限度均一致 注意：1,1,1-三氯乙烷：限度高，但是属于Ⅰ类溶剂。
– 2、异丙基苯（Ⅲ类 → Ⅱ类）
CALCULATED 残留溶剂限度计算与检测 DETECTED
• ICH Q3C（R6）提供计算方法 • 采用气相色谱法或干燥失重测定法进行检测
残留溶剂限度计算
• 残留溶剂限度是如何计算的？
浓
度
（ppm）
1000
剂
PDE（mg / day） 量（g / day）
组分 原料药 辅料1 辅料2
制剂
在处方中的量 0.3g 0.9g 3.8g 5.0g
乙腈的含量 800ppm 400ppm 800ppm 728ppm
日暴露量 0.24mg 0.36mg 3.04mg 3.64mg
超限（410ppm）
超限（410ppm）
合格（低于4.1mg/day）
残留溶剂的检测方法
ICH Q3C 分享与交流 ICH Q3C（R6） 杂质：残留溶剂的指导原则 培训师：XR.Kong
参考资料 • ICH Q3C（R6）
– 2016年10月发布
• ChP 2015 Part4 0861
– 2015年12月实施
DEFINED 残留溶剂定义与分类
• ICH Q3C（R6）对残留溶剂的定义、研究目的以及分 类
残留溶剂的定义
• 定义：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。
• 控制目的：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。
• 气相色谱法（GC）
–GC为推荐使用的方法 –参见《中国药典》2015年版 四部 通则0861 残留溶剂测定法
• 干燥失重测定法
–当仅存在Ⅲ类溶剂时，可以采用该法
残留溶剂报告
•仅可能存在Ⅲ类溶剂——干燥失重小于0.5%。 •仅可能存在Ⅱ类溶剂——全部低于限度。 •仅可能存在Ⅱ类溶剂和Ⅲ类溶剂——残留的Ⅱ类溶剂低于限度，残留的Ⅲ类溶剂 低于0.5% •如果可能存在Ⅰ类溶剂，应进行鉴定并定量。 •如果Ⅱ类溶剂高于限度或Ⅲ类溶剂高于0.5%——应对其进行鉴定和定量。
“可能存在”系指用于工艺最后一步，以及用于较前几步生产工艺、用经验证的工艺不能 一致地除尽的溶剂。
谢谢
THANK YOU
Ⅱ类溶剂限度
• 关注点
– 1、异丙基苯（5000ppm → 70 ppm，Ⅲ类 → Ⅱ类） – 2、甲基异丁基酮（5000ppm → 4500 ppm，Ⅲ类 → Ⅱ类）
Ⅲ类溶剂限度
• 限度 – Ⅲ类溶剂的限度均为5000ppm（0.5%）
• 关注点 – M），规定 为320ppm（0.032%）
残留溶剂分类
• ICH Q3C（R6）中，将溶剂分为三类： – Ⅰ类：应避免的溶剂
• 已知的人体致癌物，强疑似人体致癌物，以及环境危害物。
– Ⅱ类：应限制的溶剂
• 非遗传毒性动物致癌物质，或可能导致其他不可逆毒性如神经毒性或致畸性的溶剂。可能有 其他严重但可逆的毒性的溶剂。
– Ⅲ类：低潜在毒性的溶剂
eg.乙腈的限度计算： 10001（04g.（1/ mdagy/）day） 410 ppm
残留溶剂限度计算
• 原料药残留溶剂量能否超过限度？
– 若制剂的给药剂量超过 10g/day – 若原料、辅料中残留溶剂量超过限度
• 将制剂各成分所含的残留溶剂累加，每天的溶剂总量应低于PDE给定的值。
超限（410ppm）