Q3C残留溶剂中英文
usp 溶剂残留 中英文版
<467>溶剂残留简介：INTRODUCTIONThis general chapter applies to existing drug substances, excipients, and products. All substances and products are subject to relevant control of solvents likely to be present in a substance or product.本章节适用于现有的原料药，辅料和制剂。
应对原料药或制剂产品中可能存在溶剂的所有原料及制剂产品进行控制。
Where the limits to be applied comply with those given below, tests for residual solvents are not generally mentioned in specific monographs, because the solvents employed may vary from one manufacturer to another.当限值与下面提供的数值相符合，残留溶剂的测试方法一般不会在专论中特别，因为不同制造商所使用的溶剂不同。
The objective of this general chapter is to provide acceptable amounts of residual solvents in pharmaceuticals for the safety of the patient. The chapter recommends the use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents.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。
Q3C残留溶剂中英文
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。
EP2.4.24残留溶剂的鉴定与控制中英文对照版(带图)
残留溶剂的鉴定及控制该方法适用于： .1.在活性物质、赋形剂或药品中的未知的一类或二类溶剂残留量的鉴定；2.在活性物质、赋形剂或药品中的一类或二类溶剂残留量的限量试验；3.当二类溶剂的限度大于1000ppm（0.1%）或要求检测三类溶剂时的限量试验。
—类溶剂、二类溶剂、三类溶剂的分类见5.4以下给出了三种样品溶液的稀释方法，以及气相色谱顶空进样的系统条件。
还给出了两种气相色谱的系统条件，系统A为首选方法，同时系统B适用于一般的鉴别试验。
样品溶液的制备方法由样品的溶解性和待测的溶剂种类决定。
下列溶剂不适于用顶空进样法测定：甲酰胺、2—乙氧基乙醇、2—甲氧基乙醇、乙二醇、N-甲基吡咯烷酮、环丁砜(四氢噻吩砜)，但可采用其他的适当的方法测定。
当采用其他的方法定量测定有机残留量时，必须进行方法验证采用静态顶空进样法测定样品溶液制备1：适用于在水中易溶的物质的残留溶剂的测定样品溶液(1)：取0.200g待测物质，用水溶解并稀释至20m1样品溶液制备2：适用于在水中不溶的物质的残留溶剂的测定样品溶液(2)：取0.200g待测物质，用N,N--二甲基甲酰胺(DMF)溶解并稀释至20ml样品溶液制备3：适用于测定N,N---二甲基乙酰胺或N,N--二甲基甲酰胺的残留量，当怀疑他们存在时。
样品溶液(3)：取0.200g待测物质，用1，3—二甲基-2-咪唑啉酮（DMI）溶解并稀释至20ml如果上述方法均不适宜，那么所用稀释方法及静态顶空进样条件均必须验证其合理性。
溶剂溶液(a)：吸取一类残留溶剂标准溶液1.0ml，用水稀释至100.0ml，再吸取该溶液1.0ml，用水稀释至10.0ml。
溶剂溶液(b)：吸取适量二类溶剂溶于二甲基亚砜，用水稀释至100.0ml，再用水将该溶液稀释至限量的1/20（限量见5.4表格二）。
溶剂溶液（c）：称取1.00g溶剂或待测物质中存在的，用二甲基亚砜或水溶解，用水稀释至100.0ml，再用水将该溶液稀释至限量的1/20（限量见5.4表格一或二）。
ICH 杂质：残留溶剂的指导原则 Q3C(R6)
人用药品注册技术要求国际协调会ICH协调指导原则杂质：残留溶剂的指导原则Q3C（R6）现行第四阶段版本2016年10月20日本指导原则由相应的ICH专家工作组制定，并根据ICH进程已提交给管理当局征询意见。
在ICH进程的第四阶段，最后的草案被推荐给欧盟、日本、美国、加拿大和瑞士的管理机构采纳。
Q3C（R5）文件历史母指导原则：杂质：残留溶剂的指导原则对母指导原则所含THF的PDE信息的修订修订母指导原则所含NMP的PDE信息母指导原则：杂质：残留溶剂的指导原则对母指导原则所含异丙基苯的PDE信息的修订修订母指导原则所含甲基异丁基酮的PDE信息，并纳入三乙胺的PDE杂质：残留溶剂的指导原则ICH协调指导原则目录第一部分：1. 引言 (1)2. 指导原则的适用范围 (1)3. 通则 (2)3.1 基于风险评估的残留溶剂的分类 (2)3.2 建立暴露限度的方法 (2)3.3 2类溶剂限度的表示方法 (2)3.4 分析方法 (4)3.5 残留溶剂的报告水平 (4)4. 残留溶剂的限度 (4)4.1 应避免的溶剂 (4)4.2 应限制的溶剂 (5)4.3 低潜在毒性的溶剂 (6)4.4 没有足够毒理学数据的溶剂 (7)词汇表 (8)附录1：指导原则中包括的溶剂列表 (9)附录2：其他背景 (13)A2.1 环境领域对有机挥发性溶剂的监管 (13)A2.2 药物中的残留溶剂 (13)附录3：建立暴露限度的方法 (14)第二部分：四氢呋喃的PDE (17)第三部分：N-甲基吡咯烷酮（NMP）的PDE (19)第四部分:异丙基苯的PDE (21)第五部分:三乙胺的PDE和甲基异丁基酮的PDE (24)第一部分：杂质：残留溶剂的指导原则在1997年7月17日的ICH指导委员会会议上进入ICH进程第四阶段，并建议ICH的三方监管机构采纳该指导原则1. 引言本指导原则旨在建议为保证患者安全而应规定的药物中残留溶剂的可接受量。
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。
关于国际药品注册翻译说明
国际药品注册翻译医药翻译网的国际药品注册翻译译员多毕业于国内外著名医科大学，并在各自的国际药品注册翻译领域有过丰富翻译经验。
国际药品注册翻译人员都经过严格测试，大多有国外留学、工作经历，具有良好的国际药品注册翻译能力。
国际药品注册翻译网项目组成员对国际药品注册翻译的文化背景、语言习惯、专业术语等有深入的把握。
医药翻译网鼎力提供每位国际药品注册翻译客户质量最高、速度最快的国际药品注册翻译。
医药翻译网凭借严格的质量控制体系、规范化的运作流程和独特的审核标准已为各组织机构及来自全球的医药公司提供了高水准的国际药品注册翻译，不少的医药公司还跟我们签定了长期合作协议。
国际药品注册翻译的质量和速度质量是企业生存和发展的根本，为确保国际药品注册翻译的准确性，项目的全过程如下：一、庞大国际药品注册翻译团队保证各类国际药品注册翻译稿件均由专业人士担任。
二、规范化的国际药品注册翻译流程。
从获得资料的开始到交稿全过程进行质量的全面控制，并同时做到高效率，快速度的原则。
三、及时组建若干翻译小组，分析各项要求，统一专业词汇，确定语言风格，译文格式要求。
四、国际药品注册翻译均有严格的语言和专业技术双重校对。
从初稿的完成到统稿，从校对到最终审核定稿，甚至词汇间的细微差别也力求精确。
五、不间断的进行招聘，充足的人力资源不断汇集国际药品注册翻译界的精英和高手。
不断对内部及外聘国际药品注册翻译人员进行系统的再培训工程。
六、曾6 小时翻译4.5 万字的速度客户所需。
七、有效沟通。
国际药品注册翻译大项目组协调各方面工作：高级项目经理项目经理（Project Manager)翻译（Translation）编辑（Editing）校对（Profreading）质量控制（Quality Assurance）国际药品注册翻译技术配备一、制作部配备有先进的计算机处理设备，多台扫描仪、打印机、光盘刻录机、宽带网络接入、公司拥有独立的服务器，各项领先技术确保所有文件系统化处理和全球同步传输。
Q3C(R6)-20191004-S-Step 4杂质：残留溶剂指导原则
人用药品注册技术要求国际协调会ICH H ARMONISED G UIDELINEICH 协调指导原则杂质：残留溶剂的指导原则 Q3C(R6)最终版本2016年 10 月 20日本指导原则由相应的ICH 专家工作组制定，并根据ICH 进程已提交给管理当局征询意见。
在ICH 进程的第四阶段，最后的草案被推荐给欧盟、日本、美国、加拿大和瑞士的管理机构采纳。
Q3C（R6）文件历史母指导原则：杂质：残留溶剂的指导原则对母指导原则所含THF的PDE信息的修订修订母指导原则所含NMP的PDE信息母指导原则：杂质：残留溶剂的指导原则对母指导原则所含异丙基苯的PDE信息的修订修订母指导原则所含甲基异丁基酮的PDE信息，并纳入三乙胺的PDE乙二醇PDE修正I MPURITIES: G UIDELINE FOR R ESIDUAL S OLVENTS杂质：残留溶剂的指导原则TABLE OF CONTENTS目录PART I:IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS (4)第一部分：杂质：残留溶剂的指导原则 (4)1.INTRODUCTION引言 (4)2.SCOPE OF THE GUIDELINE 指导原则的适用范围 (5)3.GENERAL PRINCIPLES通则 (6)3.1Classification of Residual Solvents by Risk Assessment基于风险评估的残留溶剂的分类 (6)3.2 Methods for Establishing Exposure Limits 建立暴露限度的方法 (6)3.3 Options for Describing Limits of Class 2 Solvents 2 类溶剂限度的表示方法 (7)3.4 Analytical Procedures分析方法 (9)3.5 Reporting levels of residual solvents残留溶剂的报告水平 (9)4.LIMITS OF RESIDUAL SOLVENTS 残留溶剂的限度 (10)4.1 Solvents to Be Avoided应避免的溶剂 (10)4.2 Solvents to Be Limited应限制的溶剂 (10)4.3 Solvents with Low Toxic Potential低潜在毒性的溶剂 (12)4.4 Solvents for which No Adequate Toxicological Data was Found 没有足够毒理学数据的溶剂 (13)GLOSSARY术语 (14)APPENDIX 1. LIST OF SOLVENTS INCLUDED IN THE GUIDELINE附录 1：指导原则中包括的溶剂列表 (15)APPENDIX 2. ADDITIONAL BACKGROUND附录 2：其他背景 (18)APPENDIX 3. METHODS FOR ESTABLISHING EXPOSURE LIMITS附录 3：建立暴露限度的方法 (19)PART II:IMPURITIES: RESIDUAL SOLVENTS (MAINTENANCE)PDE FOR TETRAHYDROFURAN第二部分：杂质：残留溶剂（修订）四氢呋喃的 PDE (23)PART III:IMPURITIES : RESIDUAL SOLVENTS (MAINTENANCE) PDE FOR N-METHYLPYRROLIDONE (NMP) 第三部分：杂质：残留溶剂（修订）N-甲基吡咯烷酮（NMP）的 PDE25 PART IV:IMPURITIES : RESIDUAL SOLVENTS (MAINTENANCE) PDE FOR CUMENEICH Harmonised Tripartite Guideline第四部分：杂质：残留溶剂（修订）异丙基苯的 PDE (27)PART V:IMPURITIES : RESIDUAL SOLVENTS (MAINTENANCE)PDE FOR TRIETHYLAMINE AND PDE OF METHYLISOBUTYLKETONE第五部分：杂质：残留溶剂（修订）三乙胺的 PDE 和甲基异丁基酮的 PDE (31)PART I:IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS第一部分：杂质：残留溶剂的指导原则Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 17 July 1997, this Guideline is recommended for adoption to the three regulatory parties to ICH在 1997 年 7 月 17 日的 ICH 指导委员会会议上进入 ICH 进程第四阶段，并建议 ICH 的三方监管机构采纳该指导原则1.INTRODUCTION引言The objective of this guideline is to recommend acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. The guideline recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents.本指导原则旨在建议为保证患者安全而应规定的药物中残留溶剂的可接受量。
药物中的残留溶剂测定
有机溶剂的分类
分类依据： 允许日暴露量（permitted daily exposure PDE） 定义： 是指某一有机溶剂被允许摄入而不产生毒性的日平 均最大剂量，单位为mg/天
有机溶剂的分类
类别 第一类溶剂 毒性 人体致癌物、疑为人 体致癌物或环境危害 物 有非遗传致癌毒性或 其他不可逆毒性、或 其他严重的可逆毒性 对人体低毒 没有足够毒性资料 PDE（ mg/天） 0.1以下(1,1,1) 三氯乙烷除外 0.5-50
PDE : mg/天
剂量: g/天
有机溶剂的引入
根据研究对象具体情况 分析有机溶剂的引入 有机溶剂毒性
确定何种有机溶剂需要进行研究
研究方法的建立及方法学验证
研究结果的分析及质量标准的建立
有机溶剂的引入
原料药/辅料：合成过程中引入 包括： 作为合成原料或反应溶剂引入 作为反应副产物引入 由其他合成原料或其他溶剂带入 制剂 各种成份（原料药、辅料）带入 制剂制备过程中引入
有机溶剂的引入
研究集中在：原料药的第一种情况 影响因素： 有机溶剂在合成过程中使用的步骤 后续步骤中使用的有机溶剂对之前使用的溶剂的影 响 中间体的影响（中间体的纯化方法、干燥条件） 终产品精制方法和条件等等
有机溶剂的引入
制剂 控制原料药的残留溶剂，最终目的是控制制剂的残留 溶剂，使之符合规定。有时候根据制剂的一些特点， 可能对原料药残留溶剂的研究和限度要求进行特殊性 的考虑。
药物中的残留溶剂测定
浙江省药品检验所 高素英
前 言
定义:药物中的残留溶剂（ Residual Solvent ）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。 研究的性质：杂质研究的范畴 研究的目的:控制药物质量，保障病人用药安全。 在原料药合成中，溶剂的选择是合成中非常关键的因 素,选择适当的溶剂可提高得率或决定药物的性质，如 晶型、纯度和溶解度，从而影响疗效。同时，在某些 特定的制剂生产中，其工艺也要求使用特定的溶剂。 但由于溶剂没有疗效，故所有残留溶剂均应尽可能除 去，以使产品符合其规范、GMP或其他基本的质量要 求 。
- 1、下载文档前请自行甄别文档内容的完整性，平台不提供额外的编辑、内容补充、找答案等附加服务。
- 2、"仅部分预览"的文档,不可在线预览部分如存在完整性等问题,可反馈申请退款(可完整预览的文档不适用该条件!)。
- 3、如文档侵犯您的权益，请联系客服反馈,我们会尽快为您处理(人工客服工作时间：9:00-18:30)。
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。
果制剂生产中用到某种溶剂，也应进行测定。
本指导原则不适用于临床研究阶段的准新原料药、准赋形剂和准制剂。
也不适用于已上市的药品。
本指导原则适用于所有剂型和给药途径。
短期（如30天或更短）使用或局部使用时，允许存在的残留溶剂水平可以较高。
应根据不同的情况评判这些溶剂水平。
有关残留溶剂的背景附加说明见附录2。
3．通则3.1 根据危害程度对残留溶剂分类“可耐受的日摄人量”（TDI）是国际化学品安全纲要（IPCS）用于描述毒性化合物接触限度的术语。
“可接受的日摄人量”（ADI）是WHO及一些国家和国际卫生组织所用的术语。
新术语“允许的日接触量”（PDE）是本指导原则中用于定义药物中可接受的有机溶剂摄人量，以避免与同一物质的ADI混淆。
本原则中残留溶剂的评价以通用名和结构列于附录1，根据它们对人体可能造成的危害分为以下三类；（1）第一类溶剂：应避兔的溶剂为人体致癌物、疑为人体致癌物或环境危害物。
（2）第二类溶剂。
应限制的溶剂非遗传毒性动物致癌或可能导致其他不可逆毒性测神经毒性或致畸性）的试剂。
可能具其他严重的但可逆毒性的溶剂。
（3）第三类溶剂：低毒性溶剂对人体低毒的溶剂，无须制定接触限度；第三类溶剂的PDE为每天50mg或50mg以上。
3.2 建立接触限度的方法用于建立残留溶剂的PDE方法见附录3。
用于建立限度的毒理数据的总结见Pharmeuropa，V ol . 9，No . l，Suplement，April 1997.3.3 第二类溶剂限度的选择方法制定第二类溶剂的限度时有两种选择。
方法1: 使用表2中以 ppm为单位的浓度限度，假定日给药量为10g，以方程(1)计算。
方程(1) C(ppm)=PDE：mg／天 剂量：g／天这些限度对所有原料药、赋形剂和制剂均适用。
因此，这一方法可用于日剂量未知或未定的情况、只要在处方中所有的赋形剂和原料药都符合方法1给定的限度，就可以以任何比例用于制剂。
只要日剂量不超过10g，就无须进一步计算。
服用剂量超过 10g／天，应考虑用方法2。
方法2：制剂中的每一种成分不必符合方法1的限度。
药物中允许的残留溶剂限度水平，可根据表2中 PDE mg／天及已知最大日剂量，用方程（1）来计算。
只要证明已降低至实际最低水平，便可以认为这种限度是可接受的、该限度能说明分析方法的精度、生产能力和生产工艺的合理变异，并能反映当前生产的标准水平。
应用方法2时可将药物制剂的每种成分中残留溶剂叠加起来，每天的总溶剂量应低于PDE给定的值。
下面举例说明如何用方法l和2来考虑制剂中的乙睛限度。
乙睛的允许日接触量是4.1 mg／天，因此由方法1算出限度是410PPm；如现在日最大给药量是5.0g，制剂中含两种赋形剂，制剂中的成分和计算得到的最大残留乙睛量见下表：成分处方量乙睛量 日（摄人）量原料药 0.3g 800ppm0.24mg辅料一 0.9g 400ppm 0.36mg辅料二 3.8g 800PPm 3.04mg药物制剂 5.09 728ppm 3.64mg 辅料1符合方法1限度，但原料、辅料2和药物制剂不符合方法1限度，而制剂符合方法2规定的4.1mg／天，故符合本指导原则的建议值。
乙睛作为残留溶剂的另一例子，曰最大给药量5刀g，制剂中含两种赋形剂，各组分及计算得到的最大残留的乙睛最见下表：成分 处方量 乙睛量 日（摄人）量原料药 0.3g 800ppm 0.24mg辅料1 0.9g 2000ppm 1.80mg辅料 3.8g 800ppm 3.04mg药物制剂 5.0g 1016ppm 5.08mg此例制剂中乙睛限度总量既不符合方法1也不符合方法2。
生产厂可先测定制剂，以确定在处方工艺中能否降低已睛水平，如果不能将乙腈水平降至允许范围，生产厂应采取措施降低制剂中的乙腈量；若所有措施均不能降低残留溶剂的水平，厂方应提供其尝试降低残留溶剂以符合指导原则所做工作的总结报告，并以利弊分析报告证明允许该制剂存在的较高水平的残留溶剂。
3.4 分析方法残留溶剂通常用色谱技术，如用GC法测定，如可能，对药典上规定要检测的残留溶剂，应采用统一了的测定方法。
生产厂也可选用更合适的、经论证的方法来测定。
若仅存在第三类溶剂；可用非专属性的方法如干燥失重来检查。
残留溶剂的方法论证应遵循ICH指导原则：“分析方法论证：定义和术语”及“分析方法论证：方法学”。
3.5 残留溶剂的报告水平制剂生产商需要了解有关赋形剂或原料药中残留溶剂量的信息，以符合本指导原则的标准。
以下阐述了赋形剂或原料药供应商应提供给制剂牛产商的信息的～些例子。
供应商应选择以下一项：·仅可能存在第三类溶剂，干燥失重小于0.5％。
·仅可能存在第M类溶剂，X、Y……全部应低于方法1的限度。
（这里供应商应将第二类溶剂用X、Y……来表示）·仅可能存在第二类溶剂X、Y……和第三类溶剂，残留的第三类溶剂低于方法1的限度，残留的第三类溶剂低于0．5％。
如果可能存在第一类溶剂，应进行鉴定并定量。
“可能存在”系指用于工艺最后一步的溶剂和用于较前几步工艺的溶剂经论证不能全部除尽。
如果第二类溶剂高于方法1的限度或第三类溶剂高于0.5％，应鉴定并定量。
4. 残留溶剂的限度4.1应避免的溶剂因其具有不可接受的毒性或对环境造成公害，第一类溶剂在原料药、赋形剂及制剂生产中不应该使用。
但是，为了生产一种有特殊疗效的药品而不得不使用时，除非经过其他论证，否则应按表1控制，1，1，1－三氯乙烷因会造成环境公害列人表1，其限度1500ppm是基于安全性数据而定的。
表1 药物制剂中含第一类溶剂的限度（应避免使用）溶剂浓度限度（ppm）备注苯 2 致癌物四氯化碳 4 毒性及环境公害1,2－二氯乙烷 5毒性1,1－二氯乙烷 8毒性1,1,1－三氯乙烷 1500环境公害4.2 应限制的溶剂列于表2的溶剂，由于其具毒性，在制剂中应予限制，规定 PDE约 0.1mg／天，浓度约10ppm。
所列值不能反映测定所必需的分析精度，精度应为方法论证的一部分。
表2 药品中第二类溶剂溶剂 PDE（mg/天） 浓度限度（ppm）乙晴 4.1 410氯苯 3.6 360氯仿 0.6 60环氧乙烷 38.8 38801,2－二氯乙烯 18.7 1870二氯甲烷 6.0 6001,2－二甲亚砜 1.0 100N,N－二甲乙酰胺 10.9 1090N,N－二甲基甲酰胺 8.8 8801,4－二恶烷 3.8 3802－乙氧基乙醇 1.6 160乙二醇 6.2 620甲酰胺 2.2 220正己烷 2.9 290甲醇 30.0 30002－甲氧基乙醇 0.5 50甲基丁酮 0.5 50甲基环己烷 11.8 1180N-甲基吡咯烷酮 48.4 4840硝基甲烷 0.5 50吡啶 2.0 200二氧噻吩烷 1.6 160四氢萘 1.0 100甲苯 8.9 8901,1,2-三氯乙烯 0.8 80二甲苯* 21.7 2170 *通常为60% m-二甲苯，14% p-二甲苯，9% o-二甲苯和17%乙基苯。
４.３低毒溶剂第三类溶剂（见表３）可能低毒，对人体危害很小。
第三类溶剂包括人们认为在药物中以一般量存在时对人体无害的溶剂，但该类溶剂中许多尚未进行长期毒性或致癌研究。
急性毒性或短期毒性试验表明这类溶剂几乎无毒、无遗传毒性。
每日50mg或更少量无须论证即可接受（用方法１计算。
即5000ppm或0.5％）。
如果能够反映生产能力和ＧＭＰ的实际情况，更大的量也可接受。
表３在GＭＰ或其他质量要求中应限制的第三类溶剂醋酸 乙醇 甲乙酮丙酮 醋酸乙酯 甲基异丁酮苯甲醚 乙醚 2-甲基-1-丙醇1-丁醇 甲酸乙酯 戊烷2-丁醇 甲酸 正丙醇醋酸丁酯 正庚烷 正戊醇叔丁基甲基醚 醋酸异丙酯 醋酸异丁酯醋酸甲酯 2-丙醇 异丙基苯3-甲基-1-丁醇 醋酸丙酯 二甲亚砜四氢呋喃4.4 没有足够毒性资料的溶剂以下溶剂（表４）在赋形剂、原料药和制剂生产中也许会被生产商采用，但尚无足够的毒理学数据，故无ＰＤＥ值，生产厂在使用时应提供这些溶剂在制剂中残留水平的合理性论证报告。
表４无足够毒理学数据的溶剂1,1-二乙氧基丙烷 甲基异丙酮1,1-二甲基甲烷 甲基四氢呋喃2,2-二甲丙烷 石油醚异辛烷 三氯乙酸异丙醚 三氟乙酸术语遗传毒性致癌指通过影响基因或染色体而致癌。
LOEL：lowest-observed effect level的缩写。
能观察到反应的最低量（lowest-obserued effect leuel）是在研究人体或动物接触某种物质时产生任何反应的频率或严重性在生物学上显著增加的最低剂量。
修正因子是由毒理学家评定的、由生物测定的结果转换成与人体安全性相关的系数。