Q3C：杂质残留溶剂的指导原则全解
ICH_Q3C
ICHGuideline for Residual SolventsQ3CRapporteur: Dr. Shigeo KojimaDate: 16 July 1997Step 4 Document1. INTRODUCTION2. SCOPE OF THE GUIDELINE3. GENERAL PRINCIPLES3.1 CLASSIFICATION OF RESIDUAL SOLVENTS BY RISK ASSESSMENT 3.2 METHODS FOR ESTABLISHING EXPOSURE LIMITS3.3 OPTIONS FOR DESCRIBING LIMITS OF CLASS 2 SOLVENTS3.4 ANALYTICAL PROCEDURES3.5 REPORTING LEVELS OF RESIDUAL SOLVENTS4. LIMITS OF RESIDUAL SOLVENTS4.1 SOLVENTS TO BE AVOIDED4.2 SOLVENTS TO BE LIMITED4.3 SOLVENTS WITH LOW TOXIC POTENTIAL4.4 SOLVENTS FOR WHICH NO ADEQUATE TOXICOLOGICAL DATA WAS FOUNDGLOSSARYAPPENDIX 1. LIST OF SOLVENTS INCLUDED IN THE GUIDELINE APPENDIX 2. ADDITIONAL BACKGROUNDA2.1 ENVIRONMENTAL REGULATION OF ORGANIC VOLATILE SOLVENTS A2.2 RESIDUAL SOLVENTS IN PHARMACEUTICALSAPPENDIX 3. METHODS FOR ESTABLISHING EXPOSURE LIMITS1. 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 the relevant 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 SOLVENTS Two 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.(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 Option1, 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 Option1. The PDE in terms of mg/day as stated inTable 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.Component Amount informulationAcetonitrile content Daily exposureDrug substance0.3 g800 ppm0.24 mg Excipient 10.9 g400 ppm0.36 mg Excipient 2 3.8 g800 ppm 3.04 mgDrug Product 5.0 g728 ppm 3.64 mg Excipient 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.Component Amount informulationAcetonitrile content Daily exposureDrug substance0.3 g800 ppm0.24 mg Excipient 10.9 g2000 ppm 1.80 mg Excipient 2 3.8 g800 ppm 3.04 mg Drug Product 5.0 g1016 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 arisk-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, anon-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 SOLVENTS Manufacturers 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 than0.5%.∙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 3solvents 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 limit(ppm)ConcernBenzene2CarcinogenCarbon tetrachloride4Toxic and environmental hazard 1,2-Dichloroethane 5Toxic1,1-Dichloroethene8Toxic1,1,1-Trichloroethane1500Environmental 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 4.1410Chlorobenzene 3.6360Chloroform0.660Cyclohexane38.8 38801,2-Dichloroethene18.71870 Dichloromethane 6.06001,2-Dimethoxyethane 1.0100N,N-Dimethylacetamide10.91090N,N-Dimethylformamide8.88801,4-Dioxane 3.83802-Ethoxyethanol 1.6160Ethyleneglycol 6.2620Formamide 2.2220Hexane 2.9290Methanol30.030002-Methoxyethanol0.550Methylbutyl ketone0.550 Methylcyclohexane11.81180N-Methylpyrrolidone48.44840Nitromethane0.550Pyridine 2.0200Sulfolane 1.6160Tetralin 1.0100Toluene8.98901,1,2-Trichloroethene0.880Xylene*21.72170*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 acceptablewithout 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-Butanol Methyl acetate2-Butanol3-Methyl-1-butanolButyl acetate Methylethyl ketonetert-Butylmethyl ether Methylisobutyl ketoneCumene2-Methyl-1-propanolDimethyl sulfoxide PentaneEthanol1-PentanolEthyl acetate1-PropanolEthyl ether2-PropanolEthyl formate Propyl acetateFormic acid Tetrahydrofuran4.4 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 GUIDELINESolvent Other Names Structure ClassAcetic acid Ethanoic acid CH3COOH Class 3Acetone2-PropanonePropan-2-one CH3COCH3Class3Acetonitrile CH3CN Class 2Anisole MethoxybenzeneClass 3Benzene BenzolClass 11-Butanoln-Butyl alcoholButan-1-ol CH3(CH2)3OHClass32-Butanolsec-Butyl alcoholButan-2-ol CH3CH2CH(OH)CH3Class3Butyl acetate Acetic acid butyl ester CH3COO(CH2)3CH3Class 3tert-Butylmethyl ether 2-Methoxy-2-methyl-propane(CH3)3COCH3Class3Carbon tetrachloride Tetrachloromethane CCl4Class 1ChlorobenzeneClass 2Chloroform Trichloromethane CHCl3Class 2CumeneIsopropylbenzene(1-Methyl)ethylbenzeneClass 3Cyclohexane HexamethyleneClass 21,2-Dichloroethane sym-DichloroethaneEthylene dichlorideEthylene chlorideCH2ClCH2ClClass11,1-Dichloroethene1,1-DichloroethyleneVinylidene chloride H2C=CCl2Class11,2-Dichloroethene1,2-DichloroethyleneAcetylene dichloride ClHC=CHClClass2Dichloromethane Methylene chloride CH2Cl2Class 21,2-Dimethoxyethane Ethyleneglycol dimethyletherH3COCH2CH2OCH3Class2Monoglyme Dimethyl CellosolveN,N-Dimethylacetamide DMA CH3CON(CH3)2Class 2N,N-Dimethylformamide DMF HCON(CH3)2Class 2Dimethyl sulfoxide MethylsulfinylmethaneMethyl sulfoxideDMSO(CH3)2SOClass31,4-Dioxanep-Dioxane[1,4]DioxaneClass 2Ethanol Ethyl alcohol CH3CH2OH Class 32-Ethoxyethanol Cellosolve CH3CH2OCH2CH2OH Class 2Ethyl acetate Acetic acid ethyl ester CH3COOCH2CH3Class 3Ethyleneglycol1,2-Dihydroxyethane1,2-EthanediolHOCH2CH2OH Class 2Ethyl ether Diethyl etherEthoxyethane1,1'-OxybisethaneCH3CH2OCH2CH3Class 3Ethyl formate Formic acid ethyl ester HCOOCH2CH3Class 3 Formamide Methanamide HCONH2Class 2 Formic acid HCOOH Class 3 Heptane n-Heptane CH3(CH2)5CH3Class 3 Hexane n-Hexane CH3(CH2)4CH3Class 2 Isobutyl acetate Acetic acid isobutyl ester CH3COOCH2CH(CH3)2Class 3 Isopropyl acetate Acetic acid isopropyl ester CH3COOCH(CH3)2Class 3 Methanol Methyl alcohol CH3OH Class 2 2-Methoxyethanol Methyl Cellosolve CH3OCH2CH2OH Class 2 Methyl acetate Acetic acid methyl ester CH3COOCH3Class 3 3-Methyl-1-butanol Isoamyl alcohol (CH3)2CHCH2CH2OH Class 3Isopentyl alcohol3-Methylbutan-1-olMethylbutyl ketone2-HexanoneHexan-2-oneCH3(CH2)3COCH3Class 2Methylcyclohexane CyclohexylmethaneClass 2Methylethyl ketone 2-ButanoneMEKButan-2-oneCH3CH2COCH3Class3Methylisobutyl ketone 4-Methylpentan-2-one4-Methyl-2-pentanoneMIBKCH3COCH2CH(CH3)2Class32-Methyl-1-propanolIsobutyl alcohol2-Methylpropan-1-ol (CH3)2CHCH2OHClass3N-Methylpyrrolidone1-Methylpyrrolidin-2-one1-Methyl-2-pyrrolidinoneClass 2Nitromethane CH3NO2Class 2Pentane n-Pentane CH3(CH2)3CH3Class 31-Pentanol Amyl alcoholPentan-1-olPentyl alcoholCH3(CH2)3CH2OHClass31-PropanolPropan-1-olPropyl alcohol CH3CH2CH2OHClass32-PropanolPropan-2-olIsopropyl alcohol (CH3)2CHOHClass3Propyl acetate Acetic acid propyl ester CH3COOCH2CH2CH3Class 3PyridineClass 2Sulfolane Tetrahydrothiophene1,1-dioxideClass2TetrahydrofuranTetramethylene oxideOxacyclopentaneClass 3Tetralin1,2,3,4-Tetrahydro-naphthaleneClass2Toluene MethylbenzeneClass 21,1,1-Trichloroethane Methylchloroform CH3CCl3Class 11,1,2-Trichloroethene Trichloroethene HClC=CCl2Class 2Xylene*DimethybenzeneXylolClass 2*usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene 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 for prophylaxis to prevent infection or disease.2) The assumption of life-time patient exposure is not necessary for most pharmaceutical products 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 often be a part of drug products.4) Residual solvents should not exceed recommended levels except in exceptional circumstances.5) Data from toxicological studies that are used to determine acceptable levels for residual solvents should have been generated using appropriate protocols such as those described for 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., 10,000 to 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:(1)The 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 humansF1 takes into account the comparative surface area:body weight ratios for the species concerned and for man. Surface area (S) is calculated as:S = kM0.67 (2)in which M = body mass, and the constant k has been taken to be 10. The body weights used in the equation are those shown below in Table A3.1.F2 = A factor of 10 to account for variability between individualsA factor of 10 is generally given for all organic solvents, and 10 is used consistently in this guideline.F3 = A variable factor to account for toxicity studies of short-term exposureF3 = 1 for studies that last at least one half lifetime (1 year for rodents or rabbits; 7 years for cats, dogs and monkeys).F3 = 1 for reproductive studies in which the whole period of organogenesis is covered.F3 = 2 for a 6-month study in rodents, or a 3.5-year study in non-rodents.F3 = 5 for a 3-month study in rodents, or a 2-year study in non-rodents.F3 = 10 for studies of a shorter duration.In all cases, the higher factor has been used for study durations between the time points, e.g. a factor of 2 for a 9-month rodent study.F4 = A factor that may be applied in cases of severe toxicity, e.g. non-genotoxic carcinogenicity, neurotoxicity or teratogenicity. In studies of reproductive toxicity, the following factors are used:F4 = 1 for fetal toxicity associated with maternal toxicityF4 = 5 for fetal toxicity without maternal toxicityF4 = 5 for a teratogenic effect with maternal toxicityF4 = 10 for a teratogenic effect without maternal toxicityF5 = A variable factor that may be applied if the no-effect level was not established When only an LOEL is available, a factor of up to 10 could be used depending on the severity of the toxicity.The weight adjustment assumes an arbitrary adult human body weight for either sexof 50 kg. This relatively low weight provides an additional safety factor against the standard weights of 60 kg or 70 kg that are often used in this type of calculation. It is recognized that some adult patients weigh less than 50 kg; these patients are considered to be accommodated by the built-in safety factors used to determine a PDE. If the solvent was present in a formulation specifically intended for pediatric use, an adjustment for a lower body weight would be appropriate.As an example of the application of this equation, consider a toxicity study of acetonitrile in mice that is summarized in Pharmeuropa, Vol. 9, No. 1, Supplement, April 1997, page S24. The NOEL is calculated to be 50.7 mg kg-1 day-1. The PDEfor acetonitrile in this study is calculated as follows:。
ICHQ3C(R6)残留溶剂培训
• 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
• 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
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LIMITS 残留溶剂的限度
– 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）
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Ⅲ类溶剂限度
• 限度 – Ⅲ类溶剂的限度均为5000ppm（0.5%）
• 关注点 – 1、三乙胺（新增）
• 之前参考欧洲药品质量管理与医疗保健局（EDQM），规定
• 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。
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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。
eg.乙腈的限度计算： 10001（04g.（1/ mdagy/）day） 410 ppm
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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。
• ICH Q3C（R6）与《中国药典》（2015年）的对比
化学药物残留溶剂研究的技术指导原则
化学药物残留溶剂研究的技术指导原则指导原则编号：【H】G P H7-1化学药物残留溶剂研究的技术指导原则二OO五年三月目录一、概述 (1)二、基本内容 (2)(一)残留溶剂研究的基本原则 (2)1、确定残留溶剂的研究对象 (2)2、确定残留溶剂时需要考虑的问题 (2)3、残留溶剂分类及研究原则 (4)(二)研究方法的建立及方法学验证 (6)1、研究方法的建立 (6)2、方法学验证 (8)(三)研究结果的分析及质量标准的制定 (9)1、残留溶剂表示方法 (9)2、质量标准制定的一般原则及阶段性要求 (10)(四)需要关注的几个问题 (12)1、附录中无限度规定和未收载的有机溶剂 (12)2、未知有机挥发物 (12)3、多种有机溶剂综合影响 (13)4、中间体的残留溶剂 (13)5、制剂工艺对制剂残留溶剂的影响 (14)6、辅料残留溶剂的研究及对制剂的影响 (14)三、参考文献 (14)四、附录 (16)五、著者 (17)化学药物残留溶剂研究的技术指导原则一、概述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或产生而又未能完全去除的有机溶剂。
根据国际化学品安全性纲要，以及美国环境保护机构、世界卫生组织等公布的研究结果，很多有机溶剂对环境、人体都有一定的危害，因此，为保障药物的质量和用药安全，以及保护环境，需要对残留溶剂进行研究和控制。
本指导原则是在参考人用药物注册技术要求国际协调会（International Conference on Harmonization of T echnical Requirements for Registration of Pharmaceuticals for Human Use，ICH）颁布的残留溶剂研究指导原则,美国药典（the United States Pharmacopoeia，USP）、英国药典(British Pharmacopoeia, BP)、欧洲药典(European Pharmacopoeia，EP)、中国药典(Chinese Pharmacopoeia, ChP)相关内容的基础上，结合我国药物研发的特点，通过分析、研究残留溶剂问题与药物的安全性、有效性及质量可控性之间的内在关系而制定的。
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 Q C R 残留溶剂 培训
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
化学药物残留溶剂研究的技术指导原则
化学药物残留溶剂研究的技术指导原则一、概述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或产生而又未能完全去除的有机溶剂。
根据国际化学品安全性纲要，以及美国环境保护机构、世界卫生组织等公布的研究结果，很多有机溶剂对环境、人体都有一定的危害，因此，为保障药物的质量和用药安全，以及保护环境，需要对残留溶剂进行研究和控制。
本指导原则是在参考人用药物注册技术要求国际协调会（International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use，ICH）颁布的残留溶剂研究指导原则,美国药典（the United States Pharmacopoeia，USP）、英国药典(British Pharmacopoeia, BP)、欧洲药典(European Pharmacopoeia，EP)、中国药典(Chinese Pharmacopoeia, ChP)相关内容的基础上，结合我国药物研发的特点，通过分析、研究残留溶剂问题及药物的安全性、有效性及质量可控性之间的内在关系而制定的。
本指导原则总结了对残留溶剂问题的一般认识，旨在帮助药物研发者科学合理的进行残留溶剂方面的研究，也为药物评价者提供参考。
考虑到残留溶剂研究涉及的范围比较广泛，本指导原则主要对原料药的残留溶剂问题进行讨论，并以此为基础，探讨和总结药物研究过程中对残留溶剂问题的一般性原则。
药物研发者可参考本指导原则对制剂和辅料的残留溶剂问题进行研究。
考虑到药物研究开发的阶段性，本指导原则适用于药物研发的整个过程。
二、基本内容（一）残留溶剂研究的基本原则1、确定残留溶剂的研究对象从理论上讲，药物制备过程中所使用的有机溶剂均有残留的可能，均应进行残留量的研究。
但是，药物研发者可以通过对有机溶剂的性质、药物制备工艺等进行分析，提出科学合理的依据，有选择性的对某些溶剂进行残留量研究，这样，既可以合理有效的控制产品质量，又有利于降低药物研究的成本，避免不必要的浪费。
Q3c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。
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。
残留溶剂的指导原则 q3c(r8)
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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。
ICH Q3c 中文版)
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
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 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
1,1－二氯乙烯
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
第 7 页 共 18 页
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
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。
Q3C 溶剂残留和分类
摘自Q3C-残留溶剂的指导选择一类溶剂：应避免致癌物；备受怀疑的致癌物；环境危害物二类溶剂：设定残余量，限量使用非基因性动物致癌物；可能导致不可逆中毒，比如神经性中毒，畸形；可能导致其他可逆性中毒三类溶剂: 低毒对人体有潜在毒性，可以接触，但不超过50mg/day。
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.ICH规定3类只要干失小于0.5, 但1，2类并不是不能出现。
按照毒性大小和对环境的危害程度，该指导原则将溶剂分成三类（所列举的溶剂并不完全，应对合成和生产过程所有可能的残留溶剂进行评估）：第一类溶剂是指已知可以致癌并被强烈怀疑对人和环境有害的溶剂。
在可能的情况下，应避免使用这类溶剂。
如果在生产治疗价值较大的药品时不可避免地使用了这类溶剂，除非能证明其合理性，残留量必须控制在规定的范围内，如：苯（2ppm）、四氯化碳（4ppm）、1，2－二氯乙烷（5ppm）、1，1－二氯乙烷（8ppm）、1，1，1－三氯乙烷（1500ppm）。
第二类溶剂是指无基因毒性但有动物致癌性的溶剂。
按每日用药10克计算的每日允许接触量如下：2－甲氧基乙醇（50ppm）、氯仿（60ppm）、1，1，2－三氯乙烯（80ppm）、1，2－二甲氧基乙烷（100ppm）、1，2，3，4－四氢化萘（100ppm）、2－乙氧基乙醇（160ppm）、环丁砜（160ppm）、嘧啶（200ppm）、甲酰胺（220ppm）、正己烷（290ppm）、氯苯（360ppm）、二氧杂环己烷（380ppm）、乙腈（410ppm）、二氯甲烷（600ppm）、乙烯基乙二醇（620ppm）、N，N－二甲基甲酰胺（880ppm）、甲苯（890ppm）、N，N－二甲基乙酰胺（1090ppm）、甲基环己烷（1180ppm）、1，2－二氯乙烯（1870ppm）、二甲苯（2170ppm）、甲醇（3000ppm）、环己烷（3880ppm）、N－甲基吡咯烷酮（4840ppm）、。
Q3C(R7)杂质：残留溶剂指导原则(中文翻译公开征求意见稿)
注：2005 年 11 月 机构采纳。
修订前本版本命
名为 Q3C（M）：
THF
对母指导原则所含 NMP 的 PDE 信息的修订
Q3C（R2）
N-甲基吡咯烷酮（NMP）的每日允许暴露量（PDE）：根据2000 年 7 月 20 日
注：2005 年 11 月新的毒理学数据修订 PDE。
修 订 前 本 版 本 命指导委员会经第二阶段后批准修订版，并发布以便向公众征
药物中的残留溶剂在此定义为在原料药或辅料的生产中以及制剂制备过程中使用 或产生的有机挥发性化合物。这些溶剂在实际生产技术中不能完全除去。选择适当的溶 剂合成原料药可提高收率或决定药物的性质，如晶型、纯度和溶解度。因此，溶剂有时 可能是合成工艺的关键因素。本指导原则并不针对特意用作辅料的溶剂，也不针对溶剂 化物。然而这些制剂中的溶剂也应进行评价，并论证其合理性。
异丙基苯文档的 PDE 已经作为第 IV 部分整合在核心 Q3C （R4）指导原则中，指导原则更名为 Q3C（R5）。
已对表 2、表 3 和附录 1 进行更新，以反映对异丙基苯的 PDE 进行的修订。
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
Q3C（R6） Q3C（ห้องสมุดไป่ตู้6）
名为 Q3C（M）：求意见。
NMP
Q3C（R2）
指导委员会经第四阶段后批准，并建议 ICH 的 3 个监管机2002 年 9 月 12 日
注：2005 年 11 月 构采纳。
修订前本版本命
名为 Q3C（M）：
NMP
Q3C（R3）
指导委员会批准的计算公式勘误。
注：2005 年 11 月
修订前本版本命
2002 年 10 月 28 日
ICH Q3c 中文版)
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。
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。
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 1,1-二甲基甲烷 2,2-二甲丙烷 异辛烷 异丙醚
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
1,1－二氯乙烯
8
毒性
Q3C-残留溶剂的指导选择
European Medicines Agency7 Westferry Circus, Canary Wharf, London, E14 4HB, UKTel. (44-20) 74 18 85 75 Fax (44-20) 75 23 70 40E-mail: mail@emea.eu.int http://www.emea.eu.intMarch 1998 CPMP/ICH/283/95ICH Topic Q 3 C (R3)Impurities: Residual SolventsStep 5NOTE FOR GUIDANCE ONIMPURITIES: RESIDUAL SOLVENTS(CPMP/ICH/283/95)TRANSMISSION TO CPMP November 1996 TRANSMISSION TO INTERESTED PARTIES November 1996 COMMENTS REQUESTED BEFORE May 1997 FINAL APPROVAL BY CPMP September 1997 DATE FOR COMING INTO OPERATION March 1998ICH Harmonised Tripartite GuidelineTable of Contents1. INTRODUCTION (3)2. SCOPE OF THE GUIDELINE (3)3. GENERAL PRINCIPLES (4)3.1 Classification of Residual Solvents by Risk Assessment (4)3.2 Methods for Establishing Exposure Limits (4)3.3 Options for Describing Limits of Class 2 Solvents (4)3.4 Analytical Procedures (6)3.5 Reporting levels of residual solvents (6)4. LIMITS OF RESIDUAL SOLVENTS (7)4.1 Solvents to Be Avoided (7)4.2 Solvents to Be Limited (7)4.3 Solvents with Low Toxic Potential (8)4.4 Solvents for which No Adequate Toxicological Data was Found (9)GLOSSARY (10)APPENDIX 1. LIST OF SOLVENTS INCLUDED IN THE GUIDELINE (11)APPENDIX 2. ADDITIONAL BACKGROUND (16)A2.1 Environmental Regulation of Organic Volatile Solvents (16)A2.2 Residual Solvents in Pharmaceuticals (16)APPENDIX 3. METHODS FOR ESTABLISHING EXPOSURE LIMITS (16)PART II: (21)IMPURITIES : RESIDUAL SOLVENTS (MAINTENANCE) (21)PART III: (23)IMPURITIES : RESIDUAL SOLVENTS (MAINTENANCE) (23)PART I:1. 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 1The 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 the relevant 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 marketeddrug products. The guideline applies to all dosage forms and routes of administration. Higher levels ofresidual 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 internationalhealth 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 avoidconfusion of differingvalues 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 ofthree classes as follows:Class 1 solvents: Solvents to be avoided Known human carcinogens, strongly suspected human carcinogens, and environmentalhazards.Class 2 solvents: Solvents to be limited Non-genotoxic animal carcinogens or possible causative agents of other irreversible toxicitysuch as neurotoxicity or teratogenicity. Solvents suspected of other significant but reversible toxicities.Class 3 solvents: Solvents with low toxic potential Solvents with low toxic potential to man; no health-based exposure limit is needed. Class 3solvents 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 inAppendix 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.dose PDE x 1000(ppm)ion Concentrat :(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 drugsubstances 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 notexceed 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 complywith 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 theconcentration of residual solvent allowed in drug product. Such limits are considered acceptable provided that it has been demonstrated that the residual solvent has been reducedto the practical minimum. The limits should be realistic in relation to analytical precision, manufacturing capability, reasonable variation in the manufacturing process, and the limitsshould 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 lessthan 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 1limit 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.Component Amount in formulation Acetonitrile contentDaily exposure Active substance0.3 g 800 ppm 0.24 mg Excipient 10.9 g 400 ppm 0.36 mg Excipient 23.8 g 800 ppm 3.04 mg Medicinal 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 maximumadministered daily mass of a drug product is 5.0 g, and the drug product contains two excipients. Thecomposition of the drug product and the calculated maximum content of residual acetonitrile is given in the following table.Component Amount in formulation AcetonitrilecontentDaily exposure Active substance0.3 g 800 ppm 0.24 mg Excipient 10.9 g 2000 ppm 1.80 mg Excipient 23.8 g 800 ppm 3.04 mg Medicinal 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 formulationprocess 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 othersteps 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 asummary of efforts made to reduce the solvent level to meet the guideline value, and provide a riskbenefit analysis to support allowing the product to be utilised with residual solvent atahigher 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 wouldbe free to select the most appropriate validated analytical procedure for a particular application. If only Class 3 solvents are present, a nonspecific method such as loss on dryingmay 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 ofAnalytical 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 thisguideline. 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 pharmaceuticalmanufacturer. 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 below0.5%.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 tosolvents that are used in earlier manufacturing steps and not removed consistently by avalidated 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 environmentaleffect. However, if their use is unavoidable in order to produce a drug product with asignificant 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.ConcernLimitSolvent Concentration(ppm)Benzene 2 Carcinogen Carbon tetrachloride 4 Toxic and environmentalhazard1,2-Dichloroethane 5 Toxic1,1-Dichloroethene 8 Toxic1,1,1-Trichloroethane 1500 Environmentalhazard4.2 Solvents to Be LimitedSolvents in Table 2 should be limited in pharmaceutical products because of their inherenttoxicity. PDEs are given to the nearest 0.1 mg/day, and concentrations are given to the nearest10 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 4.1 410 Chlorobenzene 3.6 360 Chloroform 0.6 60 Cyclohexane 38.8 3880 1,2-Dichloroethene 18.7 1870 Dichloromethane 6.0 600 1,2-Dimethoxyethane 1.0100 N,N-Dimethylacetamide 10.91090 N,N-Dimethylformamide 8.8 8801,4-Dioxane 3.8 380 2-Ethoxyethanol 1.6 160 Ethylene glycol 6.2 620Formamide 2.2 220 Hexane 2.9 290 Methanol 30.0 3000 2-Methoxyethanol 0.5 50 Methylbutylketone 0.5 50 Methylcyclohexane 11.8 1180 N-Methylpyrrolidone 48.4 4840Nitromethane 0.5 50Pyridine 2.0 200 Sulfolane 1.6 160 Tetralin 1.0 100 Toluene 8.9 8901,1,2-Trichloroethene 0.8 80 Xylene* 21.7 2170 * usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene.4.3 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 normallyaccepted 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 inacute 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% underOption 1) would be acceptable without justification. Higher amounts may also be acceptable provided they are realistic in relation to manufacturing capability and good manufacturingpractice.Table 3. Class 3 solvents which should be limited by GMP or other qualitybased requirements.Acetic acid Heptaneacetate Acetone IsobutylAnisole Isopropylacetateacetate1-Butanol Methyl2-Butanol 3-Methyl-1-butanol Butyl acetate Methylethyl ketonetert-Butylmethyl ether Methylisobutyl ketoneCumene 2-Methyl-1-propanol Dimethylsulfoxide PentaneEthanol 1-PentanolEthyl acetate 1-PropanolEthyl ether 2-PropanolEthyl formate Propyl acetateFormic acid Tetrahydrofuran4.4 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 aPDE 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 Methylisopropylketone1,1-Dimethoxymethane Methyltetrahydrofuranether2,2-Dimethoxypropane PetroleumIsooctane Trichloroaceticacid Isopropyl 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 GUIDELINESolvent OtherNames Structure Class Acetic acid Ethanoic acid CH3COOH Class3Acetone 2-Propanone CH3COCH3 Class 3Propan-2-oneAcetonitrile CH3CN Class2Anisole Methoxybenzene OCH3Class3Benzene Benzol Class11-Butanol n-Butyl alcohol CH3(CH2)3OH Class3Butan-1-ol2-Butanol sec-Butyl alcohol CH3CH2CH(OH)CH3 Class 3Butan-2-olButyl acetate Acetic acid butyl ester CH3COO(CH2)3CH3 Class3tert-Butylmethyl ether 2-Methoxy-2-methyl-propane (CH3)3COCH3 Class3Carbon tetrachloride Tetrachloromethane CCl4 Class1Chlorobenzene ClClass2Chloroform Trichloromethane CHCl3 Class 2Cumene IsopropylbenzeneCH(CH 3)2Class 3(1-Methyl)ethylbenzeneCyclohexane Hexamethylene Class 21,2-Dichloroethane sym -Dichloroethane CH 2ClCH 2Cl Class 1Ethylene dichloride Ethylene chloride 1,1-Dichloroethene 1,1-Dichloroethylene H 2C=CCl 2 Class 1 Vinylidene chloride 1,2-Dichloroethene 1,2-Dichloroethylene ClHC =CHCl Class 2Acetylene dichloride Dichloromethane Methylene chlorideCH 2Cl 2Class 21,2-Dimethoxyethane Ethyleneglycol dimethyl ether H 3COCH 2CH 2OCH 3 Class 2 Monoglyme Dimethyl Cellosolve N,N-Dimethylacetamide DMACH 3CON(CH 3)2 Class 2 N,N-Dimethylformamide DMFHCON(CH 3)2 Class 2Dimethyl sulfoxide Methylsulfinylmethane (CH 3)2SO Class 3 Methyl sulfoxide DMSO1,4-Dioxane p-DioxaneOO Class 2[1,4]Dioxane Ethanol Ethyl alcoholCH 3CH 2OH Class 32-Ethoxyethanol Cellosolve CH3CH2OCH2CH2OH Class 23Ethyl acetate Acetic acid ethyl ester CH3COOCH2CH3 Class2 Ethyleneglycol 1,2-Dihydroxyethane HOCH2CH2OH Class1,2-Ethanediol3Ethyl ether Diethyl ether CH3CH2OCH2CH3 ClassEthoxyethane1,1’-Oxybisethane3Ethyl formate Formic acid ethyl ester HCOOCH2CH3 Class2 Formamide Methanamide HCONH2 Class Formic acid H C O O H Class 33 Heptane n-Heptane CH3(CH2)5CH3 Class2 Hexane n-Hexane CH3(CH2)4CH3 Class Isobutyl acetate Acetic acid isobutyl ester CH3COOCH2CH(CH3)2 Class 33Isopropyl acetate Acetic acid isopropyl ester CH3COOCH(CH3)2 Class2alcohol CH3OH Class Methanol MethylCellosolve CH3OCH2CH2OH Class22-Methoxyethanol Methyl3 Methyl acetate Acetic acid methyl ester CH3COOCH3 Classalcohol (CH3)2CHCH2CH2OH Class 33-Methyl-1-butanol IsoamylalcoholIsopentyl3-Methylbutan-1-ol2 Methylbutyl ketone 2-Hexanone CH3(CH2)3COCH3 ClassHexan-2-oneMethylcyclohexane Cyclohexylmethane CH3Class2Methylethyl ketone 2-Butanone CH3CH2COCH3 Class3 MEKButan-2-oneMethylisobutyl ketone 4-Methylpentan-2-one CH3COCH2CH(CH3)2 Class 34-Methyl-2-pentanoneMIBK2-Methyl-1-propanol Isobutyl alcohol (CH3)2CHCH2OH Class3 2-Methylpropan-1-olN-Methylpyrrolidone 1-Methylpyrrolidin-2-one N OCH3 Class21-Methyl-2-pyrrolidinoneNitromethane CH3NO2 Class2 Pentane n-Pentane CH3(CH2)3CH3 Class31-Pentanol Amylalcohol CH3(CH2)3CH2OH Class3Pentan-1-olPentylalcohol1-Propanol Propan-1-ol CH3CH2CH2OH Class3Propylalcohol2-Propanol Propan-2-ol (CH3)2CHOH Class3IsopropylalcoholPropyl acetate Acetic acid propyl ester CH3COOCH2CH2CH3 Class 3Pyridine NClass2Sulfonane Tetrahydrothiophene1,1-dioxideSO OClass2Tetrahydrofuran Tetramethyleneoxide O Class3 OxacyclopentaneTetralin 1,2,3,4-Tetrahydro-naphthalene Class2Toluene Methylbenzene CH3Class21,1,1-Trichloroethane Methylchlororoform CH3CCl3 Class1 1,1,2-Trichloroethene Trichloroethene HClC=CCl2 Class2Xylene* Dimethybenzene CH3CH3Class2Xylol* usually 60 % m-xylene, 14 % p-xylene, 9 % o-xylene with 17 % ethyl benzeneAPPENDIX 2. ADDITIONAL BACKGROUNDA2.1 Environmental Regulation of Organic Volatile SolventsSeveral of the residual solvents frequently used in the production of pharmaceuticalsare listed as toxic chemicals in Environmental Health Criteria (EHC) monographs andthe Integrated Risk Information System (IRIS). The objectives of such groups as theInternational Programme on Chemical Safety (IPCS), the United States EnvironmentalProtection Agency (USEPA), and the United States Food and Drug Administration(USFDA) include the determination of acceptable exposure levels. The goal is protectionof 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 mostpharmaceuticalproducts but may be appropriate as a working hypothesis to reduce risk to human health3) Residual solvents are unavoidable components in pharmaceutical production and willoften be 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 forresidual solvents should have been generated using appropriate protocols such as those described for 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., 10,000 to 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 F1x F2x F3x F4x 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 humansF1 takes into account the comparative surface area:body weight ratios for the species concerned and for man. Surface area (S) is calculated as:S = kM0.67in which M = body mass, and the constant k has been taken to be 10. The body weights used in the equation are those shown below in Table A3.1.F2 = A factor of 10 to account for variability between individuals.A factor of 10 is generally given for all organic solvents, and 10 is used consistently in this guideline.F3 = A variable factor to account for toxicity studies of short-term exposureF3 = 1 for studies that last at least one half lifetime (1 year for rodents or rabbits; 7 years for cats, dogs and monkeys).F3 = 1 for reproductive studies in which the whole period of organogenesis is covered.F3 = 2 for a 6-month study in rodents, or a 3.5-year study in non-rodents.F3 = 5 for a 3-month study in rodents, or a 2-year study in non-rodents.F3 = 10 for studies of a shorter duration.。
化学药物残留溶剂研究的技术指导原则
化学药物残留溶剂研究的技术指导原则一、概述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或产生而又未能完全去除的有机溶剂。
根据国际化学品安全性纲要，以及美国环境保护机构、世界卫生组织等公布的研究结果，很多有机溶剂对环境、人体都有一定的危害，因此，为保障药物的质量和用药安全，以及保护环境，需要对残留溶剂进行研究和控制。
本指导原则是在参考人用药物注册技术要求国际协调会（International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use，ICH）颁布的残留溶剂研究指导原则,美国药典（the United States Pharmacopoeia，USP）、英国药典(British Pharmacopoeia, BP)、欧洲药典(European Pharmacopoeia，EP)、中国药典(Chinese Pharmacopoeia, ChP)相关内容的基础上，结合我国药物研发的特点，通过分析、研究残留溶剂问题与药物的安全性、有效性及质量可控性之间的内在关系而制定的。
本指导原则总结了对残留溶剂问题的一般认识，旨在帮助药物研发者科学合理的进行残留溶剂方面的研究，也为药物评价者提供参考。
考虑到残留溶剂研究涉及的范围比较广泛，本指导原则主要对原料药的残留溶剂问题进行讨论，并以此为基础，探讨和总结药物研究过程中对残留溶剂问题的一般性原则。
药物研发者可参考本指导原则对制剂和辅料的残留溶剂问题进行研究。
考虑到药物研究开发的阶段性，本指导原则适用于药物研发的整个过程。
二、基本内容（一）残留溶剂研究的基本原则1、确定残留溶剂的研究对象从理论上讲，药物制备过程中所使用的有机溶剂均有残留的可能，均应进行残留量的研究。
但是，药物研发者可以通过对有机溶剂的性质、药物制备工艺等进行分析，提出科学合理的依据，有选择性的对某些溶剂进行残留量研究，这样，既可以合理有效的控制产品质量，又有利于降低药物研究的成本，避免不必要的浪费。
残留溶剂的指导原则
残留溶剂的指导原则残留溶剂是指在溶剂使用过程中不能完全挥发掉的溶剂残余物。
在许多行业中，残留溶剂是一种常见的环境和健康危害物质，对人体健康和环境造成潜在风险。
因此，制定和遵循残留溶剂的指导原则是非常重要的。
1.最小化使用残留溶剂的量要减少残留溶剂的问题，首先应尽量减少其使用量。
使用先进的工艺和技术，使用更低挥发性的溶剂，或者使用替代品来替代高挥发性的溶剂，能有效地降低残留溶剂的生成。
2.优先选择可再生溶剂优先选择可再生的溶剂，以最大程度减少溶剂的浪费和排放。
可再生溶剂具有更高的回收利用率和再利用价值，不仅可减少资源消耗，还能降低环境风险。
3.加强溶剂回收和再利用加强溶剂的回收和再利用，是实现降低残留溶剂的有效手段之一、通过使用适当的技术和设备，如蒸馏、吸附、膜分离等，可以将残留溶剂回收再利用，降低环境风险。
4.合理控制溶剂的使用条件在使用溶剂时，应严格遵守使用条件和操作规程，合理控制溶剂的使用量和使用方式。
遵循溶剂的最佳使用温度、浓度、搅拌速度等条件，可最大限度减少残留溶剂的生成。
5.采用防止挥发的封闭式操作在工业生产过程中，应尽可能采用封闭式设备和操作工艺，以防止溶剂的挥发和扩散。
通过密封设备、负压操作、局部排风等措施，可有效减少残留溶剂对环境和人体的危害。
6.严格遵守相关法律法规和标准制定和遵循残留溶剂管理的指导原则，既要在国家和地方层面上遵守相关的法律法规和标准，也要在企业内部建立相应的规章制度和管理体系。
通过加强监督和管理，确保残留溶剂的处理和处置符合法律法规和环保要求。
7.开展溶剂的危险性评估和监测对使用的溶剂进行危险性评估和监测，了解其挥发性、毒性、可燃性等性质和特点，及时采取相应的控制措施和防护措施。
通过定期检测和监测，及时发现和处理残留溶剂的问题，减少环境和健康风险。
总之，制定和遵循残留溶剂的指导原则是保护环境和人体健康的重要措施。
通过最小化使用残留溶剂的量、优先选择可再生溶剂、加强回收和再利用、控制使用条件、采用封闭式操作、遵守法律法规和标准、进行危险性评估和监测等措施，可以有效减少残留溶剂对环境和健康的危害。
Q3C(M) 残留溶剂(修订)：NMP和THF的日允许接触剂量(PDE)
杂质：残留溶剂（修订）N－甲基吡咯烷酮（NMP）的日允许接触剂量（PDE）ICH协议指南本指导原则于2002年9月12日ICH指导委员会上进入ICH进程的第四阶段，被推荐给三方管理当局采纳。
在1997年12月，ICH Q3C指南进入第5阶段。
专家工作组的成员达成一致意见：如果有可靠的和更确切的毒理资料作为参考，可以对相关品种的PDE作修改。
1999年形成了一个修订协议并组成一个专家修定工作组。
该协议提出对各种溶剂的PCE进行再审议并允许对指南的相关条例进行调整，包括对各种溶剂的PDE数据进行调整。
此外，协议还允许在有足够的毒性资料的前提下，可增加新的溶剂及其PDE数据。
去年下半年EWG收到有关N－甲基吡咯烷酮（NMP）新的毒性资料。
此内容已由NMP 产业集团上报给FDA。
这是一个由E.I.DUPONT DE Nemours和Co进行的为期二年的大鼠长期喂食实验（未公开发表）。
有关资料已呈送给EWA的成员们进行分析。
在当时看来，这些实验结果足以向指导委员会提出更改NMP毒性类别的建议。
在2002年2月28日至3月2日的ICH会议上，作者向指导委员会汇报了EWG分析的结论和达成的一致意见，即报NMP从第2类溶剂（PDE为48.4mg/天）改为第3类溶剂（PDE为207mg/天）。
但不久，EWG的成员又提供了能够得出更低PDE的进一步的资料和评价。
以下的章节包含如何计算新的PDE的合理的和更灵敏的方法。
动物毒性以下论文是用于计算NMP的PDE：“大鼠出生前接触NMP对其出生后成长和发育的影响”Hass U. 等，《神经毒理》致畸1994，16（3）241～249。
取怀孕Wistar大鼠，在孕期的7～20天的周期内通过吸入给药的方法给予NMP150ppm ×6小时/每日，孕期满后允许孕鼠产仔，结果未检测到对母鼠的毒性，幼仔的尺寸大小也未受给药的影响，同时未观察到机体异常。
出生后5周内，幼仔的体重下降（有显著意义）。
Q3C(M) 残留溶剂(修订)：NMP和THF的日允许接触剂量(PDE)
杂质：残留溶剂（修订）N－甲基吡咯烷酮（NMP）的日允许接触剂量（PDE）ICH协议指南本指导原则于2002年9月12日ICH指导委员会上进入ICH进程的第四阶段，被推荐给三方管理当局采纳。
在1997年12月，ICH Q3C指南进入第5阶段。
专家工作组的成员达成一致意见：如果有可靠的和更确切的毒理资料作为参考，可以对相关品种的PDE作修改。
1999年形成了一个修订协议并组成一个专家修定工作组。
该协议提出对各种溶剂的PCE进行再审议并允许对指南的相关条例进行调整，包括对各种溶剂的PDE数据进行调整。
此外，协议还允许在有足够的毒性资料的前提下，可增加新的溶剂及其PDE数据。
去年下半年EWG收到有关N－甲基吡咯烷酮（NMP）新的毒性资料。
此内容已由NMP 产业集团上报给FDA。
这是一个由E.I.DUPONT DE Nemours和Co进行的为期二年的大鼠长期喂食实验（未公开发表）。
有关资料已呈送给EWA的成员们进行分析。
在当时看来，这些实验结果足以向指导委员会提出更改NMP毒性类别的建议。
在2002年2月28日至3月2日的ICH会议上，作者向指导委员会汇报了EWG分析的结论和达成的一致意见，即报NMP从第2类溶剂（PDE为48.4mg/天）改为第3类溶剂（PDE为207mg/天）。
但不久，EWG的成员又提供了能够得出更低PDE的进一步的资料和评价。
以下的章节包含如何计算新的PDE的合理的和更灵敏的方法。
动物毒性以下论文是用于计算NMP的PDE：“大鼠出生前接触NMP对其出生后成长和发育的影响”Hass U. 等，《神经毒理》致畸1994，16（3）241～249。
取怀孕Wistar大鼠，在孕期的7～20天的周期内通过吸入给药的方法给予NMP150ppm ×6小时/每日，孕期满后允许孕鼠产仔，结果未检测到对母鼠的毒性，幼仔的尺寸大小也未受给药的影响，同时未观察到机体异常。
出生后5周内，幼仔的体重下降（有显著意义）。
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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：应避免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)PDE：mg／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。
神经毒性某种物质引起神经系统不良反应的能力。
NOEL：no-observed effect level的缩写。
不能观察到反应的量（no-obserued effect leuel）某种物质被人体或动物接触后，任何反应频率或严重性在生物学上无明显增加的最高剂量。
PDE是permitted daily exposure的缩写，指每日摄入药物中残留溶剂的可接受最大摄入量。
可逆毒性指接触某种物质时产生毒性反应，不接触时反应即消失。
深疑为人体致癌物某种物质没有致癌作用的流行病学表征，但基因毒性数据阳性，对啮齿动物具致癌作用表征。
致畸作用怀孕期间服用某一物质而产生的胎儿发育畸形。
附录1指导原则中所列的溶剂3232异丙基乙酸酯Isopropyl acetate CH3COOCH(CH3)2三氯乙烯1,1,2-Trichloroethene HClC=CCl2二甲苯*Xylene* CH3CH3*一般为60% m-二甲苯，14% p-二甲苯，9% o-二甲苯和17%乙基苯。
附录２其他背景A2.1 有机挥发性溶剂的环境管理几种药物生产中常用的残留溶剂作为有毒化合物列于环境健康标准（EHC）和危险信息系统大全（IRCS）。
一些组织如国际化学品安全性纲要（IPCS）、美国环境保护机构（EPA）和FDＡ的目标包括测定可接受的接触水平。
目的是防止长期接触化学品后可能对人体健康和对整个环境造成危害。
评估最大接触安全限度通常应进行长期试验，当无长期试验数据时，可对短期研究结果进行修正，如对短期研究数据用较大的安全因子校正后使用，其中主要描述的项目与人群长期或一生接触的周围环境有关，如：周围空气、食品、饮用水或其他介质。
A2.2 药物中的残留溶剂本指导原则中的接触限度是参考ＥＨＣ和ＩＲＩＳ中的毒性数据和方法学而建立的。
然而，在建立接触限度时，应考虑用于合成和制剂处方中溶剂残留的一些特定的假设。
即：⑴病人（不是一般人群）使用药物是为了治疗疾病或预防疾病，免受感染。
⑵对大多数药物来说不必假设病人终身服药的接触量，但作为一种工作假设可能有助于减少对人体健康产生危害。
⑶残留溶剂是药物中不可避免的成分，常常是制剂中的一部分。
⑷除特殊情况外，残留溶剂不能超过推荐水平。
⑸用于确定残留溶剂可接受水平的毒理学研究数据，应该在一些草案中（如DECD、EPA和FDA Red BooK）已有收载。
附录３建立接触限度的方法Gaylor-Kodell危害评估方法(Gaylor,D,W.AndKodell,R.l.:Linear Interpolation algoeithm for low dose assessment of toxic substance. J Environ. Pathology, 4, 305)适用于第一类致癌溶剂，只有掌握了可信赖的致癌数据，才可以用数学模型外推来建立接触限度。