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INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICALREQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USEICH HARMONISED GUIDELINEIMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTSQ3C(R6)Final versionAdopted on 20 October 2016This Guideline has been developed by the appropriate ICH Expert Working Group and hasbeen subject to consultation by the regulatory parties, in accordance with the ICH Process.At Step 4 of the Process the final draft is recommended for adoption to the regulatorybodies of ICH regions.
Q3C(R6)Document HistoryCodeHistoryDateParent Guideline: Impurities: Guideline for Residual SolventsApproval by the Steering Committee under Step 2 andrelease for public consultation.Q3CApproval by the Steering Committee under Step 4 andrecommendation for adoption to the three ICH regulatorybodies.Q3C6 November 199617 July 1997Revision of the PDE information for THF contained in the Parent GuidelineQ3C(R1)Permissible Daily Exposure (PDE) for Tetrahydrofuran(THF): revision of PDE based on new toxicological data.Q3C(R1)Approval by the Steering Committee under Step 4 andrecommendation for adoption to the three ICH regulatorybodies.Note: Prior toadding the revisionto the parentGuideline inNovember 2005, thecode was Q3C(M)for THF.Note: Prior toadding the revisionto the parentGuideline inNovember 2005, thecode was Q3C(M)for THF.Approval by the Steering Committee of the new PDE forTHF under Step 2 and release for public consultation.20 July 200012 September 2002Revision of PDE information for NMP contained in the Parent GuidelineQ3C(R2)Permissible Daily Exposure (PDE) for NMethylpyrrolidone (NMP): revision of PDE based on newtoxicological data.Approval by the Steering Committee of the Revision underStep 2 and release for public consultation.20 July 2000Q3C(R2)Approval by the Steering Committee under Step 4 andrecommendation for adoption to the three ICH regulatorybodies.12 September 2002Q3C(R3)Corrigendum to calculation formula approved by theSteering Committee.28 October 2002Q3C(R3)The parent Guideline is now renamed Q3C(R3) as the twoupdates (PDE for N-Methylpyrrolidone and PDE forTetrahydrofuran) and the corrigendum of the update forNMP have been added to the parent Guideline.November 2005Note: Prior toadding the revisionto the parentGuideline inNovember 2005, thecode was Q3C(M)for NMP.Note: Prior toadding the revisionto the parentGuideline inNovember 2005, thecode was Q3C(M)for NMP.Note: Prior toadding thecorrigendum to theparent Guideline inNovember 2005, thecode was Q3C(M)for NMP.
Parent Guideline: Impurities: Guideline for Residual SolventsQ3C(R4)Update of Table 2, Table 3 and Appendix 1 to reflect therevision of the PDEs for N-Methylpyrrolidone andTetrahydrofuran.February 2009Revision of PDE information for Cumene contained in the Parent GuidelineQ3C(R5)Q3C(R5)Permissible Daily Exposure (PDE) for Cumene: revision ofPDE based on new toxicological data.Approval by the Steering Committee under Step 2 andrelease for public consultation.Approval of the PDE for Cumene by the SteeringCommittee under Step 4 and recommendation foradoption to the three ICH regulatory bodies.The PDE for Cumene document has been integrated aspart IV in the core Q3C(R4) Guideline which was thenrenamed Q3C(R5).The Table 2, Table 3 and Appendix 1 have been updated toreflect the revision of the PDE for Cumene.26 March 20104 February 2011Revision of PDE information for Methylisobutylketone contained in the ParentGuideline and to include a PDE for TriethylamineQ3C(R6)Q3C(R6)Permissible Daily Exposure (PDE) for Triethylamine andMethylisobutylketone: revision of PDE based on newtoxicological data.9 November 2016Approval of the PDE for Triethylamine andMethylisobutylketone by the Assembly under Step 4 andrecommendation for adoption to the three ICH regulatorybodies.The PDE for Triethylamine and Methylisobutylketonedocument has been integrated as part V in the coreQ3C(R5) Guideline which was then renamed Q3C(R6).The Table 2, Table 3 and Appendix 1 have been updated toreflect the revision of the PDE for Triethylamine andMethylisobutylketone.9 November 2016Correction for the PDE and concentration limit forEthyleneglycol on Table 2 page 6, as per the correct valuecalculated in Pharmeuropa, Vol. 9, No. 1, Supplement,April 1997 S36.15 October 2018Approval by the Assembly under Step 2 and release forpublic consultation.Correction of the PDE for EthyleneglycolQ3C(R7)Q3C(R6)Further to archival searches related to the PermissibleDaily Exposure (PDE) for ethyleneglycol, the Q3C(R7)Guideline was reverted back to the Q3C(R6) Guideline.Further information is provided in the cover statementdated 22 July 2019.4 October 2019
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IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTSICH Harmonised GuidelineTABLE OF CONTENTSPART I:1.INTRODUCTION . 12.SCOPE OF THE GUIDELINE . 13.GENERAL PRINCIPLES. 23.1Classification of Residual Solvents by Risk Assessment . 23.4Analytical Procedures . 43.23.33.5Methods for Establishing Exposure Limits . 2Options for Describing Limits of Class 2 Solvents. 34.Reporting levels of residual solvents . 44.1Solvents to Be Avoided . 54.4Solvents for which No Adequate Toxicological Data was Found . 84.24.3LIMITS of RESIDUAL SOLVENTS . 5Solvents to Be Limited . 6Solvents with Low Toxic Potential . 7GLOSSARY. 9APPENDIX 1. LIST OF SOLVENTS INCLUDED IN THE GUIDELINE . 10APPENDIX 2. ADDITIONAL BACKGROUND . 14A2.1A2.2Environmental Regulation of Organic Volatile Solvents . 14Residual Solvents in Pharmaceuticals . 14APPENDIX 3. METHODS FOR ESTABLISHING EXPOSURE LIMITS . 15PART II:PDE for Tetrahydrofuran . 18PART III:PDE for N-Methylpyrrolidone (NMP) . 20PART IV:PDE for Cumene . 22PART V:PDE for Triethylamine and PDE of Methylisobutylketone . 261
PART I:IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTSHaving reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 17 July1997, this Guideline is recommended for adoptionto the three regulatory parties to ICH1.INTRODUCTIONThe objective of this guideline is to recommend acceptable amounts for residual solvents inpharmaceuticals for the safety of the patient. The guideline recommends use of less toxicsolvents and describes levels considered to be toxicologically acceptable for some residualsolvents.Residual solvents in pharmaceuticals are defined here as organic volatile chemicals that areused or produced in the manufacture of drug substances or excipients, or in the preparationof drug products. The solvents are not completely removed by practical manufacturingtechniques. Appropriate selection of the solvent for the synthesis of drug substance mayenhance 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. Thisguideline does not address solvents deliberately used as excipients nor does it addresssolvates. 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 beremoved to the extent possible to meet product specifications, good manufacturing practices,or other quality-based requirements. Drug products should contain no higher levels ofresidual solvents than can be supported by safety data. Some solvents that are known tocause unacceptable toxicities (Class 1, Table 1) should be avoided in the production of drugsubstances, excipients, or drug products unless their use can be strongly justified in a riskbenefit 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, lesstoxic solvents (Class 3, Table 3) should be used where practical. The complete list of solventsincluded 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 asnew safety data becomes available. Supporting safety data in a marketing application for anew drug product containing a new solvent may be based on concepts in this guideline or theconcept 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 ofthis guideline. Therefore, testing should be performed for residual solvents when productionor purification processes are known to result in the presence of such solvents. It is onlynecessary to test for solvents that are used or produced in the manufacture or purification ofdrug substances, excipients, or drug product. Although manufacturers may choose to test thedrug product, a cumulative method may be used to calculate the residual solvent levels in thedrug product from the levels in the ingredients used to produce the drug product. If thecalculation results in a level equal to or below that recommended in this guideline, no testingof the drug product for residual solvents need be considered. If, however, the calculated levelis above the recommended level, the drug product should be tested to ascertain whether the1
Impurities: Guideline for Residual Solventsformulation 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 productsused 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) ortopical 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 ChemicalSafety (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 definedin the present guideline as a pharmaceutically acceptable intake of residual solvents to avoidconfusion of differing values for ADI's of the same substance.Residual solvents assessed in this guideline are listed in Appendix 1 by common names andstructures. They were evaluated for their possible risk to human health and placed into one ofthree classes as follows:Class 1 solvents: Solvents to be avoidedKnown human carcinogens, strongly suspected human carcinogens, and environmentalhazards.Class 2 solvents: Solvents to be limitedNon-genotoxic animal carcinogens or possible causative agents of other irreversibletoxicity 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. Class3 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 inAppendix 3. Summaries of the toxicity data that were used to establish limits are published inPharmeuropa, Vol. 9, No. 1, Supplement, April 1997.2
Impurities: Guideline for Residual Solvents3.3 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 werecalculated using equation (1) below by assuming a product mass of 10 g administered daily.Concentration (ppm) 1000 x PDEdoseHere, PDE is given in terms of mg/day and dose is given in g/day.(1)These limits are considered acceptable for all substances, excipients, or products. Thereforethis 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 beused 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 beconsidered 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 beused with the known maximum daily dose and equation (1) above to determine theconcentration of residual solvent allowed in drug product. Such limits are consideredacceptable provided that it has been demonstrated that the residual solvent has beenreduced to the practical minimum. The limits should be realistic in relation to analyticalprecision, manufacturing capability, reasonable variation in the manufacturing process, andthe limits should reflect contemporary manufacturing standards.Option 2 may be applied by adding the amounts of a residual solvent present in each of thecomponents 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 drugproduct. 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 thedrug product contains two excipients. The composition of the drug product and thecalculated maximum content of residual acetonitrile are given in the following table.ComponentAmount informulationAcetonitrile contentDaily exposureDrug substance0.3 g800 ppm0.24 mgExcipient 23.8 g800 ppm3.04 mgExcipient 1Drug Product0.9 g400 ppm5.0 g728 ppm0.36 mg3.64 mgExcipient 1 meets the Option 1 limit, but the drug substance, excipient 2, and drug product donot meet the Option 1 limit. Nevertheless, the product meets the Option 2 limit of 4.1 mg perday and thus conforms to the recommendations in this guideline.3
Impurities: Guideline for Residual SolventsConsider another example using acetonitrile as residual solvent. The maximum administereddaily 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 acetonitrileare given in the following table.ComponentAmount informulationAcetonitrile contentDaily exposureDrug substance0.3 g800 ppm0.24 mgExcipient 23.8 g800 ppm3.04 mgExcipient 1Drug Product0.9 g2000 ppm5.0 g1016 ppm1.80 mg5.08 mgIn this example, the product meets neither the Option 1 nor the Option 2 limit according tothis summation. The manufacturer could test the drug product to determine if theformulation process reduced the level of acetonitrile. If the level of acetonitrile was notreduced during formulation to the allowed limit, then the manufacturer of the drug productshould take other steps to reduce the amount of acetonitrile in the drug product. If all ofthese steps fail to reduce the level of residual solvent, in exceptional cases the manufacturercould provide a summary of efforts made to reduce the solvent level to meet the guidelinevalue, and provide a risk-benefit analysis to support allowing the product to be utilised withresidual solvent at a higher level.3.4 Analytical ProceduresResidual solvents are typically determined using chromatographic techniques such as gaschromatography. Any harmonised procedures for determining levels of residual solvents asdescribed in the pharmacopoeias should be used, if feasible. Otherwise, manufacturerswould be free to select the most appropriate validated analytical procedure for a particularapplication. If only Class 3 solvents are present, a non-specific method such as loss on dryingmay be used.Validation of methods for residual solvents should conform to ICH guidelines Text onValidation of Analytical Procedures and Extension of the ICH Text on Validation of AnalyticalProcedures.3.5 Reporting levels of residual solventsManufacturers of pharmaceutical products need certain information about the content ofresidual 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 thatcould 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 2solvents are below the Option 1 limit and residual Class 3 solvents are below 0.5%.4
Impurities: Guideline for Residual SolventsIf 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 deleteriousenvironmental effect. However, if their use is unavoidable in order to produce a drug productwith a significant therapeutic advance, then their levels should be restricted as shown inTable 1, unless otherwise justified. 1,1,1-Trichloroethane is included in Table 1 because it isan environmental hazard. The stated limit of 1500 ppm is based on a review of the safetydata.TABLE 1. Class 1 solvents in pharmaceutical products (solvents that should be avoided).SolventConcentration ane5Carbon ne4Toxic and environmental hazard8ToxicToxic1500Environmental hazard5
Impurities: Guideline for Residual Solvents4.2 Solvents to Be LimitedSolvents in Table 2 should be limited in pharmaceutical products because of theirinherent toxicity. PDEs are given to the nearest 0.1 mg/day, and concentrations aregiven to the nearest 10 ppm. The stated values do not reflect the necessary analyticalprecision of determination. Precision should be determined as part of the validationof the method.TABLE 2. Class 2 solvents in pharmaceutical products.SolventPDE (mg/day)Concentration limit ne ne0.5502-MethoxyethanolMethylbutyl ketoneMethylisobutylketone 2N-Methylpyrrolidone 30.5500.5504545005.3530The information included for Cumene reflects that included in the Revision of PDE Information forCumene which reached Step 4 in February 2011 and was subsequently incorporated into the coreGuideline. See Part IV (pages 22-25).1The information included for Methylisobutylketone reflects that included in the Revision of PDEInformation for Methylisobutylketone which reached Step 4 in November 2016 and was subsequentlyincorporated into the core Guideline. See Part V (pages 26-34).23 The information included for N-Methylpyrrolidone reflects that included in the Revision of PDEInformation for NMP which reached Step 4 in September 2002 (two mistyping corrections made inOctober 2002), and was incorporated into the core guideline in November 2005. See Part III (pages 2021).6
Impurities: Guideline for Residual 0Tetrahydrofuran 8.98900.88021.7217060% 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 tohuman health. Class 3 includes no solvent known as a human health hazard at levelsnormally accepted in pharmaceuticals. However, there are no long-term toxicity orcarcinogenicity studies for many of the solvents in Class 3. Available data indicate that theyare less toxic in acute or short-term studies and negative in genotoxicity studies. It isconsidered that amounts of these residual solvents of 50 mg per day or less (correspondingto 5000 ppm or 0.5% under Option 1) would be acceptable without justification. Higheramounts may also be acceptable provided they are realistic in relation to manufacturingcapability and good manufacturing practice.TABLE 3. Class 3 solvents which should be limited by GMP or other quality-basedrequirements.Acetic acidHeptane1-ButanolMethyl acetateAcetoneAnisole2-ButanolButyl acetatetert-Butylmethyl etherDimethyl sulfoxideEthanolEthyl acetateEthyl etherEthyl formateFormic acidIsobutyl acetateIsopropyl acetate3-Methyl-1-butanolMethylethyl ol2-PropanolPropyl acetateTriethylamine 5The information included for Tetrahydrofuran reflects that included in the Revision of PDEInformation for THF which reached Step 4 in September 2002, and was incorporated into the coreguideline in November 2005. See Part II (pages 18-19).4The information included for Triethylamine reflects that included in the Revision of PDE Informationfor Triethylamine which reached Step 4 in November 2016 and was subsequently incorporated into thecore Guideline. See Part V (pages 26-34).57
Impurities: Guideline for Residual Solvents4.4 Solvents for which No Adequate Toxicological Data was FoundThe following solvents (Table 4) may also be of interest to manufacturers of excipients, drugsubstances, or drug products. However, no adequate toxicological data on which to base aPDE was found. Manufacturers should supply justification for residual levels of thesesolvents in pharmaceutical products.TABLE 4. Solvents for which no adequate toxicological data was found.1,1-DiethoxypropaneMethylisopropyl ketone2,2-DimethoxypropanePetroleum ctaneTrichloroacetic acidIsopropyl etherTrifluoroacetic acid8
Impurities: Guideline for Residual SolventsGLOSSARYGenotoxic 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 biologicallysignificant increases in frequency or severity of any effects in the exposed humans oranimals.Modifying Factor:A factor determined by professional judgment of a toxicologist and applied to bioassay datato 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 infrequency 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 afterexposure to the substance ends.Strongly Suspected Human Carcinogen:A substance for which there is no epidemiological evidence of carcinogenesis but there arepositive genotoxicity data and clear evidence of carcinogenesis in rodents.Teratogenicity:The occurrence of structural malformations in a developing fetus when a substance isadministered during pregnancy.9
Impurities: Guideline for Residual SolventsAPPENDIX 1. LIST OF SOLVENTS INCLUDED IN THE GUIDELINESolventOther NamesStructureClassAcetic acidEthanoic acidCH3COOHClass 3CH3CNClass Methoxybenzene1-Butanoln-Butyl alcoholBenzene2-ButanolButyl acetatetert-Butylmethyl etherCarbon tetrachlorideChlorobenzeneChloroformCumene 3(CH2)3OHButan-1-olsec-Butyl alcoholClass 3Class 3Class 1Class 3CH3CH2CH(OH)CH3Class 3Acetic acid butyl esterCH3COO(CH2)3CH3Class 3TetrachloromethaneCCl4Class ylene dichlorideCH2ClCH2ClClass 3Class 2Class 2Class 2Class 2Class 1Ethylene chloride1 The information included for Cumene reflects that included in the Revision of PDE Information forCumene which reached Step 4 in February 2011 and was subsequently incorporated into the coreGuideline. See Part IV (pages 22-25).10
Impurities: Guideline for Residual SolventsSolventOther thyleneH2C CCl2Class 11,2-Dichloroethene1,2-DichloroethyleneClHC CHClClass 2Methylene chlorideCH2Cl2Class 2DMACH3CON(CH3)2Class 2Methylsulfinylmethane(CH3)2SOClass amideN,NDimethylformamideDimethyl sulfoxide1,4-DioxaneEthanol2-EthoxyethanolEthyl acetateEthyleneglycolEthyl etherEthyl formateFormamideFormic acidHeptaneVinylidene chlorideAcetylene dichlorideEthyleneglycol dimethyletherMonoglymeDimethyl CellosolveDMFMethyl 4]DioxaneOClass 2Class 2Class 2Ethyl alcoholCH3CH2OHClass 3Acetic acid ethyl esterCH3COOCH2CH3Class l etherEthoxyethane1,1’-OxybisethaneFormic acid ethyl Class 2CH3CH2OCH2CH3Class 3HCOOCH2CH3Class 3HCOOHClass 3HCONH2CH3(CH2)5CH311Class 2Class 2Class 3
Impurities: Guideline for Residual SolventsSolventOther NamesStructureClassHexanen-HexaneCH3(CH2)4CH3Class 2Isopropyl acetateAcetic acid isopropyl esterCH3COOCH(CH3)2Class 3Methyl CellosolveCH3OCH2CH2OHIsobutyl acetateMethanol2-MethoxyethanolMethyl acetate3-Methyl-1-butanolMethylbut
Corrigendum to calculation formula approved by the Steering Committee. 28 October 2002 Q3C(R3) The parent Guideline is now renamed Q3C(R3) as the two . 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
