Q3C  Tables and List 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
August 2018 
ICH 
 
Revision 4 
 
 
   
 
Q3C  Tables and List 
 
Guidance for Industry 
 
 
 
 
Additional copies are available from: 
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Food and Drug Administration 
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or 
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Email: ocod@fda.hhs.gov 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
August 2018 
ICH 
 
Revision 4 
 
  Contains Nonbinding Recommendations 
 
Q3C  Tables and List 
Guidance for Industry1
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
 
I.  INTRODUCTION  
 
This is the companion  document for the International Council for Harmonisation  of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) guidance for industry  Q3C Impurities: 
Residual Solvents, which makes recommendations  as to what amounts of residual solvents are 
considered safe in pharmaceuticals.  
 
This document may be updated if proposals for change are submitted to the ICH Secretariat for 
consideration  by the ICH Q3C Expert Working Group (EWG).  If the EWG supports the 
proposal for change, the proposal will be submitted to the ICH Assembly for endorsement.  Any 
proposals that are endorsed by the ICH Assembly will be announced through a notice in the 
Federal Register prior to the updating  of this document.  The guidance was revised in November 
2003 to reflect updated recommendations  for N-Methylpyrrolidone  and Tetrahydrofuran; in 
February 2012 to reflect an updated recommendation  for cumene; in October 2016 to reflect 
updated recommendations  for Triethylamine  and Methylisobutylketone;  and in August 2018 to 
correct the permitted daily exposure (PDE) and concentration limit  for Ethyleneglycol  (see Table 
2 on page 6), per the correct value calculated in Appendix 5. 
 
In general, FDAs guidance documents do not establish legally  enforceable responsibilities.   
Instead, guidances describe the Agency's current thinking  on a topic and should be viewed only 
as recommendations,  unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something  is suggested or recommended, but 
not required. 
 
   
                                                             
1 This document was developed within the Expert Working Group (Quality) of the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and has been subject to 
consultation by the regulatory parties, in accordance with the ICH process.  This document was endorsed by the ICH 
Steering Committee at Step 4 of the ICH process in July 1997.  At Step 4 of the process, the final draft is 
recommended for adoption to the regulatory agencies.  This guidance was published in the Federal Register on 
December 24, 1997 (62 FR 67377), and is applicable to drug and biological products. 
 
1  Contains Nonbinding Recommendations 
 
II.  LIST OF SOLVENTS INCLUDED IN THE Q3C GUIDANCE 
 
 
 
 Solvent   Other Names  Structure   Class 
       
Acetic acid  Ethanoic acid  CHCOOH  Class 3 
3
       
Acetone  2-Propanone    CHCOCH  Class 3 
3 3
Propan-2-one 
       
Acetonitrile  CHCN  Class 2 
3
       
Anisole  Methoxybenzene  Class 3 
 
       
Benzene  Benzol  Class 1 
 
       
1-Butanol  n-Butyl alcohol  CH(CH)OH  Class 3 
3 2 3
Butan-1-ol 
       
2-Butanol  sec-Butyl alcohol  CH3CH2CH(OH)CH3  Class 3 
Butan-2-ol 
       
Butyl acetate  Acetic acid butyl   ester  CHCOO(CH)CH  Class 3 
3 2 3 3
       
tert-Butylmethyl ether  2-Methoxy-2-methyl-propane  (CH)COCH  Class 3 
3 3 3
       
Carbon tetrachloride  Tetrachloromethane  CCl4  Class 1 
       
Chlorobenzene  Class 2 
 
       
Chloroform  Trichloromethane  CHCl  Class 2 
3
     
 
Cumene  Isopropylbenzene  Class 2 
CH-CH(CH) 
(1-Methyl)ethylbenzene  6 5 3 2
       
Cyclohexane  Hexamethylene  Class 2 
 
       
     
 
     
 
1,2-Dichloroethane  CHClCHCl  Class 1 
sym-Dichloroethane  2 2
Ethylene dichloride 
Ethylene chloride 
       
1,1-Dichloroethene  1,1-Dichloroethylene  HC=CCl  Class 1 
2 2
Vinylidene chloride 
       
1,2-Dichloroethene  1,2-Dichloroethylene  ClHC=CHCl  Class 2 
Acetylene dichloride 
       
 
2  Contains Nonbinding Recommendations 
 
Dichloromethane  Methylene chloride  CHCl  Class 2 
2 2
       
1,2-Dimethoxyethane  Ethyleneglycol dimethyl ether  HCOCHCHOCH  Class 2 
3 2 2 3
Monoglyme 
Dimethyl Cellosolve 
       
N,N-               DMA  CHCON(CH)  Class 2 
3 3 2
Dimethylacetamide 
       
N,N- Dimethylformamide  DMF  HCON(CH)  Class 2 
3 2
       
Dimethyl sulfoxide  Methylsulfinylmethane  (CH)SO  Class 3 
3 2
Methyl sulfoxide 
DMSO 
       
1,4-Dioxane  p-Dioxane  Class 2 
[1,4]Dioxane 
 
       
Ethanol  Ethyl alcohol  CHCHOH  Class 3 
3 2
       
2-Ethoxyethanol  Cellosolve  CHCHOCHCHOH  Class 2 
3 2 2 2
       
Ethyl acetate  Acetic acid ethyl ester  CHCOOCHCH  Class 3 
3 2 3
     
 
1,2-Dihydroxyethane  HOCHCHOH  Class 2 
Ethyleneglycol  2 2
1,2-Ethanediol 
       
Ethyl ether  Diethyl ether  CHCHOCHCH  Class 3 
3 2 2 3
Ethoxyethane 
1,1-Oxybisethane 
       
Ethyl formate  Formic acid ethyl ester  HCOOCHCH  Class 3 
2 3
       
Formamide  Methanamide  HCONH  Class 2 
2
       
Formic acid    HCOOH  Class 3 
       
Heptane  n-Heptane  CH(CH)CH  Class 3 
3 2 5 3
       
Hexane  n-Hexane  CH(CH)CH  Class 2 
3 2 4 3
       
Isobutyl acetate  Acetic acid isobutyl ester  CHCOOCHCH(CH)  Class 3 
3 2 3 2
       
Isopropyl acetate  Acetic acid isopropyl ester  CHCOOCH(CH)  Class 3 
3 3 2
       
Methanol  Methyl alcohol  CHOH  Class 2 
3
       
2-Methoxyethanol  Methyl Cellosolve  CHOCHCHOH  Class 2 
3 2 2
       
Methyl acetate  Acetic acid methyl ester  CHCOOCH  Class 3 
3 3
       
3-Methyl-1-butanol  Isoamyl alcohol   (CH)CHCHCHOH  Class 3 
3 2 2 2
Isopentyl alcohol 
3-Methylbutan-1-ol 
       
Methylbutyl ketone  2-Hexanone  CH(CH)COCH  Class 2 
3 2 3 3
 
3  Contains Nonbinding Recommendations 
 
Hexan-2-one 
       
Methylcyclohexane  Cyclohexylmethane  Class 2 
 
       
2-Butanone  CHCHCOCH  Class 3 
3 2 3
Methylethyl ketone 
MEK 
Butan-2-one 
       
Methylisobutyl ketone  4-Methylpentan-2-one  CHCOCHCH(CH)  Class 2 
3 2 3 2
4-Methyl-2-pentanone 
MIBK 
       
2-Methyl-1-propanol  Isobutyl alcohol  (CH)CHCHOH  Class 3 
3 2 2
2-Methylpropan-1-ol 
     
N-Methylpyrrolidone  1-Methylpyrrolidin-2-one  Class 2 
1-Methyl-2-pyrrolidinone   
     
 
Nitromethane  CHNO  Class 2 
3 2
       
Pentane  n-Pentane  CH(CH)CH  Class 3 
3 2 3 3
       
1-Pentanol  Amyl alcohol  CH(CH)CHOH  Class 3 
3 2 3 2
Pentan-1-ol 
Pentyl alcohol 
       
1-Propanol  Propan-1-ol  CHCHCHOH  Class 3 
3 2 2
Propyl alcohol 
       
2-Propanol  Propan-2-ol  (CH)CHOH  Class 3 
3 2
Isopropyl alcohol 
       
Propyl acetate  Acetic acid propyl ester  CHCOOCHCHCH  Class 3 
3 2 2 3
   
 
Pyridine  Class 2 
 
     
Sulfolane  Tetrahydrothiophene 1,1-dioxide  Class 2 
 
       
Tetrahydrofuran  Tetramethylene oxide  Class 2 
Oxacyclopentane 
 
     
Tetralin  1,2,3,4-Tetrahydro-naphthalene  Class 2 
 
     
Toluene  Methylbenzene    Class 2 
       
1,1,1-Trichloroethane  Methylchloroform  CHCCl  Class 1 
3 3
       
1,1,2-Trichloroethene  Trichloroethene  HClC=CCl  Class 2 
2
       
Triethylamine  N,N-Diethylethanamine   N(CHCH)  Class 3 
2 3 3
 
4  Contains Nonbinding Recommendations 
 
     
Xylene1  Dimethybenzene  Class 2 
 
Xylol 
       
1Usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene. 
 
 
III.  SOLVENTS GROUPED BY CLASS 
 
 
Solvents in Class 1 (Table 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.   The solvent 1,1,1-Trichloroethane  is included  in Table 1 because it is 
an environmental  hazard.  The stated limit  of 1,500 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  Concern 
(ppm)   
 
Benzene          2  Carcinogen 
     
Carbon tetrachloride          4  Toxic and environmental hazard 
1,2-Dichloroethane          5  Toxic 
1,1-Dichloroethene         8  Toxic 
1,1,1-Trichloroethane  1,500  Environmental hazard 
 
 
 
 
 
 
5  Contains Nonbinding Recommendations 
 
Solvents in Class 2 (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   410 
   
Chlorobenzene    3.6    360 
Chloroform    0.6    60 
   
Cyclohexane    38.8    3,880 
 
 
Cumene                    0.7                                           70 
1,2-Dichloroethene    18.7   1,870 
  18.7 
Dichloromethane    6.0    600 
1,2-Dimethoxyethane    1.0    100 
N,N-Dimethylacetamide    10.9    1,090 
N,N-Dimethylformamide    8.8    880 
1,4-Dioxane    3.8    380 
2-Ethoxyethanol    1.6    160 
Ethyleneglycol    3.1    310 
Formamide    2.2    220 
Hexane    2.9    290 
Methanol    30.0    3,000 
2-Methoxyethanol    0.5    50 
Methylbutyl ketone    0.5    50 
Methylcyclohexane    11.8    1,180 
Methylisobutylketone2                   45                                      4,500 
N-Methylpyrrolidone    5.3    530 
Nitromethane    0.5    50 
Pyridine    2.0    200 
Sulfolane    1.6    160 
Tetrahydrofuran                     7.2                                           720 
Tetralin    1.0    100 
                                                             
2 The information included for Methylisobutylketone reflects that included in the Revision of PDE Information for 
Methylisobutylketone, which reached Step 4 in November 2016 and was subsequently incorporated into the core 
guidance.  
 
6  Contains Nonbinding Recommendations 
 
Toluene    8.9    890 
1,1,2-Trichloroethene    0.8    80 
Xylene1    21.7    2,170 
1Usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene. 
 
 
Solvents in Class 3 (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 5,000 ppm or 0.5 percent 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 (GMP). 
 
 
Table 3.  Class 3 Solvents Which Should Be Limited by GMP or Other Quality-Based 
Requirements 
 
Acetic acid  Heptane 
Acetone  Isobutyl acetate 
Anisole  Isopropyl acetate 
1-Butanol  Methyl acetate 
2-Butanol  3-Methyl-1-butanol 
Butyl acetate  Methylethyl ketone 
tert-Butylmethyl ether  2-Methyl-1-propanol 
Dimethyl sulfoxide  Pentane 
Ethanol  1-Pentanol 
Ethyl acetate  1-Propanol 
Ethyl ether  2-Propanol 
Ethyl formate  Propyl acetate 
Formic acid  Triethylamine3 
 
 
 
 
 
                                                             
3 The information included for Triethylamine reflects that included in the Revision of PDE Information for 
Triethylamine, which reached Step 4 in November 2016 and was subsequently incorporated into the core guidance.  
 
7  Contains Nonbinding Recommendations 
 
The solvents listed in 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 
were found.  Manufacturers should supply justification  for residual levels of these solvents in 
pharmaceutical products. 
 
 
Table 4.  Solvents for Which No Adequate Toxicological Data Were Found 
 
1,1-Diethoxypropane  Methylisopropyl ketone  
1,1-Dimethoxymethane  Methyltetrahydrofuran 
2,2-Dimethoxypropane  Petroleum ether 
Isooctane  Trichloroacetic acid 
Isopropyl ether  Trifluoroacetic acid 
 
 
 
8