Guidance for Industry

Q3C — Tables and List

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)

November 2003

ICH

Revision 1
Guidance for Industry

Q3C — Tables and List

Additional copies are available from:

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Food and Drug Administration 

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(Tel) 301-827-4573

http://www.fda.gov/cder/guidance/index.htm

or

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http://www.fda.gov/cber/guidelines.htm;

(Tel) Voice Information System at 800-835-4709 or 301-827-1800

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)

November 2003

ICH

Revision 1
Contains Nonbinding Recommendations

1

Guidance for Industry1

Q3C — Tables and List

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It 

does not create or confer any rights for or on any person and does not operate to bind FDA or the public. 

You can use an alternative approach if that approach satisfies the requirements of the applicable statutes 

and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for 

implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate 

number listed on the title page of this guidance. 

I. INTRODUCTION 

This is the companion document for the International Conference on Harmonisation of Technical 

Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidance for industry 

Q3C Impurities: Residual Solvents (1997), 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 International 

Conference on Harmonisation (ICH) Steering Committee. Proposals for change and the ICH 

Steering Committee final decision on any proposed changes will be announced through a notice 

in the Federal Register prior to the updating of this document. 

FDA's guidance documents, including this guidance, 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.

 

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This document was developed within the Expert Working Group (Quality) of the International 

Conference on Harmonisation of Technical Requirements for Registration of 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 bodies of the European Union, Japan, and the United 

States. This guidance was published in the Federal Register on December 24, 1997 (62 FR67377), and is 

applicable to drug and biological products. 
Contains Nonbinding Recommendations

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II. LIST OF SOLVENTS INCLUDED IN THE Q3C GUIDANCE

Solvent Other Names Structure Class

Acetic acid Ethanoic acid CH3COOH Class 3

Acetone 2-Propanone 

Propan-2-one

CH3COCH3 Class 3

Acetonitrile CH3CN Class 2

Anisole Methoxybenzene Class 3

Benzene Benzol Class 1

1-Butanol n-Butyl alcohol

Butan-1-ol

CH3(CH2)3OH Class 3

2-Butanol sec-Butyl alcohol

Butan-2-ol

CH3CH2CH(OH)CH3 Class 3

Butyl acetate Acetic acid butyl ester CH3COO(CH2)3CH3 Class 3

tert-Butylmethyl ether 2-Methoxy -2-methyl-propane (CH3)3COCH3 Class 3

Carbon tetrachloride Tetrachloromethane CCl4 Class 1

Chlorobenzene Class 2

Chloroform Trichloromethane CHCl3 Class 2

Cumene Isopropylbenzene

(1-Methyl)ethylbenzene C6H5-CH(CH3)2

Class 3

Cyclohexane Hexamethylene Class 2

1,2-Dichloroethane

sym-Dichloroethane

Ethylene dichloride

Ethylene chloride

CH2ClCH2Cl Class 1

1,1-Dichloroethene 1,1-Dichloroethylene

Vinylidene chloride

H2C=CCl2 Class 1
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1,2-Dichloroethene 1,2-Dichloroethylene

Acetylene dichloride

ClHC=CHCl Class 2

Dichloromethane Methylene chloride CH2Cl2 Class 2

1,2-Dimethoxyethane Ethyleneglycol dimethyl ether

Monoglyme

Dimethyl Cellosolve

H3COCH2CH2OCH3 Class 2

N,NDimethylacetamideDMA CH3CON(CH3)2 Class 2

N,N- Dimethylformamide DMF HCON(CH3)2 Class 2

Dimethyl sulfoxide Methylsulfinylmethane

Methyl sulfoxide

DMSO

(CH3)2SO Class 3

1,4-Dioxane p-Dioxane

[1,4]Dioxane

Class 2

Ethanol Ethyl alcohol CH3CH2OH Class 3

2-Ethoxyethanol Cellosolve CH3CH2OCH2CH2OH Class 2

Ethyl acetate Acetic acid ethyl ester CH3COOCH2CH3 Class 3

Ethyleneglycol 1,2-Dihydroxyethane

1,2-Ethanediol

HOCH2CH2OH Class 2

Ethyl ether Diethyl ether

Ethoxyethane

1,1’-Oxybisethane

CH3CH2OCH2CH3 Class 3

Ethyl 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 3

Hexane n-Hexane CH3(CH2)4CH3 Class 2

Isobutyl 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 3
Contains Nonbinding Recommendations

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3-Methyl-1-butanol Isoamyl alcohol 

Isopentyl alcohol

3-Methylbutan-1-ol

(CH3)2CHCH2CH2OH Class 3

Methylbutyl ketone 2-Hexanone

Hexan-2-one

CH3(CH2)3COCH3 Class 2

Methylcyclohexane Cyclohexylmethane Class 2

Methylethyl ketone 2-Butanone

MEK

Butan-2-one

CH3CH2COCH3 Class 3

Methylisobutyl ketone 4-Methylpentan-2-one

4-Methyl-2-pentanone

MIBK

CH3COCH2CH(CH3)2 Class 3

2-Methyl-1-propanol Isobutyl alcohol

2-Methylpropan-1-ol

(CH3)2CHCH2OH Class 3

N-Methylpyrrolidone 1-Methylpyrrolidin-2-one

1-Methyl-2-pyrrolidinone

Class 2

Nitromethane CH3NO2 Class 2

Pentane n-Pentane CH3(CH2)3CH3 Class 3

1-Pentanol Amyl alcohol

Pentan-1-ol

Pentyl alcohol

CH3(CH2)3CH2OH Class 3

1-Propanol Propan-1-ol

Propyl alcohol

CH3CH2CH2OH Class 3

2-Propanol Propan-2-ol

Isopropyl alcohol

(CH3)2CHOH Class 3

Propyl acetate Acetic acid propyl ester CH3COOCH2CH2CH3 Class 3

Pyridine Class 2

Sulfolane Tetrahydrothiophene 1,1-dioxide Class 2

Tetrahydrofuran Tetramethylene oxide

Oxacyclopentane

Class 2

Tetralin 1,2,3,4-Tetrahydro-naphthalene Class 2

Toluene Methylbenzene Class 2

1,1,1-Trichloroethane Methylchloroform CH3CCl3 Class 1
Contains Nonbinding Recommendations

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1,1,2-Trichloroethene Trichloroethene HClC=CCl2 Class 2

Xylene1 Dimethybenzene

Xylol

Class 2

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

(ppm)

Concern

Benzene

Carbon tetrachloride

 2

 4

Carcinogen

Toxic and environmental hazard

1,2-Dichloroethane 5 Toxic

1,1-Dichloroethene 8 Toxic

1,1,1-Trichloroethane 1,500 Environmental hazard
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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

1,2-Dichloroethene 18.7 1,870

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 6.2 620

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

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

Toluene 8.9 890

1,1,2-Trichloroethene 0.8 80

Xylene121.7 2,170

1Usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene.
Contains Nonbinding Recommendations

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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 Methylisobutyl ketone

Cumene 2-Methyl-1-propanol

Dimethyl sulfoxide Pentane

Ethanol 1-Pentanol

Ethyl acetate 1-Propanol

Ethyl ether 2-Propanol

Ethyl formate Propyl acetate

Formic acid
Contains Nonbinding Recommendations

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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