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
`
`i
`
`Gilead 2013
`I-MAK v. Gilead
`IPR2018-00126
`
`

`

`Guidance for Industry
`Q3C — Tables and List
`
`Additional copies are available from:
`Center for Drug Evaluation and Research (CDER)
`Division of Drug Information (HFD-240)
`Food and Drug Administration
`5600 Fishers Lane
` Rockville, MD 20857
`(Tel) 301-827-4573
`http://www.fda.gov/cder/guidance/index.htm
`
`or
`
`Office of Communication, Training, and
`Manufacturers Assistance (HFM-40)
`Center for Biologics Evaluation and Research (CBER)
`Food and Drug Administration
`1401 Rockville Pike
` Rockville, MD 20852-1448
`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
`
`ii
`
`

`

`Contains Nonbinding Recommendations
`
`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.
`
`1 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.
`
`1
`
`

`

`Contains Nonbinding Recommendations
`
`II.
`
`LIST OF SOLVENTS INCLUDED IN THE Q3C GUIDANCE
`
`Solvent
`
`Acetic acid
`
`Acetone
`
`Acetonitrile
`
`Anisole
`
`Benzene
`
`1-Butanol
`
`2-Butanol
`
`Other Names
`
`Ethanoic acid
`
`2-Propanone
`Propan-2-one
`
`Methoxybenzene
`
`Benzol
`
`n-Butyl alcohol
`Butan-1-ol
`
`sec-Butyl alcohol
`Butan-2-ol
`
`Structure
`
`CH3COOH
`
`CH3COCH3
`
`CH3CN
`
`CH3(CH2)3OH
`
`CH3CH2CH(OH)CH3
`
`Butyl acetate
`
`Acetic acid butyl ester
`
`CH3COO(CH2)3CH3
`
`tert-Butylmethyl ether
`
`2-Methoxy-2-methyl-propane
`
`(CH3)3COCH3
`
`Carbon tetrachloride
`
`Tetrachloromethane
`
`Chlorobenzene
`
`Chloroform
`
`Cumene
`
`Trichloromethane
`
`Isopropylbenzene
`(1-Methyl)ethylbenzene
`
`Cyclohexane
`
`Hexamethylene
`
`1,2-Dichloroethane
`
`1,1-Dichloroethene
`
`sym-Dichloroethane
`Ethylene dichloride
`Ethylene chloride
`
`1,1-Dichloroethylene
`Vinylidene chloride
`
`2
`
`CCl4
`
`CHCl3
`
`C6H5-CH(CH3)2
`
`CH2ClCH2Cl
`
`H2C=CCl2
`
`Class
`
`Class 3
`
`Class 3
`
`Class 2
`
`Class 3
`
`Class 1
`
`Class 3
`
`Class 3
`
`Class 3
`
`Class 3
`
`Class 1
`
`Class 2
`
`Class 2
`
`Class 3
`
`Class 2
`
`Class 1
`
`Class 1
`
`

`

`Contains Nonbinding Recommendations
`
`1,2-Dichloroethene
`
`1,2-Dichloroethylene
`Acetylene dichloride
`
`Dichloromethane
`
`Methylene chloride
`
`1,2-Dimethoxyethane
`
`Ethyleneglycol dimethyl ether
`Monoglyme
`Dimethyl Cellosolve
`
`N,N-
`Dimethylacetamide
`
`DMA
`
`N,N- Dimethylformamide
`
`DMF
`
`Dimethyl sulfoxide
`
`1,4-Dioxane
`
`Ethanol
`
`2-Ethoxyethanol
`
`Ethyl acetate
`
`Ethyleneglycol
`
`Ethyl ether
`
`Ethyl formate
`
`Formamide
`
`Formic acid
`
`Heptane
`
`Hexane
`
`Isobutyl acetate
`
`Isopropyl acetate
`
`Methanol
`
`Methylsulfinylmethane
`Methyl sulfoxide
`DMSO
`
`p-Dioxane
`[1,4]Dioxane
`
`Ethyl alcohol
`
`Cellosolve
`
`Acetic acid ethyl ester
`
`1,2-Dihydroxyethane
`1,2-Ethanediol
`
`Diethyl ether
`Ethoxyethane
`1,1’-Oxybisethane
`
`Methanamide
`
`n-Heptane
`
`n-Hexane
`
`Acetic acid isobutyl ester
`
`Acetic acid isopropyl ester
`
`Methyl alcohol
`
`ClHC=CHCl
`
`CH2Cl2
`
`H3COCH2CH2OCH3
`
`CH3CON(CH3)2
`
`HCON(CH3)2
`
`(CH3)2SO
`
`CH3CH2OH
`
`CH3CH2OCH2CH2OH
`
`CH3COOCH2CH3
`
`HOCH2CH2OH
`
`CH3CH2OCH2CH3
`
`HCONH2
`
`HCOOH
`
`CH3(CH2)5CH3
`
`CH3(CH2)4CH3
`
`CH3COOCH2CH(CH3)2
`
`CH3COOCH(CH3)2
`
`CH3OH
`
`CH3OCH2CH2OH
`
`CH3COOCH3
`
`Class 2
`
`Class 2
`
`Class 2
`
`Class 2
`
`Class 2
`
`Class 3
`
`Class 2
`
`Class 3
`
`Class 2
`
`Class 3
`
`Class 2
`
`Class 3
`
`Class 3
`
`Class 2
`
`Class 3
`
`Class 3
`
`Class 2
`
`Class 3
`
`Class 3
`
`Class 2
`
`Class 2
`
`Class 3
`
`Formic acid ethyl ester
`
`HCOOCH2CH3
`
`2-Methoxyethanol
`
`Methyl Cellosolve
`
`Methyl acetate
`
`Acetic acid methyl ester
`
`3
`
`

`

`Contains Nonbinding Recommendations
`
`(CH3)2CHCH2CH2OH
`
`Class 3
`
`3-Methyl-1-butanol
`
`Methylbutyl ketone
`
`Isoamyl alcohol
`Isopentyl alcohol
`3-Methylbutan-1-ol
`
`2-Hexanone
`Hexan-2-one
`
`Methylcyclohexane
`
`Cyclohexylmethane
`
`Methylethyl ketone
`
`Methylisobutyl ketone
`
`2-Methyl-1-propanol
`
`N-Methylpyrrolidone
`
`Nitromethane
`
`Pentane
`
`1-Pentanol
`
`1-Propanol
`
`2-Propanol
`
`2-Butanone
`MEK
`Butan-2-one
`4-Methylpentan-2-one
`4-Methyl-2-pentanone
`MIBK
`
`Isobutyl alcohol
`2-Methylpropan-1-ol
`
`1-Methylpyrrolidin-2-one
`1-Methyl-2-pyrrolidinone
`
`n-Pentane
`
`Amyl alcohol
`Pentan-1-ol
`Pentyl alcohol
`
`Propan-1-ol
`Propyl alcohol
`
`Propan-2-ol
`Isopropyl alcohol
`
`CH3(CH2)3COCH3
`
`CH3CH2COCH3
`
`CH3COCH2CH(CH3)2
`
`(CH3)2CHCH2OH
`
`CH3NO2
`
`CH3(CH2)3CH3
`
`CH3(CH2)3CH2OH
`
`CH3CH2CH2OH
`
`(CH3)2CHOH
`
`Class 2
`
`Class 2
`
`Class 3
`
`Class 3
`
`Class 3
`
`Class 2
`
`Class 2
`
`Class 3
`
`Class 3
`
`Class 3
`
`Class 3
`
`Class 3
`
`Class 2
`
`Class 2
`
`Class 2
`
`Class 2
`
`Class 2
`
`Class 1
`
`Propyl acetate
`
`Acetic acid propyl ester
`
`CH3COOCH2CH2CH3
`
`Pyridine
`
`Sulfolane
`
`Tetrahydrothiophene 1,1-dioxide
`
`Tetrahydrofuran
`
`Tetramethylene oxide
`Oxacyclopentane
`
`Tetralin
`
`Toluene
`
`1,2,3,4-Tetrahydro-naphthalene
`
`Methylbenzene
`
`1,1,1-Trichloroethane
`
`Methylchloroform
`
`CH3CCl3
`
`4
`
`

`

`Contains Nonbinding Recommendations
`
`1,1,2-Trichloroethene
`
`Trichloroethene
`
`HClC=CCl2
`
`Xylene1
`
`Dimethybenzene
`Xylol
`
`1Usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene.
`
`Class 2
`
`Class 2
`
`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
`
`Benzene
`
`Carbon tetrachloride
`1,2-Dichloroethane
`1,1-Dichloroethene
`1,1,1-Trichloroethane
`
`Concentration Limit
`(ppm)
`
` 2
`
` 4
` 5
` 8
`1,500
`
`Concern
`
`Carcinogen
`
`Toxic and environmental hazard
`Toxic
`Toxic
`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)
`4.1
`410
`Acetonitrile
`3.6
`360
`Chlorobenzene
`60
`0.6
`Chloroform
`38.8
`3,880
`Cyclohexane
`18.7
`1,870
`1,2-Dichloroethene
`6.0
`600
`Dichloromethane
`1.0
`100
`1,2-Dimethoxyethane
`10.9
`1,090
`N,N-Dimethylacetamide
`8.8
`880
`N,N-Dimethylformamide
`3.8
`380
`1,4-Dioxane
`1.6
`160
`2-Ethoxyethanol
`6.2
`620
`Ethyleneglycol
`2.2
`220
`Formamide
`2.9
`290
`Hexane
`30.0
`3,000
`Methanol
`0.5
`50
`2-Methoxyethanol
`0.5
`50
`Methylbutyl ketone
`11.8
`1,180
`Methylcyclohexane
`5.3
`530
`N-Methylpyrrolidone
`0.5
`50
`Nitromethane
`2.0
`200
`Pyridine
`1.6
`160
`Sulfolane
` 7.2
` 720
`Tetrahydrofuran
`1.0
`100
`Tetralin
`8.9
`890
`Toluene
`0.8
`80
`1,1,2-Trichloroethene
`Xylene1
`21.7
`2,170
`1Usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene.
`
`6
`
`

`

`Contains Nonbinding Recommendations
`
`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
`Acetone
`
`Anisole
`
`1-Butanol
`
`2-Butanol
`
`Butyl acetate
`
`tert-Butylmethyl ether
`
`Cumene
`
`Dimethyl sulfoxide
`
`Ethanol
`
`Ethyl acetate
`
`Ethyl ether
`
`Ethyl formate
`
`Formic acid
`
`Heptane
`
`Isobutyl acetate
`
`Isopropyl acetate
`
`Methyl acetate
`
`3-Methyl-1-butanol
`
`Methylethyl ketone
`
`Methylisobutyl ketone
`
`2-Methyl-1-propanol
`
`Pentane
`
`1-Pentanol
`
`1-Propanol
`
`2-Propanol
`
`Propyl acetate
`
`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
`1,1-Dimethoxymethane
`2,2-Dimethoxypropane
`Isooctane
`Isopropyl ether
`
`Methylisopropyl ketone
`Methyltetrahydrofuran
`Petroleum ether
`Trichloroacetic acid
`Trifluoroacetic acid
`
`8
`
`