Guidance for Industry Q3C - Tables and List [PDF version of this document] 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 Guidance for Industry1 Q3C - Tables and List Contains Nonbinding Recommendations 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. 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. 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 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,N- Dimethylacetamide DMA 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 3 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 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 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. 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           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 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 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 Methylisobutyl ketone Cumene 2-Methyl-1-propanol Dimethyl sulfoxide Pentanel Ethanol 1-Pentanol Ethyl acetate 1-Propanol Ethyl ether 2-Propanol Ethyl formate Propyl acetate Formic acid   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 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.

Updated November 13, 2003

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