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Guidance for Industry: Q3C ? Tables and List

Guidance for Industry
Q3C ? Tables and List

(PDF version of this document)
 

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:
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
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 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 Industry[1]
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.

 

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

 

 

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 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

 

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.
 

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

 

 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                  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

Pentane

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. 


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