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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
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 Industry
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 |
|
|
Acetone |
2-Propanone
Propan-2-one |
CH3COCH3 |
|
|
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 |
|
|
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 |
|
|
|
Solvent
|
PDE (mg/day) |
Concentration Limit (ppm)
|
Acetonitrile |
4.1 |
410 |
Chlorobenzene |
3.6 |
360 |
Chloroform |
0.6 |
|
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
|
Heptane |
Acetone |
Isobutyl
acetate |
Anisole |
Isopropyl
acetate |
|
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 |
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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Date created: July 7, 2006
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