Impurities can be classified into the following
categories:
·
Organic impurities (process- and drug-related)
·
Inorganic impurities
·
Residual solvents
Organic impurities can
arise during the manufacturing process and/or storage of the new drug
substance. They can be identified or unidentified, volatile or non-volatile,
and include:
·
Starting materials
·
By-products
·
Intermediates
·
Degradation products
·
Reagents, ligands and catalysts
Inorganic impurities can
result from the manufacturing process.
They are normally known and identified and include:
·
Reagents, ligands and catalysts
·
Heavy metals or other residual metals
·
Inorganic salts
·
Other materials (e.g., filter aids, charcoal)
Solvents are inorganic or organic liquids used as vehicles
for the preparation of solutions or suspensions in the synthesis of a new drug
substance. Since these are generally of known toxicity, the selection of
appropriate controls is easily accomplished.
Classification of Residual Solvents by Risk
Assessment
Class 1 solvents: Solvents to be avoided
Known human carcinogens, strongly suspected human
carcinogens, and environmental hazards.
Solvents in Class 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 to produce a drug
product with a significant therapeutic advance, then their levels should be
restricted as shown in, unless otherwise justified.
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
|
1500
|
Environmental hazard
|
Class 2 solvents: Solvents to be limited
Non-genotoxic animal carcinogens or possible causative
agents of other irreversible toxicity such as neurotoxicity or teratogenicity.
Solvents suspected of other significant but reversible toxicities.
Solvents in 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.
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
|
Cumene1
|
0.7
|
70
|
Cyclohexane
|
38.8
|
3880
|
1,2-Dichloroethene
|
18.7
|
1870
|
Dichloromethane
|
6
|
600
|
1,2-Dimethoxyethane
|
1
|
100
|
N,N-Dimethylacetamide
|
10.9
|
1090
|
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
|
3000
|
2-Methoxyethanol
|
0.5
|
50
|
Methylbutyl ketone
|
0.5
|
50
|
Methylcyclohexane
|
11.8
|
1180
|
Methylisobutylketone2
|
45
|
4500
|
N-Methylpyrrolidone3
|
5.3
|
530
|
Nitromethane
|
0.5
|
50
|
Class 3 solvents: Solvents with low toxic
potential
Solvents with low toxic potential to man; no health-based
exposure limit is needed. Class 3 solvents have PDEs of 50 mg or more per day.
Solvents in Class 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.
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
|
2-Methyl-1-propanol
|
Dimethyl sulfoxide
|
Pentane
|
Ethanol
|
1-Pentanol
|
Ethyl acetate
|
1-Propanol
|
Ethyl ether
|
2-Propanol
|
Ethyl formate
|
Propyl acetate
|
Formic acid
|
Triethylamine
|
Solvents for which No Adequate Toxicological
Data was Found
The following solvents 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 was found.
Manufacturers should supply justification for residual
levels of these solvents in pharmaceutical products.
1,1-Diethoxypropane
|
Methylisopropyl ketone
|
1,1-Dimethoxymethane
|
Methyltetrahydrofuran
|
2,2-Dimethoxypropane
|
Petroleum ether
|
Isooctane
|
Trichloroacetic acid
|
Isopropyl ether
|
Trifluoroacetic acid
|
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