Residual Solvents & Their Classification By risk Assessment

 

Residual Solvents & Their Classification By risk Assessment

Residual Solvents & Their Classification By risk Assessment

Residual Solvents

—  Residual solvents are volatile organic chemicals that are used or produced during the manufacturing of drug substances, excipients, dietary ingredients, drug products and dietary supplements.

—  The complete removal of the residual solvents from the above said products is may or may not be possible.

—  As we know that there is no role of these solvents in any therapeutic activity therefore its removal to the possible extent is very necessary to meet the safety guideline limits, products specifications and good manufacturing practices.

Classification of Residual Solvents By Risk Assessment and their limits.

—  Class 1 Solvents: Class 1 solvents are those that are to be avoided.

—  These solvents should not be employed in the manufacturing of drug substance, excipients and products due to its toxic effect or environmental hazardous nature.

—  They have reported carcinogenic effects or zone depletion effects.

—  However if its impossible to avoid these completely in manufacturing process then there availability should restricted to the following limit given in table 1.

—  Table: 1

Solvent	Concentration limit (ppm)	Effects
Benzene	2	Carcinogen
Carbon tetrachloride	4	Toxic and environmental hazard
1,2-Dichloroethane	5	Toxic
1,1-Dichloroethene	8	Toxic
1,1,1-Trichloroethan	1500	Environmental hazard

                                                                                                                                                                                                                                                                                                                                            

                                                                                                                                                        

—  Class 2 Solvents:  Class 2 solvents are those that are to be limited because of their inherit toxicities.

—  They are non-genotoxic animal carcinogens or may cause some other irreversible toxicities likewise neurotoxicity and teratogenicity.

—  They may include solvent that cause some other reversible toxic effects.

—  Solvents of class 2 with their  limits and PDEs (Permitted daily exposure) are given in table 2.

Table 2

Solvent	PDE (mg/day)	Concentration limit (ppm)
Acetonitrile	4.1	410
Chlorobenzene	3.6	360
Chloroform	0.6	60
Cyclohexane	38.8	3880
1,2-Dichloroethene	18.7	1870
Dichloromethane	6.0	600
1,2-Dimethoxyethane & Tetralin	1.0	100
N,N-Dimethylacetamide	10.9	1090
N,N-Dimethylformamide	8.8	880
1,4-Dioxane	3.8	380

 

2-Ethoxyethanol  & Sulfolane	1.6	160
Ethyleneglycol	6.2	620
Formamide	2.2	220
Hexane	2.9	290
Methanol	30.0	3000
2-Methoxyethanol  & Methylbutyl ketone	0.5	50
N-Methylpyrrolidone1	5.3	530
Methylcyclohexane	11.8	1180
Nitromethane	0.5	50
Pyridine	2.0	200
1,1,2-Trichloroethene	0.8	80
Tetrahydrofuran2	7.2	720
	1.0	100
Toluene	8.9	890
Xylene	21.7	2170

 

—  Class 3 Solvents:  class 3 includes those solvents having low toxic potential.

—  These solvents have low toxic potential to man and there is no need of health-based exposure limit.

—  It is stated that quantity of these residual solvents at a level of 50 mg per day or fewer would be acceptable without any justification.

—   The exposure of these solvents should be limited by GMP or other quality-based necessities.

—  Solvents included in this class with their limits are given in following table 3

Table 3

Acetic acid	Heptane	Acetone	Isobutyl acetate	Anisole
1-Butanol	2-Methyl-1-propanol	Methyl acetate	3-Methyl-1-butanol	Methylethyl ketone
Methylisobutyl ketone	Cumene	tert-Butylmethyl ether	Isopropyl acetate	2-Butanol
Dimethyl sulfoxide	Propyl acetate	Ethyl formate	2-Propanol	Ethyl ether
Ethyl acetate	1-Propanol	1-Pentanol	Pentane	Formic acid
Ethanol	Butyl acetate