Biopharma Consulting

Impurities General

Impurities General Guidelines ICH Q3A (R2): Impurities in New Drug Substances: ICH Q3B (R2): Impurities in New Drug Products: ICH Q3C (R6): Residual Solvents: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/03/WC500104258.pdf ICH Q3D: Elemental Impurities: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/01/WC500180284.pdf Examples Impurities for which sufficient public-domain data may be available to support qualification:
  • Acetaldehyde
  • Acetamide
  • Acetanilide
  • Aluminium
  • Benzalkonium chloride
  • Benzaldehyde
  • Benzamide
  • 1-Butanal
  • 2-Butene
  • Caprolactam
  • Cetylpyridinium chloride
  • Decamethylcyclopentasiloxane (D5)
  • 2,4-Dichlorobenzoic acid
  • Dicyclohexyl carbodiimide
  • Diethyl acetal
  • Diethyl amine
  • Diethyl fumarate
  • Diisopropyl carbodiimide
  • Diisopropylethyl amine
  • Dimethyl amine
  • Dimethylaminopyridine
  • Dimethyl ether
  • Dimethylglyoxime
  • Dipropyl amine
  • 2,4-Di-t-butylphenol
  • Dodecane
  • Dodecanethiol
  • EDTA
  • Ethylenediamine
  • Ethyl propionate
  • Ethyl trifluoroacetate
  • 2-Ethoxypropane
  • 4-Fluorobenzaldehyde
  • Hexenes/heptenes
  • Hexyl/Isobutyl chloroformate
  • 4-Hydroxybenzaldehyde
  • 5-Hydroxymethylfurfural
  • Isododecane
  • Isophthalaldehyde
  • Isopropyl amine
  • Melamine
  • Methanesulfonic acid
  • Methyl acrylate
  • Methyl formate
  • 2-Methyl-2-pentene
  • 2-Methoxypropane
  • Mineral oil (various grades)
  • Monochloroacetic acid
  • N-Methylaniline
  • N,N-Dimethylaniline
  • Nonacosane
  • 1-Phenylethyl amine
  • Phenol
  • Polydimethylsiloxane
  • Polyethyleneimine
  • Propionitrile
  • Sodium azide
  • Sodium ferrocyanide
  • Strontium
  • Sulfur
  • t-Butyl isocyanate
  • Tetrachoroethene
  • Tetramethylurea
  • Thiophenol
  • Tin
  • Tributyltin oxide
  • Triethyl amine
  • Trifluoroethanol
  • Tri-n-butyl amine
  • Trimethyl amine
  • Trimethyl amine N-oxide
  • Urea
  • Zirconium
      Solvents not listed in ICH Q3C (R6)
Solvent PDE (mg)
Class 2  
Cyclopentylmethyl ether 6.2
Cyclohexanol 15.0
1,2-Dichlorobenzene 17.9
Diisopropyl ether 49.6
DMPU 1.0
Isopropoxyethanol 1.5
Isodecane 33
Mesityl oxide 3.2
2-Methyltetrahydrofuran 5.2
Methyl acrylate 1.0
Methylamine 11
Methylcyclohexane 25
Morpholine 21
Petroleum ether (C5-C8 fraction) 12
Propanenitrile 4.0
Pyrrolidine 6.9
t-Butyl acetate 15.2
1,1,1-Trichloroethane 0.2
2,2,2-Trichloroacetic acid 3.3
2,2,2-Trichloroethanol 16
2,4,4-Trimethyl-1-pentene 30
Class 3  
Benzyl alcohol ≥ 50
t-Butanol 50
Dimethyl carbonate 100
2,2-Dimethylhexane 100
Ethyl acetoacetate 100
Ethyl propionate 50
Isobutanol 63
Isobutyl acetate 150
Methyl formate 50
n-Nonane 106
n-Octane 255
2,2,4-Trimethylpentane 100
Special Case  
Trifluoroacetic acid ≥ 10
   

Limits for Heptane Congener Impurities

Solvent ICH Q3A Qualification Threshold (ppm) TPHCWG (mg/kg/day) *PDE (mg)
2,2-Dimethylhexane 1500 2.0 N/A
2,2,4-Trimethylpentane (isooctane) 1500 2.0 N/A
2,4,4-Trimethyl-1-pentene (diisobutylene) 1500 2.0 30
Methylcyclohexane 1500 2.0 25
n-Octane 1500 2.0 255
n-Nonane 1500 N/A 106
N/A = not applicable; *PDE = Permitted Daily Exposure. Anions:
  • Besilate
  • Bromide/bromine
  • Cyanide
  • Fluoride
  • Mesilate
  • Nitrate
  • Nitrite
  • Oxalate
  • Tartrate
  • Tosilate
  • Trifluoroacetate
Excipients:
  • Acesulfame-K
  • Benzoic acid
  • BHA
  • DEGEE
  • Diethyl phthalate
  • Erucic acid
  • Glycerol monolinoleate
  • Parabens
  • Saccharin
  • Simethicone
  • Sodium benzoate
  • Sucralose
  • Polyglycerol esters of fatty acids