Analysis of non-mutagenic substances in the context of drug impurity assessment - Few are potent toxicants.
Regul Toxicol Pharmacol
; 150: 105645, 2024 Jun.
Article
de En
| MEDLINE
| ID: mdl-38761967
ABSTRACT
ICH Q3A/B guidelines provide qualification thresholds for impurities or degradation products in new drug substances and products. However, the guidelines note that certain impurities/degradation products may warrant further safety evaluation for being unusually potent or toxic. The purpose of this study was to confirm that especially toxic non-mutagenic compounds are rare and to identify classes of compounds that could warrant lower qualification thresholds. A total of 2815 compounds were evaluated, of which 2213 were assessed as non-mutagenic. For the purpose of this analysis, compounds were considered potent when the point of departure was ≤0.2 mg/kg/day based on the qualification threshold (1 mg/day or 0.02 mg/kg/day for a 50 kg human) in a new drug substance, with an additional 10-fold margin. Only 54 of the entire set (2.4%) would be considered potent based on this conservative potency analysis, confirming that the existing ICH Q3A/B qualification thresholds are appropriate for the majority of impurities. If the Q3A/B threshold, without the additional 10-fold margin is used, 14 compounds (0.6%) are considered "highly potent". Very few non-mutagenic structural classes were identified, including organothiophosphates and derivatives, polychlorinated benzenes and polychlorinated polycyclic aliphatics, that correlate with potential high potency, consistent with prior publications.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Contamination de médicament
Limites:
Animals
/
Humans
Langue:
En
Journal:
Regul Toxicol Pharmacol
/
Regul. toxiol. pharmacol
/
Regulatory toxicology and pharmacology
Année:
2024
Type de document:
Article
Pays de publication:
Pays-Bas