title: N-nitrosamines as "special case" leachables in a metered dose inhaler drug product.
abstract: N-nitrosamines are chemical entities, some of which are considered to be possible human carcinogens, which can be found at trace levels in some types of foods, tobacco smoke, certain cosmetics, and certain types of rubber. N-nitrosamines are of regulatory concern as leachables in inhalation drug products, particularly metered dose inhalers, which incorporate rubber seals into their container closure systems. The United States Food and Drug Administration considers N-nitrosamines (along with polycyclic aromatic hydrocarbons and 2-mercaptobenzothiazole) to be "special case" leachables in inhalation drug products, meaning that there are no recognized safety or analytical thresholds and these compounds must therefore be identified and quantitated at the lowest practical level. This report presents the development of a quantitative analytical method for target volatile N-nitrosamines in a metered dose inhaler drug product, Atrovent HFA. The method incorporates a target analyte recovery procedure from the drug product matrix with analysis by gas chromatography/thermal energy analysis detection. The capability of the method was investigated with respect to specificity, linearity/range, accuracy (linearity of recovery), precision (repeatability, intermediate precision), limits of quantitation, standard/sample stability, and system suitability. Sample analyses showed that Atrovent HFA contains no target N-nitrosamines at the trace level of 1 ng/canister.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., P.O. Box 368, Ridgefield, CT 06877-0368, USA. daniel.norwood@boehringer-ingelheim.com
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Norwood
authors.forename: James O
authors.initials: JO
authors.lastname: Mullis
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Feinberg
authors.forename: Letha K
authors.initials: LK
authors.lastname: Davis
mesh_terms: D000280:Administration, Inhalation; D002849:Chromatography, Gas / Q000379:methods; D004340:Drug Contamination; D004349:Drug Packaging / Q000592:standards; D006801:Humans; D009241:Ipratropium / Q000008:administration & dosage / Q000032:analysis*; D036501:Metered Dose Inhalers; D009602:Nitrosamines / Q000032:analysis*; D015203:Reproducibility of Results; D012408:Rubber / Q000737:chemistry; D014481:United States; D014486:United States Food and Drug Administration; D014835:Volatilization
chemical_list: D009602:Nitrosamines; D012408:Rubber; D009241:Ipratropium