title: Minimizing variability of cascade impaction measurements in inhalers and nebulizers.
abstract: The purpose of this article is to catalogue in a systematic way the available information about factors that may influence the outcome and variability of cascade impactor (CI) measurements of pharmaceutical aerosols for inhalation, such as those obtained from metered dose inhalers (MDIs), dry powder inhalers (DPIs) or products for nebulization; and to suggest ways to minimize the influence of such factors. To accomplish this task, the authors constructed a cause-and-effect Ishikawa diagram for a CI measurement and considered the influence of each root cause based on industry experience and thorough literature review. The results illustrate the intricate network of underlying causes of CI variability, with the potential for several multi-way statistical interactions. It was also found that significantly more quantitative information exists about impactor-related causes than about operator-derived influences, the contribution of drug assay methodology and product-related causes, suggesting a need for further research in those areas. The understanding and awareness of all these factors should aid in the development of optimized CI methods and appropriate quality control measures for aerodynamic particle size distribution (APSD) of pharmaceutical aerosols, in line with the current regulatory initiatives involving quality-by-design (QbD).
authors.affiliation: Analytical Development, AstraZeneca Charnwood, Loughborough, Leicestershire, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bonam
authors.forename: David
authors.initials: D
authors.lastname: Christopher
authors.forename: David
authors.initials: D
authors.lastname: Cipolla
authors.forename: Brent
authors.initials: B
authors.lastname: Donovan
authors.forename: David
authors.initials: D
authors.lastname: Goodwin
authors.forename: Susan
authors.initials: S
authors.lastname: Holmes
authors.forename: Svetlana
authors.initials: S
authors.lastname: Lyapustina
authors.forename: Jolyon
authors.initials: J
authors.lastname: Mitchell
authors.forename: Steve
authors.initials: S
authors.lastname: Nichols
authors.forename: Gunilla
authors.initials: G
authors.lastname: Pettersson
authors.forename: Chris
authors.initials: C
authors.lastname: Quale
authors.forename: Nagaraja
authors.initials: N
authors.lastname: Rao
authors.forename: Dilraj
authors.initials: D
authors.lastname: Singh
authors.forename: Terrence
authors.initials: T
authors.lastname: Tougas
authors.forename: Mike
authors.initials: M
authors.lastname: Van Oort
authors.forename: Bernd
authors.initials: B
authors.lastname: Walther
authors.forename: Bruce
authors.initials: B
authors.lastname: Wyka
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D002623:Chemistry Techniques, Analytical; D004867:Equipment Design; D004868:Equipment Failure; D006801:Humans; D015233:Models, Statistical; D009330:Nebulizers and Vaporizers / Q000592:standards*; D010316:Particle Size; D011208:Powders; D011786:Quality Control; D015203:Reproducibility of Results; D019141:Respiratory System Agents / Q000008:administration & dosage* / Q000737:chemistry; D013678:Technology, Pharmaceutical
chemical_list: D000336:Aerosols; D011208:Powders; D019141:Respiratory System Agents