title: A Comparison of the Performance of Efficient Data Analysis Versus Fine Particle Dose as Metrics for the Quality Control of Aerodynamic Particle Size Distributions of Orally Inhaled Pharmaceuticals.
abstract: The performance of two quality control (QC) tests for aerodynamic particle size distributions (APSD) of orally inhaled drug products (OIPs) is compared. One of the tests is based on the fine particle dose (FPD) metric currently expected by the European regulators. The other test, called efficient data analysis (EDA), uses the ratio of large particle mass to small particle mass (LPM/SPM), along with impactor sized mass (ISM), to detect changes in APSD for QC purposes. The comparison is based on analysis of APSD data from four products (two different pressurized metered dose inhalers (MDIs) and two dry powder inhalers (DPIs)). It is demonstrated that in each case, EDA is able to detect shifts and abnormalities that FPD misses. The lack of sensitivity on the part of FPD is due to its "aggregate" nature, since FPD is a univariate measure of all particles less than about 5 μm aerodynamic diameter, and shifts or changes within the range encompassed by this metric may go undetected. EDA is thus shown to be superior to FPD for routine control of OIP quality. This finding augments previously reported superiority of EDA compared with impactor stage groupings (favored by US regulators) for incorrect rejections (type I errors) when incorrect acceptances (type II errors) were adjusted to the same probability for both approaches. EDA is therefore proposed as a method of choice for routine quality control of OIPs in both European and US regulatory environments.
authors.affiliation: Pharmaceutical Practice Group, Drinker Biddle and Reath LLP, Washington, District of Columbia, USA. ttougas@icloud.com.
authors.forename: Terrence P
authors.initials: TP
authors.lastname: Tougas
authors.affiliation: Respiratory Product Development, Merck & Co., Inc., Rahway, New Jersey, USA.
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Goodey
authors.affiliation: Analytical Development, Vectura Group plc, Chippenham, Wiltshire, UK.
authors.forename: Gareth
authors.initials: G
authors.lastname: Hardwell
authors.affiliation: Jolyon Mitchell Inhaler Consulting Services Inc., London, Ontario, Canada.
authors.forename: Jolyon
authors.initials: J
authors.lastname: Mitchell
authors.affiliation: Pharmaceutical Practice Group, Drinker Biddle and Reath LLP, Washington, District of Columbia, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Lyapustina
mesh_terms: D000280:Administration, Inhalation; D000284:Administration, Oral; D000336:Aerosols / Q000737:chemistry*; D058995:Dry Powder Inhalers / Q000379:methods*; D008422:Materials Testing / Q000379:methods*; D036501:Metered Dose Inhalers; D010316:Particle Size; D011208:Powders / Q000737:chemistry*; D011786:Quality Control; D013223:Statistics as Topic / Q000379:methods*; D013678:Technology, Pharmaceutical / Q000379:methods*
chemical_list: D000336:Aerosols; D011208:Powders
keywords: aerodynamic particle size distribution; cascade impactor; efficient data analysis; fine particle dose; quality control