Addressing the Need for Controls on Particle Bounce and Re-entrainment in the Cascade Impactor and for the Mitigation of
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Review Article Addressing the Need for Controls on Particle Bounce and Re-entrainment in the Cascade Impactor and for the Mitigation of Electrostatic Charge for Aerodynamic Particle Size Assessment of Orally Inhaled Products: an Assessment by the International Consortium on Regulation and Science (IPAC-RS) William Doub,1,5
Stephen Stein,2 Jolyon Mitchell,3 and Adrian P. Goodey4
Received 21 December 2019; accepted 28 May 2020 Abstract. Multi-stage cascade impactors (CI) are accepted for the determination of metrics of the drug mass aerodynamic particle size distributions (APSD) of aerosols emitted from orally inhaled products (OIPs). This is particularly important for products where the drug to excipient ratio or particle density may not be the same in each aerodynamic size fraction; examples of such products are carrier-containing dry powder inhalers (DPIs) and suspension pressurized metered-dose inhalers (pMDIs). CI measurements have been used as the “gold standard” for acceptance of alternative methods of APSD assessment, such as laser diffraction for nebulized solutions. Although these apparatus are labor-intensive, they are accepted in regulatory submissions and quality control assessments because the mass of active pharmaceutical ingredient(s) in the aerosol can be quantified by chemical assay and measured particle size is based on the aerodynamic diameter scale that is predictive of deposition in the respiratory tract. Two of the most important factors that modify the ideal operation of an impactor are “particle bounce,” that is often accompanied by re-entrainment in the air flow passing the stage of interest, and electrostatic charge acquired by the particles during the preparation and aerosolization of the formulation when the inhaler is actuated. This article reviews how both factors can lead to biased APSD measurements, focusing on measurements involving pMDIs and DPIs, where these sources of error are most likely to be encountered. Recommendations are provided for the mitigation of both factors to assist the practitioner of these measurements. KEY WORDS: cascade impactor; particle bounce; re-entrainment; electrostatic charge; bias mitigation.
INTRODUCTION The multi-stage inertial cascade impactor (CI) remains the apparatus recommended for the assessment of emitted aerosol aerodynamic particle size distribution (APSD) as a critical quality attribute alongside the related emitted dose (mass) (ED) in regulatory submissions, for all classes of orally inhaled pharmaceutical products (OIPs) (1,2). CI measurements have been also used as “gold standard” for acceptance 1
OINDP In Vitro Analysis, 1430 Neffwold Ln, Kirkwood, MO 63122, USA. 2 Inhalation Product Development, Kindeva Drug Delivery, St. Paul, MN, USA. 3 Jolyon Mitchell Inhaler Consulting Services Inc., London, ON, Canada. 4 Analytical Sciences, Merck & Co., Inc., Kenilworth, NJ, USA. 5 To whom correspondence should be addressed. (e–mail: [email protected])
of alternative methods of APSD assessment, such as laser diffraction for nebulized soluti
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