Determination of Passive Dry Powder Inhaler Aerodynamic Particle Size Distribution by Multi-Stage Cascade Impactor: International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS) Recommendations to Support Both Product Quality Control and Clinical Programs

Abstract

The multi-stage cascade impactor (CI) is the mainstay method for the determination of the aerodynamic particle size distribution (APSD) of aerosols emitted from orally inhaled products (OIPs). CIs are designed to operate at a constant flow rate throughout the measurement process. However, it is necessary to mimic an inhalation maneuver to disperse the powder into an aerosol when testing passive dry powder inhalers (DPIs), which constitute a significant portion of available products in this inhaler class. Methods in the pharmacopeial compendia intended for product quality assurance initiate sampling by applying a vacuum to the measurement apparatus using a timer-operated solenoid valve located downstream of the CI, resulting in a period when the flow rate through the impactor rapidly increases from zero towards the target flow rate. This article provides recommendations for achieving consistent APSD measurements, including selection of the CI, pre-separator, and flow control equipment, as well as reviewing considerations that relate to the shape of the flow rate-sampling time profile. Evidence from comparisons of different DPIs delivering the same active pharmaceutical ingredients (APIs) is indicative that the compendial method for APSD measurement is insensitive as a predictor of pharmacokinetic outcomes. Although inappropriate for product quality testing, guidance is therefore provided towards adopting a more clinically realistic methodology, including the use of an anatomically appropriate inlet and mimicking patient inhalation at the DPI while operating the CI at constant flow rate. Many of these recommendations are applicable to the testing of other OIP classes.

Internal Volumes of Pharmaceutical Compendial Induction Port, Next-Generation Impactor With and Without Its Pre-separator, and Several Configurations of the Andersen Cascade Impactor With and Without Pre-separator

“…Pharmacopeial methods ( 1,2) for measuring the size distribution of particles emitted by dry-powder inhalers (DPIs) in the product quality control environment represent a trade-off between mimicking realistic patient use and the need to keep the methodology for particle size determination as simple as possible to optimize accuracy, precision, and robustness. ( 3 ) Size fractionation by multi-stage cascade impaction is the only methodology that is capable of determining the physiologically important aerodynamic particle size distribution (APSD), while also capturing enough material for quantitative determination by chemical assay of the active pharmaceutical ingredient(s) in those size fractions. ( 4 ) In realistic patient use, the patient must inhale before aerosol can be emitted from a passive DPI, which currently comprises the majority of marketed products of this class of inhaler.…”

“…( 4 ) In realistic patient use, the patient must inhale before aerosol can be emitted from a passive DPI, which currently comprises the majority of marketed products of this class of inhaler. ( 3 ) Therefore, the compendial methods require the inhaler to be attached to the cascade impactor before the test begins; then, the flow is started and is increased as quickly as possible from zero to a standard flow rate; and finally, the flow is turned off after a specified volume of air passes through the DPI. ( 1 , 2 )…”

“…( 7 ) However, the situation is entirely different at start-up, where the precise trajectory of flow rate with elapsed time can potentially influence both powder dispersion into the aerosol and subsequent transport of the aerosol through the apparatus. ( 3 )…”