Multi-Participant Blinded Investigation into Internal Losses of Medication in Commercially Available Mixing Inlets: Testing Different Orally Inhaled Product Classes Following Pharmacopeial Methods.

Background: The "Miller" design of mixing inlet (MI) enables a cascade impactor to operate at a constant flow rate while the orally inhaled product-on-test is evaluated at varying flow rates by controlling the flow of air via its side-arm. Study Purpose: As part of the European Pharmaceutical Aerosol Group (EPAG) Impactor subgroup, we report a cross-industry experimental investigation by five organizations to determine internal losses of different inhaler-generated aerosolized medications within commercially available MIs, focusing on pharmacopeial methods for product testing. Methods: Evaluations were undertaken of solution and suspension formulations delivered by pressurized metered dose inhalers (pMDIs), passive dry powder inhalers (DPIs), and compressed air-jet and vibrating mesh nebulizers. Four different apparatuses were evaluated at different constant air flow rates entering the MI side arm. The nebulizers were tested utilizing a variable adult flow profile generated by a breathing simulator. Results: Losses within the MI were generally <5%, expressed as a percentage of the delivered mass of active pharmaceutical ingredient (API) ex-inhaler. These losses were sufficiently small that they can in most cases be accommodated within the allowance of ±5% OIP label claim emitted mass/actuation in the pharmacopeial compendia for total internal losses for aerodynamic particle size distribution (APSD) determination. However, corresponding average losses were between 2.8% and 5.2% of the mass of API presented to the MI for the blister-based DPIs. APSD-derived measures were largely unaffected by the magnitude of pressurized air flow up to 60 L/min to the side-arm of the MI, except for the solution-formulated pMDI, where increasing flow rate was associated with reduced mass median aerodynamic diameter and increased geometric standard deviation, suggestive of a dependency related to ethanol co-solvent evaporation rate. Conclusions: MI loss evaluation should be considered an important part of method development to minimize internal losses of the aerosolized medication being sampled.