Pressure Drop Characteristics of the Reduced NGI Configuration with Several Common Glass Fiber Filters.

Background: Measurement of aerodynamic particle size distribution, a clinically relevant in vitro attribute of inhalable drug products, involves multistage cascade impactors and is tedious and expensive. A leading candidate for a quicker method is the reduced NGI™ (rNGI). This method involves placing glass fiber filters on top of the nozzles of a chosen NGI stage, selected often to collect all particles with an aerodynamic diameter smaller than approximately five microns. These filters contribute additional flow resistance that can alter the flow rate start-up curve, potentially affecting the size distribution and mass of the drug product dispensed by passive dry powder inhalers (DPIs). The magnitude of these additional flow resistance measurements is currently unreported in the literature. Materials and Methods: We placed glass fiber filters on top of the stage 3 nozzles of an NGI, along with the necessary support screen and hold-down ring. We measured the pressure drop across NGI stage 3 with the assistance of a delta P lid and a high-precision pressure transducer. With each filter material type and multiple individual filters, we gathered eight replicates at flow rates of 30, 45, and 60 L/min. Results: The filters typically doubled the total pressure drop through the NGI. For example, at a flow rate of 60 L/min, the Whatman 934-AH filters introduced a pressure drop of about 9800 Pa at stage 3, reducing the absolute pressure exiting the NGI to about 23 kPa below ambient, compared with a typical value of 10 kPa for the NGI alone at this flow rate. Conclusions: The pressure drop across typical filters is approximately equal to that through the NGI alone and therefore will affect the flow start-up rate intrinsic to compendial testing of passive DPIs. This change in start-up rate could cause differences between results of the rNGI configuration and those of the full NGI and will increase the required vacuum pump capacity.

Particle Size Measurements from Orally Inhaled and Nasal Drug Products.

Particle size measurement of aerosolized particles from orally inhaled and nasal drug products (OINDPs) can be used to assess the likely deposition distribution in the human respiratory tract (HRT). Size is normally expressed in terms of aerodynamic diameter, since this scale directly relates to the mechanics of particle transport from inhaler to deposition locations. The multistage cascade impactor (CI) is the principal apparatus used to size fractionate aerosols in terms of their aerodynamic particle size distributions (APSDs). Clinically meaningful metrics, such as fine and coarse particle mass fractions, can be determined from the cumulative mass-weighted APSD. In effective data analysis (EDA), CI data are reduced to small and large particle mass. The sum and ratio of these metrics are used to characterize impactor-sized mass, without the need for stage groupings or other APSD interpretation. Aerosol characterization by full-resolution CI is complex, and so, an abbreviated impactor measurement has recently come to prominence. Here, multiple stages of the CI are reduced to just one or two size fractionating stages so that measures of fine (and extrafine) particle mass from a two-stage system can be directly determined without the need to group the mass of active pharmaceutical ingredient (API) on adjacent stages. Time-of-flight-based methods determine APSD more rapidly but require refinements such as single-particle mass spectroscopy to relate size measurements to API content. Alternatives for size characterizing OINDP aerosols are few; laser diffractometry is by far the most important, especially for nasal sprays and solution-based orally inhaled formulations in which there is no confounding of data from suspended excipient(s). Laser-phase Doppler anemometry (L-PDA) has also been shown to be useful for nasal sprays. If aerodynamic size-related information is not a priority, optical microscopy combined with Raman chemical imaging offers prospects for separate determination of API components in combination product-generated aerosols.

Discriminating Ability of Abbreviated Impactor Measurement Approach (AIM) to Detect Changes in Mass Median Aerodynamic Diameter (MMAD) of an Albuterol/Salbutamol pMDI Aerosol.

This article reports on results from a two-lab, multiple impactor experiment evaluating the abbreviated impactor measurement (AIM) concept, conducted by the Cascade Impaction Working Group of the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS). The goal of this experiment was to expand understanding of the performance of an AIM-type apparatus based on the Andersen eight-stage non-viable cascade impactor (ACI) for the assessment of inhalation aerosols and sprays, compared with the full-resolution version of that impactor described in the pharmacopeial compendia. The experiment was conducted at two centers with a representative commercially available pressurized metered dose inhaler (pMDI) containing albuterol (salbutamol) as active pharmaceutical ingredient (API). Metrics of interest were total mass (TM) emitted from the inhaler, impactor-sized mass (ISM), as well as the ratio of large particle mass (LPM) to small particle mass (SPM). ISM and the LPM/SPM ratio together comprise the efficient data analysis (EDA) metrics. The results of the comparison demonstrated that in this study, the AIM approach had adequate discrimination to detect changes in the mass median aerodynamic diameter (MMAD) of the ACI-sampled aerodynamic particle size distribution (APSD), and therefore could be employed for routine product quality control (QC). As with any test method considered for inclusion in a regulatory filing, the transition from an ACI (used in development) to an appropriate AIM/EDA methodology (used in QC) should be evaluated and supported by data on a product-by-product basis.

Evaluation of Abbreviated Impactor Measurements (AIM) and Efficient Data Analysis (EDA) for Dry Powder Inhalers (DPIs) Against the Full-Resolution Next Generation Impactor (NGI).

The full-resolution next generation impactor (NGI) and three abbreviated impactor systems were used to obtain the apparent aerodynamic particle size distribution (APSD) and other quality measures for marketed dry powder inhalers (DPIs) using the compendial method and efficient data analysis (EDA). APSD for the active pharmaceutical ingredient (API) in Spiriva® Handihaler®, Foradil® Aerolizer®, and Relenza® Diskhaler® was obtained using a full-resolution NGI at 39, 60, and 90 L/min, respectively. Two reduced NGI (rNGI) configurations, the filter-only configuration (rNGI-f) and the modified-cup configuration (rNGI-mc), and the fast-screening impactor (FSI) with appropriate inserts to provide a 5-µm cut size were evaluated. The fine particle dose (FPD) obtained using the FSI for Spiriva was statistically similar to that obtained using the full NGI. However, the FPD for both Foradil and Relenza obtained using the FSI was significantly different from that obtained using the full NGI. Despite this, no significant differences were observed for the fine particle fraction (FPF) obtained using the FSI relative to that obtained from the full NGI for any of the DPIs. The use of abbreviated impactor systems appears promising with good agreement observed with the full-resolution NGI, except for small differences observed for the rNGI-mc configuration. These small differences may be product- and/or flow rate-specific, and further evaluation will be required to resolve these differences.

A Multi-laboratory in Vitro Study to Compare Data from Abbreviated and Pharmacopeial Impactor Measurements for Orally Inhaled Products: a Report of the European Aerosol Group (EPAG).

Fine particle dose (FPD) is a critical quality attribute for orally inhaled products (OIPs). The abbreviated impactor measurement (AIM) concept simplifies its measurement, provided there is a validated understanding of the relationship with the full resolution pharmacopoeial impactor (PIM) data for a given product. This multi-center study compared fine particle dose determined using AIM and PIM for five dry powder inhaler (DPIs) and two pressurized metered-dose inhaler (pMDI) products, one of which included a valved holding chamber (VHC). Reference measurements of FPDPIM were made by each organization using either the full-resolution Andersen 8-stage non-viable impactor (ACI) or Next Generation Impactor (NGI). FPDAIM was determined for the same OIP(s) with their choice of abbreviated impactor (fast screening impactor (FSI), fast screening Andersen (FSA), or reduced NGI (rNGI)). Each organization used its validated assay method(s) for the active pharmaceutical ingredient(s) (APIs) involved. Ten replicate measurements were made by each procedure. The upper size limit for FPDAIM varied from 4.4 to 5.0 µm aerodynamic diameter, depending upon flow rate and AIM apparatus; the corresponding size limit for FPDPIM was fixed at 5 µm in accordance with the European Pharmacopoeia. The 90% confidence interval for the ratio [FPDAIM/FPDPIM], expressed as a percentage, was contained in the predetermined 85-118% acceptance interval for nine of the ten comparisons of FPD. The average value of this ratio was 105% across all OIPs and apparatuses. The findings from this investigation support the equivalence of AIM and PIM for determination of FPD across a wide range of OIP platforms and measurement techniques.