Acceptance Testing of Used Cascade Impactor Stages Based on Pressure Drop Measurements in a Flow System Managed with a Critical Flow Venturi: Part II-Quantification of the Test Uncertainty Ratio for Pass/Fail Decision-Making under Pharmacopeial Constraints.

Background: The pressure drop at any cascade impactor stage is related to the open area of nozzles at that stage. Pressure drop measurement therefore can potentially test whether the nozzles of a given stage are within the range specified for continued use for testing of inhalable drug products. Previous such efforts, however, have been hindered by the measurement precision required for making a pass/fail decision about these used impactors. In this study, we articulate the error analysis for a pressure drop measurement system managed with a critical flow venturi (CFV) and show that the resultant uncertainty in the effective diameter of used Next Generation Impactor (NGI) and Andersen-type impactor stages is generally small compared to the specification range. This result enables the user to make a pass/fail decision regarding suitability for continued use. Methods: We develop the equations governing the relationship between stage pressure drop and the effective diameter of each stage of a used impactor. These equations show that pressure drop measurements can indicate only the change (if any) in the effective diameter between a previous measurement and the current measurement. Propagation-of-error principles therefore show that the uncertainty of both measurements affects the resulting uncertainty. Results: The test uncertainty ratio (analytical power) of a CFV-managed pressure drop measurement system exceeds six for all but stage one of the NGI and for stages -1 and -2 of the Andersen-type impactor. The stage-one nozzle of the NGI is readily qualified with a Class X pin. Conclusions: The CFV-managed flow system described in Part I is sufficiently precise to enable a decision to be made about whether used impactor nozzles are suitable for continued use for testing of registered inhalable drug products. Examination of the industrial viability of the technology will require long-term testing in real-world settings with comparison to optical inspection methods.

Acceptance Testing of Used Cascade Impactor Stages Based on Pressure Drop Measurements in a Flow System Managed with a Critical Flow Venturi: Part I-Laboratory Proof-of-Principle.

Background: Cascade impactors are essential for measuring the aerodynamic particle size distribution delivered by metered dose, dry powder, and similar inhalable drug products. For quality control of used impactors, periodic optical inspection of the nozzles of each impactor stage (stage mensuration) is currently the only method sufficiently precise to test whether used impactors are suitable for continued use, in accord with pharmacopeial standards. Here, we demonstrate a new method for quality control of used impactors. The method combines stage-wise pressure-drop measurement with a critical flow venturi (CFV) for air flow management. This technique avoids the unacceptably large uncertainty in conventional air flow rate measurements and instead relies on pressure and temperature measurement upstream of the CFV. These measurements can be made precisely with affordable equipment. Methods: We placed a toroidally shaped CFV downstream of a Next Generation Impactor™** (NGI) and precisely measured the stagnation pressure (±0.02%) and temperature (±0.03%) upstream of this CFV at impactor inlet flow rates close to 60 L/min. Pressure-drop measurements (±0.25%) at stages 3-7 and the micro-orifice collector were made with capacitive diaphragm transducers and with a special lid to the NGI that allowed pneumatic connection to the interstage passageways before and after each impactor stage. Results: The measured pressure drop values matched, to fractional percentage precision, those predicted by the incompressible flow theory through the nozzles and the compressible flow theory through the CFV. Conclusions: Practical equipment has been assembled that measures, to fractional percentage precision, the pressure drop through impactor nozzles at precisely managed flow conditions. The experimental results support the relevant flow principles. The results, thereby, support the use of this method for quantifying whether used impactor stages are suitable for continued use in the testing of registered inhalable drug products, in accord with pharmacopeial standards.

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.

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.

Background: Determination of aerosol aerodynamic particle size distributions (APSD) from dry-powder inhalers (DPIs), following quality control procedures in the pharmacopeial compendia, requires that the flow through the measurement apparatus, comprising induction port, optional pre-separator, and cascade impactor, starts from zero on actuation of the inhaler, using a solenoid valve to apply vacuum to the apparatus exit. The target flow rate, governed by the inhaler resistance, is reached some time afterward. Understanding the behavior of the DPI design-specific flow rate-rise time curve can provide information about the kinetics of the initial powder dispersion in the inhaler and subsequent transport through the APSD measurement equipment. Accurate and precise measures of the internal volume of each component of this apparatus are required to enable reliable relationships to be established between this parameter and those defining the flow rate-rise time curve. Methods: An improved method is described that involves progressive withdrawal of an accurately known volume of air from the interior passageways of the apparatus-on-test that are closed to the outside atmosphere. This approach is applicable for determining internal volumes of components having complex internal geometries. Filling some components with water, along with volumetric or gravimetric measurement, has proven valuable for the induction port and for checking other measurements. Results: Values of internal volume are provided for the USP (United States Pharmacopeia)/PhEur (European Pharmacopoeia) induction port, the Next-Generation Impactor (NGI™) with and without its pre-separator, and various Andersen 8-stage cascade impactor configurations with and without their pre-separators. Conclusion: These data are more accurate and precise, and therefore update those reported by Copley et al.

Measurement of Aerodynamic Particle Size Distribution of Orally Inhaled Products by Cascade Impactor: How to Let the Product Specification Drive the Quality Requirements of the Cascade Impactor.

The multi-stage inertial cascade impactor is used to determine the mass-weighted aerodynamic particle size distribution (APSD) as a critical quality attribute for orally inhaled products (OIPs). These apparatuses progressively size-fractionate the aerosol passing through a series of stages containing one or more nozzles, by increasing particle velocity. Nozzle sizes for a given multi-nozzle stage can be described collectively by effective diameter ([Formula: see text]), related to the cut-point size, providing the link to aerodynamic diameter. Users undertake stage mensuration periodically to assure that each stage [Formula: see text] remains within the manufacturer's tolerance, but there is no guidance on how frequently such checks should be made. We examine the philosophy that particle size-related specifications of the OIP should determine when an impactor is mensurated. Taking an example of a dry powder inhaler-generated aerosol sampled via a Next Generation Impactor with pre-separator, we find that there are only three critical stages that could have a material effect on the measured APSD specified as four groupings of stages following current regulatory practice. Furthermore, [Formula: see text] for the most critical stage having the smallest nozzle sizes could be relaxed by a factor of four or more before risking an inability to measure the mass fraction of API in the group containing the finest particles to a specification within ± 10% of nominal. We therefore conclude that users should consider letting the specification for APSD performance of an OIP in terms of accepted stage groupings drive the impactor quality requirements and frequency that stage mensuration is undertaken.

Investigation of dry powder inhaler (DPI) resistance and aerosol dispersion timing on emitted aerosol aerodynamic particle sizing by multistage cascade impactor when sampled volume is reduced from compendial value of 4 L.

Compendial methods determining dry powder inhaler (DPI)-emitted aerosol aerodynamic particle size distribution (APSD) collect a 4-L air sample containing the aerosol bolus, where the flow, which propagates through the cascade impactor (CI) measurement system from the vacuum source, is used to actuate the inhaler. A previous article described outcomes with two CIs (Andersen eight-stage cascade impactor (ACI) and Next-Generation Pharmaceutical Impactor (NGI)) when the air sample volume was ≤4 L with moderate-resistance DPIs. This article extends that work, examining the hypothesis that DPI flow resistance may be a factor in determining outcomes. APSD measurements were made using the same CI systems with inhalers representing low and high flow resistance extremes (Cyclohaler® and HandiHaler® DPIs, respectively). The ratio of sample volume to internal dead space (normalized volume (V*)) was varied from 0.25 to 1.98 (NGI) and from 0.43 to 3.46 (ACI). Inhaler resistance was a contributing factor to the rate of bolus transfer; the higher resistance DPI completing bolus relocation to the NGI pre-separator via the inlet when V* was as small as 0.25, whereas only ca. 50% of the bolus mass was collected at this condition with the Cyclohaler® DPI. Size fractionation of the bolus from either DPI was completed within the ACI at smaller values of V* than within the NGI. Bolus transfer from the Cyclohaler® capsule and from the HandiHaler® to the ACI system were unaffected by the different flow rise time observed in the two different flow controller systems, and the effects the ACI-based on APSD measurements were marginal.

Effect of sampling volume on dry powder inhaler (DPI)-emitted aerosol aerodynamic particle size distributions (APSDs) measured by the Next-Generation Pharmaceutical Impactor (NGI) and the Andersen eight-stage cascade impactor (ACI).

Current pharmacopeial methods for testing dry powder inhalers (DPIs) require that 4.0 L be drawn through the inhaler to quantify aerodynamic particle size distribution of "inhaled" particles. This volume comfortably exceeds the internal dead volume of the Andersen eight-stage cascade impactor (ACI) and Next Generation pharmaceutical Impactor (NGI) as designated multistage cascade impactors. Two DPIs, the second (DPI-B) having similar resistance than the first (DPI-A) were used to evaluate ACI and NGI performance at 60 L/min following the methodology described in the European and United States Pharmacopeias. At sampling times ≥2 s (equivalent to volumes ≥2.0 L), both impactors provided consistent measures of therapeutically important fine particle mass (FPM) from both DPIs, independent of sample duration. At shorter sample times, FPM decreased substantially with the NGI, indicative of incomplete aerosol bolus transfer through the system whose dead space was 2.025 L. However, the ACI provided consistent measures of both variables across the range of sampled volumes evaluated, even when this volume was less than 50% of its internal dead space of 1.155 L. Such behavior may be indicative of maldistribution of the flow profile from the relatively narrow exit of the induction port to the uppermost stage of the impactor at start-up. An explanation of the ACI anomalous behavior from first principles requires resolution of the rapidly changing unsteady flow and pressure conditions at start up, and is the subject of ongoing research by the European Pharmaceutical Aerosol Group. Meanwhile, these experimental findings are provided to advocate a prudent approach by retaining the current pharmacopeial methodology.

Relationship of stage mensuration data to the performance of new and used cascade impactors.

Cascade impaction is a standard test method for characterizing the quality of inhalable drug products. The sizes of the nozzles on each stage of the impactor are the critical dimensions for the performance of the impactor. Compendial reference methods call for periodic measurement of the size of the nozzles on each stage, a procedure known as stage mensuration. There is however currently no guidance on acceptable mensuration criteria. We aim to remedy this situation by providing a sound basis for understanding and using mensuration data, be it for acceptance criteria for new impactors or for the setting of mensuration tolerances for in-use impactors. We first show that multi-nozzle impactor stages behave as if all of the nozzles are equal in size to an effective diameter, , that is composed of the area-mean and areamedian diameters, W* and , calculated directly from the individual nozzle diameters for all nozzles on a given stage (equation 1): W= (W*)(2/3) x (W)(1/3) (1). Hence, the effective diameter provides an intuitive and technically sound basis for setting acceptance criteria for new and in-use impactors. We tabulate these criteria for the Mark II eight-stage Andersen cascade impactor and the Next Generation Pharmaceutical Impactor in a manner similar to the tables of critical impactor dimensions published in EP Supplement 5.1 and in USP 28. For two different impactors or for one impactor measured at two different times (e.g., at manufacture and in use), we find that the D50 values of a given stage are related to the effective diameters by D(50,2)/D(50,1)= (W(2)/W(1))(3/2) (2). Using the stage mensuration data for new, as-manufactured NGIs, we compare the D(50 )values of the first 125 as-manufactured NGIs with those of the archivally calibrated NGI. We further establish that the archivally calibrated NGI has D(50) values within 0.3% of an entirely perfect, hypothetical NGI with all nozzles equal to the nominal nozzle diameters. We also apply the equations to a specific mensurated impactor to show that a used impactor with some nozzles outside of the original manufacturing specifications can have the same aerodynamic performance as a new impactor.

Next generation pharmaceutical impactor: a new impactor for pharmaceutical inhaler testing. Part III. extension of archival calibration to 15 L/min.

An extension of the archival calibration of the recently developed 30-100-L/min seven-stage impactor, the Next Generation Pharmaceutical Impactor (NGI), has been undertaken at 15 L/min. The NGI stage cut sizes are 0.98-14.1 microm aerodynamic diameter at this flow rate. This 15-L/min calibration was motivated by the desire to sample the entire aerosol produced by a nebulizer when tested in accordance with a new international standard developed by the Comite Européen de Normalisation (CEN), as well as the need to test various types of inhalers at flow rates lower than 30 L/min for pediatric applications. Measurements were undertaken with monodisperse oleic acid droplets in the range of 0.7-22 microm aerodynamic diameter following a procedure established in the original 30-100-L/min calibration study. The NGI was found to be effective for particle size separation at 15 L/min. Users should decide the most applicable configuration that meets their needs, based on the following recommendations: (1) the pre-separator should not normally be used, as its performance is significantly degraded by the influence of gravity, resulting in interference with stage 1; and (2) a filter should be inserted below the micro-orifice collector (MOC), as the size corresponding to 80% collection efficiency of the MOC becomes excessively large with decreasing flow rate, so that this component becomes ineffective as a means of collecting fine particles that penetrate beyond stage 7.

Next generation pharmaceutical impactor (a new impactor for pharmaceutical inhaler testing). Part I: Design.

A new cascade impactor has been designed specifically for pharmaceutical inhaler testing. This impactor, called the Next Generation Pharmaceutical Impactor (NGI), has seven stages and is intended to operate at any inlet flow rate between 30 and 100 L/min. It spans a cut size (D50) range from 0.54-microm to 11.7-microm aerodynamic diameter at 30 L/min and 0.24 microm to 6.12 microm at 100 L/min. The aerodynamics of the impactor follow established scientific principles, giving confident particle size fractionation behavior over the design flow range. The NGI has several features to enhance its utility for inhaler testing. One such feature is that particles are deposited on collection cups that are held in a tray. This tray is removed from the impactor as a single unit, facilitating quick sample turn-around times if multiple trays are used. For accomplishing drug recovery, the user can add up to approximately 40 mL of an appropriate solvent directly to the cups. Another unique feature is a micro-orifice collector (MOC) that captures in a collection cup extremely small particles normally collected on the final filter in other impactors. The particles captured in the MOC cup can be analyzed in the same manner as the particles collected in the other impactor stage cups. The user-friendly features and the aerodynamic design principles together provide an impactor well suited to the needs of the inhaler testing community.