Targeting drug delivery to the lungs by inhalation

Most drugs targeted to the respiratory tract are used for their local action. For example, ephidrine for nasal decongestion, beta-2 agonists for bronchodilatation, and inhaled steroids to suppress the inflammation seen in asthmatic airways. Since the drug is delivered directly to its required site, only a small quantity is needed for an adequate therapeutic response, and consequently there is a low incidence of systemic side effects compared with oral or intravenous administration. More recently, it has become apparent that the lining of the respiratory tract, from nasal mucosa to airways and alveoli, may be used for the absorption of a drug for its systemic effect. This route of administration may be particularly attractive if it avoids the metabolic destruction encountered when some drugs are administered by alternative routes (for instance, peptides and proteins are rapidly destroyed by peptidases when Oven by the oral route). If there is a lack ofclinical response to an aerosolized drug, it is important to question whether the drug has failed or whether delivery to the site of action is inadequate. To deliver therapeutic agents by inhalation to the lower respiratory tract, inhaled drug particles must have appropriate aerodynamic characteristics. In addition, the anatomy and pathophysiology of the patient's respiratory tract, mode of inhalation through the inhaler, and the characteristics of the inhalational device itself, may significantly affect drug deposition.     

Comparison of Aerodynamic Particle Size Distribution Between a Next Generation Impactor and a Cascade Impactor at a Range of Flow Rates

Wide variation in respiratory flow rates between patients emphasizes the importance of evaluating the aerodynamic particle size distribution (APSD) of dry powder inhaler (DPI) using a multi-stage impactor at different flow rates. US Pharmacopeia recently listed modified configurations of the Andersen cascade impactor (ACI) and new sets of cut-off diameter specifications for the operation at flow rates of 60 and 90 L/min. The purpose of this study was to clarify the effect of these changes on the APSD of DPI products at varied flow rates. We obtained APSD profiles of four DPIs and device combinations, Relenza®-Diskhaler® (GlaxoSmithKline Co.), Seebri®-Breezhaler® (Novartis Pharma Co.), Pulmicort®-Turbuhaler® (Astrazeneca Co.), and Spiriva®-Handihaler® (Nippon Boehringer Ingelheim Co.) using Next Generation Impactors (NGIs) and ACIs at flow rates from 28.3 to 90 L/min to evaluate the difference in the use of previous and new sets of cut-off diameter specifications. Processing the data using the new specifications for ACI apparently reduced large differences in APSD obtained by NGI and ACI with the previous specifications at low and high flow rates in all the DPIs. Selecting the appropriate configuration of ACI corresponding to the flow rate provided comparable APSD profiles of Pulmicort®-Turbuhaler® to those using NGIs at varied flow rates. The results confirmed the relevance of the current US Pharmacopeia specifications for ACI analysis in obtaining APSD profiles of DPI products at wide flow rates.     

Relative Precision of Inhaler Aerodynamic Particle Size Distribution (APSD) Metrics by Full Resolution and Abbreviated Andersen Cascade Impactors (ACIs): Part 1

The purpose of this study was to compare relative precision of two different abbreviated impactor measurement (AIM) systems and a traditional multi-stage cascade impactor (CI). The experimental design was chosen to provide separate estimates of variability for each impactor type. Full-resolution CIs are useful for characterizing the aerosol aerodynamic particle size distribution of orally inhaled products during development but are too cumbersome, time-consuming, and resource-intensive for other applications, such as routine quality control (QC). This article presents a proof-of-concept experiment, where two AIM systems configured to provide metrics pertinent to QC (QC-system) and human respiratory tract (HRT-system) were evaluated using a hydrofluoroalkane-albuterol pressurized metered dose inhaler. The Andersen eight-stage CI (ACI) served as the benchmark apparatus. The statistical design allowed estimation of precision with each CI configuration. Apart from one source of systematic error affecting extra-fine particle fraction from the HRT-system, no other bias was detected with either abbreviated system. The observed bias was shown to be caused by particle bounce following the displacement of surfactant by the shear force of the airflow diverging above the collection plate of the second impaction stage. A procedure was subsequently developed that eliminated this source of error, as described in the second article of this series (submitted to AAPS PharmSciTech). Measurements obtained with both abbreviated impactors were very similar in precision to the ACI for all measures of in vitro performance evaluated. Such abbreviated impactors can therefore be substituted for the ACI in certain situations, such as inhaler QC or add-on device testing.     

Quantitative deposition of ultrafine stable particles in the human respiratory tract

Theoretical models of particle deposition in the respiratory tract predict high fractional deposition for particles of less than 0.1 micron, but there are few confirming experimental data for those predictions. We have measured the deposition fraction of a nonhygroscopic aerosol in the human respiratory tract. The aerosol had a count mean diameter of 0.044 micron SD of 1.93, as measured with an electrical aerosol analyzer, and was produced from a 0.01% solution of bis(2-ethylhexyl) sebacate using a condensation generator. Subjects inhaled the aerosol using a controlled respiratory pattern of 1 liter tidal volume, 12/min. Deposition was calculated as the difference in concentration between inhaled and exhaled aerosol of five size fractions corrected for system deposition and dead-space constants. Three deposition studies were done on each of five normal male volunteers. Means (+/- SE) for the five size fractions were 0.024 micron, 0.71 +/- 0.06; 0.043 micron, 0.62 +/- 0.06; 0.075 micron, 0.53 +/- 0.05; 0.13 micron, 0.44 +/- 0.04; and 0.24 micron, 0.37 +/- 0.06. These data demonstrate that deposition of inhaled particles in the 0.024- to 0.24-micron size range is high and increases with decreasing size. These observations agree with and validate predictions of mathematical models.     

Mouse respiratory tract dendritic cell subsets and the immunological fate of inhaled antigens

It is widely accepted that tissue dendritic cells (DC) function as immune sentinels by alerting T cells to foreign antigen after delivering and presenting it in the draining lymph nodes. Over the last two decades, studies in animal models, particularly rodents, have demonstrated that respiratory tract DC are crucial for the adaptive immune response to inhaled antigen. Indeed, the fate of inhaled antigen is inextricably linked to the function of respiratory tract DC. In this review, we will discuss the characteristics of respiratory tract DC from mice and recent data that may help to explain their role in the fate of inhaled antigen.     

Factors Influencing Aerodynamic Particle Size Distribution of Suspension Pressurized Metered Dose Inhalers

Pressurized metered dose inhalers (pMDIs) are frequently used for the treatment of asthma and chronic obstructive pulmonary disease. The aerodynamic particle size distribution (APSD) of the residual particles delivered from a pMDI plays a key role in determining the amount and region of drug deposition in the lung and thereby the efficacy of the inhaler. In this study, a simulation model that predicts the APSD of residual particles from suspension pMDIs was utilized to identify the primary determinants for APSD. These findings were then applied to better understand the effect of changing drug concentration and micronized drug size on experimentally observed APSDs determined through Andersen Cascade Impactor testing. The experimental formulations evaluated had micronized drug mass median aerodynamic diameters (MMAD) between 1.2 and 2.6 μm and drug concentrations ranging from 0.01 to 1% (w/w) with 8.5% (w/w) ethanol in 1,1,1,2-tetrafluoroethane (HFA-134a). It was determined that the drug concentration, micronized drug size, and initially atomized droplet distribution have a significant impact in modulating the proportion of atomized droplets that contain multiple suspended drug particles, which in turn increases the residual APSD. These factors were found to be predictive of the residual particle MMAD for experimental suspension HFA-134a formulations containing ethanol. The empirical algebraic model allows predicting the residual particle size for a variety of suspension formulations with an average error of 0.096 μm (standard deviation of 0.1 μm).KEY WORDS: aerodynamic particle size distribution (APSD), formulation, pressurized metered dose inhaler (pMDI), suspension     

A mechanistic framework for a priori pharmacokinetic predictions of orally inhaled drugs

The fate of orally inhaled drugs is determined by pulmonary pharmacokinetic processes such as particle deposition, pulmonary drug dissolution, and mucociliary clearance. Even though each single process has been systematically investigated, a quantitative understanding on the interaction of processes remains limited and therefore identifying optimal drug and formulation characteristics for orally inhaled drugs is still challenging. To investigate this complex interplay, the pulmonary processes can be integrated into mathematical models. However, existing modeling attempts considerably simplify these processes or are not systematically evaluated against (clinical) data. In this work, we developed a mathematical framework based on physiologically-structured population equations to integrate all relevant pulmonary processes mechanistically. A tailored numerical resolution strategy was chosen and the mechanistic model was evaluated systematically against data from different clinical studies. Without adapting the mechanistic model or estimating kinetic parameters based on individual study data, the developed model was able to predict simultaneously (i) lung retention profiles of inhaled insoluble particles, (ii) particle size-dependent pharmacokinetics of inhaled monodisperse particles, (iii) pharmacokinetic differences between inhaled fluticasone propionate and budesonide, as well as (iv) pharmacokinetic differences between healthy volunteers and asthmatic patients. Finally, to identify the most impactful optimization criteria for orally inhaled drugs, the developed mechanistic model was applied to investigate the impact of input parameters on both the pulmonary and systemic exposure. Interestingly, the solubility of the inhaled drug did not have any relevant impact on the local and systemic pharmacokinetics. Instead, the pulmonary dissolution rate, the particle size, the tissue affinity, and the systemic clearance were the most impactful potential optimization parameters. In the future, the developed prediction framework should be considered a powerful tool for identifying optimal drug and formulation characteristics.     

Validating CFD predictions of respiratory aerosol deposition: effects of upstream transition and turbulence

A number of computational fluid dynamics (CFD) studies have explored local deposition patterns of inhaled aerosols in the respiratory tract. These studies have highlighted the effects of multiple physiologic, geometric, and particle characteristics on deposition. However, very few studies have reported local or sub-branch quantitative comparisons to in vitro particle deposition data. The objective of this study is to numerically investigate the effects of transition and turbulence on highly localized particle deposition in a respiratory double bifurcation model in order to quantitatively validate CFD results. To perform the validations, local comparisons have been made to a specific in vitro case study of 10 microm particles depositing in a model of respiratory generations G3-G5. To achieve this objective, two geometric cases have been considered. The first case includes only the double bifurcation model. The second case includes a portion of the experimental particle delivery geometry, where transitional flow is expected. To evaluate the effectiveness of two-equation turbulence models in this system, the flow field solutions have been computed using laminar, standard k-omega, and low Reynolds number (LRN) k-omega approximations. Results indicate that even though the Reynolds number remained below the critical limit required for full turbulence, transition and turbulence have a significant impact on the flow field and local particle deposition patterns. For the experimental case considered, turbulence impacted the local deposition of 10 microm particles primarily by influencing the initial velocity and particle profiles. As such, both the laminar and LRN k-omega flow models provided good local quantitative matches to the in vitro deposition data, provided that the correct initial particle profile was specified. Implications of this study include the need for local quantitative validations of particle deposition results, the importance of correct inlet conditions, and the need to consider upstream effects in experimental and computational studies of the respiratory tract. Applications of these results to realistic respiratory geometries will require consideration on upstream flow conditions in the lung, transient flow, and intermittent turbulent structures.     

Multivariate Data Analysis as a Semi-quantitative Tool for Interpretive Evaluation of Comparability or Equivalence of Aerodynamic Particle Size Distribution Profiles

The purpose of this article is to investigate the performance of multivariate data analysis, especially orthogonal partial least square (OPLS) analysis, as a semi-quantitative tool to evaluate the comparability or equivalence of aerodynamic particle size distribution (APSD) profiles of orally inhaled and nasal drug products (OINDP). Monte Carlo simulation was employed to reconstitute APSD profiles based on 55 realistic scenarios proposed by the Product Quality Research Institute (PQRI) working group. OPLS analyses with different data pretreatment methods were performed on each of the reconstituted profiles. Compared to unit-variance scaling, equivalence determined based on OPLS analysis with Pareto scaling was shown to be more consistent with the working group assessment. Chi-square statistics was employed to compare the performance of OPLS analysis (Pareto scaling) with that of the combination test (i.e., chi-square ratio statistics and population bioequivalence test for impactor-sized mass) in terms of achieving greater consistency with the working group evaluation. A p value of 0.036 suggested that OPLS analysis with Pareto scaling may be more predictive than the combination test with respect to consistency. Furthermore, OPLS analysis may also be employed to analyze part of the APSD profiles that contribute to the calculation of the mass median aerodynamic diameter. Our results show that OPLS analysis performed on partial deposition sites do not interfere with the performance on all deposition sites.     

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.     

Aerosol particle deposition in human lungs

The pneumoconiosis developing after inhalation of air-borne dusts in the work place depends on the relation between the value of particle deposition in the respiratory tract and the rate of particle clearance from sites of their deposition. For testing the deposition in humans an aerosol of paraffin oil was given to a cohort of healthy persons. The characteristic parameters of the aerosol had been defined. The concentration of particles in 5 channels were measured in both the inhaled and exhaled air samples using the particle counter ROYCO 225. The deposition fraction was calculated from the relation of particle amount in expired air to the amount in inhaled air in each distribution class. In this preliminary report the results comparable with the prediction mathematical curve are discussed.     

Mechanisms of Pharmaceutical Aerosol Deposition in the Respiratory Tract

Aerosol delivery is noninvasive and is effective in much lower doses than required for oral administration. Currently, there are several types of therapeutic aerosol delivery systems, including the pressurized metered-dose inhaler, the dry powder inhaler, the medical nebulizer, the solution mist inhaler, and the nasal sprays. Both oral and nasal inhalation routes are used for the delivery of therapeutic aerosols. Following inhalation therapy, only a fraction of the dose reaches the expected target area. Knowledge of the amount of drug actually deposited is essential in designing the delivery system or devices to optimize the delivery efficiency to the targeted region of the respiratory tract. Aerosol deposition mechanisms in the human respiratory tract have been well studied. Prediction of pharmaceutical aerosol deposition using established lung deposition models has limited success primarily because they underestimated oropharyngeal deposition. Recent studies of oropharyngeal deposition of several drug delivery systems identify other factors associated with the delivery system that dominates the transport and deposition of the oropharyngeal region. Computational fluid dynamic simulation of the aerosol transport and deposition in the respiratory tract has provided important insight into these processes. Investigation of nasal spray deposition mechanisms is also discussed.     

Effects of bronchodilator particle size in asthmatic patients using monodisperse aerosols.

Aerosol particle size influences airway drug deposition. Current inhaler devices are inefficient, delivering a heterodisperse distribution of drug particle sizes where, at best, 20% reaches the lungs. Monodisperse aerosols are the appropriate research tools to investigate basic aerosol science concepts within the human airways. We hypothesized that engineering such aerosols of albuterol would identify the ideal bronchodilator particle size, thereby optimizing inhaled therapeutic drug delivery. Eighteen stable mildly to moderately asthmatic patients [mean forced expiratory volume in 1 s (FEV1) 74.3% of predicted] participated in a randomized, double-blind, crossover study design. A spinning-top aerosol generator was used to produce monodisperse albuterol aerosols that were 1.5, 3, and 6 microm in size, and also a placebo, which were inhaled at cumulative doses of 10, 20, 40, and 100 microg. Lung function changes and tolerability effects were determined. The larger particles, 6 and 3 microm, were significantly more potent bronchodilators than the 1.5-microm and placebo aerosols for FEV1 and for the forced expiratory flow between exhalation of 25 and 75% of forced vital capacity. A 20-microg dose of the 6- and 3-microm aerosols produced FEV1 bronchodilation comparable to that produced by 200 microg from a metered-dose inhaler. No adverse effects were observed in heart rate and plasma potassium. The data suggest that in mildly to moderately asthmatic patients there is more than one optimal beta2-agonist bronchodilator particle size and that these are larger particles in the higher part of the respirable range. Aerosols delivered in monodisperse form can enable large reductions of the inhaled dose without loss of clinical efficacy.     

Models of human lung airways and their application to inhaled particle deposition

Models of the human respiratory tract were developed based on detailed morphometric measurements of a silicone rubber cast of the human tracheobronchial airways. Emphasis was placed on the “Typical Path Lung Model” which used one typical pathway to represent a portion of the lung, such as a lobe, or to represent the whole lung. The models contain geometrical parameters, including airway segment diameters, lengths, branching angles and angles of inclination to gravity, which are needed for estimating inhaled particle deposition. Aerosol depositions for various breathing patterns and particle sizes were calculated using these lung models and the modified Findeisen-Landahl computational scheme. The results agree reasonably well with recent experimental data. Regional deposition, including lobar deposition fractions, are also calculated and compared with results based on the ICRP lung deposition model.     

Effects of oral airway geometry characteristics on the diffusional deposition of inhaled nanoparticles

The deposition of ultrafine aerosols in the respiratory tract presents a significant health risk due to the increased cellular-level response that these particles may invoke. However, the effects of geometric simplifications on local and regional nanoparticle depositions remain unknown for the oral airway and throughout the respiratory tract. The objective of this study is to assess the effects of geometric simplifications on diffusional transport and deposition characteristics of inhaled ultrafine aerosols in models of the extrathoracic oral airway. A realistic model of the oral airway with the nasopharynx (NP) included has been constructed based on computed tomography scans of a healthy adult in conjunction with measurements reported in the literature. Three other geometries with descending degrees of physical realism were then constructed with successive geometric simplifications of the realistic model. A validated low Reynolds number k-omega turbulence model was employed to simulate laminar, transitional, and fully turbulent flow regimes for the transport of 1-200 nm particles. Results of this study indicate that the geometric simplifications considered did not significantly affect the total deposition efficiency or maximum local deposition enhancement of nanoparticles. However, particle transport dynamics and the underlying flow characteristics such as separation, turbulence intensity, and secondary motions did show an observable sensitivity to the geometric complexity. The orientation of the upper trachea was shown to be a major factor determining local deposition downstream of the glottis and should be retained in future models of the respiratory tract. In contrast, retaining the NP produced negligible variations in airway dynamics and could be excluded for predominantly oral breathing conditions. Results of this study corroborate the use of existing diffusion correlations based on a circular oral airway model. In comparison to previous studies, an improved correlation for the deposition of nanoparticles was developed based on a wider range of particle sizes and flow rates, which captures the dependence of the Sherwood number on both Reynolds and Schmidt numbers.     

The Effect of Nonideal Cascade Impactor Stage Collection Efficiency Curves on the Interpretation of the Size of Inhaler-Generated Aerosols

Cascade impactors, operating on the principle of inertial size separation in (ideally) laminar flow, are used to determine aerodynamic particle size distributions (APSDs) of orally inhaled product (OIP) aerosols because aerodynamic diameter can be related to respiratory tract deposition. Each stage is assumed typically to be an ideal size fractionator. Thus, all particles larger than a certain size are considered collected and all finer particles are treated as penetrating to the next stage (a step function stage efficiency curve). In reality, the collection efficiency of a stage smoothly increases with particle size as an “S-shaped” curve, from approximately 0% to 100%. Consequently, in some cases substantial overlap occurs between neighboring stages. The potential for bias associated with the step-function assumption has been explored, taking full resolution and two-stage abbreviated forms of the Andersen eight-stage nonviable impactor (ACI) and the next-generation pharmaceutical impactor (NGI) as example apparatuses. The behavior of unimodal, log-normal APSDs typical of OIP-generated aerosols has been investigated, comparing known input values to calculated values of central tendency (mass median aerodynamic diameter) and spread (geometric standard deviation, GSD). These calculations show that the error introduced by the step change assumption is larger for the ACI than for the NGI. However, the error is sufficiently small to be inconsequential unless the APSD in nearly monodisperse (GSD ≤1.2), a condition that is unlikely to occur with realistic OIPs. Account may need to be taken of this source of bias only for the most accurate work with abbreviated ACI systems.     

Improved Quality Control Metrics for Cascade Impaction Measurements of Orally Inhaled Drug Products (OIPs)

This study of aerodynamic mass-weighted particle size distribution (APSD) data from orally inhaled products (OIPs) investigated whether a set of simpler (than currently used) metrics may be adequate to detect changes in APSD for quality control (QC) purposes. A range of OIPs was examined, and correlations between mass median aerodynamic diameter and the ratio of large particle mass (LPM) to small particle mass (SPM) were calculated. For an Andersen cascade impactor, the LPM combines the mass associated with particle sizes from impactor stage 1 to a product-specific boundary size; SPM combines the mass of particles from that boundary through to terminal filter. The LPM–SPM boundary should be chosen during development based on the full-resolution impactor results so as to maximize the sensitivity of the LPM/SPM ratio to meaningful changes in quality. The LPM/SPM ratio along with the impactor-sized mass (ISM) are by themselves sufficient to detect changes in central tendency and area under the APSD curve, which are key in vitro quality attributes for OIPs. Compared to stage groupings, this two-metric approach provides better intrinsic precision, in part due to having adequate mass and consequently better ability to detect changes in APSD and ISM, suggesting that this approach should be a preferred QC tool. Another advantage is the possibility to obtain these metrics from the abbreviated impactor measurements (AIM) rather than from full-resolution multistage impactors. Although the boundary is product specific, the testing could be accomplished with a basic AIM system which can meet the needs of most or all OIPs.     

Product Lifecycle Approach to Cascade Impaction Measurements

Over the lifecycle of an orally inhaled product (OIP), multi-stage cascade impactor (CI) measurements are used for different purposes and to address different questions. Full-resolution CIs can provide important information during product development and are widely used but are time- and resource-intensive, highly variable, and suboptimal for OIP quality control (QC) testing. By contrast, Efficient Data Analysis (EDA) combined with Abbreviated Impactor Measurement (AIM) systems pertinent either for QC and-possibly-for adult Human Respiratory Tract (pHRT) has been introduced for OIP performance assessment during and post-development. This article summarizes available evidence and discusses a strategy for using either abbreviated or full-resolution CI systems depending on the purpose of the measurement, such that adequate, accurate, and efficient testing of aerodynamic particle size distribution (APSD) of OIPs can be achieved throughout the lifecycle of a product. Under these proposals, a comprehensive testing program should initially be conducted by full-resolution CI in OIP development to ascertain the product's APSD. Subsequently, correlations should be established from the selected AIM CIs to the corresponding full-resolution system, ideally developing specifications common to both techniques. In the commercial phase, it should be possible to release product using AIM/EDA, keeping the full-resolution CI for investigations, change control, and trouble-shooting, thus optimizing resources for APSD characterization throughout the product lifecycle. If an in vitro-in vivo relationship is established and clinically relevant sizes are known, an AIM-pHRT could serve as a quick indicator that clinically relevant fractions have not changed and also, in the management of post-approval changes.     

Good Cascade Impactor Practice (GCIP) and Considerations for “In-Use” Specifications

The multi-stage cascade impactor (CI) is widely used to determine aerodynamic particle size distributions (APSDs) of orally inhaled products. Its size-fractionating capability depends primarily on the size of nozzles of each stage. Good Cascade Impactor Practice (GCIP) requires that these critical dimensions are linked to the accuracy of the APSD measurement based on the aerodynamic diameter size scale. Effective diameter (D _eff) is the critical dimension describing any nozzle array, as it is directly related to stage cut-point size (d ₅₀). d ₅₀ can in turn be determined by calibration using particles of known aerodynamic diameter, providing traceability to the international length standard. Movements in D _eff within manufacturer tolerances for compendial CIs result in the worst case in shifts in d ₅₀ of <±10%. Stage mensuration therefore provides satisfactory control of measurement accuracy. The accurate relationship of D _eff to d ₅₀ requires the CI system to be leak-free, which can be checked by sealing the apparatus at the entry to the induction port and isolating it from the vacuum source and measuring the rate of pressure rise before each use. Mensuration takes place on an infrequent basis compared with the typical interval between individual APSD determinations. Measurement of stage flow resistance (pressure drop; ΔP _stage) could enable the user to know that the CI stages are fit for use before every APSD measurement, by yielding an accurate measure of D _eff. However, more data are needed to assess the effects of wear and blockage before this approach can be advocated as part of GCIP.     

Product quality research institute evaluation of cascade impactor profiles of pharmaceutical aerosols, part 3: Final report on a statistical procedure for determining equivalence

The purpose of this article is to report final results of the evaluation of a chi-square ratio test proposed by the US Food and Drug Administration (FDA) for demonstrating equivalence of aerodynamic particle size distribution (APSD) profiles of nasal and orally inhaled drug products. A working group of the Product Quality Research Institute previously published results demonstrating some limitations of the proposed test. In an effort to overcome the test's limited discrimination, the group proposed a supplemental test, a population bioequivalence (PBE) test for impactor-sized mass (ISM). In this final report the group compares the chi-square ratio test to the ISM-PBE test and to the combination of both tests. The basis for comparison is a set of 55 realistic scenarios of cascade impactor data, which were evaluated for equivalence by the statistical tests and independently by the group members. In many instances, the combined application of these 2 tests appeared to increase the discriminating ability of the statistical procedure compared with the chi-square ratio test alone. In certain situations the chi-square ratio test alone was sufficient to determine equivalence of APSD profiles, while in other situations neither of the tests alone nor their combination was adequate. This report describes all of these scenarios and results. In the end, the group did not recommend a statistical test for APSD profile equivalence. The group did not investigate other in vitro tests, in vivo issues, or other statistical tests for APSD profile comparisons. The studied tests are not intended for routine quality control of APSD.