Interchanging Reusable and Disposable Nebulizers Used with Home-Based Compressors May Result in Inconsistent Dosing: A Laboratory Investigation with Device Combinations Supplied to the US Healthcare Environment.

INTRODUCTION: Reusable nebulizer-compressor combinations deliver inhaled medications for patients with chronic lung diseases. On hospital discharge, the patient may take home the disposable nebulizer that was packaged and combine it with their home compressor. Though this practice may reduce waste, it can increase variability in medication delivery. Our study compared several reusable and disposable nebulizers packaged with compressor kits used in the US. We included a common disposable hospital nebulizer that may not be supplied with popular home kits but may be brought home after a hospitalization or emergency department visit. We focused on fine droplet mass < 4.7 µm aerodynamic diameter (FDM<4.7 µm), associated with medication delivery to the airways of the lungs. METHODS: We evaluated the following nebulizer-compressor combinations (n = 5 replicates): 1. OMBRA® Table Top Compressor with MC 300® reusable and Airlife™ MistyMax™ 10® disposable nebulizer, 2. Sami-the-Seal® compressor with SideStream® reusable and disposable nebulizers and Airlife™ MistyMax 10™ disposable nebulizer, 3. VIOS® compressor with LC Sprint® reusable, and VixOne® and Airlife™ MistyMax™ disposable nebulizers, 4. Innospire® Elegance® compressor with SideStream® reusable and disposable nebulizers and Airlife™ MistyMax 10™ disposable nebulizer, 5. Willis-the-Whale® compressor with SideStream® reusable and disposable nebulizers and Airlife™ MistyMax 10™ disposable nebulizer, 6. Pari PRONEB® Max compressor with LC Sprint® reusable and Airlife™ MistyMax 10™ disposable nebulizer. We placed a 3-ml albuterol solution (0.833 mg/ml) in each nebulizer. A bacterial/viral filter was attached to the nebulizer mouthpiece to capture emitted medication, with the filter exit coupled to a simulator of a tidal breathing adult (rate = 10 cycles/min; Vt = 600 ml; I/E ratio = 1:2). The filter was replaced at 1-min intervals until onset of sputter. Droplet size distributions (n = 5 replicates/system) were determined in parallel by laser diffractometry. RESULTS: Cumulative FDM<4.7 µm varied from 381 ± 33 µg for the best performing combination (Proneb/LC-Sprint) to 150 ± 21 µg for the system with the lowest output (VIOS®/MistyMax 10™). CONCLUSIONS: Substituting one nebulizer for another can result in large differences in medication delivery to the lungs.

Laboratory Performance Testing of Aqueous Nasal Inhalation Products for Droplet/Particle Size Distribution: an Assessment from the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS).

Although nasal inhalation products are becoming more and more important for the delivery of medicines, characterization of these products for quality control and assessment of bioequivalence is complicated. Most of the problems encountered are associated with the assessment of aerodynamic droplet/particle size distribution (APSD). The droplets produced by the various nasal devices are large, and for suspension products, individual droplets may contain multiple drug particles or none at all. Assessment of suspension products is further complicated by the presence of solid excipient particles. These complications make it imperative that the limitations of the instruments used for characterization as well as the underlying assumptions that govern the interpretation of data produced by these instruments are understood. In this paper, we describe various methodologies used to assess APSD for nasal inhalation products and discuss proper use, limitations, and new methodologies on the horizon.

Good Practices for the Laboratory Performance Testing of Aqueous Oral Inhaled Products (OIPs): an Assessment from the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS).

Multiple sources must be consulted to determine the most appropriate procedures for the laboratory-based performance evaluation of aqueous oral inhaled products (OIPs) for the primary measures, dose uniformity/delivery, and aerodynamic particle (droplet) size distribution (APSD). These sources have been developed at different times, mainly in Europe and North America, during the past 25 years by diverse organizations, including pharmacopeial chapter/monograph development committees, regulatory agencies, and national and international standards bodies. As a result, there is a lack of consistency across all the recommendations, with the potential to cause confusion to those developing performance test methods. We have reviewed key methodological aspects of source guidance documents identified by a survey of the pertinent literature and evaluated the underlying evidence supporting their recommendations for the evaluation of these performance measures. We have also subsequently developed a consistent series of solutions to guide those faced with the various associated challenges when developing OIP performance testing methods for oral aqueous inhaled products.

Non-Pharmaceutical Techniques for Obstructive Airway Clearance Focusing on the Role of Oscillating Positive Expiratory Pressure (OPEP): A Narrative Review.

Mucus secretion in the lungs is a natural process that protects the airways from inhaled insoluble particle accumulation by capture and removal via the mucociliary escalator. Diseases such as cystic fibrosis (CF) and associated bronchiectasis, as well as chronic obstructive pulmonary disease (COPD), result in mucus layer thickening, associated with high viscosity in CF, which can eventually lead to complete airway obstruction. These processes severely impair the delivery of inhaled medications to obstructed regions of the lungs, resulting in poorly controlled disease with associated increased morbidity and mortality. This narrative review article focuses on the use of non-pharmacological airway clearance therapies (ACTs) that promote mechanical movement from the obstructed airway. Particular attention is given to the evolving application of oscillating positive expiratory pressure (OPEP) therapy via a variety of devices. Advice is provided as to the features that appear to be the most effective at mucus mobilization.

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.

Addressing the Need for Controls on Particle Bounce and Re-entrainment in the Cascade Impactor and for the Mitigation of Electrostatic Charge for Aerodynamic Particle Size Assessment of Orally Inhaled Products: an Assessment by the International Consortium on Regulation and Science (IPAC-RS).

Multi-stage cascade impactors (CI) are accepted for the determination of metrics of the drug mass aerodynamic particle size distributions (APSD) of aerosols emitted from orally inhaled products (OIPs). This is particularly important for products where the drug to excipient ratio or particle density may not be the same in each aerodynamic size fraction; examples of such products are carrier-containing dry powder inhalers (DPIs) and suspension pressurized metered-dose inhalers (pMDIs). CI measurements have been used as the "gold standard" for acceptance of alternative methods of APSD assessment, such as laser diffraction for nebulized solutions. Although these apparatus are labor-intensive, they are accepted in regulatory submissions and quality control assessments because the mass of active pharmaceutical ingredient(s) in the aerosol can be quantified by chemical assay and measured particle size is based on the aerodynamic diameter scale that is predictive of deposition in the respiratory tract. Two of the most important factors that modify the ideal operation of an impactor are "particle bounce," that is often accompanied by re-entrainment in the air flow passing the stage of interest, and electrostatic charge acquired by the particles during the preparation and aerosolization of the formulation when the inhaler is actuated. This article reviews how both factors can lead to biased APSD measurements, focusing on measurements involving pMDIs and DPIs, where these sources of error are most likely to be encountered. Recommendations are provided for the mitigation of both factors to assist the practitioner of these measurements.

Reflections on Digital Health Tools for Respiratory Applications.

Background: In May 2019, the International Society for Aerosols in Medicine (ISAM) and the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) held a one-day workshop on digital health tools for respiratory therapies, with speakers representing views of patients, pharmaceutical and technology companies, physicians, and payors. Methods: Workshop presentations, audience discussions, and research of relevant literature form the basis of this article. Results: Conversations and publications to date illustrate the broad, and growing, interest in digital technologies, but also highlight a few gaps. The key messages are: (1) There are many great technologies, from simple to complex, but there is still an imperfect understanding of the problems that digital tools need to solve. The current approach often starts with a technology "solution" and then identifying the problems that it could address. This is a poor design practice: the offered technology may not represent the optimum solution to that problem; and that "problem" itself may not represent issues that patients or the health care system deem to be of high priority. (2) Respiratory medicine currently lacks widely accepted and easily measured biomarkers or hand-held diagnostic technologies that could be commercialized for complex/heterogeneous diseases such as asthma (unlike in other areas, e.g., diabetes). (3) There are no obvious solutions that integrate the perspectives of the many stakeholders-from patients to physicians to payors-to make the new field commercially viable, and the incentives of various parties in the health care system are misaligned. (4) A continued dialog, information sharing, mutual education, and collaborations are important in bringing the promise of digital respiratory medicine to fruition. Conclusions: Digital tools for diagnosis and management of respiratory conditions are an active area of research and development but long-term success in this field will depend on identifying real needs, and integrating the often-diverging interests of the various partners in each country's health care system.

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.

Innovative preclinical models for pulmonary drug delivery research.

Introduction: Pulmonary drug delivery is a complex field of research combining physics which drive aerosol transport and deposition and biology which underpins efficacy and toxicity of inhaled drugs. A myriad of preclinical methods, ranging from in-silico to in-vitro, ex-vivo and in-vivo, can be implemented.Areas covered: The present review covers in-silico mathematical and computational fluid dynamics modelization of aerosol deposition, cascade impactor technology to estimated drug delivery and deposition, advanced in-vitro cell culture methods and associated aerosol exposure, lung-on-chip technology, ex-vivo modeling, in-vivo inhaled drug delivery, lung imaging, and longitudinal pharmacokinetic analysis.Expert opinion: No single preclinical model can be advocated; all methods are fundamentally complementary and should be implemented based on benefits and drawbacks to answer specific scientific questions. The overall best scientific strategy depends, among others, on the product under investigations, inhalation device design, disease of interest, clinical patient population, previous knowledge. Preclinical testing is not to be separated from clinical evaluation, as small proof-of-concept clinical studies or conversely large-scale clinical big data may inform preclinical testing. The extend of expertise required for such translational research is unlikely to be found in one single laboratory calling for the setup of multinational large-scale research consortiums.

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.

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.

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.

Evaluation of Nasal Inlet Ports Having Simplified Geometry for the Pharmacopeial Assessment of Mass Fraction of Dose Likely to Penetrate Beyond the Nasopharynx: a Preliminary Investigation.

Nasal cavity breakthrough to the airways of the lungs is associated with nasally inhaled droplets whose size is smaller than ca. 10 µm aerodynamic diameter that behave as an aerosol rather than a spray in terms of their transport. The purpose of the present laboratory-based study was to evaluate a nasal product quality control procedure involving a new inlet for the quantification of mass of such droplets emitted by commercially available aqueous nasal spray pump products by cascade impactor. This inlet is more representative of the adult nasal vestibule in terms of entry angle for the spray as well as internal volume for plume expansion. Sampling was also undertaken via a spherical 1-L glass expansion vessel as inlet, previously established for quantification of these aerosol droplets. The selected solution- and suspension-formulated products containing azelastine and fluticasone propionate respectively were shown to contain < 1% of the total spray mass per actuation associated with droplets < 14.1 µm aerodynamic diameter. These measurements were consistent with laser diffraction-based measurements of the entire droplet size distribution. Comparable measures of aerosol droplet mass fraction were obtained when the spray was sampled by the cascade impactor method using either the 1-L glass expansion chamber or the new metal inlet as entry for the spray produced by either product evaluated. We conclude that the metal inlet has the potential to be adopted as a suitable induction port in the assessment of nasal product quality, where currently no standardized inlet exists.

Development of a novel digital breath-activated inhaler: Initial particle size characterization and clinical testing.

BACKGROUND: Delivery of inhaled respiratory medications have been associated with variable delivery of drug due to errors in device operations and have not been designed to monitor true delivery of medication. A fully digital breath-activated inhaled (DBAI) delivery platform has been developed with integrated firmware and software to address these limitations. METHODS: the device was designed to produce similar aerosol particle output to a marketed albuterol MDI and to the albuterol/ipratropium combination in a soft mist inhaler (SMI). Cascade impactor studies were conducted to demonstrate comparable aerodynamic particle size distribution (APSD) metrics. Efficacy was evaluated by pharmacodynamic studies involving spirometry in two separate protocols with adult subjects having COPD (albuterol DBAI vs. albuterol MDI - Study A, albuterol/ipratropium DBAI single arm - Study B). RESULTS: The total emitted doses (TED) were 81.9 ±â€¯10.3, 109.3 ±â€¯15.0 and 121.9 ±â€¯7.0 µg/actuation for the DBAI, SMI and MDI respectively, and the fine (respirable) particle doses (FPD) were 56.2 ±â€¯6.0, 61.7 ±â€¯5.5 and 79.4 ±â€¯2.7 µg/actuation. MMADs for albuterol sulfate were 1.93 ±â€¯0.11, 1.75 ±â€¯0.19, and 2.65 ±â€¯0.05 µm for the DBAI, Respimat soft mist inhaler (SMI) and MDI respectively. The corresponding GSDs were 1.96 ±â€¯0.16, 2.79 ±â€¯0.25, and 1.48 ±â€¯0.02 µm. The corresponding respirable fractions were 68.7 ±â€¯3.2%, 57.3 ±â€¯10.5%, and 65.2 ±â€¯2.4%. Spirometric study A enrolled 23 subjects (age 64 ±â€¯7.3 years, 39% male, FEV1 45 ±â€¯14% predicted). Study B enrolled 23 subjects (age 65 ±â€¯8.6 years, 43% male, FEV1 47 ±â€¯10% predicted). For Study A, FEV1 at 20 min post-dose improved by 120 (167) mL (p = 0.002) for the DBAI device and 109 (183) mL (p = 0.008) for the MDI device (p = 0.86 for between group differences). For Study B, FEV1 (20 min post-dose) improved by 216 (126) mL (p < 0.001). CONCLUSION: The DBAI generated highly respirable aerosols containing albuterol sulfate that were similar to the MDI and SMI in respirable fraction but lower in dose. Subsequent pharmacodynamic studies delivering albuterol sulfate alone and in combination with ipratropium bromide confirmed similar responses for the DBAI compared with the other inhalers, which could possibly be related to a response ceiling. The DBAI breath-activated capability combined with the ability to monitor actual delivery of medication may improve effectiveness by overcoming patient miscoordination.

Laboratory Study Comparing Pharmacopeial Testing of Nebulizers with Evaluation Based on Nephele Mixing Inlet Methodology.

Determination of fine droplet dose with preparations for nebulization, currently deemed to be the metric most indicative of lung deposition and thus in vivo responses, involves combining two procedures following practice as described in the United States Pharmacopeia and the European Pharmacopeia. Delivered dose (DD) is established by simulating tidal breathing at the nebulizer, collecting the medication on a filter downstream of the nebulizer mouthpiece/facemask. Fine droplet fraction (FDF

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.

Development and Evaluation of a Family of Human Face and Upper Airway Models for the Laboratory Testing of Orally Inhaled Products.

Many orally inhaled products are supplied with a facemask instead of a mouthpiece, enabling aerosolized medication to be transferred from the inhaler to the lungs when the user lacks the capability to use a mouthpiece. Until recently, laboratory evaluation of an orally inhaled product-facemask was frequently undertaken by removing the facemask, treating the facemask adapter as being equivalent to a mouthpiece. Measurements of delivered drug mass were therefore subject to bias arising from the absence of dead volume, had the facemask been present. We have described the development of the Aerosol Delivery to an Anatomic Model (ADAM) infant, small child, and adult faces and upper airways, and their subsequent evaluation. Each model possesses physical features of appropriate size, and the soft tissues are also simulated. Rudimentary underlying bony structure is also present, because its purpose is only to provide support, enabling the mechanical response of the facial soft tissues when a facemask is applied to be realized. A realistic upper airway (nasopharynx for the infant model, naso- and oropharynx for the child and oropharynx for the adult models) is also incorporated, so that each model can be used to determine the mass of inhaled medication likely to penetrate as far as the lungs where therapy is intended to be applied. Measurements of the mass of pressurized metered-dose inhaler-delivered salbutamol at a filter distal to the upper airway of each model, simulating age-appropriate tidal breathing, were remarkably consistent, almost all being in the range 0.3 to 1.0 µg/kg across the model age ranges, when expressed as a fraction of body weight.