relevant references
SCIENTIFIC JOURNALS
Doub WH, Shah V, Limb S, Guo C, Liu X, Ngo D.; “Developing an in vitro understanding of patient experience with hydrofluoroalkane-metered dose inhalers.”; J Pharm Sci. 2014 Nov;103(11):3648-3656. doi: 10.1002/jps.24167. Epub 2014 Sep 16. PMID: 25228114
ABSTRACT: As a result of the Montreal Protocol on Substances that Deplete the Ozone Layer, manufacturers of metered dose inhalers began reformulating their products to use hydrofluoroalkanes (HFAs) as propellants in place of chlorofluorocarbons (CFCs). Although the new products are considered safe and efficacious by the US Food and Drug Administration (FDA), a large number of complaints have been registered via the FDA’s Adverse Events Reporting System (FAERS)—more than 7000 as of May 2013. To develop a better understanding of the measurable parameters that may, in part, determine in vitro performance and thus patient compliance, we compared several CFC- and HFA-based products with respect to their aerodynamic performance in response to changes in actuator cleaning interval and interactuation delay interval. Comparison metrics examined in this study were: total drug delivered ex-actuator, fine particle dose (<5 µm), mass median aerodynamic diameter, plume width, plume temperature, plume impaction force, and actuator orifice diameter. Overall, no single metric or test condition distinguishes HFA products from CDC products, but, for individual products tested, there were a combination of metrics that differentiated one from another. ©Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
Liu X, Doub WH, Guo C. “Assessment of the Influence Factors on Nasal Spray Droplet Velocity Using Phase-Doppler Anemometry (PDA).” AAPS PharmSciTech. 2011 Mar;12(1):337-43. doi: 10.1208/s12249-011-9594-1. Epub 2011 Feb 1. PMID: 21286880 Free PMC Article
ABSTRACT: Droplet velocity is an important parameter that can be used to characterize nasal spray products. In this study, a phase-Doppler anemometry (PDA) system was used to measure the droplet velocities of nasal sprays. A survey of seven commercial nasal spray products showed a range of droplet velocities from 6.7 to 19.2 m/s, all significantly different from each other. A three-level, four-factor Box-Behnken design of experiments (DOE) methodology were applied to investigate the influences of actuation parameters and formulation properties on nasal spray droplet velocity using a set of placebo formulations. The DOE study shows that all four input factors (stroke length, actuation velocity, concentration of the gelling agent, and concentration of the surfactant) have significant influence on droplet velocity. An optimized quadratic model generated from the DOE results describes the inherent relationships between the input factors and droplet velocity thus providing a better understanding of the input factor influences. Overall, PDA provides a new in vitro characterization method for the evaluation of inhalation drugs through assessment of spray velocity and may assist in product development to meet drug delivery equivalency requirements. ©2011 American Association of Pharmaceutical Scientists
Liu X, Doub WH, Guo C. “Evaluation of droplet velocity and size from nasal spray devices using phase Doppler anemometry (PDA).” Int J Pharm. 2010 Mar 30; 388(1-2): 82-7. doi: 10.1016/j.ijpharm.2009.12.041. Epub 2010 Jan 5. PubMed PMID: 20043981
ABSTRACT: The impaction force from an inhalation product is an important characteristics by which to characterize the spray plume. It is one of the plume characteristics that can be perceived by a patient, and is expected to be good measures of local delivery equivalence for inhalation drugs. A Stable Micro Systems TA-XT.plus Texture Analyser equipped with 750 g load cell was used to measure the impaction force of several nasal sprays and metered-dose inhalers (MDIs). A survey of several commercial nasal spray and MDI products shows that impaction forces of these products varies from 1.5 to 6.5 g force and are significantly different from each other. A 3-level, 4-factor Box-Behnken design was applied to the study of impaction force of nasal sprays using placebo solutions. The influences of four factors: actuation stroke length, actuation velocity, concentration of gelling agent, and concentration of surfactant, were investigated. Of those factors examined here, actuation velocity exerts the greatest effect on impaction force. Impaction force is a discriminative parameter for in vitro testing of nasal spray and MDI products. Since impaction force is more directly related to patient sensation and aerosol deposition in the nasal mucus than other, more traditional parameters, it may provide a better way to evaluate in vitro equivalence in support of abbreviated new drug applications (ANDAs) for orally inhaled and nasal drug products. ©2009 Wiley-Liss, Inc.
Guo C, Ye W, Kauffman J, Doub WH. “Evaluation of impaction force of nasal sprays and metered-dose inhalers using the Texture Analyser.” J Pharm Sci. 2009 Aug; 98(8):2799-806. doi: 10.1002/jps.21648. PMID: 19097159
ABSTRACT: The impaction force from an inhalation product is an important characteristic by which to characterize the spray plume. It is one of the plume characteristics that can be perceived by a patient and is expected to be good measures of local delivery equivalence for inhalation drugs. A Stable Micro Systems TA-XT.plus Texture Analyser equipped with 750 g load cell was used to measure the impaction force of several nasal sprays and metered-dose inhalers (MDIs). A survey of several commercial nasal spray and MDI products shows that impaction forces of these products varies from 1.5 to 6.5 g force and are significantly different from each other. A 3-level, 4-factor Box-Behnken design was applied to the study of impaction force of nasal sprays using placebo solutions. The influences of four factors: actuation stroke length, actuation velocity, concentration of gelling agent, and concentration of surfactant, were investigated. Of those factors examined here, actuation velocity exerts the greatest effect on impaction force. Impaction force is a discriminative parameter for in vitro testing of nasal spray and MDI products. Since impaction force is more directly related to patient sensation and aerosol deposition in the nasal mucus than other, more traditional parameters, it may provide a better way to evaluate in vitro equivalence in support of abbreviated new drug applications (ANDAs) for orally inhaled and nasal drug products. ©2009 Wiley-Liss, Inc.
Guo, C., K. Stine, J. Kauffman, and W. H. Doub. “Assessment of the Influence Factors on In Vitro Testing of Nasal Sprays Using Box-Behnken Experimental Design.” European Journal of Pharmaceutical Sciences, Volume 35, Issue 5, 18 December 2008, Pages 417-426
ABSTRACT: The purpose of the research was to investigate the influences of actuation parameters and formulation physical properties on nasal spray delivery performance using design of experiment (DOE) methodology. A 3-level, 4-factor Box-Behnken design with a total of 27 experimental runs was used in this study. Nine simulated aqueous formulations with different viscosities and surface tensions were prepared using carboxymethylcellulose sodium (CMC, gelling agent) and Tween80 (surfactant) each at three concentration levels. Four factors, actuation stroke length, actuation velocity, concentration of gelling agent, and concentration of surfactant were investigated for their influences on measured responses of shot weight, spray pattern, plume geometry and droplet size distribution (DSD). The models based on data from the DOE were then optimized by eliminating insignificant terms. Pfeiffer nasal spray pump units filled with the simulated formulations were used in the study. Nasal pump actuation stroke length exerts a strong, independent influence on shot weight, and also slightly affects spray pattern and plume geometry. Actuation velocity and concentration of gelling agent have significant effects on spray pattern, plume geometry and DSD, in a complicated manner through interaction terms. Concentration of surfactant has little, if any, influence on nasal spray characteristics. Results were fitted to quadratic models describing the inherent relationships between the four factors evaluated and nasal spray performance. The DOE study helped us to identify the source of variability in nasal spray product performance, and obtained better understanding in how to control the variability. Moreover, the quadratic models developed from the DOE study quantitatively describe the inherent relationships between the factors and nasal spray performance characteristics. With the assistance of the response surfaces developed from the DOE model, the time and labor in designing a nasal spray product to achieve desired product performance characteristics can be reduced. PMID: 18832029 [PubMed – indexed for MEDLINE]
Guo C, Doub WH. “The Influence of Actuation Parameters on In Vitro Testing of Nasal Spray Products.” J Pharm Sci. 2006 Sep; 95(9):2029-40. PMID: 16865693
ABSTRACT: Nasal spray drug products are normally characterized via measurement of shot weight, spray pattern, plume geometry, and droplet size distribution (DSD). In this project, the actuation parameters, such as stroke length, actuation velocity, and actuation acceleration, were investigated to ascertain how they affect nasal spray characteristics. Pfeiffer nasal spray pump units filled with water were used in the study. Actuation parameters were adjusted using an electronic automated actuation system, SprayVIEW™ NSx. Spray pattern and plume geometry measurements were carried out using a high speed optical spray characterization system, SprayVIEW™ NSP, and DSD analysis was performed using a Malvern 2600 laser diffraction system. Our results show that different actuation parameters affect the nasal spray characteristics in different ways and to different degrees. Among all the actuation parameters, stroke length and actuation velocity have significant effects on the nasal spray characteristics, while the other actuation parameters have little, if any, effect. Compared to spray pattern, plume geometry and DSD, shot weight provides very little characterization information. The findings from this work suggest that, for in vitro bioavailability (BA) and bioequivalence (BE) studies of nasal spray products, the actuation parameters, stroke length, and velocity must be carefully selected. Spray pattern, plume geometry, and DSD appear to provide critical data for assessment of nasal pump performance. ©2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95:2029–2040, 2006
Liao, L. L., Ramos, K., & Farina, D. (2019): “A Novel Characterization of Emitted Aerosol Velocity Profiles from Metered Dose and Soft Mist Inhalers (pMDI and SMI).” In DDL 2019 (Vol. 30, pp. 287–290). Edinburgh, UK: Aerosol Society.
ABSTRACT:
In a recent FDA guidance document, characterization of the emitted aerosol spray velocity profiles (spray velocity) was proposed as an alternative approach to comparative clinical endpoint bioequivalence (BE) studies. The spray velocity has been reported as an important parameter for drug-device combination products such as pMDIs and SMIs. This paper describes a clear methodology for measuring the spray velocity with the leading edge of the plume and presents results from four (4) US approved inhalation products. In this study, we extended the well-established SprayVIEW® technique for providing time-synchronized plume characterization in a novel way to determine the spray velocity from pMDI and SMI test samples available in the USA.
Comments related to Docket No. FDA-2018-D-1098-0001. Proveris Scientific Corporation (2018)
DESCRIPTION: The comments contained in this document reflect the collective thoughts of Proveris Scientific Corporation. Our comments are intended solely to help clarify the issues discussed in the FDA draft guidance document and to hopefully improve the interpretation and understanding of the FDA’s new requirements.
Summary of comment topics:
- Plume geometry measurement
- Defining product actuation force for clarity
- Force and distance to advance dose counter
- Control of shaking parameters
- Spray Pattern for additional applications
- Measurement parameters for breath actuated MDIs
Sherryl Baxter1, Ben Myatt2, Stephen Stein3, Adrian Parkinson4, Frank Chambers5, Bill Doub6, Jernej Grmas7, Julie Suman8, Keith Miller9, Biswadip Sinha10, Linda Liao11, Ian Carter12, Dino Farina11, Segolene Sarrailh13, Manfred Fischer14, Declan Walsh15, Lee Nagao16. AAPS PharmSciTech (2022). doi.org/10.1208/s12249-022-02278-w
ABSTRACT: Plume characterization for orally inhaled and nasal drug products (OINDP) provides valuable information during OINDP development. Spray pattern and plume geometry techniques, methods, and technology have evolved over the past 20 years since the publication of the original 1998 FDA MDI DPI draft guidance. The International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) discusses the historical context and background to plume geometry and spray pattern characterization studies; provides an analysis of the current regulatory context; addresses results from its industry
surveys on application and value of such testing; and presents case studies and best practices—seeking to provide insights to regulatory bodies and other stakeholders. Assessment and consideration of published studies and industry experience note the value of plume geometry and spray pattern in development, and that further data is needed regarding their use in assessing formulation characteristics. Continued dialogue between industry and regulatory bodies is needed to establish the optimum use of these techniques.
Chauhan, H., Liu-Cordero, S. N., Jones, D., & Okorodudu, B. (2018). “Evaluating Spray Characteristics of Multi-dose Nasal Spray Devices Across Different Actuator Designs.” In RDD Asia 2018 (pp. 1–6).
ABSTRACT: Developing a successful innovator or generic multi-dose nasal spray can be a difficult process, in part, because of the inseparable relationship between the device components and the formulation. Attempting to speed up development of a new product or matching the performance of an existing actuator component with a new device can lead to a temptation to evaluate potential device component candidates with water rather than waiting for development of the intended formulation. Likewise, formulators wanting to quickly screen an increasing array of actuator nozzles available from multiple suppliers may feel the pressure to test with water before a pilot drug-
containing formulation becomes available. Building on terminology and insights presented at RDD 2018, this paper shows the importance of testing the device and formulation in a coordinated way using efficient screening tools. This approach allows the impact of formulation variables, such as viscosity and surface tension, on sprayed product performance to be rapidly discerned as actuator nozzles, the pump assembly and diptube are optimized. This study focuses on how differences between specific nasal spray device components can influence the resulting spray pattern, and how these changes can also be dependent on the properties and composition of the liquid that is metered and sprayed. Understanding the effects of actuator and formulation on spray pattern can have a significant impact on successful product development.
Chauhan, H., Liu-Cordero, S. N., Liao, L., & Werbeck, J. (2018). “Impact of Actuator Design on Multi-dose Nasal Spray Characteristics.” In RDD 2018 (pp. 497–502).
ABSTRACT: The competitive global market for inhalation and nasal sprays is expected to rise to a valuation of 35 billion USD by 2023 specifically for generic drugs [1]. Developing a successful multi dose nasal spray can be a difficult process. A number of components and critical parameters need to be precisely controlled to achieve desired dose delivery. Numerous studies have focused on the effects of formulation aspects (viscosity, surface tension) [2, 3] on the drug performance. However, device components, including the nozzle/actuators, the pump assembly and diptube (Figure 1) also play a significant role. This study focuses on differences between specific device components within the nasal spray. The pump is responsible for metered delivery of the dose and thereby determines the shot weight of the product. The spray characteristics (spray pattern, droplet size distribution) of the nasal spray are influenced by formulation, as well as the device, especially the actuator (consisting of the nozzle orifice and swirl chamber). The movement of the liquid formulation inside the actuator forms a rotating cone by the combination of rotational and axial motion before exiting the spray orifice at high velocity (Figure 1). The present data focuses on the effect of different actuators by keeping the pump consistent across water and a drug formulation. Understanding the effects of actuator and formulation on spray pattern can have a significant impact on successful product development.
Delvadia, R. R., Wei, X., Longest, P. W., Venitz, J., & Byron, P. R. (2016). “In Vitro Tests for Aerosol Deposition. IV: Simulating Variations in Human Breath Profiles for Realistic DPI Testing.” Journal of Aerosol Medicine and Pulmonary Drug Delivery, 29(2), 196–206.
ABSTRACT: The amount of drug aerosol from an inhaler that can pass through an in vitro model of the mouth and throat (MT) during a realistic breath or inhalation flow rate vs. time profile (IP) is designated the total lung dose in vitro, or TLD in vitro. This article describes a clinical study that enabled us to recommend a general method of selecting IPs for use with powder inhalers of known airflow resistance (R) provided subjects followed written instructions either alone or in combination with formal training.
Chauhan, H., & Liao, L. (Lingzhi). (2019). “Spray pattern as a screening tool during early development of nasal sprays.” Inhalation, (June), 1–6.
ABSTRACT: Evaluation of device/formulation compatibility during early development is key to producing a successful nasal spray product. However, traditional tests (such as shot weight) may provide limited information by focusing mainly on spray pump performance. Further, droplet size distribution testing may fail to provide accurate measurements for certain formulations, such as those based on ethanol. In contrast, spray pattern and plume geometry can offer comprehensive insight into overall spray characteristics via flow visualization and are highly sensitive to changes in critical parameters such as device design and formulation. This article will focus on the influence of formulation viscosity on device selection and the ways spray pattern can be used as a screening tool to select an optimum device/formulation combination.
Liao, L., Chauhan, H., Newcomb, A., Liu-Cordero, S. N., & Leveille, C. (2017). “Spray pattern: A rapid and sensitive early development tool for respiratory drug products.” Inhalation, (October)
ABSTRACT: The study presented in this article was designed to examine spray pattern against changes in the sump design for pressurized metered dose inhaler (pMDI) products, specifically orifice diameter, orifice length and sump chamber depth parameters . These parameters were found, in a previous study, to have the most significant effects on spray performance. The results here corroborate the previous study’s findings and demonstrate how small variations in sump design, as well as variability introduced by other factors (canister, valve, formula-tion), drive significant changes in spray pattern area. Proveris Scientific’s SprayVIEW® measurement system can detect these small changes. This type of analysis gives valuable insight about various factors to control during the product development stage for both generic and new reference products.
Hatley, R. H. M., Parker, J., Pritchard, J. N., & von Hollen, D. (2017). “Variability in Delivered Dose from Pressurized Metered-Dose Inhaler Formulations Due to a Delay Between Shake and Fire.” Journal of Aerosol Medicine and Pulmonary Drug Delivery, 30(1), 71–79.
ABSTRACT: Pressurized metered-dose inhalers (pMDIs) should be shaken before use to prevent creaming or sedimentation of the drugs in solution; however, data published on this topic are limited, and it is rarely specified how soon after shaking the device should be actuated. Delays between shaking and firing the pMDI have previously been shown to cause significant inhomogeneity in delivered dose. We studied the effect of various shake-fire delays on the drug delivered from five commercially available pMDIs commonly prescribed for asthma and chronic obstructive pulmonary disease to assess the potential variability in delivered dose.
Farkas, Á., Lizal, F., Jedelsky, J., Elcner, J., Horváth, A., & Jicha, M. (2019). Simulation of Airway Deposition of an Aerosol Drug in Copd Patients. Pharmaceutics, 11(4), 1–10.
ABSTRACT: Medical aerosols are key elements of current chronic obstructive pulmonary disease (COPD) therapy. Therapeutic effects are conditioned by the delivery of the right amount of medication to the right place within the airways, that is, to the drug receptors. Deposition of the inhaled drugs is sensitive to the breathing pattern of the patients which is also connected with the patient’s disease severity. The objective of this work was to measure the realistic inhalation profiles of mild, moderate, and severe COPD patients, simulate the deposition patterns of Symbicort® Turbuhaler® dry powder drug and compare them to similar patterns of healthy control subjects. For this purpose, a stochastic airway deposition model has been applied. Our results revealed that the amount of drug depositing within the lungs correlated with the degree of disease severity. While drug deposition fraction in the lungs of mild COPD patients compared with that of healthy subjects (28% versus 31%), lung deposition fraction characteristic of severe COPD patients was lower by a factor of almost two (about 17%). Deposition fraction of moderate COPD patients was in-between (23%). This implies that for the same inhaler dosage severe COPD patients receive a significantly lower lung dose, although, they would need more.
Newcomb A., Liu-Cordero S., (2017). “What is quality by design and why should you care?” Proveris Scientific Whitepaper. Proveris Scientific Corporation.
ABSTRACT: Getting to market with an orally inhaled or nasal drug product is a difficult and complicated undertaking. Each product includes a miniature “machine” or medical device packaged with the formulation to create a complete drug-delivery system. The fact that each product is a complete delivery system rather than a simple dosage form adds more complexity at every stage of development. These complexities can result in longer approval times, multiple Food and Drug Administration (FDA) submissions, and more time responding to queries from the FDA2. Following a well-executed QbD approach helps to reduce the development complexity and get product to market more quickly.
Jed Wingrovea, Magda Swedrowskab, Regina Scherließc, Mark Parryd, Mervin Ramjeeawond, David Taylorb, Gregoire Gauthier , Louise Brown , Stephanie Amiel , Fernando Zelaya , Ben Forbes . Journal of Controlled Release Volume 302, 28 May 2019, Pages 140-147, https://doi.org/10.1016/j.jconrel.2019.03.032
a King’s College London, Institute of Psychiatry, Psychology & Neuroscience, London SE5 8AF, UK b King’s College London, Institute of Pharmaceutical Science, London SE1 9NH, UK
c Kiel University, Department of Pharmaceutics and Biopharmaceutics, 24118 Kiel, Germany
d Intertek-Melbourn, Melbourn SG8 6DN, UK
e Nemera, La Verpillière 38292, France
f Unilever R&D, Colworth Science Park, Sharnbrook, Bedford MK44 1LQ, UK
g Diabetes Research Group, King’s College London, King’s College Hospital Campus, Weston Education Central, London, UK
h Institute of Diabetes and Obesity, King’s Health Partners, London, UK
ABSTRACT: This study aimed to characterise three nasal drug delivery devices to evaluate their propensity to deliver human insulin solutions to the nasal cavity for redistribution to the central nervous system. Brain delivery was evaluated using functional magnetic resonance imaging to measure regional cerebral blood flow. Intranasal insulin administration has been hypothesised to exploit nose-to-brain pathways and deliver drug directly to the brain tissue whilst limiting systemic exposure. Three nasal pump-actuator configurations were compared for delivery of 400 IU/mL insulin solution by measuring droplet size distribution, plume geometry, spray pattern and in vitro deposition in a nasal cast. The device with optimal spray properties for nose to brain delivery (spray angle between 30° and 45°; droplet size between 20 and 50 μm) also favoured high posterior-superior deposition in the nasal cast and was utilised in a pharmacological magnetic resonance imaging study. Functional magnetic resonance imaging in healthy male volunteers showed statistically significant decreases in regional cerebral blood flow within areas dense in insulin receptors (bilateral amygdala) in response to intranasally administered insulin (160 IU) compared to saline (control). These changes correspond to the expected effects of insulin in the brain and were achieved using a simple nasal spray device and solution formulation. We recommend that a thorough characterisation of nasal delivery devices and qualitative/quantitative assessment of the administered dose is reported in all studies of nose to brain delivery so that responses can be evaluated with respect to posology and comparison between studies is facilitated.
Finlay, W., Farina, D.J., Tavernini S., and Martin, A.R., Department of Mechanical Engineering, University of AB, Edmonton, AB, Canada, 2 Proveris Scientific Corporation, Hudson, MA, United States. Frontiers in Drug Delivery, Respiratory Drug Delivery (May 2022). doi.org/10.3389/fddev.2022.901289
ABSTRACT: To date, in vitro estimation of doses delivered by an inhaler to the different major regions of the lung has required combining particle size measurements of the inhaled aerosol within silico deposition models. Such a two-step process is labor and time intensive. Here, we describe instead the development of an apparatus that allows direct estimation of regional lung deposition by measurement of doses collected on purpose-built metal grid filters that mimic tracheobronchial deposition efficiency. Placing these filters downstream of the Alberta Idealized Throat and upstream of a final filter allows collection of doses depositing in the extra thoracic, tracheobronchial, and alveolar regions. Artificial electrostatic deposition on the metal tracheobronchial filters is prevented by a custom inline electrostatic neutralizer. We use the resulting apparatus to estimate regional deposition with a variety of dry powder inhalers during realistic, time-varying inhalation maneuvers and three pMDIs with a constant flow rate of 30 l/min. These results are compared to those obtained with the traditional two step approach that combines cascade impaction with a regional deposition model. Good agreement is found between the two approaches, indicating that the present direct method may be an efficient, time-saving alternative method for in vitro estimation of regional lung doses.
Tavernini, S., Farina, D.J., Martin, A.R. et al. Using Filters to Estimate Regional Lung Deposition with Dry Powder Inhalers. Pharm Res 38, 1601–1613 (2021). doi.org/10.1007/s11095-021-03082-0
ABSTRACT: Purpose To develop an in vitro method to rapidly evaluate regional lung doses delivered by pharmaceutical inhalers. Currently, cascade impactor measurements are used, but these are resource intensive and require significant post processing of in vitro data to arrive at regional deposition
estimates. Methods We present a specialized filter apparatus that mimics tracheobronchial (TB) deposition of pharmaceutical aerosols emitted by commercially available dry powder inhalers (DPIs). The filter housing includes an electrostatic neutralizer to eliminate artificial electrostatic filtration effects. Regional deposition (tracheobronchial and alveolar) for four DPIs (Onbrez Breezhaler, Flovent Diskus, Pulmicort Turbuhaler, and Asmanex Twisthaler) was estimated using cascade impactor measurements and an in silico regional deposition model. These estimates were compared to direct measurements of regional deposition as provided by the TB filter mimic and an absolute filter placed downstream of the TB filter housing, representing the alveolar dose. Results The two methods were shown to provide similar estimates of extra thoracic, tracheobronchial, and alveolar deposition, as well as total recovery of active pharmaceutical ingredients.
CONCLUSION: Because of its design, the TB filter apparatus makes it possible to estimate regional deposition with inhalers directly using variable inhalation profiles without any additional equipment or changes to the experimental configuration. This method may be useful to expedite development of both innovative and generic drug products as it provides regional respiratory tract deposition estimates using fewer
resources than existing methods.
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