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
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
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
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
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
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
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.
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 Our comments are intended solely to help clarify the issues discussed in the FDA draft guidance document and to hopefully improve the interpretation and understanding of the FDA’s new requirements.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 . 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.
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)
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.
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.
Newcomb A., Liu-Cordero S., (2017). “What is quality by design and why should you care?” Proveris Scientific Whitepaper. Proveris Scientific Corporation.
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
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
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.