Poster presented at RDD Europe 2023 Conference; 2023 May 2 – 5, Antibes (Nice), France. 1Proveris® Scientific Corporation, Hudson MA USA, 2Koura, Thornton Science Park, Cheshire, UK
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Linda Liao1, Ameet Sule2, Ben Okorodudu1, Ian Flaherty1, Heli Chauhan1, Andrew Newman2, Sunita Sule2, Richard Turner2. Poster presented at Digital RDD 2020; 2020 April 26 – 30; Digital Conference.
1Proveris® Scientific Corporation, Hudson, Massachusetts, USA
2H&T Presspart, Blackburn, Lancashire, UK
BACKGROUND: For aerosol drug products, traditional in vitro methods often show little correlation with in vivo performance in clinical studies, which tend to be costly and time intensive. In 2012, US FDA started the Generic Drug User Fee Amendments (GDUFA) program, aiming to expedite the delivery of safe and effective generic drugs to the public and improve upon the predictability of the review process.1 In the interim, numerous product-specific guidances were released for orally inhaled and nasal drug products (OINDPs). In May 2019, FDA released a product-specific guidance for beclomethasone dipropionate delivered by MDI that proposed approaches using new, alternative in vitro characterization studies that were more representative and/or predictive of the clinical effect in the deep lung. Measurement of the evaporation rate of the aerosol is among the recommended alternative approaches.
Due to the mechanism of aerosolization of pMDI products, aerodynamic properties—such as evaporation rate—impact drug delivery and lung deposition. However, it is extremely difficult to capture the variable bulk mass of aerosols without interrupting the spray, and limited studies regarding the evaporation rate have been reported.
In this study, we extended the basics of the well-established SprayVIEW technique (which produces calibrated, time-synchronized image sequences of the entire aerosol spray and duration) with a novel measurement method to quantify the evaporation fraction (as a measure of the evaporation rate) from non-commercial pMDI product samples across 3 different ethanol concentrations.
Linda (Lingzhi) Liao, Karina Ramos, and Dino Farina. Poster presented at Drug Delivery to the Lungs 2019; 2019 Dec 11 – 13; Edinburgh, Scotland
BACKGROUND: The May 2019 FDA guidance document for beclomethasone dipropionate mentions, for the first time, an alternative approach to comparative clinical endpoint bioequivalence (BE) studies that includes characterization of the emitted aerosol spray velocity profiles (spray velocity). However, no description or details for how to perform such characterization studies were given. This paper describes a clear methodology for measuring the spray velocity and presents results from four (4) US approved inhalation products. The spray velocity has been reported as being closely related to effective pulmonary delivery, and hence would be an important parameter for drug-device combination products such as pMDIs and SMIs. 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.
D. Farina. Poster presented at AAPS Annual Meeting and Exposition 2008; 2008 Nov 16 – 20; Atlanta, GA.
INTRODUCTION: The purpose of this presentation is to describe the holistic Proveris by Design™[1] methodology for characterizing pMDI performance using quality by design (“QbD”) principles advocated by the FDA and industry [2][3][4], and to apply the methodology to a commercially representative product. A commercially available pMDI product was characterized using the patented Proveris by Design process. Results included measurements of the product’s Design Space based on manual actuation using male and female trained testers. The Control Space was determined from the Design Space measurements and the Operating Space was confirmed using metered spray weight measurements. The Plume Geometry performance of the product was determined using Proveris’s patented SprayVIEW® equipment running Viota® software.
BACKGROUND: The current FDA guidance documents related to in vitro testing of nasal spray and inhalation solution, suspension and spray drug products [5], recommends the use of automated actuation systems to perform the in vitro tests for these spray drug products and that settings for these systems should be relevant to proper usage of the product by trained patients. Furthermore, where actuation settings are not available from the pump supplier, the guidance document specifies that “settings should be documented based on exploratory studies in which the relevant parameters are varied to simulate in vitro performance upon hand actuation.” The Proveris by Design process presented here leverages this recommendation to significantly streamline product development efforts and simplify the transfer of development methods to the production arena.
Organizations that have followed the Proveris by Design process typically save 12-18 months of development time resulting in millions of dollars of cost savings, significantly reduce the risk associated with nasal and aerosol product development, all while improving the quality of regulatory submission packages (e.g. ANDA, NDA, IND) and promoting PAT and QbD principles now advocated by the FDA [2][3][4].
D. Farina, D., Z. Pitluk, S. Pallas. Poster presented at AAPS Annual Meeting and Exposition 2013; 2013 Nov 10 – 14; San Antonio, TX.
INTRODUCTION: The purpose of the study was to identify conditions where a stable spray pattern could be produced using pMDIs. We chose a QbD approach to determine the effects of shaking on spray pattern performance of a fluticasone/salmeterol MDI product and used the results to determine if an optimal shaking regime for the product exists within the product’s control space. Because there is no known spray pattern size associated with “good shaking”, a decrease in the variability of the spray patterns was used as the indication of a good shaking routine.
BACKGROUND: Determining and defining the proper shaking regime for suspension metered dose inhaler (“MDI”) products that allows the formulation to be properly mixed and deliver the correct dose is a difficult challenge for product developers. It is well known that the spray pattern areas will change as a device is fired through life if the device is not shaken properly or the canister/valve temperature is not allowed to recover (i.e. the device is not operating isothermally). The change in spray pattern area is a function of the ratio of the formulation to propellant which changes in an unshaken or non-isothermal device. In this study, we took advantage of Proveris’s automated shake and fire actuation technology for MDIs to explore a shaking control space for the product based on a Design of Experiments model. Identification of the proper shaking routine as evidenced by stable spray pattern areas through life would allow the application of the spray pattern test for fast screening of the correct formulation fill level.
Pitluk, Z., S. Pallas, J. Graaf, D. Farina. Poster presented at The Aerosol Society Conference, Drug Delivery to the Lungs 24; 2013 Dec 11 – 13; Edinburgh, Scotland.
INTRODUCTION: This paper presents a comparison of impaction and non-impaction spray pattern methods as recommended by the U.S. FDA in a recently published draft guidance describing in vitro tests for establishing bioequivalence (BE) of test and reference metered dose inhalers (MDIs) containing albuterol sulfate [1]. The spray pattern results for both methods were collected at 3 cm from the MDI actuator mouthpiece edge from albuterol sulfate MDI product samples using an automated actuation system with parameters derived from a previously conducted QbD-based usage study of trained testers within the product’s targeted patient population as recommended by the U.S. FDA [2]. The impaction and non-impaction measurements were collected using a fax paper method and the Proveris SprayVIEW® NMDI instrument respectively. Results include: 1) comparisons of spray pattern Dmin, Dmax, and Ovality (ratio of Dmax to Dmin) measurements for each method; 2) spray pattern area measurements for the non-impaction method according to FDA recommendations [1],[2]; and 3) high-speed laser illuminated videos of the aerosol plume impacting the fax paper surface. Qualitative images and the ovality ratio results confirmed that the methods produced similarly shaped spray patterns. However, the impaction method results showed significantly more variability, with smaller reported Dmin and Dmax values, than the non-impaction results. The high-speed laser illuminated videos showed a significant amount of particle bounce from the fax paper surface and the clear formation of the normally “free-jet” plume transforming into a “wall-jet” plume due to the surface’s presence – both consistent with the smaller reported spray pattern results.
Poster presented at Inhalation Asia Conference 2015.
INTRODUCTION: Few published sources exist to help guide pMDI formulation and device development that incorporate an understanding of the complex relationships driving product performance. Current analytical methods are complicated and labor intensive, and provide little insight into commonly occurring defects in pMDIs or their performance during development and release testing. The three new measurement technologies and analysis techniques described in this poster rapidly promote a knowledge-driven understanding of the complex relationships between the critical quality attributes and process variables that drive pMDI in vitro performance This paper will examine the following:
1. The importance of shaking;
2. The connection between DCU and spray pattern using predictive models; and
3. New technology for rapidly screening for actuator mold defects to aid in APSD testing.
Newcomb, A., D. Farina. Poster presented at The Aerosol Society Conference, Drug Delivery to the Lungs 26; 2015 Dec 9 – 11; Edinburgh, Scotland.
INTRODUCTION: This paper explores how a design of experiments (“DoE”) approach was employed to provide a foundational understanding of the effects of shaking on dose content uniformity (“DCU”) and spray pattern performance of commercially available albuterol pressurized metered dose inhaler (“pMDI”) products. The pMDIs tested were suspension formulations with different excipients that are all known to be sensitive to shaking based on their respective usage instructions for patients (i.e. the instructions only include language such as “…shake well before each use…”). The DoE focused on controlling and systematically varying the duration, angle, and frequency of shaking immediately prior to automated actuation and measuring the resultant DCU and spray pattern performance of the emitted aerosols. DCU was selected as an obvious output for in vitro performance based on accepted regulatory guidance documents. Specific optical spray pattern measurements were included in the DoE to see if such measurements could be correlated to the shaking conditions, and if so, how these measurements could be used to build an alternative model for efficient, high resolution, in vitro performance prediction for through life testing of pMDIs. The results indicate that the pMDIs tested have statistically significant differences in their performance sensitivities to shaking and that these differences should be explained to patients for optimal benefit.
