(M1330-06-32) Reducing Environmental Bias in Measurements of Plume Geometry for Pressurized Metered-Dose Inhalers (pMDIs)

Purpose: Plume geometry (PG) data is required to demonstrate in vitro bioequivalence for generic drug approval and is collected to characterize pMDIs through the development cycle [1, 2]. There has been debate regarding the value of PG reflecting observations of high intra-product variability, poor correlations to product critical quality attributes (CQAs) and perceived analyst subjectivity [3]. At the same time, it has been recognized for decades that the aerosol performance of pMDIs is impacted by changes in temperature (Temp) and relative humidity (RH) [4-7]; accordingly, suitable environmental controls are often implemented prior to routine quality control (QC) testing of pMDIs. The primary objective of this study is to investigate whether changes in RH at a specified temperature impact PG measurements for a series of commercially-available pMDIs with a secondary goal of quantifying the impact of any bias observed.

Methods: Single lots of six 120 actuation products: two HFA134a fluticasone propionate suspension formulations (Flovent^® HFA, 110 / 220 mcg), two HFA134a beclomethasone dipropionate solution formulations (QVAR^® RediHaler^TM, 40 / 80 mcg) and two HFA227ea budesonide and formoterol fumarate dihydrate suspension formulations (Symbicort^®, 80/4.5 and 160/4.5 mcg) were tested using a SprayVIEW^® system (Proveris Scientific, Hudson, Massachusetts, U.S.) located within a Temp- and RH-controlled laboratory. Actuators supplied with each product were used with the devices held securely by relevant holders sourced from Proveris Scientific. PG measurements were collected in four runs of Temp and RH conditions: Lo/Hi, Lo/Lo, Hi/Lo, and Hi/Hi. For each product, three devices with three replicates per device were collected at each condition for a total of 216 measurements. Testing parameters for each product type were independently determined. Using a Vereo^® SFMDx actuator (Proveris Scientific), each device was characterized and primed per package insert prior to initial collections. All products were re-primed prior to subsequent runs. Rotary shaking at 90° was utilized only for products requiring shaking. PG angle and width measurements were processed using Proveris software with data analysis using JMP software (SAS Institute Inc., v15.2).

Results: Environmental Temp and RH data with average conditions recorded per product run are shown in Table 1. Control of Temp was generally better than RH both in achieving the targeted setpoint and in minimizing variation. RH control, especially at the low level, was partially dependent on the weather. Runs 2 and 3 were collected within a short timeframe with similar weather conditions, leading to RH values that are comparable. Conversely, differences in weather from runs 1 to 4 led to a ~3.5% difference in the achieved RHs. PG angle data for each of the four product runs are shown in Figure 1 with tabulated data shown in Table 2. PG width was observed to be highly correlated to angle; consequently, width data has been excluded with overall conclusions expected to apply equally across both measurements. To quantify the magnitude of observed biases, the percent difference for each PG angle relative to the high RH was normalized to the average RH range experienced by each product leading to results for each Temp expressed as a percent change per RH unit. Both strengths of the Flovent and QVAR products showed a statistically significant reduction in PG angle as RH decreased with impact ranging from -0.12 to -0.49 percent change in angle per RH unit. High strength Symbicort was insensitive to changes in RH at the low Temp, whereas, the high strength/high Temp and the low strength/both Temps showed statistically significant increases in plume angle of about 0.09 to 0.17 percent change per RH unit with a trend opposing that observed for the HFA-134a products.

Conclusion: Measurements of PG angle across six commercially available pMDI products have been shown to be sensitive to changes in RH for 11 of the 12 product/Temp combinations studied. RH changes of 10 units (e.g., a change from 40% to 50% RH) can introduce a 5% bias to plume angle results in the most sensitive products. This environmentally-induced bias is likely one factor that has contributed to the high intra-product variability observed historically for this characterization technique. Temp is better controlled than RH in most QC labs with the latter often changing with the weather. There are several resulting opportunities from this study: 1) understand product sensitivity to environmental factors during method development; 2) implement appropriate environmental controls and monitoring in testing labs; 3) re-assess whether correlations between PG measures and other CQAs can be made.

References: [1] FDA Draft Guidance (2018): Guidance for Industry (Draft). Metered dose inhaler (MDI) and Dry Powder Inhaler (DPI) Products – Quality Considerations.
[2] FDA Product Specific Draft Guidance for Fluticasone Propionate MDI (2018).
[3] Baxter S, Parkinson A, Myatt B, Sinha B, Doub B, De S, Chambers F, Kraaij M, Fischer M, Grmas J, Nagao L: Spray Pattern Testing Relevance and Methodology: An IPAC-RS Survey. In Respiratory Drug Delivery Europe. Volume 2, 2019: 321-326.
[4] Garner S, Wiest D, Bradley J: Albuterol Delivery by Metered-Dose Inhaler with a Pediatric Mechanical Ventilatory Circuit Model. Pharmacotherapy 1994, 14: 210–214.
[5] Diot P, Morra L, Smaldone G: Albuterol delivery in a model of mechanical ventilation. Am. J. Respir. Crit. Care Med. 1995, 152: 1391–1394.
[6] Lange C, Finlay W: Overcoming the Adverse Effect of Humidity in Aerosol Delivery via Pressurized Metered-Dose Inhalers during Mechanical Ventilation. Am J Respir Crit Care Med 2000, 161: 1614–1618.
[7] Shemirani F, Hoe S, Lewis D, Church T, Vehring R, Finlay W: In Vitro Investigation of the Effect of Ambient Humidity on Regional Delivered Dose with Solution and Suspension MDIs. Journal of Aerosol Medicine and Pulmonary Drug Delivery Aug 2013, 215-222.


Figure 1: Plume Geometry Angle Data Visualized by Drug, Strength and Run


Table 1: Average Environmental Conditions for Each Product Run


Table 2: Plume Geometry Angle Data Showing Relative Humidity Impact While Holding Temperature Constant