(M1030-07-44) Engineering of Thin-Film Freeze-Dried Monoclonal Antibody Powders with Enhanced Flow Properties for Vacuum Drum Filling into UniDose Nasal Spray System

Purpose: Respiratory viruses primarily infect via nasal epithelium, making this administration route ideal for both prophylactic and therapeutic intervention [1,2]. While monoclonal antibodies (mAbs) have been shown to effectively neutralize respiratory viruses, conventional parenteral administration results in insufficient mAb concentrations within the nasal mucosa [3–5], where viral entry and early replication occur, thereby limiting efficacy. Previous studies demonstrated that thin-film freeze-drying (TFFD) can be used to transform aqueous mAb solutions into dried films [6–8] that can be delivered to the posterior nasal cavity using Aptar UniDose powder (UDSp) nasal spray system [7]. However, TFFD films exhibit poor flowability and high hygroscopicity, making them challenging to handle and process in automated powder filling systems. The purpose of this study is to modify the TFFD mAb films to improve their flow properties for improved handling and vacuum drum filling while maintaining their performance for nasal delivery.

Methods: TFFD was used to prepare nine formulations containing fixed ratios of AUG3387 mAb, mannitol, and leucine (15:80:5, w/w) with varying concentrations of magnesium stearate (MgSt) and hydroxypropyl methylcellulose (HPMC). Powders were micronized in sealed vials using a mixer-mill. Flow properties (e.g., Hausner ratio (HR), Carr's index (CI), Angle of Repose (AOR)) were characterized before and after the powders were exposed to controlled high relative humidity (RH = 60%) to identify powders that have desirable flow properties and can best maintain them during handling. A Harro Höfliger Drum TT benchtop filler was used under controlled conditions ( < 20°C, < 20% RH) to fill a selected AUG3387 mAb powder into UDSp system at target weights of 0.5 mg and 1.0 mg, with manually filled UDSp systems serving as a control. Drum filling performance was evaluated for mass uniformity. Spray performance was evaluated by measuring emitted plume geometry, spray pattern, particle size distribution, shot weight, and regional nasal deposition in a 3D-printed nasal cast model with a constant flow (10 L/min).

Results: F8 TFFD AUG3387 mAb powder containing 1% MgSt and 1% HPMC was selected for drum filling due to its desirable flow properties after controlled humidity exposure (12.8% change in CI and 4.7% in HR versus 44.3% and 19.0%, respectively for unmodified control powder). The F8 mAb powder was successfully filled into UDSp systems using drum filling at both 0.5 and 1.0 mg target weights without any signs of cavitation, powder bridging, or ejection failures. As shown in Table 1, acceptable weight uniformity (overall means of 0.54 ± 0.09 mg and 1.11 ± 0.08 mg for 0.5 mg and 1.0 mg targets, respectively), particularly during steady-state operation with middle fills achieving improved fill uniformity (RSDs of 6.0% for 0.5 mg fills and 4.1% for 1.0 fills) with all weights within ±15% of target values. Lastly, nasal deposition (Figure 1) of emitted F8 TFFD AUG3387 mAb powder demonstrated generally similar regional distribution profiles between drum- and hand-filled UDSp systems, with drum filled systems achieving 50.3 to 51.5% of emitted dose deposited in the posterior nasal cavity (sum of % of emitted dose in the upper/middle/lower turbinate and nasopharynx regions) and 55.8 to 62.9% of emitted dose for hand-filled ones, with some variation in vestibule deposition. A two-way ANOVA showed no significant effect of fill weight (p-value 0.37) and no significant interaction between fill method and fill weight (p-value 0.22).

Conclusion: This work demonstrates the successful development of a TFFD mAb powder with improved flow properties through the addition of 1% MgSt and 1% HPMC. This optimized formulation enabled successful vacuum drum filling of TFFD mAb powders into UDSp nasal spray systems with acceptable fill weight uniformity, particularly at the 1.0 mg fill weight. Importantly, both drum-filled and hand-filled UDSp systems achieved high percentage of emitted dose deposition in the posterior nasal cavity and the effect of filling method (drum vs. hand) did not significantly change based on fill weight. These findings help bridge the gap between benchtop proof-of-concept and commercial manufacturing, establishing that TFFD mAb powders can be successfully integrated into industry-friendly manufacturing equipment without compromising the unique advantages of this powder engineering technology platform for respiratory drug delivery.

References: 1. Chen, M.; Pekosz, A.; Villano, J.S.; Shen, W.; Zhou, R.; Kulaga, H.; Li, Z.; Smith, A.; Gurung, A.; Beck, S.E.; et al. Evolution of Nasal and Olfactory Infection Characteristics of SARS-CoV-2 Variants. J Clin Invest 2024, 134, doi:10.1172/JCI174439.
2. Cilloniz, C.; Torres, A.; Luna, C.M.; Hurtado, J.C.; Marcos, M.Á. Respiratory Viruses: Their Importance and Lessons Learned from COVID-19. European Respiratory Review 2022, 31, 220051, doi:10.1183/16000617.0051-2022.
3. DeFrancesco, L. COVID-19 Antibodies on Trial. Nat Biotechnol 2020, 38, 1242, doi:10.1038/S41587-020-0732-8.
4. Ku, Z.; Xie, X.; Hinton, P.R.; Liu, X.; Ye, X.; Muruato, A.E.; Ng, D.C.; Biswas, S.; Zou, J.; Liu, Y.; et al. Nasal Delivery of an IgM Offers Broad Protection from SARS-CoV-2 Variants. Nature 2021 595:7869 2021, 595, 718–723, doi:10.1038/s41586-021-03673-2.
5. Kip, K.E.; McCreary, E.K.; Collins, K.; Minnier, T.E.; Snyder, G.M.; Garrard, W.; McKibben, J.C.; Yealy, D.M.; Seymour, C.W.; Huang, D.T.; et al. Evolving Real-World Effectiveness of Monoclonal Antibodies for Treatment of COVID-19: A Cohort Study. Ann Intern Med 2023, 176, M22-1286, doi:10.7326/M22-1286.
6. Xu, H.; Sahakijpijarn, S.; Moon, C.; Emig, C.J.; Mena, M.; Henry, S.J.; Vitug, A.; Ventura, C.J.; Kuehl, P.J.; Revelli, D.; et al. Inhalable Dry Powders of a Monoclonal Antibody against SARS-CoV-2 Virus Made by Thin-Film Freeze-Drying. Int J Pharm 2024, 662, 124511, doi:10.1016/J.IJPHARM.2024.124511.
7. Yu, Y.S.; Xu, H.; AboulFotouh, K.; Williams, G.; Suman, J.; Sahakijpijarn, S.; Cano, C.; Warnken, Z.N.; Wu, K.C.W.; Williams, R.O.; et al. Intranasal Delivery of Thin-Film Freeze-Dried Monoclonal Antibodies Using a Powder Nasal Spray System. Int J Pharm 2024, 653, doi:10.1016/J.IJPHARM.2024.123892.
8. Hufnagel, S.; Xu, H.; Sahakijpijarn, S.; Moon, C.; Chow, L.Q.M.; Williams, R.O.; Cui, Z. Dry Powders for Inhalation Containing Monoclonal Antibodies Made by Thin-Film Freeze-Drying. Int J Pharm 2022, 618, doi:10.1016/J.IJPHARM.2022.121637.

Acknowledgements: The AUG-3387 mAb and the UDSp nasal spray systems were generously provided by TFF Pharmaceuticals, Inc. and Aptar Pharma, respectively. This research was supported in part by Catalent Pharma Solutions, Inc.


Table 1. Mass uniformity of TFFD AUG3387 mAb powder in UniDose® powder cartridges using Drum TT at both 0.5 mg and 1.0 mg target fill weights. (N = 15 cartridges total)


Figure 1. Total deposition (as % of emitted dose) of F8 TFFD AUG3387 mAb emitted from drum-filled and hand-filled UDSp systems (0.5 mg and 1.0 mg) in the posterior nasal cavity region in a 3D-printed nasal cast pre-coated with a simulated nasal fluid. Data presented is mean ± SD (n = 3).