(T1330-08-44) Feasibility of Spray Drying Biotherapeutics: A Material Sparing Screening Process

Purpose: Spray drying is an appealing process for generating powdered drug product intermediates of biotherapeutic actives as the resultant product does not require special handling or low temperature storage. This is of particular interest for inhaled delivery via dry powder inhalers to improve patient compliance and reduce cost by eliminating the need for in-person intravenous injections. However, the process itself poses a risk to these molecules due to their inherent sensitivity to shear and air-liquid interfaces, temperature, and solution environment. Understanding these relative risks before conducting an initial spray of a material is desirable. As such, this work aimed to develop a material-sparing screening procedure to determine whether a given biotherapeutic active is a candidate for spray drying and if-so, guide selection of the subsequent manufacturing conditions.

Methods: Bevacizumab, Nivolumab, and Prembrolizumab were used as model actives to develop the screening procedure. Dialysis was performed using Slide-A-Lyzer dialysis cassettes to remove any surfactants present in the as-received solutions and generate a mock-spray solution consisting of approximately 1:1 active:trehalose in a 1mM buffer. These alongside the as-received protein solutions were then subjected to stresses mimicking the spray drying environment. Solutions are monitored over time at various temperatures (at or below the unfolding temperature, as determined from multicell dynamic scanning calorimetry) to assess thermal degradation kinetics. To simulate the shear and air-liquid interfacial stresses of the atomization process, a countertop setup of a pump and atomization nozzle was used. This set-up can be broken down into 3 unique steps, individually assessing the risk from the pump and tubing material, exposure to the metal of the nozzle, and finally the full atomization. Analysis of stressed samples was performed by size exclusion chromatography, dynamic light scattering, and ELISA activity assays.

Results: Aggregation was shown to be the dominant structural change for the model actives for both thermal and shear stresses applied, but differences in the relative sensitivities are distinguished, illustrating its versatility in understanding risks for individual compounds. For example, of the three model actives Nivolumab was the most sensitive to atomization, but the most thermally stable with no observed aggregation even after 1 hour at 60°C. Bevacizumab was selected for manufacture by spray drying, with outlet temperature selection guided by this screening process, resulting in the generation of a spray dried powder with no impact to its bioactivity.

Conclusion: A material-sparing screening procedure, which uses only ~5-10mL of protein solution, has been developed as a means of assessing spray drying feasibility. Implementation of this flow chart can help determine whether a given biotherapeutic is a candidate for spray drying and if-so, help determine the subsequent manufacturing conditions and establish an early baseline between performance and observed structural changes that could be helpful for guiding future specifications of product quality.

References: Shepard, K.B., Vodak, D.T., Kuehl, P.J. et al. Local Treatment of Non-small Cell Lung Cancer with a Spray-Dried Bevacizumab Formulation. AAPS PharmSciTech 22, 230 (2021). https://doi.org/10.1208/s12249-021-02095-7

SEC and DLS results from the shear stress test for the three model actives.



Illustration of the bench top atomization set up, and the three individual stages of atomization that can be studied independently.



Thermal degradation kinetics at 60°C as monitored by SEC for the three model actives