(W1030-02-13) Spray-Drying of Peptides: From Small to Clinical Scale

Purpose: Spray-drying is a widely applied drying technique for bioactive peptides, offering an effective means to improve their stability, control release profiles and perform taste masking. Although peptides are known to have a thermosensitive nature, spray-drying is particularly advantageous as it enables rapid solvent evaporation with minimal thermal degradation. Furthermore, it serves as a powerful particle engineering tool, allowing precise control over particle size, morphology, and surface properties — key attributes that influence dissolution behaviour, flowability, and downstream processing of powders. Additional benefits of this technique include scalability, cost-effectiveness, continuous operation, and compatibility with a wide range of formulation components. As such, spray-drying has gained significant interest in the development of (oral) peptide formulations. As the market of peptides is increasing significantly (driven by the successful Ozempic®), there arises the need to develop processes with high throughput without compromise the stability of the peptide. At industrial scales, this can be an issue due to the high temperatures at which peptides are exposed, by increased residence times in the spray drier (due to a more turbulent flow) and no control of product temperature. During this study, pure peptide solutions were evaluated regarding scalability, and impact on its stability and product properties was assessed.

Methods: a. Spray drying An aqueous solution of peptide A (66.5 kDa) was used for the spray drying (SD) trials. SD was executed on the Procept 4M8-TriX and SDxL spray dryers equipped with a large cyclone and ultrasonic nozzle (25 kHz). Process parameters can be found in Fig. 1. b. Analyses i. Powder properties Particle size distribution and shape/morphology were evaluated via dry powder laser diffraction (RODOS-HELOS, Sympatec) and scanning electron microscopy (SEM, Phenom Pro Suite, Phenom), respectively. Bulk density was determined with a graduated cylinder and residual water content (RWC) was measured via Karl Fischer titration (V10S Compact Volumetric, Mettler-Toledo). ii. Stability Peptide assay was evaluated via UPLC, after dissolving the spray-dried samples in PBS buffer.

Results: Preliminary evaluation (data not shown) showed that a feasible and efficient spray drying process of peptide A (yield > 80% and relatively high spray rate of 7.5 g/min) could be obtained with the Procept 4M8-TriX spray drier. Obtained powders showed good flowability, with a D50 of ± 50 µm and a RWC ≤ 5%. In order to define the critical process parameters and the process window that can affect process and product quality, a design of experiments (DoE) was performed (Fig. 1). During the DoE, solid load and inlet temperature (T_in) and airflow were evaluated for the impact on outlet temperature (T_out), yield, RWC and particle size. A first evaluation of the results show that T_out < 90 °C were only obtained at low inlet temperature and airflow (tests 001 and 005). For these, the highest RWC was also obtained, which remained below 7% (generally accepted as good target for biologics). Morphology was evaluated via SEM and, regardless used process parameters, a mixture of wrinkled and dimpled particles was obtained (Fig. 2). Good models were obtained to describe variations of T_out and RWC. For yield and particle size no good model was obtained, likely due to the limited variations observed. Coefficient plot (Fig. 3) shows that inlet airflow and temperature had the highest impact on the T_out and RWC, but with opposite effects: positive for T_out and negative for RWC. As inlet temperature has a high coefficient, this parameter should be adapted during industrial productions to target T_out. Based on these results, the Procept SDxL equipment was evaluated to increase in the throughput in 5-fold, while targeting a similar process and product attributes. Similar T_out as for test 001 was targeted by adjusting T_in, for which a high recovery of 88% was obtained. Moreover, similar D50 and RWC were also obtained (Fig. 1 and Fig. 2). The purity of the final product was evaluated and found to of 98.68%, confirming that no degradation occurred during spray drying at large scale. The Procept spray drier works with a laminar airflow (avoiding the dried particles coming in contact with the hot airstream), and the injection of the additional cyclone cooled gas (enabling control of product temperature during processing), which are favorable for the processing of peptides and other biologic materials.

Conclusion: This study demonstrated that the spray drying process of a peptide could be scaled 5 times from a Procept 4M8Trix equipment to the Procept SDxL, without compromising peptide stability. The identification of the critical process parameters resulted in a fast scale-up without spending too much material and controlling the important quality attributes of the peptide, without addition of excipients.


Fig. 1: Spray drying process parameters


Fig. 2: SEM images


Fig. 3: Coefficient plot for outlet temperature (top) and residual water content (bottom)