Spray Drying of Monoclonal Antibodies for Subcutaneous Injection: Models and Pitfalls

INTRODUCTION Even though considerable research has been devoted to the drying of monoclonal antibodies (mAbs) and other pharmaceutical proteins, the majority of this research has focused on lyophilisation or spray drying (SD) for inhalation. Powders for reconstitution and subcutaneous (SC) injection need to comply with a significantly different set of product characteristics than those for inhalation. Therefore, following a formulation screening, the impact of spray drying process parameters on both powder characteristics and short- and long-term stability was determined for a model mAb formulation, using a design of experiments (DoE) approach that combined statistical tools with a set of orthogonal analytical techniques. MATERIALS AND METHODS The mAb formulation was spray dried using a ProCepT Micro-Spray with inlet air flow rate, inlet air temperature, nozzle air flow rate, feed rate, feed concentration and nozzle diameter as factors which were varied at three levels according to a D-optimal design. The following responses were measured and evaluated for this study: Yield, angle of repose, residual water content (Karl Fischer titration), reconstitution time, particle size distribution (laser diffraction), particle morphology (SEM), solid state characterisation (XRPD and DSC), aggregation (SEC, DLS, OD600). RESULTS Descriptive statistical models were obtained for several responses, suggesting the inlet air flow rate to be one of the overall most influential process parameters. Large variations in particle morphology were observed with SEM, revealing that particle size distribution models, although statistically significant, were not representative for any relevant powder property. Additionally, the location of powder collection, i.e. collector/cyclone versus transport tube, had a noticeable influence on the particle size distribution of the spray dried powders. CONCLUSIONS Descriptive models were generated for a model mAb, which could prove to be useful tools in improving our understanding of process parameter influences on the mAb stability and particle characteristics of powders for reconstitution. The presented data also emphasises the importance of using orthogonal techniques and keeping the physicochemical meaning of responses in mind when designing a (bio)pharmaceutical drying process.status: publishe