With a longer history of use, freeze-drying presents a plethora of fundamentally important research works on the mechanism behind cryo-stabilization and lyo-stabilization of proteins. In comparison, the literature on pharmaceutical protein spray-drying is only a few decades old.
While protein formulations are often transformed to solid-state by freeze-drying, one of the limitations is that it takes several days to convert the solution into a solid powder cake. In situations, where accelerated manufacturing and supply are needed (e.g. pandemic like COVID-19), the one-step transformation of liquid formulations to particles through atomization and rapid evaporation in spray-drying can offer an enormous advantage.
Spray-drying, an inherently continuous process, can adapt production capacity to product demand, allowing to dramatically reduce the lead time, effort and energy consumption of drug powder production, thereby resulting in both an economic and health benefit. Also, the process can be further advanced to be operated and controlled with minimal manual intervention. Freeze-drying, does not offer the same possibility, and being a multi-step batch process with inefficient and uneven heat and mass transfer, often raises concerns in terms of vial-to-vial variability and inhomogeneous quality of the dried products. To this end, the application of innovative process analytical technologies (PAT) in spray-drying, i.e. in-line monitoring of droplet size distribution, moisture content, particle size distribution, etc. can enable real time quality monitoring of the intermediate and final products, potentially avoiding large laboratory testing efforts. Also, continuous recording of process-related data using soft sensors for RH, temperature, pressure, viscosity, etc. can bring a great advantage. Besides analytical and hardware advancements, heat and mass transfer modeling of the spray-drying process using computational fluid dynamics (CFD), various drying kinetics and flow sheet engineering models are state-of-the art and their use holds a great potential for the further enhancement of the protein spray-drying field. Overall, the combination of PAT and mechanistic modeling can add a great incentive to widen the industrial implementation of protein pharmaceuticals via spray-drying.
Although relatively new to the pharmaceutical drying industry and limited in number of products approved, contemporary research suggests that the use of spray-drying is rapidly progressing. The main downfall of spray-drying tends to be the high processing temperatures/shear forces used, which certainly pose a risk, when processing thermolabile/shear sensitive biologics. When high drying temperatures can lead to degradation, the use of non-aqueous volatile solvents in the feed solution could provide an opportunity to significantly reduce the drying time and temperature and thus, avoid product degradation.
Also, in the case of oxidation sensitive products, the use of an inert gas is possible and can avoid any detrimental effects caused by the use of air. One of the recurring concerns regarding spray-dried formulations is that the moisture content of the final product is slightly higher than the one typically achieved through freeze-drying. Thus, further secondary drying via vacuum dehydration might be necessary. The impact of secondary drying to the formulation microstructure, mechanical relaxation of the powders and protein integrity and eventual reconstitution behavior is important to understand and deserves a thorough scientific investigation in future. Given that sufficient scientific bases and a rational workflow for the rapid design, optimization and production of protein drug products are established, spray-drying opens up the possibility to tighter process control (employing PAT) and offers a wider array of opportunities in terms of particle and powder engineering.
One of the immense challenges, when applying spray-drying to the production of sterile protein product manufacturing, is establishing and maintaining an aseptic operation. While limited number of spray-drying companies and contract manufacturers offer nowadays the technology and services for aseptic spray-drying, its wider adoption for diverse parenteral manufacturing is prohibitively expensive. In this context, the development of a partially sterile spray-drying process could be a viable alternative. In this, processing would be executed under conditions that could guarantee low bioburden of the final product. Under conditions, which are not fully aseptic, yet provide dosage forms that meet the desired quality criteria, the aforementioned could provide an overall high benefit-to-cost ratio, when manufacturing sterile protein drug products.
Downstream processing of spray-dried powders intended for reconstitution include: handling, transport, and metering into vials, followed by stoppering. Automated powder filling into vials is based on a wide variety of principles dependent upon the filling machine types, i.e. dosator nozzle-based, tamp, pneumatic, vacuum, etc. Design, development and application of an optimized vial filling process are critical steps for mitigating the variability of product quality namely, fill weight variability, agglomeration, moisture content, re-dispersity, and stability. Dry powder filling is a complex process and the filling dose accuracy depends upon the rational selection of filling principle and process parameters with respect to the specific powder properties such as bulk density, flowability, stickiness, electrostatics, etc. Also types of vials, siliconized versus normal ones, and their surface properties can impact of powder emptying or wetting during reconstitution and thus, require a due research. While pharmaceutical protein spray-drying literature is emerging rapidly, surprisingly, there is a scarcity of studies dealing with the automated vial filling of these products. This could be due to the limited availability of small-scale filling devices. Thus, the success of spray-drying in biopharmaceutical industries will need an integrated mindset where a holistic approach to both spray-drying and filling is adopted.
The fundamental knowledge concerning the formulation principles behind the development of spray-dried protein biopharmaceuticals are far behind the ones available for freeze-dried products. While the mechanism of cryo-protection and lyo-protection of protein structure during freeze-drying by some common sugar and amino acid excipients are recently unraveled to some extent, similar mechanistic studies encompassing the spray-drying stress (higher temperature, increase interfacial area of droplets, and shear forces) are largely missing. Very recent studies using (levitated or sessile) single droplets of some food and pharmaceutical proteins, present encouraging results on particle morphology formation and drying/diffusion kinetics. Further availability of such data from a wide range of protein and excipient types will build the foundation for developing universal mechanisms that can potentially help deriving spray-drying models that are truly predictive of product quality.
Every step in the spray-drying process of proteins needs precise understanding, optimization and control to prevent the loss of activity in the final product. The extent to which the different steps contribute to the (in)stability of the protein may significantly differ for different process equipment and processing conditions as well as protein formulation types and involved excipients. For spray-drying of a defined formulation of a particular protein, considerations about manufacture can be split into equipment and process-related factors.
Original article: Joana T. Pinto, Eva Faulhammer, Johanna Dieplinger, Michael Dekner, Christian Makert, Marco Nieder & Amrit Paudel(2021)Progress in spray-drying of protein pharmaceuticals: Literature analysis of trends in formulation and process attributes,Drying Technology,39:11,1415-1446,DOI: 10.1080/07373937.2021.1903032