Removal of water through drying provides numerous benefits in addition to improved stability, including ease of handling/storage and reduction in transportation costs. These factors are critical in products for which:
Bulk drug substance (DS) is not converted into drug product (DP) immediately.
Formulation/fill-finish activities and DS manufacture take place at different sites.
Currently, these challenges are being met by freezing the bulk DS, however this necessitates implementing a robust system (i.e., facility, equipment, validation, etc.) for maintaining the integrity and stability of the DS at low temperature during storage and transport. All drying techniques share a common objective (i.e., removal of water), however conceptually they are different and may require modifications based on the properties of the compound. The need to preserve high product quality of labile molecules and maintain aseptic processing has limited the number of process technology employed in the pharmaceutical industry.
Lyophilization is the most widely acceptable technique for improving the stability of pharmaceutical compounds and several commercially approved products are available. As such, lyophilization represents the gold standard to which alternative drying methods must be compared.
Spray Drying vs Freeze Drying
The spray drying process is conceptually simple; a solution is fed through an atomizer to create a spray, which is exposed to a heated gas stream to promote rapid evaporation. When sufficient liquid mass has evaporated, the remaining solid material in the droplet forms particles which are then separated from the gas stream using a filter or a cyclone. Particle formation time is a function of the initial liquid droplet size, the composition of the droplet, and evaporation rate. The rate of particle formation is a key parameter that dictates the required residence time and hence the scale of equipment and processing parameters required to produce the desired particle size at the target production rate.
In addition to its ability to control powder properties, the key advantages of spray drying compared to conventional freeze-drying include:
Shorter process cycle time
Scalability
The ability to process at atmospheric pressure
Similar to lyophilization, protein denaturation has been reported during spray drying due to desiccation- and surface-associated stresses, often necessitating the use of excipients for stabilization. Even though the drying gas temperature may exceed 100℃ in a typical spray drying condition, thermal denaturation of proteins is commonly not observed, mainly because the temperature of the droplet barely exceeds the wet bulb temperature of water (～40℃). Additionally, the protein denaturation temperature is a function of water content, increasing sharply with decreasing water content. Although one must keep in consideration the risk of prolonged particle exposure to drying gas in the collector vessel, dry proteins are relatively stable, demonstrating denaturation temperatures typically exceeding 100℃.
Besides drying of proteins, spray drying has been utilized to successfully prepare a number of dry vaccines, including measles vaccine and tuberculosis vaccine. Spray drying represents the most mature alternative drying technology to lyophilization. The process provides an opportunity to engineer particle size and shape, which can enable delivery methods that are infeasible using other drying techniques. Spray drying can also be accomplished more quickly than lyophilization in most cases. It allows for the processing of material under atmospheric pressure, offering energy savings.
Spray drying does come with some unique caveats. Aseptic processing for spray drying is more challenging than it is for lyophilization. Additionally, a secondary drying method may be required if very low residual water content is desired in the final product, which may reduce the time and energy savings for spray drying as compared to lyophilization. Furthermore, there may be difficulties associated with handling hygroscopic and/or electrostatically charged powders. The fact that material recovery is <100% is also an issue when considering its implementation for high-cost therapeutics. Still, proper process design can overcome many of these limitations, highlighting the great potential of spray drying as an alternative to lyophilization that may enable continuous manufacturing.
Aseptic spray dryer is still in the early stage of implementation but robust steps have recently been undertaken in the design of these units as well as in aseptic powder filling, a complementing unit operation. Another area of potential growth is the use of spray drying to produce inhalable drugs; one of the major drawbacks associated with conventional lactose blends is the need to balance adhesive-cohesive forces between the drug and the carrier, with a significant amount of drug not detaching from the lactose and being inevitably deposited in the mouth/throat; spray drying can be used to overcome this challenge by enabling the preparation of composite particles where, via a precise fine-tuning of particle size distribution during development.