The processing technology that has been characterized the most extensively to convert biologics into respirable powders is spray drying. Spray drying is a high temperature drying technology, and so one may not think it would be amenable to processing of biologics. However, evaporative cooling at the droplet surface leads to lower thermal exposure (e.g., to ~40°C) and the very short contact times in the drying chamber (on the order of seconds) means that this process may be acceptable for most biologics. Degradation of biologics can be avoided via formulation and process optimization [4-8].
These processing technologies impart unique stresses to the biologic molecules; therefore, the formulation strategy should be individualized to each biologic. Not surprisingly, the choice of excipients will differ for spray freeze drying and lyophilization where excipients provide protection against freezing stress (cryoprotectants), while for spray drying the excipients are chosen to stabilize against heat degradation and/or gas-liquid interfacial stress. Table 1 summarizes the key differences between the various solid-state production processes.
Figure 1: Typical product temperature profiles for the three drying technologies
Lyophilization followed by milling
In lyophilization, vials filled with the sterile-filtered solution are transferred to stainless steel trays for lyophilization. The general process steps in lyophilization are as follows:
1. Freezing – the temperature is lowered at a specific rate to a desired setpoint depending on the formulation properties and stored for a specified time.
2. Annealing – this is an optional step but is sometimes applied to achieve homogenization of the frozen solution with respect to crystal and pore distribution.
3. Primary Drying – the temperature is increased to the desired drying temperature under a reduced pressure, whereby the ice sublimates. Most of the water (80-90%) in the pores is removed during this drying period.
4. Secondary Drying –water is removed that is more tightly bound or situated deeper in the cake by increasing both the pressure and the temperature (to approximately 20°C).
The lyophilized cake then needs to be milled to achieve fine respirable particles. Milling can be carried out using various techniques (e.g., jet milling, cryo milling [9]). The milling process exposes the biologic to thermal perturbations and mechanically stress, both of which can degrade the biologic and result in crystallization of amorphous components (e.g., mannitol) that can reduce their functionality with respect to dispersion and stability.
Figure 2: Operating temperatures and pressures for the three drying technologies adapted from [13]
Thin Film Freeze Drying (TFFD)
The TFFD technology has been developed to overcome both the long drying time of lyophilization and the requirement for milling to generate the respirable particles (Figure 3). The TFFD process steps are:
1. Freezing – Millimeter-sized droplets are dropped onto the surface of cryogenically cooled stainless steel drum, whereby the liquid spreads into a thin film and is simultaneously frozen. The film is removed from the drum surface by a scraper and recovered in a bath of liquid nitrogen. The powder matrix is typically composed of both micro- and nano-particles.
2. Removal of Nitrogen – The collected suspension is transferred to a -80°C freezer to evaporate the excess nitrogen.
3. Freeze Drying – The frozen film of droplets is dried until the target residual moisture is reached.
The resulting powder is highly porous having a low density and high surface area. Upon dispersion, the powder easily breaks up into respirable-sized particles suitable for pulmonary delivery.
TFFD generates very high powder surface areas of 50-150 m2/g, which may be challenging with respect to controlling water uptake/hygroscopicity and mechanical stability. Scalability and commercialization have yet to be demonstrated. Several small molecule and biopharmaceuticals have been conceptually produced using the technology [2,3].
Figure 3. Illustration of Thin Film Freeze Drying from [3]
Spray Freeze Drying
Spray freeze drying combines elements of spray drying with freeze-drying. The process consists of two main steps as follows:
1. Droplet Generation and Freezing
a. Droplet Generation - Through the use of atomization technology similar to those used for spray drying, droplets of controlled size are generated. Ultrasonic and piezo-electric nozzles generate large droplets while two-fluid nozzles generate smaller droplets acceptable for inhalation aerosols.
b. Freezing – The generated droplets are frozen be either collecting the droplets in a bath of liquid nitrogen or by letting the droplet flow through a chamber cooled by liquid nitrogen. The droplets are collected by evaporating the excess nitrogen or directly under the freezing chamber.
2. Freeze Drying – The frozen droplets are transferred into a freeze dryer, where they are dried under vacuum similar to freeze drying described above. However, due to the higher surface area of the droplet relative to the cake, the drying time is substantially reduced.
Similar to TFFD, the powders are highly porous. However, mechanical stability of the particles may be a limitation. While spray freeze drying does not expose the biologic to thermal stress, there is exposure to the gas-interface. Several biopharmaceuticals have been produced using SFD [1].
Figure 4: Spray drying set-up for manufacture of inhalation formulations.
Spray Drying
The advantages of this technology for production of respirable powders containing biologics are its high manufacturing capacity due to continuous manufacturing ability, low-cost and short drying time relative to lyophilization. Milling is not needed post spray drying, as the technology offers exquisite control to vary the powder properties such as particle size, density, and morphology [10]. The spray drying process consists of four main steps (Figure 4):
1. Atomization – the liquid (solution or suspension) is atomized into droplets creating a large liquid surface area thus facilitating rapid drying in the gas stream. Two-fluid nozzles are typically used to produce respirable-sized droplets, in which the gas stream impinges upon the liquid stream at high velocity to generate fine droplets.
2. Contact between the droplet and the drying gas – The droplets are mixed with the drying gas. The overall flow (and thereby temperature) profile is governed by the gas disperser and is a fixed design feature of the spray drier. The inlet temperature of the drying gas is the highest temperature that the droplets experience, but the exposure to this temperature is only for a very short duration (<1 second). Solvent evaporation from the droplets cools the surface of the droplets and reduces the temperature of the drying gas to its outlet temperature. Thus, the dried particles are exposed to the lower temperature of the outlet drying gas during most of the drying process.
Both air and nitrogen are used as drying gases, but for pharmaceutical applications typically nitrogen is preferred to avoid both potential oxidation issues and explosion risk if organic solvents are involved. For sustainability, in closed-cycle spray dryers, the nitrogen is recycled after the solvent has been condensed out of the gas stream.
3. Drying – The solvent is removed from the droplets by evaporation to leave a dry particle. The driving force for solvent transport, and thus the speed of particle formation, depends on both the drying temperature and the relative saturation of the solvent in the drying gas. The drying chamber needs to be tall enough to accommodate the length of the atomization plume leaving the nozzle and to ensure that the droplet has enough time to dry. The diameter of the spray dryer is ideally designed based on the angle of the nozzle and the flow field (rotary atomizers release droplets vertically and therefore are wider and shorter than nozzle spray dryers). However, spray driers are often manufactured with a fixed height and diameter, and so the process must be modified to fit the dryer geometry which can lower its capacity. Drying time is typically around 60 seconds for commercial spray driers.
4. Particle collection – After the particles have been dried, they need to be separated from the gas and this is done by either cyclone collection or using a bag filter. A cyclone uses inertial forces to separate particles from the drying gas. Its efficiency is governed by the gas velocity and the particle size and density. Inhalable particles are typically small with low densities and so high gas velocities are required to efficiently be collected. These higher flow rates can lead to mechanical stress and particle breakage. The other option is to use a bag filter where particles are separated by applying surface filtration (Figure 4) and recovered from the filter bag by reverse pulse-jet cleaning (i.e., a high-pressure nitrogen pulse is injected into the bag to shake the powder loose). The advantage of bag filter collection is its high recovery, but the drawbacks are longer drying times (i.e. additional time in high temperature zone and high humidity) and a more sensitive process.
In spray drying, even though the inlet drying temperature is high, the product does not experience this as the majority of energy is used for evaporation and therefore due to evaporative cooling the molecule only reaches the wet-bulb temperature [11], which is substantially lower than the inlet temperature of the gas stream. Only when most of the water has been evaporated does the product temperature increase to the outlet temperature of the gas stream.
The main stresses experienced by molecules during spray drying are: thermal stress, shear stress for the molecules present at the gas-liquid interface, and dehydration stress.
Despite the high drying temperatures spray drying has been used to successfully generate respirable powders for several biopharmaceuticals [2,3,12-14]. When optimal excipients are used, the short drying time coupled with evaporative cooling leads to minimal impact on the biologic properties [5,15].
Another key operation in the production of an inhalable biologics is to fill the powder accurately into blisters or capsules depending on the choice of inhaler device. Several powder filling technologies are available for aseptic operation at low relative humidities. However, because the powder can be cohesive or electrostatically charged and the inhaled dose is typically low (e.g., 1-50 mg), the powder filling operation needs to be considered from the beginning of formulation and process development.
References
1. Wanning S, Süverkrüp R, Lamprecht A. Pharmaceutical spray freeze drying. Int J Pharm. 2015;488:136-153. http://dx.doi.org/10.1016/j.ijpharm.2015.04.053.
2. Prahhawatvet T, Cui, Williams III RO. Pharmaceutical dry powders of small molecules prepared by thin-film freezing and their applications – A focus on the physical and aerosol properties of the powders. J Drug Del Sci Tech. 2023;79.
3. Sahakijpijarn S. et al, Using thin film freezing to minimize excipients in inhalable tracolimus dry powder formulations. Int J Pharm. 2020:V586.
4. Chan H-K. et al. Spray dried powders and powder blends of recombinant human deoxyribonuclease (rhDNase) for aerosol delivery. Pharm Res. 1997;14(4):431–437. DOI: 10.1023/a:1012035113276
5. Maa YF, Nguyen PAT, Hsu SW. Spray-Drying of Air-Liquid Interface Sensitive Recombinant Human Growth Hormone. J Pharm Sci. 1998; 87(2): 152-159.
6. Maa Y-F. et al. Protein inhalation powders: spray drying vs spray freeze drying. Pharm Res. 1999;16(2):249–254. [PubMed: 10100310]
7. Kunda NK. et al. Evaluation of the thermal stability and the protective efficacy of spray-dried HPV vaccine, Gardasil(R) Hum Vaccin Immunother. 2019. doi:10.1080/21645515.2019.1593727.
8. Saboo S. et al. Optimized Formulation of a Thermostable Spray-Dried Virus-Like Particle Vaccine against Human Papillomavirus. Molecular Pharm. 2016;13:1646-1655. doi:10.1021/acs.molpharmaceut.6b00072.
9. Ito T, Yamazoe E, Tahara K. Dry Powder Inhalers for Proteins Using Cryo-Milled Electrospun Polyvinyl Alcohol Nanofiber Mats. Molecules. 2022;27(16):5158. doi: 10.3390/molecules27165158
10. Singh A, Van den Mooter G. Spray drying formulation of amorphous solid dispersions. Adv Drug Del Rev. 2016;100:27-50. http://dx.doi.org/10.1016/j.addr.2015.12.010.
11. Alhajj N, O'Reilly NJ, Cathcart H. Designing enhanced spray dried particles for inhalation: a review of the impact of excipients and processing parameters on particle properties. Powder Technol. 2021;384:313-331. https://doi.org/10.1016/j.powtec.2021.02.031.
12. Weers JG, Tarara TE, Clark AR. Design of fine particles for pulmonary drug delivery. Expert Opin Drug Deliv. 2007;4(3):297-313. doi: 10.1517/17425247.4.3.297.
13. Vehring R. Pharmaceutical Particle Engineering via Spray Drying. Pharm Res. 2008;25(5):999-1022. https://doi.org/10.1007/s11095-007-9475-1.
14. Maa YF, Hsu CC. Protein denaturation by combined effect of shear and air-liquid interface. Biotechnol Bioeng. 1997;54(6):503-12.
15. Vass P. et al. Drying technology strategies for colon-targeted oral delivery of biopharmaceuticals. J Cont Rel. 2019;296:162-178. https://doi.org/10.1016/j.jconrel.2019.01.023.