Give it a dry: Why spray drying is preferred for biotherapeutics
Dr Andrew Naylor, research and development director, Upperton Pharma Solutions, explains why spray drying might be the preferred method for biotherapeutics.
Biologics. Biotherapeutics. Biotech drugs. Biotechnologically produced proteins. Whichever your preferred name, it is clear that an increasing number of these modern therapeutics are entering drug development pipelines, with a growing number launched to market each year. Biotherapeutics are an important part of modern medicine as they can be designed to specifically target almost any disease mechanism, offering efficacious treatment with reduced side effects.
Biotherapeutics are produced by, or involve, living cells, with a high level of control over their manufacture to ensure quality, safety and efficacy. To date, therapeutic areas include vaccines, protein therapies and antibodies. Given the high sophistication and cost of manufacture and the sensitivity of the molecules, alongside the all too common failure of new therapeutic candidates in clinic, effective formulation development is vital.
Most biotherapeutics are provided as a drug substance in a liquid state, perhaps as a slurry post fermentation and filtration, or as a nanosuspension. Typically, these are frozen to reduce instability, and only thawed when required. It may be relatively straightforward to formulate these into liquid dosage forms such as injectables or oral suspensions, but to improve stability and further exploit and investigate preferable dosage routes then a dry powder will be required.
Producing a dry powder form of a biotherapeutic has many advantages over the liquid form; smaller volume therefore reduced storage space requirements, greater physical stability, the removal of the need for frozen storage and the opportunity to explore delivery routes more popular with patients, such as oral or inhaled administration.
Drying in pharmaceutical applications
Spray drying is a well-established process widely used in pharmaceutical applications for encapsulation or to make amorphous solid dispersions. Dryers use the combination of an atomised feed solution and a heated gas to generate a dry powder, which is collected using cyclone, filter or electrostatic technology.
Traditionally, lyophilisation has been used for drying in pharmaceutical applications as there is a perceived risk of exposing thermally labile APIs and biotherapeutics to the elevated temperatures of the spray drying process. Yet in reality many of these molecules can be successfully spray dried without any loss of potency, which is down to the mechanism of drying encountered during the spray drying process.
During spray drying the feed solution is atomised into the drying chamber through a nozzle. In pharmaceutical applications this is most commonly a two-fluid nozzle, which atomises the feed into droplets using compressed air. The design of these nozzles means that the cooler atomisation air protects the liquid from the high temperature of the drying gas, right up to the point of atomisation. Once atomised the droplets dry rapidly, and evaporative cooling from the drying process keeps the temperature of the droplets low. Heat exposure of the product being dried is therefore minimal. With the right formulation and process development, this evaporative-cooling and rapid drying means that even the most delicate biomolecules can be spray dried with little or no loss of activity.
Stabilisation techniques
In common with other drying processes, it is usually necessary to include excipients to provide complete protection of the molecule and stability throughout the process. There are three critical points during the manufacture and storage where the biotherapeutic can be vulnerable; on solution atomisation, during the drying process, and on storage post drying. There are a wide variety of excipients that have been utilised to develop spray dried powders with excellent assay and long-term stability.
Surfactants, such as polysorbates or pluronics, offer protection at the liquid-air interface during the atomisation stage, preventing protein aggregation or denaturation.
Stabilisation during the drying process is achieved by the use of excipients that can form hydrogen-bonds with the biotherapeutic. Sugars such as trehalose, raffinose, or dextran are commonly used as matrix formers. Due to their high glass transition temperatures they can offer excellent long-term storage stability. Combinations of amino acids such as histidine, glycine, proline and arginine, or divalent metal ions such as zinc, can be added to maintain the protein structure, reduce protein aggregation and minimise chemical degradation thus improving stabilisation.
Once a stable, dry powder version of a biotherapeutic has been formulated, the powder can follow traditional pharmaceutical development routes, with granulation, tabletting and capsule filling common place. Spray drying has the added advantage of often producing powders that are perfectly suited for inhaled drug delivery, with excellent aerosolisation properties. Further excipients can be included in the feed solution formulation to comprise part of the spray dried powder, or blended with the powder after spray drying according to the onward application.
Summary
Biotherapeutics are an important part of modern medicine, delivering treatments to serious illnesses including cancer, rheumatoid arthritis and heart disease. However, development can be challenging. There is a need to store bulk drug solutions frozen due to poor stability of solutions at ambient temperatures. Liquid dosage forms are also less favoured by consumers, therefore drying of the delicate biotherapeutics is necessary.
The fast, semi-continuous and scalable qualities of spray drying offer clear advantages over the slower lyophilisation process. Inclusion of excipients into liquid feed solutions can protect even the most delicate of molecules from the spray drying process, opening the technique to complex biologics. Once dried, the product can then follow traditional formulation development pathways, with manufacture of conventional oral or inhaled products with superior stability. Rapid throughput by spray drying can accelerate formulation development timelines, enabling faster access of medicines to patients.