April 12, 2019 PAP-Q1-2019-CL-002
Traditionally, drugs delivered via inhalation were intended for the treatment of respiratory diseases, most notably COPD and asthma. These drugs were based on small molecule APIs and formulated initially as pressurized metered dose inhalers, but they are increasingly being formulated as dry powders.
Researchers have continued to pursue new molecules for those respiratory diseases, and recently have been expanding efforts to develop inhalation drugs for other respiratory diseases, such as tuberculosis, lung cancer and infections, as well as systemic diseases like diabetes. This translates into a growing and more diverse clinical development pipeline in inhalation, including biopharmaceuticals.
This increased focus on inhalation delivery reflects the benefits offered by this route of administration. In addition to the advantages over parenteral administration, inhalation also circumvents some of the challenges with oral. Delivery by inhalation bypasses the harsh conditions in the GI tract, allowing the administration of lower doses with reduced side effects, particularly for respiratory drugs delivered directly to the site of action. Delivery of some drug substances into the lungs encourages direct absorption into the bloodstream for enhanced systemic delivery; this may lead to the more rapid onset of action.
There are additional benefits to developing inhalation formulations for biologic drugs that are conventionally administered parenterally. The clearest benefit is improved patient adherence by eliminating the need for injection. For biologics targeting lung diseases, patients are also already used to using inhalers. Inhalation formulations may provide greater stability of the biologic drug substance, particularly for dry powders. Dry powder inhalation formulations may also eliminate the need for cold-chain storage and transport, reducing the complexity and cost of production and simplifying logistics.
The pipeline of biologic molecules in development as inhaled medicines ranges from oligonucleotides, peptides and proteins, antibodies and nanobodies, with molecular weights ranging from a few kDa to more than 500 kDa. Larger molecules are more difficult to successfully develop as inhaled formulations, given the increased likelihood of chemical and physical stability challenges. For systemic delivery, reduced bioavailability and absorption mechanism uncertainty in the lungs are also concerns for larger biomolecules.
The bioactivity of biomolecules depends largely on their structural integrity. Owing to their multiple conformational possibilities, biologics processing can lead to additional challenges related to denaturation, aggregation and other forms of structural change, with potential for loss of activity and increased immunogenicity.
Biologics for pulmonary delivery have been formulated as nebulizers and dry powder inhalers (DPIs), which are typically more compatible with biomolecules.
Successful DPI delivery to the lungs requires an integrated strategy for inhalation formulation development, including particle engineering, formulation design, analytical characterization and device performance.
Particle engineering is key to success in the formulation of biologics for inhalation, but biopharmaceutical sponsors typically lack that knowledge. For small molecules, milling and wet polishing are common techniques to create optimally sized particles, but these are often not applicable for biologics. Instead, spray drying is the most commercially advanced solution for particle engineering.
Unlike traditional DPI formulations — physical mixtures of a carrier and micronized API — biologic DPI formulations require the formation of composite engineered particles in which the API is embedded in an excipient matrix, allowing for the stabilization of the biologic and efficient pulmonary delivery. To achieve these goals, an understanding of the interactions between the active and excipients and their impact on performance is mandatory. The drying conditions and the choice of excipients are driven by the need to prevent denaturation, aggregation and dehydration caused by exposure to shear and heat stress. Excipients increase the stability of the amorphous matrix and the powder aerosolization. The spray drying process is readily scalable, ensuring that particles generated during development will have the same properties as those manufactured in the commercial plant.
Insights into molecular structure, physical and chemical stability, expertise in formulation design and extensive analytical capabilities for characterization of the formulation components are necessary to ensure that the inhaled biologic maintains its integrity, safety and activity. Knowledge of powder properties (e.g., flowability) and final aerodynamic performance also contribute to successful development.
At Hovione, our expertise in particle engineering is intimately integrated with our capabilities in characterization and formulation. We offer fully integrated services for DPI formulation development and manufacturing for clinical supplies and commercial-scale drug products. An integrated team of scientists and engineers with diverse expertise support the development of scalable processes and drug product manufacturing. Our team has experience dealing with drug products, advanced models and methodologies, leading to lean and efficient development, which expedites the path from early development to commercialization. This development-by-design (DbD) methodology enables us to balance development costs and risks and find the sweet spot between manufacturability and formulation performance.
The use of a QbD approach for both processes and analytical methods development allows for optimal solutions, assuring that quality is maintained throughout development. This approach enables a strong understanding of the impact of critical process and method parameters on their respective attributes, defining the design space and establishing an effective control strategy to reduce variability.
Hovione has amassed extensive historical data on spray drying and incorporated them into proprietary modeling systems that allow close correlation of laboratory and commercial conditions. We are thus able to reduce the number of manufacturing runs required to establish a commercial-scale spray-drying process. In parallel, we built and consolidated extensive capabilities and expertise in analytical characterization of challenging spray-dried formulations.
All this expertise at Hovione is the key to success in bridging particle engineering and biologics formulation for the development of DPI biopharmaceuticals.
Constança Cacela leads Hovione’s R&D Analytical Development area in Portugal. She joined the Analytical Chemistry department in 2006, leading a team with expertise in physical chemistry, particularly solid state and particle characterization. Constança holds a Ph.D. in physical chemistry and has several years of experience investigating the mechanisms that govern amorphous formation and stabilization as well as solid–solid phase transitions and the impact of those on the performance of oral and inhaled drugs.