There is growing demand for dry-powder inhalation formulations of drugs to treat both respiratory and systemic diseases. Composite particle technology is allowing the development of more efficient formulations, even for challenging molecules. Spray drying is an enabling technology for composite particle preparation. Formulators must be aware, however, of the tradeoffs between properties that improve aerodynamic performance in the lung but negatively impact process yields or throughputs.
Traditional DPI formulations are physical mixtures of a coarse carrier and micronized API with an aerodynamic particle size of 1 to 5 microns. It is important to note that understanding the properties of the API — as well as any excipients that are used and their possible interactions — is key to the successful formulation of drugs for use in dry-powder inhalers. Precise control of capsule filling once the carrier and API are blended together in the final formulation is also crucial. DPI drugs are typically formulated at very low doses; the filling process must be very precise in order to ensure accurate dosing.
While use of a carrier is an established formulation strategy and these formulations are relatively easy to develop, they can suffer from variability of the API and of the carrier, leading to lack of homogeneity in the filled capsules due to the very low doses. Composite particles are therefore receiving increased attention as an attractive alternative to carrier-based formulations. In these DPI formulations, the API is embedded in an excipient matrix, and all of the ingredients in the formulation are incorporated into engineered particles that can be inhaled. As a result, the API is more efficiently delivered to the lung for improved performance.
Composite particles are also appealing in the formulation of biomolecules, including peptides and proteins, as DPI therapies. These sensitive molecules cannot withstand the traditional technologies used for carrier-based formulations. Particle engineering can help stabilize such challenging molecules and enable their delivery to the lung, which provides a very large area for absorption and delivery to the bloodstream.
Delivery to the lung is an attractive alternative to parenteral delivery, which is the most common type of formulation for biomolecules. Following oral delivery, these biomolecules either do not survive the harsh conditions within the GI tract or are subject to first-pass metabolism. Parenterals also often require cold storage, and in some cases can only be administered via intravenous methods, which may require a visit to the hospital and can lead to reduced patient compliance.
The size of biomolecules will impact their suitability for DPI formulation, however. Peptides that are too small might be eliminated from the lung, while the complexity of drug formulation increases significantly for larger biologics. Consequently, the range of peptides and proteins that can be delivered through the lung is determined by their physiochemical and structural properties, as well as their behavior under physiological conditions.
Spray drying is an enabling technology for the preparation of composite particles for inhalation formulations. It is also ideal for generating engineered particles of biologic drug substances. During spray drying, a solution of the drug substance and suitable excipients is subjected to mild flash drying, which allows for careful control of particle properties (particle size, bulk density, degree of crystallinity, etc.).
The process is readily scalable, which ensures that composite particles generated at commercial scale have the same properties as those designed during the development phase. Spray drying is also applicable for challenging thermally sensitive and hygroscopic/sticky compounds, including biomolecules. The mild conditions and the careful choice of surfactant and glass-forming excipients help prevent denaturation, aggregation and undesired degradation or dehydration due to stress exposure. In composite particles, it also provides the advantage of improving the particle properties for efficient inhaled powder formulations.
We at Hovione have been providing spray-drying services to the pharmaceutical industry for over 12 years. The major challenge in scaling up spray-drying processes for inhalation is to ensure that the particle properties are maintained across scales, namely a small particle size and low residual water content, when increasing process throughput in larger spray-drying units. We use extensive proprietary modeling capabilities to closely correlate laboratory conditions to those at commercial scale, allowing a reduction of the number of manufacturing runs required to establish an effective commercial-scale spray-drying process based on laboratory data. Engineering solutions are implemented to expedite scale-up and ensure that fine inhalation powders are generated and efficiently collected in commercial units under high-process throughputs, such as multi-nozzle atomization heads and custom-made high-efficiency cyclones.
As mentioned above, most dry-powder inhalation formulations contain very low doses of the active pharmaceutical ingredient — as low as a few milligrams. In traditional capsule filling, the amount of product filled into each capsule is measured using the gross capsule weight after filling. For example, if a capsule weighs 50 mg for a fill weight of 5 mg, the significant variations in the filling weight might not be detected: a difference of only 1 mg in fill weight in a capsule with a 5 mg fill weight equates to a 20% deviation. Consequently, Hovione is moving to the use of low-compaction, dosator-based, precision capsule-filling units with 100% net-weight verification for both pilot and commercial manufacturing.
The fine particle fraction (FPF) of DPI formulations typically determines the performance of these types of drugs upon aerosolization. Using quality-by-design principles, we have found, however, that there is a negative correlation between these values and the manufacturability of DPI formulations, with respect to their rheological and capsule-filling rejection rates. Using advanced modeling tools, we are able to quantitatively define these relationships and show customers how the yield of a process is affected by changes in FPF values.
For carrier formulations, the particle size distribution of the API and the percentage of fine lactose in a formulation are the main parameters that influence aerodynamic performance. In addition, the formulation has a significant impact on blending and capsule-filling yields. Specifically, formulations that enable improved FPFs are detrimental to the process yield, leading to significant product loss in the blending and capsule-filling steps.
As a result, there is a need to balance the desired aerodynamic performance with the manufacturability properties of any given DPI formulation. Specifically for carrier formulations, whenever possible the fine lactose percentage should be minimized to < 10% and low fill weights of < 10 mg should be avoided in order to achieve the best balance between manufacturability and aerodynamic performance.
For composite particle formulations, similar relationships are observed. Namely, higher FPF are typically obtained for lower-process throughputs.
For new projects, we use information about the physicochemical properties of the API, the targeted disease and type, patient population and intended device design to determine which technology in our portfolio will be best suited for formulation of a DPI therapy. At the proof of concept stage we establish the in vitro aerodynamic performance and confirm that the targets are being met.
Early during the development of the formulation and capsule-filling process, manufacturability and performance are both investigated by assessing the effect of different key parameters on the FPF value, and the ideal balance is identified. As we have established scalable carrier-based formulation methods and spray-drying processes, the lessons obtained at the development stage are applicable to larger-scale processes as well. In fact, we specifically do not develop stopgap solutions for any stage of a project. All processes are designed to provide the desired performance at any scale, including commercial production. This approach makes it possible to identify optimum formulations early on in the project, which leads to reduced development times and costs. It also reduces the risks associated with process transfer and scale-up.
The development of scalable processes is just one aspect of our strategy to offer fully integrated services to our pharmaceutical partners. At our site in Portugal, we offer comprehensive solutions for DPI formulation development, manufacturing for clinical supplies and small commercial-scale drug products. A single team supports the development of scalable processes, and methodologies are used to predict the right balance of manufacturability and formulation performance. The result is timeline compression and seamless project management. In addition, with our capabilities in low-dose/high-yield capsule filling — including MultiNett 100% net-weight verification and potent API handling — as well as our extensive experience in both carrier-based and composite-particle formulation development, we are able to develop highly efficient DPI formulations for even the most challenging drug substances.
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