Tim Gardner, director of Manufacturing & NPI at Vectura explores the considerations to make when manufacturing formulations for dry powder inhaled products.
The use of dry powder inhalers (DPIs) to deliver drugs have traditionally been focused on treating respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), as the pulmonary administration of the active ingredients provides direct and rapid action.
DPI products are a combination of the active pharmaceutical ingredient (API), formulated with excipients and carrier molecules, within a device. The design and development of these must be conducted in symbiosis, as each directly impacts upon the other. Only when the drug substance can be delivered effectively by an appropriate device can the drug be seen to be successful; however, the implications for commercial manufacturing of products should be considered as early as possible within the design, to ensure that the drug’s efficacy is matched by economic viability.
Early Phase Manufacturing Development
Challenges to meet manufacturing demands in early phase development usually involve the supply chain for device components, excipients, and APIs. Establishing a strong team to project manage and ensure equipment and material is available to meet project timelines is crucial, allowing performance to be measured and the procurement of additional equipment and resources at speed if necessary.
Early phase development provides the opportunity to capture critical data, which can then be evaluated for later phases. The equipment used and processes developed should be synergistic with those to be used in scale-up – this reduces the required data capture for defining the critical process parameters (CPPs) and critical quality attributes (CQAs). Avoiding duplication of tasks allows time to be used effectively to gather data for quality assurance and GxP requirements, and involving late-stage manufacturing experts in the development teams can assist in streamlining processes.
Formulation Manufacturing
The majority of DPI formulations are a mixture of API and a carrier excipient to improve the performance of the powder. Force control agents, such as magnesium stearate, are added to reduce particle adhesion and improve powder flow. There are a range of blending approaches, characterised by the amount of shear applied during mixing, with more cohesive particles generally requiring higher shear forces for mixing.
Low-shear blending (e.g., tumble mixing) may be used for particles with low cohesion, or those that are more fragile or heat-sensitive. High-shear blending causes particles to impact each other or the wall of the mixer, allowing more cohesive particles to distribute evenly through the carrier excipient. The optimal blending approach will depend on the characteristics of the API. Maintaining uniformity is a key challenge for blending processes, especially since the blending parameters can affect the formulation’s homogeneity and stability.
Particle engineering, such as spray drying, can be used to control the particle size, shape and density of components to produce formulations without the need for blending with carrier excipients. This can be particularly useful for high-dosage products where a blend would require too high a powder load, or for large molecules that require low-energy processing. Since the particle morphology is influenced by the spray-drying procedure, it is important to understand how processing may affect formulation performance during scale up, as there may be necessary controls and storage requirements to ensure consistency of delivery characteristics.
Scale-Up Challenges
There are many factors that impact the performance of a powder formulation and delivery device, so understanding these critical parameters early and establishing robust processes can mitigate the risks associated with scale up, which invariably lead to reworking, costing both time and money.
A challenge that is particularly applicable to respiratory drug development is deciding what constitutes an appropriate scale of manufacturing at each stage of development. In early development phases, when materials are often in limited supply, there is an inevitable trade-off between the scale of manufacture and the number of batches that can be produced to build the necessary scientific understanding. Manufacture at the intended commercial scale involves large batch sizes, which can be time-consuming and expensive, and so is often not performed until the later stages of development.
Developing validated scale-up models in the early phases can demonstrate the ability to achieve comparable drug product performance from batches made at laboratory-scale and commercial-scale, so using equipment that is directly scalable from that used during early phase development, prevents unnecessary duplication in setting CQAs and CPPs. This allows a significant amount of the development work to be conducted in the laboratory at development scale, minimising material costs and enabling faster execution of experiments, whilst giving confidence in the ability to move to the larger scale at a later date. This also allows capital investment at any commercial supply manufacturing site to be made later, based on a risk-based approach for the project.
Device Choice Implications
Device choice impacts the manufacturing of both the device and formulation, and DPIs can include either capsule- or blister-based platforms. Blisters offer enhanced light and moisture protection for drug products, with potential shelf-life advantages. In early development, capsule-based devices are favoured, as they offer flexible dosing and a relatively quick pathway to clinical phases. However, capsule developments can be complex, as dry powder blends can be influenced by the capsule material, and the interaction between capsule and formulation. Capsule composition, water content, lubricant level, and surface quality can all result in the formulation’s physical properties.
Commercially-available capsules are primarily gelatin, or hydroxypropyl methylcellulose (HPMC). It is important to understand the characteristics of both formulation and device so that the most appropriate capsule type can be matched. In addition, tight control of manufacturing environmental conditions and long term packaging considerations are necessary to maintain stability and performance of capsule-based DPIs.
De-Risking Scale Up
Simplicity is paramount, and reducing complex documentation is key to meeting tight deadlines for demand when drug shortages are being faced. The early adoption of Lean Manufacturing techniques ensures optimal utilisation of resource and equipment by identifying bottlenecks and constraints, as well as challenging existing set up, clean down and turn round processes to enable efficient capacity planning.
Planning in early stages for commercial requirements reduces the risk of having to spend time and resources reworking designs or processes, so involving experts with experience of commercial manufacturing at an early stage is vital.