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Formulation characteristics must be optimized, following device selection, to achieve the desired performance for the capsule loaded in the dry powder inhaler.
Capsules used in dry powder inhalers (DPI) are, in many ways, different from those that are orally administered. “From a regulatory perspective, capsules for inhalation must comply with the compendialrequirements for inhalation products,” highlights Frédérique Bordes-Picard, manager, Pharmaceutical Business Development, Lonza Pharma & Biotech. “More stringent microbiological specifications are required compared to capsules intended for oral use, which are defined in a compendium of monographs.”
“From a performance perspective, orally administered capsules are designed to disintegrate and release the formulation in the stomach or intestine,” explains Sven Stegemann, PhD, director,Pharmaceutical Business Development, Lonza Pharma & Biotechand professor, Graz University of Technology. “Capsules for inhalation, on the other hand, act as a container for the formulation and work in combination with a DPI device, which ensures capsule opening, followed by the release of the appropriate dose of fine drug particles into the lungs. To achieve this, the capsule polymer selection must be rational and strategic, and might require further fine-tuning during the development. The difference between a DPI and an oral capsule is the different function they play in the drug-delivery system and the specific knowledge and capability that is required to commercially manufacture both DPI and oral capsules.”
Bordes-Picardand Stegemann spoke to Pharmaceutical Technology about the key considerations in the development of DPI capsules.
PharmTech: What are the properties required for DPI capsules and why are these properties important?
Bordes-Picardand Stegemann: The properties of DPI capsules will depend on the powder formulation filled into the capsules and the selected delivery device. In general, the capsules should be inert to the active ingredients, and a fine balance between powder adhesion and segregation is important. The inner surface properties of DPI capsules have to be designed in a way that the powder can be freely released from the capsule with minor powder retention. To achieve this objective, the capsule might need to be tailored to the specific device dynamics and the opening mechanism.
For devices that pierce the capsules with needles (e.g., model RS01 from Plastiape), the capsules should not generate a loss of particles and should leave a clean puncture after needle retraction. When the capsules are opened through shear forces (e.g., the Twister model from Aptar), they need to be flexible enough to separate without breaking or other damage that would hinder the powder from being released. There are also other properties that might be required for a specific formulation-for example, to ensure chemical stability, such as a capsule’s water content.
PharmTech: What sort of testing do you have to carry out on DPI capsules? What are the purposes of these tests?
Bordes-Picardand Stegemann: During the development process, a series of tests are run to understand each of the complex interactions between the relevant factors and components on the performance of the inhalation product. Throughout this process, the specifications of each component will be fine-tuned, including the capsule, and the process parameters will be defined and verified while manufacturing to scale. Once this is done, the product should be manufactured in a reproducible manner achieving the desired product performance batch after batch.
These specifications are assured through a series of proper analytical methods, which include the capsules as well as the other components of the final product. The general pharmacopeia requirements should be tested as well as product specific requirements, which are defined in tandem with the pharmaceutical manufacturer.
PharmTech: What are the key considerations when developing a capsule formulation for DPI applications?
Bordes-Picardand Stegemann: The key considerations for DPI product development are not too different from those of a standard oral product. Everything starts with a target product profile, where the technical requirements need to be defined, as well as the patient or user requirements.
Because of the multifactorial interactions of the formulation, including the capsule and the device, a key consideration is selecting and adjusting the DPI device first. Capsule selections are based on the technical features of the device. There is substantial information available on the technical aspects of devices, for example, using computational fluid dynamics. It is, however, important to also take into consideration the targeted patient population, usability, and user experience.
After a device is chosen, a formulation is optimized and, depending on its specific characteristics (i.e., dose, stability, water activity, hygroscopicity), the optimal DPI capsule is selected. Lastly, studying the impact of individual characteristics allows for fine tuning of the formulation and the most appropriate specifications of the DPI capsule to be set to achieve the desired performance.
PharmTech: What would you identify as the critical quality attributes (CQAs) for capsule formulations of DPIs and how do you ensure reproducibility and consistency of DPI performance?
Bordes-Picardand Stegemann: A better question might be: how would you identify the real CQAs? Due to multiple variables and their complex interactions, a thorough quality by design (QbD) process is required, beginning with the material science of the API, the excipients and the capsule, through the processing science, and then eventually, simulations.
This process includes risk assessments of each factor within their standard variability, including the components that go into the process and the overall process itself. This is why it is important to develop DPI products in multidisciplinary teams, identify formulation- and product-specific CQAs and critical process parameters (CPPs) to control them with appropriate analytical methods using process analytical technologies (PAT). The result is that the reproducibility and consistency of the final product is a responsibility of the pharmaceutical manufacturer working together with the suppliers. The final quality is the result of the entire supply chain.
To give an example, if the DPI capsule has a targeted moisture range specified as a CQA, the commonly defined storage conditions would not only need to be secured during shipment, receipt of goods, and warehousing, but also during the entire manufacturing process as capsule moisture is directly impacted by their environmental conditions.
PharmTech: What are the challenges of scaling up DPI capsule production and how do you address them?
Bordes-Picardand Stegemann: The major challenges when scaling up DPI product manufacturing are related to the very small fill quantities (typically below 40 mg) and to powder formulations that are made of fine particle sizes with poor flow characteristics. In the blending process, for example, the mechanical forces that act on the fine API particles and the coarse carrier particles are completely different when at a few grams scale compared with at a several kilograms scale. This difference has a direct effect on the powder dispersion and homogeneity of the formulation blend, the attachment and detachment forces, and the static charging.
Content uniformity of fills with poor flow characteristics and/or small fill quantities need to be addressed early on during the development too. However, progress in the development of filling machine engineering have provided new technologies specifically made for DPI filling, allowing for high-precision dosing (even with former difficult powder characteristics) as well as a 100% accurate weight check. Consequently, working with different stakeholders, including excipient and capsule suppliers, machine manufacturers, and QbD experts early on and throughout the development and scale up, is the most efficient way to successful DPI product development.