Drug developers are increasingly looking at capsule-based dry powder inhaler (cDPI) combinations to deliver innovative formulations to patients. The combination is highly accessible and becoming increasingly popular for all the right reasons, Frederique Bordes-Picard, business development manager for Innovative Products at Lonza Capsules and Health Ingredients says.
Capsules are by far the preferred dose form for a broad range of patient-centric reasons. They can also simplify drug development and manufacturers have been reliably manufacturing capsule-based medicines since the beginning of the modern era.
Drug development in the pulmonary delivery arena is fast-growing. Further, the delivery route’s inherent efficiencies continue to make it attractive to pharma developers. For example, drug developers have access to a variety of proven cDPI inhaler technologies and the technology can be economical to manufacture and distribute.
All of this, as well as streamlined New Drug Application (NDA) and Investigational New Drug (IND) FDA approval regimens (including orphan drug and 505(b)(2) routes) mean new applications for cDPIs are being targeted for development and entering the pipeline with increasing frequency.
No ‘standard’ capsule for cDPIs
Offering precise, affordable dose delivery to patients, cDPI drug product designs require critical focus on aligning the formula, capsule and device to ensure optimal performance of the final cDPI combination drug product. Each formulation is unique and presents different challenges when combining capsule, formulation and inhaler into a safe, efficient and reliable medication for patients.
Pharma drug developers, as well as capsule manufacturers, understand that firstly, there is no such thing as a “standard” DPI capsule that is perfect for every cDPI application. Secondly, all three components (capsule, formulation and device) must be assessed carefully and specifications on critical parameters carefully set.
Achieving the right combination
To achieve the best combination, it’s important to carefully characterise each component’s critical parameters relative to each other. Optimal performance of cDPI combinations is often characterised by the emitted dose and fine particle mass or fraction.
All three components must work together to ensure their optimal performance, and for each, critical parameters should be identified, and specifications set accordingly:
Designing a better cDPI combination
Following a QbD (Quality by Design) approach will help identify critical parameters and ensure components and process are adequately defined to ensure optimal performance.
It’s important to begin the cDPI combination development process by finding specifically engineered capsules that help address drug substance compatibility issues relative capsule material and inhaler actuation.
Each component can add complexities that call for resolution and certain compromises, and that’s why collaboration is important. Combination device drug product programs tend to be more successful with suppliers experienced in developing these kinds of products.
Usually the device is selected first. As development continues, focus shifts to gaining an understanding of the formulation’s characteristics and its prerequisites (dose, particle size distribution, chemical stability, water sensitivity). With this information a DPI capsule can be customised and tailored to address the formulation needs and functional characteristics of the device.
[FDA’s view of QbD, 2006]
A case study of cDPI development potential
Recently, Lonza supported a pharmaceutical manufacturer with an innovative project involving a new combination drug. In this case, a formulation with spray-dried particles presented specific challenges to overcome in combination with the capsule. First, the water-sensitive formulation required capsule filling environmental conditions of less than 30% RH. The inhaler specified employs a needle to pierce the capsule on actuation, and the developer needed a highly transparent capsule to support visual confirmation of inhalation performance.
Determining optimal LOD specification in three steps
For this particular project, Lonza suggested a three-step approach to help determine the optimal loss-on-drying (LOD) for the capsule:
The first step was to assess the formulation’s LOD activity once filled into the capsule. The objective was to determine or set a stable system and minimise the exchange of water between the formulation and the capsule. In this case, to align with the formulation water activity, HPMC capsules’ optimal LOD was set at 4%.
When it comes to capsule LOD specifications, it is important to find the right balance of attributes that support the chemical stability of the formulation but not generate undesirable issues like static charges leading to potentially higher powder retention inside the capsule.
Ultimately, the best solution in this case was a HPMC capsule with a customised water content profile to meet the needs of this challenging formulation. It was important to understand the optimal capsule material for the formulation, but also the optimal conditions for filling and finishing it downstream.
Parting thoughts on cDPI product R&D
As mentioned earlier, there is no such thing as a standard DPI capsule. Every program is unique but understanding the interactions between the capsule and the other major components is critical. What is also critical to program success is engaging supplier expertise and services through close collaboration and leveraging this as early as possible in cDPI development.
Lastly, seek a detailed understanding of your capsule supplier’s manufacturing process, DPI settings, and the controls they have in place to ensure product quality and robust performance. Ultimately this will mean more reliable ways to speed product development and put effective, affordable cDPIs into the hands of more patients around the world.