Formulation Development Challenges and Pitfalls when Developing Dry Powder Inhalers
The global dry powder inhaler (DPI) market continues to rapidly grow. This is riding on the back of various factors such as growing prevalence of respiratory diseases such as asthma, COPD and others. Moreover, rising demand for advanced healthcare devices for the treatment of chronic diseases is envisioned to increase the demand for DPI’s.
DPIs are the preferred dosage form for respiratory diseases because the maximum drug load is delivered directly to the lungs, thus minimizing any unwanted systemic effects that can occur with oral or parenteral delivery. Despite the increasing need for respiratory drugs, there is still a high barrier to entry for new products due to the challenges with DPI development.
In this blog piece, Martin Wing-King, our Director of Project Management, will cover the development challenges and pitfalls involved in the development of DPI products. He will cover aspects from drug substance to formulation development, and device design.
What is a DPI?
A DPI consists of a powder (either engineered or API) on a carrier particle that is delivered using a device. The device is actuated and inhaled in order to produce a jet or burst of powder that is typically delivered to the lungs as the target delivery site.
There are many factors to consider when developing a DPI, including:
1. The shape of the drug particle affects the performance of the DPI, so It is imperative to have a clear understanding of the drug substance’s physiochemical characteristics, including:
- Particle size
- Chemical purity
- Residual solvents
2. Particle engineering plays a key role when developing a DPI. The shape, size and the uniformity of the particle determine how they behave once aerosolised and dispersed within the lung. Important considerations to take into account include:
- Can the drug substance be micronized to a suitable particle size for inhalation?
- Can an engineered particle be developed via spray drying to avoid the need for a carrier particle?
3. Selecting the right carrier particles for your API will determine the delivery performance of your DPI. Carrier particles are used to improve the flowability of the API to the target delivery site, they increase dispersion of drug particles during emission and they also dilute the drug in order to improve accurate dose delivery. (1)
- The most common carrier used in DPI products is lactose, however you must determine which particle size distribution (PSD) and morphology is best suited for the drug substance
- Do you need to use an additional excipient to improve stability and/or performance?
4. Selecting the delivery device type and container closure is the next step. Unlike oral and parenteral dosage forms, DPIs involve a complex interaction between the delivery mechanism and the patient which can present many challenges, so you must consider the following:
- What kind of device is being used? Passive or active
- How patient friendly?
- Reservoir, capsule or blister strips
- Does the formulation or device need specific container closure to protect from moisture?
5. Container closure systems can also impact the successful delivery of your DPI.
A DPI container closure system consists of the device constituent part and any protective secondary packaging. Current designs of DPI products include pre-metered and device-metered DPIs, either of which can be driven by a patient’s inspiration alone (passive) or with power-assistance of some type (active) for production of drug particles intended for inhalation. (2) Important things to keep in mind when selecting your DPI’s container closure system include:
- Understanding the patient demographic for your DPI can greatly impact the selection of containment closure system
- The type of manufactured drug product and product expiation can greatly influence the type of container closure system
6. Process development also needs to be well understood in order to develop a robust product. Considerations should be made on how easy the developed process can be scaled up.
- The first stage is typically with powder blend development. The typical variables here are a type of blender (low shear or high shear), sequence of addition, blend speed, time and evaluation of environmental conditions such as temperature and humidity.
Once a robust blend is developed, then the next stage would be filling of the powder into the device or capsule/blister for actuation. There are a range of different filling techniques (auger screw, dosator, tamping, vacuum drum etc) available for filling of the powders, selecting the most appropriate mode of filling and associated equipment is also important to ensure that the powder performs as expected after actuation.
There are pros and cons with each of the available filling techniques, so these need to be carefully evaluated to get suitable product performance with also an eye on scale up in the future.
Understanding the risks and challenges involved with developing a robust DPI product lays the foundation for the best chances of success. For more information on Quotient’s inhaled drug development capabilities visit: https://www.quotientsciences.com/solutions/inhaled-drug-development/
1. Influence of physical properties of carrier on the performance of dry powder inhalers
Tingting Peng, Shiqi Lin, Boyi Niu, Xinyi Wang, Ying Huang, Xuejuan Zhang, Ge Li, Xin Pan, Chuanbin Wu
Acta Pharm Sin B. 2016 Jul; 6(4): 308–318. Published online 2016 May 4.
2. Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Products - Quality Considerations Guidance for Industry
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) April 2018 Pharmaceutical Quality/CMC Revision 1