When treating conditions that affect the lungs such as asthma or chronic obstructive pulmonary disease (COPD), inhaled delivery of drugs is often the most preferable choice, and there are a number of device platforms available to innovators. These include dry powder inhalers (DPIs), pressurized metered-dose inhalers (pMDIs) and nebulizers, but the decision as to which to use is dependent on a number of factors, and it is best to start from a “device agnostic” position, to avoid being swayed by previous projects or a technology bias towards a single platform.

Device factors
As with every drug program, development should start with considering the target product profile (TPP), and look to the requirements of the drug product in terms of the initial product inspiration, formulation characteristics and the required outcomes for the patient, such as the desired payload. From there, innovators can consider the dosing regimen, and assess what technology is appropriate in terms of the features a device needs, as well as what regulatory challenges may present, and ultimately what device may make commercial sense.

The device technology choice cannot be seen as a standalone decision- it must factor in the technical requirements of the active pharmaceutical ingredient (API) and its associated physical properties and dosage requirements; as well as the practical requirements, focusing on the target patients’ needs, such as age, usability, lifestyle and expectations based on other available devices. As well as matching the API’s formulation to an appropriate device, consideration must also be given to the ability to manufacture the device effectively, and in line with design, release specifications and any necessary analytical approaches to conform with the TPP and user requirements.

Choosing a DPI
Pulmonary administration of an API provides direct, rapid action, and a DPI allows a patient to breathe medicine into their lungs quickly. Being breath-activated, a DPI releases the drug into the lungs through the act of the patient breathing, and there are a variety of devices available: some with a supply of the drug inside, and others where the drug needs to be added to the device before use.

There are some immediate factors that exclude a DPI from being the first choice as a delivery platform: patients with arthritis or low strength, such as pediatrics, may be unable to actuate the devices or inhale at a high enough flow rate; and DPIs are not suitable for drugs requiring a high payload.

However, for appropriate drugs and patient populations, DPIs give innovators the opportunity for accelerated development to achieve clinical milestones: where, for example, a capsule device may be appropriate for early-stage proof of concept studies; and then for commercial purposes, blister-based, multi-dose, commercially validated devices may be more suitable and the device can be changed.

De-risking DPI device design
For ease of development, innovators may choose to use an established platform technology, and leverage previously verified and validated functional elements of a device, combining them as needed to meet the TPP. The alternative is to look at a bespoke, tailored device, but this brings with it greater development time and expense, and potential regulatory challenges.

A new product that takes advantage of an existing delivery platform affords a degree of proof that the product will be scalable to a commercial process, and issues around manufacturing scale-up are less likely. Human factors testing is critical when selecting a device for a target patient population as they will show how the device behaves in the hands of the likely patients.

Innovators must use constant feedback review criteria to ensure the TPP is being met, and by defining acceptance criteria by liaising with all cross-functional groups within the development team (including formulators, regulatory advisors, analytical experts and manufacturing engineers), the risks can be minimized as the drug product progresses to ensure the greatest chance of success.

Bespoke DPI devices
Developing a bespoke, tailored DPI device to improve delivery has advantages, however, innovators must be mindful of the need to align the device development process with the requirements of the regulators and ensure that sufficient evidence of suitability is included in the registration package. The FDA’s 21 CFR Part 820.30 states that, “Design validation shall ensure that devices conform to defined user needs and intended uses and shall include testing of production units under actual or simulated use conditions.” The various regulatory bodies all have slightly different requirements, and it is important to include an assessment of whether a device will meet the demands of the regulators in all the regions where it is likely to be launched.

The starting point when designing a new device should always be the definition of its target market, user needs, and possible regulatory pathway. Innovators need to work with engineers and designers to focus on who the device is for, and what the requirements of both the drug and the patient population are to ensure success.

With this list of top-level criteria defined, numerous different concepts are usually proposed, which are then evaluated and ranked in terms of both benefits and disadvantages. Those that are the closest match to the requirements would be advanced through to the more detailed design stage, where practical considerations such as the devices’ manufacturability and scalability would be assessed.

It is vital to capture and record procedures systematically, aligning and refining ideas and results with prototyping, governance and approach to quality. Research into the wider market for the disease that is being treated by the drug product to see what similar products are available helps to understand potential opportunities or problems in the commercial environment.

The next step is to take these detailed design concepts and make sample devices using methods such as 3D printing, which allows a thorough assessment of a design and gives a real sense of how it might work in the hands of a patient. These prototypes also allow laboratory tests to determine how the formulated drug is likely to behave in the device, and for early mechanical tests to be carried out against the key functional parameters. These assessments will allow a list of critical quality attributes (CQAs) for the device to be defined.

These CQAs will cover a wide range of considerations, such as materials for construction, packaging, labelling, and the potential need for cleaning / disinfection between uses – all of which will need to be aligned with compatibility with the formulation. The cost of goods and manufacturing, and potential commercial factors need to be considered in terms of lifespan of a device and product, so that the needs of patients are matched with the wider stakeholders, including the supply chain, prescriber and payor.

Promising devices can then be made into more robust prototypes, and technology, such as computer aided design and rapid molding tools, can allow for this to be done relatively quickly. There are essential developmental tests that can only be done on rigid plastic prototypes, including drop tests and mechanical abuse level loading type tests, as well as environmental tests (the conditions of which are noted in ISO20072) that cannot be carried out effectively without a plastic device.

Alongside functional tests, again, human factors studies should be carried out. These tests may require multiple iterations of device design and prototypes, but time spent to identify issues at this stage is preferable to a project failing in late-stage clinical trials because the device was not suitable. As and when the device prototype meets all the requirements, the next step is verification.

The device development process typically follows a stage gate process, where the project is reviewed with a board of representatives from across the relevant disciplines. The development is structured so that, initially, the TPP, user requirements, including the user needs and intended uses are reviewed at the first stage gate, followed by the concepts at the second stage gate, formal designs, device verification, manufacturing equipment, validation and finally preparation for market. It is important that device performance continues to be monitored by a post-market surveillance team to assess whether lifecycle management activities are required.

Device validation
Whereas testing a product against a specification can be carried out through statistical analysis, validation of any product must align with the TPP and original list of user needs and prove that it meets all those original requirements. Validation may be subject to a human factors test, where the prototype is put into the hands of the patients, and proven to be effective with only the patient instruction leaflet as a guide for the user. A clinical trial may also constitute validation that it does what it should. Ultimately, the patient decides whether a device is effective, and it must be robust, and deliver the product accurately every time.

Environmental impact of design
A factor of growing importance in design of DPI devices is the environmental impact of its materials of construction. Typically, these will be a range of polymers and plastics, with some metal parts such as springs and piercing mechanisms. Obviously, all materials must not have a compatibility issue with the drug formulation in terms of leaching contaminants into a drug that could adversely affect the drug’s stability, or the patient using the device. However, more work is being carried out to investigate the potential of designing devices that have a reduced amount of plastic and minimal components. Plant-based polymers would be an option to afford biodegradability, but support from regulators would be necessary for this to advance further; with current industry focus being on the option of recyclability of components, and designing long-life devices with multi-use systems.

Future design considerations
Development of DPIs is complex, and the device is just one part of the product. Effective development is reliant on drug formulations working in partnership with the device, and the combination being robust and efficient to manufacture at scale. There is no one-size-fits-all answer to DPIs, with each program having different design factors and patient needs. DPIs provide a cost-effective route to development of medicines, with the potential to accelerate the time to clinic using a phase-appropriate approach—for example, by using a non-proprietary capsule device to move quickly into the clinic during early development, before switching to a multi-dose device for late-phase clinical trials and commercialization. By integrating development functions and working on formulation and device design in partnership, the understanding of drug/device performance characteristics and process parameters allows efficient bridging and scale-up, bringing better medicines to patients faster.