Breathing easy: Approval for inhalation devices
Leon Birch, principal scientist at life sciences contract research organisation Broughton, discusses the regulatory requirements for novel inhalation therapy devices.
Handheld nebulisers based on ultrasonic/piezo technology have the potential to overcome many of the challenges of traditional nebuliser technology.
Inhalation therapy involves using a device to administer drugs to the throat, lungs, or oesophagus. The ability to deliver therapies into the alveolar spaces of the lung results in rapid absorption into oxygenated blood, allowing inhalation therapy to achieve efficacy with a lower dose than via tablet or intravenous injection, potentially reducing the risk of side effects and adverse events.
There are several types of inhalation therapy devices: nebulisers, pressurised metered dose inhalers (pMDIs), soft mist inhalers (SMIs), and dry powder inhalers (DPIs). Nebulisers atomise a liquid into a mist using mechanical action and are considered easier to use than inhalers; the user simply places the mouthpiece over their mouth and breathes normally. They are therefore commonly prescribed for young children, older or more frail patients, patients experiencing an asthma attack, or patients with comorbidities such as arthritis or visual or hearing impairments.
The development of handheld nebuliser technology overcomes some of the traditional limitations of nebulisers — in particular, making them more portable. Applications of handheld nebuliser technology include the nicotine industry as a way of developing e-cigarettes to be offered on prescription to patients as part of a smoking cessation regime. This brings advantages over traditional e-cigarette technology by improving repeatability and control, and potentially reducing levels of harmful and potentially harmful constituents associated with traditional heater coil systems.
Regulatory considerations
A handheld nebuliser marketed for nicotine delivery can achieve regulatory approval for the consumer market via the European Tobacco Products Directive (TPD). In the UK and EU, handheld nebuliser technology for medicines will go through the marketing authorisation application (MAA) route to market, as well as achieving either CE mark for European use, or UKCA marking for the UK market.
If nebulisers containing nicotine are to be available on prescription as medicinal products, the MHRA guidance suggests that the pMDI route should be followed. This means that part of the regulatory approval process involves demonstrating delivered dose uniformity (DDU). Unlike other inhalation therapy devices, products for nebulisation are not typically subject to DDU testing per inhalation and are instead measured on drug delivery rate and total drug delivered during a treatment time period. However, the guidance also states that a dose can be considered as ten inhalations. This takes into account the drug delivery rate over ten inhalations whilst giving allowances for potentially greater variability between individual inhalations.
Delivering the dose
DDU is typically measured over at least ten inhalations, from the beginning, middle and end of the product’s life, with at least three containers from two different batches tested. In the EU/UK, DDU specifications are 9/10 doses within 25% of the mean and 10/10 doses within 35% of the mean. The test setup typically involves firing the device into a sampling apparatus, where a filter collects the dose of active substance, which is then analysed, typically by using high-performance liquid chromatography (HPLC).
However, discussions are needed about whether these technologies should be classified as a pMDI or a nebuliser, as this would impact the EMA's Committee for Medicinal Products for Human Use (CHMP) requirements for DDU and drug delivery rate.
Designing for regulatory approval
There are simple things the manufacturer can do at the design stage to create a device that delivers acceptable DDU. Handheld nebuliser technology can be optimised (in terms of its vibration frequency, mesh size, and formulation characteristics) to control the particle size distribution of the resultant aerosol and hence influence the efficacy and drug delivery. For example, the frequency determines the amount and size of particles in the aerosol and can be fine-tuned to the viscosity and density of the formulation. Optimising a design at an early stage gives manufacturers the best possible chance of meeting regulatory criteria.
Navigating the route to market for novel inhalation therapy devices can be tricky. Working with a partner experienced in product development services, including regulatory applications, test methodologies, and product optimisation maximises your chances of efficiently bringing a new inhalation therapy to market.