Against a backdrop of intense efforts to realise the full potential of intranasal drug delivery, test requirements can be difficult to navigate. In this Q&A, Jamie Clayton, CEO, shares insights into how the market is evolving and what this means for testing.
In this blog:
- A snapshot of the current nasal drug product market.
- How nasal drug product testing is evolving to meet changing development needs.
- A review of compendial specifications and current gaps.
Estimated reading time: 10 minutes
How does the nasal drug product market look right now?
The nasal drug product market is buoyant, with much of the current interest driven by the expanding range of intranasal applications.
Most nasal drug products act topically to relieve symptoms of conditions such as rhinosinusitis, allergies and colds. These medicines, often sold over the counter (OTC), currently dominate and underpin the commercial nasal drug product market.
But they are not the primary focus of research.
In recent decades, nasal drug products have been commercialised for:
- Vaccination, particularly for respiratory pathogens.
- Systemic drug delivery.
- Bypassing the blood brain barrier, for direct drug delivery to the central nervous system (CNS).
Examples include nasal flu vaccines, nasal sprays for migraine treatment, and rescue medicines such as Baqsimi and Narcan for the emergency treatment of hypoglycaemia and opioid overdose, respectively. These products illustrate the compelling advantages of the intranasal route: ease of administration and patient acceptability, rapid onset, and avoidance of first-pass metabolism.
It is potential in these areas that drives much of the current research, and which, by extension, dominates discussions around testing.
Why is nasal drug product testing changing?
Nasal drug product testing is changing because newer applications require developers to understand more about where the dose goes and what happens after deposition. For traditional topical products, established test methods focus largely on characterising what leaves the device and the potential for drug to penetrate to the lungs. Established nasal drug product test methods provide the information needed to guide this process, focusing on:
- The geometry and dimensions of the delivered spray.
- The size of the droplets within it.
- The fraction of fine particles (<10 µm), and by extension the likelihood of drug penetration to the lung.
However, for applications such as vaccination, systemic and nose-to-brain drug delivery there are additional factors to consider, including:
- Regional deposition in the nasal cavity. For instance, the nasopharynx may be targeted to induce mucosal immunity while the olfactory region is the preference for nose-to-brain delivery.
- Rate of product clearance. How quickly the drug clears from its deposition site via mechanisms such as mucociliary clearance relative to…
- …Rate of product uptake. How quickly the drug dissolves, beginning the journey from deposition site to the site of drug action.
In other words, newer applications require more information and a better understanding of how to deliver the drug to the target site while preventing it from reaching areas it should not.
This information drives both device and formulation development, which are advancing rapidly. Nasal drug products may be sprays, powders or aerosols; single-dose or multidose; and may use active or passive delivery mechanisms. Formulations are also becoming more complex, with developers turning to ingredients such as mucoadhesive agents and permeation enhancers, or advanced powder engineering, to navigate the intranasal route precisely.
For testing, this means developing new or extended methods that are effective and relevant across a widening range of products and applications, and that provide information not only on what leaves the device, but where the dose deposits and what happens next.
What guidance is available for nasal drug product testing and where are the gaps?
Regulatory guidance, including FDA product-specific guidances, and compendial specifications are available for core aspects of nasal drug product testing, but important gaps remain, particularly for newer areas such as regional deposition and dissolution testing.
Established guidance broadly aligns with that for relevant orally inhaled products (OIPs). More specifically, nasal aerosol and nasal powder testing requirements are somewhat aligned with those for MDIs and DPIs, respectively, except for particle-sizing requirements.
Recent updates of most relevance to nasal drug products include revised EMA guidance, the new Ph. Eur. Chapter 2.9.54, Uniformity of Delivered Dose of Inhalation and Nasal Preparations, plus revisions to the Ph. Eur. monograph on Nasal preparations (0676). A further new chapter – 2.9.56 – is also in preparation. These updates will bring clarity on the use of abbreviated impactor systems and test set-ups for assessment of the sub-10 μm fraction respectively.
However, gaps in the guidance will remain, most noticeably where there has been relatively rapid evolution of the technology and its application.
For example, there is no guidance on assessing regional deposition within the nasal cavity, and no compendial specification. This is also true for dissolution testing.
Even where compendial specifications exist, as with delivered dose uniformity (DDU) testing, they are arguably less prescriptive than those for OIPs. Instead, they identify factors to consider, leaving ample room for interpretation.
The result is considerable uncertainty about how to develop a defensible testing strategy for a specific product or application.
What testing challenges are you most often asked about?
The questions we’re asked most often concern choosing the best test set-up for DDU testing, assessing regional deposition within the nasal cavity, and how best to quantify the sub-10 μm fraction. We’re also increasingly asked about the relevance of dissolution testing.
For DDU testing, the need for vertical or near-vertical actuation raises the question of how to ensure complete dose collection, while the need to consider or apply mechanical actuation points towards automated firing.
Following the dose from the device, the next challenge we’re routinely asked about is how to assess regional deposition in the nasal cavity. Debate tends to centre on whether to use an anatomical nasal cast or a more idealised nasal geometry, such as the Alberta Idealised Nasal Inlet. Nasal casts are clearly more physiologically realistic, but only for a very narrow patient population. Drug recovery can also be difficult, leading to poor reproducibility. For routine testing, idealised or averaged geometries are therefore likely to become the preferred option, as they have for mouth–throat geometries.
The risk of off-target deposition raises the question about the best way to assess the sub-10 μm fraction, which potentially penetrates to the lung. Issues routinely raised in this area include the suitability of laser diffraction and the optimal test set-up for different devices, notably whether to use a full multistage cascade impactor or abbreviated apparatus. We have an excellent blog on the risks of using laser diffraction and plenty to reference on cascade impaction for nasal drug products, though the planned compendial chapter will undoubtedly be helpful in clarifying requirements.
Lastly, I’m routinely asked about the relevance of dissolution testing for nasal drug products, as this is a hot topic for OIPs. Dissolution is the first step towards systemic delivery via the nose with the low volume of nasal fluid and mucociliary clearance combining to create challenging conditions for drug dissolution and absorption. Dissolution testing is therefore relevant for all non-topical therapeutics. There is extensive literature on OIP dissolution testing to draw on, and test set-ups can be readily modified for nasal drug products.
What should laboratories be watching for next?
Laboratories should be watching emerging regulatory and compendial requirements, evolving best practice and the growing emphasis on patient-relevant testing. More specifically, updates to Chapter 2.9.18 and the new Chapter 2.9.56 will be important milestones.
Nasal drug product testing is evolving rapidly, and compendial methods will need to keep pace. Although formal refinement may take time, laboratories should actively monitor regulatory thinking and emerging best practice. Nasal drug products are already a key focus for groups such as the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS), as demonstrated by the recent Nasal Innovation Forum. Engaging with these initiatives will help laboratories anticipate change and build more robust, defensible testing strategies.
Just as important will be the development of genuinely patient-friendly products: devices that a broad patient population can use easily and consistently. Insertion angle, insertion depth and inhalation manoeuvre can all significantly influence delivery to the target site. Realising the full potential of intranasal drug delivery will therefore depend on device designs that promote correct use, supported by testing that guides development and reveals the consequences of incorrect patient technique.
In subsequent posts in our nasal blog series, we’ll explore these testing challenges in greater depth and share updates as best practice takes shape. Register now to stay informed and ensure you don’t miss the practical guidance to come.
