An observation of generics in the nasal spray market will reveal to the keen observer an opportunity. Whilst the overall nasal spray market is currently experiencing limited growth, the market share of generics is increasing at a much faster rate. Seeing this, Nemera has established a unique approach for developing devices in this field. This approach follows seven steps:
1. Understand the market and identify the best reference nasal sprays to target.
2. Appraise the regulation and, by isolating the most stringent requirements, use it to drive the programme.
3. Establish the identity of the device (e.g. bill of materials, performance, patient use) using a supply of the reference from different markets.
4. Develop the device, based on Nemera’s pump platform, to have equivalent performance to the reference device with the reference drug formulation.
5. Test the performance, comparing the Nemera device with the reference with iso-formulation in a comprehensive study, to demonstrate bioequivalence.
6. Prepare the “datapack” containing robust statistical analysis to be delivered to the client, the data therein being used simultaneously to support the drug registration process and justify the device selection.
7. Repeat the study with the final drug.
Understanding the market
Over half of the topical nasal preparations market is for corticosteroids, due to the fact that they remain the frontline treatment for moderate to severe allergic rhinitis as the most effective option for relieving nasal symptoms. The second thing to note is that the entire topical nasal formulations market is growing and evolving.
There are two key trends that can be observed as driving this evolution: the increasing competition from generics and the established brands shifting from a prescription-only to an over-the-counter (OTC) model.
Such trends are to be expected in a mature market and contribute to steady growth. However, the generics market will increase significantly. As such Nemera has selected a number of corticosteroids as part of their bioequivalence program.
Appraising the regulation
When looking at ICS as a global market it is important not to underestimate the complexity of the regulatory landscape. Across the world there are several co-existing regulatory ecosystems, each with a different approach to bioequivalence:
• US FDA is the most frequently mentioned, often considered to have the most stringent regulation.
• EU regulation has the nuance that each member country may have a different interpretation of the regulations and directives.
• China CFDA regulation is still very much under construction, even if the aim seems to be to synchronize with the US FDA.
As Nemera focuses on the most stringent regulation during development, here we shall use the FDA as the exemplar for how Nemera supports the registration process. Under FDA guidelines, whatever the regulatory position of the targeted reference product (i.e. prescription only or OTC not under monograph), a generic product will follow the same process for its first submission and must therefore answer to the same requirements. When modifying the dossier, that is to say when making a variation upon the first submission (e.g. to add a second source), there are two ways to go about it. The first is to repeat the same process as the first submission and the second is to use a simple equivalence of performances of the pumps, thereby bypassing the need to follow the full guidance on bioequivalence for generics.
When going through the process of registering a generic however, it may be more relevant for authorities to compare the variation directly to the reference product. That is why it is important to test bioequivalence directly from the original reference product. Thanks to its deep experience with these processes, Nemera can strongly support a submission document with the chapters linked to the device.
Establish the identity
In simple terms, a nasal spray is the combination of two regulated products, a drug and a device, which together make the combination product. Nemera’s expertise is in the latter of these two, the spray device, but it remains crucial to acknowledge throughout the design process that the device is part of the greater combination product. The device is a major contributor to treatment efficacy, patient safety and robustness of the combination product.
Nemera performs studies to ensure that the three main functions of device performance are under control at all stages of development:
• Preserving drug product integrity
• Delivering an exact preset dose
• Delivering drug product to the targeted site
Develop the device
The discussion of device identity invariably brings us to the spray, which in point of fact is the hardest aspect to control, thus it is spray generation where the greatest effort must be expended during development of the device. With this in mind, let’s turn to the heart of a nasal spray device: the pump. The pump has multiple functions, one previously touched upon is metering, ensuring the delivery of a preset dose.
Another primary function of the pump is to generate a flow and, furthermore, control flow rate and pressure level to master the generation of the spray. The flow rate and pressure profiles are dependent upon the pump technology and the actuation profile, with the nominal dose of the pump also having influence due to its impact on spray duration.
Moving from heart to head, the next key part of the device to focus on in development is the nozzle, which is surprisingly complex. Inside a nozzle tip are several vertical channels which then enter into convergent channels to move the rising liquid into a swirl chamber before exiting through the orifice at the tip of the nozzle. It is noteworthy how small the dimensions of all these parts are, typically in the range of 0.2-0.4 mm, especially given the complex geometry. As such, high precision manufacturing is required to ensure that the final combination product generates a consistent spray after scale-up to industrial manufacture.
The spray forms the basis for analyzing how well and how consistently the device will deliver drug product inside the nasal cavity. These droplets, and hence the spray, are hugely impacted by the viscosity, and to a slightly lesser extent the surface tension, of the drug formulation. Batch-to-batch variability of viscosity can be significant and must be taken into account when designing a spray with a defined target as is the case in the bioequivalence approach. Because the impact of viscosity is so tremendous, the factors that affect viscosity, such as temperature, the delay between actuations and the fluid memory effect (i.e. whether or not the product has been shaken), must in turn be considered.
Nemera approaches this complex development process with multiple tools:
• Experimental testing and a database of results helps track input and performance data as well as aiding in the analysis of influencing factors and trends.
• The capacity to manufacture fully functional, novel nozzles in a matter of weeks, including metrology control, enables the exploration of the design space and shorter tuning loops.
• Computational fluid dynamics (CFD) modelling allows for a richer understanding of the physics involved. CFD can also be used to run sensitivity analysis on specific parameters, as seen earlier in this article.
• Finally, mathematical modelling makes the link between input variables and output performance.
Understanding the sensitivity of the performance in the design space allows the set-up of control strategies, ensuring robust and controlled performance when it comes to mass production. And, by incorporating data analysis and mathematical modelling into development, Nemera achieves acute refinement of the design, all building to one ultimate goal: to have the spray on target.
Testing the performance
Nemera has developed its own testing laboratory using cutting-edge technology.
Customized testing methods are used to cover all aspects of a nasal device from broad parameters (dosage accuracy, leakage, weight loss, etc) to in-depth spray characterization (droplet size distribution, spray pattern, plume geometry). Tests are also performed on the component materials to establish extractable profiles. All of which can be customized to the needs of clients and partners.
Nemera brings great benefits to partners looking to develop a generic nasal spray, a process far more complex and involved than it may first appear, but which growing market demand worldwide shows is increasingly likely to be a worthwhile endeavor. Able to offer expertise in market understanding, regulatory affairs, device development and statistical analysis, Nemera also prides itself on being a co-operative, committed and responsive device design partner.