The challenges associated with dissolution for inhaled and nasal products stem from the fact that there is no set method defined in the USP that covers them. The sponsor will need to evaluate which of the four commonly used dissolution methods would be the most appropriate for their product or whether a bespoke method is required. Specialist CRO’s often have experience with multiple customers / products and can certainly help with the selection.
From what I have observed, most researchers use USP Apparatus 2 (paddle) or USP Apparatus 5 (paddle over disk), and the University of Bath and the FDA have published methods for evaluating BE for mometasone furoate suspensions using this approach. In every case, sponsors will need to conduct some method development and validation to ascertain a suitable solvent system, stirring speed, sampling times, etc. It is also worth remembering that this test is a comparison of T vs R, and thus the media used does not necessarily have to mimic the properties of nasal mucosal fluid.
Do you expect the agency will allow alternative approaches to BE testing for other OINDPs?
The FDA has expressed its interest in developing alternative approaches for inhaled drug products, including MDIs and DPIs, in a number of forums, including recently at RDD Europe 2023 and at a workshop the agency co-sponsored with the Center for Research on Complex Generics.
There is scope for this in the future, but it requires more work and understanding to bridge what is generally a larger in-vitro to in-vivo gap for inhaled products (compared with nasal). The platform and framework have, however, been put in place with these latest guidance updates.
For now, this still seems some time away, but many groups are working on optimizing current analytical test methods and developing new in-vitro and in-silico tools to hopefully one day make this a reality. Some of the tools that have drawn interest from the FDA include the use of anatomical throat models and realistic breathing profiles for advanced APSD; new dissolution methods; the use of sub-micron particle sizing techniques to complement MDRS; and Fluidda’s functional respiratory imaging (FRI).
