Dissolution is a critical factor in the successful delivery and uptake of orally inhaled drug products (OIDPs). Bioavailability and therapeutic effect, both locally and systemically, are known to be influenced by the dissolution characteristics of aerosolised particles in the fluid lining the respiratory tract.
As such, in the development of generic OIDPs, dissolution testing plays an increasingly important role in demonstrating expected in vivo performance as part of a regulatory submission. Indeed, within the US Food & Drug Administration’s (FDA) recently updated product-specific guidances, comparative in vitro dissolution data is included as part of the evidence base for evaluating bioequivalence for dissolution-rate limited drugs only.
But while other dosage forms, such as oral tablets, have established mechanisms for determining dissolution kinetics, the same cannot be said for OIDPs. Currently, there is no industry-endorsed standardised method either for the collection of aerosolised doses from devices such as metered-dose inhalers (MDIs) and dry-powder inhalers (DPIs), or for approaches to develop and validate dissolution methodologies.
Nanopharm has successfully pioneered important developments in this area over recent years, applying its extensive expertise in inhalation science to deliver advances in dissolution testing in lockstep with the FDA’s evolving position. A foundational part of this work was a study, carried out with the backing of FDA grant funding, detailing the development of a robust and standardised aerosol dose collection system that would allow for accurate in vitro assessment of dissolution and microstructure in OIDPs.1
Within the dose collection process, capturing a homogenous distribution of the full aerosolised dose onto a membrane is a prerequisite for facilitating accurate dissolution measurements, but it presents a difficult challenge. The study evaluated the performance of Nanopharm’s bespoke aerosol dose collection (ADC) system in this context, with the design optimised to collect the entire impactor stage mass dose on a high surface area filter under low airflow velocity.
The system was validated for dose independency through comparison to in vitro Next Generation Impactor recovery based on increasing numbers of actuations, with the results showing good correlation. Visualisations using alcoholic ink also highlighted that the dose was uniformly deposited across the whole filter surface, while minimal aggregation and in situ agglomeration formation was confirmed via representative scanning electron microscope (SEM) micrographs.
Dissolution studies were carried out on the collected samples using an adapted USP Apparatus V (Paddle over Disk) to derive data on dissolution characteristics. This included dissolution release profiles for fluticasone propionate (FP) 250 µg DPI and 125 µg MDI; investigation into the relationship between mean absorption time and dissolution kinetics for a series of low solubility inhaled corticosteroids; and dissolution characteristics of three different product strengths of FP MDI, FP DPI, and salmeterol/FP DPI products.
Ultimately, the findings showed that the dissolution profiles obtained using the ADC, both for commercial MDI and DPI products, were independent of loaded dose over a wide range of drug loading. Evidently, with lower variability in the collected dose, there was a corresponding lowering of the risk of variability in the dissolution analysis. The ADC could, therefore, be shown to provide a highly reliable platform for allowing quantitative comparisons to be made between formulation characteristics and dissolution behaviour.
In the wake of these conclusions, the ADC system has been further developed by Nanopharm, becoming established as a standardised method for dissolution comparison as part of our alternative bioequivalence offering. Known as DissoHale, the system facilitates robust evidence-gathering based on the collected aerosol dose, whether in terms of dissolution or microstructural assessments (e.g. via MDRS).
Crucially, DissoHale sits entirely in line with the FDA’s evolving position on the use of advanced in vitro and in silico methods to demonstrate bioequivalence for generic OIDPs. Indeed, the FDA’s product-specific guidances explicitly advise applicants to describe the method used for dose sample collection. This sends a clear message that scrutiny will be applied in this area, and that regulatory expectations are centred around the use of validated, discriminatory, dose independent models.
As evidenced by the findings from this study, which itself was supported by FDA grant funding, suitable aerosol collection apparatus such as DissoHale rise to this challenge. For generics companies, it underlines the value of combining validated approaches with proven expertise in inhalation science to accelerate and simplify the development of generic OIDPs.
In the next chapter we will review ‘A Systematic Approach in the Development of the Morphologically-Directed 2021’. In the meantime you can download the full white paper here. To find out more about how how we can support your alternative bioequivalence pathway, please contact Dan Morland at d.morland@nanopharm.co.uk.
