What products are covered by the new guidance, and what are the potential benefits of avoiding a comparative clinical endpoint BE trial?
The February PSG releases included 14 updates and 6 new guidances for OINDPs. It is these new PSGs that are especially interesting.
| Active Ingredient | Route | Dosage form | RLD No. |
| Budesonide / formoterol fumarate / glycopyrrolate | inhalation | aerosol, metered | 212122 |
| Formoterol fumarate / glycopyrrolate | inhalation | aerosol, metered | 208294 |
| Mannitol | inhalation | powder | 022368 |
| Mannitol | inhalation | powder | 202049 |
| Zanimivir | inhalation | powder | 021036 |
| Naloxone hydrochloride | nasal | spray, metered | 208969 |
While the updated guidances for inhaled products maintain the classic route for the demonstration of BE, the new PSGs include alternative, clearly defined clinical endpoint-free routes for all 5 of the listed inhalation products. The mannitol and zanamivir products are all dry powder inhalers; the other two are suspension metered dose inhalers. With respect to nasal drug products, both revised and new PSGs include alternative approaches for establishing BE. The agency then issued additional similar PSGs for suspension MDIs, DPIs and nasal sprays in May and August.
Does the guidance call for the adoption of new in vitro testing strategies?
Yes. Although most of the in vitro tests will be familiar – single actuation content (SAC), aerodynamic particle size distribution (APSD), priming and repriming, plume geometry and spray pattern – there are also new and/or extended test requirements. These include realistic APSD, dissolution, and characterization of the polymorphic form of the drug substance, as proposed for zanamivir. Particle morphology of the emitted dose as typically measured by Morphologically Directed Raman Spectroscopy (MDRS) is now increasingly referenced across both classic and alternative strategies for establishing BE.
For completeness, it is also worth noting that the new PSGs additionally call for charcoal block PK studies when demonstrating BE in the absence of a clinical endpoint and highlight the potential benefits of deploying techniques such as computational fluid dynamics (CFD) and physiologically-based pharmacokinetic (PBPK), though application remains optional.
