Copley Application Specialist Clair Brooks discusses new EMA guidance on data requirements associated with the transition to low global warming potential (LGWP) propellants in metered dose inhalers and strategies for the successful application of in vitro testing within this context.
How does the 2023 EMA Q&A clarify data requirements for the LGWP transition with respect to information the regulators will request to support MDI reformulation?
The EMA document titled “Questions and answers on data requirements when transitioning to low global warming potential (LGWP) propellants in oral pressurised metered dose inhalers” covers data requirements associated with the transition to LGWP propellants in MDIs across different scenarios, ranging from an initial market authorization or extension application to a direct replacement in an existing product, with clear distinctions made for propellants already in use in approved products. The document references several established EMA guidelines, drawing attention to the existing route for demonstrating therapeutic equivalence to an existing reference product via in vitro testing alone.
Companies like Chiesi and AstraZeneca that are pioneering MDI reformulation are doing so with propellants that have not yet been approved as part of an inhaled product authorization, Chiesi with HFA 152a and AstraZeneca with HFO1234ze(e). In such circumstances, the quality data requirements outlined by the EMA include the provision of full details for the propellant, as required for the use of any novel excipient, and non-clinical data requirements extend to toxicology and pharmacokinetic assessment. In particular, the guidance highlights the need to test the impact of the propellant on ciliary function and airway sensitivity for the assessment of local tolerance as well as an evaluation of clinical safety via at least one study of at least 3 months duration.
However, since Chiesi and AstraZeneca are now into Phase 3 trials with the first LGWP MDIs, those following may soon be in the easier position of seeking approval with a propellant already in use in an approved OIP, at which point the focus narrows to product quality assessment and the demonstration of therapeutic equivalence. The new guidance includes specific data requirements relating to new propellant use such as the need to assess whether there are any “propellant aspects which may impact the usability of the product such as expelling pressure, taste, feeling in the mouth and flammability, as applicable,” for any target patient population, and to discuss and justify any changes to the device arising from a switch.
With respect to possible changes in exposure to the active ingredient(s), the EMA Q&A confirms the suitability of the existing stepwise route for demonstrating therapeutic equivalence — in vitro, to PK study, to PD study — indicating a pathway to market authorization via in vitro testing alone. Achieving this goal is undoubtedly demanding, but the availability of the route highlights the importance of leveraging in vitro test methods to maximum effect.
In the absence of specific guidance from the FDA relating to LGWP propellants, differences in the EMA and FDA requirements for generic submissions might be pertinent to the propellant transition. In contrast to the stepwise approach advocated by the EMA, both the FDA 505 (j) pathway for generics and the 502(b)(2) pathway for supergenerics favor a “weight of evidence” approach to the demonstration of therapeutic equivalence based on both in vitro and in vivo data. In this context, it can be argued that establishing more evidence from in vitro tests reduces reliance on in vivo testing and similarly points to the need for robust, reliable, and relevant in vitro methods.
