The 3Es of MDI Reformulation: Economics, Equivalence and Efficiency

Assessing the market impact of transitioning to low global warming potential (GWP) metered dose inhalers (MDIs), new EMA guidance and the associated analytical demands.

Depending on your perspective, it may be exciting, impressive, sobering or stressful to think that low GWP MDIs are expected to become a commercial reality next year.

In 2019, when Chiesi Group announced plans to launch ‘the first carbon minimal pressurised metered dose inhaler’, the target date of 2025 must have seemed a distant ambitionⁱ. However, recent updates suggest on-track progress with Phase I and IIa trials using HFA-152A as a replacement propellant^i,iii. AstraZeneca is similarly successfully through Phase I trials and has commenced Phase III with a combination of budesonide, glycopyrronium and formoterol fumarate in an HFO1234ze formulation^ii,iii. And just recently GSK added its first public announcement in the area, announcing plans to start Phase III trials of a low carbon version of its salbutamol MDI product Ventolin, using a next generation propellant, in the first half of this year^iv. A new Q&A from the European Medicines Agency on data requirements for the demonstration of bioequivalence (BE) for low GWP orally inhaled MDIs reflects this growing momentum^v.

The need for re-formulation is directly associated with the Kigali Amendment to the Montreal Protocol and the associated EU regulation on Fluorinated gases (F-gases), which both require phase down of the production and use of HFCs (hydrofluorocarbons)^vi. Alongside these regulations there is also an industry desire to move away from HFCs based on individual company goals to reduce Scope 3 emissions in line with ESG (Environment, Social and Governance) strategies. Either way, the MDI landscape looks set for a seismic shift, and sooner rather than later.

Economics: The ripple effects of Kigali and early reformulation success

Propellants account for a large proportion of MDI manufacturing costs: ~30% in the case of an HFA 134a MDI^vii. The potential for fluctuations in market price to directly impact the economics of the MDI market is therefore considerable.

Developed countries are leading the way with respect to implementing the Kigali Amendment and we can already see the associated impact on market price. A 2020 report from the European Commission noted that ‘the price of conventional HFCs on the EU market has been strongly affected by the phase-down’ ^viii, with HFC costs steady but still ‘several times higher than on the world market’ ^ix, around that time.

Over coming decades such effects are likely to ripple around the globe as the respective regulations and international agreements are progressively implemented. The HFC market will gradually tighten, and higher prices are inevitable. This phenomenon has been seen before, indeed it could be argued that this was precisely the effect that, ultimately, drove the first major MDI reformulation of the transition away from CFCs. As change accelerates, the componentry associated with HFC MDIs will also become scarcer, putting further pressure on costs.

What this means is that even if your company doesn’t have urgent Scope 3 emission targets to meet, and even if you’re in a part of the world where the Kigali timescales extend out to the 2040s, the economic imperative to transition will grow.

And the prize for early success? Healthcare providers also have ambitious net zero targets to meet and may embrace alternative devices but for some applications, notably acute relief, MDIs are uniquely attractive. There is a well-defined need for competitively priced low GWP MDIs.

Equivalence: The requirements of re-formulation

The new EMA Q&A elucidates the path to regulatory approval for reformulated products, pointing to the possibility of demonstrating BE via in vitro testing alone. Once HFA-152A- and HFO1234ze-based MDIs have been commercialised, these propellants will become ‘established’ rather than ‘new’ which means information on local tolerance and clinical safety will no longer be required for each application; BE testing will become the defining focus of reformulation efforts.

The Q&A references the criteria listed in EMA guidance from 2009 for the in vitro demonstration of BE, including the need to demonstrate that^x:

Any qualitative and/or quantitative differences in excipients should not influence the performance of the product (e.g. delivered dose uniformity, etc.), aerosol particle behaviour (e.g. hygroscopic effect, plume dynamic and geometry) and/or be likely to affect the inhalation behaviour of the patient (e.g. particle size distribution affecting mouth/throat feel or “cold Freon” effect).

These criteria highlight how, with the right in vitro methods, we can not only confirm that a reformulated MDI will perform the same but also that it will deliver a comparable ‘user experience’ for the patient.

Efficiency: Lightening the testing load

It follows that effectively leveraging all relevant in vitro methods is key for those looking to bring low GWP MDIs to market as quickly as possible and it is helpful to highlight the benefits of automation within this context. For MDI testing, selective automation is associated with two critical gains:

• Reduced variability, an improvement in precision that enables more robust BE assessment.
• Higher productivity, an increase in throughput with less manual input.

Consider for example a switch from manual device actuation – where the analyst shakes, primes and actuates the MDI – to the use of an automated shake and fire platform. Experimental studies indicate that this can deliver a time saving of around 30% while at the same time having a statistically significant, positive impact on the precision of both delivered dose and APSD data^xi. To say nothing of the improvement in health, safety and motivation for analysts routinely carrying out arduous tasks such as the firing to waste associated with through life testing. Commercial tools for automating specific aspects of drug recovery, from dose uniformity sampling apparatus and cascade impactors, offer similar benefits.

In summary, if you’re in the foothills of MDI reformulation and assessing the climb, then consider the following:

• The economics are complex and dynamic, the status quo may not remain economically viable for that long.
• Demonstrating BE via in vitro testing alone is sure to be the quickest and least expensive approach; sharpen your in vitro tools accordingly.
• Invest in automation solutions to lighten the testing load and improve data quality.

In future blogs, we’ll be covering the tests used to demonstrate BE in more detail but if your focus is automation then take a look at the new Vertus III, our automated shake, fire and flow control platform. With a range of interchangeable plates, it makes stepping through many of the tests associated with demonstrating BE straightforward and efficient.

ⁱ Chiesi news release, 27/07/2022. Available to view at: https://www.chiesi.com/en/first-carbon-minimal-pmdi-is-on-track-with-the-goal-to-benefit-patients-and-planet/.
ⁱⁱ F. Buttini et al ‘Metered dose inhalers in the transition to low GWP propellants: what we know and what is missing to make it happen, Expert Opinion on Drug Delivery, 20:8, 1131-1143.
ⁱⁱⁱ AstraZeneca news release, 22/02/2022. Available to view at: https://www.astrazeneca.com/media-centre/press-releases/2022/astrazeneca-progresses-ambition-zero-carbon-programme-with-honeywell-partnership-to-develop-next-generation-respiratory-inhalers.html.
^iv GSK news release, 21/11/2023. Available to view at: https://www.gsk.com/en-gb/media/press-releases/gsk-announces-major-step-towards-sustainability-ambitions-with-advancement-of-low-carbon-ventolin-programme-to-phase-iii-trials/.
^v European Medicines Agency, Committee for Medicinal Products for Human Health, ‘Questions and answers on data requirements when transitioning to low global warming potential (LGWP) propellants in oral pressurised metered dose inhalers’, EMA/477469/202323, 30 October 2023.
^vi UK Government explanatory memorandum. Available to view at: https://assets.publishing.service.gov.uk/media/5a81d9dd40f0b62302699809/EM_Kigali.pdf
^vii J.N Pritchard ‘The Climate is Changing for Metered Dose Inhalers and Action is Needed.’ Drug Des Dev Ther 2020; 14: 3043- 3055.
^ix European Commission report, 16/12/2020. Available to view at: https://climate.ec.europa.eu/system/files/2020-12/20201216_c_2020_8842_en.pdf.
^x European Medicines Agency, Committee for Medicinal Products for Human Health, ‘Guideline on the Requirements for Clinical Documentation for Orally Inhaled Products (OIP) including the Requirements for Demonstration of Therapeutic Equivalence between Two Inhaled Products for use in the Treatment of Asthma and Chronic Obstructive Pulmonary Disease (COPD) in Adults and for use in the Treatment of Asthma in Children and Adolescents.’ CPMP/EWP/4151/00 Rev. 1 ,22 January 2009.
^xi A Sule et al ‘Comparative evaluation of automation shake and fire system vs. manual inhaler for pMDI inhaler’ Respiratory Drug Delivery 2016.