Developing the Next Generation of Inhalers
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Pressurized metered dose inhalers (pMDIs) are the dominant form of treatment for millions of asthma sufferers. But, with the need to phase out high global warming potential (GWP) propellants that are currently integral to device function, what does the future look like for pMDI use?
Inhalation therapy is a cornerstone of treatment for many respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and asthma. These two conditions affect hundreds of millions of people globally – an estimated 328 million people suffer from COPD and 262 million from asthma.
The popularity of pMDIs
Since their introduction in 1956, pMDIs have become the dominant treatment of choice for common respiratory diseases – a search of the IQVIA database shows that, in the 12 months prior to June 2019, there were over 480 million prescribed – approximately 2,400 doses are taken every second somewhere in the world. The prevalence of pMDIs is related to their economics; pMDIs are cheaper to produce than dry powder inhalers, for example. Studies also show that they result in better outcomes, a 2019 study found that switching from dry powder inhalers (DPIs) to pMDIs was associated with decreased asthma exacerbations and improved asthma control.
The basic makeup of a pMDI is a drug formulation (in suspension or solution) with a closure that delivers the required dosage efficiently and consistently. Typically, they are in the form of a pressurized canister that contains the active substance and propellant, a plastic holder or housing, and a mouthpiece.
The problem with pMDIs
The main problem with pMDIs is their large carbon footprint – they reportedly account for three percent of the NHS’s annual carbon emissions (13 percent within primary care). This large footprint is predominantly due to the use of certain propellants, whose role in the device is to provide the pressure needed to atomize the drug formulation into an aerosol.
When pMDIs were first brought to market, the propellants of choice were chlorofluorocarbons (CFCs), as these offered good toxicological profiles and the required physical properties. However, these were phased out following the Montreal Protocol in 1987, to help protect the stratospheric ozone. This came at a great cost to pharmaceutical businesses, which invested millions into bringing alternative products to market.
Hydrofluorocarbons (HFCs), part of a group of greenhouse gases known as F-gases, were the replacement for CFCs and are now relied upon as pMDI propellants. While they lack the ozone-damaging properties of CFCs, they remain potent greenhouse gases, with GWPs of up to 3,350 times that of CO2. The EU began regulating the use of HFCs more than a decade ago, and a 2016 amendment to the Montreal Protocol, known as the Kigali Amendment, now targets a complete phase-out.
Another thing to consider is the regulations surrounding per- and polyfluoroalkyl substances (PFAS). In July 2021, the Organization for Economic Cooperation and Development (OECD) updated its definition of PFAS to include certain medical-grade F-gases that can be used as propellants. However, Germany, the Netherlands, Denmark, Norway and Sweden have proposed restrictions on PFAS in Europe, which will likely involve a more stringent timeline than the F-gas regulations. Nevertheless, this remains a fluid situation and is currently under consultation.
The UK has already laid out plans to regulate the use of high-GWP pMDIs as the NHS works towards Net Zero. The concern is that the introduction of regulations before the pharmaceutical industry is ready could result in a shortage of medicines – and affect the treatment of hundreds of millions of people.
What does the future look like?
To reduce the carbon footprint of the treatment of respiratory disease, the first option is swapping pMDIs for another type of device, such as a DPI. These devices deliver medicine to the lungs in the form of a dry powder, with the formulation typically held in a capsule. DPIs contain no propellants and estimates of their lifecycle carbon footprint are reported to be 24 times lower than a propellant-based device. However, some patients may not be able to generate sufficient inspiratory flow to actuate a DPI correctly, meaning they are not suitable for every patient. Cost is another concern, as DPIs are currently more expensive to produce, although this may change with time.
A total shift away from pMDIs seems unlikely after many years of dominance. Instead, it is expected that many pharmaceutical businesses will be redesigning pMDIs with alternative propellants. So far, two strong contenders have been identified: HFC 152a (GWP = 138) and HFO 1234ze (GWP = <1).
Incorporating new propellants will require long-term human safety studies, extractables and leachables assessments, chemical stability testing and compatibility with existing formulation components (the API or excipients) to be established before a market authorization is granted. Pharmaceutical manufacturers may also have to invest in new manufacturing equipment and processes. Completing these processes will be expensive and time-consuming for pharmaceutical businesses, who will be looking for ways to make the change as efficiently and cost-effectively as they can, while still ensuring patient safety.
Work is already underway to introduce novel propellants – in 2022, Koura opened the world’s first HFC 152a production facility for pMDIs in Runcorn, UK, which Chiesi Farmaceutici has agreed to use for product development and clinical trials. AstraZeneca, on the other hand, is working on an HFO 1234ze pMDI, which has already passed through Phase I clinical trials. Both companies have announced ambitious plans to launch their new pMDIs by 2025. Smaller companies are working on products too, typically alongside inhalation specialist CROs to help expedite their route to market.
The next few years is a critical time for the development of inhaled medicine devices. It is likely we will see higher prescription rates of DPIs, but also the continued development of low-GWP propellants, so that pMDIs can continue to treat respiratory disease patients across the globe, without contributing to climate change.
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