Metered Dose Inhalers (MDIs)

Inhaled therapy is essential for the treatment of asthma and chronic obstructive pulmonary disease (COPD).

Why MDIs and DPIs are both used. There are two main types of inhalers for the delivery of respiratory drugs: the metered dose inhaler (MDI), which uses HFCs (mainly HFC-134a, and some HFC-227ea) as the propellant and the dry powder inhaler (DPI). The choice of the most suitable inhaler is a complex decision taken between doctor and patient. MDIs with spacers provide a cost-effective option for patients with low inspiratory flow, such as patients with severe lung disease and very young children, and for severe asthma attacks (where nebulisers are the alternative).

“Complex considerations are necessary when patients and healthcare professionals make an informed choice about a patient’s inhaled therapy, taking into account therapeutic options, patient history, patient preference, ability (e.g., dexterity, inspiratory flow, vision) and adherence, patient-borne costs, as well as environmental implications, with the overall goal of ensuring patient health. Patient choice may be enhanced with an increase in publicly available information about the environmental impact of different inhaler products. Healthcare professionals and their patients may benefit from this information to take environmental impact into account in their choice of inhaler.”
Ref: United Nations Environment Programme (UNEP) Medical and Chemical Technical Options Committee 2022 Assessment Report.

Asthma and chronic obstructive pulmonary disease (COPD) are the most common chronic diseases of the respiratory tract.

Asthma increased rapidly in the second half of the 20th century, but its prevalence continues to increase in the developing world, partly due to air pollution and now affects over 330 million people worldwide. Both are identified as key health targets by the WHO.

MDIs use a propellant to deliver drug to the lungs.

“An inhalation propellant must be safe for human use and meet several other criteria relating to safety and efficacy. Traditionally the list would include: (i) liquefied gas, (ii) low toxicity, (iii) non-flammable, (iv) chemically inactive and stable, (v) acceptable to patients (in terms of taste and smell), (vi) appropriate solvency characteristics, and (vii) appropriate density.” From the United Nations Environment Programme (UNEP) Medical and Chemical Technical Options Committee 2022 Assessment Report.

HFC based MDIs were introduced in the EU in 1994 to replace CFCs. MDIs have been subjected to extensive regulatory assessments for safety, efficacy and quality. HFC MDIs are available to cover all key classes of drugs used in the treatment of asthma and COPD. The number of patients using HFC based asthma inhalers in the EU is estimated to be at least 10 million.

Ref: International Primary Care Respiratory Group – Potential impact of the draft PFAS legislation on patients with asthma and chronic lower respiratory diseases in the European Union | IPCRG.

New Low GWP propellants for MDIs.

Irrespective of their proven benefits for the treatment of asthma and COPD and their continued availability under the F-Gas Regulation, the GWPs of HFC-134a (F-Gas AR4 1430) and HFC-227ea (F-Gas AR4 3220) have increased the focus on their use as propellants for MDIs. However, the selection of a potential candidate and a new propellant development programme requires significant investment.

“An inhalation propellant must be safe for human use and meet several other criteria relating to safety and efficacy. Traditionally the list would include: (i) liquefied gas, (ii) low toxicity, (iii) non-flammable, (iv) chemically inactive and stable, (v) acceptable to patients (in terms of taste and smell), (vi) appropriate solvency characteristics, and (vii) appropriate density. Not all of these requirements may be essential for an alternative propellant, but careful study and justification would be required to support any significant change. It is, however, extremely difficult to identify chemicals fulfilling all of these criteria, and which are also environmentally acceptable.”
Ref: United Nations Environment Programme (UNEP) Medical and Chemical Technical Options Committee 2022 Assessment Report.

New Low GWP Propellants

In December 2019, a European pharmaceutical company announced a low GWP HFC-152a metered dose inhaler (MDI) with plans to introduce it by the end of 2025. HFC-152a will reduce the carbon footprint of the MDI by about 90% to a level similar to a dry powder inhaler (DPI), due to its low GWP (F-Gas AR4 124). The boiling point of HFC-152a (-24.7°C) is very similar to that for HFC-134a (-26.2°C). However, whereas HFC-134a is non-flammable, HFC-152a is moderately flammable with a lower flammable limit (LFL) of 3.8%, and therefore its adoption requires MDI manufacturing to address additional flammability safety issues. Inhalation safety and toxicology studies are also required. Work to fill in gaps in the industrial toxicity was initiated in 2016 and is now successfully completed. A Drug Master File is expected to be completed soon, and a medical grade production facility was opened in March 2022.

In January 2020, another European pharmaceutical company announced that it would launch its next-generation inhaler to treat asthma and chronic obstructive pulmonary disease (COPD) with near-zero GWP propellants by 2025. It expects the propellant used in the next generation pressurised metered-dose inhalers (pMDI) to have a GWP that is 90-99% lower than propellants used in older pMDIs.

It is expected that HFC-134a and HFC-227ea will continue to be used for MDIs for a considerable time, not least due to the timescale for any transition to lower GWP propellants.

Carbon Footprint

The estimated carbon dioxide equivalent of an average dose of an HFC-134a MDI (200 gCO2-eq, is comparable to the climate impact of everyday items, such as a 330ml can of Cola (170 gCO2-eq), 250 ml of orange juice (360 gCO2-eq), and a kilometre driven in a small car (99 gCO2-eq). DPIs have a carbon footprint less than one-tenth the impact of currently used HFC MDIs. However low GWP MDIs, using HFC-152a or HFO-1234ze(E), have a carbon footprint similar to DPIs. A more comprehensive review of carbon footprints and life cycle environmental impacts has recently been published (Comprehensive review of carbon footprints and lifecycle assessments of inhalers. Carbon footprints and life cycle assessments of inhalers: A review of published evidence. Fulford et al 2022.

https://doi.org/10.3390/su14127106

Reported and calculated carbon footprints of a selection of respiratory devices and treatment methods

From the United Nations Environment Programme (UNEP) Medical and Chemical Technical Options Committee 2022 Assessment Report., except for HFC-152a MDI from Life cycle environmental impacts of inhalers Harish KumarJeswani and Adisa Azapagic, Journal of Cleaner Production, Volume 237, November 2019, https://doi.org/10.1016/j.jclepro.2019.117733, except for HFO-1234ze(E), excluding prescription and delivery from https://doi.org/10.1136/thorax-2022-BTSabstracts.66, excluding prescription and delivery