MDIs are impacted by global f-gas legislation, which seeks to reduce emissions from use of fluorinated gases. The Kigali Amendment (2016) to the Montreal Protocol places obligations on all countries to phase down the use and emission of hydrofluorocarbons (HFCs) to slow the pace of global warming. The Kigali Amendment has now been ratified by 155 states, including the EU. National and regional legislation, resulting from Kigali, will begin to limit the use of HFCs in MDIs, including the American Innovation and Manufacturing Act (AIM Act; 2020), various US state legislation including California’s SB 1206, 2024 EU f-gas regulations, and anticipated f-gas legislative proposals in the UK.

Both current medical grade propellants, HFA-227ea and HFA-134a, use industrial HFCs as the starting material, which is then purified. Reduction in large-scale industrial use of HFA-227ea and HFA-134a means that the supply of these ​materials is becoming constrained, and regulations which remove the MDI exemption mean these two propellants have limited future commercial viability.

The supply of HFA-227ea is already at a critical point​. There is virtually no industrial use of HFA-227ea due to its high GWP. Although it was historically used in fire-suppression systems, other materials have replaced its use. The price of HFA-227ea continues to rise as raw materials for production are becoming difficult to procure. There is one last manufacturer of medical grade HFA-227ea, who will likely not produce after 2025​.

The supply of HFA-134a is becoming increasingly difficult, and the price for this propellant is also expected to rise​. Industrial use (e.g., air-conditioning and refrigeration) is declining quickly due to adoption of lower GWP alternatives at lower prices (e.g., HFA-152a) and the impact of Kigali-related legislation​. One manufacturer of HFA-134a, Koura, has also invested heavily in HFA-152a capabilities and is driving the transition​. Major users of medical grade HFA-134a such as Chiesi, AstraZeneca, and GSK have publicly stated plans for transition to lower GWP alternatives in the 2025-2027 time frame.

It is highly likely that, although some legislation, such as that recently published in the EU, will​ start the process of transition, it will be economics rather than regulation ​that will ultimately force companies to speed up this change. As supply of higher GWP propellants becomes more limited and costs continue to rise, use of lower GWP propellants will ensure the continued viability of many MDI products.

PFAS (per- and polyfluoroalkyl substances) are a group of chemicals mainly characterized ​by bonds between fluorine and carbon atoms. They are often termed “forever chemicals” as in some cases they do not easily degrade in the environment. The most common definition used for PFAS is chemicals with at least one fully fluorinated carbon atom​. They are used in a wide range of applications​.

Both current MDI propellants (HFA-227ea and HFA-134a) are PFAS under the most common definition​. Of the alternative propellants, HFO-1234ze is also a PFAS under these definitions. Potential future regulations surrounding PFAS, such as the proposed restrictive legislation from the European Chemicals Agency (ECHA) which would ban HFO-1234ze and similar substances, also impact the use of currently used and proposed propellants. At this stage, the ECHA proposal is held up in the EU legislative process due to the weight of public consultation responses, which means it could be several years before the issue impacts MDIs, but companies do need to be aware of this when planning to transition to lower GWP propellants.

Regulatory agencies have recognized the need for transition to lower GWP propellants in MDIs due to environmental concerns and global regulations on HFCs. While they haven’t issued formal statements specifically endorsing the use of new propellants, both the FDA and EMA have demonstrated their support for this transition through issuing guidance documents (such as questions and answers from EMA regarding data requirements), public discussion of the transition at various conferences and workshops (such as an FDA presentation at the 2024 Respiratory Drug Delivery conference), and engaging with industry on possible regulatory pathways for change.

The fate of current marketing authorizations for HFA-134a and HFA-227ea MDIs is likely to follow precedents set by the phase-out of CFC products. In both the US and EU, these products were “discontinued from marketing” rather than “withdrawn.” This distinction is important, as withdrawal typically involves safety or efficacy concerns.

In the US, FDA regulation 21 CFR 314.161 outlines the process for withdrawal, which involves either Agency initiative or petition submissions. The EU has similar considerations under Directive 2001/83/EC, with specific articles (107i, 20, and 31) addressing safety, quality, manufacturing, or efficacy issues that could lead to withdrawal. However, based on the CFC precedent, it’s more likely that MDIs using HFA-134a and HFA-227ea will be phased out through discontinuation of marketing rather than formal withdrawal procedures.

Marketing applications that remain on file with health authorities may be available for reference, and/or for post-approval changes​. This allows previous demonstration of the safety and effectiveness of the API/dosage form to be referenced in future product applications and/or post-approval changes to the existing product​. In the EU, marketing authorizations not used for marketing for 3 years will be cancelled under “sunset clause” provisions, but the data associated with them may continue to be referred to.

In the EU, options include new marketing authorization applications (either full or abridged), extension applications for approved medicinal products, and variation procedures for replacing existing propellants.

In the US, applicants may pursue a new drug application (NDA) through either a full 505(b)(1) application or an abbreviated 505(b)(2) application. Alternatively, they may file an abbreviated new drug application (ANDA) under 505(j). For existing products, a prior approval supplement (PAS) to an existing NDA or ANDA may also be a potential pathway^.

The choice of regulatory pathway for transitioning to lower GWP propellants depends on the product’s development stage and the regulatory agency involved (EMA or FDA).

For products developed with lower GWP propellants from the start, options include a full or abridged marketing authorization application (MAA) with the EMA, or various new drug application (NDA) and abbreviated new drug application (ANDA) pathways with the FDA. Products initially developed with hydrofluorocarbons (HFCs) have different pathways depending on their status. If transitioning prior to marketing application, similar options to new lower GWP products are available. For products with marketing applications already filed but wishing to transition during review, extension applications or amendments to existing applications are appropriate. Post-approval transitions can be handled through variation procedures with the EMA or potentially with prior approval supplements with the FDA.

Each scenario requires careful consideration of the specific product, the extent of changes from existing formulations, and available supporting data. Consultation with regulatory authorities is advisable to determine the most appropriate pathway for each unique situation, as the choice can significantly impact the time line and requirements for bringing the transitioned product to market.

EMA has outlined detailed considerations in their guidance document, as well as a 2023 IPAC-RS workshop on data requirements. The guidance includes sections on general principles, quality data requirements, nonclinical data requirements, and specific considerations for addressing safety and tolerance aspects of novel propellants. The document also covers data requirements for local tolerance, clinical safety, and potential changes in exposure to the active substance. Additionally, it addresses data requirements for children and adolescents, product information considerations following a propellant change, and risk management.

The FDA will focus on several key areas, as indicated in 2018 draft guidance and a 2023 IPAC-RS workshop. These include propellant characteristics, formulation and device details, quality tests, and product characterization studies. The FDA also considers “significant change” criteria and the comparability of delivered dose uniformity (DDU) and aerodynamic particle size distribution (APSD). Quality data to support new lower GWP products are crucial, encompassing information on the drug substance, drug product, and any data applicable for a new product that can reference previously submitted information.

Both regulatory bodies emphasize the importance of comprehensive data packages that demonstrate the safety, efficacy, and quality of the new formulation with lower GWP propellants. The specific requirements for any product may vary based on its characteristics and the extent of changes from existing formulations. Manufacturers should consult detailed guidelines provided by the EMA and FDA to ensure their data packages meet all necessary criteria for successful registration.