Developments gather pace for the use of HFC-152a and HFO-1234ze(E) in MDIs
HFC-152a and HFO-1234ze(E) have been identified as low GWP alternatives for HFC-134a and HFC-227ea propellants in pressurised metered dose inhalers (pMDIs). These new propellants for pMDIs are under development, with recent announcements indicating progress for manufacturing lines and medical trials. HFC-152a is flammable with a direct GWP of 124 (AR4, F-gas 2024/573 value) but it is not in scope of the current regulatory actions on PFAS in the EU. HFO-1234ze(E) is classed as non-flammable under the applicable test conditions for this application, with a direct GWP 1.37 [1] (AR6, F-gas 2024/573 value) and is included in the PFAS definition used to define the scope of the proposal for an EU restriction of PFAS. Both HFC-134a, non-flammable, GWP 1430 (AR4) and HFC-227ea, non-flammable, GWP 3220 (AR4) are also included in the PFAS definition used to define the scope of the proposal for an EU restriction of PFAS.
It should be noted that technical discussions are currently ongoing regarding the proposed PFAS restriction. The International Pharmaceutical Aerosol Consortium (IPAC) and the International Pharmaceutical Consortium on Regulation & Science (IPAC-RS) in their preliminary joint comments [2] to ECHA stated “We respectfully request a lengthier derogation for the two medical propellants currently used in MDIs: HFC-134a and HFC-227ea consistent with the one granted to other medical device sectors.” And “We respectfully request a permanent exemption for HFO 1234ze as a medical propellant for MDIs.”
According to the MCTOC Assessment Report [3], the first pMDIs containing HFC-152a are expected to launch in 2025, and with the first anticipated product launch in 2025 for pMDIs containing HFO-1234ze(E). The report also discusses manufacturing of pMDIs using these propellants. Due to its flammability, safe manufacturing processes for HFC-152a would need to be developed for pMDIs. HFO-1234ze(E) is classified as non-flammable (per ASTM E-681 and ISO 10156) but possesses a flammable range of 8.0–8.5 volume percent in air (at one atmosphere under certain conditions), requiring consideration in manufacturing processes.
A contract research organization, dedicated to providing pressurized metered dose inhaler (pMDI) research and development (R&D), has announced the installation of a new low-GWP manufacturing line to meet global needs for pMDI investigation. The line will manufacture pMDIs containing HFO-1234ze (E) and HFC-152a propellants and will allow 2.5 -10-kilogram batches to be manufactured [4]. In the USA, the FDA has awarded a contract to provide the FDA with information related to the formulation, manufacture, device design and quality aspects related to low-GWP propellant MDIs and their utility to replace existing propellant MDIs [5]. Partnerships between pharmaceutical companies and MDI propellant manufacturers of HFO-1234ze(E) and HFC-152a have been announced and progress is being made on the required clinical trials with plans to file regulatory submissions assuming trials are successful [6-9].
Background on pMDIs and treatment of asthma and COPD (chronic obstruction pulmonary disease)
Pressurised metered dose inhalers (pMDIs), dry powder inhalers (DPIs), aqueous soft mist inhalers (SMIs), and other delivery systems such as nebulisers all play a role in the treatment of asthma and COPD. An inhalation propellant must be safe for human use and meet several other criteria relating to safety, efficacy, and quality. 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 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 new propellants fulfilling all these criteria, and which are also environmentally acceptable [2].
References
[1] See EFCTC Newsletter of January 2024, Update on the atmospheric degradation of HFOs and HCFOs for a discussion on indirect GWPs.
[2] International Pharmaceutical Aerosol Consortium (IPAC) and the International Pharmaceutical Consortium on Regulation & Science (IPAC-RS) Preliminary joint comments to ECHA REACH on proposal to restrict PFAS (May 2023) available at ECHA Comments submitted to date on restriction report on PFAS - ECHA (europa.eu) Part 6 Ref 4063 Attachment
[3] 2022 MCTOC Assessment Report, section 10.2.7 New propellants for pMDIs, available at MCTOC-Assessment-Report-2022.pdf (unep.org)
[4] PharmiWeb.com New low-GWP manufacturing line.
[5] OINDP News FDA contracts for LGWP propellant study
[6] finance.yahoo.com Collaboration for Low GWP Propellant Conversion for HFC-152a
[7] OINDP News Partners on development of HFO-1234ze MDIs
[8] OINDP News Partnership on development of MDIs using HFO-1234ze(e) propellant
[9] OINDP News Upcoming Phase 3 trials of HFA 152a version of an MDI