Low Global Warming Potential (LGWP) Propellants
Pressurized metered dose inhalers (pMDIs) are currently the mainstay treatment of asthma and chronic obstructive pulmonary disease (COPD) in the US, Europe, and globally. Other delivery systems exist (e.g., dry powder inhalers and nebulizers) but may not be suitable for all patients and are not available for all therapeutic molecules. Currently, hydrofluoroalkanes HFA-134a and HFA-227 are used as “propellants” to expel medical formulation from pMDI canisters and to create a “puff” for patient to inhale. Due to environmental concerns, these propellants will most likely be phased out in the near future and become unavailable for medical use. Two potential replacements have been identified, HFA-152a and hydrofluoroolefin HFO-1234ze(E). Neither of these have yet been used in an approved pMDI, and HFO-1234ze(E) could moreover be banned under the recent proposal from the European Chemicals Agency (ECHA) restricting manufacture and use of per- and polyfluoroalkyl substances (PFASs). Nevertheless, pharmaceutical companies are exploring ways to reformulate current pMDIs away from HFA-134a and HFA-227, as they may soon become unavailable due to statutory prohibition or economics. Regulatory guidance on the requirements for the switch are currently lacking. It is therefore necessary to clarify regulatory requirements for implementing the change from the current to next-generation propellants, in order to enable an uninterrupted supply of life-saving medicines to patients.
In the 1990’s, chlorofluorocarbons (CFCs) were replaced with HFA 134a and HFA-227 for (then) environmental concerns. To implement the switch, product manufacturers had to develop New Drug Applications (NDAs) in the US, or similar dossiers in Europe. To meet regulatory requirements, industry sponsors had to conduct costly and time-consuming clinical studies as well as develop completely new chemistry-manufacturing-controls (CMC) programs.
The contemporary replacement propellants are thought to be more physicochemically similar to HFA-134a and HFA-227 than these HFAs were to CFC. It seems reasonable, therefore, that a more facile switch (e.g., via a supplemental NDA in the US or a similar pathway in Europe) would be suitable for approved pMDIs currently on the market. This approach would balance the need to avoid disruptions in the supply of life-saving medicines to patients, while documenting the safety, efficacy and quality of pMDIs based on new propellants. To clarify specific requirements and thus enable the development and approval of such pMDIs, a dialogue among industry, regulators, and other stakeholders is urgently needed.
IPAC-RS Survey - Stakeholder Perspectives on Switching Current pMDIs to New Propellants
IPAC-RS conducted a survey of all interested stakeholders on Stakeholder Perspectives on Switching Current pMDIs to New Propellants.
This survey aimed to understand the perspectives of industry, regulators, and other stakeholders regarding the forthcoming switch to new propellants. The output of this survey will be used to inform further actions, such as a Workshop where stakeholders' concerns and potential solutions can be discussed.
'Questions and answers on data requirements when replacing hydrofluorocarbons as propellants in oral pressurised metered dose inhalers' (EMA/CHMP/83033/2023) dated 30 March 2023
IPAC-RS IPAC ECHA REACH Feedback Final Subission (Sept 20, 2023)