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New legislation and regulatory changes are causing shifts within the inhaled drug delivery market. By updating pressurised metered dose inhaler (pMDI) design and formulations, pharmaceutical companies can stay ahead in the changing market landscape. Ross Errington, Head of Drug Product Development at Recipharm, explores how evolving pMDIs can future-proof inhaled drug delivery.
Inhaled drug delivery is growing rapidly. The market is forecast to be worth $76.9 billion by 2027, with the pMDI segment alone set to reach $22 billion by 2031. One of the major factors driving the inhaled drug delivery market growth is the global increase in chronic respiratory conditions, such as asthma and chronic obstructive pulmonary disease (COPD). In 2019, 262 million cases of asthma were reported, along with 455,000 asthma-associated deaths. In the same year, COPD was responsible for 3.23 million deaths, making it a leading cause of mortality worldwide.
Delivering drugs to the lungs using pMDIs is the most common method in the treatment of chronic respiratory diseases. Due to their common design, resulting in manufacturing efficiency, ease of use and proven efficacy, pMDIs enable cost-effective treatment of large numbers of patients, including the elderly and children.
While the benefits of pMDIs and the rise of chronic respiratory disorders are driving growing demand, the regulatory environment is evolving quickly, impacting future pMDI production plans for the pharmaceutical industry. In this changing landscape, pharmaceutical companies must carefully consider pMDI design, formulation and manufacturing processes to stay ahead of various legislative developments, including updated medical device regulations, the phasedown of hydrofluoroalkane (HFA) propellants and restrictions on polyfluorinated alkyl substances (PFAS).
Annex 1 of the EU Medical Device Regulation
In 2017, the EU Medical Device Regulation (MDR) replaced the existing Medical Device Directive (MDD) and the Active Implantable Medical Device Directive (AIMDD). Previously, the MDD and the AIMDD governed the design of all medical devices, including those used for inhaled drug delivery.
The introduction of the MDR means that all new and existing devices used with medicinal products (including combination products, such as pMDIs) need to conform to the general safety and performance requirements (GSPRs), or Annex 1 of the MDR.
The Kigali Amendment to the United Nations’ Montreal Protocol
For decades since the CFC-HFA transition, HFAs have been the principal propellants used in pMDIs. However, HFAs have a high global warming potential (GWP) and long atmospheric life. The Kigali Amendment to the United Nations’ Montreal Protocol (2016) aims to phase down HFA use by 80-85% by 2047, to maintain global temperature rise at or below 2oC. Changing regulations in key pMDI markets (the EU, the UK and the US) following the Kigali Amendment will require HFAs to be phased down — or in some cases out — in all applications. Even though the updated deadlines for the phasedown have not yet been confirmed in all territories, early investment in low-GWP alternatives is an opportunity to future-proof pMDI propellants and minimise disruption of critical medicine supplies to patients.
European REACH Regulations
In January 2023, Germany, the Netherlands, Norway, Sweden and Denmark submitted a joint proposal under the European REACH regulations for the restriction of PFAS. Further restrictions and bans have the potential to affect not only existing propellants, HFA-134a and HFC-227ea, but also 1,3,3,3-tetrafluoropropene (HFO-1234ze(E)), a near-zero GWP gas currently being investigated as an alternative pMDI propellant.
Proposals are in the early stages of review and the first consultation received over 5,600 submissions, indicating significant changes are required before it comes into force. However, the proposed introduction date is 2025. Any pMDIs containing PFAS gases in the scope of the final regulation would need to be removed from the EU market 18 months after the introduction of the ban, which further highlights the potential for pharmaceutical companies to stay ahead of regulations by acting early.
How Can Pharmaceutical Companies Future-Proof pMDIs?
Low-GWP propellants that have the potential to future-proof pMDIs are being explored, including HFA-152a and HFO-1234ze(E). With early investment, pharmaceutical companies can anticipate market shifts and stay ahead of compliance changes for their pMDI drug products.
The following considerations can accelerate the development of pMDIs with alternative propellants:
- Compatibility with drug formulation and container closure system
Maintaining seal integrity and valve delivery performance throughout life are two important considerations to ensure performance matching between reformulated and existing pMDIs. Interactions of valve and canister construction materials, as well as physical and chemical properties of the propellant, excipients and active ingredients all need to be assessed.
At the point of fill, it is important to confirm that the valve seals effectively with the canister. The canister profile and valve seal material properties are critical in this interaction.
Over time and across a range of environmental conditions, seal integrity must remain intact, controlling any potential leakage from the canister. Construction materials must remain stable, ensuring any extractables or leachables remain within specification.
- Propellant physicochemical properties
Propellant physicochemical properties influence the drug formulation in a pMDI. Embracing new propellants with similar properties to existing HFAs (vapour pressure, density, compatibility with surfactants and solvents) may require less alteration of drug formulations.
- Safety and impact of propellants
Any new propellant must be safe for human ingestion and early assessment of toxicity can speed up new propellant development. In the same vein, assessment for flammability is required for safe handling throughout product development, manufacturing and storage.
- Propellant and pMDI scalability
Ensuring scalability is critical for the success of both new respiratory treatments and reformulated existing pMDI products when changing the propellant. Considering the activities required for successful scale-up of manufacture, alongside formulation and device design at the beginning of product development, can reduce the time to commercialisation.
Getting Ahead of Regulations to Ensure Compliance
As well as investing in alternative propellants, pharmaceutical companies should also consider the implications of the MDR to future-proof pMDIs for the EU market. Updating quality management systems (QMS) and good manufacturing practice (GMP) protocols will ensure compliance ahead of the end of the MDR transition period. Tracking the performance of pMDIs post-commercialisation can also be achieved with updated clinical evaluation procedures, enhanced clinical data collection and post-market surveillance.
Regulatory filing is another process that can be accelerated with investment early in development. By using a notified body to review information regarding GSPRs under Annex 1 of the MDR, it can be confirmed that the pMDI product conforms to requirements.
Relying on Trusted Partners to Support pMDI Future-Proofing
Future-proofing inhaled drug delivery products has many benefits for any pharmaceutical company. However, updating the design and formulation of pMDIs as well as staying ahead of regulatory changes is a significant undertaking.
Partnerships with trusted contract development and manufacturing organisations (CDMOs) bring the regulatory knowledge and technical expertise required for pMDI development. Ultimately, future-proofing pMDIs in the evolving inhaled drug delivery market will enable pharmaceutical companies to provide continued therapy to the patients who benefit from them.