DEVICE DEVELOPMENT - How to Ensure pMDI Drug Products Are Fit for the Future Market Landscape

INTRODUCTION

Demand for pressurized metered dose inhalers (pMDIs) continues to grow, driven by increases in the prevalence of serious chronic respiratory diseases across the globe. pMDIs offer a num­ber of performance and useability advantages that make them ideal for therapies treating these conditions.

However, the market landscape is changing fast, particularly when it comes to the regulatory environment governing medical devices and the propellants used in pMDIs. There have been strin­gent revisions to the EU Medical Device Regulation affecting the classification of components that may be used in pMDIs device developers and manufacturers need to be aware of.

The Kigali Amendment to the Montreal Protocol – an inter­national agreement to gradually reduce the consumption and production of hydrofluorocarbons (HFCs) to reduce global warm­ing – also impacts the pMDI market. This is due to the device’s current use of HFCs as a propellant. The Amendment has led to significant legislative updates in major pMDI markets, including the US, EU, and UK, with the potential to affect future pMDI usage.

Efforts to meet the targets of the Kigali Amendment are being complicated by new proposals to update the EU’s Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) regulation. The proposed changes will restrict the manufacturing and use of polyfluorinated alkyl substances (PFAS) – there is con­cern this will impact the use of alternative low-GWP F-gases that could help the pharmaceutical industry transition away from HFC propellants. The proposals also have the potential to restrict the usage of coatings typically used in the container closure system for some pMDI products.

With all of this in mind, pharmaceutical companies need to carefully consider both the design of their pMDI devices and their manufacturing processes to ensure they continue to be compliant with a diverse range of fast-changing regulations. How can pharmaceutical companies ensure their pMDI products are fit for the future?

A FAST-GROWING MARKET

The pulmonary or respiratory drug delivery market was val­ued at $57.4 billion in 2022 and is expected to reach $76.9 bil­lion by 2027.¹ pMDIs account for a large proportion of this increase – the market for pMDIs alone is anticipated to be worth more than $22 billion by 2031, up from $16 billion in 2022, with a CAGR of 3.1% throughout the forecast period.²

An increase in diagnoses around the world of chronic pul­monary conditions, such as asthma and chronic obstructive pul­monary disorder (COPD), is one of the key drivers behind this ongoing market expansion. In 2019, COPD killed 3.22 million people globally, and the number of deaths rose by 17.5% be­tween 2007 and 2017.^3,4 COPD affects 1 in 10 of the adult pop­ulation and is one of the three most common causes of death worldwide.⁵ Asthma, meanwhile, affected an estimated 262 mil­lion people in 2019 and caused 455,000 deaths.⁶

Unique features of pMDIs make them particularly suitable for use in combination products to treat these conditions. They are efficient to manufacture, meaning they are cost-effective to provide to patients living with chronic conditions. They offer unique breath-independent actuation, re­ducing the inspiratory flow rates needed to achieve adequate drug deposition in the lung.⁷ This makes them ideal for treating both elderly people and children, provid­ing HCPs with confidence the patient is re­ceiving a uniform drug dose every time.

With this in mind, it is no surprise there is such a clear correlation between global prevalence of chronic pulmonary diseases, and increases in demand for pMDIs.

A REGULATORY ENVIRONMENT IN FLUX

There are three key updates that pharmaceutical companies need to be aware of:

Impacts of the EU Medical Device Regulation (MDR): The MDR has been established to replace the Medical De­vice Directive (MDD) and the Active Im­plantable Medical Device Directive (AIMDD), two separate directives gov­erning the design of all devices used for medical purposes, including inhalation device technology. Under the provisions of the MDR, all new and existing devices (undergoing a significant change) used with medicinal products (combination products, such as pMDIs) must show conformity to the general safety and performance requirements (GSPRs) or Annex I of the MDR. In February 2023, the MDR transition periods were ex­tended, meaning there will be a delay in MDR implementation for specific classifications.

Changes in propellant regulations in key markets following the signing of the United Nations (UN) Kigali Amendment: In 2016, UN member states signed the Kigali Amendment to the Montreal Protocol, which aims to phase down global consumption of hy­drofluorocarbons (HFCs) by 80%-85% by 2047.⁸ HFCs are widely used across many industries, including the pharma sector, as propellants – and they have been the principal propellants in pMDIs for decades. However, the most widely used HFCs have been shown to have an impact on global warming due to their high Global Warming Potential (GWP) and long atmospheric life (AL). As a result of the Amendment, new leg­islation has been enacted in key pMDI markets, including the EU, UK, and the US, and in some cases is being updated in order to accelerate the phasedown. At the time of writing, it is unclear what the revised timelines will be for phasing down the use of these gases in pMDIs in all key markets. Nevertheless, it is im­portant to begin the transition to low-GWP propellants now to ensure ongo­ing compliance when the timelines are confirmed.

Joint restriction proposal submitted under the European REACH regula­tions for PFAs: Submitted in January 2023 by the national authorities of Ger­many, the Netherlands, Norway, Swe­den, and Denmark – this calls for further restrictions or even bans on HFCs and hydrofluoroolefins (HFOs).⁹ This includes any CF2 group or a CF3 group substance, such as HFC and HFO propellants and refrigerants. The restrictions would potentially include gases, such as 1,3,3,3-Tetrafluoro­propene [HFO-1234ze(E)], which are being explored as low-GWP alterna­tives for current pMDI propellants. Any restrictions on their manufacture and use would have negative implications for the industry’s efforts to continue to supply effective inhalation drug prod­ucts, while working toward meeting global regulations phasing down HFC use. While this is just a proposal at the time of writing, if it does pass, and the ban is enforced from 2025, then the in­dustry would have just 18 months from that date to remove any pMDIs contain­ing these gases from the EU market.

FACTORS TO CONSIDER DURING DEVELOPMENT

To prepare for the future and ensure continued compliance, pharmaceutical companies will have to consider a number of design, formulation, manufacturing, quality control, and regulatory factors.

Device & Formulation Design Requirements
The Kigali Amendment has particu­larly significant ramifications for the design of the container closure system of pMDI devices and the formulations administered by them, due to the need to explore alter­native propellants that are more sustain­able. To date, a number of potential alternatives to the current propellants used in pMDIs are being evaluated – not just HFO-1234ze(E), but also 1,1-difluo­roethane (HFA-152a). However, the selec­tion process for new propellants is complex and several aspects need to be considered:

Safety & impact on the environment: The safety of the new propellant in iso­lation needs to be investigated, in addi­tion to its safety when combined with the pMDI container closure system and the medicines being delivered. This dual focus has always been a challenge when formulating combination prod­ucts. However, the addition of relatively unknown propellants further compli­cates the process. It is also important to consider low toxicity. It is of course vital that any propellant is safe for human ingestion and there is no detrimental impact/interaction with drugs. Flamma­bility of the propellant is also an issue that needs to be considered, and ATEX certification of the production line ma­chinery will need to be addressed if there is any explosive risk.

Compatibility with device & formula­tion: Any new propellant must be com­patible with pMDI container closure systems such as cans and valves as well as the actives and other ingredients within the drug formulation. Compati­bility between the new propellants and container closure systems can be en­sured by maintaining seal integrity and valve delivery performance through the product shelf-life. Acceptable levels of leachables and extractables are also key, making comprehensive testing es­sential. Propellant vapor pressure and molecular weight also need to be con­sidered when determining the propel­lant leak rate. This can be evaluated by exposing the filled canisters to extreme temperatures and pressures and then testing them at different points in time. However, ahead of this process, it is possible to use calculations to accu­rately predict propellant leakage rate, as well as establish the root cause of any deviation from the acceptance cri­teria.

Physical & chemical properties of the propellant: The physical and chemical properties of the propellants are impor­tant when formulating medicines into pMDIs. Two of the leading propellants being explored have similar properties to currently used HFCs in terms of vapor pressure, density, and compatibility with surfactants and solvents such as ethanol. This suggests radical changes to formulation platforms may not be re­quired, but appropriate studies are needed to confirm this.

Scalability concerns: The ability to scale up manufacturing processes for devices and formulations using any new propellant is an important considera­tion. Failure to take this into account at the design stage could lead to costly de­lays in commercialization, whether for new treatments or for reformulation of existing pMDI treatments.

Regulatory Issues to be Factored Into Future Commercialization Processes
Changes to the design of their pMDI devices and formulations in response to the new legislation being introduced in key markets as a result of the Kigali Amend­ment are not the only measures pharma­ceutical companies will have to take to prepare their pMDI drug products for the future. They will also have to factor in changes in the way they manage regula­tory approvals and quality control processes for new or updated devices to meet the requirements of new device reg­ulations around the world. In particular, to ensure compliance with the MDR in the EU, they will have to think about the following:

Quality management system (QMS) changes: Under the new MDR, phar­maceutical companies will have to up­date their design control and Good Manufacturing Practice (GMP) proto­cols. They will have to include new clin­ical evaluation procedures, enhancing the collection of clinical data. A Post-Market Surveillance (PMS) system will also need to be in place to monitor the real-world performance of the pMDI after commercialization.

Supervision of notified bodies: The MDR has expanded requirements con­cerning the designation of notified bod­ies. Developers must find a notified body to review information regarding the general safety and performance re­quirements (GSPRs) under Annex 1 of the MDR in order to issue an opinion that the product conforms with the re­quirements. This will need to be consid­ered at the development stage for any new drug development project, or de­vice re-design to ensure the regulatory filing process moves as smoothly as possible.

EXPERT SUPPORT IS VITAL

The market for pMDIs is changing rapidly. Pharmaceutical companies need to take action now if they want to continue to benefit from the unique convenience and manufacturability benefits of pMDIs.

The prospect of having to update not just the design of devices and formula­tions, but the regulatory and commercial­ization processes can be daunting for many companies. However, with the right expert support, they can be confident they have the tools they need to continue to meet stringent requirements.

Contract development and manufac­turing organizations (CDMOs) that spe­cialize in pMDI development have the experience and in-depth design and reg­ulatory knowledge to help. With their as­sistance, pharmaceutical companies can keep their pMDI products up to date with the latest market and legislative changes so they can continue to provide the best possible treatments for patients living with chronic pulmonary diseases.

 REFERENCES

1. https://www.globenewswire.com/en/news-rel­ease/2022/12/16/2575393/28124/en/Pul­monary-Drug-Delivery-Systems-Market-Report-2022-Improved-Patient-Compliance-and-Ease-of-Use-Drives-Adoption.html.
2. https://www.transparencymarketresearch.com/ metered-dose-inhalers-market.html.
3. https://www.who.int/data/gho/data/themes/ mortality-and-global-health-estimates/ghe-lead­ing-causes-of-death.
4. GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018;392:1736–1788.
5. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2095–2128.
6. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a sys­tematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396(10258):1204-22.
7. https://pubmed.ncbi.nlm.nih.gov/ 10157898/#:~:text=The_advantages_of_pMDIs_are,drug_deposition_in_the_lung.
8. https://treaties.un.org/Pages/ViewDetails. aspx?src=IND&mtdsg_no=XXVII-2-f&chapter=27&clang=_en
9. https://r744.com/european-chemical-agency-publishes-proposal-to-restrict-pfas-chemicals-in­cluding-some-f-gases-and-tfa/.

Ross Errington is Head of Drug Product Development for the Advanced Delivery Systems Business at Recipharm. He is a chemist by training and has 30 years of experience in pharmaceutical product development and manufacture, specializing in inhaled delivery systems.