Navigating the complexities of pressurized metered-dose inhalers (pMDIs) in a rapidly changing market presents significant challenges but also substantial opportunities for pharmaceutical companies. The global MDI market was estimated to be valued at 23.82 billion by 2032, growing with a compound annual growth rate (CAGR) of 3.2% [1]. While these devices are a cornerstone of respiratory care, their development is more technically and commercially demanding than ever. For many teams, the traditional approach of separating drug formulation from device design can create a host of issues, from project delays and performance problems to expensive regulatory hurdles.
However, adopting an integrated approach to drug and device development can help navigate this landscape and set up pMDI products for market and patient success. By aligning formulation, engineering and testing from the earliest stages of development, companies can mitigate risks and improve the probability of a successful product. This strategy streamlines the development process and also helps ensure the final product is both clinically effective and compliant with evolving pMDI regulatory standards.
In this article, Craig Sommerville, Senior Vice President at Kindeva, explores the critical need for a holistic, integrated approach to pMDI development and how this strategy can de-risk projects while ensuring both clinical and commercial success. He draws on his extensive experience to explain how combining drug formulation and device design from the outset can overcome the technical and commercial hurdles facing the industry today.
The evolution of pMDI development
The history of the pMDI is a story of continuous innovation, driven by both scientific progress and environmental necessity. The first pMDI was a revolutionary step in drug delivery, allowing for the precise, portable and self-administered delivery of medication that fundamentally changed how respiratory diseases are treated. The initial propellants used, chlorofluorocarbons (CFCs), were highly effective but were eventually phased out due to their environmental impact on the ozone layer. This led to a major industry-wide transition to hydrofluoroalkane (HFA) propellants in the 1990s and early 2000s.
Today, the industry stands at another critical inflection point. With increasing global awareness of climate change, the focus has shifted to propellants with a lower global warming potential (GWP), often referred to as next-generation propellants (NGPs). This transition presents scientific and engineering challenges, driven by evolving regulations, societal demands for sustainability and corporate commitments to environmental, social and governance (ESG) goals. Unlike the CFC-to-HFA transition, which was primarily driven by environmental regulations, this new transition is also being shaped by market forces, with an increased focus on corporate social responsibility and carbon footprint reduction.
This new wave of innovation brings with it a unique set of complexities. The barriers to entry are high, requiring significant investment in bespoke equipment, specialist infrastructure and a deep understanding of process safety. Moreover, the industry is seeing a consolidation of players, both on the innovator side and the contract development and manufacturing organization (CDMO) side. In this environment, a misaligned development approach can lead to misaligned timelines, performance issues and costly regulatory setbacks. Instead, drug formulation and device teams should aim to integrate and work together as early as possible in development.
Early integration can help drive pMDI development progress
Developing a pMDI is a multifaceted process involving a complex interplay between the drug formulation and the device components. The active pharmaceutical ingredient (API) must be compatible with the propellant, the valve and the canister, and the entire system must deliver a consistent, stable and reproducible dose to the patient.
Drug and device teams operating in silos can lead to different timelines and different priorities, which can cause several common pitfalls:
• Incompatibility issues
A drug formulation might be optimized for a specific chemical profile, only for it to be discovered later that it’s incompatible with the valve or the actuator materials. For instance, some formulations may leach from the device components, compromising both drug stability and device performance.
• Performance problems
The aerosol generated by the device may not have the optimal particle size distribution (PSD), leading to inefficient or off-target drug delivery to the lungs. Without early collaboration, device engineers may not have access to the full properties of the formulation, leading to a suboptimal actuator or nozzle design and a potentially costly redesign cycle.
• Regulatory setbacks
A lack of alignment on key technical specifications or testing protocols can result in delays or even rejection during the regulatory submission process. Regulators are increasingly focused on a holistic view of the pMDI as a combination product and they require a strong data package that demonstrates the seamless integration of drug and device.
In contrast, an integrated approach brings formulation and device development teams together from the start. By fostering a collaborative environment, developers can address potential issues before they become costly problems. This means formulation teams work directly with device engineers to select compatible materials and design a system that optimizes drug product performance, efficacy and patient safety. This collaborative synergy ensures that the product is not just a sum of its parts but a truly integrated system designed for success.
Key alignment points in an integrated strategy
By aligning on several key points, companies can put an integrated strategy in place and help ensure smooth and successful pMDI development, from early-stage research to large-scale commercial production.
1. Formulation and device co-development
As the formulation and device are interdependent rather than independent elements, co-development is the cornerstone of an integrated approach. As a starting point, development teams should consider the following:
• Propellant selection
The choice of NGP (such as HFA-152a or HFO-1234ze) will inform many of the downstream decisions. Each propellant has different physical and chemical properties that can affect the stability, performance and safety of the final product. For example, some NGPs are more flammable than others, which requires specific safety protocols and equipment design from the outset.
• Drug-propellant-excipient compatibility
The drug substance must be stable in the chosen propellant. Excipients, such as surfactants and cosolvents, can be used to ensure the drug remains suspended or dissolved and to control particle size. Conducting compatibility studies early can help identify any potential issues.
• Component selection
Compatibility between the formulation and device components, including the valve, canister and actuator, helps ensure the robustness of the device to withstand the propellant pressure. A material incompatibility could lead to drug degradation, valve failure and patient safety risks.
• Aerosol performance
Optimizing the design of the nozzle and the actuator ensures that the correct aerosol plume geometry and particle size distribution are produced. This is critical for ensuring the drug reaches the correct part of the lungs and is bioavailable.
2. Process design and scale-up
After successful formulation and device optimization at a laboratory scale, the pMDI can be transitioned to large-scale manufacturing. This is where process development and engineering teams become critical.
• Quality by Design (QbD)
Adopting a QbD approach is a key solution for ensuring a robust and reproducible manufacturing process. This involves identifying critical quality attributes (CQAs) of the final product and linking them to critical process parameters (CPPs). By understanding how process variables affect product quality, companies can build a manufacturing process that is consistently in control and can be easily scaled.
• Pilot and clinical-scale production
Designing an integrated scale-up strategy can help ensure a smooth transition from pilot to clinical and, eventually, commercial-scale production. Early investment in the right infrastructure and equipment can support a seamless transition and avoid the costly and time-consuming pitfalls of late-stage redesign.
• Supply chain resilience
The global supply chain for pMDI components is complex and can involve multiple stakeholders. As the industry transitions to new propellants and materials, a robust supply chain strategy can help with sourcing and qualifying materials and components.
Meeting regulatory expectations
Regulatory compliance should be integrated into the process from the beginning to ensure smooth pMDI development. Regulators are increasingly focused on a holistic view of the pMDI as a combination product. They want to see that the development team has a deep understanding of the interactions between the drug and device, and that this understanding is backed by robust data.
• Leadership and advocacy
The regulatory landscape for NGPs is still evolving, making engaging with regulatory bodies like the FDA and EMA through industry consortia and advocacy groups crucial. This proactive engagement helps shape the future of pMDI regulations and ensures that development strategies are aligned with upcoming requirements. For example, industry groups are working to define new standards for testing and approval of products using NGPs.
• Patient usability and human factors
Successful pMDI products are easy for the patient to use correctly. Human factors studies and usability testing are vital to ensure the device design, labeling and instructions are clear and effective. This reduces the risk of user error, which can compromise treatment efficacy.
• ESG and sustainability goals
Regulators, governments, patients and the wider society are interested in more sustainable solutions. By developing products with a lower carbon footprint, companies can meet both regulatory imperatives and their own corporate sustainability goals. The market is increasingly driving this change, with financial penalties and reduced availability of high-GWP propellants, also making the transition to NGPs an economic strategy.
Simplifying the path from concept to clinic
In a complex and demanding market, partnering with an integrated CDMO can significantly simplify the path from concept to commercialization. A CDMO with a heritage in both drug formulation and device manufacturing offers a unique advantage: a single team that can manage all aspects of pMDI development, backed by years of experience.
This integrated support simplifies the supply chain, reduces communication complexities and ensures that all aspects of the project are aligned with a common goal. By leveraging the CDMO’s deep expertise and infrastructure, companies can de-risk their pMDI programs, accelerate timelines and get life-changing therapies to patients faster.
With the right strategy and a collaborative approach, the future of pMDI technology goes beyond just making more sustainable products to building a better, more efficient and more reliable system for respiratory care.
Reference and notes
- Zion Market Research – Metered Dose Inhalers Market Insights https://www.zionmarketresearch.com/report/metered-dose-inhalers-market
