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Inhalation February 2026 11 greater mechanistic understanding and more phys- iologically relevant tools capable of simulating lung delivery, evaluating post-aerosolization activity and accurately predicting deposition and uptake. e current lack of such tools may limit progress in the field and highlights a critical opportunity for innova- tion in inhaled formulation science. Beyond formulation-specific challenges, inhaled drug development faces broader issues. Significant time commitments can be required to refine formu- lations, complete preclinical assessment and progress through clinical phases. Correspondingly, costs may escalate, driven by the need for multiple formulation iterations, device compatibility testing and exten- sive in vivo studies. is extended timeline can also reduce the effective patent life of new drugs, impact- ing commercial returns. Overall, inhaled drug formulation development is a multifaceted challenge that spans scientific, techni- cal, commercial and environmental domains. Over- coming these hurdles requires expert formulation knowledge but also may benefit from the integration of innovative predictive methodologies that could reduce reliance on trial-and-error and accelerate the path to successful therapies. An empirical approach to overcoming formulation challenges Traditionally, inhaled formulation development has relied on empirical methods, supported by the exper- tise of formulation teams and iterative laboratory testing. "Design of experiments" approaches have been widely adopted to provide greater structure and efficiency to this process. To mitigate risks and improve the chances of success, formulators often deploy a range of experimental techniques to analyze and optimize key parameters such as particle size, morphology and device compatibility. One common approach involves the extensive physicochemical characterization of an API and any excipients uti- lized. Techniques such as laser diffraction, scanning electron microscopy and calorimetry methods pro- vide critical insights into particle size distribution, surface morphology and thermal behavior. Similarly, impactor measurements enable the detailed charac- terization of aerodynamic particle size distribution (APSD) and fine particle fraction (FPF) for different formulation-device combinations. is data can then be used to inform formulation decisions to modify and tailor particle properties or incorporate excipi- ents to modify the formulation properties for opti- mal lung deposition. While these laboratory-based methods provide a strong foundation for inhaled product develop- ment, they are often resource-intensive and time- consuming. Early-stage formulation development can involve numerous iterations, with no guarantee Iterative inhaled formulation development e selection of an optimal formulation for active pharmaceutical ingredients (APIs) in inhaled drug delivery is a complex process. e performance of an inhaled therapeutic depends upon the successful combination of API, formulation and drug delivery device, and the selection of each element for compati- bility directly influences drug development timelines. e optimal formulation for a drug is influenced by the characteristics of the API, such as its solubility, stability and potency, and selection of the drug deliv- ery device, particularly where novel technologies are being co-developed. Identifying these inherent API characteristics and delivery device is also essential for defining the target product profile (TPP), with each API requiring a unique optimization strategy [11]. ere are advantages and limitations to each inhaled drug delivery device, including payload capacity, moisture protection, turbulence generation, airflow resistance and dose isolation [12]. Availability can also be a key consideration, as many inhalation devices are protected by intellectual property rights or exclu- sivity agreements, so the choice of device for proof- of-concept work is often limited to what is accessible. Additionally, formulators are often guided in their choices by prior successes; however, each novel API presents distinct challenges. e physical properties of an API may limit certain development approaches, potentially demanding a more "engineered particle" strategy to succeed. Furthermore, knowledge of the pharmaceutical modality may influence the lung tar- get, thereby affecting the optimal particle size and morphology of the formulation. Ultimately, there is no "one-size-fits-all" formulation approach and nav- igating the learning curve associated with unfamiliar APIs demands significant time and resources, often resulting in an iterative development process that may be influenced by luck. One of the most persistent challenges in inhaled drug development is the lack of predictive tools that reli- ably reflect in vivo performance. While initiatives such as the inhalation-based Biopharmaceutics Clas- sification System (iBCS) [13] aim to systematize our understanding of inhaled drug behavior, conven- tional in vitro assays still offer limited insight into the fate of aerosolized formulations after inhalation, par- ticularly for biologics. Unlike small molecules, bio- logics such as peptides, proteins and nucleic acids are structurally fragile and require specialized evaluation following aerosolization, as the process may compro- mise their integrity and therapeutic effect [14-17]. However, most in vitro cell culture studies apply these compounds in bulk liquid form rather than as aerosols, failing to replicate deposition and delivery mechanisms within the lungs or to assess whether biological activity is retained post-aerosolization. e development of inhaled biologics therefore demands