Authors: Justin Lacombe, Ph.D., Chief Scientific Officer, and Komal Patel, Associate Director, Pharmaceutical Development, Experic
Inhalation drug delivery is evolving beyond respiratory diseases, unlocking new opportunities for targeted, systemic treatment. Dry powder inhalers (DPIs) offer distinct advantages over liquid formulations, including improved stability, faster absorption, and enhanced patient convenience. However, developing DPIs presents unique challenges, from formulation complexities and device compatibility to regulatory hurdles and scalable manufacturing. Advancements in particle engineering, excipient selection, and analytical methods are driving innovation in this space, while strategic partnerships with experienced CDMOs are helping to accelerate development and commercialization. As interest in inhaled biologics, RNA therapeutics, and vaccine delivery grows, DPI technology is poised to transform drug development and expand treatment possibilities across multiple therapeutic areas.
Expanding the Potential of Inhalation Therapies
The increasing demand for drug products that enhance ease of use and patient convenience — critical factors in improving medication adherence — has fueled growing interest in inhalation-based drug delivery. Advances in powder processing technologies, targeted excipients, and innovative inhalation devices, including Internet-connected and low-resistance models, have expanded the potential applications of this approach. At the same time, evolving regulatory guidance has provided greater clarity, facilitating the development of more inhalation-based therapeutics.
Historically, inhalation drug delivery was largely confined to treating respiratory diseases, such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease (COPD). In these indications, recent innovation has focused on shifting from monotherapies to combination treatments, with triple-combination therapies becoming a new pinnacle in COPD care. Pulmonary arterial hypertension and cystic fibrosis also continue to see new drug development efforts, but the most significant advancements in inhalation therapy have emerged outside of respiratory diseases.
Today, inhalation is increasingly being explored as a means of systemic drug delivery, utilizing the lungs and nasal cavity as gateways to the circulatory and central nervous systems. Nasal dry powder formulations are gaining attention for their potential to enhance drug absorption and provide a non-invasive route for delivering therapies to the brain. By bypassing first-pass hepatic metabolism — an inherent challenge of oral drugs — this route allows for lower doses to achieve the same therapeutic effect while minimizing systemic side effects. This advantage is particularly relevant for conditions such as migraines, central nervous system disorders, and metabolic diseases, where rapid drug absorption and targeted delivery can enhance treatment efficacy.
Excitement is growing around the potential of inhaled biologics, particularly for RNA-based therapeutics and vaccines. Inhalation delivery is also gaining traction in oncology research, with studies exploring its role in improving the bioavailability and tolerability of cancer treatments. Meanwhile, emerging technologies such as microspheres and nanospheres are being investigated for their ability to enhance drug stability and optimize the pharmacokinetics of inhaled therapeutics, further broadening the landscape of inhalation drug development.
Why Dry Powder Inhalation Is Gaining Ground
Inhalation drug delivery offers significant advantages over other administration routes. By bypassing first-pass hepatic metabolism, inhaled drugs can achieve therapeutic effects with lower doses, reducing the risk of systemic side effects. Additionally, inhalation is non-invasive, eliminating the discomfort associated with injections while offering targeted delivery to the lungs for localized or systemic effects. The portability of inhalation devices further enhances patient convenience and adherence.
While both liquid and dry powder formulations can be used for inhalation, dry powder inhalers (DPIs) offer distinct benefits. Unlike liquid-based inhalers and nasay sprays, DPIs do not require sterile manufacturing processes, which are significantly more expensive and operationally demanding. This cost and complexity advantage, combined with increasing regulatory shifts away from high global warming potential (GWP) propellants, makes DPIs an attractive alternative. Additionally, DPIs are less complex than nebulizers or soft mist inhalers, making them easier to manufacture, transport, and use.
DPIs also facilitate fast and efficient drug absorption. The large surface area and high vascularization of the lungs allow for rapid uptake into the bloodstream, addressing solubility and bioavailability challenges that affect many small-molecule active pharmaceutical ingredients (APIs). This efficiency makes DPIs particularly well-suited for highly potent APIs (HPAPIs), which are becoming increasingly prevalent in drug development pipelines.
Beyond performance, dry powder formulations offer advantages in stability and logistics. Reduced water content lowers the risk of chemical degradation and inhibits microbial growth, improving product shelf life and process consistency. Additionally, dry powders are often more resilient to temperature fluctuations, minimizing the need for stringent temperature-controlled storage and transport — an especially critical factor for global distribution.
For vaccines, DPIs present unique advantages over liquid nasal formulations. The need to deliver larger quantities of biological material in liquid form can lead to protein aggregation, which may compromise efficacy or trigger unwanted immunogenic responses. By contrast, dry powder vaccines eliminate this risk while also simplifying administration. Unlike injectables, DPIs do not require trained healthcare professionals for delivery, making them ideal for mass immunization efforts, especially in resource-limited settings.
Engineering Dry Powder Formulations for Targeted Absorption
The formulation of dry powders for inhalation is shaped by multiple factors, including the characteristics of the API, the intended therapeutic indication, and the specific anatomical target for drug deposition. These elements collectively determine the optimal particle properties, excipients, and, ultimately, the most suitable inhalation device for effective drug delivery.
One of the first steps in formulation development is identifying the ideal site of drug absorption — whether targeting the lungs for systemic delivery or the nasal cavity for direct access to the brain. In general, particles of approximately five microns in size are most effective at reaching the alveoli in the lungs, where thin membranes facilitate systemic absorption. Many inhaled therapies aim for this deep lung deposition to optimize bioavailability and therapeutic outcomes.The sinus cavity also presents a valuable absorption site, particularly for drugs targeting central nervous system (CNS) disorders. Certain structures within the nasal cavity — such as the olfactory bulb — are being investigated as pathways for direct drug transport into the brain, offering an alternative to crossing the blood–brain barrier. Targeting nasal enervation via nasal dry powders holds particularly promise for treating migraines and cluster headaches.
Achieving the desired delivery target requires precise control over particle characteristics, including shape, structure, size, and size distribution. Particle engineering techniques are essential for optimizing these properties. While traditional powder blending methods may be suitable in some cases, the conversion of liquid formulations into dry powders often necessitates specialized technologies such as spray drying, lyophilization followed by milling, or thin-film freezing. Each method has unique advantages depending on the API’s chemical properties and the intended delivery profile.
Solubility and permeability are additional critical considerations in inhalation formulation design. Unlike oral solid dosage (OSD) forms, where high solubility is often a prerequisite for bioavailability, inhaled drugs can sometimes benefit from lower solubility and higher permeability to enhance lung absorption. Research in this area has accelerated in recent years, particularly with a growing understanding of how solubility affects drug deposition and uptake in pulmonary tissues. These insights are shaping the next generation of inhalation therapies, refining strategies to maximize therapeutic efficiency.
Selecting the Right Delivery Device for Optimal Performance
The choice of a device is just as critical as the formulation itself. Different inhalers operate via distinct mechanisms that affect airflow, dispersion, and drug deposition, making it essential to pair each drug product with a device that ensures consistent and effective delivery. However, technical performance alone is not enough — usability is equally important. Even a well-designed formulation will fail in the market if the device is too complex or inconvenient for patients to use correctly.
Ideally, device and formulation development should occur in parallel, allowing prototype devices to be tested alongside formulation iterations. However, this rarely happens in practice. More commonly, developers either adapt an existing marketed device to fit their formulation or finalize the drug formulation first and then identify a compatible inhaler. Both approaches require fine-tuning to ensure robust performance, with potential trade-offs in efficiency and regulatory complexity.
A flexible development approach is often the best solution. Designing a base platform for both the device and the formulation allows for iterative adjustments — such as modifying the hole size of the aerosol engine to refine the dispersion profile — without having to start from scratch.
The timing of formulation and device development is another crucial consideration. Developers aiming for rapid entry into first-in-human trials may initially formulate their candidate as a capsule before transitioning to an inhalation format in later clinical phases or as part of a life cycle management strategy. This approach, however, necessitates comparability studies to demonstrate equivalence. Conversely, starting with an inhalation formulation from the outset involves an upfront commitment to a device that may later present usability challenges, requiring additional development and regulatory approvals.
Ultimately, successful DPI development requires balancing speed, flexibility, and long-term performance. Maintaining consistent particle properties and device compatibility across the product life cycle is essential, reinforcing the value of parallel formulation and device development wherever possible.
Expertise Matters: Overcoming the Complexities of DPI Development
Successful development of DPI products requires deep expertise in both formulation and final product development, including the intricate interplay between drug formulation and device performance. One of the primary challenges in DPI formulation is the limited availability of excipients. While new excipients could enhance drug delivery and stability, regulatory uncertainty often deters developers from exploring novel options due to the significant time and cost required for approval.
Manufacturability is another critical factor. A formulation is only viable if it can be produced consistently and cost-effectively at scale. Extremely small particles with high surface areas, while beneficial for drug delivery and absorption, can pose significant challenges in processing — leading to cohesion, electrostatic interactions, and difficulties in powder flow. Once a process is utilized and proven out for phase I or II GMP clinical material production, modifying it later in development can be extraordinarily time-consuming and expensive, making it essential to get it right from the outset.
Scalable manufacturing of DPI formulations demands specialized technologies, equipment, and technical expertise. Spray drying, for example, requires not only precise control over particle formation but also particle capture capabilities. Maintaining high-performance equipment and implementing robust analytical method development are crucial for ensuring process consistency, quality control, and regulatory compliance from early-stage development through commercial production.
A well-defined control strategy is essential to preserving the critical quality attributes of the drug product throughout its life cycle. This extends beyond formulation to include comprehensive supply chain management, covering excipients, device components, and, where applicable, propellants.
A quality-by-design (QbD) approach provides a structured framework for optimizing inhalation formulations from the outset, reducing development risks and ensuring product robustness. Additionally, usability studies play a key role in determining whether devices are truly patient-friendly — an aspect often overlooked until late in development, when changes are more costly.
Regulatory and intellectual property considerations further complicate DPI development. A recent legal challenge regarding Orange Book patent listings for inhalation devices highlights the evolving regulatory landscape. The Federal Trade Commission (FTC) has ruled that patents covering inhalation devices alone, without mentioning the active drug substance, should not be included in the Orange Book.1 While this decision has been upheld by the Federal Circuit Court, Teva Pharmaceuticals is currently seeking Supreme Court review. If the FTC ruling stands, it could open the market to new device options, particularly for generics, reshaping competition in the inhalation drug space.
Finding the Right CDMO Partner for DPI Development
The complexity of DPI product development — spanning formulation, device compatibility, analytical testing, and scalable manufacturing — often leads drug developers to seek the expertise of contract development and manufacturing organizations (CDMOs). However, not all CDMOs possess the specialized capabilities required for successful DPI development. Selecting a partner with deep technical knowledge and a proven track record is critical to ensuring a robust, high-performance manufacturing process that consistently delivers high-quality products in a timely and cost-effective manner.
A CDMO supporting inhalation drug development must demonstrate expertise in both process development and analytical method development, backed by years of experience across multiple inhaled products. Those offering custom device development must also have strong competencies in device engineering and optimization. Inhalation delivery is a highly specialized field requiring deep knowledge of formulation science, device mechanics, regulatory compliance, and the complex interactions between drug particles and inhalation systems.
One of the most critical technical considerations in DPI development is aerodynamic particle size distribution (APSD), which determines where the API is deposited within the respiratory tract. More than 40 variables can influence APSD results, making it prone to misinterpretation and inconsistency if not handled with precision. A CDMO must have the expertise to conduct and interpret APSD studies accurately, ensuring that in vitro results align with in vivo drug performance. Additionally, patient training on proper inhaler use is crucial, as incorrect technique can significantly impact drug delivery and therapeutic outcomes.
Experic distinguishes itself from other CDMOs by offering a unique combination of expertise, specialized equipment, and tailored support for inhalation drug development. Unlike large CDMOs that often focus on high-volume production, Experic is well-positioned to serve small to mid-sized pharmaceutical companies that may be overlooked by major providers. The company’s flexible and responsive approach ensures that clients have direct access to senior leadership and scientific experts, providing a highly collaborative and personalized development experience.
Reference
1. Del Dotto, Kelly Allenspach and Brian D. Coggio. “Recent Decisions and FTC Challenges Dictate Caution When Listing Patents in the Orange Book. ”FIH Blog. 3 Mar. 2025.