Dry powder inhalation is rapidly emerging as a powerful platform for expanding access to biologics, vaccines, peptides, and nucleic acid therapies through pulmonary and intranasal delivery. As developers look beyond traditional injectable formats, advances in spray drying, particle engineering, and device integration are opening new possibilities for targeted treatment, improved patient adherence, and greater product stability without cold chain dependence. In this article, experts discuss the evolving respiratory delivery landscape, the technologies shaping the field, and development strategies for addressing formulation, analytical, manufacturing, and regulatory complexity while initiating risk mitigation in the early stages. Deployed properly, such strategies can position promising programs for clinical and commercial success.

Drug Development & Delivery recently interviewed, Kim Shepard, PhD, Director, Advanced Drug Delivery, Lonza Advanced Synthesis, and Beatriz Fernandes, PhD, Principal Investigator, Lonza Advanced Synthesis, about their research presented at the Respiratory Drug Delivery Conference.

What Does the Current Respiratory Delivery Landscape Look Like, and What Are Some Examples of Dry Powder Inhalation (DPI) Technologies Being Used in the Manufacturing of These Treatments?

Dr. Fernandes: The dry powder inhalation (DPI) field has evolved substantially over the past several decades, building on early carrier-based small-molecule products for asthma and chronic obstructive pulmonary disease (COPD). Over time, small-molecule DPIs have become a mainstay of pulmonary therapy and are now used extensively for a range of respiratory indications. In parallel, interest in DPI formats for more complex modalities has grown. The first inhaled insulin product was approved in 2006.¹ Although there are fewer approved biologic DPIs for pulmonary delivery, recent innovations with large proteins, messenger RNA (mRNA), and short-interfering RNA (siRNA) appear to be promising approaches. The 2016 FDA approval of the first intranasally delivered small-molecule DPI product² ushered in a decade of rapid expansion. Although there are no approved intranasal dry powder biologics as of yet, this is an innovative new area with great potential, including mucosal vaccination and the emerging field of nose-to-brain delivery, which shows great promise for delivering molecules across the blood-brain barrier.

For DPIs, two main technology classes are used to generate respirable particles: top-down size reduction (most commonly micronization by jet milling) and bottom-up particle engineering such as spray drying. The latter approach is a unit operation that starts with a liquid feedstock and turns it into a dry powder with controlled particle size. Spray drying is broadly applicable to both large and small molecules, and can engineer particles of a range of size distributions. Whereas both jet milling and spray drying can be used for DPI delivery of small molecules, spray drying is the leading technology for biologics. Both types of technologies offer the advantages of improved patient adherence and ease of distribution.

What Strategies Are Most Effective in Developing Dry Powder Inhalation Therapies, and What Key Risks Do CDMOs Consider During Development and Manufacturing?

Dr. Fernandes: The most important consideration in developing DPI therapies is to start with the end in mind: patient needs come first, including the indication, delivery target, dose, and phase-appropriate risks. Our approach is to start with a quick assessment of the API formulation and small-scale process. Then in parallel, we perform formulation optimization and scale-up manufacturing, while formal analytical method development proceeds concurrently. At this time, we’ll do an early-phase risk assessment to uncover any high-risk items so they can be mitigated early with formulation tweaks or process adjustments. Oftentimes, early risk assessment coincides with manufacture of supplies for a toxicology study. We then enter the clinical readiness phase in which the demonstration batch of the process is conducted with clinically representative equipment and materials, as well as finalization of the release methods, leading to tech transfer to our Early Phase Clinical facility.

There are several categories of risk to consider in DPI development and manufacturing. The first category encompasses API and physicochemical risks, in that factors such as particle size, solid state, drug-excipient interactions, and chemical degradation during particle engineering can directly affect lung deposition and stability. If these risks aren’t understood early, downstream development is immediately constrained. Formulation development risks – including inadequate aerosol performance, instability, limited excipients, device compatibility, and loss of activity (especially for biologics) – are core determinants of clinical efficacy and shelf-life. Manufacturing and scale-up risks are the primary cause of clinical-to-commercial batch failures³; for example, spray drying and jet milling apply mechanical, thermal, and environmental stresses during atomization, drying, collection, and encapsulation. There are also risks related to analytical robustness; without reliable aerodynamic particle size distribution (APSD) methods, appropriate assays for biologics, and tools to manage solid-state complexity, the manufacturer cannot release the product or demonstrate bioequivalence. Finally, there are risks due to CMC complexity, mainly due to the fact that DPI products are combination products, regulatory guidance for inhaled biologics is still evolving, and regulatory timelines are often long. All these risks are interdependent, requiring an integrated, quality-by-design approach that must start early to reduce the chances of late-stage surprises, cost escalation, and timeline risk.

Your RDD Workshop Emphasized Early Risk Identification as a Critical Success Factor. What Are the Most Important Risks Developers Should Identify at the Outset, and How Can Early-Stage Decisions Help De-Risk Programs Before Costs and Timelines Escalate?

Dr. Fernandes: Successful scale-up of DPI development requires early identification and control of solution, atomization, drying, and collection stresses. Risk mitigation should start with up-front identification of API, dose, and delivery-route constraints, followed by use of the target product profile to guide formulation, process, and CMC strategy; these considerations can help the manufacturer align technical ambition with phase-appropriate risk. Early identification and prioritization of formulation, manufacturing, analytical, and regulatory risk can yield understanding of how these risks are interconnected across the development lifecycle.³ It is also important to apply spray-drying best practices, including use of materials-sparing tools to de-risk scale-up. Ultimately, success in DPI isn’t about solving every problem early; it’s about identifying the right risks early and making informed trade offs before costs and timelines escalate.

At RDD 2026, You Highlighted How Dry Powder Inhalation (DPI) Is Gaining Traction for Biologic APIs, Particularly for Respiratory and Intranasal Delivery. What Unmet Challenges Is This Approach Helping to Address, and Where Are You Seeing the Most Meaningful Innovation Today?

Dr. Shepard: Biologic APIs have grown to comprise roughly 50% of pharmaceutical development pipelines⁴, and the vast majority of these are delivered by infusion or injection.⁵ That’s great for many situations, but in some cases, non-invasive delivery or targeted local treatment can be quite beneficial to patients. That, essentially, is the rationale for respiratory delivery of biologics. This approach is particularly promising for localized treatment of lung diseases such as lung cancer, COPD, pulmonary arterial hypertension, and pulmonary fibrosis. Other indications of interest include non-invasive systemic delivery of smaller biologics (e.g., peptides, siRNA) via the lung or the nose, as well as targeted delivery to the central nervous system using the nasal olfactory route. In addition, most biologics are liquid dosage forms requiring cold chain⁶; this is where a dry powder respiratory formulation can be particularly useful, where long-term stability at 25ºC can often be achieved. For a dry powder vaccine for nasal or pulmonary delivery, eliminating a cold chain requirement can be hugely beneficial for global distribution in areas with limited resources.

From a CMC Perspective, What Are the Most Common Challenges in Developing Intranasal Dry Powder Biologics and How Can CDMOs Help Address These Complexities Across Formulation, Analytics, and Device Integration?

Dr. Shepard: With an intranasal dry powder biologic, the CMC challenges fall into two areas: the intranasal dry powder part, and the dry powder biologic part. Bring these together and you have quite a bit to consider! For intranasal dry powders, we focus on spray drying as a manufacturing technique. Particle engineering of nasal powders, particularly when they are spray dried from an aqueous feedstock, can be tricky to sufficiently dry with good yield. We have modified our spray dryer chambers to enable sufficient residence time in the dryer to ensure improved yield at the target particle size.

Bringing together the right powder with the right intranasal device is also a critical aspect of development. Depending on the target deposition region, patient attributes, and business case, the developer may choose different types of DPIs. For example, a patient who is unable to inhale powder on demand will require an active device that propels the powder into the nasal passages. Some patients may need to take their dose infrequently (such as for a vaccine), or daily, which may impact whether a reloadable or single-use device is prioritized. For all dry powder biologics, whether delivered for nasal or pulmonary deposition, chemical and physical stabilization of the delicate biologic API is a critical CMC concern. The formulation must preserve potency and activity, while mitigating molecule fragmentation or aggregation.

In Your Presentation, You Highlighted Several Recent Case Studies Across Vaccines, Peptides, and mRNA and Discussed What’s Next in This Space. What Lessons Do These Examples Reveal, and How Will Partnerships With CDMOs Be Critical to Scaling and Enabling Broader Adoption?

Dr. Shepard: The case studies we presented featured an intranasal GLP-1, a protein-based vaccine, and an mRNA lipid nanoparticle (LNP) dry powder for nasal delivery. In each case, we demonstrated proof of concept that spray drying these materials with good potency, aerosol properties, and 25ºC stability is possible even for these challenging modalities. In a highly innovative, emerging field such as dry powder nasal biologics, a CDMO partner who is skilled at navigating uncertainty and risk mitigation is critical. If we want to realize the benefits of these non-invasive, shelf-stable therapies, a quality-by-design approach can enable the clinical progress and commercial volumes envisioned for these products.

References

1. FDA Approves First Ever Inhaled Insulin Combination Product for Treatment of Diabetes (press release). U.S. Food and Drug Administration, 2006 Jan 27. https://web.archive.org/web/20090710031817/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108585.htm
2. Avanir Pharmaceuticals Announces FDA Approval of ONZETRA™Xsail™(AVP-825) for the Acute Treatment of Migraine in Adults. Avanir Pharmaceuticals, Inc., 2016 Jan 28. https://www.prnewswire.com/news-releases/avanir-pharmaceuticals-announces-fda-approval-of-onzetra-xsail-avp-825-for-the-acute-treatment-of-migraine-in-adults-300211773.html
3. Langer E. Pharma By The Numbers: Batch Failures in Pharma Manufacturing. BioPharm International. 2025 Dec 11. https://www.biopharminternational.com/view/biopharma-by-the-numbers-batch-failures-in-biopharma-manufacturing
4. Moran N. Biologics in Development Outnumber Small Molecules for the First Time. BioWorld. 2026 Apr 9. https://www.bioworld.com/articles/730211-biologics-in-development-outnumber-small-molecules-for-the-first-time?v=preview
5. Millar A. How Research Groups are Tackling the Problem of Biologic Drug Delivery. Pharm Technol. 2020 Jul 21. https://www.pharmaceutical-technology.com/features/how-research-groups-are-tackling-the-problem-of-biologic-drug-delivery/?cf-view&cf-closed
6. Yu YB, Briggs KT, Taraban MB, Brinson RG, Marino JP. Grand Challenges in Pharmaceutiucal Research Series: Ridding the Cold Chain for Biologics. Pharm Res. 2021;38(1):3-7.