EXECUTIVE INTERVIEW - Respiratory Drug Development: Lonza Experts Share Trends & Key Takeaways

Each year, experts gather at Respiratory Drug Development (RDD) to discuss all aspects of drug delivery to the lungs and nose. Drug Development & Delivery recently interviewed Beatriz Fernandes, Principal Scientist for Research and Development, and Kim Shepard, Director, Technology Head Respiratory Delivery, at Lonza, to discuss their presentations at RDD, current trends, and the future of the inhalation space.

 Q: Can you briefly describe your presentations at RDD 2024?

 Beatriz Fernandes: At RDD 2024, I was delighted to present the workshop titled Integrated Carrier-Based Formulation Development: Process & Performance Considerations. During the session, I explored an integrated approach to developing and manufacturing dry powder inhaler formulations containing micronized active pharmaceutical ingredients (APIs) blended with a coarse excipient. Carrier-based formulations remain a traditional yet relevant platform for pulmonary delivery of dry powder inhalers, with numerous marketed products, such as the most successful carrier-based dry powdered inhaler (DPI) device, Advair/Seretide Diskus®.

These formulations consist of stable crystalline APIs diluted in approved excipients like lactose, featuring good powder flowability during downstream processing and minimizing development risk. They are highly effective for lower dosages and have also been used to deliver larger doses (>3 mg). As these formulations entail multiple steps from API to final form (crystallization, micronization, blending, and filling), de-risking drug product development involves a good understanding of each manufacturing step and its impact on safety, performance, and stability of the final product.

The workshop emphasized critical attributes to consider at each process step, such as jet milling and low/high shear mixing and provided a development and scale-up strategy illustrated by case studies.

Kim Shepard: Building upon insights presented during the workshop, the Lonza team also shared findings from two posters resulting from our R&D collaboration with The Access to Advanced Health Institute (AAHI) on a dry powder intranasal tuberculosis vaccine. First, the team demonstrated a spray-dried powder consisting of the antigen ID93 paired with two different emulsion-based adjuvant types: GLA-SE and SLA-SE. These dry powders were shown to be an appropriate size for nasal delivery, and compatible with two intranasal delivery devices. A second body of work considered in detail the manufacturing challenges associated with spray-drying scale-up of intranasal-size dry powder particles.

 Q: What are the implications and findings for developing treatments addressing unmet needs in tuberculosis and other diseases?

 Kim Shepard: In the AAHI collaborative work, we support the development of a non-invasive, shelf-stable vaccine for tuberculosis, with the goal of distribution to underserved populations worldwide. Tuberculosis is a leading cause of infectious disease mortality, despite being treatable and having a vaccine commercially available. The Bacillus Calmette-Guerin (BCG) vaccine is only effective in young children, and the treatment course has poor patient compliance due to its expense and up to 8-month duration. By focusing on a preventative, non-invasive, shelf-stable vaccine, the spray dried formulation under development holds great promise to impact global communities.

 Beatriz Fernandes: In addition to vaccines such as BCG, our work is focused on the treatment of respiratory diseases by delivering drugs topically to the lungs. This ensures higher drug loads at the site of action with minimized side effects. However, for the treatment of lung infections such as tuberculosis, or other rare lung diseases such as PAH, higher doses are required compared to therapies intended for the treatment of asthma or chronic obstructive pulmonary disease (COPD). Although these high-load formulations entail challenges, particle-engineered products such as TOBI® Podhaler (inhaled tobramycin) and Bronchitol® (inhaled mannitol) have been developed and successfully marketed.

The presented carrier-based platform can also be used for higher dosage delivery by increasing the fraction of micronized API in the mixture, such as the commercial antiviral DPI Relenza (10 mg of zanamivir), or even delivering neat API. As highlighted by Dr. Hugh Smyth in his talk Patient Focused Device Systems for High Payload Therapies at this year’s RDD, micronized API densities vary significantly but are usually higher than the spray-dried material, allowing for high fill weights with similar volumes, and consequently reducing the number of inhalations required, improving patient compliance.

As the fraction of micronized API increases, the control over its properties becomes more significant, as a slight particle size distribution variation can lead to a significant delivered dose change in the final product. Therefore, it is crucial to have a quality-by-design approach to the micronized process development, as well as ensure an integrated product development in which the impact of the micronization process on the final product is clearly understood.

 Q: What is your take on views from this year’s RDD event? Any trends that stand out?

 Beatriz Fernandes: RDD 2024 was an inspiring event led by a number of engaging presentations from experts in inhalation drug product development. With dedicated knowledge spaces covering topics including nasal delivery, aqueous advancements, dry powder inhalers, and MDIs, as well as innovation and its translation from the laboratory to practical applications, I left feeling excited for all that’s to come in this space.

There are four main takeaways from the event. First, there are numerous strategies to overcome current imaging modalities to observe dynamic events in the lung. There is now research that opens doors to understanding tumor growth, capillary remodeling in pneumonia-injured lungs, and even the deposition and diffusion of droplets and particles in the lung. With this, there continues to be an ongoing need for further understanding of lung dynamics and the potential of new technologies as valuable tools in drug development.

Second, nasal delivery continues to be a prominent topic. Following the Covid-19 pandemic, research on dry powder vaccines has emerged as a cost-effective solution without the need for a cold chain, making it suitable for global distribution, including in low-income countries.

Third, there has been significant progress in providing alternatives to comparative clinical endpoints, emphasizing the importance of a strategic approach to biorelevant in vitro and in silico characterization. Methodologies such as dissolution studies, deposition, and PK modeling are now recommended and included in product-specific guidance documents.

Lastly, pulmonary delivery for treating lung infections remains a top priority. However, this approach presents challenges due to the need to deliver high powder loads to the lung. Achieving a balance between patient conditions, device, powder amount, drug load, and required dose is essential to optimize patient compliance and treatment effectiveness.

Q: What are key challenges facing drug manufacturers today?

Beatriz Fernandes: For carrier-based formulations containing micronized API, the primary challenges facing drug manufacturers today revolve around process reproducibility and scale-up. Establishing dependable scale-up laws for powder mixers remains one of the primary industrial concerns. As a result, ensuring the safety, stability, and effectiveness of the final product necessitates a quality-by-design integrated approach. Concepts such as milling energy and mixing energy emerge as valuable tools to ensure a seamless scale-up process. Furthermore, it’s crucial to thoroughly understand equipment characteristics at different scales and their influence on process conditions for each product. In some cases, equipment characteristics can even be customized to suit the target product.

Kim Shepard: As engineered particle technology advances, a wider range of APIs are moving through the respiratory development pipeline, including highly potent small molecules, proteins, peptides, and nucleic acid therapeutics. Responding to the unique formulation and manufacturing requirements for each class of therapies to achieve the desired target product profile remains a central challenge for manufacturers. Particularly for inhaled biologics, regulatory guidance is still developing alongside the technology. The industrial consortium IPAC-RS has brought together stakeholders from across the innovator and CDMO spectrum to address these issues.

Q: What are future trends in spray-drying and formulation development?

Beatriz Fernandes: The major trends are related to nasal spray-dried products, which offer the potential to incorporate mucoadhesive excipients and customize particle size to target specific nasal regions, and spray drying of biologics, including mRNA vaccines, which has garnered significant interest over the years. Since the withdrawal of Exubera™ over 10 years ago, there are currently over 60 biologic molecules for inhalation in various stages of development in pipelines. It’s crucial to ensure that large-scale technology is prepared for these molecules, and Lonza has been actively working on this aspect.

Kim Shepard: Another trend that was discussed extensively at RDD was the need for high-dose therapeutics administered to the lung. Traditionally, only nebulizers have been able to achieve doses approaching 100 mg of API for pulmonary delivery. Recent work has focused strongly on dry powder delivery at high dose. A combination of innovative devices and formulations is necessary to overcome the challenge of high dose aerosolization.

Q: What steps is Lonza taking to stay ahead and innovate in this space?

Kim Shepard: To respond to the needs of the respiratory pipeline, Lonza has innovated in a range of areas. In March, Lonza announced the expansion of our service offerings for spray-dried biologics for pulmonary delivery. We are excited to bring dry powder inhalable formulations of protein, peptide, or nucleotide APIs into the clinic for our clients. Along the same lines, Lonza’s R&D group has also been innovating in the area of dry powder inhaled vaccines. The AAHI collaboration previously discussed is one excellent example and stay tuned for future news about inhalable mRNA LNP dry powders.

We also recently discussed in a webinar Lonza’s enhanced atomization and process analytical technologies to improve spray-drying scale-up for pulmonary powders. We have also prioritized particle engineering solutions for highly potent APIs, including spray drying, micronization/blending, and filling capabilities to enable OEB 5 compounds.