Kimberly Shepard, Ph.D., associate principal engineer in R&D at Lonza Small Molecules presented the webinar "Local Delivery for Treatment of Lung Cancer: Manufacturing formulations for dry powder inhaler by spray drying." In it, Dr. Shepard discussed how spray drying can be used to address many of the challenges associated with today’s late-stage lung cancer treatments. She also reviewed two case studies about the use of spray drying for the formulation of two FDA-approved lung cancer treatments and the improved efficacy observed as a result. The following Q&A session was held after this webinar, where Dr. Shepard was able to address attendee questions about the details of the presentation and case studies.
Q: When spray drying with L-leucine and trehalose for 5-aza, can you see a single glass transition temperature? If so, does it mean L-leucine is amorphous and not crystalline at the surface of particles? And does it offer a better powder dispersibility from L-leucine at the surface?
Dr. Shepard: In our example with 5-AZA, we did some analyses to demonstrate that L-leucine is crystalline in a separate phase from the amorphous, trehalose, and drug phase. We confirmed that by using powder X-ray diffraction to see if the L-leucine crystalline phase shows up. Also, in the differential scanning calorimetry [DSC] trace, we wouldn’t see a melt for L-leucine. It does not degrade/melt until almost 300 degrees Celsius, at which point nearly all other components of the formulation would be degraded. Therefore, the data indicated a single amorphous phase containing trehalose and the active and a separate crystalline phase of L-leucine. The goal is for the L-leucine to be crystalline, as this will be more effective at improving the dispersibility of the powder.
Q: Is L-leucine approved as an inactive ingredient by the FDA for inhalation spray-dried products?
Dr. Shepard: L-leucine is an endogenous substance made by the body, but it is not yet precedented as an inactive ingredient in a formulation for delivery to the lungs. Lonza is currently working on projects where L-leucine is part of the formulation in clinical trials, so we are hoping one of these will move forward to a regulatory filing soon.
Q: Can surfactants be used as excipients in the spray-drying process? If so, what concentrations could you use?
Dr. Shepard: Surfactants can definitely be used as excipients in the spray-drying process; however, the lung is very sensitive to the presence of surfactants, so we typically try to avoid their use in pulmonary formulations when possible. When surfactants are used― predominantly for oral formulation―we try to make sure the concentration is less than 10% by weight in the formulation, and generally as small as possible.
Q: How much of the drug gets transferred to the circulation?
Dr. Shepard: For these cancer therapeutics, our goal is for the lung tissue to first be exposed but then for some of it to enter systemic circulation. This is dependent on the exact molecule and dosage. As demonstrated in both case studies, the lung is the primary area of exposure, but there was also some presence of the drug in the liver and brain tissue.
Q: Is this approach applicable to proteins that do not act locally in the lung?
Dr. Shepard: It would have to be a very specific case for proteins to be able to enter systemic circulation through the lung. This is because proteins are quite large and the permeability through the cell membrane will be very low for something of that size. In general, proteins are more applicable to local delivery than to the lungs.
Q: Can you speak to the success rate of using these formulation strategies for proteins and/or peptides, and what are the qualities of proteins/ peptides that infer success for dry powder formulation?
Dr. Shepard: We have used this formulation strategy for the manufacture of proteins and peptides by dry powder using spray drying. The biggest concern when doing so would be whether the biologic molecule can withstand the thermal and shear exposure encountered during spray drying. We can limit the exposure of the material to, say, 50 or 55 degrees Celsius during drying, and the shear can be minimized by changing atomization conditions or selecting the appropriate pump. Prior to spray drying, our team completes a formulation screening in a buffer solution to analyze its thermal properties using the DSC and determines the point when unfolding or degradation of the material begins to occur. If it is stable at, for example, 60 degrees Celsius and does not begin to unfold until 65 or 70 degrees Celsius, then the material is considered a good candidate for spray drying.
Q: Is there an alternative to L-leucine in this process? Can surfactants be used instead?
Dr. Shepard: Studies performed by the Vehring Group at the University of Alberta have shown that L-leucine is certainly one of the best excipients but that, in general, amino acids do not perform quite the same function as surfactants.² The L-leucine needs to crystallize out of the spray-drying solution during droplet drying, creating nanocrystals of L-leucine that enrich on the surface of the droplet. The exact balance of the solubility of the molecule during spray drying and its crystalline tendencies are what aids in dispersibility. The two molecule types have different functions in a formulation.
Q: What is the level of L-leucine used to not fully fill the deflations of the particles? Is the L-leucine level a function of the specific surface of the particles?
Dr. Shepard: I personally did not do this research, but there was an extensive amount done by the Vehring Group where they reviewed different loadings of L-leucine and looked at the effects of particle size. For the kinds of particles that we reviewed, 10% to 25% weight percent leucine is the sweet spot where the material stays surface enriched and does not fill up the
inside. We used 20% in both of our case studies.
Q: What are some of the feasibility tests you might perform to determine whether a monoclonal antibody is a good fit for spray drying?
Dr. Shepard: If we were going to be looking at a material that is sensitive to temperature, we would perform initial testing prior to spray drying to see at what temperature it begins to degrade. For the small molecules in our case studies, that was not as much a concern because they are thermally stable at 200 degrees, so we are not quite as much in the danger zone.
Q: What is the efficiency of the inhalation of dry powder, meaning the amount of drug inhaled and actually reaching the lung?
Dr. Shepard: In our case studies, the emitted dose, or the material that actually comes out of the device, ranged from 50% to 80%. In terms of how much powder actually gets into the lung, fine particle fraction is about 60% to 80%. In general, it is usually about half to three-quarters of the dose are under five microns in aerodynamic diameter.
Q: In the case studies mentioned, what were the main process hurdles during the development and scaling if applied to the process?
Dr. Shepard: It is important to consider how you are going to collect the powder, as doing so with small inhalation particles can be challenging. This is not an issue at a small scale, but there will be some obstacles you need to overcome as you move to larger scales. Another challenge we faced is atomization. As you scale up, you usually use a larger flow rate and atomizer, and it can be difficult to ensure you are achieving the same size particles as you did at the smaller scale. The issue is compounded for inhalation because we have very little flexibility in the size distribution of our particles. We need them to be between one and five microns, or they are not going to do their job. Our team performs extensive work for all of our inhalation programs to make sure we are getting what we need, with some compounds being more challenging than others.
Q: Does disease state inflammation change the pharmacokinetics of the inhaled formulation with spray-dried products?
Dr. Shepard: This is certainly something you have to consider, but it is difficult to answer in detail because that is going to change for each particular disease state and molecule.
Q: Does increased exposure in the brain and liver mean that inhaled therapeutics have a higher systemic exposure than when administered intravenously?
Dr. Shepard: We did not find higher systemic expo- sure ― since systemic means it goes directly into the bloodstream and exposure is therefore 100% ― but we did find for the 5-AZA case study that by using the lung as the delivery system, we had better exposure to the brain tissue than we did for IV administration.
1. American Lung Association. (May 2020). Lung Cancer Fact Sheet. https://www.lung.org/lung-health-diseases/ lung-disease-lookup/lung-cancer/resource-library/lung-cancer-fact-sheet
2. R. Vehring. Pharmaceutical Particle Engineering via Spray Drying. Pharm. Res. 25: 5 (2008). M. A. Boraey, S. Hoe, H. Sharif, D. P. Miller, D. Lechuga-Ballesteros, R. Vehring. Improvement of the dispersibility of spray-dried budesonide powders using leucine in an ethanol