Blisters provide the best protection to moisture, and are the most appropriate choice for dry powder biologics. However, not all blister designs are created equal. In this blog post we explore what makes our blister designs for Quattrii and Aeolus so suitable.
Dry powder biological aerosols hold immense potential to transform the treatment of respiratory and systemic diseases [1][2]. This rapidly evolving field is driven by unmet medical needs, promising clinical results, and significant investment in research and development. However, dry powder biologics are particularly sensitive to environmental conditions, such as humidity, so choosing a device with the right primary packaging is essential.
This blog post is a summary of our article published in OnDrugDelivery: Blisters, Bonds and Biologics [0].
Why is moisture such a big problem?
Dry powders need to stay dry. This is an inherent requirement for respiratory dry powders. Moisture can cause the powders to clump up, reducing aerosolisation efficacy and can also cause the active ingredients to degrade. Moisture protection throughout shelf-life is an important consideration for all dry powder formulations. So why is it such a big deal for biologics in particular?
Complex structures
Unlike small-molecule drugs, biologics often have complex secondary, tertiary, and quaternary structures that are intrinsic to their therapeutic activity (Figure 1). Biological modalities usually exist in the liquid state and water plays a crucial role in keeping the complex structures intact.
Figure 1: Biologics often have complex secondary, tertiary, and quaternary structures that are intrinsic to their therapeutic activity.
Supported in amorphous matrix
Before drying, biologic molecules are dissolved in an aqueous solution containing stabilizing excipients, often sugars like trehalose or sucrose. During the drying process (e.g. spray-drying) the biologic molecules are locked in amorphous matrix formed by the sugar, which supports the structure of the biologic (Figure 2).
Figure 2: Amorphous matrix of excipient molecule supporting biologic structure.
Amorphous matrices are highly hygroscopic
An amorphous matrix has a disordered molecular arrangement (Figure 3, right), which is important to allow it to flex around the complex shape of the biologic structure. However, amorphous matrices are highly hygroscopic, meaning they readily absorb moisture, which can trigger crystallization – the matrix rearranges into a crystalline structure and crushes the biologic. Hence, superior moisture ingress protection is critical for ensuring storage of dry powder biologics.
Figure 3: An amorphous matrix (right) has a disordered molecular arrangement, compared to a crystalline matrix (left) which is highly ordered.
Why blisters?
Dry powder inhalers can be categorised into three groups based on the primary packaging of the formulation: reservoir, capsule, and blister devices. In a reservoir device the drug is stored directly in the device, resulting in minimal moisture protection once the inhaler is removed from the tertiary packing. For this reason and others, reservoir devices are unsuitable for delivering inhaled biologics.
Capsules verses blisters
Capsule devices are generally unit dose devices, such as the Berry RS01, where the user loads a capsule into the device for each dose.
Capsules have minimal inherent moisture ingress protection, and so the capsule is stored in a blister until needed. This has several disadvantages compared to storing the formulation directly in a blister:
- Additional cost of capsule plus blister
- Additional user steps of removing the capsule from the blister and inserting into the device
- Increased time between piercing the blister and inhalation of the formulation. For biologic formulations which are extremely sensitive to moisture ingress, several minutes of exposure to atmospheric humidity may be too long, particularly in humid climates.
Furthermore, the conditions within the blister must be carefully controlled. If the environment inside the blister is too dry, the capsule shell becomes brittle and fragile making it difficult to pierce, as the capsule may shatter instead of opening cleanly.
Blister design considerations
We have explored why blisters are ideal for storing dry powder biologics. However, there are several factors to consider when selecting a blister design to optimise for inhaled biologics.
Pierce or peel?
There are two primary mechanisms for “opening” the foil of the blister: pealing or piercing. Devices such as GSK’s Diskus and Ellipta incorporate a mechanical system that peels open the foil to expose the dose at the right moment before inhalation.
Figure 4: Disassembled Diskus device, showing used blister strip on the right, where the lid foil has been peeled off.
Pealing back the foil has the advantage that the foil is moved out of the way, such that it cannot impede the aerosolisation of the powder. However, to ensure that the foil does not rupture when pealed back, the strength of the seal must be intentionally limited, which limits the moisture protection. Therefore, to achieve the best moisture protection, the foil must be pierced. With considered piercer design, the pierced foil flaps can be folded out of the way of the airflow.
Blister size and shape
If blisters are to be pierced, then there must be space left inside the blister for the piercers to protrude into the blister volume. This means that the blisters cannot be brim-filled. Although this requires the volume of the blisters to be larger, allowing for head space in the blister makes the filling process easier and the sealing more robust, due to reduced risk of powder spilling onto the sealing surface.
Quattrii and Aeolus make use of the headspace within the blister to set up cyclonic flow patterns, performing the deagglomeration of the formulation within the blister. For carrier-based formulations, Quattrii and Aeolus classify and retain the carrier fraction within the blister [4].
Inhaled biologics will require higher doses than traditional inhaled therapies for asthma and COPD, necessitating larger blister cavities to accommodate more powder (Figure 5). Furthermore, engineered powders with small particle size distributions (PSD) are cohesive (Geldart Class C) and pack inefficiently, leading to low densities.
The optimum blister cavity shape maximises volume whilst minimising surface area, to minimise the area onto which powder can be deposited and retained – especially important for carrier-free formulations. Maximizing blister depth is also important to allow height for piercers to protrude into the blister volume. Sharp piercers are required to ensure reliable clean piercing without rupturing the foil but generally require greater height than more blunt shapes.
Figure 5: Quattrii 1,414 µL blister
On the other hand, over-stretching the coldform will lead to loss of moisture protection, due to the aluminium layer rupturing. Typically, for standard 3-ply coldform, the stretch should be limited to less than 32%. A paraboloid is the most efficient blister shape, achieving the maximum volume and depth for a given diameter, whilst staying below the critical 32% stretch.
Blister shape also influences airflow patterns, affecting how powder is delivered to the patient. Efficient airflow is critical for aerosolization and overcoming interparticle forces. The highly cohesive engineered particles require significant aerosolization power to achieve effective deagglomeration. Both high velocity airflows and high momentum collisions of particles enhance deagglomeration.
Conclusions
Dry powder biologics are particularly sensitive to moisture ingress. A well-designed large-volume blister-based inhaler device is the optimal solution for delivering biologic aerosols to the lung, due to the superior moisture ingress protection of blisters and the dose requirements. If you would like to learn more about how Quattrii or Aeolus can help bring your formulation to market, get in touch!
References
[0] Jameson, H., Farrow, D., “Blisters, Bonds and Biologics: How to achieve stability of Dry Powder Biologics”, ONdrugDelivery Magazine, Issue 170 (Feb 2025), pp 24 – 28.
[1] Sécher, T., Heuzé-Vourc’h, N. (2023). Pulmonary Delivery of Antibody for the Treatment of Respiratory Diseases. In: Lam, J., Kwok, P.C.L. (eds) Respiratory Delivery of Biologics, Nucleic Acids, and Vaccines. AAPS Introductions in the Pharmaceutical Sciences, vol 8. Springer, Cham. https://doi.org/10.1007/978-3-031-47567-2_2
[2] Ecenarro Probst S, Buttini F, “Inhalable Therapeutic Biologics, a Paradigm Shift for Non-Invasive Efficient Medical Treatments”. ONdrugDelivery Magazine, Issue 92 (Nov 2018), pp 40-44.
[3] Shepard, K.B., Zeigler, D., Caldwell, W.B., Ferguson, M. (2023). Dry Powder Formulation of Monoclonal Antibodies for Pulmonary Delivery. In: Lam, J., Kwok, P.C.L. (eds) Respiratory Delivery of Biologics, Nucleic Acids, and Vaccines. AAPS Introductions in the Pharmaceutical Sciences, vol 8. Springer, Cham. https://doi.org/10.1007/978-3-031-47567-2_3
[4] Jameson H, Harris, D, High Delivered Dose in a Single Inhalation for Carrier-Based Formulations by Retaining Carrier-Fraction in DPI Blister, Respiratory Drug Delivery, 2025
[5] Berkenfeld K, Carneiro S, Carolina C, Laffleur F, Formulation strategies, preparation methods, and devices for pulmonary delivery of biologics, European Journal of Pharmaceutics and Biopharmaceutic 204, 2024
[6] Poozesh S, Connaughton P, Sides S, Lechuga-Ballesteros D, Patel S, Manikwar P, Spray drying process challenges and considerations for inhaled biologics, Journal of Pharmaceutical Sciences 114 (2025) 766−781
