Students are asked to come up with an innovative idea regarding one of the challenges proposed by the Student Contest organizers. These challenges stem from actual problems and areas of improvement in the freeze-drying industry and R&D; many of them concern pharmaceuticals and probiotics, but food sustainability, innovative energy production process and eco-sustainable processses are some of the other fields of growing interest:

1. Formulation Stability: Stability of the formulation, as that of the API compound, to freezing, on drying and after freeze-drying (on shelf), and minimising the impact of reconstitution is essential, but some widely used excipients like sucrose may be not suitable for diabetics. Formulation selection is a complex 3-layered problem and may be particularly challenging in case of liposomal formulations and microsphere formulations, where morphology must also be preserved, and in case of biologics.
2. Process Optimization, Energy efficiency and New Applications: Optimizing the energy consumption of the freeze-drying process is essential for both economic and environmental reasons, especially in fields of applications different from pharmaceuticals, where the value of the product is lower. Finding ways to reduce energy use without compromising product quality is a challenge, as the economic sustainability of the process for food and probiotics. Sustainable application of freeze drying to different new fields, including sustainable energy production, is another challenge.
3. Product Temperature Monitoring: Controlling the temperature of the product during the entire freeze-drying process is crucial to avoid overheating, which can lead to product damage or changes in physical characteristics. Developing PATs that allow for non-invasive and individual vial monitoring is essential for maintaining product quality and consistency.
4. Residual water content: The residual water content is a critical quality attribute of lyophilized products. Developing PATs that allow for non-invasive and individual vial monitoring of the residual water content is essential to guarantee product quality and stability.
5. Cake appearance: The cake appearance is a critical quality attribute of pharmaceutical lyophilized products. Developing PATs that allow for fast, automatic, and non-invasive detection of out-of-spec samples is desirable for maintaining product quality. A bigger challenge is to develop algorithms to differentiate between a cracked cake vs. a true cake defect and minimize the rejection of cracked cakes.
6. Container Closure Integrity: Ensuring the integrity of vials or other containers used for freeze drying is critical to prevent contamination and maintain the sterility of the final product.
7. Freezing Control: Controlling the freezing process is important to achieve a uniform ice structure, which can affect the final product’s quality, stability, and batch uniformity. Several methods have been proposed to induce “controlled nucleation”, but application in large scale apparatus may be challenging. The control of the freezing rate may be relevant, too: to this respect heat flux sensors are available at the lab scale, but their integration into large scale dryers without experiencing loss of performance as a consequence of CIP/SIP is still challenging.
8. Lyophilization of Biologics: Freeze drying of biopharmaceuticals, such as proteins and vaccines, and cell-derived products presents unique challenges due to their sensitivity to temperature and potential degradation phenomena. Development of formulations is particularly demanding in this case, where also the reconstitution step may be very sensitive (osmotic effects for cell are an example). In case of cells and viral based therapies, freeze-drying + reconstitution can lead to changes in colloidal attributes such as size and shape.
9. Optimization of product containers: The design of new types of containers could be beneficial to heat and mass transfer occurring in the various stages of the process, both in case of single dose products and for bulk products. The easiness of loading/unloading, as well as potential sterility requirements must be addressed. A challenge is also maintaining vacuum or inert gas atmosphere in alternative small-scale containers (e.g., microtubes or cryotubes), often suitable for freezing but not for freeze-drying. Something to consider in the design of other containers is the cost aspect (for example development of low cost and robust dual chamber containers).
10. Getting a uniform batch: The amount of heat transferred from the chamber to the product in a batch freeze-dryer is not the same in every position, thus resulting in a non-uniform temperature/residual humidity in the product. How can these differences be minimized?
11. Solutions for small scale freeze-drying of infectious biological materials: Retrofitting of small-scale freeze-dryers, which do not have the containment and safe operating capabilities to handle such materials is a challenge, as the development of process for this type of dangerous material generally require piloting at small/development scale.