PhD Defence by Giovanni Aprile

Principal supervisor
Professor Kim Dam-Johansen, DTU Chemical Engineering

Co supervisors
Associate Professor Hao Wu
DTU Chemical Engineering

Professor Gürkan Sin
DTU Chemical Engineering

Project Director Tommy Skovby
H. Lundbeck

Examiners
Associate Professor Martin Høj
DTU Chemical Engineering (chairman)

Director Peter Husted Madsen
H. Lundbeck

Professor Jens-Petter Andreassen
Norweigan University of Science and Technology
Norway

Chairperson at defence
Senior researcher Anne Juul Damø, DTU Chemical Engineering

Popular Summary

Today, the continuous manufacturing (CM) paradigm is widely accepted as a key enabler for process intensification in the pharmaceutical industry. The framework grants improved product robustness, consistency, process control, utility efficiency and reduced waste, with a considerably smaller footprint than batch processes of comparable throughput.

CM also enables shifting from a step-based production to an integrated manufacturing framework, potentially eliminating scale up procedures from lab-scale to production-scale. Unsurprisingly, regulatory bodies recognize the CM formalism as a means to provide consistent supply of medicines, mitigating drugs shortages’ risks. Throughout a whole pharmaceutical manufacturing (PM) process, crystallization is the most efficient unit operation to purify starting material, isolate intermediates, and produce the final drug substance in its desired crystalline form.

Such crystalline material is characterized by specific critical quality attributes (CQAs) such as purity, crystal size distribution (CSD), crystal shape, and polymorphic form, that are known to affect both product- (dissolution, bioavailability) and process- (filtration, drying, milling, tableting) performance. Continuous crystallizers have been well established in the agrochemical, commodity, dairy, and food industry for decades, with large-volume productions (kg to tons per hour).

However, wellcharacterized continuous crystallizers with robust and predictable performance in much smaller PM scales remain a key challenge. To date, there is (i) no satisfying technological solution addressing the PM needs (robust, miniaturized) and (ii) no commercial off-the-shelf mL-scale continuous crystallizer (<100 mL) capable of reducing the API consumption during R&D.

This PhD project deals with the development of novel crystallizer configurations and process design methods oriented to the crystallization of APIs with strict requirements for the control of crystal size and shape. The project includes the development of methods for the development of plug-flow based crystallization processes, the characterization of a novel continuous crystallizer cascade, and a process intensification strategy for optimized downstream processability of a commercial pharmaceutical product.