Implementation of 3D printing in a cancer centre.

Introduction
Gustave Roussy is a world leader in oncology, including paediatric oncology. Galenical development work by the pharmacy department in collaboration with the paediatrics department has led to the development of a temozolomide suspension, KIMOZO^®, which is marketed in Europe. On the back of this success, and in view of the shift towards outpatient cancer care and the increasing personalization of treatment, we were asked to consider how to improve compliance with treatment and how to produce forms and doses adapted to children with cancer. To do this, we turned to 3D printing of medicines.

Choice of equipment and production area
As 3D printing of medicinal products is a recent development in clinical use, to our knowledge only two trial in Spain and the Netherlands has made it possible to set up real-life 3D printing ¹. In these two trials, the technological solution was semi-solid extrusion (SSE). This technology is very interesting because it is easy to access, but its resolution is lower than that of the basic technology, which is FDM fused depositing method or DPE direct powder extrusion. These technologies are based on the creation of a filament, which is then melted and printed. The advantage of FDM is very good resolution, but it requires a filament to be manufactured by HME (hot melt extrusion) beforehand. The manufacture of these filaments requires high quality extruders, which is currently one of the obstacles to implement that technology in hospitals. The direct powder extrusion, on the other hand, uses a powder mixture to produce an instant print without the need for a filament, by making the filament and printing it - the only problem being the flow of the powder. With that in mind, we opted for a versatile printer that could work with all three technologies and with a printing plate large enough to produce 200 printlets per series. The printer we chose was the fabrX^® medimaker ² (London), which was installed in April 2022. In terms of production, to protect operators from the risks associated with printing vapours, we are in a low-pressure atmosphere control room, with fresh air renewal.

Regulations and current projects
At present, we routinely produce a magistral preparation. The active ingredient is solubilised in a PEG derivative and then deposited as a liquid in a hard capsule, as in a previous project². This has made it possible to treat ambulatory patients instead of injecting them intravenously. Two multicentre clinical trials are currently being written to confirm the results obtained from these preparations. As far as clinical trials are concerned, the situation is more complicated. We came up against a refusal from ansm because our experimental compound is a BCS class 2 drug (low solubility, good absorption) and a request for a strict bioequivalence trial, delaying the start of our trial. For our compound in preparation, on the other hand, the absence of an oral form of this product on the market means that we are currently in the pre-submission phase, following scientific advice from the ANSM.

The benefits of i3D and planned applications
In summary, we are currently working in two areas with 3D printing:
* Replacing our capsules and solutions or oral suspensions with more suitable forms such as gummies or dispersible films, as in the case of cyclophosphamide,
* Develop new forms for products such as ONC201 or for clinical trials.
An institutional project has just been validated to produce "polypill" combinations of up to 3 molecules in a single dose, combining antiemetics and chemotherapies. The aim is twofold: to improve compliance and to encourage outpatient treatment by allowing chemotherapies currently administered intravenously to be switched to oral form if no suitable oral form is available.

1. Lafeber I, Tichem JM, Ouwerkerk N, et al. 3D printed furosemide and sildenafil tablets: Innovative production and quality control. Int J Pharm. 2021;603:120694. doi:10.1016/j.ijpharm.2021.120694
2. Secretan PH, Vieillard V, Thirion O, et al. 3D-Printed, Liquid-Filled Capsules of Concentrated and Stabilized Polyphenol Epigallocatechin Gallate, Developed in a Clinical Trial. Antioxidants (Basel). 2023;12(2):424. Published 2023 Feb 9. doi:10.3390/antiox12020424