The process for Lu-177 n.c.a. was custom developed and designed by the FIELD-LAB team themselves. Recently, Marion Chomet gave a presentation on the practical aspects of this development at the NKRV meeting at the VUmc in Amsterdam. “Our goal is to create a small-scale production process of Lu-177 n.c.a. as an Active Pharmaceutical Ingredient (API) under Good Manufacturing Practice (GMP) conditions”, says Chomet. “As our process uses especially designed equipment, we need to be sure that the equipment is robust and will be validated. It is not that we bought it ready-made from a company, that guarantees quality.”

In order to be able to transfer the process from the R&D lab to GMP production, the process is being designed to be handled in hot cells, using telemanipulators. Chomet: “All the equipment has been designed, but we are still optimizing. The current process is almost completely automated. However, some manual handlings are still required and need to be able to be performed with telemanipulators within the hot cell. Another challenge is that we work with multiple tubings and connecting parts. We would like to use as many disposable materials as possible to prevent extensive validation of materials that needs to be reused.  However, if you have, for example, a leakage or you need to replace a piece of disposable equipment, this will not be as ‘easy’ in a closed hot cell as it was in the R&D setting, in which every part of equipment is easily accessible.  In that case fixed materials might be the better choice.

But what is the difference between Lu-177 c.a. and Lu-177 n.c.a.? The difference lies in the production route. Carrier added is produced, using a direct irradiation method in which Lu-176 is irradiated. However, Lu-176 is not removed in the process, lowering thus the specific activity as both Lu-176 and Lu-177 are isotopes of  Lu-177. Also, the direct method leads to the side production of the radioactive impurity Lu-177m (t_1/2=160 days) which poses issues regarding radiation protection and disposal of Lu-177 waste in hospitals.

The indirect method for Lu-177 n.c.a. uses enriched Ytterbium-176 as target material, generating a very low amount of Lu-177m. The Lu-177 produced is further processed and separated from the irradiated Ytterbium material ensuring thus a higher specific activity. In the n.c.a production route, Lu-177 is chemically close to Yb-176, but can still be isolated . However, via this method the ratio Yb:Lu after irradiation is about 5000:1, which poses a great challenge for separation of Lutetium from Ytterbium.

Finally, we are currently testing all critical process parameters and listing all materials to be used. We have performed a material risk assessment (MRA) for the chemicals and are currently busy with the MRA of the materials and disposables. Some of them will probably require testing via an Extractables and leachables study to ensure, for example, that no metals or other contaminants might end up in our end product.”

Once the process will be ready to be implemented in FIELD-LAB, Chomet and her colleagues will be able to provide a few patient doses of Lutetium-177 n.c.a. under GMP conditions for clinical phase I and phase II studies, a major milestone for FIELD-LAB.