Implementation of dose banding of Nivolumab.

23 November 2020

Pauline Boyer1, Elise Goiffon1, Sandrine Occhipinti1, Régine Chevrier1 (1) Oncology Clinical Pharmacy Unit, Centre Jean Perrin, Clermont-Ferrand, France.

In order to optimize our production, and the waiting time of our patients, our Unit has searched for a molecule that can be produced in dose banded chemotherapy. Nivolumab appeared as a good candidate, its fixed dose of 240 mg covering almost all of our production and allowing a simple management. These infusions can be produced in 2 isolators: manually in both or with a pump in one.

We verified that the stability of the diluted Nivolumab solution was compatible with dose banding.
We validated our manufacturing process by carring out 3 Media Fill Tests (MFT), simulating the manufacturing of an infusion by replacing the solvent and the active molecule with culture medium, for each manufacturing condition.
The fertility of the batch of MFT kits was first checked by inoculation of S. aureus and C. Albicans on 2 separate bags.
A total of 9 MFTs were performed, involving all the operators. They were placed in an oven (32.5°C ± 2.5°C) and checked at D3, D7 (turning of bags), D10 and D14, to ensure that there was no turbidity.
Our manufacturing process and storage methods were then validated by a sterility test mimicking an infusion manufacturing by injecting water for injection into a solvent bag, then performing a microbiological analysis after 21 days of storage.
After defining our optimal stocks, we added the dose banded of Nivolumab 240 mg in Chimio®, and compared the average dispensing time of the infusions before and after the implementation of dose banding.

Diluted Nivolumab is stable for 28 days [1], allowing for dose banding.
The fertility tests of the MFT kits were conform after 14 days of culture.
No turbidity was observed in any of the 9 MFT, validating our aseptic manufacturing process under all manufacturing conditions.
No microbiological contamination was found during sterility tests.
The average dispensing time before dose banding was 25 minutes, ranging from 6 minutes (anticipated evening infusions), to 1 hour and 23 minutes (during high activity period). In comparison, the average dispensing time for dose banded infusions is 6 minutes [1 - 14 min]. The allocation of the infusions is easily managed by the "Dose Banding" tool of Chimio®.

The dose banding of Nivolumab infusions has smoothed our activity, and reduced the dispensing time and therefore the waiting time of patients, allowing also a better organization of the day hospital service. Our unit is already manufacturing 5 other dose banded molecules and is currently looking for new candidates to further improve our performance.

[1] Vieillard V, Bardo P, Akrout W, Le Guyader G, Astier A, Paul M. Stabilité physico-chimique de solutions diluées de Nivolumab à 1 mois, 2017.

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