Quality control of 5-fluorouracil infusers through packaging

4 October 2023

M. Nehlil, M. Annereau, T. Busson, A. Rieutord, H. Aboudagga, A. Dowek
Institut Gustave Roussy, Villejuif, France

Analytical quality control of intravenous cancer preparations ensures that patients receive the right drug at the right dose. This control requires sampling. Some types of packaging, as infuser, have no sampling site and cannot be analytically controlled. The aim of this project was to validate the accuracy of 5-fluorouracil (5FU) dose, non-invasively through packaging, using Raman spectroscopy (RS).

Materials and methods
A portable Raman spectrometer (i-Raman Prime, 785 nm, Metrohm®) was used. A 5FU quantification model using partial least squares (PLS) regression over a concentration range from 5 mg/mL to 50 mg/mL through vials was first validated using the accuracy profile method recommended by the Société Française des Sciences et Techniques Pharmaceutiques (SFSTP) with a β interval of 95 % and a limit of acceptance of +/- 15 %. Three series of 5 concentration levels were prepared on 3 different days to build the calibration set. In order to estimate the accuracy and the precision of the method, 3 validation standards were prepared in triplicate for each series. To transpose the vial model to the measurement of infusers, 3 infusers of known concentrations were analyzed. A total of 9 infusers from routine production were then analyzed in the production area.

The spectral region of interest was set between 400 and 2200 cm-1 . Pre-treatments were performed on the entire dataset and included Savitzky-Golay smoothing, a weighted least-squares baseline correction and a second derivative. The vial model was approved for the studied range. Analyzing the reference infusers enabled the correction of the predicted results by a part of their multiplicative bias (1.6479, p<0.05). The average relative error, calculated as an absolute value, was 8.89% [3.16 - 14.62] IC95. These results are compatible with the intended routine use of SR for 5FU infusers’ quality control.

The in-vial quantification of 5FU was validated according to SFSTP recommendations over the therapeutic range. The correction of the measurement bias between the vial and the infuser measurement allowed a partial correction of the packaging effect. The feasibility of routine 5FU infuser quantification, through the infuser, has thus been demonstrated. Further tests on patient formulations are currently being performed to confirm the robustness of the method, before applying it routinely to the analytical quality control of hospital-prepared 5FU infusers.

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