Analytical control of 5-fluorouracil dispensers, finally possible?

Introduction
5-Fluorouracil (5FU) is one of the most prescribed anticancer drugs, mainly in the treatment of colorectal cancer. Its administration scheme consists of a bolus combined with administration over several days using a diffuser. The preparation of the diffuser is done in 2 steps: injection of the solvent (NaCl) for purging of the extender and the dilution volume, then the filling of the required volume of 5FU. In our unit, this preparation is done or for a specific patient or most of the time by batches. As elastomeric diffusers cannot be sampled, quality control is based on double visual control and gravimetry. Recently, new non-elastomeric diffusers operating with a CO2 release were developed. This technology associated with a bidirectional valve allows an analytical control.
The objective of this work is to evaluate the feasibility of analytical control.

Materials & method
Validation of the analytical method according to ICH Q2R1 (linearity, accuracy, repeatability, reproducibility). A continuous flow UV-DAD high performance liquid chromatography (FIA) method using a Dionex^® Ultimate 3000 chain and Chromeleon^® 7.0 software was developed.
Preparation of 18 2-day diffusers allowing the calculation of the absolute relative error (RE) between the measured and theoretical concentration and the calculation of the percentage of second samples. The acceptance limits of the analytical control were ± 15% of the theoretical concentration. A double visual control was performed in addition to the analytical control before pharmaceutical release.

Results & Discussion
The conditions of our 5-FU FIA method were 100% water (mobile phase), 1.5 ml/min (flow rate), 1 µl injection volume, λ = 269 nm. The method was linear R²=0.998 (12 - 50 mg/ml), fair (mean recovery rate = 99.4% [96%; 103.2%]), repeatable (CV = 1.0%) and reproducible (CV =1.4%). The doses prepared were between 3400 and 5000 mg. 61 % of the controls (n=11) had an RE < 10 %, 28 % of the controls (n=5/18) had an RE between 10 and 15 %, and 11% of the controls (n=2) had an RE > 15% (29% and 35%). After homogenization these two RE were 3 % and 0.3%. 100 % of the diffusers could be released pharmaceutically. These 11% of 2nd vials are to be compared to the 1.3% obtained for our production. A homogenization method with three syringe return trips should be implemented.

Conclusion
This quality control is an asset for this new device. For a referencing, other criteria are to be studied: regularity of the flow, ergonomics of filling, secure sampling, and comfort for the patient (weight, size). Other quality control methods have been researched but they all require either special equipment (Raman) or new manufacturing processes to be set up (creation of a mother bag and distribution).

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