Two-chamber bags: A New Packaging Solution for Unstable Injectable Anticancer Drug Preparations?

Objective
The limited short-term stability of several injectable anti-cancer drugs (AKs) presents significant organizational and economic challenges for healthcare facilities. This instability often requires the adoption of downgraded procedures for drug administration outside of production unit operating hours. Given that hydrolysis is the primary degradation mechanism for AKs, a bi-compartment pouch prototype (PBiC) has been developed in collaboration with a partner laboratory. This prototype allows for the separation of the AK from its solvent, facilitating on-demand dilution. The objective of this study is to evaluate the technical feasibility of this prototype.

Materials and methods
Evaluation of the heat seal integrity of the PBiC was conducted both visually and using liquid chromatography (LC) with an ultraviolet detector on days 0, 7, 14, 21, and 28. The compartments were filled to their maximum capacity: Compartment A with 1% fluorescein and Compartment B with water for injection, then subjected to either pressure (10 kg, n=3) or freezing (-80°C, n=3). A stability study of busulfan (Fresenius^®, with a reported stability of 15 hours per the Summary of Product Characteristics) was also performed in the PBiC. This involved analyzing the variation in busulfan content using LC coupled with mass spectrometry (LC-MS) under different conditions (2-8°C, n=6, and 25°C, n=6, protected from light) on days 0, 3, 7, 14, 21, and 28, following the development of an internal standard assay method (busulfan-D8).

Results
No migration of fluorescein from Compartment A to B was detected on Day 7. By Day 14, one pressurized pouch and one frozen pouch exhibited a clear rupture of the heat seal. The LC-MS method demonstrated specificity (no interference), linearity (R² > 0.99), and accuracy and precision (CV < 3%). The busulfan content in undiluted PBiC stored at 2-8°C showed variations of 95.35 ± 5.71% on Day 3, 101.46 ± 5.02% on Day 7, 96.33 ± 5.00% on Day 14, 96.86 ± 6.29% on Day 21, and 97.68 ± 3.31% on Day 28. When stored at room temperature, the busulfan content was 101.56 ± 4.43% on Day 3, 98.48 ± 8.16% on Day 7, 96.09 ± 8.09% on Day 14, 95.71 ± 4.06% on Day 21, and 96.86 ± 4.52% on Day 28.

Discussion/Conclusion
The PBiC demonstrated excellent resistance to extreme conditions after 7 days, and pure busulfan remained stable within the PBiC for up to 28 days, including at room temperature. These findings suggest that the PBiC could serve as a reliable solution for the early preparation of this anti-cancer drug. Ongoing studies on container-content interactions will further support these results. Additionally, individual studies for each relevant anti-cancer drug will be necessary to expand the PBiC’s applicability. In the long term, this new device could prove invaluable for managing unstable and/or costly drugs, even outside of production unit operating hours.