Generics and Biosimilars Initiative Journal (GaBI Journal). 2024;13(2):73-4.
DOI: 10.5639/gabij.2024.1302.015

Author byline as per print journal: Irene Krämer, PhD; Frank Erdnuess, PhD; Judith Thiesen, PhD

Abstract:
This study assessed the physicochemical stability of Bortezomib Accord 2.5 mg/mL solutions for subcutaneous and intravenous injection under various storage conditions. Bortezomib 2.5 mg/mL solutions for subcutaneous injection remained stable for up to 84 days in punctured vials and polypropylene syringes under light-protected conditions at room temperature, with negligible changes in pH, colour, or particulate matter. Diluted 1 mg/mL solutions retained stability for 72 hours (room temperature, exposed to light), 42 days (room temperature, protected from light), and 84 days (refrigerated, protected from light). These findings provide valuable insights for clinical practice and medication management protocols.

Submitted: 29 February 2024; Revised: 15 April 2024; Accepted: 26 April 2024; Published online first: 6 May 2024

The proteasome inhibitor bortezomib is indicated either alone or in combination for the treatment of multiple myeloma and ­mantle cell lymphoma. Bortezomib Accord 2.5 mg/mL solution for injection is approved for subcutaneous injection without further dilution and for intravenous administration after dilution with 0.9% sodium chloride solution to a 1 mg/mL bortezomib solution [1].

To determine the physicochemical stability of Bortezomib Accord 2.5 mg/mL solution for subcutaneous injection and diluted bor­tezomib 1 mg/mL solution for intravenous injection in punctured original glass vials and polypropylene (PP) syringes under different storage conditions for up to 84 days.

Bortezomib Accord 2.5 mg/mL solution for injection in punctured original vials and transferred into 2 mL PP syringes (Becton Dickinson) were stored light protected at 20°–25°C (room temperature) for 84 days and without light protection for 120 hours. Diluted 1 mg/mL bortezomib test solutions were achieved by adding the appropriate amount of 0.9% sodium chloride injection solution to Bortezomib Accord 2.5 mg/mL vials. These diluted solutions were stored in the original glass vials as well as (for information only: solutions were tested in original vials and after transfer into 5 mL PP syringes) transferred into 5 mL PP syringes, either light protected at 2°C–8°C and 20°C–25°C for 84 days or exposed to light at 20°C–25°C for 72 hours. Samples were taken and analysed initially and at predetermined time points. Physical stability analysis comprised measurements of pH and visual inspections for changes in colour, clarity, or the presence of particulate ­matter. In addition, sub-visible particle numbers were counted initially and at the end of each observation period (acceptance limit: ≥10 μm particles = ≤6,000/container; ≥25 μm = ≤600/container). Chemical stability of bortezomib was assessed by high-­performance liquid chromatography (HPLC) analysis and UV detection [2]. Acceptance criteria were set to ±5% of the label claim for bortezomib 2.5 mg/mL test solutions and to ±10% of the initial measured bortezomib concentration for diluted 1 mg/mL bortezomib test ­solutions [2].

Bortezomib Accord 2.5 mg/mL solution for injection in punctured original vials and PP syringes stored at room temperature/normal room light and at room temperature/light protected remained physicochemically stable over the whole observation period of 5 days and 84 days, respectively.

Diluted Bortezomib Accord 1 mg/mL solutions remained phy­sicochemically stable over the study period of 72 hours when stored at room temperature and normal light, and for 42 days when stored at room temperature exposed to light. They remained stable over the study period of 84 days when stored refrigerated, irrespective of the container type used (original vials, 5 mL PP syringes).

Neither colour change, nor turbidity nor visible particles became noticeable during visual inspection. Sub-visible particle numbers were within the acceptance limits set. Results of pH measurements showed only slight variations (less than 0.4 units) during the observation period.

HPLC assays revealed bortezomib concentrations >97% throughout the entire observation period of up to 84 days. Peak areas under the curve (AUC) of related substances in most cases did not exceed the acceptance limits set. However, when bortezomib 1 mg/mL solutions in original vials and PP syringes were stored protected from light at room temperature, a specified impurity peak exceeded the acceptance limit (≥1%) after day 42 of storage.

Thus, bortezomib 1 mg/mL solutions are established to be phy­sicochemically stable for 42 days when stored over prolonged periods at room temperature, as detailed in Table 1.

References
1. Accord Healthcare Limited. Summary of product characteristics for Bortezomib Accord 2.5 mg/mL solution for injection. Available from: https://accord-healthcare-products.co.uk/products/b/bortezomib-solution
2. Accord Healthcare Limited/Intas Pharmaceuticals Limited. Data for HPLC assay and acceptance criteria on file; 14-10-21 and 15-11-21.

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