Generics and Biosimilars Initiative Journal (GaBI Journal). 2024;13(2):62-4.
DOI: 10.5639/gabij.2024.1302.011

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

Study objectives: To determine the physicochemical stability of Doxorubicin Accord 2 mg/mL concentrate in original glass vials after first opening and after transfer to polypropylene (PP) syringes as well as diluted Doxorubicin Accord solutions (0.05 mg/mL, 1.6 mg/mL) in 0.9% sodium chloride or 5% glucose solution in polyolefine (PO) bottles stored at 2 °C–8°C for up to 96 days.
Methods: Test solutions were aseptically prepared with Doxorubicin Accord 2 mg/mL and stored light protected at 2°C–8°C. Samples were taken and analysed initially (Day 0) and at predetermined time points. Physicochemical stability was assessed via pH measurements, visual inspections and high-performance liquid chromatography (HPLC) assay.
Results: Doxorubicin Accord 2 mg/mL concentrate in original vials after first opening and in PP syringes remained physicochemically ­stable when stored light protected under refrigeration over the entire observation period of 28 days and 96 days, respectively. Diluted Doxorubicin Accord solutions stored light protected in PO bottles at 2°C–8°C remained physicochemically stable over the observation period of 84 days, irrespective of vehicle solution (0.9% sodium chloride, 5% glucose solution) and concentration (0.05 mg/mL, 1.6 mg/mL).
Conclusion: Residues of Doxorubicin Accord 2 mg/mL concentrate in punctured original vials or after transfer to PP syringes can be used for 28 days and 96 days, respectively, when stored at 2°C–8–°C. Doxorubicin Accord diluted with 0.9% sodium chloride solution or 5% glucose solution in PO-bottles (concentration range 0.05 mg/mL to 1.6 mg/mL) can be prepared in advance and used over a period of 84 days, when stored light protected at 2°C–8°C.

Doxorubicin is an anthracycline antineoplastic agent that inhibits DNA synthesis by intercalation and interfers with topoisomerase II. It shows a broad spectrum of anticancer activity and is used in combination chemotherapy for treatment of a variety of tumours and haematologic disorders. Doxorubicin consists of the insoluble tetracyclic aglycone doxorubicinone linked to the amino sugar daunosamine. It is unstable in acidic conditions (resulting in hydrolysis of the glycoside bond) as well as in alkaline media (leading to de­­­­­­­gradation of the aglycone). Physicochemical stability of diluted doxorubicin solutions (ranging from 0.1 mg/mL to 1.4 mg/mL in either 0.9% sodium chloride or 5% glucose as vehicle solution) has been reported in the literature for up to 69 days [1–3]. According to the Summary of Product Characteristics (SmPC), diluted Doxorubicin Accord solutions (with either 0.9% sodium chloride or 5% glucose as the vehicle solution) are physicochemically stable for 28 days at 2°C–8°C and for 7 days at 25°C [4].

To determine the physicochemical stability of Doxorubicin Accord 2 mg/mL concentrate in punctured original glass vials and in 50 mL polypropylene (PP) syringes, as well as after ­dilution with 0.9% sodium chloride or 5% glucose solution in 500 mL polyethylene (PE) bottles at two doxorubicin concentrations (0.05 mg/mL, 1.6 mg/mL) for up to 96 days.

Doxorubicin test solutions were aseptically prepared under EU Class A conditions using the European Medicines Agency (EMA) licensed Doxorubicin Accord 2 mg/mL (batch numbers ASDXRP1018 and P05413) as the starting material. Diluted test solutions were obtained by adding the appropriate amount of Doxorubicin Accord 2 mg/mL to 0.9% sodium chloride or 5% glucose solution in 500 mL polyethylene (PE) bottles to achieve doxorubicin 0.05 mg/mL and 1.6 mg/mL solutions. All test solutions were stored at 2°C–8°C protected from light. Samples were taken and analysed initially (Day 0) and at predetermined time points, as shown in Table 1.

Assessment of physical stability comprised visual inspections under standard laboratory light against a black and white background for any changes in colour, clarity, or the presence of particulate matter. pH measurement was conducted with a glass electrode calibrated with standard buffer solutions (diluted solutions only). Chemical stability was assessed via high-performance liquid chromatography (HPLC) assay, which was validated for linearity of analytical response and acceptable precision [5]. The stability-indicating nature of the assay was proven for non-specific degradation of the parent drug. Acceptance criteria were set to ±5% of the initial doxorubicin concentration for Doxorubicin Accord 2 mg/mL concentrate in punctured vials, and to ±10% of the initial doxorubicin concentration for test solutions in PE bottles and PP syringes [5].

Doxorubicin Accord 2 mg/mL concentrate in punctured original vials and in PP syringes remained physicochemically stable when stored refrigerated over the entire observation period of 28 days and 96 days, respectively. Neither colour change, turbidity, nor any particles were detected during visual inspection. The HPLC assays revealed only slight variations of doxorubicin concentrations at different time points which are considered to be related to assay variability, see Table 2.

Diluted doxorubicin 0.05 mg/mL and 1.6 mg/mL solutions in PE bottles remained physicochemically stable when stored light protected at 2°C–8°C over the observation period of 84 days, as shown in Table 3.

References
1. Wood MJ, Irwin WJ, Scott DK. Stability of doxorubicin, daunorubicin and epirubicin in plastic syringes and minibags. J Clin Pharm Ther. 1990;15(4):279-89.
2. Beijnen JH, Neef C, Meuwissen OJ, Rutten JJ, Rosing H, Underberg WJ. Stability of intravenous admixtures of doxorubicin and vincristine. Am J Hosp Pharm. 1986;43(12):3022-7.
3. Stewart JT, Warren FW, King DT, Venkateshawaran TG, Ponder GW, Fox JL. Stability of ondansetron hydrochloride, doxorubicin hydrochloride, and dacarbazine or vincristine sulfate in elastomeric portable infusion devices and polyvinylchloride bags. Am J Health Syst Pharm. 1997;54(8):915-20.
4. Accord Healthcare Limited. Summary of product characteristics for Doxorubicin Accord 2 mg/mL concentrate for solution for infusion. Available from: https://cdn.accord-healthcare.com/ie/public/spc/spc_doxorubicin_2_mg.ml_concentrate_for_solution_for_infusion.pdf
5. Accord Healthcare Limited. Data for HPLC assay and acceptance criteria on file; 04-02-14.

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