Generics and Biosimilars Initiative Journal (GaBI Journal). 2024;13(2):103-4.
DOI: 10.5639/gabij.2024.1302.023

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

Abstract:
The physicochemical stability of Azacitidine Accord, a pyrimidine analogue antineoplastic agent, was assessed after reconstitution with cold water for injection (WFI) and storage in original glass vials and polypropylene (PP) syringes at different temperatures. At 2°C–8°C, stability was observed for 3 days in both containers. At -20°C, stability was maintained for 60 days regardless of container type. These findings support refrigerated storage for 72 hours and frozen storage for prolonged stability. Minimizing exposure to room temperature is crucial to maintain efficacy during handling and transportation.

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

Azacitidine is a pyrimidine analogue antineoplastic agent, indicated for treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia, and acute myeloid leukaemia. Azacitidine Accord 25 mg/mL powder for suspension for injection (100 mg or 150 mg per vial) is subcutaneously injected after reconstitution with water for injection (WFI) to obtain 4 mL or 6 mL of azacitidine suspension 25 mg/mL, respectively [1]. In aqueous solutions, azacitidine is rapidly degraded by temperature-dependent irreversible hydrolysis. To extend the physicochemical stability of azacitidine, refrigerated water for injection must be used for reconstitution [2–6]. Even after reconstitution with refrigerated WFI, a 10% loss in azacitidine concentration is reported after storage at room temperature for about 4 hours [2]. Thus, in clinical practice, handling of azacitidine suspension at room temperature must be limited to a minimum, and cold chain storage and transportation must be maintained throughout.

To evaluate the physicochemical stability of Azacitidine Accord after reconstitution with cold WFI to a 25 mg/mL suspension and storage in original glass vials and polypropylene (PP) syringes at –20°C (frozen) and 2°C–8°C (refrigerated).

Azacitidine test suspensions were prepared by adding 4 mL of refrigerated WFI (2°C– 8°C) to each vial Azacitidine Accord powder 100 mg/vial. The t est suspensions were stored in the original vials and, after transfer to 5 mL PP syringes, either in a refrigerator at 2°C– 8°C or in a freezer at – 20°C ± 5°C . The s torage periods for refrigerated test suspensions were 3 days in the original glass vials and 15 days in the PP syringes . The s torage periods for frozen test suspensions were 60 days. Samples were taken and analysed initially and at predetermined time points, see Table 1. Physical stability was determined by measuring pH (specification 5.0– 8.0) and visual inspection for changes in colour and appearance. Chemical stability was assessed by high-performance liquid chromatography (HPLC) analysis [7]. The a cceptance criteria were set to azacitidine concentration of ±5% of the label claim [7].

Azacitidine Accord 25 mg/mL suspension kept in the original vials and PP syringes at 2°C–8°C fulfilled the acceptance criteria after 3 days of storage. Azacitidine test suspensions in PP syringes failed the acceptance criteria (intact azacitidine concentration >95% of the initial concentration) at Day 4 and Day 5 of refrigerated storage. Azacitidine Accord 25 mg/mL suspensions stored at –20°C were found to be physicochemically stable over the entire test period of 60 days, irrespective of container material (glass vial, 5 mL PP syringe), as shown in Table 1.

Azacitidine Accord 25 mg/mL powder for suspension for injection, reconstituted with refrigerated water for injection, can be prepared in advance by pharmacy-based cytotoxic preparation units and used over a period of 72 hours when stored refrigerated at 2°C–8°C. Frozen storage at –20°C prolongs the physicochemical in-use stability to 60 days. In daily practice, the total time at room temperature (from the start of reconstitution to the transfer of azacitidine suspension to the refrigerator or freezer, as well as the thawing process) must be limited to a minimum, and cold chain transportation must be maintained.

Analysis was performed and documented by an accredited external laboratory. Results were carefully checked for plausibility and cautiously interpreted.

This study was funded by Accord Healthcare.

Competing interests: The authors Irene Krämer, Frank Erdnuess, and Judith Thiesen have no competing interests to declare.

Provenance and peer review: Not commissioned; externally peer reviewed.

Professor Irene Krämer, PhD
Frank Erdnuess, PhD
Judith Thiesen, PhD
 
Department of Pharmacy, University Medical Center of the Johannes Gutenberg University Mainz, 1 Langenbeckstraße, DE-55131 Mainz, Germany

References
1. Accord Healthcare Limited. Summary of product characteristics for Azacitidine Accord 25 mg/mL powder for suspension for injection. Available from: https://www.accord-healthcare.com/ie/system/files/smpc-v011.pdf
2. Walker SE, Charbonneau LF, Law S, Earle C. Stability of azacitidine in sterile water for injection. Can J Hosp Pharm. 2012;65(5):352-9.
3. Balouzet C, Chanat C, Jobard M, Brandley-Piat M-L, Chast F. Stability of 25 mg/mL azacitidine suspensions kept in fridge after freezing. Pharm Technol Hosp Pharm. 2017;2(1):11-6.
4. Tutino A, Lai M. Cold water reconstitution of Vidaza with subsequent refrigerated storage prolongs drug stability. Eur J Oncol Pharm. 2012;5(3):24-5.
5. Legeron R, Xuereb F, Djabarouti S, Saux M-C, Breilh D. Chemical stability of azacitidine suspensions for injection after cold-chain reconstitution of powder and storage. Am J Health Syst Pharm. 2013;70(23):2137-42.
6. Trambloy Q, Vigneron J, Clarot I, Blaise F, D’Huart E, Demoré B. Physicochemical ­stability of azacitidine suspensions at 25 mg/mL in polypropylene syringes stored under different conditions of storage. Pharm. Technol Hosp Pharm 2022; 7(1):20220003. https://doi.org/10.1515/pthp-2022-0003
7. Accord Healthcare Limited/Intas Pharmaceuticals Limited. Data for HPLC assay and acceptance criteria on file; 05-03-21.

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