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

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

Introduction

Cisplatin is a platinum-containing antineoplastic agent. The platinum atom is surrounded by two chloride atoms and two ammonia molecules in the cis position. Intracellularly, the chloride ligands are displaced by water, resulting in positively charged platinum complexes that react with the nucleophilic sites on DNA, and cause inter- and intra-strand DNA crosslinks. The platinum adducts inhibit transcription and replication, finally resulting in cell death.

Cisplatin is approved for the treatment of various solid tumours, for example, lung, bladder, testicular carcinoma, either alone or in combination therapy [1]. Prior to administration, Cisplatin Accord 1 mg/mL must be diluted with sodium chloride-containing vehicle solutions. In solutions with low chloride concentrations, cisplatin degrades rapidly. According to the Summary of Product ­Characteristics (SmPC), chloride concentrations in diluted Cisplatin Accord infusion solutions should not fall below 0.45% [1]. If diluted with 0.9% sodium chloride infusion solutions, physicochemical stability is ensured for 24 hours at room temperature, when protected from light. At refrigerated temperatures, precipitation may occur [1]. The physicochemical stability of cisplatin brand products diluted with 0.9% sodium chloride solution is established for up to 28 days when stored light protected [2–4]. Cisplatin concentrations in infusion solutions exposed to light decline more rapidly [5].

Study objectives

To determine the physicochemical stability of Cisplatin Accord 1 mg/mL concentrate in punctured original vials, in 50 mL polypropylene (PP) syringes, and of diluted cisplatin solutions (0.01 mg/mL, 0.4 mg/mL) in 500 mL polyethylene (PE) bottles pre-filled with 0.9% sodium chloride solution when stored at 20°C–25°C for a maximum period of 96 days.

Methods

Cisplatin test solutions were prepared under EU Class A conditions and in accordance with the principles of Good Manufacturing Practice. A total of four different test solutions were prepared using the European Medicines Agency (EMA) licensed ­Cisplatin Accord 1 mg/mL (batch number N09223). The test solutions were stored at 20°C–25°C and ­normal room light conditions for up to 96 days. Analysis will be discontinued if the results exceed the limits at one time point. Samples were taken and analysed initially (Day 0) and at predetermined time points. For detailed information, refer to Table 1.

Physical stability was assessed by pH measurements using a (glass electrode calibrated with standard buffer solutions at pH 1.68, 4.01, 7.00, 10.01 and 12.45), and visual inspections under standard laboratory light against a black and white background for any changes in colour, clarity, or the presence of particulate matter.

Chemical stability was assessed via high-performance liquid chromatography (HPLC) assay, which has been validated for linearity of analytical response and acceptable precision [6]. The assay was proven to be stability-indicating for non-specific degradation of the parent drug. For the undiluted solution, the acceptance level was set to 95%–105% of the label claim. Acceptance criteria for diluted solutions were defined as initial ±10% of the label claim [6].

Results

Cisplatin Accord 1 mg/mL in punctured vials revealed to be physicochemically stable for 14 days when stored at 20°C–25°C and under normal room light. When transferred to PP syringes and stored light protected at 20°C–25°C, the loss in cisplatin concentration was less than 2% after 30 days and amounted to 18% after 60 days. Thereby, cisplatin concentration fell below the acceptance level of 95%–105% of the label claim. In both test solutions, neither colour changes nor turbidity nor visible particles were observed during visual inspection. For detailed results, refer to RTable 2.

Cisplatin solutions diluted with 0.9% sodium chloride solution to concentrations of 0.01 mg/mL and 0.4 mg/mL were shown to be physicochemically stable when stored at 20°C–25°C and normal room lighting for 35 days. Cisplatin concentrations declined by more than 5% and 7%, respectively. After these time points, cisplatin concentrations fell below the acceptance limit of initial ±10% of label claim. For detailed results, see Table 3.

Conclusion

Cisplatin Accord solution concentrate, 1 mg/mL, remained physicochemically stable after the first opening in punctured original glass vials and after transfer into PP syringes for a maximum period of 14 days (maximum storage period) and 30 days, respectively, when stored at 20°C–25°C and under normal room lighting. Undiluted Cisplatin Accord 1 mg/mL residues in punctured original vials and PP syringes can be used cost-effectively for up to 14 days and 30 days, respectively.

After dilution with 0.9% sodium chloride solution, cisplatin infusion solutions were found to be physicochemically stable for a maximum of 35 days when stored at 20°C–25°C under normal room lighting. After 60 days of storage, the loss of cisplatin concentration exceeded the 10% limit set.

Diluted Cisplatin Accord infusion solutions (0.01 mg/mL–0.4 mg/mL) in PE bottles may be prepared in advance by pharmacy-based cytotoxic units and used for a maximum of 35 days.

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

Funding sources

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.

Authors

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 Cisplatin Accord 1 mg/mL concentrate for solution for infusion. Available from: https://cdn.accord-healthcare.com/ie/public/spc/ie-spc-clean_9.pdf
2. Pujol Cubells M, Prat Aixela J, Girona Brumos V, Durant Pou S, Villaronga Flaque M. Stability of cisplatin in sodium chloride 0.9% intravenous solution related to the container’s material. Pharm World Sci. 1993;15(1):34-6.
3. Rochard E, Barthes D, Courtois P. Stability of cisplatin in ethylene vinylacetate portable infusion-pump reservoirs. J Clin Pharm Ther. 1992;17(5):315-8.
4. Sewell G. Physical and chemical stability of cisplatin infusions in PVC containers. Eur J Oncol Pharm. 2010;4(3):11-3.
5. Zieske PA, Koberda M, Hines JL, Knight CC, Sriram R, Raghavan NV, et al. Characterization of cisplatin degradation as affected by pH and light. Am J Hosp Pharm. 1991;48(7):1500-6.

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