Physicochemical stability of Vinorelbine Accord in punctured original vials and after dilution with 0.9% sodium chloride or 5% glucose solution

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

Study objectives: To determine the physicochemical stability of Vinorelbine Accord in original vials after first puncture and after dilution to concentrations between 0.1 mg/mL and 3.0 mg/mL in commonly used infusion fluids and containers.
Methods: Test solutions were prepared aseptically, and stored light protected at room temperature or under refrigeration for up to 28 days. Initially and at predetermined time points, physical stability was assessed by visual inspection and pH measurement. Chemical stability was determined by a validated, stability-indicating high-performance liquid chromatography (HPLC) method.
Results: Physicochemical stability of vinorelbine in punctured vials was given for 28 days at 2°C–8°C. Diluted vinorelbine solutions in glass bottles or polyolefine remained physicochemically stable at room temperature or under refrigeration for 4 days and 28 days, respectively. Diluted solutions in polypropylene syringes remained stable for 7 days at 2°C–8°C.
Conclusion: Residues of Vinorelbine Accord in punctured original glass vials can be used cost-effectively for up to 28 days when stored refrigerated. Infusion solutions diluted to vinorelbine concentrations between 0.1 mg/mL and 3 mg/mL can be prepared in advance and used over a period of 7 days (polypropylene syringes) and 28 days (glass bottles, polyolefine bags) when stored refrigerated or 4 days when stored at room temperature.

Submitted: 12 February 2024; Revised: 15 April 2024; Accepted: 26 April 2024; Published online first: 6 May 2024

Introduction

Vinorelbine belongs to the group of antineoplastic vinca alkaloids, which inhibit microtubule formation and thereby cause cell cycle arrest in the metaphase. The main indications are non-small cell lung cancer and metastatic breast cancer. Vinorelbine solutions are only suitable for intravenous use. The licensed originator and generic drug products contain vinorelbine bitartrate. Prior to infusion, the solution concentrate (10 mg/mL) is diluted either with 0.9% NaCl or 5% glucose solution. According to the Summary of Product Characteristics (SmPC), diluted Vinorelbine Accord infusion solutions are physicochemically stable for 24 hours at 25°C [1]. Diluted vinorelbine solutions prepared from different brand products are known to be physicochemically stable for up to 30 days when stored refrigerated or at room temperature [2–4].

Study objectives

To determine the physicochemical stability of Vinorelbine Accord 10 mg/mL in punctured original vials and after dilution with 0.9% sodium chloride or 5% glucose solution in 50 mL polypropylene (PP) syringes, glass bottles, and polyolefine (PO) bags at different concentrations under different storage conditions for a maximum period of 28 days.

Methods

Vinorelbine test solutions were prepared under EU Class A conditions and in accordance with the principles of Good Manufacturing Practice. A total of 15 different test solutions were prepared using the European Medicines Agency (EMA) licensed Vinorelbine Accord 10 mg/mL (batch number P08326). Test solutions were stored light protected, either refrigerated (2°C–8°C) or at room temperature (20°C–25°C), for up to 28 days. Samples were taken and analysed initially (Day 0) and at predetermined time points. For detailed information, refer to Table 1.

Table 1

Physical stability analysis comprised pH measurements (glass electrode calibrated with standard buffer solution) and visual inspections under standard laboratory light against a black and white background for any change in colour, clarity or for the presence of particulate matter.

Chemical stability was assessed via HPLC assay, which has been validated for linearity of analytical response and acceptable precision. The assay was proven to be stability-indicating for non-specific degradation of the parent drug [5]. For the undiluted solution stored in the punctured vial, 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 [5].

Results

Vinorelbine Accord 10 mg/mL concentrate in punctured vials remained unchanged when stored refrigerated. Neither colour change, nor turbidity, or visible particles were noticed during visual inspection. Results of pH measurements showed only slight variations (less than 0.1 unit) during the observation period. In the HPLC chromatograms, no signs of chemical degradation of vinorelbine were found, slight variations of the vinorelbine concentrations on different time points are related to the assay variability, see Table 2.

Table 2

Diluted vinorelbine test solutions remained physicochemically stable independent of the vehicle solutions (0.9% sodium chloride, 5% glucose solution) or primary containers used (50 mL polypropylene syringes, polyolefine bags, glass bottles) when stored light protected at 2°C–8°C or at 20°C–25°C for up to 28 days. For detailed results, see Tables 3, 4a, 4b, 5a, and 5b. These results are consistent with published data reporting the stability of diluted vinorelbine solutions of different brand products for up to 30 days at concentrations between 0.1 mg/mL and 1.0 mg/mL in polyvinylchloride (PVC), polyethylene, or glass containers [2–4].

Table 3

Table 4a

Table 4b

Table 5a

Table 5b

Conclusion

Vinorelbine Accord solution concentrate 10 mg/mL and diluted infusion solutions were found to be physicochemical stable for up to 28 days after first opening in the punctured original glass vials and after dilution with 0.9% sodium chloride or 5% glucose infusion solution at concentrations between 0.1 mg/mL and 3.0 mg/mL stored light protected at 2°C–8°C. Results were independent from the type of infusion containers (neutral glass bottles, polyolefine bags, polypropylene syringes). Remnants of the solution in punctured original glass vials can be used cost-effectively for up to 28 days when stored refrigerated. Diluted infusion solutions with vinorelbine concentrations between 0.1 mg/mL and 3 mg/mL may be prepared in advance by pharmacy-based cytotoxic preparation units and used over a period of 7 days (polypropylene syringes) and 28 days (glass bottles, polyolefine bags) when stored refrigerated. Storage of diluted solutions at room temperature over 4 days does not affect stability.

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 Krmer, 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 Vinorelbine Accord 10 mg/mL concentrate for solution for infusion. Available from: https://accord-healthcare-products.co.uk/products/v/vinorelbine-solution
2. Bauer M, Pierre Fabre Medicament, Boulogne. Navelbine compatibility with PVC perfusion bags and neutral glass bottles. Dossier: PM259 A34. 1990;2.
3. Dine T, Luyckx M, Cazin JC, Brunet C, Cazin M, Goudaliez F, et al. Stability and compatibility studies of vinblastine, vincristine, vindesine and vinorelbine with PVC infusion bags. Int J Pharm. 1991;77(2-3):279-85.
4. Beitz C, Einberger C, Wehling M. Stabilität und Kompatibilität von Zytostatika-Zubereitungen mit Infusionsbehältern aus Polyethylen. Krankenhauspharmazie. 1999;20:121-5.
5. Accord Healthcare Limited. Data for HPLC assay and acceptance criteria on file; 29-07-15.

Author for correspondence: Judith Thiesen, PhD, Department of Pharmacy, University Medical Center of the Johannes Gutenberg University Mainz, 1 Langenbeckstraße, DE-55131 Mainz, Germany

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