Physicochemical stability of Docetaxel Accord 20 mg/mL concentrate diluted with 0.9% sodium chloride or 5% glucose solution in non-PVC bags

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

Study objectives: To determine the physicochemical stability of Docetaxel Accord infusion solutions 0.3 mg/mL and 0.9 mg/mL in non-PVC-bags either pre-filled with 0.9% sodium chloride solution or 5% glucose solution for up to 98 days.
Methods: Docetaxel Accord 20 mg/mL was diluted with 0.9% sodium chloride solution or 5% glucose solution in non-PVC bags to achieve final docetaxel concentrations of 0.3 mg/mL and 0.9 mg/mL. Test solutions were stored at room temperature for a maximum period of 24 hours and refrigerated for maximum 98 days. Samples were taken and analysed at predetermined time points. Analysis comprised pH measurements, visual inspections, and high-performance liquid chromatography (HPLC) analysis.
Results: Diluted docetaxel solutions in non-PVC bags stored at room temperature and under refrigeration remained physicochemically stable over the observation period of 24 hours and 98 days, respectively. Results were irrespective of diluent (0.9% sodium chloride, 5% glucose) and concentration (0.3 mg/mL, 0.9 mg/mL).
Conclusion: Diluted Docetaxel Accord solutions in non-PVC bags can be prepared in advance and used over a period of 24 hours when stored at room temperature and 98 days when stored at 2°C–8°C.

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

Introduction

Docetaxel is a semisynthetic taxoid antineoplastic agent. The taxane derivative induces polymerization of tubulin monomers and, at the same time, inhibits depolymerization, leading to cell cycle arrest in G2/M phase and ultimately cell death. Docetaxel medicinal products are approved for the treatment of breast, non-small cell lung, prostate, head and neck cancer, as well as gastric adenocarcinoma [1]. Since docetaxel is poorly soluble in water, in licensed medicinal products it is solubilized with polysorbate 80 and ethanol. Docetaxel Accord 20 mg/mL is proven to be physicochemically stable after first opening over a period of 21 days stored at room temperature, not protected from light [2]. Prior to administration, Docetaxel Accord 20 mg/mL must be diluted with 0.9% sodium chloride or 5% glucose infusion solution to a maximum concentration of 0.74 mg/mL [1]. According to the Summary of Product Characteristics (SmPC), in-use stability of infusion solutions is given for six hours at temperatures below 25°C [1]. Diluted docetaxel infusion solutions prepared with docetaxel 10 mg/mL medicinal products as starting material revealed to be physicochemically stable for up to 56 days, irrespective of the storage temperature [3–6].

Study objectives

The aim of this study was to determine the physicochemical stability of Docetaxel Accord 20 mg/mL concentrate after dilution with 0.9% sodium chloride or 5% glucose solution in non-PVC bags to nominal docetaxel concentrations 0.3 mg/mL and 0.9 mg/mL, stored at room temperature or refrigerated for a maximum period of 24 hours or 98 days, respectively.

Methods

Docetaxel 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 by using the European Medicines Agency (EMA) licensed Docetaxel Accord 20 mg/mL concentrate (batch number M00157). Diluted test solutions were stored under refrigeration (2°C– 8°C) and at room temperature (20°C– 25°C). Samples were taken and analysed initially (Day 0) and at predetermined time points. For detailed information, please refer to Table 1.

Table 1

The physical stability of test solutions was assessed by pH measurement ( using a glass electrode) and visual inspections under standard laboratory light conditions for any changes in colour, clarity, or the presence of particulate matter in a clean test tube.

Chemical stability was assessed by an high-performance liquid chromatography (HPLC) assay, which has been validated for linearity of analytical response and acceptable precision [7]. The assay was proven to be stability-indicating for non-specific degradation of the parent drug. Acceptance criteria were set to ±10% of the label claim for diluted test solutions [7]. In parallel, the ethanol content of test solutions was measured by gas chromatography. The acceptance limit was set to ±10% of the initial ethanol content [7].

Results

Diluted Docetaxel Accord solution 0.9 mg/mL in non-PVC bags stored at 20°C– 25°C remained unchanged over the 24-hour study period, regardless of the type of vehicle solution used (0.9% sodium chloride, 5% glucose solution), as shown in Table 2.

Table 2

Diluted Docetaxel Accord test solutions (0.3 mg/mL, 0.9 mg/mL), stored in non-PVC bags at 2°C– 8°C, remained physicochemical ly stable regardless of the vehicle solution used (0.9% sodium chloride, 5% glucose solution) for up to 98 days. Neither colour change, nor turbidity, nor visible particles were observed during visual inspection. Results of pH measurements showed only slight variations (less than 0.1 unit) during the observation period. The HPLC assays revealed only slight variations of docetaxel concentrations at different time points, which are related to the assay variability. The ethanol content fulfilled the acceptance criteria throughout the entire inspection period. For detailed results, see Tables 3 and 4.

Table 3

Table 4

These results are in accordance with the results of previous studies, when diluted docetaxel solutions of the formerly approved 10 mg/mL formulation were found to be physicochemically stable for a maximum of 56 days, regardless of the storage temperature [2–5].

Conclusion

Diluted Docetaxel Accord infusion solutions 0.3 mg/mL and 0.9 mg/mL prepared with 0.9% sodium chloride or 5% glucose diluent in pre-filled non-PVC bags remained physicochemically stable over the observation period of 24 hours when stored at room temperature and for 98 days when stored at 2°C– 8°C. Therefore, diluted docetaxel infusion solutions within the concentration range of 0.3 mg/mL to 0.9 mg/mL can be prepared in advance by pharmacy-based cytotoxic preparation units and used over a period of 98 days when refrigerated.

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. Summary of product characteristics for Docetaxel Accord 20 mg/1 mL concentrate for solution for infusion. Available from: https://cdn.accord-healthcare.com/ie/public/spc/downloadspc_docetaxel_20mg_0.pdf
2. Accord Healthcare. Docetaxel stability data-holding study report. Data on file 2018.
3. Thiesen J, Krämer I. Physico-chemical stability of docetaxel premix solution and docetaxel infusion solutions in PVC bags and polyolefine containers. Pharm World Sci. 1999;21(3):137-41.
4. Walker SE, Charbonneau F, Law S. Stability of docetaxel solutions after dilution in ethanol and storage in vials and after dilution in normal saline and storage in bags. Can J Hosp Pharm. 2007;60(4):231-7.
5. Lazzarini R, Salvadori S, Trapella C, Guerrini R, Marzola E, Pasini G, et al. Physicochemical stability of cabazitaxel and docetaxel solutions. Eur J Hosp Pharm. 2015;22:150-5.
6. Macleod S, Sewell GJ. Physical and chemical stability of docetaxel infusions in polyolefin bags containing 0.9% sodium chloride or 5% glucose at 5°C and 25°C. Eur J Hosp Pharm Pract. 2011;17(2):39-43.
7. Accord Healthcare Limited. Data for HPLC assay and acceptance criteria on file; 30-05-14.

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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