Flocculation of etoposide preparations: what are the influencing factors?

The centralized cytotoxic preparation unit (CCPU) produces approximately 400 etoposide (ETO) infusion bags per year. According to the Summary of Product Characteristics (SmPC) for marketed ETO formulations, the drug diluted in 0.9% sodium chloride is stable for 48 hours at room temperature at concentrations up to 0.4 mg/mL. In addition, stability data for highly concentrated ETO preparations (10 mg/mL) can be found in the literature.
Over an 18-month period, eleven non-conformities were reported due to the observation of flocculated bags prior to their expiry. Most of these involved highly concentrated preparations. Only two of these preparations had been compounded in accordance with the SmPC dilution guidelines. These incidents have led to pump occlusion alarms, uncertainty regarding the administered dose, and disruption of both clinical services and CCPU activities. They often require interventions on-call and re-preparation of infusion bags.
To date, the mechanism underlying these flocculations has not been clearly elucidated in the literature. The objective of this study was therefore to identify the factors influencing the occurrence of flocculation.
All steps in the ETO bag production process were mapped. An experimental design was implemented to vary key parameters: injection device and filling speed (needle versus Chemolock® [ICU Medical]), storage temperature (35.6–46.4°F, 64.4–68°F, 91.4°F), final container type (syringe or bag), formulation brand (Accord®, Hikma®, Viatris®, and Teva®), presence or absence of air in the container, and preparation concentration (ranging from 0.1 to 10 mg/mL). The potential role of excipients was investigated by adding polysorbate 80 to some of the ETO bags and by preparing bags containing only PEG 300 at concentrations typically used in ETO formulations.
All bags were regularly inspected via visual examination for macroscopic particle formation. In total, 115 bags were prepared in three phases: 70 ETO bags based on the above experimental design, followed by 27 bags containing only PEG 300, and 18 additional ETO bags varying only in air content and concentration.
The main factors associated with flocculation were storage temperature fluctuations and ETO concentrations between 0.4 and 10 mg/mL. Preparations outside this concentration range appeared less prone to flocculation. Conversely, other parameters—such as filling speed and excipient composition—did not appear to significantly influence flocculation.
To strengthen these findings, additional batches will be prepared at concentrations of 0.4 and 10 mg/mL, varying storage temperature, air content, and diluent (0.9% NaCl or 5% glucose).

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