In-use psysico-chemical stability of daratumumab upon preparation of intra-venous infusion

Monoclonal antibody therapies can be susceptible to degradation, precipitation, and surface adsorption under the conditions encountered during dilution for intravenous (IV) infusion. However, extended in-use conditions are not included in stability assessment of biologics prior to regulatory approval. Dara-tumumab, a CD38-targeting, human IgG1κ monoclonal antibody used in the treatment of multiple mye-loma, is available as 20 mg/mL concentrate for solution for infusion. After dilution in 0.9% saline (sodi-um chloride) using the appropriate aseptic technique, solutions are reported to be physically and chem-ically stable for 24 h at refrigerated conditions (2-8 °C) protected from light [1]. This study assessed the in-use stability of daratumumab diluted at clinically relevant concentration in an hospital setting over a 10-d period. Daratumumab (Darzalex®, Janssen- Cilag International NV) from three different batches was diluted to concentrations of 1.2 and 2.0 mg/mL in 50 mL-LDPE infusion bags containing 0.9% saline solution for IV injection (B. Braun, Italy). The stability indicating methods (i.e., turbidimetry, SEC-HPLC, DLS, pH, osmolality, NTA) were applied based on the results of a forced degradation study based on different stress conditions [2]. Tests to determine baseline concentrations were conducted immediately after the final infusion bag dilution and samples were stored at refrigerated conditions (2-8 °C) protected from light over time. All samples remained clear for the duration of the study with no precipitates or particulate matter de-tected with the naked eye. No change in colour or turbidity was observed over the study period. The pH of both dilutions shifted from 5.5 to 5.7 throughout the study period. Regarding the osmolarity, the value ranged from 295-205 mOsm/Kg. All SEC-HPLC chromatograms of daratumumab were characterized by a single major peak with an elu-tion time of 11 min and a minor signal with a retention time around 13 min. The ratio between these peaks remained over the tested period. No clear trend in the presence of sub-visible particles was observed by DLS analysis, nor was this af-fected by infusion bag material or protein concentration. Indeed, the main peak of daratumumab was detected at about 13 nm which accounted for up 98% and 95% for 1.2 mg/mL and 2.4 mg/mL solution, respectively. The NTA analysis on samples stored for 10 days confirmed these data as the particles per frame were comparable to those obtained using the 0.9% saline solution. This preliminary data demonstrated the physico-chemical stability of daratumumab over a 10-day period when diluted 0.9% saline at clinically relevant concentrations and stored in LDPE infusion bag at 2-8 °C. The evaluation of biological activity is required to confirm the extended stability.