Development and practical validation of BUBBLESS tapping instrument for efficient bubble removal during antibody drug mixing

BACKGROUND: Antibody drugs play a central role in modern medical treatments, despite their tendency to aggregate under physical stimuli being a major challenge. Generically, these are prone to foaming, and bubble from syringes is typically manually removed by means of tapping. Hence, this study aimed to develop and evaluate the efficacy of a tapping instrument for bubble removal from syringes with minimal physical stress. METHODS: The instrument was designed with a columnar shape to minimize contact area with the syringe surface. This instrument was named BUBBLESS, a coined term combining “bubble” and “less.” To measure the force applied to syringes, a cutting-force measurement system was employed. Twelve participants each drew 50 mL of distilled water into syringes and removed naturally occurring bubbles. Bubble removal was performed three times each by hand and using BUBBLESS per participant. Infliximab was the model antibody drug to evaluate aggregation, and its solutions were immediately imaged, following bubble removal by manual or BUBBLESS tapping, under a laser microscope. RESULTS: A columnar shape, based on its contact area with the syringe, and polyacetal resin were used for developing BUBBLESS (weight: approximately 38.0 g). The median maximum force (interquartile range [IQR]) applied to the syringe was 129.1 (113.1–175.2) N by hand and 60.7 (47.9–80.9) N with BUBBLESS (p < 0.0001). The median total applied force (IQR) was 1,665,283 (1,176,238–2,445,051) N by hand and 575,061 (400,170.3–731,369.6) N with BUBBLESS (p < 0.0001). Laser microscopy revealed visible aggregation of infliximab following manual tapping but almost none after BUBBLESS tapping. No further changes were observed during a 10-min observation period in either case. The largest recorded horizontal and vertical diameters were approximately 12.5 and 13.4 μm, respectively, with no further changes observed in the aggregate during the 10-min observation period. CONCLUSIONS: This study shows the potential of the BUBBLESS tapping method as a novel approach to suppress antibody drug aggregation.