Viscosity increase/gelation of therapeutic IgG monoclonal antibodies induced by Zn2+: One possible root cause of clogging of staked-in-needle prefilled syringes

We investigated the elution of zinc ions (Zn2+) from the elastomer of rigid needle shields (RNS) attached to staked-in-needle prefilled syringes (SIN-PFS) and the physicochemical impacts of Zn2+ on therapeutic IgG monoclonal antibody (mAb) solutions. The elution of metal ions from typical RNS elastomer under realistic buffer and storage conditions was investigated by inductively coupled plasma-mass spectrometry. Among the metal ions examined, only Zn2+ was detected. The elution of Zn2+ from RNS elastomer was found to be buffer-dependent. We investigated the influence of Zn2+ on the viscosity of seven mAb solutions at 180 mg/mL. The effect of Zn2+ clearly depended on antibody type. Drastic increases in viscosity or gelation were observed in four out of the seven mAbs. Dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS) showed the effect of Zn2+ on mAb viscosity was explained by the colloidal destabilization of mAb solutions. Thus, Zn2+ leaching from RNS elastomer may possibly increase viscosity or cause gelation, and consequently cause possible needle clogging during long-term storage. DLS and SAXS can predict reactivity of mAbs to Zn2+, and require only small amounts of samples. This makes it possible to predict compatibility with RNS elastomer and evaluate needle clogging risk in SIN-PFSs in the early stages of mAb development.