Investigating Zinc Migration from Rigid Needle Shield to Drug Formulation in Needle Tip of Pre-filled Syringe

Abstract

Objective: This study investigates the underexplored mechanisms of needle clogging in pre-filled syringes (PFSs), focusing on zinc (Zn) ions, which have been reported to promote protein gelation and increase formulation viscosity. We present direct evidence of Zn migration from the rigid needle shield (RNS) into drug products, aiming to elucidate the migration pathways and the role of Zn in clogging. Methods: Pre-filled syringes containing a therapeutic monoclonal antibody (mAb) were stored at 5°C and subjected to stress conditions at 40°C for up to six months. Inductively coupled plasma mass spectrometry (ICP-MS) measured metal ion levels, while synchrotron-based X-ray phase-contrast computed tomography (SR-XPCT) and X-ray fluorescence (SR-XRF) provided in situ visualization of Zn distribution in dry materials under stress. Results: We found that Zn leaches from the RNS into the drug formulation during liquid-RNS contact. ICP-MS revealed higher Zn levels, along with aluminum and titanium, in clogged needles compared to clean ones. SR-XRF identified Zn hot spots within the dried drug product, while SR-XPCT displayed 3D visualization of Zn particle accumulation at the needle tip. Notably, Zn migration accelerated at 40°C, with minimal detection at 5°C, indicating the significant influence of temperature. Conclusions: This study offers the first experimental evidence of Zn migration from the RNS into drug formulations within staked-in-needle PFSs. While Zn is not solely responsible for needle clogging, its presence in both RNS and the drug suggests a contributory role. These insights can inform strategies for improving PFS performance and reliability.