Chemical-gas Sterilization of External Surface of Polymer-based Prefilled Syringes and Its Effect on Stability of Model Therapeutic Protein.

To reduce the risk of infection during intravitreal injections, the external surface of prefilled syringes (PFSs) must be sterilized. Usually, ethylene oxide (EO) gas or vaporized hydrogen peroxide (VHP) is used for sterilization. More recently, nitrogen dioxide (NO2) gas sterilization has been developed. It is known that gas permeability is approximately zero into glass-PFSs. However, polymer-PFSs (P-PFSs) have relatively high gas permeability. Therefore, there are concerns about the potential impact of external surface sterilization on drug solutions in P-PFSs. In this study, P-PFSs [filled with water for injection (WFI) or human serum albumin (HSA) solution] were externally sterilized using EO, VHP, and NO2 gases. For the WFI-filled syringes, the concentration of each gas that ingressed into the WFI was measured. For the HSA solution-filled syringes, the physical and chemical degradation of HSA molecules by each sterilant gas was quantified. For the EO- or VHP-sterilized syringes, the ingressed EO or hydrogen peroxide (H2O2) molecules were detected in the filled WFI. Additionally, EO-adducted or oxidized HSA molecules were observed in the HSA-filled syringes. In contrast, the NO2-sterilized WFI-filled syringes exhibited essentially immeasurable ingressed NO2, and protein degradation was not detected in HSA-filled syringes.

Influence of Protein Adsorption on Aggregation in Prefilled Syringes.

Protein aggregate formation in prefilled syringes (PFSs) can be influenced by protein adsorption and desorption at the solid-liquid interface. Although inhibition of protein adsorption on the PFS surface can lead to a decrease in the amount of aggregation, the mechanism underlying protein adsorption-mediated aggregation in PFSs is unclear. This study investigated protein aggregation caused by protein adsorption on silicone oil-free PFS surfaces [borosilicate glass (GLS) and cycloolefin polymer (COP)] and the factors affecting the protein adsorption on the PFS surfaces. The adsorbed proteins formed multilayered structures that consisted of two distinct types of layers: proteins adsorbed on the surface of the material and proteins adsorbed on top of the proteins on the surface. A pH-dependent electrostatic interaction was the dominant force for protein adsorption on the GLS surface, while hydrophobic effects were dominant for protein adsorption on the COP surface. When the repulsion force between proteins was weak, protein adsorption on the adsorbed protein layer was increased for both materials and as a result, protein aggregation increased. Therefore, a formulation with high colloidal stability can minimize protein adsorption on the COP surface, leading to reduced protein aggregation.