An Assessment of the Ability of Submicron- and Micron-Size Silicone Oil Droplets in Dropped Prefillable Syringes to Invoke Early- and Late-Stage Immune Responses

Abstract

a b s t r a c tA number of biopharmaceuticals are available as lyophilized formulations along with a prefilled syringe (PFS) containing water for injection (WFI). Submicron-and micron-size droplets of lubricating silicone oil (SO) applied to the inner surface of the PFS barrel might migrate into the WFI, to which protein pharmaceuticals can adsorb, potentially inducing an immune response. In the present study, we subjected siliconized cyclo-olefin polymer PFSs filled with WFI to dropping stress to simulate actual shipping conditions as well as evaluated the risk associated with the released SO droplets. The results confirmed the undesirable effects of SO on therapeutic proteins, including adsorption to SO droplets and increased secretion of several innate cytokines from human peripheral blood mononuclear cells of a small donor panel. Assessment of immunogenicity in vivo using BALB/c mice revealed a slight increase in the plasma concentrations of antidrug antibodies over 21 days in response to SO-containing antibody samples compared to the absence of SO. These results indicate that SO droplets form complexes with pharmaceutical proteins that can potentially invoke early-and late-stage immune responses. Therefore, the use of SO-free cyclo-olefin polymer PFSs as primary containers for WFI could contribute to the enhanced safety of reconstituted biopharmaceuticals.

Mechanical Shock During Shipping of Medications: The Roles of Packaging and Transportation Vendors

“…13,14 Furthermore, mechanical shockeinduced increases in the concentration of protein particles and silicone oil droplets have been shown in cell-and murine-based models to promote adverse immunogenicity to therapeutic protein products. 15 These findings support our assertion that drop stress that is insufficient to cause visible damage to biologic medications may be sufficient to cause product damage at the subvisible level, which in turn could play a role in adverse effects in patients.…”

Effect of injection solutions in the dispersion of syringe lubricant (silicone oil)

“…Larger or smaller pure droplets are deemed more inert, but may still cause adsorption and increased immunoreactivity to therapeutic proteins. 4 The size and shape of SO droplets were evaluated in 5 solutions: saline, bacteriostatic saline, water for injection, bacteriostatic water (all from Hospira Inc, Lake Forrest, IL), and Kybella. A negative control, glass syringe (Artiglass, Padua, Italy), a positive control (Artiglass lubricated with 0.1 mL of Siluron 2000 [Fluoron GmbH, Ulm, Germany]), and 3 brands of lubricated syringes: 1 mL Luer-Lok (Becton Dickinson, Franklin Lakes, NJ), 1 mL Luer-Lok (Saldanha Rodrigues, Manaus, Brazil), and 1 mL Luer-Slip (Injex, Ourinhos, Brazil) were tested for each solution under nonagitated or agitated (10 consecutive flicks with the needle side facing upward) conditions.…”

“…The density of lotion sunscreen application is commonly lower than the area density (2 mg/cm 2 ) used to test sun protection factor (SPF) levels, leading to lower than expected photoprotection. [2][3][4] Few have examined aerosol All solvents exhibited a great number of droplets within optimal phagocytic range. Saline (0.9% sodium chloride): median, 0.9 m 2 (interquartile range [IQR], 0.5-1.6 m 2 ; maximum area [max], 7.6 m 2 ); with agitation, 1.2 m 2 (IQR, 0.8-1.9 m 2 ; max, 8.6 m 2 ).…”

Automatic Identification of the Stress Sources of Protein Aggregates Using Flow Imaging Microscopy Images

“…[10][11][12][13][14][15][16][17] Our recent study showed that pharmaceutical proteins adsorb to the surface of submicron-and micron-size droplets of lubricating silicone oil (SO) that migrate into the solution from the inner surface of the PFS barrel, and that the resulting complexes are capable of invoking immune responses. 18 Therefore, the detection and quantification of protein aggregates in biopharmaceutical products together with strategies to prevent proteinaceous particle formation are necessary to mitigate the immunogenicity of biotherapeutics. 19,20 The determination of the most probable source of a stress/ perturbation can aid in the development of quality control strategies.…”