Characterization of protein rheology and delivery forces for combination products.

Characterization of a protein-device combination product over a wide range of operating parameters defined by end-user requirements is critical for developing a product presentation that is convenient for patient use. In addition to the device components, several product attributes, such as product rheology and product-container interactions, govern the functionality of a delivery system. This article presents results from a characterization study conducted for a high-concentration antibody product in a prefilled syringe. Analytical models are used to study the rheological behavior and to estimate delivery forces over a broad design space comprising temperature, concentration, and shear stress. Data suggest that high-viscosity products may exhibit significant shear thinning under the shear rates encountered under desired injection times.

Direct visualization of protein adsorption to primary containers by gold nanoparticles.

Adsorption of proteins to primary containers can result in protein loss, protein denaturation, or aggregation. We report a simple and effective method to directly detect and visualize adsorption of proteins to container surfaces by staining adsorbed proteins with gold nanoparticles, which bind proteins nonspecifically. The gold nanoparticle staining method was applied to study adsorption to siliconized glass prefilled syringes (PFSs) of a therapeutic protein in a liquid formulation. The protein was found to preferentially adsorb to glass surfaces over siliconized surfaces in PFSs. The presence of adsorbed proteins on glass surfaces was confirmed by in situ Raman spectroscopy. Gold nanoparticle staining patterns revealed that adsorption of proteins to hydrophobic cyclic olefin polymer plastic vials was minimized compared with hydrophilic type I glass vials. Bovine serum albumin (BSA) also preferentially adsorbed to glass surfaces compared with siliconized surfaces as revealed by the gold staining patterns in PFS incubated with BSA, supporting the use of albumin to minimize loss of proteins in glass containers. The method is particularly valuable for high-concentration protein formulations in which adsorption of proteins to containers cannot be easily detected by other methods.

Variability in syringe components and its impact on functionality of delivery systems.

Prefilled syringes and autoinjectors are becoming increasingly common for parenteral drug administration primarily due to the convenience they offer to the patients. Successful commercialization of such delivery systems requires thorough characterization of individual components. Complete understanding of various sources of variability and their ranking is essential for robust device design. In this work, we studied the impact of variability in various primary container and device components on the delivery forces associated with syringe injection. More specifically, the effects of barrel size, needle size, autoinjector spring force, and frictional forces have been evaluated. An analytical model based on underlying physics is developed that can be used to fully characterize the design space for a product delivery system. LAY ABSTRACT: Use of prefilled syringes (syringes prefilled with active drug) is becoming increasingly common for injectable drugs. Compared to vials, prefilled syringes offer higher dose accuracy and ease of use due to fewer steps required for dosage. Convenience to end users can be further enhanced through the use of prefilled syringes in combination with delivery devices such as autoinjectors. These devices allow patients to self-administer the drug by following simple steps such as pressing a button. These autoinjectors are often spring-loaded and are designed to keep the needle tip shielded prior to injection. Because the needle is not visible to the user, such autoinjectors are perceived to be less invasive than syringes and help the patient overcome the hesitation associated with self-administration. In order to successfully develop and market such delivery devices, we need to perform an in-depth analysis of the components that come into play during the activation of the device and dose delivery. Typically, an autoinjector is activated by the press of a button that releases a compressed spring; the spring relaxes and provides the driving force to push the drug out of the syringe and into the site of administration. Complete understanding of the spring force, syringe barrel dimensions, needle size, and drug product properties is essential for robust device design. It is equally important to estimate the extent of variability that exists in these components and the resulting impact it could have on the performance of the device. In this work, we studied the impact of variability in syringe and device components on the delivery forces associated with syringe injection. More specifically, the effect of barrel size, needle size, autoinjector spring force, and frictional forces has been evaluated. An analytical model based on underlying physics is developed that can be used to predict the functionality of the autoinjector.

Distribution of silicone oil in prefilled glass syringes probed with optical and spectroscopic methods.

Prefilled glass syringes (PFSs) have become the most commonly used device for the delivery of recombinant protein therapeutics in parenteral formulations. In particular, auto-injectors preloaded with PFSs greatly facilitate the convenient and efficient self-administration of protein therapeutics by patients. Silicone oil is used as a lubricant in PFSs to facilitate the smooth motion of the plunger during injection. However, there have been few sophisticated analytical techniques that can qualitatively and quantitatively characterize in-situ the morphology, thickness, and distribution of silicone oil in PFSs. In this paper, we demonstrate the application of three optical techniques including confocal Raman microscopy, Schlieren optics, and thin film interference reflectometry to visualize and characterize silicone oil distribution in PFS. The results showed that a container coating process could produce unevenly distributed silicone oil on the glass barrel of PFSs. An insufficiency of the amount of silicone oil on the glass barrel of a PFS can cause stalling when the device is preloaded into an auto-injector. These analytical techniques can be applied to monitor the silicone oil distribution in PFSs.