Investigating and Addressing Challenges Associated with Filling Protein Drug Products.

The fill-finish process for vials and syringes, although considered standard in the biopharmaceutical industry, comes with numerous technical challenges when manufacturing high concentration products. This paper includes case studies, illustrating the operational challenges associated with the filling unit operation for three of the commonly used filling technologies for biopharmaceutical products - piston pump, time over pressure pump and peristaltic pump. First case study consists of a piston pump filling operation and evaluates impact of product related parameters such as a) protein concentration, b) product viscosity and c) surface tension.

Subvisible Particles in Solutions of Remicade in Intravenous Saline Activate Immune System Pathways in In Vitro Human Cell Systems.

Among patients that receive Remicade® therapy, more than 20% have adverse infusion related reactions and approximately 50% have immunogenic responses. Upon characterization of initial Remicade®-IV solution we observed a high concentration of subvisible particles that could inadvertently be delivered to patients. This solution was processed through the IV infusion system, mimicking the typical clinical administration setup - either with or without an in-line filter connected to the IV line.

Protein Nanoparticles Promote Microparticle Formation in Intravenous Immunoglobulin Solutions During Freeze-Thawing and Agitation Stresses.

In this study, we investigated the potential roles of nanoparticles (<100 nm) and submicron (100-1000 nm) particles in the formation of microparticles (>1000 nm) in protein formulations under some pharmaceutically relevant stress conditions. Exposure of intravenous immunoglobulin solutions to the interface-associated stresses of freeze-thawing or agitation resulted in relatively large increases in microparticle concentrations, which depended directly on the levels of pre-existing nano- and submicron particles. Thus, agglomeration of nanoparticles and submicron particles appears to play a role in microparticle formation under these stresses.

Microparticles and Nanoparticles Delivered in Intravenous Saline and in an Intravenous Solution of a Therapeutic Antibody Product.

Intravenous (IV) infusion is used for administration of a large proportion of biologic therapeutics, including most monoclonal antibody products. In this study, we determined the subvisible particle levels in IV solutions and after the solutions were processed with an IV administration setup that mimicked the typical clinical method of administration. IV saline in bags manufactured by both Hospira and Baxter contained 1600-8000 microparticles/mL and 4-73 × 10 nanoparticles/mL in solution.

Transmission electron microscopy as an orthogonal method to characterize protein aggregates.

Aggregation of protein-based therapeutics is a challenging problem in the biopharmaceutical industry. Of particular concern are implications for product efficacy and clinical safety because of potentially increased immunogenicity of the aggregates. We used transmission electron microscopy (TEM) to characterize biophysical and morphological features of antibody aggregates formed upon controlled environmental stresses.

Pharmacokinetics of DS-96, an alkylpolyamine lipopolysaccharide sequestrant, in rodents.

The pharmacokinetics of DS-96, an N-alkylhomospermine analog designed to sequester bacterial lipopolysaccharides, has been determined in rodent species. The elimination half-life in mice and rats are about 400 and 500 min, respectively, with other PK parameters being quite similar in the two rodent species. Interestingly, the mouse intravenous plasma concentration time curves exhibit an apparent absorption phase.