Homogeneous Heat Transfer During Freeze-Drying Using Cyclic Olefin Polymer Vials.

In pharmaceutical freeze-drying processes, batch homogeneity is an important quality attribute. In this context, the edge-vial-effect is a challenging phenomenon. Shortly, this effect describes that vials at the edges of the shelf dry faster and at a higher temperature compared to vials in the middle of the shelf. Studies by Ehlers et al. revealed that this effect mainly origins from the number of neighbor vials cooling each other, which is reduced for vials in corners and edges compared to vials in the middle. Due to the reduced heat transfer in cyclic olefin polymer (COP) vials, the adverse edge-vial-effect should be greatly reduced allowing a better batch uniformity. In this focused study, glass and COP vials are compared regarding this effect on a fully loaded shelf. A reference experiment with vials placed at distance using a specially designed frame is presented as well.

Biodistribution of Drug/ADA Complexes: The Impact of Immune Complex Formation on Antibody Distribution.

The clinical use of therapeutic monoclonal antibodies (mAbs) for the treatment of cancer, inflammation, and other indications has been successfully established. A critical aspect of drug-antibody pharmacokinetics is immunogenicity, which triggers an immune response via an anti-drug antibody (ADA) and forms drug/ADA immune complexes (ICs). As a consequence, there may be a reduced efficacy upon neutralization by ADA or an accelerated drug clearance. It is therefore important to understand immunogenicity in biological therapies. A drug-like immunoglobulin G (IgG) was radiolabeled with tritium, and ICs were formed using polyclonal ADA, directed against the complementary-determining region of the drug-IgG, to investigate in vivo biodistribution in rodents. It was demonstrated that 65% of the radioactive IC dose was excreted within the first 24 h, compared with only 6% in the control group who received non-complexed 3H-drug. Autoradiographic imaging at the early time point indicated a deposition of immune complexes in the liver, lung, and spleen indicated by an increased radioactivity signal. A biodistribution study confirmed the results and revealed further insights regarding excretion and plasma profiles. It is assumed that the immune complexes are readily taken up by the reticuloendothelial system. The ICs are degraded proteolytically, and the released radioactively labeled amino acids are redistributed throughout the body. These are mainly renally excreted as indicated by urine measurements or incorporated into protein synthesis. These biodistribution studies using tritium-labeled immune complexes described in this article underline the importance of understanding the immunogenicity induced by therapeutic proteins and the resulting influence on biological behavior.

Microwave-Assisted Freeze-Drying: Impact of Microwave Radiation on the Quality of High-Concentration Antibody Formulations.

Microwave-assisted freeze-drying (MFD) offers significant time savings compared to conventional freeze-drying (CFD). While a few studies have investigated the stability of biopharmaceuticals with low protein concentrations after MFD and storage, the impact of MFD on high-concentration monoclonal antibody (mAb) formulations remains unclear. In this study, we systematically examined the effect of protein concentration in MFD and assessed protein stability following MFD, CFD, and subsequent storage using seven protein formulations with various stabilizers and concentrations. We demonstrated that microwaves directly interact with the active pharmaceutical ingredient (API), leading to decreased physical stability, specifically aggregation, in high-concentration antibody formulations. Furthermore, typically used sugar:protein ratios from CFD were insufficient for stabilizing mAbs when applying microwaves. We identified the intermediate drying phase as the most critical for particle formation, and cooling the samples provided some protection for the mAb. Our findings suggest that MFD technology may not be universally applicable to formulations well tested in CFD and could be particularly beneficial for formulations with low API concentrations requiring substantial amounts of glass-forming excipients, such as vaccines and RNA-based products.