Risk reduction in biotherapeutic products.

Ensuring the safety of therapeutic modalities produced and purified from biological systems is of high concern. Regulatory authorities and the biopharmaceutical industry are continuously seeking to improve methods for the detection, identification, inactivation and removal of potentially contaminating pathogens in biotherapeutic products. Current methods for pathogen detection and identification are designed to discover adventitious as well as known microbial species in product samples. Many of these approaches require weeks or even months of observation, and the time involved is often a constraint on product release. This review focuses on current practices and technologies that have emerged in recent years, and highlights advances that have accelerated the time required for, and accuracy of, pathogen detection and identification. The biopharmaceutical industry has employed a multifaceted approach in pathogen detection, including the rigorous screening of blood/plasma donations; documented sourcing and screening of raw materials; thorough testing of production cell substrates and cell culture harvest material during processing, and at the stage of a final purified drug substance; and the evaluation of microbe clearance during purification operations. All these practices strive to ensure safety and mitigate the risk to patients undergoing biotherapeutic treatment.

Identification of reciprocally regulated gene modules in regenerating dorsal root ganglion neurons and activated peripheral or central nervous system glia.

Differential gene expression in the rat after injury of dorsal root ganglion neurons in vivo, and simulation injury of Schwann cells and oligodendrocytes in vitro was analyzed using high-density cDNA microarrays. The analyses were carried out to study the genetic basis of peripheral nerve regeneration, and to compare gene regulation in glia of the central (oligodendrocyte) and peripheral (Schwann cell) nervous systems. The genes showing significant differential regulation in the three study groups represented all aspects of cellular metabolism. However, two unexpected observations were made. Firstly, a number of identical genes were differentially regulated in activated Schwann cells, activated oligodendrocytes and regenerating DRG neurons. Specifically, a group of 113 out of 210 genes that were down-regulated in Schwann cells upon lipopolysaccharide (LPS) treatment, were identical to genes up-regulated in the injured, regenerating DRG. Furthermore, a group of 53 out of 71 genes that were down-regulated in interferon gamma (IFN-gamma)/LPS-activated oligodendrocytes, were identical to genes up-regulated in the DRG neurons. Finally, 22 genes were common to these three groups, i.e., down-regulated in activated oligodendrocytes, down-regulated in activated Schwann cells, and up-regulated in regenerating DRG neurons. Secondly, a group of 16 cell-cycle and proliferation-related genes were up-regulated in the DRG following sciatic nerve crush, despite the absence of cells undergoing mitosis in the DRG, or any significant presence of apoptosis-related gene expression. Therefore, it appears that in these three cell types, large sets of genes are reciprocally regulated upon injury and/or activation. This suggests that the activation of the injury-related gene expression program in cell derivatives of the neuroectoderm involves, in part, highly conserved genetic elements.