Technical Considerations for Use of Oligonucleotide Solution API.

The most common approach for the manufacture of oligonucleotides includes isolation of the active pharmaceutical ingredient (API) via lyophilization to provide a solid product, which is then dissolved to provide an aqueous formulation. It is well known from the development and manufacture of large molecules ("biologics") that API production does not always require isolation of solid API before drug product formulation, and this article provides technical considerations for the analogous use of oligonucleotide API in solution. The primary factor considered is solution stability, and additional factors such as viscosity, concentration, end-to-end manufacturing, microbiological control, packaging, and storage are also discussed. The technical considerations discussed in this article will aid the careful evaluation of the relative advantages and disadvantages of solution versus powder API for a given oligonucleotide drug substance.

Unexplored benefits of controlled ice nucleation: Lyophilization of a highly concentrated monoclonal antibody solution.

The study explores new benefits of controlled ice nucleation during lyophilization. A highly concentrated monoclonal antibody product was lyophilized using conventional (uncontrolled) and controlled ice nucleation freezing and the processes were compared for their impact on process performance, reconstitution time, and product quality attributes. Glass fogging was observed during the conventional ice nucleation freezing step and is investigated. A mechanical stress study was also conducted on the lyophilized product manufactured using uncontrolled and controlled ice nucleation to measure and compare propensity toward aggregation upon physical stresses associated with shipping and handling. Reduction in primary drying time and reconstitution time was achieved with controlled ice nucleation. In contrast to significant fogging observed for uncontrolled nucleation, glass fogging was absent in vials subjected to controlled ice nucleation. Uncontrolled nucleation freezing produced higher number of particles when subjected to mechanical stress prior to reconstitution compared to controlled nucleation lyophilized samples. The study confirms published benefits of controlled ice nucleation (e.g. reduction in primary drying time). The manuscript reports for the first time the advantage that controlled ice nucleation may offer in regards to glass fogging during lyophilization. The reduced number of particles in the controlled nucleated samples exposed to mechanical stress suggest that frictional forces play an important role in governing the stability of protein in the lyophilized state.

An industry perspective on the monitoring of subvisible particles as a quality attribute for protein therapeutics.

Concern around the lack of monitoring of proteinaceous subvisible particulates in the 0.1-10 microm range has been heightened (Carpenter et al., 2009, J Pharm Sci 98: 1202-1205), primarily due to uncertainty around the potential immunogenicity risk from these particles. This article, representing the opinions of a number of industry scientists, aims to further the discussion by developing a common understanding around the technical capabilities, limitations, as well as utility of monitoring this size range; reiterating that the link between aggregation and clinical immunogenicity has not been unequivocally established; and emphasizing that such particles are present in marketed products which remain safe and efficacious despite the lack of monitoring. Measurement of subvisible particulates in the <10 microm size range has value as an aid in product development and characterization. Limitations in measurement technologies, variability from container/closure, concentration, viscosity, history, and inherent batch heterogeneity, make these measurements unsuitable as specification for release and stability or for comparability, at the present time. Such particles constitute microgram levels of protein with currently monitored sizes >or=10 microm representing the largest fraction. These levels are well below what is detected or reported for other product quality attributes. Subvisible particles remain a product quality attribute that is also qualified in clinical trials.