Working within the Design Space: Do Our Static Process Characterization Methods Suffice?

The Process Analytical Technology initiative and Quality by Design paradigm have led to changes in the guidelines and views of how to develop drug manufacturing processes. On this occasion the concept of the design space, which describes the impact of process parameters and material attributes on the attributes of the product, was introduced in the ICH Q8 guideline. The way the design space is defined and can be presented for regulatory approval seems to be left to the applicants, among who at least a consensus on how to characterize the design space seems to have evolved. The large majority of design spaces described in publications seem to follow a "static" statistical experimentation and modeling approach. Given that temporal deviations in the process parameters (i.e., moving within the design space) are of a dynamic nature, static approaches might not suffice for the consideration of the implications of variations in the values of the process parameters. In this paper, different forms of design space representations are discussed and the current consensus is challenged, which in turn, establishes the need for a dynamic representation and characterization of the design space. Subsequently, selected approaches for a dynamic representation, characterization and validation which are proposed in the literature are discussed, also showcasing the opportunity to integrate the activities of process characterization, process monitoring and process control strategy development.

Preclinical evaluation of a chemically detoxified pneumolysin as pneumococcal vaccine antigen.

The use of protein antigens able to protect against the majority of Streptococcus pneumoniae serotypes is envisaged as stand-alone and/or complement to the current capsular polysaccharide-based pneumococcal vaccines. Pneumolysin (Ply) is a key virulence factor that is highly conserved in amino acid sequence across pneumococcal serotypes, and therefore may be considered as a vaccine target. However, native Ply cannot be used in vaccines due to its intrinsic cytolytic activity. In the present work a completely, irreversibly detoxified pneumolysin (dPly) has been generated using an optimized formaldehyde treatment. Detoxi-fication was confirmed by dPly challenge in mice and histological analysis of the injection site in rats. Immunization with dPly elicited Ply-specific functional antibodies that were able to inhibit Ply activity in a hemolysis assay. In addition, immunization with dPly protected mice against lethal intranasal challenge with Ply, and intranasal immunization inhibited nasopharyngeal colonization after intranasal challenge with homologous or heterologous pneumococcal strain. Our findings supported dPly as a valid candidate antigen for further pneumococcal vaccine development.