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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.

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Aims:  To develop an easy‐to‐use and pathogen‐free protocol giving reliable information on the bioavailability of iron in a medium. Methods and Results:  In aerobic conditions, iron bioavailability is very low, and most of its forms cannot be assimilated by micro‐organisms. Media with similar iron contents can differ considerably in iron bioavailability, something that is not easily achieved using conventional physicochemical methods. The assay developed in the present work is based on a pyoverdin siderophore release by fluorescent Pseudomonas in response to iron stress. Conclusions:  The test was applied to a complex medium used for the production of diphtheria toxin (DT). A significant difference between the bioavailable iron level and the total chemical concentrations contributed by the various compounds used to make the medium could thus be detected. This can be explained by the formation of salt complexes trapping the iron, which thus cannot be used directly by the micro‐organism for its metabolism. Significance and Impact of the Study:  The assay can easily be applied to any medium designed for the production of iron‐regulated compounds. This is particularly useful when dealing with processes that use pathogenic strains as was shown in the case based on DT production.

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