Application of Quality by Design Principles for the Definition of a Robust Crystallization Process for Casopitant Mesylate

GlaxoSmithKline (GSK) has identified casopitant as a potent NK1 antagonist. It was selected for its potential activities on a number of therapeutic targets such as inflammatory bowel disease, overactive bladder, CNS disorders and others. The mesylate salt of casopitant was selected for full development using a quality by design (QbD) approach in which a control strategy was developed from a design space, underpinned by process understanding and risk analysis for an enhanced level of quality assurance. As the concepts of design space and control strategy in the QbD framework move on from their inception to implementation, the ambiguity of definition has led to considerable discussion, diversity of opinions and uncertainty around how best to define these ideas. This contribution provides an outline of the sequential experimentation and analyses that led to the construction of a Bayesian approach to the ICH Q8 definition of Design Space. This uses a predictive approach for multiple response surface optimisation to identify a region of process operating conditions where all quality attributes of the active pharmaceutical ingredient (API) are likely to meet specifications with a high degree of confidence. Boundaries of assurance for design space and control strategy are introduced that provide a basis for defining dynamic operating ranges that should enhance the scope of operation and manufacturing flexibility that the regulatory agencies are encouraging. This new paradigm provides an opportunity to move away from the traditional concept of documenting static normal operating ranges (NOR) and proven acceptable ranges (PAR) univariately in a table or providing them as a list to regulators as part of regulatory submissions. While the latter approach is practical for documentation and serves as a simple instruction to manufacturing as to where a process should be allowed to run, it is not ideally suitable for describing a multidimensional design space. Model/parameter-based control is discussed through a worked example on the casopitant crystallisation step of a particle-forming routine.