Application of the QbD Principles in the Development of the Casopitant Mesylate Manufacturing Process. Process Research Studies for the Definition of the Control Strategy of some Drug Substance-CQAs for Stages 2a, 2b, and 2c

Abstract

Casopitant was identified as a potent NK 1 antagonist by Glaxo-SmithKline (GSK). It was selected as part of a wide drug discovery programme within GSK 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. The manufacturing process to casopitant mesylate was developed and optimised by following a Quality by Design approach, whereby a control strategy was developed, underpinned by process understanding and risk analysis, for an enhanced level of quality assurance. Quality process parameters and specifications levels for the Stages 2a, 2b, and 2c are the elements of the control strategy of the manufacturing process discussed in detail in this paper. The Design of Experiment approach has been extensively used to support the definition of the proven acceptable ranges for the process. The aim is to show the process development studies carried out to ensure quality control for the final drug substance.

A Quantitative Assay of Sodium Triacetoxyborohydride

“…The yield was nearly identical to that obtained using a higher corrected charge (1.2 equiv) with higher-potency STAB (96.0 wt %; see the Experimental Section). This represents a significant reduction in the STAB charge beyond “excess” or the suggested minimal 1.4–1.5 equiv …”

“…Sodium triacetoxyborohydride (STAB) is a widely employed reducing agent for reductive amination reactions . Because STAB is water- and air-sensitive, the potency of a particular lot of reagent, once opened, is expected to gradually decrease over time.…”

“…An accurate potency measurement could have several advantages with respect to the large-scale use of STAB. Knowing the actual strength of the solid can help users predict an accurate minimal charge required for full conversion, as opposed to the “excess” typically recommended . This has implications for the cost associated with the commercial reagent as well as the thermal and H 2 evolution hazards that accompany quenching of the excess charge.…”

Detection, identification and quantification of a new de-fluorinated impurity in casopitant mesylate drug substance during late phase development: An analytical challenge involving a multidisciplinary approach

“…The commercial process to synthesize casopitant mesylate (1) is a multi-stage convergent process (Scheme 1) [12]. In an advanced phase of development, an impurity was detected by HPLC during monitoring of the quality of the intermediate (3).…”

Robust Crystallization Process Development for the Metastable δ-form of Pyrazinamide

“…The introduction of current good manufacturing practices (cGMP) for the 21st century by U.S. Food and Drug Administration (FDA) has generated interest in Quality by Design (QbD) among pharmaceutical industries, research institutes, and universities. − Through this initiative, FDA encourages pharmaceutical companies to build quality, safety, and efficacy into new products based on sound science and risk management. The QbD approach, by which quality is built-in rather than tested into the product, is described in published guidelines (ICH Q8, ICH Q9, and ICH Q10). − One important aspect of QbD is the development of a design space, which is defined in ICH Q8 as “the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality”.…”