API Quality by Design Example from the Torcetrapib Manufacturing Process

Abstract

The concept and application of quality by design (QbD) principles has been and will undoubtedly continue to be an evolving topic in the pharmaceutical industry. However, there are few and limited examples that demonstrate the actual practice of incorporating QbD assessments, especially for active pharmaceutical ingredients (API) manufacturing processes described in regulatory submissions. We recognize there are some inherent and fundamental differences in developing QbD approaches for drug substance (or API) vs drug product manufacturing processes. In particular, the development of relevant process understanding for API manufacturing is somewhat challenging relative to criteria outlined in ICH Q8 ( http://www.ich.org/cache/compo/276–254–1.html ) guidelines, which are primarily oriented toward application of QbD for drug product manufacturing. This position paper provides a perspective of QbD application for API manufacture using an example from the torcetrapib API manufacturing process. The work includes a risk assessment, examples of multivariate design, and a proposed criticality assessment, all of which coalesce into an example of design space. Torcetrapib was a project in phase III development as a potent and selective inhibitor of cholesteryl ester transfer protein before being terminated in late 2006. The intent of Pfizer was to submit torcetrapib under the QbD paradigm (route selection, robustness, and reagent/solvent selection during phases I to III are significantly important in establishing a manufacturing process that would have the most flexibility in the final design space. For more information on this development phase for torcetrapib see Damon et al., Org Process Res Dev, 10(3):464–71, 2006, Org Process Res Dev, 10(3):472–80, 2006).