Impact of Quality by Design in Process Development on the Analytical Control Strategy for a Small-Molecule Drug Substance

Development of the arzoxifene hydrochloride drug substance manufacturing process, first via a traditional approach and subsequently via an enhanced approach, provides an informative case study in quality by design (QbD). The primary focus of this paper is to illustrate the impact and advantages of QbD on the impurity control strategy. By operating the process at the extremes during design space studies, a larger collection of organic impurities and higher levels of typical impurities are observed in the intermediates. This enables a more thorough understanding of the ability of the process to purify the drug substance and results in a more complete and robust set of intermediate specifications as well as broader and more robust analytical methods. We demonstrate that, when each of the synthetic steps are operated within the design space, the byproduct impurities in the intermediates will not exceed levels found to be rejected in subsequent steps, ensuring that the drug substance will meet its critical quality attributes. Through the rigorous application of an enhanced process development approach, we have designed quality into the arzoxifene hydrochloride drug substance. As a result, real-time release of the intermediate batches is proposed to increase the process throughput and avoid the expense of nonvalue-added testing.