Impact of Quality by Design in Process Development on the Analytical Control Strategy for a Small-Molecule Drug Substanc
- PDF / 1,219,881 Bytes
- 18 Pages / 595.276 x 790.866 pts Page_size
- 46 Downloads / 210 Views
RESEARCH ARTICLE
Impact of Quality by Design in Process Development on the Analytical Control Strategy for a Small-Molecule Drug Substance Bryan C. Castle & Robert A. Forbes
Published online: 8 November 2013 # Springer Science+Business Media New York 2013
Abstract 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.
Keywords Arzoxifene hydrochloride . Quality by design (QbD) . Critical quality attribute (CQA) . Enhanced process development approach . Impurity control strategy . Real-time release (RTR) B. C. Castle : R. A. Forbes (*) Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, IN, USA e-mail: [email protected] B. C. Castle e-mail: [email protected]
Introduction Arzoxifene Arzoxifene hydrochloride is a selective estrogren receptor modulator (SERM) which was under development for the treatment of osteoporosis and reduction of the risk of breast cancer for postmenopausal women [1]. The route of administration was an oral daily dose of 20 mg tablet. At the end of the phase III clinical trial, the decision was made not to submit the compound for regulatory approval [2]. While arzoxifene met the primary endpoint of the phase III trial, which was significant reduction of the risk of vertebral fracture and invasive breast cancer in postmenopausal women, there was no statistically significant difference from placebo in key secondary endpoints (nonvertebral fractures, clinical vertebral fractures, cardiovascular events, and cognitive function). Adverse events included venous thromboembolic events, hot flushes, and gyenecological events, more frequent than placebo. At the time of project termination, a final draft of the common technical document (CTD) had been completed. The draft regulatory submission included full imp
Data Loading...
