Abstract
Design of experiments (DOE)-based analytical quality by design (AQbD) method evaluation, development, and validation is gaining momentum and has the potential to create robust chromatographic methods through deeper understanding and control of variability. In this paper, a case study is used to explore the pros, cons, and pitfalls of using various chromatographic responses as modeling targets during a DOE-based AQbD approach. The case study involves evaluation of a reverse phase gradient HPLC method by a modified circumscribed central composite (CCC) response surface DOE.Solid models were produced for most responses and their validation was assessed with graphical and numeric statistics as well as chromatographic mechanistic understanding. The five most relevant responses with valid models were selected for multiple responses method optimization and the final optimized method was chosen based on the Method Operable Design Region (MODR). The final method has a much larger MODR than the original method and is thus more robust.This study showcases how to use AQbD to gain deep method understanding and make informed decisions on method suitability. Discoveries and discussions in this case study may contribute to continuous improvement of AQbD chromatography practices in the pharmaceutical industry.
Highlights
Drug development using a quality by design (QbD) approach is an essential part of the Pharmaceutical cGMP Initiative for the twenty-first century (FDA Pharmaceutical cGMPs For The 21st Century — A Risk-Based Approach. 2004) established by the FDA
Representative chromatogram under nominal conditions Careful planning and pre-runs executed at select star points allowed for successful execution of the Design of experiments (DOE) with all expected peaks eluting within the running time for all the 30 runs
It uses a systematic approach to understand and control variability and build robustness into chromatographic methods. This ensures that analytical results are always close to the product true value and meet the target measurement uncertainty, enabling informed decisions on drug development, manufacturing, and quality control
Summary
Drug development using a quality by design (QbD) approach is an essential part of the Pharmaceutical cGMP Initiative for the twenty-first century (FDA Pharmaceutical cGMPs For The 21st Century — A Risk-Based Approach. 2004) established by the FDA. This initiative seeks to address unmet patient needs, unsustainable rise of healthcare costs, and the reluctance to adopt new technology in pharmaceutical development and manufacturing. These issues were the result of old regulations that are very rigid and made continuous improvement of previously approved drugs both challenging and costly. The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) embraced this initiative and began issuing QbD relevant quality guidelines in 2005. The in-progress version of ICH Q14 (ICH Q14 2018) will offer AQbD guidelines for analytical procedures and promote the use of QbD principles to achieve a greater understanding and control of testing methods and reduction of result variability
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