The aim of this study was to apply quality-by-design principles to build in a more scientific and risk-based multifactorial strategy in the development of an ultrahigh-pressure liquid chromatography (UHPLC) method for omeprazole and its related impurities.
Through the International Conference on Harmonization (ICH), this concept resulted in ICH guideline Q8(R2) in which quality-by-design is defined as "a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management" (3).Although ICH guideline Q8(R2) doesn't explicitly take analytical method development into account and no other regulatory guideline has been issued, the quality-by-design concept can be extended to a systematic approach that includes the definition of the methods goal, risk assessment, design of experiments, developing a design space, verification of the design space, implementing a control strategy, and continual improvement to increase method robustness and knowledge (4). The novelty and opportunity in this approach is that working within the design space of a specific method can be seen as an adjustment and not a postapproval change (4).
A systematic approach should replace the still common "screening," also known as a trial-and-error approach, in which one factor at a time (OFAT) is varied until the best method is found. The OFAT approach is time-consuming and often results in a nonrobust method because interactions between factors are not considered.
Today, systematic concepts use experimental design plans as an efficient and fast tool for method development. In a full or fractional, factorial design, a couple experiments are carried out in which one or more factors are changed at the same time. By using statistical software tools (for example, Design Expert from Stat-Ease, Inc.), the effect of each factor on the separation can be calculated and the data can be used to find the optimum separation (4). In our laboratory, this concept is used when the development of nonchromatographic methods is necessary.
However, the easiest and fasted way of developing a liquid chromatographic method is by using chromatography modeling, especially in combination with ultrahigh-pressure liquid chromatography (UHPLC) technology. Based on a small number of experiments, these software applications can predict the movement of peaks when parameters such as eluent composition or pH, flow rate, column temperature, column dimensions, and particle size are changed (5–11). When necessary, the developed method can be transferred (back) to high performance liquid chromatography (HPLC).
In our laboratory we have been using visual chromatographic modeling (software packages) for many years now in HPLC and UHPLC method development and it has resulted in very robust methods (4,12–14). The aim of this study was to apply quality-by-design principles to build in a more scientific and risk-based, multifactorial strategy in the development of a new UHPLC method for testing the purity of omeprazole.
Omeprazole belongs to the group of proton-pump inhibitors and is one of the most widely prescribed drugs. It suppresses gastric acid secretion by specific inhibition of the enzyme hydrogen-potassium adenosine triphosphatase (H+, K +-ATPase). Omeprazole formulations are used to treat acid reflux, heartburn, ulcer disease, and gastritis (15).