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.
The quality-by-design concept was outlined years ago by Joseph M. Juran (1) and is used in many industries to improve the
quality of products and services simply by planning quality from the beginning. Since the US Food and Drug Administration
(FDA) announced its "Pharmaceutical Current Good Manufacturing Practices (cGMPs) for the 21st Century" initiative (2) in 2002,
a quality-by-design approach has also been sought in the pharmaceutical industry.
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
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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 of 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 fastest way of developing a liquid chromatographic method is by using chromatography modelling, 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).