This paper builds a bridge between the pioneering work of Csaba Horváth at the dawn of high pressure liquid chromatography during the 1970s and the present state of the art technologies in the field more than four decades later. In recognition of a lifetime of achievement, a small piece in Csaba Horváth's large work together with Imre Molnár is specifically honored. The work emphasizes the importance of understanding retention phenomena, which started with Csaba Horváth’s Solvophobic Theory and nowadays is the base of the ever-growing Quality by Design movement. It is shown how the latest advances in modeling software can be used to gain insight into retention behavior and how this knowledge can be applied to the development of robust reversed phase liquid chromatography methods.

A multifactorial optimization of three critical HPLC parameters is described. Gradient time (tG), temperature (T), and ternary composition (B1:B2) are optimized for the separation of 22 pharmaceutically relevant analytes based on 12 experimental runs. The effects of these variables on critical resolution and selectivity were examined as all three factors were varied simultaneously. Robust conditions for separation were defined using the Design Space and then verified. This paper demonstrates the applicability of this approach to rapid development of high-quality LC methods using DryLab.

This paper describes the use of "knowledge space" and "design space" for Quality by Design of chromatographic methods using DryLab. The authors look specifically at the selection of the proper range of gradient steepness for experimental input data and its effect on predicted results. They demonstrate that the interpolated simulation as well as the extrapolated simulation results, when the initial slopes were close in range to the target slope, provided good predictions with overall percent error difference of experimental retention times of less than 1%.

This paper describes a multifactorial optimization of four critical HPLC method parameters, i.e. gradient time (tG), temperature (T), pH and ternary composition (B1:B2) based on 36 experiments. The effect of these experimental variables on critical resolution and selectivity was carried out in such a way as to systematically vary all four factors simultaneously. The basic element is a gradient-time temperature (tG-T) plane, which is repeated at three different pHs of the eluent A and at three different ternary compositions of eluent B between methanol and acetonitrile. The so-defined volume enables the investigation of the critical resolution for a part of the Design Space of a given sample. Further improvement of the analysis time, with conservation of the previously optimized selectivity, was possible by reducing the gradient time and increasing the flow rate. Multidimensional robust regions were successfully defined and graphically depicted.

Quality-by-design (QbD) is a systematic approach to drug development, which begins with predefined objectives, and uses science and risk management approaches to gain product and process understanding and ultimately process control. The concept of QbD can be extended to analytical methods. QbD mandates the definition of a goal for the method, and emphasizes thorough evaluation and scouting of alternative methods in a systematic way to obtain optimal method performance. Candidate methods are then carefully assessed in astructured manner for risks, and are challenged to determine if robustness and ruggedness criteria are satisfied. As a result of these studies, the method performance can be understood and improved if necessary, and a control strategy can be defined to manage risk and ensure the method performs as desired when validated and deployed. In this review, the current state of analytical QbD in the industry is detailed with examples of the application of analytical QbD principles to a range of analytical methods, including high-performance liquid chromatography, Karl Fischer titration for moisture content, vibrational spectroscopy for chemical identification, quantitative colormeasurement, and trace analysis for genotoxic impurities.

An ultra performance liquid chromatographic (UPLC) method was developed for simultaneous determination of seven steroid (dienogest, finasteride, gestodene, levonorgestrel, estradiol, ethinylestradiol, and norethisterone acetate) active pharmaceutical ingredient (API) residues. Two gradients—two column temperature basic model runs were carried out and DryLab was used to predict the optimal solvent ratio, which would give sufficient resolution (Rs > 1.5) between the compounds and peaks originated from sampling matrix. The new, generic method is presented, with which it is possible to verify the cleaning process of a steroid producing equipment line used for the production of various pharmaceuticals. The UPLC method was validated using an UPLC™ BEH C18 column with a particle size of 1.7m (50mm×2.1mm) and acetonitrile–water (48:52, v/v) as mobile phase at a flow rate of 0.55 ml/min. Method development and method validation for cleaning control analysis are described. The rapid UPLCmethod is suitable for cleaning control assays within good manufacturing practices (GMP) of the pharmaceutical industry.