To take advantage of the sub-2-μm particle, the industry needed a new instrument. The calculated pressure drop at the optimum flow rate for maximum efficiency across a 10-cm column packed with 1.7-μm particles is about 15,000 psi. Therefore, a pump capable of delivering solvent at these pressures is required. The pump must compensate for solvent compressibility across a wide range of potential pressures to achieve smooth and reproducible flow in both isocratic and gradient separation modes. The injection process should be relatively pulse-free. The detector must have a high sampling rate to capture enough data points across the peak to perform accurate and reproducible recognition and integration of the analyte peak. The detector cell must have minimal dispersion (volume) to preserve the efficiency of the separation. The interior surface of the column hardware must be smooth to facilitate packing of the smaller particles. The end frits must retain the small particles but resist clogging.

The first commercially available system designed for small particle columns was launched in 2004. The technology was called ultrahigh because the pressure required to pump the mobile phase through a column packed with 1–2 μm particles at the necessary velocity is nearly twice as high as that for traditional HPLC. These systems were designed to handle the high pressures associated with the small particle sizes, and the maximum pressure is 15,000 psi. The dwell volume for these systems is approximately 110 μL.

However, once the systems were introduced, it became the industry's responsibility to implement the new technology. Methods needed to be developed, and the limitations of the system needed to be learned. After some initial work with these systems, the authors discovered that to develop quality analytical methods, an analyst must incorporate quality by design. A method must be developed using scientific information and prior knowledge to achieve specific goals. Because UHPLC is relatively new to the industry, analysts may lack this prior knowledge. A good understanding of chromatographic concepts such as column void volumes, peak volumes, extra column dispersion, and dwell volumes is needed to develop UHPLC methods. An HPLC method cannot simply be converted to a UHPLC method and produce optimal chromatography. To facilitate this understanding, the authors had to return to the textbook approach of method development and not merely rely on a trial-and-error process and prior column performance experience. Important information that must be considered even before going into the laboratory is the physical and chemical properties of the analyte of interest, the availability of standards and degradants, and the goals of the method as well as the analysts who will use the method routinely.

According to the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines, a method must be validated to be linear, accurate, and precise. However, in reality, a method used in industry must also be unquestionably robust. The end user must be able to perform the method on a daily basis without undue problems. The method development chemist must take into account the end user's laboratory. Highly technical method preparations or complex chromatographic interpretations require experienced analysts with the time to dedicate to the procedure. In industry, the quality control chemist is the typical end user of the methods. The quality control chemist may not be trained to interpret complex chromatography and is nearly always short on time. Therefore, the goal of method development is to create a procedure that is simple, fast, accurate, and robust while meeting all of the ICH guidelines. UHPLC can be implemented to meet these objectives.