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Question of the month - January 2019

What process would you follow to develop a liquid chromatography method for organic pharmaceutical impurities?

We would recommend a three-step process if you are performing this procedure from the beginning. The three steps are: discovery, method development and transfer to routine.

In the discovery step the strategy is to identify all the components in your sample and your potential impurities. For this the requirements are high resolution separations to give a high peak capacity, as well as multiple detection mechanisms to make sure you don’t miss any peaks. This would imply long column lengths to increase resolution (this is likely to generate high backpressures, so requires an UHPLC system capable of withstanding elevated backpressures) and complementary detectors such as UV, charged aerosol detection (CAD) and mass spectrometry (MS).

When all the potential impurities are detected, you need to identify those above ICH Q3A/Q3B ID thresholds. Impurity reference standards can provide ultimate proof here. Keep in mind that for genotoxic impurities (such as NDMA/NDEA) the normal Q3A/Q3B rules do not apply. Once you have identified the corresponding impurities you can move to the next stage.

Flexibility in the separation is key for the method development stage, where a quarternary UHPLC system is often used for greater buffer blending options. A variety of columns of differing selectivities are used to find the most appropriate column, and typically only one detector is used at this stage.

In the final stage, the strategy is to transfer the workflow to the routine environment for use in QA/QC testing. This requires a fast and robust analysis to meet high throughput and low cost requirements. This is achieved by using a low maintenance and intuitive HPLC or UHPLC instrument (HPLC = lower instrument costs and lower pressure, which could impact throughput; UHPLC = higher instrument costs, but higher pressures for faster analysis and increased peak capacity). The column chemistry was selected during the method development phase and the column used here would be short for fast separations. Potentially two detectors would be used at this stage for comprehensive detection and confirmation, for example UV and single quadrupole mass spectrometry detection respectively.

The routine method needs to provide means to quantify the specified impurities, either by direct use of corresponding reference standards, or by development of relative response factors (RRFs). Determination of RRFs requires the use of neat impurity samples, so here too impurity reference standards can provide essential help.

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