The control of genotoxic impurities is crucial for ensuring regulatory compliance, and with the implementation of the ICH M7 guidance for impurity assessment and control, it is more important than ever for drug manufacturers to employ effective strategies for dealing with toxic or mutagenic impurities.
Where there is a risk that potential genotoxic impurities are likely to still be present in the final drug substance or drug product, then reliable, robust and sensitive methods are required for accurate determination. However, genotoxic impurities and degradants can present specific analytical challenges, for example, containing non-UV chromophores and a wide variety of ionizable groups, etc., which can make method development more challenging. Additionally, with the introduction of the recent M7 guidance and the more precise definition of acceptable intake limits, there may also be a need to achieve lower detection limits during routine testing.
In this work, we present the process of developing a robust, dual-detection UPLC method suitable for the routine testing of esters of benzenesulfonic and p-toluenesulfonic acids. The approach utilizes both UV and mass detection for fast and accurate monitoring and quantitation. The impact of different chromatographic parameters (columns, pHs and organic solvents) on the separation of the sample components will be evaluated and in addition to the chromatographic parameters, we will investigate different factors that can affect the quality of mass information and the sensitivity of the method. The selection of mobile phase, sample diluent and acquisition parameters to optimize the quality and sensitivity of the MS detector results will be discussed and the linearity, sensitivity and specificity of the method will be shown.
Using this approach, we show that the esters of benzenesulfonic and p-toluenesulfonic acids can be accurately measured in the 1.5 to 15 ng/mL range using mass detection, allowing significantly lower detection limits than those achievable using a PDA detector. The additional benefit of this approach is the ease with which methods can be transferred to routine testing labs required to monitor low level genotoxic impurities. This is a result of recent developments in technology and the wider acceptance of the need and benefits of modern technology for ensuring the quality of drug substance and drug product.