International Conference on Harmonization requires a quality concept for impurities during the drug development process is proposed based on the requirements featured in the impurity guidelines. Because of the particular nature of the drug development process, one crucial element is qualification. Once an impurity profile is qualified by the first toxicological studies, attention is then focused on the comparison made, by means of comprehensive analytical monitoring, between qualified impurities and those of new batches. The clear assignment of impurities to toxicologically-qualified impurities can be addressed using multidimensional information, such as retention times, molecular mass or spectral properties. The advantages of use of the hyphenated LC–MS technique in performing this ‘impurity inventory’ are discussed by the authors using the example of peptide drugs. As part of an integrated quality concept for impurities during drug development, the multidimensional evaluation of impurity profiles by LC–MS coupling is presented using peptide drugs as an example. This quality concept can be regarded as an adaptation of the ICH-requirements to the special situation during the drug development process. The primary goal is to obtain qualitative molecular weight information for impurity peaks detected at the same UV wavelength as for the impurity test procedure. The approach is focused on the investigation, if the impurities in a clinical batch were also present in the toxicologically qualified batch(es). Depending on the relevance of individual impurities in further batches or as degradation products, the molecular weight can be used as a starting point for further characterization and identification. Often, eluents with volatile buffers required for MS result in different selectivities and/or inferior chromatographic separation and sensitivity compared with nonvolatile buffers (e.g. phosphates). In these cases, peak ‘tracking’ especially for small peaks can become critical. A procedure is presented for on-line coupling of LC methods with non-volatile eluents to mass spectrometry. Impurity profile of an active pharmaceutical ingredient (API) is a very important task for all stages of drug development. A systematic approach for tracking impurity profile of API is described. Various real pharmaceutical applications are presented through successful examples of impurity profile tracking for novel APIs A general strategy including selection of a reversed phase high performance liquid chromatographic (RP-HPLC) impurity profile method based on screening various stationary phases and changing the pH of the mobile phase and elucidation of impurity structures through the utilization of LC–MS, preparative-LC and NMR is demonstrated. A series of studies were conducted on the peak purity check by using the LC-UV diode-array and LC–MS detections. The advantages and disadvantages of each technique in the evaluation of peak purity are discussed.
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