Impurities and Degradants

ICH Topics Q3A(R)/Q3B ‘Impurities in New Drug Substances’ classifies impurities into organic impurities (process and drug related), inorganic impurities and residual solvents (which are covered in more detail in ICH Topic Q3C).

Following identification of the parent drug, known production impurities and impurities derived from by-products created during the manufacturing process need to be identified. Assessments should also be made if changes in the formulation of raw materials or intermediates occur. For drug products the possibility of inter reactions between the formulated product and flavourings should also be considered.

The ability of mass spectrometry techniques to identify both unknown impurities by mass and structure as well as separate peaks which co-elute chromatographically present real benefits in identifying previously unseen impurities quickly and concisely:

  • LC-ESMS and/or LC-APCI-MS, using either a chromatographic method provided by the study sponsor, or a new method developed by SGS M-Scan for the purpose, is used to determine the molecular weights of the components of interest. If a method has been developed using only chromatography, the later reversion to mass spectrometry techniques may not be easy as some chromatography methods are not compatible with MS analysis.
  • LC-MS/MS using ESMS is used to generate structurally informative fragments to assist in tentative structural elucidation and hence identification of the components of interest.
  • Alternatively preparative HPLC can be carried out to collect pure fractions of the components which are then analysed using tandem mass spectrometry to provide structurally significant fragment ions to assist in tentative structural elucidation and hence identification.
  • Accurate mass measurements can be made on the components of interest to provide empirical formula to add confidence to any structural identity proposed following tandem MS analysis. Accurate mass analysis can also be performed on specific fragment ions produced during tandem MS analysis if required.
  • HNMR can be performed on pure fractions (providing sufficient material can be obtained, minimum of 100µg per sample) collected from preparative HPLC, to add further confidence to any proposed structural assignment or compound identification.

For impurity determination the analytical procedures should be validated as suitable for the detection and quantification of the impurity according to ICH Topics Q2A/ Q2B ‘Guidelines for Analytical Validation’.