Degradants preclinical development

Preclinical development IND/CTA filing Evaluation Impurity, degradant, and metabolite identification. 

Elucidation of the role of the 205 proteasome in protein degradation and as a target for cancer chemotherapy could not have been achieved without small molecule inhibitors, some of which have served strictly as research tools, while others have progressed through preclinical development and clinical trials.18,28,29 These molecules represent a variety of structural classes, including peptide boronic acids such as bortezomib and CEP-187 70,30 epoxyketones (e.g. carfilzomib)31 and the y-lactam-(3-lactone family of inhibitors (Figure 12.1). 

Preclinical development IND/CTA Evaluation 1- Impurity 2- Degradent 3- MetahoUcidentification 4- Quantitative hioanalysis... 

Similar to the examples described for small molecules, the resulting biomolecule degradant profile is used to predict potential problems before they appear during preclinical scale-up, formulation, and stability experiments. Furthermore, this information may serve as a diagnostic tool for structure identification during the clinical development and manufacturing stages. 

Changes in the manufacturing process and degradation products produced during storage may result in a product that differs from that used in preclinical and clinical development. The significance of these changes should be evaluated. 

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