Risk-based approach for method development: quality by design strategy in the analysis of nintedanib and its related impurities by LC-MS

The adoption of Quality by Design (QbD) concept has been significantly rising over the years especially in the field of optimization of analytical methods. The use of QbD principles in method development allows advantages to be achieved in terms of gained knowledge and risk management. Nintedanib (NTB) is an oral orphan drug approved by the US FDA in October 2014 and EMA in January 2015 for the treatment of idiopathic pulmonary fibrosis and for the treatment of patients with non-small cell lung cancer in a combination therapy with docetaxel after first-line chemotherapy. A simple and sensitive RP-HPLC-MS method for the determination of NTB and its potential impurities was developed according to QbD principles and validated. The Method Operable Design Region (MODR) was defined as a multivariate zone of input parameters where the desired performances of the method were obtained with a selected degree of probability. The relationship between critical method parameters (CMPs; column flow rate, oven temperature, organic solvent composition, formic acid percentage, gradient slope) and critical method attributes (CMAs; selectivities between the main compound peak and the adjacent impurities peaks and analysis time) was established applying design of experiments methodology. After a scouting phase, aimed at the selection of suitable stationary phase and column dimensions in order to approach the analytical target, the effect of the different levels of the five CMPs on the CMAs was evaluated in the screening study. Response surface methodology was then carried out on three selected CMPs by applying a Box-Behnken Design and pointed out the presence of interaction effects by means of contour and sweet spot plots. The defined mathematical models and Monte Carlo simulations were used to identify the MODR. The complete separation of the analytes was obtained in about 10 min. Validation of the method was carried out according ICH guidelines and the method was successfully applied to the analysis of real samples of NTB soft capsules for quality control purposes.