Rapid process development of chromatographic process using direct analysis in real time mass spectrometry as a process analytical technology tool

• A method is proposed for rapid process development, which integrates PAT into DoE.
• The method is applied in the case study of chromatographic loading process.
• DART-MS is used as a PAT tool for fast obtaining the breakthrough curves.
• The breakthrough curves obtained by DART-MS and HPLC are in accordance.
• Impacts of process parameters on adsorption is obtained rapidly using the method.

The concept of quality by design (QbD) is widely applied in the process development of pharmaceuticals. However, the additional cost and time have caused some resistance about QbD implementation. To show a possible solution, this work proposed a rapid process development method, which used direct analysis in real time mass spectrometry (DART-MS) as a process analytical technology (PAT) tool for studying the chromatographic process of Ginkgo biloba L., as an example. The breakthrough curves were fast determined by DART-MS at-line. A high correlation coefficient of 0.9520 was found between the concentrations of ginkgolide A determined by DART-MS and HPLC. Based on the PAT tool, the impacts of process parameters on the adsorption capacity were discovered rapidly, which showed a decreased adsorption capacity with the increase of the flow rate. This work has shown the feasibility and advantages of integrating PAT into QbD implementation for rapid process development.

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