(404c) Rapid Process Development of Chromatographic Process Using Direct Analysis in Real Time Mass Spectrometry As a Process Analytical Technology (PAT) Tool

The concept of quality by design (QbD)^[1] is now broadly accepted by the pharmaceutical manufacturing industry and widely applied in the process development of pharmaceuticals. In the QbD implementation, usually a design of experiments (DoE) is conducted to build the relationship between material attributes, process parameters and quality attributes. However, it is time consuming and cost intensive to conduct the DoE experiments and then measure the quality attributes of the products or intermediates produced. The additional cost and time have caused some resistance about QbD implementation.^[2] Therefore, methods for rapid process development are in urgent need. Integrating process analytical technology (PAT)^[3]into DoE is one of the methods worthy of consideration. To show how PAT can enhance rapid process development, this work introduces direct analysis in real time mass spectrometry (DART-MS) as a PAT tool for the DoE study of the chromatographic process of a botanical drug.

Botanical drugs are widely used in China for the prevention and treatment of diseases and chromatographic process is a key purification operation to improve the safety and efficacy of botanical drugs. The chromatographic process usually includes loading, washing, eluting and regeneration stages. Many process parameters are involved in the process and their impacts should be investigated in the process development, according to the QbD initiative. In studying chromatographic loading, dynamic adsorption breakthrough curve of the target component is commonly measured, which can reflect the adsorption capacity of the chromatography column.^{[4, 5]}And the impacts of process parameters on the breakthrough curves are investigated to optimize the adsorption capacity. Traditionally, in the research, many effluent samples at different loading time are collected and analyzed by high performance liquid chromatography (HPLC), which is time and labor intensive. In addition, a proper sampling frequency is difficult to determine before the research. A high frequency leads to increased time of HPLC analysis and a too low frequency may deter the successful plotting of breakthrough curves. Besides, since the breakthrough points are not well recognized during the loading experiments, the material is usually loaded excessively to ensure that the breakthrough points have been reached, which results in additional cost of the material. However, when a PAT tool has been introduced into the research, these issues can be largely addressed.

DART is a novel ambient ionization source that allows direct sampling and ionization in the open air^[6]. In the analysis, compounds in the sample are ionized by the electrically discharged gas produced by the DART ion source and then lead to the MS analyzer. In the past few years, DART-MS has been applied successfully in analytical chemistry.^[7-9]The sample-preparation-free and noncontact analysis features make DART-MS a promising PAT tool.

In this work, DART-MS is used as a PAT tool for studying chromatographic loading. In the research, a device for the online DART-MS analysis is set up and coupled to the chromatographic process to collect the MS spectra of the effluent. The characteristic ions are selected for determining the target compounds and the breakthrough curves are measured online. The impacts of two parameters (i.e. the concentrations of the target compounds in the material and the flow rate) on the adsorption capacity are studied by DoE. The results show that the PAT tool can be successfully applied to obtain the breakthrough curve, which allows us to get rid of the time consuming offline analysis. A mathematical model between the adsorption capacity and the two parameters studied are established and the adsorption capacity is optimized based on the model. This work has shown the significance of integrating PAT into QbD implementation for rapid process development.

References

[1] International Conference on Harmonisation. "ICH harmonised tripartite guideline: Pharmaceutical development Q8(R2)". 2009. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf[accessed 2012-04-28].

[2] Savic, I. M., Marinkovic, V. D., Tasic, L., Krajnovic, D., Accreditation and Quality Assurance 2012, 17, 627-633.

[3] FDA. "Guidance for industry, PAT—a framework for innovative pharmaceutical development, manufacturing and quality assurance". 2004. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070305.pdf[accessed Aug 27 2012].

[4] Li, J., Chase, H. A., J. Chromatogr. A 2009, 1216, 8759-8770.

[5] Perez-Almodovar, E. X., Carta, G., J. Chromatogr. A 2009, 1216, 8339-8347.

[6] Cody, R. B., Laramee, J. A., Durst, H. D., Anal. Chem. 2005, 77, 2297-2302.

[7] Chernetsova, E. S., Morlock, G. E., Mass Spectrom. Rev. 2011, 30, 875-883.

[8] Hajslova, J., Cajka, T., Vaclavik, L., Trac-Trends in Analytical Chemistry 2011, 30, 204-218.

[9] Zeng, S. S., Wang, L., Chen, T., Wang, Y. F., Mo, H. B., Qu, H. B., Anal. Chim. Acta 2012, 733, 38-47.