(591b) Real-Time Process Monitoring in Continuous Manufacturing of Oral Solid Dosages Using Raman Process Analytical Technology

The growing recognition of the limitations of batch manufacturing and recent advances in Process Analytical Technology (PAT) have led to the shift towards continuous manufacturing (CM). However, the implementation of continuous manufacturing has its challenges and continues to be an area of intense research interest. Near-infrared (NIR) spectroscopy has been the choice of PAT tool in the pharmaceutical industry for online measurements of powder composition in drug product manufacturing, but it has its limitations in measuring low concentrations. Raman spectroscopy is an alternative vibrational spectroscopy method that has also received attention to monitor the drug concentration in powders and is studied in this work.

Important components in implementing the CM strategy are: (1) real-time measurement and monitoring, (2) process control, (3) fault detection, (4) diagnosis of exceptional events, and (5) tracking and isolation of non-compliant product¹. This research focuses on the first foundational component – real-time measurement and monitoring – using the spectroscopy-based PAT tools. The measurement of the active pharmaceutical ingredient (API) concentration in low drug load blends has been a known challenge². Raman spectroscopy can be utilized to predict the API concentration in such low drug load products. Also, it is important to have the right spectroscopic sensor at the right sensor location to achieve the true benefits of the in-situ measurement. The feed frame of the tablet press has been selected as a promising location as it provides various benefits³ and has only been explored in to a limited extent in the literature. The blend composition measured multiple unit operations upstream of tableting may not be truly representative of the API concentration in the final tablets. Locations close to tablet compression provide better API concentration estimates in the final product. Also, real-time measurement of API at the tablet press location can aid in immediate rejection of the out of specification tablets.

The present study aims to develop a reliable PAT method using Raman spectroscopy to determine the API concentration in real-time in continuous tablet manufacturing of Low Drug Load Product. This includes checking the model robustness against process conditions, understanding the difference in Raman spectra between static powder sample and moving powder stream inside feed frame, and understanding the issue of fluorescence with some of the ingredient excipients. Previous study has shown the use of Raman spectroscopy in measuring API concentration with 8% API (w/w)⁴. The second objective is to integrate the Raman sensor in the existing pilot plant facility at Purdue to send the data and results of concentrations to the Distributed Control System (DCS) using proper communication protocols to enable effective statistical process control of the critical quality attributes (CQA) and pave way to develop feedback control. This study investigates the application of Raman spectroscopy for real-time measurement of a continuous tableting process and the feasibility of Raman-based feedback control in the manufacturing of pharmaceutical solid dosage forms.

Reference:

1. Moreno M, Liu J, Su Q, et al. Steady-State Data Reconciliation Framework for a Direct Continuous Tableting Line. J Pharm Innov. 2018. doi:10.1007/s12247-018-9354-9
2. Nagy B, Farkas A, Borbás E, Vass P, Nagy ZK, Marosi G. Raman Spectroscopy for Process Analytical Technologies of Pharmaceutical Secondary Manufacturing. AAPS PharmSciTech. 2019;20(1). doi:10.1208/s12249-018-1201-2
3. De Beer T, Burggraeve A, Fonteyne M, Saerens L, Remon JP, Vervaet C. Near infrared and Raman spectroscopy for the in-process monitoring of pharmaceutical production processes. Int J Pharm. 2011;417(1-2):32-47. doi:10.1016/j.ijpharm.2010.12.012
4. Li Y, Anderson CA, Drennen JK, Airiau C, Igne B. Method Development and Validation of an Inline Process Analytical Technology Method for Blend Monitoring in the Tablet Feed Frame Using Raman Spectroscopy. Anal Chem. 2018;90(14):8436-8444. doi:10.1021/acs.analchem.8b01009