(344g) Real-Time Monitoring and Control of API Concentration in a Tablet Press for Continuous Manufacturing of Tablets

Authors: 
Maeda, J., Daiichi Sankyo
Escotet-Espinoza, M. S., Rutgers University
Singh, R., Rutgers, The State University of New Jersey
Ierapetritou, M., Rutgers, The State University of New Jersey
Active pharmaceutical ingredient (API) concentration in powder blends is a critical material attribute (CMA) that is considered one of the most important product critical quality attributes (CQAs) for their final product (tablets). To determine the API concentration before tableting, real-time monitoring of API concentration before and after compaction has been performed for a variety of batch and continuous processes via Near-Infrared (NIR) spectroscopy [1, 2]. This analytical technology, which has been highly encouraged within the Quality by Design (QbD) and Process Analytical Technology (PAT) frameworks, has shown to be a valuable for detecting issues in CMAs during the process and has become a critical in-process sensor in the pharmaceutical industry [3].

This work presents a feed-forward controller for continuous manufacturing by using a NIR-based real-time monitoring technology at a tablet press feed frame. The basic idea behind feed forward control is to measure important process variables and take corrective action before the disturbances upset the process. The feed forward controller therefore needs to receive information about the known and predictable effects of process disturbances before those occur [4]. The proposed methodology involves measuring the inherent variability in the API concentration of material coming from the process and adjusting tablet weight to maintain overall API potency in tablets. We measured the residence time distribution (RTD) information from the rotary tablet press together with the NIR from the feed frame to develop the proposed framework as follows.

We evaluated the RTD of our Fette 1200i tablet press unit. A step change of API concentration of powder blend was given before the feed frame and the API concentration by the feed-frame NIR and compressed tablets were measured [5]. Based on these profiles, RTD of the feed frame was shown to have a similar RTD profile as a continuous stirred tank reactor (CSTR). RTD of the turret was found to be negligibly short and no difference was observed between the profiles of the feed-frame and tablets. The estimated RTDs are useful for prediction of the CQA and its controls. The formulation for our case study consisted of micronized acetaminophen, microcrystalline cellulose (Avicel® PH102), and magnesium stearate at a ratio of 15:84:1 by weight, respectively. A portable JDSU NIR probe was attached in the feed frame, sampling the powder spectra through one of the unit’s glass windows. Five (5) different blends ranging from 10 – 20% API concentration were made as calibrations for the NIR model. NIR spectra were measured in-line using the 5 powders blends to build the calibration model in situ. A calibration model with small calibration error was constructed by partial least squares (PLS) analysis. Validation experiments with four different acetaminophen concentrations demonstrated that the constructed model has high accuracy during long-term operation.

Overall, based on the feed-frame’s RTD profile and the information from the NIR sensor’s model, a feed-forward controller was developed to account for changes in powder blend API concentration and adjust tablet weight to decrease variability of API potency in tablets. It was verified by both software simulations and experiments that API potency could be maintained at the target value by the feed-forward control compared to the open-loop process.

References

1. Vanarase, A.U., et al., Real-time monitoring of drug concentration in a continuous powder mixing process using NIR spectroscopy. Chemical Engineering Science, 2010. 65(21): p. 5728-5733.

2. Jarvinen, K., et al., In-line monitoring of the drug content of powder mixtures and tablets by near-infrared spectroscopy during the continuous direct compression tableting process. Eur J Pharm Sci, 2013. 48(4-5): p. 680-8.

3. USFDA, Guidance for Industry: PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, U.D.o.H.a.H. Services, Editor. 2004: Rockville, MD.

4. Myerson, A.S., et al., Control Systems Engineering in Continuous Pharmaceutical Manufacturing. J. Pharm. Sci., 2015. 104: p. 832-839.

5. Ward, H.W., et al., Monitoring blend potency in a tablet press feed frame using near infrared spectroscopy. Journal of Pharmaceutical and Biomedical Analysis, 2013. 80: p. 18-23.