Process analytical technology for continuous manufacturing tableting processing: A case study

[Display omitted] •PAT is a key control tool for Continuous Manufacturing of solid dosage forms supporting real time release.•Tableting process is controlled by 2 PAT probes: blend uniformity in the press feeder and content uniformity of tablets.•The NIRS method allow a 100% on-line control of tablets at a speed up to 70,000 tablets per hour.•Chemometric solutions have been evaluated to monitor the tableting process: qualitative and quantitative approaches.•The quantitative approach was optimized in order to obtain a robust calibration. The use of Near Infrared Spectroscopy (NIRS) as a fast and non-destructive technique was employed for the control and monitoring of the tableting step during a continuous manufacturing process. Two NIRS methods were optimized in order to in-line control the blend uniformity in the tablet feed frame and the API concentration of freshly pressed tablets prior the ejection. The novelty of this work first lies in the acquisition speed of NIR spectra reaching up to 70,000 tablets/h. Partial Least Square (PLS) regression was used as chemometric tool for the computation that resulted in excellent predictive calibration results. A coefficient of correlation (r) value of 0.99 was obtained for both probes. The root mean square error of calibration (RMSEC) and the root mean square error of prediction (RMSEP) were respectively 1.8% and 1.8% for active content in the tablet feeder and 2.2% and 2.3% for the tablet content. In addition, calibration performance and robustness of the methods were evaluated. Moreover several qualitative methods were proposed to monitor the tableting process in different stages of development (single wavelength, Principal Component Analysis, and Independent Component Analysis). In early phase development, the requirement/quality of the input material is not established yet; hence the use of a qualitative approach allows to confirm the suitability of the PAT methodology for in-process material monitoring & control. Later, the qualitative approach constitutes the foundation for the quantitative approach when input materials are fixed and larger production size occurs. The proposed strategy is a performant PAT tool for continuous manufacturing and a step forward to real time release.