Sanchez-Paternina, Adriluz

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    Evaluation of sources of error in dynamic processes and material traceability in continuous pharmaceutical manufacturing through real-time spectroscopic analysis
    (2021-05-05) Sanchez-Paternina, Adriluz; Romañach, Rodolfo J.; College of Arts and Sciences - Sciences; Méndez-Román, Rafael; Torres-Candelaria, Jessica; Alcalá, Manel; Department of Chemistry; Bellido, Carmen M.
    This dissertation focuses on the development of real-time spectroscopic methods to investigate the sources of variation in dynamic processes using variographic analysis and accomplish material traceability for continuous solids pharmaceutical manufacturing. In the first study, variographic analysis was investigated as a method to determine the sampling and analytical errors when the drug concentration of pharmaceutical powder blends is determined by near-infrared spectroscopy. Variograms provided an estimate of the process variance and the minimum possible error (MPE) defined as the sum of the total sampling error and the total analytical error under the specific sampling scenario. In this study, small total sampling and analytical errors were found. The MPE was 75–342 times higher for the 95.00 [% w/w] blends when compared to the short-term precision of the analytical NIR method. In the second study, the implementation of residence time distribution (RTD) methodology for in-process raw material traceability was realized. The residence time distribution models enabled material tracking through the continuous system. Mean residence time values between 1.49 to 1.91 minutes were obtained from the consecutive step changes of experiments. The maximum and minimum length of batch transition periods calculated were 0.30 and 0.44 minutes, respectively. The third set of collaborative studies describes implementing the theory of sampling and variographic analysis to evaluate the blending and sampling processes in continuous and batch manufacturing. The study reveals that the sampling realized in the FT-NIR interface in the chute of the pharmaceutical continuous manufacturing line assured a complete description of the sample heterogeneity. A variographic analysis was developed to evaluate the efficiency of the mixing procedures. The mixing procedure composed of a tumble and vibration blender presented a variogram with low variance and low sill. This result indicates low residual heterogeneity in the powder blends, a good state of mixing, and minimal process variation. In a second study, the tablet feed frame is evaluated as a sampling unit through variographic analysis. The results of variographic analysis showed variograms with reduced variances values and minimal changes of the sill. Low MPE values were found for the validation blends, indicating small sampling and analytical errors.
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    Near infrared spectroscopic transmission measurements for pharmaceutical powder mixtures and theory of sampling (TOS) applied in pharmaceutical industry quality control (Qc) practices
    (2015) Sanchez-Paternina, Adriluz; Romañach, Rodolfo J.; College of Arts and Sciences - Sciences; Lysenko, Sergiy; Torres Candelaria, Jessica; Department of Chemistry; Colón-Rivera, Celia R.
    This thesis presents two projects that involve the implementation of near infrared spectroscopy. NIR spectroscopy is a fast and non-destructive spectroscopy that in combination with multivariate analysis is a very useful tool for the development of pharmaceutical processes and the implementation of continuous manufacturing. The first project is based on measurements of transmission in powder blends (chapter 2). This study shows the development of calibration models using NIR transmission in powders. The study explains the necessary instrumental settings for transmission measurements in powders. The transmission measurements for powders were obtained using the Bruker Optics, Fourier Transform Near Infrared Spectrometer (FT-NIR) where a modified sample measurement cup was used. Transmissions in powders were developed because there is an absence of commercial instruments for transmission measurements in pharmaceutical powder processes. The comparison between NIR transmission spectra for powder and tablet samples and the development of calibration models was performed at three different resolutions of 64, 32, and 16 cm-1 . Transmission in powder and diffuse reflectance in powder was also compared in this study The second project is based in the implementation of the Theory of Sampling (TOS) using NIR spectroscopy (chapter 3). This study has two parts, the first part consists in the evaluation of levels of heterogeneity of several samples using NIR and the determination of sampling error (Part a). The heterogeneity of the material has a large influence on the sampling process; this statement was demonstrated in this study. The second part consists in the development of a stream sampling method to facilitate the implementation of variographic analysis and use of replication experiments in the development of pharmaceutical formulations (part b). This second study shows that variographic analysis and TOS could be very valuable in the development of pharmaceutical formulations in combination with NIR spectroscopy.