In-line and real-time process monitoring of a freeze drying process using Raman and NIR spectroscopy as complementary process analytical technology (PAT) tools.
ABSTRACT The aim of the present study was to examine the complementary properties of Raman and near infrared (NIR) spectroscopy as PAT tools for the fast, noninvasive, nondestructive and in-line process monitoring of a freeze drying process. Therefore, Raman and NIR probes were built in the freeze dryer chamber, allowing simultaneous process monitoring. A 5% (w/v) mannitol solution was used as model for freeze drying. Raman and NIR spectra were continuously collected during freeze drying (one Raman and NIR spectrum/min) and the spectra were analyzed using principal component analysis (PCA) and multivariate curve resolution (MCR). Raman spectroscopy was able to supply information about (i) the mannitol solid state throughout the entire process, (ii) the endpoint of freezing (endpoint of mannitol crystallization), and (iii) several physical and chemical phenomena occurring during the process (onset of ice nucleation, onset of mannitol crystallization). NIR spectroscopy proved to be a more sensitive tool to monitor the critical aspects during drying: (i) endpoint of ice sublimation and (ii) monitoring the release of hydrate water during storage. Furthermore, via NIR spectroscopy some Raman observations were confirmed: start of ice nucleation, end of mannitol crystallization and solid state characteristics of the end product. When Raman and NIR monitoring were performed on the same vial, the Raman signal was saturated during the freezing step caused by reflected NIR light reaching the Raman detector. Therefore, NIR and Raman measurements were done on a different vial. Also the importance of the position of the probes (Raman probe above the vial and NIR probe at the bottom of the sidewall of the vial) in order to obtain all required critical information is outlined. Combining Raman and NIR spectroscopy for the simultaneous monitoring of freeze drying allows monitoring almost all critical freeze drying process aspects. Both techniques do not only complement each other, they also provided mutual confirmation of specific conclusions.
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ABSTRACT: Freeze drying is a complex, time consuming and thus expensive process, hence creating a need for understanding the material behaviour in the process environment and for process optimization. Near-infrared (NIR) spectroscopy offers the opportunity to monitor physicochemical changes of the formulation during freeze-drying. The aim of this work was to examine whether NIR spectroscopy allows in-line monitoring of all components during the entire freeze-drying process of a multi-component pharmaceutical formulation (a solution of fenofibrate and mannitol in a mixture of tertiary-butyl alcohol, and water). To extract useful information of all components in the formulation from the large multivariate data-sets obtained during in-line spectroscopic monitoring, several spectral pre-processing techniques and spectral data analysis techniques such as the mean of selected wavenumbers (Mws), the correlation coefficient (CorrCoef) and principal component analysis (PCA) have been evaluated and compared. To find out whether these chemometric techniques are also able to differentiate between changes in the process settings influencing the freeze-drying process of the formulation, freeze-drying processes were performed at four different conditions. Results demonstrated that in-line measurements using NIR spectroscopy were possible in an icy environment and that a further process understanding could be obtained. Data-analysis revealed the crystallization behaviour of each of the four components. In addition, using the three pre-processing techniques allowed observe the sublimation of the solvents. Mws and CorrCoef have proven to be adequate methods for monitoring the main physicochemical changes of product during the processes; this affirmation was confirmed by observing the outputs of PCA for entire processes.Journal of pharmaceutical and biomedical analysis 04/2014; 97C:39-46. · 2.45 Impact Factor
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ABSTRACT: Coupling an infrared (IR) camera to a freeze dryer for on-line monitoring of freeze-drying cycles is described for the first time. Normally, product temperature is measured using a few invasive Pt-100 probes, resulting in poor spatial resolution. To overcome this, an IR camera was placed on a process-scale freeze dryer. Imaging took place every 120 s through a Germanium window comprising 30,000 measurement points obtained contact-free from -40°C to 25°C. Results are presented for an empty system, bulk drying of cheese slurry, and drying of 1 mL human serum in 150 vials. During freezing of the empty system, differences of more than 5°C were measured on the shelf. Adding a tray to the empty system, a difference of more than 8°C was observed. These temperature differences probably cause different ice structures affecting the drying speed during sublimation. A temperature difference of maximum 13°C was observed in bulk mode during sublimation. When drying in vials, differences of more than 10°C were observed. Gradually, the large temperature differences disappeared during secondary drying and products were transformed into uniformly dry cakes. The experimental data show that the IR camera is a highly versatile on-line monitoring tool for different kinds of freeze-drying processes. © 2014 European Union.Journal of Pharmaceutical Sciences 06/2014; · 3.13 Impact Factor
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ABSTRACT: The aim of the present study was to apply an integrated process analytical technology (PAT) approach to control and monitor the effect of the degree of supercooling on critical process and product parameters of a lyophilization cycle. Two concentrations of a mAb formulation were used as models for lyophilization. ControLyo™ technology was applied to control the onset of ice nucleation, whereas tunable diode laser absorption spectroscopy (TDLAS) was utilized as a noninvasive tool for the inline monitoring of the water vapor concentration and vapor flow velocity in the spool during primary drying. The instantaneous measurements were then used to determine the effect of the degree of supercooling on critical process and product parameters. Controlled nucleation resulted in uniform nucleation at lower degrees of supercooling for both formulations, higher sublimation rates, lower mass transfer resistance, lower product temperatures at the sublimation interface, and shorter primary drying times compared with the conventional shelf-ramped freezing. Controlled nucleation also resulted in lyophilized cakes with more elegant and porous structure with no visible collapse or shrinkage, lower specific surface area, and shorter reconstitution times compared with the uncontrolled nucleation. Uncontrolled nucleation however resulted in lyophilized cakes with relatively lower residual moisture contents compared with controlled nucleation. TDLAS proved to be an efficient tool to determine the endpoint of primary drying. There was good agreement between data obtained from TDLAS-based measurements and SMART™ technology. ControLyo™ technology and TDLAS showed great potential as PAT tools to achieve enhanced process monitoring and control during lyophilization cycles. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm SciJournal of Pharmaceutical Sciences 05/2014; · 3.13 Impact Factor