PLASMA EMISSION SPECTROSCOPY

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2 1/6/29 3. PURPOSE WIRELESS TEMPERATURE MEASUREMENTS: TEMPRIS Temperature Remote Interrogation System position of the TEMPRIS sensors: inside the vials, NIR and plasma emission spectroscopy and TEMPRIS for continuous and simultaneous in-line, non-invasive and real-time monitoring of a) phenomena taking place during a freeze drying process of a mannitol solution (5% w/v) b) endpoints of the freeze-drying different stages c) solid state characterization bottom evaluation of complementary properties spectroscopy NIR spectroscopy plasma emission spectroscopy TEMPRIS MATERIALS AND METHODS FREEZE DRYING CONDITIONS 5 % (w/v) mannitol solutions; 3 vials - β-mannitol (D(-)-mannitol Ph. Eur., VWR Int., Leuven, Belgium) - δ-mannitol (Analar, VWR Int., Leuven, Belgium) - α-mannitol (prepared by re-crystallization) - mannitol hemi-hydrate process phase probe\lyofilisatiestudie\yvanvdh\screening 9\experiment spc 4 x 1 5 experiment 9 = α β pressure in freeze drier freeze drier ( C) (mbar) freezing primary drying secondary drying hemi-hydrate δ 4 Intensity shelf temperature in time (min) (1/cm) 112 shift (cm-1) Christ Epsilon 2-6 D freeze dryer IMPLEMENTATION OF PROCESS ANALYSERS IN FREEZE DRYER spectroscopy NIR spectroscopy plasma emission spectroscopy TEMPRIS 2

3 1/6/29 RAMAN SPECTROSCOPIC CONDITIONS Rxn1 spectrometer (Kaiser Optical Systems) fibre optic non-contact probe air cooled CCD detector (back-illuminated deep depletion design) laser wavelength: 785 nm resolution: 4 cm-1 laser power: 4 mw software: HoloGRAMSTM, HoloREACTTM, MATLAB 6.5, Grams 7.1 exposure time: 3 s spectra were collected every minute during the process ( > 25h) > 15 spectra per process monitored spectral range: 117 cm-1 baseline correction and normalization NIR SPECTROSCOPIC CONDITIONS PLASMA EMISSION SPECTROSCOPY (LYOTRACK 1) Fourier-Transform NIR spectrometer (Thermo Fisher Scientific) fibre optic non-contact probe InGaAs detector quartz halogen lamp resolution: 16 cm-1 spectral range: 4 cm-1 each spectrum is the result of 32 scans software: Thermo Fisher Scientific s Result software 1.3., SIMCA-P spectra were collected every minute during the process (> 25h) > 15 spectra per process spectra were recorded at bottom of vial baseline correction (SNV) cold plasma ionization device (Lyotrack 1, Adixen, France) quartz tube directly contacts the lyophilization chamber top of freeze drier chamber radiofrequency source of 44 MHz ratio water vapor/nitrogen is measured during drying SOLID STATE CHARACTERIZATION inspection of and NIR spectra X-ray powder diffractometry (at-line) Tempris system (IQ Mobil Solutions GmbH, Wolfratshausen, Germany) 8 sensors 3 used: - completely immersed, hitting vial bottom - top of product - above product PROCESS ANALYSIS univariate - plasma emission spectroscopy - wireless temperature measurements multivariate 1 spectrum/min bottom freeze drying process > 25 hours 1 NIR spectrum/min interrogation unit Carlog software (IQ Mobil Solutions GmbH, Wolfratshausen, Germany) huge amount of data (> 15 spectra/process) 17 freezing step data drying step data PCA PCA 18 3

4 1/6/29 probe\lyofilisatiestudie\yvanvdh\screening probe\lyofilisatiestudie\yvanvdh\screening 1\experiment 1\experiment 1\experiment 1 49.spc 161.spc 51.spc c:\documents andprobe\lyofilisatiestudie\yvanvdh\screening Settings\Thomas De Beer\Mijn documenten\ data\screening 1 (unsaved) probe\lyofilisatiestudie\yvanvdh\screening 1\experiment 1 18.spc RAMAN DATA ANALYSIS RAMAN AND NIR PROBE FOCUSSED ON THE SAME VIAL spectrum spectrum RESULTS - 1 process > 25 hours - 1 spectrum per min spectrum 51 spectrum (1/cm) -1 (1/cm).2 (1/cm) (1/cm) -1(cm ))) 114 shift(cm -1-1 shiftshift (cm ) shift (cm once water was converted into ice during the freezing step:.16 (1/cm) shift (cm-1) NIR spectrum.14 spectrum PC PC 1 2 RAMAN DATA ANALYSIS: SECONDARY DRYING (4 C) 21 NIR DATA ANALYSIS: SECONDARY DRYING (4 C).1 NIR ANALYSIS (1/cm)

5 1/6/29 freezing step + start primary drying 3 chamber pressure 2 9 temperature ( C) min min 5 63 min product temperature min 214 min min 2 pressure (mbar) -4 shelf temperature 174 min 1-5 process time (min) freezing step + primary drying end of primary drying + start secondary drying PLASMA EMISSION SPECTROSCOPY freezing step + primary drying

6 1/6/29 PLASMA EMISSION SPECTROSCOPY freezing step + primary drying + secondary drying CONCLUSIONS complementary process analysers are required for complete inline and real-time processmonitoring of freezedrying: complement, confirm, correct spectroscopy + plasma emission spectroscopy Future Prospectives increased process understanding (DoE) process modelling and process predictions batch modelling of optimum process allowing real-time process control Acknowledgements Prof. Dr. W. Baeyens (promotor), A. Burggraeve PAT Research Group, Dept. of Pharmaceutical Analysis, Ghent University, Belgium Prof. Dr. C. Vervaet (promotor), Prof. Dr. J.P. Remon (co-promotor) Laboratory of Pharmaceutical Technology, Dept. of Pharmaceutical Technology, Ghent University, Ghent, Belgium Dr. Wiggenhorn, Prof. Dr. Friess, Prof. Dr. Winter Department of Pharmacy, Ludwich-Maximilians-University, Munich, Germany exhibition stand 34 R. Veillon, C. Debacq, Y. Mayeresse, B. Moreau GSKbio, Rixensart, Belgium