Real-time tablet API analysis: a comparison of a palm-size NIR spectrometer to HPLC method Presented by: Chris Pederson, Product Applications Engineer, JDS Uniphase Corp. Co-Authors: Nada O Brien, JDS Uniphase Corp. Benoît Igne, Duquesne University January 24, 2014 Presented at: IFPAC 2014, 28th INTERNATIONAL FORUM AND EXHIBITION PROCESS ANALYTICAL TECHNOLOGY (Process Analysis & Control)
Agenda Introduction & Objective Sources of uncertainty Instrument and Performance Overview USP 1119 Calibration model strategies Manufacturing of samples Accuracy of HPLC NIR Performance Calibration approaches Test Set Performance Conclusions 2
The Future of Spectroscopy 1970 s 1980 s 1990 s- 2000 s 2010 s 3
The Future of Spectroscopy 1970 s 1980 s 1990 s- 2000 s 2010 s 4
Pharmaceutical Unit Operations Lubricants Excipients API Drying Compression Mixing & Granulation Coating Packaging 5
Pharmaceutical Unit Operations Raw Material ID Material Conformity Lubricants Excipients API Drying Compression Mixing & Granulation Coating Packaging 6
Pharmaceutical Unit Operations Raw Material ID Material Conformity Lubricants Excipients API Drying Compression Mixing & Granulation Coating Packaging Blend Uniformity Real time suspension monitoring 7
Pharmaceutical Unit Operations Raw Material ID Material Conformity Moisture Content, LOD Lubricants Excipients API Drying Compression Mixing & Granulation Coating Packaging Blend Uniformity Real time suspension monitoring 8
Pharmaceutical Unit Operations Lubricants Raw Material ID Material Conformity Excipients Moisture Content, LOD Tablet Hardenss Roller Compaction API Drying Compression Mixing & Granulation Coating Packaging Blend Uniformity Real time suspension monitoring 9
Pharmaceutical Unit Operations Lubricants Raw Material ID Material Conformity Excipients Moisture Content, LOD Tablet Hardenss Roller Compaction API Drying Coating thickness API coating detection Compression Mixing & Granulation Coating Packaging Blend Uniformity Real time suspension monitoring 10
Pharmaceutical Unit Operations Lubricants Raw Material ID Material Conformity Excipients API Drying Moisture Content, LOD Tablet Hardenss Roller Compaction Compression Coating thickness API coating detection Final Product Conformity Mixing & Granulation Coating Packaging Blend Uniformity Real time suspension monitoring 11
Objective Determine the suitability of analysis of an active pharmaceutical ingredient in tablets using MicroNIR, an ultracompact NIR spectrometer, as an alternative approach to HPLC Understand how sources of variability observed during routine manufacturing affect NIR calibration model Validate and test NIR models for analysis of routine manufacturing samples Investigate the sensitivity of two NIR calibration model strategies to batch-to-batch manufacturing variability 12
Uncertainty (error) of NIR technology Instrument variation Well defined: - USP 1119 provides guidance 13
Uncertainty (error) of NIR technology Instrument variation Reference Method Error Well defined: - USP 1119 provides guidance Use Blind Duplicate testing to quantify 14
Uncertainty (error) of NIR technology User & Sample Error Environmental & Seasonal Effects Instrument variation Reference Method Error Well defined: - USP 1119 provides guidance Use Blind Duplicate testing to quantify Account for in NIRS Calibration Development and sampling 15
Uncertainty (error) of NIR technology User & Sample Error Environmental & Seasonal Effects Instrument variation Reference Method Error Well defined: - USP 1119 provides guidance Use Blind Duplicate testing to quantify Account for in NIRS Calibration Development and sampling Three combined represent total NIR method error! - Think of tolerance stack-up in Engineering 16
Instrument Overview & Performance: US Pharmacopeia Chapter 1119
Instrument: MicroNIR 1700 Fully integrated USB 2.0 powered spectrometer Package contains Linear Variable Filter (LVF) dispersion, integrated tungsten lamps, detector array, control and readout electronics 950 1650 nm range Weighs 2 oz. (60 grams) 128 pixel InGaAs Photodiode Array Spectrometer Design: LVF is mounted directly over a linear detector array with multiple pixel elements. Light illuminates the LVF & the wavelength transmitted through the filter is dependent on its linear position along the filter Each pixel element of the linear array will detect a specific wavelength 18
Performance stability testing per USP 1119 guidelines The MicroNIR 1700 was tested over a 160-day period Absorbance spectra of each of the following standards collected on each day tested: Six photometric standards: - R99, R80, R40, R20, R10, R02 One wavelength standard: - NIST SRM 1920A Results: Photometric slope accurate within ±0.05 RMS noise (measurement repeatability) consistently below maximum Wavelength repeatability accurate within ±0.2 nm 19
Photometric Linearity Results USP1119 Guideline: Slope = 1.0 ± 0.05 20
Photometric Linearity Results USP1119 Guideline: Slope = 1.0 ± 0.05 21
Photometric Linearity Results USP 1119 Guideline: Intercept, 0.0 ± 0.05 22
Photometric Linearity Results USP 1119 Guideline: Intercept, 0.0 ± 0.05 23
High Flux RMS Noise Results USP1119 Guideline: Max high-flux RMS noise 0.8 (E-03) 24
High Flux RMS Noise Results USP1119 Guideline: Max high-flux RMS noise 0.8 (E-03) 25
Low Flux RMS Noise USP1119 Guideline: Max low-flux RMS noise 2.0 (E-03) 26
Low Flux RMS Noise USP1119 Guideline: Max low-flux RMS noise 2.0 (E-03) 27
Wavelength Uncertainty Results USP1119 Guideline: +/- 1.0 nm across 1100-2200nm 28
Wavelength Uncertainty Results Calculated standard deviation of each peak location over this 160 day study. MicroNIR is quite consistent in wavelength, with a typical standard deviation of <0.1nm. The peak at 1013.8nm is more inconsistent due to the fact that this absorption peak is very shallow in the MicroNIR spectrum 29
MicroNIR Wavelength Reproducibility NIST SRM 2036 (Avian WCR 2066) more suitable standard for MicroNIR 1700 bandwidth Recent production results for 32 instruments 30
Measurement Set-up MicroNIR 1700 mounted in enclosure Tablets centered on MicroNIR Window 31
API Concentration in Tablets: Manufacturing Process APAP HPMC Intra-LAC MCC Extra-LAC MgSt % w/w 27.3 3.9 7.8 45.5 15.0 0.5 APAP HPMC Lactose Fluid bed: blend Fluid bed: granulate Lab-scale Compression 1 kg granulation batches Laboratory-scale Carver press (13mm, right cylindrical 700 mg) Lactose MCC Mg Stearate Fluid bed: dry Extragranular blend Pilot-scale Compression Pilot-scale Similar Elizabeth-HATA Density Rotary Tablet Press 8kp target, 38 station (9.5mm, biconvex compacts, 350 mg) A total of 165 samples were available for calibration, 100 for test, and 60 for validation, 32
Reference Analysis: HPLC Method followed modified USP for APAP Instrument: Waters 2790 HPLC Column: Supelco Ascentis C18, 15 x 4.6 mm, 3 μm Mobile phase 80:17:3 water:methanol:acetic acid 50 μl injection 1.2 ml/min 45 C UV detection at 243 nm Standard error of prediction = 0.026 mg/ml 0.52% for method development 0.83% for all testing R 2 = 0.9999 95% CI for zero intercept 33
Calibration model strategies Basic Focus on formulation and tablet shape Risk-based Identify additional risk factors that may deteriorate model performance to include in calibration model 34
Calibration samples Basic Risk-Based Granulation 1 December 2012 Granulation 1 December 2012 Granulation 2 June 2013 Lab DOE MFG DOE Lab DOE MFG DOE 11 32 55 75 %RH Test sets Basic: granulation 1 Risk-based: granulations 1 and 3 Validation sets Basic: granulation 2 Risk-based: granulation 4 35
Calibration & Test controlled lab results with MicroNIR Basic Approach 45 calibration and 35 test tablets produced with the same granulation and with limited environmental changes RMSEP value using the MicroNIR spectrometer was 0.83%, w/w. 36
Sum of Squared Q Residuals Predicted APAP (%w/w) Q Residuals Validation Results for Basic calibration approach 45 4 x 10-4 40 3 35 2 30 1 25 20 15 10 10 15 20 25 30 35 40 45 Reference APAP (%w/w) Calibration Test Validation 0 0 50 100 150 200 Hotelling's T 2 7 x 10-6 6 5 4 3 RMSEC (%w/w) RMSECV (%w/w) RMSEP test (%w/w) RMSEP val (%w/w) R 2 Cal R 2 Test R 2 Val 1.14 1.25 2.32 6.64 0.970 0.945 0.294 2 1 0 900 1000 1100 1200 1300 1400 1500 1600 1700 Wavelength (nm) 37
Sum of Squared Q Residuals Predicted APAP (%w/w) Q Residuals Validation results for Risk-based calibration approach 45 x 10-4 40 2 35 30 1 25 20 15 10 10 15 20 25 30 35 40 45 Reference APAP (%w/w) Calibration Test Validation 0 0 5 10 15 20 25 Hotelling's T 2 0.9 0.8 0.7 0.6 1 x 10-6 0.5 RMSEC (%w/w) RMSECV (%w/w) RMSEP test (%w/w) RMSEP val (%w/w) R 2 Cal R 2 Test R 2 Val 1.369 1.446 2.042 1.14 0.957 0.912 0.981 0.4 0.3 0.2 0.1 0 900 1000 1100 1200 1300 1400 1500 1600 1700 Wavelength (nm) 38
Summary: HPLC versus MicroNIR RMSEC (%w/w) RMSECV (%w/w) RMSEP test (%w/w) RMSEP val (%w/w) R 2 Cal R 2 Test R 2 Val Basic NIR Calibration Risk-based NIR Calibrations 1.14 1.25 2.32 6.64 0.970 0.945 0.294 1.369 1.446 2.042 1.14 0.957 0.912 0.981 RMSEP HPLC 0.52 0.83 0.999 RMSEP of the Risk-Based calibration approach (1.14) is close to the performance of the HPLC (0.83) Controlled laboratory samples RMSEP was 0.83, but didn t account for normal environmental and manufacturing variances 39
Conclusions MicroNIR has been tested as possible option for individual tablet API assay based on NIR RMSEP approaching HPLC RMSEP Risked-based approach resulted in robust calibration model through initial manufacturing test batches Ignoring dynamic environmental conditions resulted in poorer model performance in terms of accuracy and robustness Inclusion of batch-to-batch variability should be considered for NIR Disadvantage is more batches are required If possible, pool samples from DOE for process optimization - e.g., fluid bed granulation batches with different granule target moisture content, spray rate, etc. MicroNIR has the ability to provide real-time monitoring and control capabilities for pharmaceutical manufacturing processes It is an affordable and versatile analytical tool for improving your processes and ensuring product quality 40
Acknowledgements A special thanks to Duquesne University Center for Pharmaceutical Technology for their collaboration on this project. 41
Thank you! For more information visit: www.jdsu.com/go/micronir Or contact: Chris Pederson chris.pederson@jdsu.com Phone: (707) 525-7929
Back-up Slides:
Key Specifications Weight Dimensions Spectral Range Optical Resolution Spectral Sampling Interval Detector Power Requirement Measurement Time 60 grams (2 oz) 45mm diameter x 42mm height Standard: 950-1650nm; Extended: 1150-2150nm <1.25% of center wavelength, i.e. at 1000nm wavelength, resolution is <12.5nm; at 2000nm, <25nm resolution. Standard: 6.25nm per pixel Extended: 8.1nm per pixel 128 pixel element InGaAs (uncooled) USB powered, <500mA at 5V 0.5 second (5ms integration, 100 integrations) Operating -20 to +50 C, (non-condensing) Temperature Storage Temperature -40 to +70 C, (non-condensing) 44
%T Linear Variable Filter (LVF) Technology LVF is a one dimensional array of continuously varying bandpass filter Coating materials are thin-film multilayers deposited with wedge in one axis. Materials typically inorganic type: SiO 2, Ta 2 O 5 produced by ionassisted physical vapor deposition techniques resulting in dense coating with high reliability and stability. No moving parts Completely passive device 100 80 60 40 Mirror Spacer Mirror Substrate Polychromatic Light 20 0 1100 1400 1700 Wavelength (nm) 45