Process analytical technology (PAT) has shown great potential for in-line tableting process monitoring. The study focuses on the development and validation of an in-line near-infrared (NIR) spectroscopic method for the determination of content uniformity of blends in a tablet feed frame. An in-line NIR method was developed after careful evaluation of the impact of potential experimental factors on the robustness and model accuracy and precision. The NIR method was validated according to the principles outlined in International Conference on Harmonization–Q2 for validation of analytical procedures and was demonstrated to be suitable for monitoring blend content for the formulation under evaluation. Reliable measurements of blend homogeneity rely on representative sampling. To reach the appropriate scale of scrutiny for a unit dose, the study assessed factors that influence the effective sample size measured by NIR. Spectral averaging, integration time, and feed frame paddle wheel speed were found to influence the effective sample size measured by the NIR probe. The effective sampling size was also estimated by comparing the distribution of predicted values with the reference values. The development of a robust, in-line PAT method was facilitated by thorough understanding of the sensitivity of PAT sensors to factors affecting pharmaceutical processes and products.
SuQ.MorenoM.GiridharA., et al.“A Systematic Framework for Process Control Design and Risk Analysis in Continuous Pharmaceutical Solid-Dosage Manufacturing”. J. Pharm. Innov.2017. 12(4): 327–346.
2.
LeeS.L.O’ConnorT.F.YangX., et al.“Modernizing Pharmaceutical Manufacturing: from Batch to Continuous Production”. J. Pharm. Innov.2015. 10(3): 191–199.
3.
De BeerT.BurggraeveA.FonteyneM., et al.“Near Infrared and Raman Spectroscopy for the In-process Monitoring of Pharmaceutical Production Processes”. Int. J. Pharm.2011. 417(1): 32–47.
4.
MoesJ.J.RuijkenM.M.GoutE., et al.“Application of Process Analytical Technology in Tablet Process Development using NIR Spectroscopy: Blend Uniformity, Content Uniformity and Coating Thickness Measurements”. Int. J. Pharm.2008. 357(1–2): 108–118.
5.
ReichG.“Near-Infrared Spectroscopy and Imaging: Basic Principles and Pharmaceutical Applications”. Adv. Drug Delivery Rev.2005. 57(8): 1109–1143.
6.
MartínezL.PeinadoA.LiesumL.“In-line Quantification of Two Active Ingredients in a Batch Blending Process by Near–Infrared Spectroscopy: Influence of Physical Presentation of the Sample”. Int. J. Pharm.2013. 451(1): 67–75.
7.
ColónY.M.FlorianM.A.AcevedoD., et al.“Near Infrared Method Development for a Continuous Manufacturing Blending Process”. J. Pharm. Innov.2014. 9(4): 291–301.
8.
FonteyneM.VercruysseJ.De LeersnyderF., et al.“Blend Uniformity Evaluation During Continuous Mixing in a Twin Screw Granulator by In-line NIR Using a Moving F-test”. Anal. Chim. Acta.2016. 935(Supplement C): 213–223.
9.
Van SnickB.HolmanJ.CunninghamC., et al.“Continuous Direct Compression as Manufacturing Platform for Sustained Release Tablets”. Int. J. Pharm.2017. 519(1): 390–407.
10.
VargasJ.M.Roman-OspinoA.D.SanchezE., et al.“Evaluation of Analytical and Sampling Errors in the Prediction of the Active Pharmaceutical Ingredient Concentration in Blends From a Continuous Manufacturing Process”. J. Pharm. Innov.2017. 12(2): 155–167.
11.
Mateo-OrtizD.ColonY.RomañachR.J., et al.“Analysis of Powder Phenomena Inside a Fette 3090 Feed Frame Using In-line NIR Spectroscopy”. J. Pharm. Biomed. Anal.2014. 100(Supplement C): 40–49.
12.
GosselinR.DurãoP.AbatzoglouN., et al.“Monitoring the Concentration of Flowing Pharmaceutical Powders in a Tableting Feed Frame”. Pharm. Dev. Technol.2017. 22(6): 699–705.
13.
WahlP.R.FruhmannG.SacherS., et al.“PAT for Tableting: Inline Monitoring of API and Excipients via NIR Spectroscopy”. Eur. J. Pharm. Biopharm.2014. 87(2): 271–278.
14.
De LeersnyderF.PeetersE.DjalabiH., et al.“Development and Validation of an In-line NIR Spectroscopic Method for Continuous Blend Potency Determination in the Feed Frame of a Tablet Press”. J. Pharm. Biomed. Anal.2018. 151: 274–283.
15.
PauliV.RoggoY.PellegattiL., et al.“Process Analytical Technology for Continuous Manufacturing Tableting Processing: A Case Study”. J. Pharm. Biomed. Anal.2019. 162: 101–111.
KetterhagenW.R.“Simulation of Powder Flow in a Lab-Scale Tablet Press Feed Frame: Effects of Design and Operating Parameters on Measures of Tablet Quality”. Powder Technol.2015. 275(Supplement C): 361–374.
18.
WardH.W.BlackwoodD.O.PolizziM., et al.“Monitoring Blend Potency in a Tablet Press Feed Frame Using Near Infrared Spectroscopy”. J. Pharm. Biomed. Anal.2013. 80(Supplement C): 18–23.
19.
ŠašićS.BlackwoodD.LiuA., et al.“Detailed Analysis of the Online Near–Infrared Spectra of Pharmaceutical Blend in a Rotary Tablet Press Feed Frame”. J. Pharm. Biomed. Anal.2015. 103(Supplement C): 73–79.
20.
FeinbergM.BoulangerB.DewéW., et al.“New Advances in Method Validation and Measurement Uncertainty Aimed at Improving the Quality of Chemical Data”. Anal. Bioanal. Chem.2004. 380(3): 502–514.
21.
LiW.JohnsonM.C.BruceR., et al.“The Effect of Beam Size on Real-Time Determination of Powder Blend Homogeneity by an Online Near Infrared Sensor”. J. Pharm. Biomed. Anal.2007. 43(2): 711–717.
22.
OkaS.S.Escotet-EspinozaM.S.SinghR., et al.“Design of an Integrated Continuous Manufacturing System”. In: KleinebuddeP.KhinastJ.RantanenJ. (eds). Continuous Manufacturing of Pharmaceuticals., Hoboken, NJ: Wiley, 2017, Chap. 12, pp. 430.
23.
ShiZ.AndersonC.A.Scattering Orthogonalization of Near–Infrared Spectra for Analysis of Pharmaceutical Tablets”. Anal. Chem.2009. 81(4): 1389–1396.
24.
HetrickE.M.ShiZ.BarnesL.E., et al.Development of Near Infrared Spectroscopy-Based Process Monitoring Methodology for Pharmaceutical Continuous Manufacturing Using an Offline Calibration Approach”. Anal. Chem.2017. 89(17): 9175–9183.
25.
El-HagrasyA.S.D’AmicoF.DrennenJ.K.“A Process Analytical Technology Approach to Near–Infrared Process Control of Pharmaceutical Powder Blending. Part I: D-optimal Design for Characterization of Powder Mixing and Preliminary Spectral Data Evaluation”. J. Pharm. Sci.2006. 95(2): 392–406.
26.
AlamM.A.ShiZ.DrennenJ.K., et al.“In-line Monitoring and Optimization of Powder Flow in a Simulated Continuous Process Using Transmission Near Infrared Spectroscopy”. Int. J. Pharm.2017. 526(1): 199–208.
27.
IgneB.ShiZ.DrennenJ.K., et al.Effects and Detection of Raw Material Variability on the Performance of Near-Infrared Calibration Models for Pharmaceutical Products”. J. Pharm. Sci.2014. 103(2): 545–556.
28.
AlamM.A.DrennenJ.AndersonC.A.“Designing a Calibration Set in Spectral Space for Efficient Development of an NIR Method for Tablet Analysis”. J. Pharm. Biomed. Anal.2017. 145(Supplement C): 230–239.
29.
CárdenasV.CordobésM.BlancoM., et al.“Strategy for Design NIR Calibration Sets Based on Process Spectrum and Model Space: An Innovative Approach for Process Analytical Technology”. J. Pharm. Biomed. Anal.2015. 114(Supplement C): 28–33.
30.
BondiR.W.IgneB.DrennenJ.K., et al.“Effect of Experimental Design on the Prediction Performance of Calibration Models Based on Near-Infrared Spectroscopy for Pharmaceutical Applications”. Appl. Spectrosc.2012. 66(12): 1442–1453.
31.
IervolinoM.RaghavanS.L.HadgraftJ.“Membrane Penetration Enhancement of Ibuprofen Using Supersaturation”. Int. J. Pharm.2000. 198(2): 229–238.
32.
IgneB.HossainM.N.DrennenJ.K., et al.“Robustness Considerations and Effects of Moisture Variations on Near Infrared Method Performance for Solid Dosage Form Assay”. J. Near Infrared Spectrosc.2014. 22(3): 179–188.
33.
LongG.L.WinefordnerJ.D.“Limit of Detection A Closer Look at the IUPAC Definition”. Anal. Chem.1983. 55(07): 712A–724A.
34.
H. Martens, T. Næs. “Methods for Calibration”. In: Multivariate Calibration. Chichester, UK: Wiley, 1992. Pp. 73–115.
35.
WentzellP.D.Vega MontotoL.“Comparison of Principal Components Regression and Partial Least Squares Regression Through Generic Simulations of Complex Mixtures”. Chemom. Intell. Lab. Syst.2003. 65(2): 257–279.
36.
LiY.AndersonC.A.DrennenJ.K., et al.“Method Development and Validation of an Inline Process Analytical Technology Method for Blend Monitoring in the Tablet Feed Frame Using Raman Spectroscopy”. Anal. Chem.2018. 90(14): 8436–8444.
37.
PanT.BarberD.Coffin-BeachD., et al.“Measurement of Low-Dose Active Pharmaceutical Ingredient in a Pharmaceutical Blend Using Frequency-Domain Photon Migration”. J. Pharm. Sci.2004. 93(3): 635–645.
38.
HuangM.KimM.S.ChaoK., et al.“Penetration Depth Measurement of Near-Infrared Hyperspectral Imaging Light for Milk Powder”. Sensors.2016. 16(4): 441.
39.
ItoA.WatanabeT.YadaS., et al.“Prediction of Recrystallization Behavior of Troglitazone/Polyvinylpyrrolidone Solid Dispersion by Solid-State NMR”. Int. J. Pharm.2010. 383(1–2): 18–23.
40.
ShiZ.AndersonC.A.“Application of Monte Carlo Simulation-Based Photon Migration for Enhanced Understanding of Near Infrared (NIR) Diffuse Reflectance. Part I: Depth of Penetration in Pharmaceutical Materials”. J. Pharm. Sci.2010. 99(5): 2399–2412.
41.
AnderssonM.SvenssonO.FolestadS., et al.“NIR Spectroscopy on Moving Solids Using a Scanning Grating Spectrometer—Impact on Multivariate Process Analysis”. Chemom. Intell. Lab. Syst.2005. 75(1): 1–11.
42.
VanaraseA.U.JärvinenM.PaasoJ., et al.“Development of a Methodology to Estimate Error in the On-Line Measurements of Blend Uniformity in a Continuous Powder Mixing Process”. Powder Technol.2013. 241(Supplement C): 263–271.
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