Cappuyns, Philippe

De Beer, Thomas

Escotet-Espinoza, Manuel Sebastian

Ghijs, Michael

Muzzio, Fernando J

Nopens, Ingmar

Van Assche, Ivo

Vanbillemont, Brecht

English

Ghent University Academic Bibliography

INTEGRATED MODELFlowsheet model of the rotary tablet pressMethods:• All models integrated in gSOLIDS (PSE)• Dynamic modelling of transient phasesFLOWSHEET MODELING OF THE COMPRESSION STEP OF A CONTINUOUS WET GRANULATION PRODUCTION LINELABORATORY OF PHARMACEUTICAL PROCESS ANALYTICAL TECHNOLOGYB. Vanbillemont1, M. Ghijs2, M.S. Escotet-Espinoza3, P. Cappyuns4, I. Van Assche4, F.J. Muzzio3, I. Nopens2, T. De Beer11Laboratory of Pharmaceutical Process Analytical Technology, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium2BIOMATH, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium3Chemical and Biochemical Engineering, School of Engineering, Rutgers, The State University of New Jersey, 98 Brett Road, Piscataway NJ 08854, USA4The Janssen Pharmaceutical Companies of Johnson and Johnson, Turnhoutseweg 30, 2340 Beerse, BelgiumINTRODUCTIONMathematical models of the unit operations match the QbD paradigm.  Flowsheet modelling is a framework for gaining process and product knowledge by employing:● Sensitivity analysis (risk assessment, CPP & CMA definition) ● Soft sensors● State-of-Control determination (dynamic optimisation, minimize waste streams) ● Controller designs● Scenario analysis (interactions between unit operations and quality management)     ● Product timings ( traceability and rejection strategy)AIM: A flowsheet model, of the compression step from a wet granulated product, consisting of 4 submodels. Implementable in an overall powder-to tablet flowsheet.① Residence time distribution (RTD) model   ➔ ② Die filling model   ➔ ③ Potency model   ➔ ④ Tablet Hardness modelContactbrecht.vanbillemont@ugent.bewww.ugent.be/fw/pharmaceutical-analysis/en/research/patUniversiteit Gent@ugentGhent UniversityCONCLUSION & FUTURE APPLICATIONSConclusion• Standalone flowsheet model of the compression step developed, integratable in a continuous powder-to-tablet line flowsheet (ConSigma-25, GEA pharma systems).• Model capable of dynamically predicting tablet properties from varying CPP and critical material attributes (CMA).Future applications• Gather process insights and develop applications using the flowsheet.• Decision support tool for regulatory process filing.RTD MODELPowder dosing valve and feedframeMethods:• Step change of 5% NaSaccharin, determined withoffline Raman spectroscopy of tablets.• Design of experiments (DoE) with all critical process parameters (CPP) → multiple linear regression (MLR) of the model parameters.• Continuous stirred tank model with plug flow (tp + tcstr).Results:• Spectroscopic PLS model with RSMEcv of 0,1726 %.• Mean residence time between 50 and 110 s.• tp and tcstr are dependent on the turret speed.DIE FILLING & POTENCY MODELDie filling stage of a rotary pressMethods:• Tablet volume from tooling dimensions and fill depth.• Mean tablet weight determined by regression of granules with varying bulk and tapped density.• Solid tablet volume prediction using true density.• Potency estimated with the API granule concentration.Results:• 21.8th percentile between bulk and tapped indicative for granule density at filling position.• First principle model with RMSE of 0.9930 %.• Weight and potency dependent on granule properties.TABLET HARDNESS MODELCompression stage of a rotary pressMethods:• Compactibility estimation by regression of 90 different conditions with a Kuentz and Leuenberger (K&L) model.• Impact of granules with varying granule sizes (Span) and residual moisture (LoD) on tablet hardness.→ MLR model with LoD and Span for K&L parameters.Results:• Max tensile strength ~ LoD and Span• Critical density ~ LoD• K&L - MLR model has RMSEcv of 0.1447 MPaFig1. RTD Step change model fit Fig3. K&L model fitFig4.  Flowsheet Scenario Input changesFig5.  Outputs of flowsheet Fig2.  Mean tablet weight model fitGRANULESBulk densityTapped densityAPI concentrationResidual moistureGranule size distributionTABLETSMean weightMean PotencyMean HardnessCPPFill depthTurret speedMain compression height

Flowsheet modeling of the compression step of a continuous wet granulation production line

Vanbillemont, Brecht0000904098588020023105559769043120720000-0002-6730-8152202A4EAE-F0EE-11E1-A9DE-61C894A0A6B4

Ghijs, MichaelGE300000905303028020019244740000-0002-6398-88162404E3A4-F0EE-11E1-A9DE-61C894A0A6B4

Nopens, IngmarLA260019942824128010013710900000-0001-6670-3700F5D054AA-F0ED-11E1-A9DE-61C894A0A6B4

De Beer, ThomasFW020019972147418010016996780000-0001-6296-0443F69EB3AE-F0ED-11E1-A9DE-61C894A0A6B4

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https://biblio.ugent.be/publication/8671816/file/8671817

Flowsheet modeling of the compression step of a continuous wet granulation production line

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