Development of a fluid bed granulation process control strategy based on real-time process and product measurements.

This article describes the results of three case studies conducted consecutively, in order to develop a process control strategy for a top-spray fluid bed granulation process. The use of several real-time particle size (i.e., spatial filter velocimetry and focused beam reflectance measurement) and moisture (i.e., near infrared (NIR) and Lighthouse near infrared spectroscopy) analyzers was examined. A feed-forward process control method was developed, where in-line collected granulation information during the process spraying phase was used to determine the optimum drying temperature of the consecutive drying phase. Via real-time monitoring of process (i.e., spraying temperature and spray rate) and product (i.e., granule size distribution and moisture) parameters during the spraying period, the batch bulk density was predicted at the end of the spraying cycle, using a PLS model. When this predicted bulk density was not meeting the desired value, the developed control method allowed the calculation of an adjusted drying temperature leading to the desired batch bulk density at the end of the granulation process. Besides the development of the feed-forward control strategy, a quantitative PLS model for in-line moisture content prediction of the granulated end product was built using the NIR data.

[1]  J. Coello,et al.  Near-infrared spectroscopy in the pharmaceutical industry. , 1998, The Analyst.

[2]  J. Rantanen,et al.  Use of the Near-Infrared Reflectance Method for Measurement of Moisture Content During Granulation , 2000, Pharmaceutical development and technology.

[3]  D. Wurster,et al.  Preparation of compressed tablet granulations by the air-suspension technique. II. , 1960, Journal of the American Pharmaceutical Association. American Pharmaceutical Association.

[4]  M Sherry Ku,et al.  Asymmetry effect of particle size distribution on content uniformity and over-potency risk in low-dose solid drugs. , 2010, Journal of pharmaceutical sciences.

[5]  Peter Langguth,et al.  Role of continuous moisture profile monitoring by inline NIR spectroscopy during fluid bed granulation of an Enalapril formulation , 2011, Drug development and industrial pharmacy.

[6]  Denita Winstead,et al.  Study growth kinetics in fluidized bed granulation with at-line FBRM. , 2008, International journal of pharmaceutics.

[7]  Jouko Yliruusi,et al.  Gaining fluid bed process understanding by in-line particle size analysis. , 2009, Journal of pharmaceutical sciences.

[8]  R. Barnes,et al.  Standard Normal Variate Transformation and De-Trending of Near-Infrared Diffuse Reflectance Spectra , 1989 .

[9]  R. Reed,et al.  In-line monitoring of moisture content in fluid bed dryers using near-IR spectroscopy with consideration of sampling effects on method accuracy. , 2005, Analytical chemistry.

[10]  P. Teppola,et al.  Labscale fluidized bed granulator instrumented with non-invasive process monitoring devices , 2010 .

[11]  Manel Bautista,et al.  On-line monitoring of a granulation process by NIR spectroscopy. , 2010, Journal of pharmaceutical sciences.

[12]  S. Goebel,et al.  Online-Messung der Produktfeuchte und Korngrösse in der Wirbelschicht mit der Nah-Infrarot-Spektroskopie , 1998 .

[13]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[14]  Theodora Kourti,et al.  Multivariate dynamic data modeling for analysis and statistical process control of batch processes, start‐ups and grade transitions , 2003 .

[15]  J. Rantanen,et al.  In-line moisture measurement during granulation with a four-wavelength near-infrared sensor: an evaluation of process-related variables and a development of non-linear calibration model , 2001 .

[16]  M. Mazzotti,et al.  Modeling and Experimental Analysis of PSD Measurements through FBRM , 2000 .

[17]  Mirko Peglow,et al.  Restoration of particle size distributions from fiber-optical in-line measurements in fluidized bed processes , 2011 .

[18]  Petrak Dieter,et al.  In-line particle sizing for real-time process control by fibre-optical spatial filtering technique (SFT) , 2011 .

[19]  T. De Beer,et al.  Evaluation of in-line spatial filter velocimetry as PAT monitoring tool for particle growth during fluid bed granulation. , 2010, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[20]  Chimanlall Goolcharran,et al.  A PAT Approach to Enhance Process Understanding of Fluid Bed Granulation Using In-line Particle Size Characterization and Multivariate Analysis , 2010, Journal of Pharmaceutical Innovation.

[21]  A. Peinado,et al.  Development, validation and transfer of a near infrared method to determine in-line the end point of a fluidised drying process for commercial production batches of an approved oral solid dose pharmaceutical product. , 2011, Journal of pharmaceutical and biomedical analysis.

[22]  D. Petrak Simultaneous Measurement of Particle Size and Particle Velocity by the Spatial Filtering Technique , 2002 .

[23]  Tormod Næs,et al.  Related versions of the multiplicative scatter correction method for preprocessing spectroscopic data , 1995 .

[24]  O. Antikainen,et al.  Controlling granule size by granulation liquid feed pulsing. , 2008, International journal of pharmaceutics.

[25]  Wolfgang Marquardt,et al.  Process Analysis by Means of Focused Beam Reflectance Measurements , 2009 .

[26]  J. Rantanen,et al.  On-line monitoring of moisture content in an instrumented fluidized bed granulator with a multi-channel NIR moisture sensor , 1998 .

[27]  Sebastian Schmidt-Lehr,et al.  Online-Kontrolle der Partikelgröße während einer Wirbelschichtgranulation : Untersuchung einer neuartigen Lasersonde zur besseren Kontrolle des Partikelgrößenwachstums in der Wirbelschichtgranulation , 2007 .

[28]  D. Petrak,et al.  Optical Probe for the In-Line Determination of Particle Shape, Size, and Velocity , 2006 .

[29]  Kenneth R Morris,et al.  Determination of fluidized bed granulation end point using near-infrared spectroscopy and phenomenological analysis. , 2005, Journal of pharmaceutical sciences.

[30]  J. Rantanen,et al.  In-line moisture measurement during granulation with a four-wavelength near infrared sensor: an evaluation of particle size and binder effects. , 2000, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[31]  Julia Utz,et al.  A PAT approach to improve process understanding of high shear wet granulation through in-line particle measurement using FBRM C35. , 2010, Journal of pharmaceutical sciences.

[32]  C Vervaet,et al.  Near infrared and Raman spectroscopy for the in-process monitoring of pharmaceutical production processes. , 2011, International journal of pharmaceutics.

[33]  H. Vromans,et al.  Granule Characterization During Fluid Bed Drying by Development of a Near Infrared Method to Determine Water Content and Median Granule Size , 2007, Pharmaceutical Research.

[34]  Reginald B. H. Tan,et al.  Monitoring Granulation Rate Processes Using Three PAT Tools in a Pilot-Scale Fluidized Bed , 2008, AAPS PharmSciTech.

[35]  T. De Beer,et al.  Batch statistical process control of a fluid bed granulation process using in-line spatial filter velocimetry and product temperature measurements. , 2011, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[36]  D. Wurster,et al.  Air-suspension technique of coating drug particles; a preliminary report. , 1959, Journal of the American Pharmaceutical Association. American Pharmaceutical Association.

[37]  Andrew G. Glen,et al.  APPL , 2001 .

[38]  Y. Roggo,et al.  A review of near infrared spectroscopy and chemometrics in pharmaceutical technologies. , 2007, Journal of pharmaceutical and biomedical analysis.

[39]  P. Frake,et al.  Process control and end-point determination of a fluid bed granulation by application of near infra-red spectroscopy , 1997 .