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Continuous Feeding-Blending in Pharmaceutical Continuous Manufacturing

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Continuous Pharmaceutical Processing

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 42))

Abstract

Pharmaceutical continuous manufacturing has steadily progressed from the proof of concept to the pilot and industrial production in the past two decades, some of which have recently been approved by the US Food and Drug Administration (FDA), resulting in a greater demand on experience in process design and operation in pharmaceutical continuous manufacturing. Unlike many of the individual unit operations that are themselves continuous operations, such as roller compaction, tableting, etc., and have been well studied previously, only the characterization of a continuous feeding-blending system will be discussed in detail in this chapter, which undergoes the most substantial change with a transition from batch to continuous manufacturing.

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References

  • Aissa AA, Duchesne C, Rodrigue D. Transverse mixing of polymer powders in a rotary cyliner part I: active layer charaterization. Powder Technol. 2012;219:193–201.

    Article  CAS  Google Scholar 

  • Austin J, Gupta A, McDonnell R, Reklaitis GV, Harris MT. A novel microwave sensor to determine particulate blend composition on-line. Anal Chim Acta. 2014;819:82–93.

    Article  CAS  PubMed  Google Scholar 

  • Bauer BH. The current state of control loop performance monitoring-a survey of application in industry. J Process Control. 2016;38:1–10.

    Article  CAS  Google Scholar 

  • Blackshields CA, Crean AM. Continuous powder feeding for pharmaceutical solid dosage form manufacture: a short review. Pharm Dev Technol. 2018;23(6):554–60.

    Article  CAS  PubMed  Google Scholar 

  • Boukouvala F, Niotis V, Ramachandran R, Muzzio FJ, Ierapetritou MG. An integrated approach for dynamic flowsheet modeling and sensitivity analysis of a continuous tablet manufacturing process. Comput Chem Eng. 2012;42:30–47.

    Article  CAS  Google Scholar 

  • Bridgwater J. Mixing of powders and granular materials by mechanical means - a perspective. Particuology. 2012;10(4):397–427.

    Article  Google Scholar 

  • Câmara MM, Soares RM, Feital T, Anzai TK, Diehl FC, Thompson PH, Pinto JC. Numerical aspects of data reconciliation in industrial applications. Processes. 2017;5(4):56.

    Article  CAS  Google Scholar 

  • Cao H, Mushnoori S, Higgins B, Kollipara C, Fermier A, Hausner D, et al. A systematic framework for data management and integration in a continuous pharmaceutical manufacturing processing line. Process. 2018; In press.

    Google Scholar 

  • Chen Z, Lovett D, Morris J. Process analytical technologies and real time process control a review of some spectroscopic issues and challenges. J Process Control. 2011;21(10):1467–82.

    Article  CAS  Google Scholar 

  • Cholayudth P. Establishing blend uniformity acceptance criteria for oral solid-dosage forms. Pharm Technol. 2017;41(2):42–52.

    CAS  Google Scholar 

  • Coperion. Micro screw feeders. 2018, June 14. Retrieved from Coperion: https://www.coperion.com/en/products-services/process-equipment/feeders/micro-screw-feeders/.

  • Coupe A. P2, or not P2: that is the question from development to design. CMAC annual open day, 2015, Glasgow.

    Google Scholar 

  • Darby ML, Nikolaou M. MPC: current practice and challenges. Control Eng Pract. 2012;20:328–42.

    Article  Google Scholar 

  • Engisch W, Muzzio F. Method for characterization of loss-in-weight feeder equipment. Powder Technol. 2012;228:395–403.

    Article  CAS  Google Scholar 

  • Engisch W, Muzzio F. Feed rate deviations caused by hopper refill of loss-in-weight feeders. Powder Technol. 2015;283:389–400.

    Article  CAS  Google Scholar 

  • Faqih A, Alexander A, Muzzio F, Tomassone M. A method for predicting hopper flow characteristics of pharmaceutical powders. Chem Eng Sci. 2007;62:1536–42.

    Article  CAS  Google Scholar 

  • FDA, U. U.S. Guidance for industry: Q8(2) pharmaceutical development. Maryland: Food and Drug Administration; 2009.

    Google Scholar 

  • Franklin GF, Powell JD, Workman ML. Digital control of dynamic systems. 2nd ed., World student series ed: Reading, Mass Addison-Wesley; 1990.

    Google Scholar 

  • Ganesh S, Troscinski R, Schmall N, Lim J, Nagy Z, Reklaitis G. Application of x-ray sensors for in-line and non-invasive monitoring of mass flow rate in continuous tablet manufacturing. J Pharm Sci. 2017;106(12):3591–603.

    Article  CAS  PubMed  Google Scholar 

  • García-Muñoz S, Butterbaugh A, Leavesley I, Manley L, Slade D, Bermingham S. A flowsheet model for the development of a continuous process for pharmaceutical tablets: an industrial perspective. AICHE J. 2018;64:511–25.

    Article  CAS  Google Scholar 

  • Guo S, Liu P, Li Z. Inequality constrained nonlinear data reconciliation of a steam turbine power plant for enhanced parameter estimation. Energy. 2016;103:215–30.

    Article  Google Scholar 

  • Hoo K, Piovoso MJ. Process and controller performance monitoring: overview with industrial applications. International Journal of Adaptive Control and Signal Processing. 2003;17:635–62.

    Article  Google Scholar 

  • Ierapetritou M, Muzzio F, Reklaitis G. Perspectives on the continuous manufacturing of powder-based pharmaceutical processes. AICHE J. 2016;62(6):1846–62.

    Article  CAS  Google Scholar 

  • Ierapetritou M, Sebastian E-EM, Singh R. Process simulation and control for continuous pharmaceutical manufacturing of solid drug products. In: Kleinebudde P, Khinast J, Rantanen J, editors. Continuous manufacturing of pharmaceuticals: Hoboken NJ, Wiley; 2017. p. 33–105.

    Google Scholar 

  • Jelali M. Control performance management in industrial automation: assessment, diagnosis and improvement of control loop performance. London: Springer-Verlag; 2013.

    Book  Google Scholar 

  • Kemeny G, Stuessy G. Imaging the blending processes. Pharm Manuf. 2012, January 03:1–2.

    Google Scholar 

  • Lakerveld R, Benyahia B, Braatz RD, Barton PI. Model-based design of a plant-wide control strategy for a continuous pharmaceutical plant. AICHE J. 2013;59(10):3671–85.

    Article  CAS  Google Scholar 

  • Lakerveld R, Benyahia B, Heider PL, Zhang H, Wolfe A, Testa CJ, et al. The application of an automated control strategy for an integrated continuous pharmaceutical pilot plant. Orgainc Process Research & Development. 2015;19:1088–100.

    Article  CAS  Google Scholar 

  • Lee SL, O’Connor TF, Yang X, Cruz CN, Chatterjee S, Madurawe RD, et al. Modernizing pharmaceutical manufacturing: from batch to continuous production. J Pharm Innov. 2015;10(3):191–9.

    Article  Google Scholar 

  • LFA. What is the importance of blend uniformity in the pharmaceutical industry. Retrieved 20 June 2018 from LFA tablet presses: https://www.lfatabletpresses.com/articles/importance-blend-uniformity.

  • Li X, Wang N, Wang L, Kantor I, Robineau J-L, Yang Y, Marechal F. A data-driven model for the air-cooling condenser of thermal power plants based on data reconciliation and support vector regression. Appl Therm Eng. 2018;129:1496–507.

    Article  Google Scholar 

  • Liu J, Su Q, Moreno M, Laird C, Nagy Z, Reklaitis G. Robust state estimation of feeding-blending systems in continuous pharmaceutical manufacturing. Chemical Engineering Reserach and Design. 2018;134:140–53.

    Article  CAS  Google Scholar 

  • Marikh K, Berthiaux H, Mizonov V, Barantseva E. Experimental study of the stirring conditions taking place in a pilot plant continuous mixer of particulate solids. Powder Technol. 2005;157:138–43.

    Article  CAS  Google Scholar 

  • Markl D, Wahl PR, Menezes JC, Koller DM, Kavsek B, Francois K, et al. Supervisory control system for monitoring a pharmaceutical holt melt extrusion process. AAPS PharmSciTech. 2013;14(3):1034–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mason RL, Young JC. Multivariate statistical process control with industrial applications. Philadelphia: The American Statistical Association and the Society for Industrial and Applied Mathematics; 2002.

    Book  Google Scholar 

  • Moreno M, Liu J, Ganesh S, Su Q, Yazdanpanah N, O’Connor T, et al. Steady-state data reconciliation of a direct compression tableting line. AIChE annual meeting. Minneapolis: AIChE Annual Meeting; 2017.

    Google Scholar 

  • Nowak S. Improving feeder performance in continuous pharmaceutical operations. Pharm Technol. 2016;40(10):68–73.

    Google Scholar 

  • Oka S, Muzzio F. Continuous powder blenders for pharmaceutical applications. Heidelberg: Springer; 2012.

    Google Scholar 

  • Oka SS, Escotet-Espinoza MS, Singh R, Scicolone JV, Hausner DB, Ierapetritou M, Muzzio FJ. Design of an integrated continuous manufacturing system. In: Kleinebudde P, Khinast J, Rantanen J, editors. Continuous manufacturing of pharmaceuticals: Hoboken NJ, Wiley; 2017. p. 405–46.

    Google Scholar 

  • Osorio J, Vanarase A, Romanach R, Muzzio F. Continuous powder mixing. In: Cullen P, Romanach R, Abatzoglou N, Rielly C, editors. Pharmaceutical blending and mixing. Chichester: Wiley; 2015.

    Google Scholar 

  • Pernenkil L. Continuous blending of dry pharmaceutical powders. Boston: Massachusetts Institute of Technology; 2008.

    Google Scholar 

  • Pernenkil L, Cooney CL. A review on the continuous blending of powders. Chem Eng Sci. 2006;61(2):720–42.

    Article  CAS  Google Scholar 

  • Portillo P, Ierapetritou M, Muzzio F. Characterization of continuous convective powder mixing processes. Powder Technol. 2008;182(3):368–78.

    Article  CAS  Google Scholar 

  • Previdi F, Belloli D, Cologni A, Savaresi SM, Cazzola D, Madaschi M. Control system design for a continuous gravimetric blender. Preprints of the 18th IFAC world congress, pp. 1025–1030, 2011, Milano, Italy.

    Google Scholar 

  • Qin SJ. Control performance monitoring-a review and assessment. Comput Chem Eng. 1998;23:173–86.

    Article  CAS  Google Scholar 

  • Rafiee A, Behrouzshad F. Data reconciliation with application to a natural gas processing plant. J Nat Gas Sci Eng. 2016;31:538–45.

    Article  Google Scholar 

  • Ramachandran R, Arjunan J, Chaudhury A, Ierapetritou MG. Model-based control-loop performance of a continuous direct compaction process. J Pharm Innov. 2011;6:249–63.

    Article  Google Scholar 

  • Rehrl J, Kruisz J, Sacher S, Khinast J, Horn M. Optimized continuous pharmaceutical manufacturing via model-predictive control. Int J Pharm. 2016;510:100–15.

    Article  CAS  PubMed  Google Scholar 

  • Rockoff JD. Drug making breaks away from its old ways. 2015, Feb 8. Retrieved October 6, 2016, from The Wall Street Journal: http://www.wsj.com/articles/drug-making-breaks-away-from-its-old-ways-1423444049.

  • Rogers A, Hashemi A, Ierapetritou M. Modeling of particulate processes for the continuous manufacturing of solid-based pharmaceutical dosage forms. Processes. 2013;1:67–127.

    Article  CAS  Google Scholar 

  • Scheibelhofer O, Balak N, Wahl PR, Koller DM, Glasser BJ, Khinast JG. Monitoring blending of pharmaceutical powders withi multipoint NIR spectroscopy. AAPS PharmSciTech. 2013;14(1):234–44.

    Article  CAS  PubMed  Google Scholar 

  • Sen M, Dubey A, Singh R, Ramachandran R. Mathematical development and comparison of a hybrid PBM-DEM description of a continuous powder mixing process. J Powder Technol. 2013;2013:1–11.

    Article  Google Scholar 

  • Singh R, Gernaey KV, Gani R. Model-based computer-aided framework for design of process monitoring and analysis systems. Comput Chem Eng. 2009;33(1):22–42.

    Article  CAS  Google Scholar 

  • Singh R, Ierapetritou M, Ramachandran R. System-wide hybrid model predictive control of a continuous pharmaceutical tablet manufacturing process via direct compaction. Eur J Pharm Biopharm. 2013;85(3 Part B):1164–82.

    Article  CAS  PubMed  Google Scholar 

  • Singh R, Sahay A, Muzzio F, Ierapetritou M, Rohit R. A systematic framework for onsite design and implementation of a control system in a continuous tablet manufacturing process. Comput Chem Eng. 2014;66:186–200.

    Article  CAS  Google Scholar 

  • Singh R, Muzzio FJ, Ierapetritou M, Rohit R. A combined feed-forward/feed-back control system for a QbD-based continuous tablet manufacturing process. Processes. 2015a;3:339–56.

    Article  Google Scholar 

  • Singh R, Sen M, Ierapetritou M, Ramachandra R. Integrated moving horizon-based dynamic real-time optimization and hybrid MPC-PID control of a direct compaction continuous tablet manufacturing process. J Pharm Innov. 2015b;10:233–53.

    Article  Google Scholar 

  • Su Q, Moreno M, Giridhar A, Reklaitis GV, Nagy ZK. A systematic framework for process control design and risk analysis in continuous pharmaceutical solid-dosage manufacturing. J Pharm Innov. 2017;12:327–46.

    Article  Google Scholar 

  • Su Q, Bommireddy Y, Gonzalez M, Reklaitis GV, Nagy ZK Variation and risk analysis in tablet press control for continuous manufacturing of solid dosage via direct compaction. The 13th international symposium on process systems engineering PSE 2018a, San Diego.

    Google Scholar 

  • Su Q, Moreno M, Ganesh S, Reklaitis GV, Nagy ZK. Resilience and risk analysis of fault-tolerant process control design in continuous pharmaceutical manufacturing. J Loss Prev Process Ind. 2018b;55:411–22.

    Article  Google Scholar 

  • Su Q, Bommireddy Y, Shah Y, Ganesh S, Moreno M, Liu J, et al. Data reconciliation in the Quality-by-Design (QbD) implementation of pharmaceutical continuous tablet manufacturing. Int J Pharm. 2019a;563:259–72.

    Article  CAS  PubMed  Google Scholar 

  • Su Q, Ganesh S, Moreno M, Bommireddy Y, Gonzalez M, Reklaitis GV, Nagy ZK. A perspective on Quality-by-Control (QbC) in pharmaceutical continuous manufacturing. Comput Chem Eng. 2019b;125:216–31.

    Article  CAS  Google Scholar 

  • Valdetaro ED, Schirru R. Simultaneous model selection, robust data reconciliation and outlier detection with swarm intelligence in a thermal reactor power calculation. Ann Nucl Energy. 2011;38(9):1820–32.

    Article  CAS  Google Scholar 

  • Vanarase AU, Muzzio FJ. Effect of operating conditions and design parameters in a continuous powder mixer. Powder Technol. 2011;208(1):26–36.

    Article  CAS  Google Scholar 

  • Vanarase AU, Alcalà M, Jerez Rozo JI, Muzzio FJ, Romañach RJ. Real-time monitoring of drug concentration in a continuous powder mixing process using NIR spectroscopy. Chem Eng Sci. 2010;65:5728–33.

    Article  CAS  Google Scholar 

  • Velázquez C, Florían M, Quinones L. Monitoring and control of a continuous tumble mixer. Computer Aided Chemical Engineering. 2018;41:471–87.

    Article  Google Scholar 

  • Warman M. Continuous processing in secondary production. In: Ende DJAM, editor. Chemical engineering in the pharmaceutical industry - R&D to manufacturing. New Jersey: Wiley; 2011. p. 837–51.

    Google Scholar 

  • Weinekotter R, Gericke H. Mixing of solids: Kluwer Academic Publishers, Dordrecht, the Netherlands; 2000.

    Google Scholar 

  • Weiss GH, Romagnoli JA, Islam KA. Data reconciliation-an industrial case study. Computers Chemical Engineering. 1996;20(12):1441–9.

    Article  CAS  Google Scholar 

  • Yoon S, Galbraith S, Cha B, Liu H. Chapter 5 - Flowsheet modeling of a continuous direct compression process. Computer Aided Chemical Engineering. 2018;41:121–39.

    Article  CAS  Google Scholar 

  • Yu LX, Amidon G, Khan MA, Hoag SW, Polli J, Raju GK, Woodcock J. Understanding pharmaceutical quality by design. AAPS J. 2014;16(4):771–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao XJ, Gatumel C, Dirion JL, Berthiaux H, Cabassud M. Implementation of a control loop for a continuous powder mixing process. Proceeding of the 2013 AIChE annual meeting, 2013, San Francisco.

    Google Scholar 

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Correspondence to Zoltan K. Nagy .

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Su, Q., Reklaitis, G.V., Nagy, Z.K. (2020). Continuous Feeding-Blending in Pharmaceutical Continuous Manufacturing. In: Nagy, Z., El Hagrasy, A., Litster, J. (eds) Continuous Pharmaceutical Processing. AAPS Advances in the Pharmaceutical Sciences Series, vol 42. Springer, Cham. https://doi.org/10.1007/978-3-030-41524-2_6

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