Integrated continuous manufacturing in pharmaceutical industry: current evolutionary steps toward revolutionary future

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

• 1. Gutmann B, Cantillo D, Kappe CO. Continuous-Flow technology—A tool for the safe manufacturing of active pharmaceutical ingredients. Angew. Chem. Int. Ed. Engl. 54(23), 6688–6728 (2015).
  Medline CASGoogle Scholar
• 2. US FDA. CFR- Code of Federal regualtion Title 21 (2018). www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm
  Google Scholar
• 3. Lee SL, O'connor TF, Yang X et al. Modernizing pharmaceutical manufacturing: from batch to continuous production. J. Pharm. Innov. 10, 191–199 (2015).
  Google Scholar
• 4. Ierapetritou M, Muzzio F, Reklaitis G. Perspectives on the continuous manufacturing of powder-based pharmaceutical processes. AIChE J. 62(6), 1846–1862 (2016).
  CASGoogle Scholar
• 5. Getz KA, Kaitin KI. Open innovation: The new face of pharmaceutical research and development. Exp. Rev. Clin. Pharm. 5(5), 481–483 (2012).
  Medline CASGoogle Scholar
• 6. U.S. Food and Drug Adminstration (Fda). Q7 Good manufacturing practice guidance for active pharmaceutical ingredients (2018). www.fda.gov/regulatory-information/search-fda-guidance-documents/q7-good-manufacturing-practice-guidance-active-pharmaceutical-ingredients-guidance-industry
  Google Scholar
• 7. Mascia S, Heider PL, Zhang H et al. End-to-end continuous manufacturing of pharmaceuticals: integrated synthesis, purification and final dosage formation. Angew. Chem. Int. Ed. Engl. 52(47), 12359–12363 (2013).
  Medline CASGoogle Scholar
• 8. Rathore AS, Agarwal H, Sharma AK, Pathak M, Muthukumar S. Continuous processing for production of biopharmaceuticals. Prep. Biochem. Biotechnol. 45(8), 836–849 (2015).
  Medline CASGoogle Scholar
• 9. Aksu B, De Beer T, Folestad S et al. Strategic funding priorities in the pharmaceutical sciences allied to Quality by Design (QbD) and Process Analytical Technology (PAT). Eur. J. Pharm. Sci. 47(2), 402–405 (2012).
  Medline CASGoogle Scholar
• 10. Page T, Dubina H, Fillipi G et al. Equipment and analytical companies meeting continuous challenges. May 20–21, 2014 Continuous Manufacturing Symposium. J. Pharm. Sci. 104(3), 821–831 (2015).
  CASGoogle Scholar
• 11. Page TG. US20110208436A1 (2011).
  Google Scholar
• 12. Allison G, Cain YT, Cooney C et al. Regulatory and quality considerations for continuous manufacturing May 20–21, 2014 Continuous Manufacturing Symposium. J. Pharm. Sci. 104(3), 803–812 (2015).
  CASGoogle Scholar
• 13. Chatterjee S. FDA perspective on continuous manufacturing. Presented at: IFPAC Annual Meeting, Baltimore, MD, USA, 22–25 January 2012.
  Google Scholar
• 14. Leuenberger H. New trends in the production of pharmaceutical granules: batch versus continuous processing. Eur. J. Pharm. Biopharm. 52(3), 289–296 (2001).
  Medline CASGoogle Scholar
• 15. Poechlauer P, Manley J, Broxterman R, Gregertsen B, Ridemark M. Continuous processing in the manufacture of active pharmaceutical ingredients and finished dosage forms: an industry perspective. Org. Proc. Res. Dev. 16(10), 1586–1590 (2012).
  CASGoogle Scholar
• 16. Burcham CL, Florence AJ, Johnson MD. Continuous manufacturing in pharmaceutical process development and manufacturing. Annu. Rev. Chem. Biomol. Eng. 9, 253–281 (2018).
  MedlineGoogle Scholar
• 17. Warikoo V, Godawat R, Brower K et al. Integrated continuous production of recombinant therapeutic proteins. Biotechnol. Bioeng. 109(12), 3018–3029 (2012).
  Medline CASGoogle Scholar
• 18. Pollock J, Coffman J, Ho SV, Farid SS. Integrated continuous bioprocessing: economic, operational, and environmental feasibility for clinical and commercial antibody manufacture. Biotechnol. Prog. 33(4), 854–866 (2017).
  Medline CASGoogle Scholar
• 19. Byrn S, Futran M, Thomas H et al. Achieving continuous manufacturing for final dosage formation: challenges and how to meet them. May 20-21, 2014 Continuous Manufacturing Symposium. J. Pharm. Sci. 104(3), 792–802 (2015).
  CASGoogle Scholar
• 20. International Organization for Standardization (ISO). ISO 9000:2015. 20 March 2019 (2015). www.iso.org/standard/45481.html
  Google Scholar
• 21. Myerson AS, Krumme M, Nasr M, Thomas H, Braatz RD. Control systems engineering in continuous pharmaceutical manufacturing. May 20-21, 2014 Continuous Manufacturing Symposium. J. Pharm. Sci. 104(3), 832–839 (2015).
  CASGoogle Scholar
• 22. May SA. Flow chemistry, continuous processing, and continuous manufacturing: a pharmaceutical perspective. J. Flow Chem. 7(3), 137–145 (2017).
  CASGoogle Scholar
• 23. Matsunami K, Nagato T, Hasegawa K, Sugiyama H. A large-scale experimental comparison of batch and continuous technologies in pharmaceutical tablet manufacturing using ethenzamide. Int. J. Pharm. 559, 210–219 (2019).
  Medline CASGoogle Scholar
• 24. Zomer S, Zhang J, Talwar S, Chattoraj S, Hewitt C. Multivariate monitoring for the industrialisation of a continuous wet granulation tableting process. Int. J. Pharm. 547(1–2), 506–519 (2018). • Highlights the importance of the multivariate statistical analysis for integrating the vast data gathered from the Process Analytical Technology units during continuous manufacturing.
  Medline CASGoogle Scholar
• 25. Papadakis E, Woodley JM, Gani R. Chapter 24 - Perspective on PSE in pharmaceutical process development and innovation. In: Computer Aided Chemical Engineering. Singh RYuan Z (Eds). Elsevier, Cambridge, MA, USA, 597–656 (2018).
  Google Scholar
• 26. Alam MA, Shi Z, Drennen JK 3rd, Anderson CA. In-line monitoring and optimization of powder flow in a simulated continuous process using transmission near infrared spectroscopy. Int. J. Pharm. 526(1–2), 199–208 (2017).
  Medline CASGoogle Scholar
• 27. Santos B, Carmo F, Schlindwein W et al. Pharmaceutical excipients properties and screw feeder performance in continuous processing lines: a Quality by Design (QbD) approach. Drug Dev. Ind. Pharm. 44(12), 2089–2097 (2018).
  Medline CASGoogle Scholar
• 28. Van Snick B, Dhondt J, Pandelaere K et al. A multivariate raw material property database to facilitate drug product development and enable in silico design of pharmaceutical dry powder processes. Int. J. Pharm. 549(1–2), 415–435 (2018). • Suggests the application of principle component analysis to limit the ingredients needed and therefore simplify the product development stage of the continuous manufacturing.
  Medline CASGoogle Scholar
• 29. Yu LX. Pharmaceutical quality by design: product and process development, understanding, and control. Pharm. Res. 25(4), 781–791 (2008).
  Medline CASGoogle Scholar
• 30. Hubert C, Lebrun P, Houari S, Ziemons E, Rozet E, Hubert P. Improvement of a stability-indicating method by Quality-by-Design versus Quality-by-Testing: a case of a learning process. J. Pharm. Biomed. Anal. 88, 401–409 (2014).
  Medline CASGoogle Scholar
• 31. Su Q, Ganesh S, Moreno M et al. A perspective on Quality-by-Control (QbC) in pharmaceutical continuous manufacturing. Comp. Chem. Eng. 125, 216–231 (2019).
  CASGoogle Scholar
• 32. Rathore AS, Winkle H. Quality by design for biopharmaceuticals. Nat. Biotech. 27(1), 26 (2009).
  Medline CASGoogle Scholar
• 33. Yu LX, Amidon G, Khan MA et al. Understanding pharmaceutical quality by design. AAPS J. 16(4), 771–783 (2014).
  Medline CASGoogle Scholar
• 34. Grymonpre W, Bostijn N, Herck SV et al. Downstream processing from hot-melt extrusion towards tablets: a quality by design approach. Int. J. Pharm. 531(1), 235–245 (2017).
  Medline CASGoogle Scholar
• 35. Lakio S, Ervasti T, Tajarobi P et al. Provoking an end-to-end continuous direct compression line with raw materials prone to segregation. Eur. J. Pharm. Sci. 109, 514–524 (2017).
  Medline CASGoogle Scholar
• 36. Schlindwein W, Bezerra M, Almeida J, Berghaus A, Owen M, Muirhead G. In-Line UV-Vis Spectroscopy as a Fast-Working Process Analytical Technology (PAT) during Early Phase Product Development Using Hot Melt Extrusion (HME). Pharmaceutics 10(4), 1–25 (2018).
  Google Scholar
• 37. Srai JS, Badman C, Krumme M, Futran M, Johnston C. Future supply chains enabled by continuous processing–opportunities and challenges. May 20-21, 2014 Continuous Manufacturing Symposium. J. Pharm. Sci. 104(3), 840–849 (2015).
  CASGoogle Scholar
• 38. Tomba E, De Martin M, Facco P et al. General procedure to aid the development of continuous pharmaceutical processes using multivariate statistical modeling – an industrial case study. Int. J. Pharm. 444(1–2), 25–39 (2013).
  Medline CASGoogle Scholar
• 39. Silva AF, Sarraguca MC, Fonteyne M et al. Multivariate statistical process control of a continuous pharmaceutical twin-screw granulation and fluid bed drying process. Int. J. Pharm. 528(1–2), 242–252 (2017).
  Medline CASGoogle Scholar
• 40. Stauffer F, Vanhoorne V, Pilcer G, Chavez PF, Vervaet C, De Beer T. Managing API raw material variability during continuous twin-screw wet granulation. Int. J. Pharm. 561, 265–273 (2019).
  Medline CASGoogle Scholar
• 41. Rogers A, Hashemi A, Ierapetritou M. Modeling of particulate processes for the continuous manufacture of solid-based pharmaceutical dosage forms. Processes 1(2), 67–127 (2013).
  CASGoogle Scholar
• 42. Toson P, Siegmann E, Trogrlic M et al. Detailed modeling and process design of an advanced continuous powder mixer. Int. J. Pharm. 552(1), 288–300 (2018).
  Medline CASGoogle Scholar
• 43. Persson LC, Porter CJH, Charman WN, Bergström CaS. Computational prediction of drug solubility in lipid based formulation excipients. Pharmaceutical Res. 30(12), 3225–3237 (2013).
  Medline CASGoogle Scholar
• 44. O'connell JP, Gani R, Mathias PM, Maurer G, Olson JD, Crafts PA. Thermodynamic property modeling for chemical process and product engineering: Some perspectives. Ind. Eng. Chem. Res. 48(10), 4619–4637 (2009).
  Google Scholar
• 45. Boukouvala F, Chaudhury A, Sen M et al. Computer-aided flowsheet simulation of a pharmaceutical tablet manufacturing process incorporating wet granulation. J. Pharm. Innov. 8(1), 11–27 (2013).
  Google Scholar
• 46. Boeckx J, Page TG, Waldron MS. WO2010128359A1 (2017).
  Google Scholar
• 47. Escotet-Espinoza MS, Vadodaria S, Singh R, Muzzio FJ, Ierapetritou MG. Modeling the effects of material properties on tablet compaction: A building block for controlling both batch and continuous pharmaceutical manufacturing processes. Int. J. Pharm. 543(1), 274–287 (2018).
  Medline CASGoogle Scholar
• 48. García-Muñoz S, Butterbaugh A, Leavesley I, Manley LF, Slade D, Bermingham S. A flowsheet model for the development of a continuous process for pharmaceutical tablets: an industrial perspective. AIChE J. 64(2), 511–525 (2018).
  CASGoogle Scholar
• 49. Wang Z, Escotet-Espinoza MS, Ierapetritou M. Process analysis and optimization of continuous pharmaceutical manufacturing using flowsheet models. Comput. Chem. Eng. 107, 77–91 (2017). •• Develops an integrated flowsheet model for better understanding of continuous manufacturing process. This systematic approach involved sensitivity analysis, feasibility analysis and optimization for continuous direct compression process.
  CASGoogle Scholar
• 50. Fernandez EG, Cordero S, Benitez M et al. Rapid development and optimization of tablet manufacturing using statistical tools. AAPS PharmSciTech 9(2), 620–627 (2008).
  Medline CASGoogle Scholar
• 51. Collins LM, Dziak JJ, Li R. Design of experiments with multiple independent variables: a resource management perspective on complete and reduced factorial designs. Psych. Met. 14(3), 202–224 (2009).
  MedlineGoogle Scholar
• 52. Nasr MM, Krumme M, Matsuda Y et al. Regulatory perspectives on continuous pharmaceutical manufacturing: moving from theory to practice: September 26-27, 2016, international symposium on the continuous manufacturing of pharmaceuticals. J. Pharm. Sci. 106(11), 3199–3206 (2017).
  Medline CASGoogle Scholar
• 53. Gao Y, Ierapetritou M, Muzzio F. Periodic section modeling of convective continuous powder mixing processes. AIChE J. 58(1), 69–78 (2012).
  CASGoogle Scholar
• 54. Kruisz J, Rehrl J, Sacher S, Aigner I, Horn M, Khinast JG. RTD modeling of a continuous dry granulation process for process control and materials diversion. Int. J. Pharm. 528(1–2), 334–344 (2017).
  Medline CASGoogle Scholar
• 55. Martinetz MC, Karttunen AP, Sacher S et al. RTD-based material tracking in a fully-continuous dry granulation tableting line. Int. J. Pharm. 547(1–2), 469–479 (2018).
  Medline CASGoogle Scholar
• 56. Laske S, Paudel A, Scheibelhofer O, Author T. A review of PAT strategies in secondary solid oral dosage manufacturing of small molecules. J. Pharm. Sci. 106(3), 667–712 (2017).
  Medline CASGoogle Scholar
• 57. Maniruzzaman M, Douroumis D. Continuous manufacturing and process analytical tools. Int. J. Pharm. 496(1), 1–2 (2015).
  Medline CASGoogle Scholar
• 58. International Conference on Harmonisation (Ich). Guidance for industry: Q8 (R2) (pharmaceutical development). Center for Drug Evaluation and Research (2009). www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf
  Google Scholar
• 59. (Fda) FDA. Guidance for industry, PAT-A framework for innovative pharmaceutical development, manufacturing and quality assurance (2004). www.fda.gov/media/71012/download
  Google Scholar
• 60. Esmonde-White KA, Cuellar M, Uerpmann C, Lenain B, Lewis IR. Raman spectroscopy as a process analytical technology for pharmaceutical manufacturing and bioprocessing. Anal. Bioanal. Chem. 409(3), 637–649 (2017).
  Medline CASGoogle Scholar
• 61. Ganesh S, Troscinski R, Schmall N, Lim J, Nagy Z, Reklaitis G. Application of x-ray sensors for in-line and noninvasive monitoring of mass flow rate in continuous tablet manufacturing. J. Pharm. Sci. 106(12), 3591–3603 (2017).
  Medline CASGoogle Scholar
• 62. Nagy B, Farkas A, Magyar K, Demuth B, Nagy ZK, Marosi G. Spectroscopic characterization of tablet properties in a continuous powder blending and tableting process. Eur. J. Pharm. Sci. 123, 10–19 (2018).
  Medline CASGoogle Scholar
• 63. Rathore AS, Wood R, Sharma A, Dermawan S. Case study and application of process analytical technology (PAT) towards bioprocessing: II. Use of ultra-performance liquid chromatography (UPLC) for making real-time pooling decisions for process chromatography. Biotechnol. Bioeng. 101(6), 1366–1374 (2008).
  Medline CASGoogle Scholar
• 64. Maniruzzaman M, Nair A, Renault M et al. Continuous twin-screw granulation for enhancing the dissolution of poorly water soluble drug. Int. J. Pharm. 496(1), 52–62 (2015).
  Medline CASGoogle Scholar
• 65. Xu X, Vallabh CKP, Hoag SW, Dave VS, Cetinkaya C. Early detection of capping risk in pharmaceutical compacts. Int. J. Pharm. 553(1-2), 338–348 (2018).
  Medline CASGoogle Scholar
• 66. Maniruzzaman M, Nokhodchi A. Continuous manufacturing via hot-melt extrusion and scale up: regulatory matters. Drug Discov. Today 22(2), 340–351 (2017).
  Medline CASGoogle Scholar
• 67. Reich G. Near-infrared spectroscopy and imaging: basic principles and pharmaceutical applications. Adv. Drug Deliv. Rev. 57(8), 1109–1143 (2005).
  Medline CASGoogle Scholar
• 68. Blanco M, Bautista M, Alcalà M. API determination by NIR spectroscopy across pharmaceutical production process. AAPS PharmSciTech 9(4), 1130–1135 (2008).
  Medline CASGoogle Scholar
• 69. Vo AQ, He H, Zhang J, Martin S, Chen R, Repka MA. Application of FT-NIR analysis for in-line and real-time monitoring of pharmaceutical hot melt extrusion: a technical note. AAPS PharmSciTech 19(8), 3425–3429 (2018).
  Medline CASGoogle Scholar
• 70. Acevedo D, Muliadi A, Giridhar A, Litster JD, Romanach RJ. Evaluation of three approaches for real-time monitoring of roller compaction with near-infrared spectroscopy. AAPS PharmSciTech 13(3), 1005–1012 (2012).
  Medline CASGoogle Scholar
• 71. Crowley ME, Hegarty A, Mcauliffe MaP et al. Near-infrared monitoring of roller compacted ribbon density: investigating sources of variation contributing to noisy spectral data. Eur. J. Pharm. Sci. 102, 103–114 (2017).
  Medline CASGoogle Scholar
• 72. Tezyk M, Milanowski B, Ernst A, Lulek J. Recent progress in continuous and semi-continuous processing of solid oral dosage forms: a review. Drug Dev. Ind. Pharm. 42(8), 1195–1214 (2016).
  Medline CASGoogle Scholar
• 73. Riolo D, Piazza A, Cottini C et al. Raman spectroscopy as a PAT for pharmaceutical blending: advantages and disadvantages. J. Pharm. Biomed. Anal. 149, 329–334 (2018).
  Medline CASGoogle Scholar
• 74. Acevedo D, Yang X, Mohammad A et al. Raman spectroscopy for monitoring the continuous crystallization of carbamazepine. Org. Process Res. Dev. 22(2), 156–165 (2018).
  CASGoogle Scholar
• 75. Abu-Absi NR, Kenty BM, Cuellar ME et al. Real time monitoring of multiple parameters in mammalian cell culture bioreactors using an in-line Raman spectroscopy probe. Biotechnol. Bioeng. 108(5), 1215–1221 (2011).
  Medline CASGoogle Scholar
• 76. Chavan RB, Thipparaboina R, Yadav B, Shastri NR. Continuous manufacturing of co-crystals: challenges and prospects. Drug Deliv. Transl. Res. 8(6), 1726–1739 (2018).
  Medline CASGoogle Scholar
• 77. U.S. Food and Drug Adminstration (Fda). Quality considerations for continuous manufacturing guidance for industry. Human Drug Information (2019). www.fda.gov/media/121314/download
  Google Scholar
• 78. Farias M, Carneiro R. Simultaneous quantification of three polymorphic forms of carbamazepine in the presence of excipients using Raman spectroscopy. Mol. 19(9), 14128–14138 (2014).
  MedlineGoogle Scholar
• 79. Matthews TE, Coffman C, Kolwyck D, Hill D, Dickens JE. Enabling robust and rapid raw material identification and release by handheld raman spectroscopy. PDA J. Pharm. Sci. Technol. doi:10.5731/pdajpst.2018.009563 (2019) (Epub ahead of print).
  MedlineGoogle Scholar
• 80. Fonteyne M, Wickstrom H, Peeters E et al. Influence of raw material properties upon critical quality attributes of continuously produced granules and tablets. Eur. J. Pharm. Biopharm. 87(2), 252–263 (2014).
  Medline CASGoogle Scholar
• 81. Escotet-Espinoza MS, Vadodaria S, Singh R, Muzzio FJ, Ierapetritou MG. Modeling the effects of material properties on tablet compaction: A building block for controlling both batch and continuous pharmaceutical manufacturing processes. Int. J. Pharm. 543(1–2), 274–287 (2018).
  Medline CASGoogle Scholar
• 82. Kushner J, Langdon BA, Hiller JI, Carlson GT. Examining the impact of excipient material property variation on drug product quality attributes: a quality-by-design study for a roller compacted, immediate release tablet. J. Pharm. Sci. 100(6), 2222–2239 (2011).
  Medline CASGoogle Scholar
• 83. Wahl PR, Treffer D, Mohr S, Roblegg E, Koscher G, Khinast JG. Inline monitoring and a PAT strategy for pharmaceutical hot melt extrusion. Int. J. Pharm. 455(1–2), 159–168 (2013).
  Medline CASGoogle Scholar
• 84. Ooi SM, Sarkar S, Van Varenbergh G, Schoeters K, Heng PW. Continuous processing and the applications of online tools in pharmaceutical product manufacture: developments and examples. Therap. Del. 4(4), 463–470 (2013).
  CASGoogle Scholar
• 85. Shanmugam S. Granulation techniques and technologies: recent progresses. BioImpacts. BI 5(1), 55 (2015).
  Medline CASGoogle Scholar
• 86. Kleinebudde P. Roll compaction/dry granulation: pharmaceutical applications. Eur. J. Pharm. Biopharm. 58(2), 317–326 (2004).
  Medline CASGoogle Scholar
• 87. Herting MG, Kleinebudde P. Studies on the reduction of tensile strength of tablets after roll compaction/dry granulation. Eur. J. Pharm. Biopharm. 70(1), 372–379 (2008).
  Medline CASGoogle Scholar
• 88. Farrenkopf J. Relevant aspects of roller compaction covering the impact of excipients, milling devices, fines and feasibility prediction (2009).
  Google Scholar
• 89. Singh R, Ierapetritou M, Ramachandran R. An engineering study on the enhanced control and operation of continuous manufacturing of pharmaceutical tablets via roller compaction. Int. J. Pharm. 438(1), 307–326 (2012). • Develops a new integrated framework for manufacturing, on-line monitoring and closed-loop control to enhance CQAs performance of CM.
  Medline CASGoogle Scholar
• 90. Agrawal R, Naveen Y. Pharmaceutical processing: a review on wet granulation technology. Int. J. Pharm. Front. Res. 1(1), 65–83 (2011).
  CASGoogle Scholar
• 91. Vervaet C, Remon JP. Continuous granulation in the pharmaceutical industry. Chem. Eng. Sci. 60(14), 3949–3957 (2005).
  CASGoogle Scholar
• 92. Ghebre-Sellassie I, Mollan Jr MJ, Pathak N, Lodaya M, Fessehaie M. US6499984B1 (2002).
  Google Scholar
• 93. Baronsky-Probst J, Moltgen CV, Kessler W, Kessler RW. Process design and control of a twin screw hot melt extrusion for continuous pharmaceutical tamper-resistant tablet production. Eur. J. Pharm. Sci. 87, 14–21 (2016).
  Medline CASGoogle Scholar
• 94. Nicolaï N, De Leersnyder F, Copot D et al. Liquid-to-solid ratio control as an advanced process control solution for continuous twin-screw wet granulation. AIChE J. 64(7), 2500–2514 (2018).
  CASGoogle Scholar
• 95. Seem TC, Rowson NA, Ingram A et al. Twin screw granulation: a literature review. Powder Technol. 276, 89–102 (2015).
  CASGoogle Scholar
• 96. Maniruzzaman M, Nair A, Scoutaris N, Bradley MS, Snowden MJ, Douroumis D. One-step continuous extrusion process for the manufacturing of solid dispersions. Int. J. Pharm. 496(1), 42–51 (2015).
  Medline CASGoogle Scholar
• 97. Mcclements DJ. Recent progress in hydrogel delivery systems for improving nutraceutical bioavailability. Food Hydrocol. 68, 238–245 (2017).
  CASGoogle Scholar
• 98. Van Hauwermeiren D, Verstraeten M, Doshi P et al. On the modelling of granule size distributions in twin-screw wet granulation: Calibration of a novel compartmental population balance model. Powder Technol. 341, 116–125 (2019).
  CASGoogle Scholar
• 99. Zhang Y, Law Y, Chakrabarti S. Physical properties and compact analysis of commonly used direct compression binders. AAPS PharmSciTech 4(4), 489–499 (2003).
  Google Scholar
• 100. Van Snick B, Holman J, Cunningham C et al. Continuous direct compression as manufacturing platform for sustained release tablets. Int. J. Pharm. 519(1–2), 390–407 (2017).
  Medline CASGoogle Scholar
• 101. Jivraj M, Martini LG, Thomson CM. An overview of the different excipients useful for the direct compression of tablets. Pharm. Sci. Tech. Today 3(2), 58–63 (2000).
  Medline CASGoogle Scholar
• 102. Chattoraj S, Sun CC. Crystal and Particle Engineering Strategies for Improving Powder Compression and Flow Properties to Enable Continuous Tablet Manufacturing by Direct Compression. J. Pharm. Sci. 107(4), 968–974 (2018).
  Medline CASGoogle Scholar
• 103. Kowalski J, Lakshman JP, Serajuddin ATM, Tong W, Vasanthavada M. WO2009134848A1 (2011).
  Google Scholar
• 104. Simonaho S, Ketolainen J, Ervasti T, Toiviainen M, Korhonen O. Continuous manufacturing of tablets with PROMIS-line — Introduction and case studies from continuous feeding, blending and tableting. Eur. J. Pharm. Sci. 90, 38–46 (2016).
  Medline CASGoogle Scholar
• 105. Ervasti T, Simonaho S, Ketolainen J et al. Continuous manufacturing of extended release tablets via powder mixing and direct compression. Int. J. Pharm. 495(1), 290–301 (2015).
  Medline CASGoogle Scholar
• 106. Bostijn N, Van Renterghem J, Dhondt W, Vervaet C, De Beer T. A continuous manufacturing concept for a pharmaceutical oral suspension. Eur. J. Pharm. Sci. 123, 576–583 (2018).
  Medline CASGoogle Scholar
• 107. Walsh G. Biopharmaceuticals and biotechnology medicines: an issue of nomenclature. Eur. J. Pharm. Sci. 15(2), 135–138 (2002).
  Medline CASGoogle Scholar
• 108. Hong MS, Severson KA, Jiang M, Lu AE, Love JC, Braatz RD. Challenges and opportunities in biopharmaceutical manufacturing control. Comp. Chem. Eng. 110, 106–114 (2018).
  CASGoogle Scholar
• 109. Shire SJ. Formulation and manufacturability of biologics. Curr. Opin. Biotech. 20(6), 708–714 (2009).
  Medline CASGoogle Scholar
• 110. Tamizi E, Jouyban A. The potential of the capillary electrophoresis techniques for quality control of biopharmaceuticals: a review. Electroph. 36(6), 831–858 (2015).
  Medline CASGoogle Scholar
• 111. Rosa PaJ, Azevedo AM, Sommerfeld S, Mutter M, Bäcker W, Aires-Barros MR. Continuous purification of antibodies from cell culture supernatant with aqueous two-phase systems: from concept to process. Biotechnol. J. 8(3), 352–362 (2013).
  Medline CASGoogle Scholar
• 112. Boi C. Membrane adsorbers as purification tools for monoclonal antibody purification. J. Chromatogr. B 848(1), 19–27 (2007).
  Medline CASGoogle Scholar
• 113. Konstantinov K, Godawat R, Warikoo V, Jain S. Integrated continuous manufacturing of therapeutic protein drug substances (2017). https://patents.google.com/patent/US9650412B2/en
  Google Scholar
• 114. Ransohoff TC, Bisschops MaT. WO2012078677A3 (2012).
  Google Scholar
• 115. Baumann M, Baxendale IR. The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry. Beilstein. J. Org. Chem. 11, 1194–1219 (2015).
  Medline CASGoogle Scholar
• 116. Adamo A, Beingessner R, Behnam M et al. On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system. Science 352(6281), 61–67 (2016). •• Reconfigurable manufacturing platform was developed to synthesize and formulate different active pharmaceutical ingredients in a small-sized plant with real-time monitoring.
  Medline CASGoogle Scholar
• 117. Crowell E, Lu AE, Love KR et al. On-demand manufacturing of clinical-quality biopharmaceuticals. Nat. Biotech. 36, 988–995 (2018).
  CASGoogle Scholar
• 118. Gross TD, Chou S, Bonneville D et al. Chemical development of NBI-75043. Use of a flow reactor to circumvent a batch-limited metal− Halogen exchange reaction. Org. Proc. Res. Dev. 12(5), 929–939 (2008).
  CASGoogle Scholar
• 119. Therre J, Oost C. WO2001016237A2 (2001).
  Google Scholar
• 120. Vanarase AU, Osorio JG, Muzzio FJ. Effects of powder flow properties and shear environment on the performance of continuous mixing of pharmaceutical powders. Powder Technol. 246, 63–72 (2013).
  CASGoogle Scholar
• 121. Tazzia CL, Villalobos MA, Harris MA. Process for continuous production of epoxy resins (2012). https://patents.google.com/patent/US8242234B2/en
  Google Scholar
• 122. Born SC, Dittrich JV, Takiza BT, Mascia S. Continuous drum dryer and methods of use thereof (2017). https://patents.google.com/patent/WO2017136765A1/en
  Google Scholar
• 123. Patil H, Kulkarni V, Majumdar S, Repka MA. Continuous manufacturing of solid lipid nanoparticles by hot melt extrusion. Int. J. Pharm. 471(1), 153–156 (2014).
  Medline CASGoogle Scholar
• 124. Hou D, Xie C, Huang K, Zhu C. The production and characteristics of solid lipid nanoparticles (SLNs). Biomaterials 24(10), 1781–1785 (2003).
  Medline CASGoogle Scholar
• 125. Maherani B, Arab-Tehrany E, R Mozafari M, Gaiani C, Linder M. Liposomes: a review of manufacturing techniques and targeting strategies. Curr. Nanosci. 7(3), 436–452 (2011).
  CASGoogle Scholar
• 126. Dimov N, Kastner E, Hussain M, Perrie Y, Szita N. Formation and purification of tailored liposomes for drug delivery using a module-based micro continuous-flow system. Sci. Rep. 7(1), 12045 (2017).
  MedlineGoogle Scholar
• 127. Wagner A, Vorauer-Uhl K, Katinger H. Liposomes produced in a pilot scale: production, purification and efficiency aspects. Eur. J. Pharm. Biopharm. 54(2), 213–219 (2002).
  Medline CASGoogle Scholar
• 128. Ruysschaert T, Marque A, Duteyrat J, Lesieur S, Winterhalter M, Fournier D. Liposome retention in size exclusion chromatography. BMC Biotech. 5(1), 11 (2005).
  MedlineGoogle Scholar
• 129. Costa A, Burgess DJ. Systems and methods for continuous manufacturing of liposomal drug formulations (2019). https://patents.google.com/patent/US20190029959A1/en
  Google Scholar
• 130. Aboofazeli R. Nanometric-scaled emulsions (nanoemulsions). Iran. J. Pharm. Res. 9(4), 325–326 (2010).
  MedlineGoogle Scholar
• 131. Sah E, Sah H. Recent trends in preparation of poly (lactide-co-glycolide) nanoparticles by mixing polymeric organic solution with antisolvent. J. Nanomat. 16(1), 61 (2015).
  Google Scholar
• 132. Choi G, Kakumanu S, Schmitz L, Robinson GL, Beckett CD, Laugharn Jr JA. Continuous manufacturing of carboxyamidotriazole-encapsulated nanoemulsions using adaptive focused acoustics: potential green technology for the pharmaceutical industry. J. Biomed. Eng. Informatics. 1(19), 20 (2016).
  Google Scholar
• 133. Jeevanandam J, Barhoum A, Chan YS, Dufresne A, Danquah MK. Review on nanoparticles and nanostructured materials: history, sources, toxicity and regulations. Beilstein. J. Nanotechnol. 9, 1050–1074 (2018).
  Medline CASGoogle Scholar
• 134. Fonseca T, Duarte I, Temtem M, Vicente J. Continuous production of particles. WO2016156841A1 (2018). https://patents.google.com/patent/WO2016156841A1/en?oq=WO2016156841A1
  Google Scholar
• 135. Gottlieb S. FDA budget matters: investing in advanced domestic manufacturing. FDA Blog (2018).
  Google Scholar
• 136. U.S. Food and Drug Adminstration (Fda). FDA supports critical research to spur innovation for continuous manufacturing technology to support and advance drug and biologics development (2018). www.fda.gov/news-events/fda-brief/fda-supports-critical-research-spur-innovation-continuous-manufacturing-technology-support-and
  Google Scholar
• 137. Jolliffe HG, Gerogiorgis DI. Plantwide design and economic evaluation of two Continuous Pharmaceutical Manufacturing (CPM) cases: Ibuprofen and artemisinin. Comp. Chem. Eng. 91, 269–288 (2016).
  CASGoogle Scholar
• 138. Transparency Market Research. Pharmaceutical continuous manufacturing market (application - active pharmaceutical ingredient, biologics, and dry powders; end users - pharmaceutical companies and contract manufacturing organization) global industry analysis, size, share, growth, trends, and forecast 2017 - 2025 (2017). www.transparencymarketresearch.com/pharmaceutical-continuous-manufacturing-technology-market.html
  Google Scholar
• 139. Global pharmaceutical continuous manufacturing market to surpass USD 3406.0 million by 2024 www.globenewswire.com/news-release/2018/09/06/1566507/0/en/Global-Pharmaceutical-Continuous-Manufacturing-Market-to-Surpass-USD-3406-0-Million-By-2024-Zion-Market-Research.html
  Google Scholar
• 140. Wallack T. Novartis to give MIT $65m to find new way to produce drugs. The Boston Globe (2007). http://archive.boston.com/business/articles/2007/09/28/novartis_to_give_mit_65m_to_find_new_way_to_produce_drugs/
  Google Scholar
• 141. Matsuda Y. Global Regulatory Landscape. AAPS PharmSciTech 20(1), 2 (2019).
  Google Scholar
• 142. Urquhart L. Regulatory watch: FDA new drug approvals in Q1 2018. Nat. Rev. Drug Discov. 17(5), 309 (2018).
  Medline CASGoogle Scholar
• 143. Diprospero D. Continuous OSD manufacturing - A product & patient perspective. Int. Soc. Pharm. Engl. (2018). https://ispe.org/pharmaceutical-engineering/ispeak/continuous-osd-manufacturing-product-patient-perspective
  Google Scholar
• 144. Macdonald G. Janssen working on other continuous processes post US FDA OK for Prezista. In: PharmaTech (2016).
  Google Scholar
• 145. Kim E. Abemaciclib: first global approval. Drugs 77(18), 2063–2070 (2017).
  MedlineGoogle Scholar
• 146. Schneider EK, Reyes-Ortega F, Wilson JW et al. Development of HPLC and LC–MS/MS methods for the analysis of ivacaftor, its major metabolites and lumacaftor in plasma and sputum of cystic fibrosis patients treated with ORKAMBI or KALYDECO. J. Chromatogr. B 1038, 57–62 (2016).
  CASGoogle Scholar
• 147. Vertex Pharmaceuticals Company. Vertex reports full-year and fourth-quarter 2017 financial results. (2018). https://investors.vrtx.com/news-releases/news-release-details/vertex-reports-full-year-and-fourth-quarter-2017-financial
  Google Scholar
• 148. Vertex Pharmaceuticals Company. Vertex reports full-year and fourth-quarter 2018 financial results. (2019). https://investors.vrtx.com/news-releases/news-release-details/vertex-reports-full-year-and-fourth-quarter-2018-financial
  Google Scholar
• 149. Lohr L. Abemaciclib (verzenio™). Onc. Times 40(6), 12 (2018).
  Google Scholar
• 150. Eli Lilly Q4: Looking at low verzenio sales and the loxo oncology acquisition https://seekingalpha.com/article/4239475-eli-lilly-q4-looking-low-verzenio-sales-loxo-oncology-acquisition
  Google Scholar
• 151. Matsunami K, Miyano T, Arai H, Nakagawa H, Hirao M, Sugiyama H. Decision support method for the choice between batch and continuous technologies in solid drug product manufacturing. Ind. Eng. Chem. Res. 57(30), 9798–9809 (2018). • The research paper included an innovated model for choosing between batch and CM based on economic analysis.
  CASGoogle Scholar