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

Continuous manufacturing (CM) has the potential to provide pharmaceutical products with better quality, improved yield and with reduced cost and time. Moreover, ease of scale-up, small manufacturing footprint and on-line/in-line monitoring and control of the process are other merits for CM. Regulating authorities are supporting the adoption of CM by pharmaceutical manufacturers through issuing proper guidelines. However, implementation of this technology in pharmaceutical industry is encountered by a number of challenges regarding the process development and quality assurance. This article provides a background on the implementation of CM in pharmaceutical industry, literature survey of the most recent state-of-the-art technologies and critically discussing the encountered challenges and its future prospective in pharmaceutical industry.

[1]  J. Kushner,et al.  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. , 2011, Journal of pharmaceutical sciences.

[2]  Runze Li,et al.  Design of experiments with multiple independent variables: a resource management perspective on complete and reduced factorial designs. , 2009, Psychological methods.

[3]  R. Aboofazeli Nanometric-Scaled Emulsions (Nanoemulsions) , 2010, Iranian journal of pharmaceutical research : IJPR.

[4]  Peng Wang,et al.  Chemical Development of NBI-75043. Use of a Flow Reactor to Circumvent a Batch-Limited Metal−Halogen Exchange Reaction , 2008 .

[5]  Fani Boukouvala,et al.  Computer-Aided Flowsheet Simulation of a Pharmaceutical Tablet Manufacturing Process Incorporating Wet Granulation , 2013, Journal of Pharmaceutical Innovation.

[6]  A. Nokhodchi,et al.  Continuous manufacturing via hot-melt extrusion and scale up: regulatory matters. , 2017, Drug discovery today.

[7]  P. Poechlauer,et al.  Continuous Processing in the Manufacture of Active Pharmaceutical Ingredients and Finished Dosage Forms: An Industry Perspective , 2012 .

[8]  James M. B. Evans,et al.  End-to-end continuous manufacturing of pharmaceuticals: integrated synthesis, purification, and final dosage formation. , 2013, Angewandte Chemie.

[9]  J Baronsky-Probst,et al.  Process design and control of a twin screw hot melt extrusion for continuous pharmaceutical tamper-resistant tablet production. , 2016, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[10]  Bernhardt L Trout,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. , 2017, Journal of pharmaceutical sciences.

[11]  R. Valdés,et al.  Rapid Development and Optimization of Tablet Manufacturing Using Statistical Tools , 2008, AAPS PharmSciTech.

[12]  Michael K Danquah,et al.  Review on nanoparticles and nanostructured materials: history, sources, toxicity and regulations , 2018, Beilstein journal of nanotechnology.

[13]  Yu Wang,et al.  On-demand manufacturing of clinical-quality biopharmaceuticals , 2018, Nature Biotechnology.

[14]  Attila Farkas,et al.  Spectroscopic characterization of tablet properties in a continuous powder blending and tableting process , 2018, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[15]  Hiroshi Nakagawa,et al.  Decision Support Method for the Choice between Batch and Continuous Technologies in Solid Drug Product Manufacturing , 2018 .

[16]  M. R. Mozafari,et al.  Liposomes: A Review of Manufacturing Techniques and Targeting Strategies , 2011 .

[17]  S. Majumdar,et al.  Continuous manufacturing of solid lipid nanoparticles by hot melt extrusion. , 2014, International journal of pharmaceutics.

[18]  C. Xie,et al.  The production and characteristics of solid lipid nanoparticles (SLNs). , 2003, Biomaterials.

[19]  John Robertson,et al.  General procedure to aid the development of continuous pharmaceutical processes using multivariate statistical modeling - an industrial case study. , 2013, International journal of pharmaceutics.

[20]  Ariel R. Muliadi,et al.  Evaluation of Three Approaches for Real-Time Monitoring of Roller Compaction with Near-Infrared Spectroscopy , 2012, AAPS PharmSciTech.

[21]  Esther S. Kim,et al.  Abemaciclib: First Global Approval , 2017, Drugs.

[22]  Lawrence X. Yu,et al.  Modernizing Pharmaceutical Manufacturing: from Batch to Continuous Production , 2015, Journal of Pharmaceutical Innovation.

[23]  Marcus Baumann,et al.  The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry , 2015, Beilstein journal of organic chemistry.

[24]  K. Getz,et al.  Open innovation: the new face of pharmaceutical research and development , 2012, Expert review of clinical pharmacology.

[25]  G. K. Raju,et al.  Understanding Pharmaceutical Quality by Design , 2014, The AAPS Journal.

[26]  RTD modeling of a continuous dry granulation process for process control and materials diversion. , 2017, International journal of pharmaceutics.

[27]  Zilong Wang,et al.  Process analysis and optimization of continuous pharmaceutical manufacturing using flowsheet models , 2017, Comput. Chem. Eng..

[28]  Michał Teżyk,et al.  Recent progress in continuous and semi-continuous processing of solid oral dosage forms: a review , 2016, Drug development and industrial pharmacy.

[29]  Richard D. Braatz,et al.  Challenges and opportunities in biopharmaceutical manufacturing control , 2018, Comput. Chem. Eng..

[30]  Satu Lakio,et al.  Continuous manufacturing of extended release tablets via powder mixing and direct compression. , 2015, International journal of pharmaceutics.

[31]  Jean Paul Remon,et al.  Continuous granulation in the pharmaceutical industry , 2005 .

[32]  Thomson,et al.  An overview of the different excipients useful for the direct compression of tablets. , 2000, Pharmaceutical science & technology today.

[33]  Martin D. Johnson,et al.  Annual Review of Chemical and Biomolecular Engineering Continuous Manufacturing in Pharmaceutical Process Development and Manufacturing , 2018 .

[34]  P. Hubert,et al.  Improvement of a stability-indicating method by Quality-by-Design versus Quality-by-Testing: a case of a learning process. , 2014, Journal of pharmaceutical and biomedical analysis.

[35]  Mohammed Maniruzzaman,et al.  Continuous manufacturing and process analytical tools. , 2015, International journal of pharmaceutics.

[36]  Changquan Calvin Sun,et al.  Crystal and Particle Engineering Strategies for Improving Powder Compression and Flow Properties to Enable Continuous Tablet Manufacturing by Direct Compression. , 2017, Journal of pharmaceutical sciences.

[37]  Thomas E Matthews,et al.  Enabling Robust and Rapid Raw Material Identification and Release by Handheld Raman Spectroscopy , 2019, PDA Journal of Pharmaceutical Science and Technology.

[38]  G. Walsh Biopharmaceuticals and biotechnology medicines: an issue of nomenclature. , 2002, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[39]  Charles Cooney,et al.  Regulatory and Quality Considerations for Continuous Manufacturing May 20-21, 2014 Continuous Manufacturing Symposium. , 2015, Journal of pharmaceutical sciences.

[40]  Anh Q. Vo,et al.  Application of FT-NIR Analysis for In-line and Real-Time Monitoring of Pharmaceutical Hot Melt Extrusion: a Technical Note , 2018, AAPS PharmSciTech.

[41]  Richard D Braatz,et al.  Control Systems Engineering in Continuous Pharmaceutical Manufacturing May 20-21, 2014 Continuous Manufacturing Symposium. , 2015, Journal of pharmaceutical sciences.

[42]  Ana M Azevedo,et al.  Continuous purification of antibodies from cell culture supernatant with aqueous two-phase systems: from concept to process. , 2013, Biotechnology journal.

[43]  W. Schlindwein,et al.  In-Line UV-Vis Spectroscopy as a Fast-Working Process Analytical Technology (PAT) during Early Phase Product Development Using Hot Melt Extrusion (HME) , 2018, Pharmaceutics.

[44]  Shen Yu,et al.  Twin Screw Granulation – A Literature Review , 2015 .

[45]  Marianthi G. Ierapetritou,et al.  Modeling the effects of material properties on tablet compaction: A building block for controlling both batch and continuous pharmaceutical manufacturing processes , 2018, International journal of pharmaceutics.

[46]  Steven J Shire,et al.  Formulation and manufacturability of biologics. , 2009, Current opinion in biotechnology.

[47]  Buket Aksu,et al.  Strategic funding priorities in the pharmaceutical sciences allied to Quality by Design (QbD) and Process Analytical Technology (PAT). , 2012, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[48]  Bernhardt L Trout,et al.  Achieving Continuous Manufacturing for Final Dosage Formation: Challenges and How to Meet Them May 20-21 2014 Continuous Manufacturing Symposium. , 2015, Journal of pharmaceutical sciences.

[49]  Niklas Sandler,et al.  Influence of raw material properties upon critical quality attributes of continuously produced granules and tablets. , 2014, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[50]  Hirokazu Sugiyama,et al.  A large‐scale experimental comparison of batch and continuous technologies in pharmaceutical tablet manufacturing using ethenzamide , 2019, International journal of pharmaceutics.

[51]  Sibu Chakrabarti,et al.  Physical properties and compact analysis of commonly used direct compression binders , 2003, AAPS PharmSciTech.

[52]  V. Vanhoorne,et al.  Managing API raw material variability during continuous twin‐screw wet granulation , 2019, International journal of pharmaceutics.

[53]  Rajesh Thipparaboina,et al.  Continuous manufacturing of co-crystals: challenges and prospects , 2018, Drug Delivery and Translational Research.

[54]  M C Martinetz,et al.  RTD‐based material tracking in a fully‐continuous dry granulation tableting line , 2018, International journal of pharmaceutics.

[55]  J. Drennen,et al.  In-line monitoring and optimization of powder flow in a simulated continuous process using transmission near infrared spectroscopy. , 2017, International journal of pharmaceutics.

[56]  A. Rathore,et al.  Quality by design for biopharmaceuticals , 2009, Nature Biotechnology.

[57]  Johannes Khinast,et al.  Detailed modeling and process design of an advanced continuous powder mixer , 2018, International journal of pharmaceutics.

[58]  Suzanne S Farid,et al.  Integrated continuous bioprocessing: Economic, operational, and environmental feasibility for clinical and commercial antibody manufacture , 2017, Biotechnology progress.

[59]  Stephan Laske,et al.  A Review of PAT Strategies in Secondary Solid Oral Dosage Manufacturing of Small Molecules. , 2017, Journal of pharmaceutical sciences.

[60]  Andreas Wagner,et al.  Liposomes produced in a pilot scale: production, purification and efficiency aspects. , 2002, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[61]  N. Szita,et al.  Formation and purification of tailored liposomes for drug delivery using a module-based micro continuous-flow system , 2017, Scientific Reports.

[62]  P. P. Lottici,et al.  Raman spectroscopy as a PAT for pharmaceutical blending: Advantages and disadvantages , 2018, Journal of pharmaceutical and biomedical analysis.

[63]  Ian R. Lewis,et al.  Raman spectroscopy as a process analytical technology for pharmaceutical manufacturing and bioprocessing , 2016, Analytical and Bioanalytical Chemistry.

[64]  David Cantillo,et al.  Continuous-flow technology—a tool for the safe manufacturing of active pharmaceutical ingredients. , 2015, Angewandte Chemie.

[65]  Rafiqul Gani,et al.  Thermodynamic Property Modeling for Chemical Process and Product Engineering: Some Perspectives , 2009 .

[66]  Maunu Toiviainen,et al.  Continuous manufacturing of tablets with PROMIS-line - Introduction and case studies from continuous feeding, blending and tableting. , 2016, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[67]  T. De Beer,et al.  On the modelling of granule size distributions in twin-screw wet granulation: Calibration of a novel compartmental population balance model , 2019, Powder Technology.

[68]  Krist V. Gernaey,et al.  Liquid‐to‐solid ratio control as an advanced process control solution for continuous twin‐screw wet granulation , 2018 .

[69]  P. Kleinebudde Roll compaction/dry granulation: pharmaceutical applications. , 2004, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[70]  Peter Poechlauer,et al.  Equipment and Analytical Companies Meeting Continuous Challenges May 20-21 2014 Continuous Manufacturing Symposium. , 2015, Journal of pharmaceutical sciences.

[71]  A. Jouyban,et al.  The potential of the capillary electrophoresis techniques for quality control of biopharmaceuticals—A review , 2015, Electrophoresis.

[72]  D. Mcclements Recent progress in hydrogel delivery systems for improving nutraceutical bioavailability , 2017 .

[73]  Chaitanya Krishna Prasad Vallabh,et al.  Early detection of capping risk in pharmaceutical compacts , 2018, International journal of pharmaceutics.

[74]  M. Blanco,et al.  API Determination by NIR Spectroscopy Across Pharmaceutical Production Process , 2008, AAPS PharmSciTech.

[75]  Salvador García-Muñoz,et al.  A flowsheet model for the development of a continuous process for pharmaceutical tablets: An industrial perspective , 2018 .

[76]  Marianthi Ierapetritou,et al.  An engineering study on the enhanced control and operation of continuous manufacturing of pharmaceutical tablets via roller compaction. , 2012, International journal of pharmaceutics.

[77]  Satu Lakio,et al.  Provoking an end‐to‐end continuous direct compression line with raw materials prone to segregation , 2017, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[78]  Marianthi G. Ierapetritou,et al.  Periodic section modeling of convective continuous powder mixing processes , 2012 .

[79]  Jun Zhang,et al.  Multivariate monitoring for the industrialisation of a continuous wet granulation tableting process , 2018, International journal of pharmaceutics.

[80]  Sudarshan Ganesh,et al.  Application of X-Ray Sensors for In-line and Noninvasive Monitoring of Mass Flow Rate in Continuous Tablet Manufacturing. , 2017, Journal of pharmaceutical sciences.

[81]  Eva Roblegg,et al.  Inline monitoring and a PAT strategy for pharmaceutical hot melt extrusion. , 2013, International journal of pharmaceutics.

[82]  V. Vanhoorne,et al.  Multivariate statistical process control of a continuous pharmaceutical twin-screw granulation and fluid bed drying process. , 2017, International journal of pharmaceutics.

[83]  S. Shanmugam Granulation techniques and technologies: recent progresses , 2015, BioImpacts : BI.

[84]  S. Lesieur,et al.  Liposome retention in size exclusion chromatography , 2005, BMC biotechnology.

[85]  Cristiana Boi,et al.  Membrane adsorbers as purification tools for monoclonal antibody purification. , 2007, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[86]  Y. Matsuda Global Regulatory Landscape , 2018, AAPS PharmSciTech.

[87]  R. Carneiro,et al.  Simultaneous Quantification of Three Polymorphic Forms of Carbamazepine in the Presence of Excipients Using Raman Spectroscopy , 2014, Molecules.

[88]  Jean Paul Remon,et al.  A multivariate raw material property database to facilitate drug product development and enable in‐silico design of pharmaceutical dry powder processes , 2018, International journal of pharmaceutics.

[89]  Daniel Cummings,et al.  Integrated continuous production of recombinant therapeutic proteins , 2012, Biotechnology and bioengineering.

[90]  W. Schlindwein,et al.  Pharmaceutical excipients properties and screw feeder performance in continuous processing lines: a Quality by Design (QbD) approach , 2018, Drug development and industrial pharmacy.

[91]  G. Reklaitis,et al.  Perspectives on the continuous manufacturing of powder‐based pharmaceutical processes , 2016 .

[92]  N. Scoutaris,et al.  One-step continuous extrusion process for the manufacturing of solid dispersions. , 2015, International journal of pharmaceutics.

[93]  Gabriele Reich,et al.  Near-infrared spectroscopy and imaging: basic principles and pharmaceutical applications. , 2005, Advanced drug delivery reviews.

[94]  Anurag S Rathore,et al.  Continuous Processing for Production of Biopharmaceuticals , 2015, Preparative biochemistry & biotechnology.

[95]  S. Y. Wong,et al.  On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system , 2016, Science.

[96]  T. De Beer,et al.  A continuous manufacturing concept for a pharmaceutical oral suspension , 2018, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[97]  Lawrence X. Yu Pharmaceutical Quality by Design: Product and Process Development, Understanding, and Control , 2008, Pharmaceutical Research.

[98]  P. Kleinebudde,et al.  Studies on the reduction of tensile strength of tablets after roll compaction/dry granulation. , 2008, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[99]  M. Maniruzzaman,et al.  Continuous twin-screw granulation for enhancing the dissolution of poorly water soluble drug. , 2015, International journal of pharmaceutics.

[100]  Jagjit Singh Srai,et al.  Future Supply Chains Enabled by Continuous Processing-Opportunities Challenges May 20-21 2014 Continuous Manufacturing Symposium. , 2015, Journal of pharmaceutical sciences.

[101]  Paul Wan Sia Heng,et al.  Continuous processing and the applications of online tools in pharmaceutical product manufacture: developments and examples. , 2013, Therapeutic delivery.

[102]  Qinglin Su,et al.  A perspective on Quality-by-Control (QbC) in pharmaceutical continuous manufacturing , 2019, Comput. Chem. Eng..

[103]  H Leuenberger,et al.  New trends in the production of pharmaceutical granules: batch versus continuous processing. , 2001, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[104]  Dimitrios I. Gerogiorgis,et al.  Plantwide design and economic evaluation of two Continuous Pharmaceutical Manufacturing (CPM) cases: Ibuprofen and artemisinin , 2015, Comput. Chem. Eng..

[105]  Nicholas R. Abu-Absi,et al.  Real time monitoring of multiple parameters in mammalian cell culture bioreactors using an in-line Raman spectroscopy probe. , 2011, Biotechnology and bioengineering.

[106]  Marianthi G. Ierapetritou,et al.  Modeling of Particulate Processes for the Continuous Manufacture of Solid-Based Pharmaceutical Dosage Forms , 2013 .

[107]  Michael A. P. McAuliffe,et al.  Near‐infrared monitoring of roller compacted ribbon density: Investigating sources of variation contributing to noisy spectral data , 2017, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[108]  V. Vanhoorne,et al.  Downstream processing from hot-melt extrusion towards tablets: A quality by design approach. , 2017, International journal of pharmaceutics.

[109]  Scott A. May,et al.  Flow Chemistry, Continuous Processing, and Continuous Manufacturing: A Pharmaceutical Perspective , 2017, Journal of Flow Chemistry.

[110]  C Vervaet,et al.  Continuous direct compression as manufacturing platform for sustained release tablets. , 2017, International journal of pharmaceutics.

[111]  Christel A. S. Bergström,et al.  Computational Prediction of Drug Solubility in Lipid Based Formulation Excipients , 2013, Pharmaceutical Research.

[112]  Fernando J. Muzzio,et al.  Effects of powder flow properties and shear environment on the performance of continuous mixing of pharmaceutical powders , 2013 .