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Computer Aided
Chemical Engineering
Process Systems
Engineering for Pharmaceutical
Manufacturing
Volume 41
This page intentionally left blank
Computer Aided
Chemical Engineering
Process Systems
Engineering for Pharmaceutical
Manufacturing
Volume 41
Edited by
Ravendra Singh
Rutgers, The State University of New Jersey,
Piscataway, NJ, United States of America
Zhihong Yuan
Tsinghua University, Beijing, China
Elsevier
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Contents
Contributors ............................................................................................................xix
Preface ................................................................................................................. xxiii
CHAPTER 1 New Product Development and Supply Chains

in the Pharmaceutical Industry ............................................1
Catherine Azzaro-Pantel
1. Introduction .....................................................................................1
2. Typical Features of Pharmaceutical Industry.................................2
2.1. Analysis of the Product Development Process ......................2
2.2. Life Cycle of a Drug ..............................................................3
2.3. Drug Market Features.............................................................5
2.4. Supply Chain Management ....................................................5
3. Management of Product Development Pipeline ............................8
3.1. Methodological Approaches...................................................8
3.2. Related Optimization Works ................................................11
4. Capacity Planning .........................................................................18
5. Management of the Whole Pharmaceutical
Supply Chain.................................................................................19
6. Conclusions ...................................................................................22
References.......................................................................................... 23
CHAPTER 2 The development of a pharmaceutical oral

solid dosage forms .................................................................27
Rahamatullah Shaikh, Dónal P. O’Brien, Denise M. Croker,
Gavin M. Walker
1. Introduction ...................................................................................27
2. Pharmaceutical Preformulation and Its Significance in the
Development of Solid Dosage Forms ..........................................28
2.1. Solid-State Properties ...........................................................28
2.2. Solubility...............................................................................29
2.3. Dissolution Studies ...............................................................32
2.4. Stability Studies ....................................................................33
2.5. Drug-Excipient Compatibility Studies .................................34
2.6. Physical Properties of Pharmaceutical Solids......................34
3. Drug Product Manufacturing........................................................35
3.1. Diluents .................................................................................38
3.2. Binders ..................................................................................38
v
vi Contents
3.3. Disintegrating Agents ...........................................................41

3.4. Lubricant ...............................................................................41
3.5. Coating Materials .................................................................42
4. Manufacturing Methods for Oral Solid Dosage Form.................45
4.1. Direct Compression ..............................................................46
4.2. Granulation ...........................................................................47
5. Type of Unit Operation ................................................................50
5.1. Pharmaceutical Process Design Methodology .....................50
5.2. Unit Operation Design..........................................................51
6. Batch Versus Continuous Processing ...........................................58
7. Process Analytical Technology ....................................................60
8. Conclusions ...................................................................................63
References.......................................................................................... 63
CHAPTER 3 Innovative process development and

production concepts for small-molecule API
manufacturing ..........................................................................67
John M. Woodley
1. Introduction ...................................................................................67
2. Pharmaceutical Production Processes ..........................................68
2.1. Production of High-Molecular-Weight Pharmaceutical
Products.................................................................................69
2.2. Production of Low-Molecular-Weight Pharmaceutical
Products.................................................................................69
3. Innovative Solutions to Accelerate the Development
of API Production Processes ........................................................71
3.1. Virtual Experimentation .......................................................71
3.2. Databases and Property Prediction.......................................71
3.3. Template Processes...............................................................72
3.4. Summary ...............................................................................74
4. Innovative Solutions to Improve API Production
Processes .......................................................................................74
4.1. Process Analytical Technology ............................................75
4.2. Process Integration and Intensification ................................76
4.3. Solvent Selection ..................................................................77
4.4. Biocatalysis...........................................................................77
4.5. Flow Chemistry ....................................................................78
5. Example: Sitagliptin .....................................................................79
6. Future Perspectives .......................................................................80
References.......................................................................................... 81
Contents vii
CHAPTER 4 Plantwide technoeconomic analysis and

separation solvent selection for continuous
pharmaceutical manufacturing: Ibuprofen,
artemisinin, and diphenhydramine ...................................85
Samir A. Diab, Hikaru G. Jolliffe, Dimitrios I. Gerogiorgis
1. Introduction ...................................................................................86
2. CPM of Ibuprofen, Artemisinin, and Diphenhydramine .............88
2.1. Continuous-Flow Syntheses .................................................88
2.2. Batch and Continuous Separation Schemes.........................90
3. Economic Analysis .......................................................................95
4. Results and Discussion .................................................................99
4.1. API Recoveries and Material Efficiencies...........................99
4.2. Economic Analysis .............................................................104
5. Conclusions .................................................................................109
Acknowledgments ........................................................................... 110
Appendix A. API Recoveries and PMIs ..........................................................110
Appendix B. CapEx, OpEx and Sensitivity Analyses .....................................110
References........................................................................................ 118
CHAPTER 5 Flowsheet modeling of a continuous direct

compression process ...........................................................121
Seongkyu Yoon, Shaun Galbraith, Bumjoon Cha, Huolong Liu
1. Introduction .................................................................................121
1.1. Flowsheet modeling............................................................123
2. Continuous Direct Compression.................................................125
2.1. Powder Feeding ..................................................................125
2.2. Methods of Modeling for Powder Feeding........................127
2.3. Powder Blending ................................................................129
2.4. Modeling Methods for Powder Blending...........................130
2.5. Tablet press.........................................................................133
2.6. Modeling methods for the Tablet Press .............................133
References........................................................................................ 137
Further Reading ............................................................................... 139
CHAPTER 6 Applications of a plant-wide dynamic model of

an integrated continuous pharmaceutical plant:
Design of the recycle in the case of multiple
impurities .................................................................................141
Brahim Benyahia
1. Introduction .................................................................................141
2. Process Description.....................................................................142
viii Contents
3. Plant-Wide Model.......................................................................144
4. Results and Discussions..............................................................146
4.1. Impact of Wash Factors .....................................................149
4.2. Impact of Purge Ratio ........................................................151
5. Conclusions .................................................................................155
References........................................................................................ 156
CHAPTER 7 Advanced multiphase hybrid model development

of fluidized bed wet granulation processes ................159
Ashutosh Tamrakar, Dheeraj R. Devarampally,
Rohit Ramachandran
1. Introduction to Granulation Modeling .......................................159
1.1. Fluid Bed Model Development: Multiphase Flow
and Granulation ..................................................................161
1.2. Different Modeling Techniques .........................................164
2. Multiphase Model Development and Implementation:
Fluidized Bed Wet Granulation..................................................169
2.1. CFD-DEM: Model Development .......................................169
2.2. PBM: Compartmental Model Development ......................172
2.3. CFD-DEM-PBM: Model Implementation .........................175
3. Results and Discussion ...............................................................177
3.1. CFD-DEM Simulation Results...........................................177
3.2. PBM Results and Validation of Hybrid Model .................182
4. Summary .....................................................................................184
References........................................................................................ 184
CHAPTER 8 Global sensitivity, feasibility, and flexibility

analysis of continuous pharmaceutical
manufacturing processes ...................................................189
Zilong Wang, Marianthi Ierapetritou
1. Introduction .................................................................................189
2. Global Sensitivity Analysis ........................................................191
2.1. Methods...............................................................................192
2.2. Visualization of Sensitivity Results ...................................200
3. Feasibility and Flexibility Analysis............................................201
3.1. Methods...............................................................................202
3.2. Visualization of Results......................................................208
3.3. Extensions ...........................................................................209
4. Software ......................................................................................209
5. Conclusion and Future Perspectives...........................................209
References........................................................................................ 211
Contents ix
CHAPTER 9 Crystallization process monitoring and control

using process analytical technology .............................215
Levente L. Simon, Elena Simone, Kaoutar Abbou Oucherif
1. Introduction .................................................................................216
2. QbD and PAT .............................................................................216
3. Liquid- and Solid-Phase Monitoring ..........................................218
3.1. ATR-FTIR and Ultraviolet-Visible Spectroscopy .............218
3.2. Conductivity Measurements ...............................................219
3.3. Refractive Index Measurement ..........................................219
3.4. Turbidity Measurement ......................................................219
3.5. FBRM .................................................................................220
3.6. PVM and Endoscopy..........................................................220
3.7. Raman Spectroscopy ..........................................................221
3.8. Acoustic Spectroscopy (Ultrasound)..................................221
4. Monitoring and Control of Batch Crystallization Processes .....221
4.1. Optimal Switching Between Nucleation and
Seed Ripening Using Control Charts .................................221
4.2. Concentration Feedback Control........................................222
4.3. ADNC .................................................................................224
4.4. Polymorphic Feedback Control..........................................226
4.5. Polymorphic Control by Optimal Solvent Selection .........229
5. Monitoring and Control of Continuous Crystallization
Processes .....................................................................................231
5.1. ADNC of Continuous Crystallization Processes ...............231
5.2. Polymorphic Control in Continuous Crystallization..........234
5.3. Encrustation Monitoring in Continuous Crystallization ....235
References........................................................................................ 237
Further Reading ............................................................................... 242
CHAPTER 10 BioProcess performance monitoring using

multiway interval partial least squares ........................243
Shallon Stubbs, Jie Zhang, Julian Morris
1. Motivation and Background .......................................................243
2. Combining data Unfolding and Interval Splicing Techniques ..244
2.1. Three-Dimensional Data Unfolding...................................244
2.2. Combining Data Unfolding and Interval Splicing.............245
3. Fed-Batch Penicillin Simulator Prediction and Fault
Monitoring...................................................................................248
3.1. Fed-Batch Penicillin Production Process Simulator
Overview.............................................................................248
3.2. Prediction and Process Monitoring ....................................250
x Contents
4. Prediction and Monitoring Results.............................................252

4.1. Predictive Model Performance...........................................252
4.2. Process Performance Monitoring .......................................254
5. Conclusions .................................................................................257
Funding Sources .............................................................................. 258
References........................................................................................ 258
CHAPTER 11 Process dynamics and control of API

manufacturing and purification processes ..................261
Maitraye Sen, Ravendra Singh, Rohit Ramachandran
1. Introduction, Objectives, and Background.................................261
2. Integrated Process .......................................................................264
3. Model Development ...................................................................266
3.1. Population Balance Model .................................................266
3.2. Crystallizer..........................................................................266
3.3. Filter....................................................................................268
3.4. Dryer ...................................................................................269
3.5. Mixer...................................................................................270
3.6. Principal Component Analysis-Based ROM .....................273
3.7. Numerical Technique .........................................................276
4. Design Strategy of the Hybrid MPC-PID and PID Only
Control System............................................................................276
4.1. Hybrid MPC-PID Design ...................................................276
4.2. PID Only Design ................................................................278
4.3. Design of Controller ...........................................................280
4.4. MPC-PID Controller Equations .........................................281
5. Performance of the Hybrid Control System...............................282
5.1. Comparison of Hybrid MPC-PID Scheme With
PID Only Scheme ...............................................................284
6. Conclusions .................................................................................289
References........................................................................................ 290
CHAPTER 12 PAT for pharmaceutical manufacturing process

involving solid dosages forms ..........................................293
Andres D. Román-Ospino, Vanessa Cárdenas,
Carlos Ortega-Zuñiga, Ravendra Singh
1. Introduction .................................................................................293
2. Basics on Near-Infrared Spectroscopy and Scattering Effects ..293
2.1. Spectral Data Pretreatment.................................................295
Contents xi
3. Chemometrics in NIR Monitoring Methods ..............................297

4. Preparation of NIR Calibration Sets...........................................302
5. Sampling for API Concentration Calibration Models ...............304
5.1. “Polymer Film Layers” Model to Study Scattering
in Homogeneous Samples ..................................................307
5.2. Variographic Analysis to estimate the total
sampling error.....................................................................308
6. Real-Time Monitoring of Pharmaceutical Manufacturing
Process Using PAT .....................................................................310
7. Conclusions .................................................................................313
References........................................................................................ 313
CHAPTER 13 Model-based control system design and

evaluation for continuous tablet manufacturing
processes (via direct compaction, via roller
compaction, via wet granulation) ...................................317
Ravendra Singh
1. Introduction .................................................................................318
2. Continuous Tablet Manufacturing Process ................................321
2.1. Process Description ............................................................321
2.2. Process Model.....................................................................323
3. Systematic Framework for Design of Control System ..............324
4. Control Algorithms .....................................................................326
4.1. Proportional Integral Derivative (PID) Controller.............326
4.2. Model Predictive Control (MPC).......................................327
5. Control Strategies .......................................................................329
5.1. Feedback (FB) Control Strategy ........................................329
5.2. Feedforward (FF) Control Strategy....................................330
5.3. Combined Feedforward/Feedback (FF/FB) Control
Strategy ...............................................................................331
6. Design of Control System for Continuous Pharmaceutical
Tablet Manufacturing Process ....................................................334
7. Control of Continuous Direct Compaction (DC)
Process.........................................................................................337
7.1. Classical Regulatory PID-Based Feedback Control ..........337
7.2. Combined Feedforward/Feedback Control Strategy..........339
8. Control of Continuous Tablet Manufacturing Process
via Roller Compaction (RC).......................................................342
xii Contents
9. Control of Continuous Tablet Manufacturing Process

via Wet Granulation (WG) .........................................................344
9.1. Control of Average Granule Size and Bulk Density
(Feedback Control) .............................................................346
9.2. Control of Drug Concentration
(Combined Feedforward/Feedback Control)......................347
10. Conclusions .................................................................................347
References........................................................................................ 348
CHAPTER 14 Fast stochastic model predictive control of

end-to-end continuous pharmaceutical
manufacturing ........................................................................353
Joel A. Paulson, Stefan Streif, Rolf Findeisen,
Richard D. Braatz, Ali Mesbah
1. Introduction .................................................................................353
2. ICM Pharmaceutical Plant Case Study ......................................356
2.2. Plant Simulator ...................................................................359
2.3. Control Problem .................................................................359
3. Problem Formulation ..................................................................360
3.1. The Importance of Accounting for Uncertainty
in MPC................................................................................362
4. Uncertainty Propagation Using Generalized Polynomial
Chaos...........................................................................................363
4.1. Polynomial Chaos Expansions ...........................................363
4.2. Galerkin Projection for Index-1 Stochastic DAEs............. 365
5. Quadratic Dynamic Matrix Control ...........................................367
5.1. Step Response Modeling ....................................................368
5.2. Recursive Update of Model ...............................................368
5.3. Output Feedback Via Disturbance Update Rule................369
6. Fast MPC With Probabilistic Parameter Uncertainty ................370
6.1. Step Response Modeling of Output PCE Coefficients......370
6.2. Objective Function .............................................................371
6.3. Disturbance Update and QP Formulation ..........................372
7. End-to-End Continuous Pharmaceutical Manufacturing Case
Study ...........................................................................................373
8. Conclusions .................................................................................375
References........................................................................................ 375
Contents xiii
CHAPTER 15 Advanced control for the continuous dropwise

additive manufacturing of pharmaceutical
products ....................................................................................379
Elçin Içten, Gintaras V. Reklaitis, Zoltan K. Nagy
1. Introduction .................................................................................379
2. Process Control Strategy.............................................................380
2.1. Low-Level Control System ................................................382
2.2. Surrogate-Model-Based Supervisory Control
System.................................................................................384
2.3. Effect of Critical Process Parameters on
Product Quality...................................................................384
3. Polynomial Chaos Expansion-Based Surrogate Model
Development ...............................................................................388
4. Surrogate-Model-Based Optimization of Temperature
Profiles ........................................................................................395
5. Conclusions .................................................................................399
References........................................................................................ 399
CHAPTER 16 Control system implementation and plant-wide

control of continuous pharmaceutical
manufacturing pilot plant (end-to-end
manufacturing process) ......................................................403
Richard Lakerveld
1. Introduction .................................................................................403
2. Active and Passive Control of Continuous Pharmaceutical
Processes .....................................................................................404
3. Plant-Wide Process Control........................................................408
4. Implementation of Plant-Wide Control for a Case Study
of an End-to-End Continuous Pharmaceutical Process .............410
4.2. Synthesis of a Plant-Wide Control Structure.....................412
4.3. Validation of Plant-Wide Control Strategy Using
Dynamic Simulations .........................................................415
4.4. Experimental Validation of Basic Control Structure.........417
4.5. Performance Optimization Using Advanced
Controllers ..........................................................................422
5. Conclusions and Outlook............................................................425
References........................................................................................ 427
xiv Contents
CHAPTER 17 Automation of continuous pharmaceutical

manufacturing process........................................................431
Ravendra Singh
1. Introduction .................................................................................431
2. Direct compaction Continuous Tablet Manufacturing
Process.........................................................................................432
3. Automation of Direct Compaction Continuous
Pharmaceutical Manufacturing Process......................................433
4. Integration of Feeder With Control Platform.............................434
5. Integration of Blender and Comill With Control Platform .......437
6. Integration of Tablet Press With Control Platform....................438
7. Integration of Variables to Historian..........................................441
9. Conclusions .................................................................................444
References........................................................................................ 445
CHAPTER 18 Implementation of control system into

continuous pharmaceutical manufacturing
pilot plant (powder to tablet) ............................................447
Ravendra Singh
1. Introduction .................................................................................447
2. Systematic Framework for Implementation of the Control
System .........................................................................................449
2.1. Spectroscopic Sensor-Based Control System
Implementation ...................................................................450
2.2. Nonspectroscopic Sensor-Based Control System
Implementation ...................................................................451
3. Case Study: Direct Compaction Continuous Tablet
Manufacturing Process................................................................452
4. Implementation of Control System in Continuous Tablet
Manufacturing Pilot Plant...........................................................453
5. Spectroscopic Sensor-Based Control System: Drug
Concentration Control (Loop 1) .................................................455
5.1. Real-Time Monitoring of Drug Concentration
for Feedback Control..........................................................456
5.2. Implementation of Drug Concentration
Control Loop.......................................................................457
5.3. MPC Model Development for Drug Concentration
Control ................................................................................458
Contents xv
6. Nonspectroscopic Sensor-Based Control System:

Powder-Level Control (Loop 2) .................................................461
6.1. Real-Time Monitoring of Powder Level
and Implementation of Control Loop ................................463
6.2. MPC Model Development for Powder-Level Control ......463
8. Conclusions .................................................................................467
References........................................................................................ 468
CHAPTER 19 Monitoring and control of a continuous

tumble mixer ...........................................................................471
Carlos Velázquez, Miguel Florı́an, Leonel Quiñones
1. Introduction .................................................................................471
1.1. Low Shear Mixing..............................................................471
1.2. Tumble Mixer Operation....................................................473
2. Phenomenological Modeling of Tumble Mixing.......................474
2.1. Batch ...................................................................................474
2.2. Continuous ..........................................................................474
3. Tumble Mixer and Accessories ..................................................475
3.1. Sensors ................................................................................476
3.2. Actuators .............................................................................477
4. Control Strategies .......................................................................477
4.1. API Concentration ..............................................................478
4.2. Relative Standard Deviation...............................................479
4.3. Powder-Flow Rate ..............................................................480
5. Example of Control of a Continuous Tumble Mixer.................480
5.1. Integrated Continuous Mixer System Description.............480
5.2. Results and Discussion .......................................................484
6. Conclusions .................................................................................486
References........................................................................................ 487
CHAPTER 20 Flexible continuous manufacturing—based

on S88 batch standards and object-oriented
design ........................................................................................489
Paul Brodbeck
1. Introduction .................................................................................489
2. Business Case for Multiprocess and Multiproduct Plants .........490
2.1. Pharmaceutical Moving Away From Blockbuster Drugs..490
2.2. Pharmaceutical Industry Shift to CM ................................491
xvi Contents
2.3. Fixed Continuous Process Drawbacks ...............................491

2.4. FDA Supports CM..............................................................492
2.5. Other Government Agency—BARDA,
NSF Supports CM ..............................................................492
3. Object-Oriented Plant Design.....................................................493
3.1. Flexibility/Modular Design/Agile Manufacturing ............. 493
3.2. Object-Oriented Plant Design Defined ..............................494
3.3. Object-Oriented Design Software—History ......................494
3.4. Object-Oriented Design—Class Based ..............................494
3.5. Object-Oriented Design Software—Benefits.....................495
4. Object-Oriented Plant Design—Based on S88 Batch................495
4.1. Class-Based Approach........................................................495
4.2. Batch is the Current State of the Art .................................496
5. S88 Fixed Units—ALIASES ......................................................502
5.1. Flex Batch—Dynamic Links..............................................503
5.2. Flex Plant—Recipe Control ...............................................504
5.3. CM Functionality................................................................505
6. Conclusions .................................................................................513
References........................................................................................ 514
Further Reading ............................................................................... 515
CHAPTER 21 Planning pharmaceutical clinical trials under

outcome uncertainty ............................................................517
Brianna Christian, Selen Cremaschi
1. Introduction .................................................................................519
2. A Mathematical Programming Model for Clinical
Trial Planning Under Perfect Information .................................523
2.1. Definition of Decision Variables .......................................523
2.2. The Objective Function ......................................................524
2.3. Constraints ..........................................................................525
3. A Stochastic Programming Approach to Account for
Clinical Trial Outcome Uncertainty ...........................................526
4. Complexity of the Deterministic Equivalent of the MSSP .......530
5. A Heuristic Decomposition Algorithm Based on Solving
a Series of Two-Stage Stochastic Programs ..............................531
6. A Knapsack Problem-Based Decomposition Approach for
Solving Clinical Trial Planning Problem ...................................533
7. Clinical Trial Planning Case Studies..........................................536
8. Improvements to the Knapsack Problem-Based
Decomposition Approach ...........................................................540
Contents xvii
9. A Parallel Branch-and-Bound Algorithm for Solving

the Clinical Trial Planning MSSP ..............................................543
9.1. Bound Generation...............................................................545
9.2. Results.................................................................................545
10. Conclusions and Future Directions ............................................547
References........................................................................................ 548
CHAPTER 22 Integrated production planning and inventory

management in a multinational pharmaceutical
supply chain............................................................................551
Naresh Susarla, Iftekhar A. Karimi
1. Introduction .................................................................................552
2. Problem Statement......................................................................558
3. Mathematical Formulation..........................................................559
4. Numerical Evaluation .................................................................563
5. Conclusions .................................................................................565
References........................................................................................ 565
CHAPTER 23 Optimal production of biopharmaceutical

manufacturing ........................................................................569
Songsong Liu, Lazaros G. Papageorgiou
1. Introduction .................................................................................572
2. Literature Models Overview.......................................................574
2.1. Deterministic Models .........................................................575
2.2. Stochastic Model ................................................................580
2.3. Summary .............................................................................581
3. Model Extensions........................................................................582
3.1. Optimization with Purity Restriction .................................582
3.2. Biobjective Optimization....................................................585
4. Conclusions .................................................................................586
Appendix.......................................................................................... 587
A.1. Integer Variable Discretization .........................................587
A.2. Chromatography Sequence................................................588
A.3. Protein Mass ......................................................................588
A.4. Resin Volume ....................................................................588
A.5. Flow Rate...........................................................................589
A.6. Product and Buffer Volume ..............................................589
A.7. Processing Time.................................................................590
xviii Contents
A.8. Costs...................................................................................591
A.9. Objective Function.............................................................592
References........................................................................................ 592
CHAPTER 24 Perspective on PSE in pharmaceutical
process development and innovation ............................597
Emmanouil Papadakis, John M. Woodley, Rafiqul Gani
1. Introduction .................................................................................597
2. Integrated Framework for Pharmaceutical Process
Development ...............................................................................600
2.1. Framework Architecture.....................................................600
3. Framework Work Flow and Data Flow .....................................602
3.1. Section A. Reaction Pathway .............................................602
3.2. Section B. Reaction Analysis .............................................603
3.3. Section C. Separation Synthesis.........................................606
3.4. Section D. Process Evaluation ...........................................609
4. Supporting Model-Based Methods and Tools............................614
4.1. Methods...............................................................................614
4.2. Knowledge Databases.........................................................617
4.3. Model Libraries ..................................................................620
4.4. Computational Tools ..........................................................620
5. Application Example: Ibuprofen Synthesis................................621
5.1. Problem Definition .............................................................623
5.2. Section A. Reaction Pathway Identification ......................623
5.3. Section B. Reaction Analysis .............................................628
5.4. Section C. Separation Synthesis.........................................639
5.5. Section D. Process Analysis/Simulation and
Analysis...............................................................................646
5.6. Summary .............................................................................650
6. Concluding Remarks...................................................................650
References........................................................................................ 652
Further Reading ............................................................................... 655
Index.......................................................................................................................657
Contributors
Kaoutar Abbou Oucherif
Eli Lilly and Company, Indianapolis, IN, United States
Laboratoire de G
enie Chimique, Universite de Toulouse, CNRS, Toulouse, France
Brahim Benyahia
Loughborough University, Loughborough, United Kingdom
Richard D. Braatz
Massachusetts Institute of Technology, Cambridge, MA, United States
Paul Brodbeck
QbD Process Technologies, Allendale, NJ, United States
Vanessa Cárdenas
University of Puerto Rico, Mayaguez, PR, United States
Bumjoon Cha
The University of Massachusetts Lowel, Lowell, MA, United States
Brianna Christian
Auburn University, Auburn, AL, United States
Selen Cremaschi
Auburn University, Auburn, AL, United States
Denise M. Croker
University of Limerick, Limerick, Ireland
Dheeraj R. Devarampally
Rutgers, The State University of New Jersey, Piscataway, NJ, United States
Samir A. Diab
University of Edinburgh, Edinburgh, United Kingdom
Rolf Findeisen
Otto von Guericke University Magdeburg, Magdeburg, Germany
Miguel Florı́an
Shaun Galbraith
Rafiqul Gani
Technical University of Denmark, Kgs. Lyngby, Denmark
Dimitrios I. Gerogiorgis
Elçin Içten
Amgen Inc., Cambridge, MA, United States
xix
xx Contributors
Marianthi Ierapetritou
Hikaru G. Jolliffe
Iftekhar A. Karimi
National University of Singapore, Singapore, Singapore
Richard Lakerveld
The Hong Kong University of Science and Technology, Clear Water Bay, Hong
Kong
Huolong Liu
Songsong Liu
Swansea University, Swansea, United Kingdom
Ali Mesbah
University of California, Berkeley, CA, United States
Julian Morris
Newcastle University, Newcastle Upon Tyne, United Kingdom
Zoltan K. Nagy
Purdue University, West Lafayette, IN, United States
Dónal P. O’Brien
Carlos Ortega-Zuñiga
Emmanouil Papadakis
Lazaros G. Papageorgiou
UCL (University College London), London, United Kingdom
Joel A. Paulson
University of California, Berkeley, CA, United States
Leonel Quiñones
Rohit Ramachandran
Gintaras V. Reklaitis
Purdue University, West Lafayette, IN, United States
s D. Román-Ospino
Andre
Contributors xxi
Maitraye Sen
Rahamatullah Shaikh
Levente L. Simon
€nchwilen, Switzerland
Syngenta Crop Protection AG, Mu
Elena Simone
University of Leeds, Leeds, United Kingdom
Ravendra Singh
Stefan Streif
Chemnitz University of Technology, Chemnitz, Germany
Shallon Stubbs
Samsung Display Co., Ltd., Yongin, Republic of Korea
Naresh Susarla
National University of Singapore, Singapore, Singapore
Ashutosh Tamrakar
Carlos Velázquez
Gavin M. Walker
Zilong Wang
John M. Woodley
Seongkyu Yoon
Jie Zhang
Newcastle University, Newcastle Upon Tyne, United Kingdom
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Preface
The pharmaceutical industry is a global business sector with more than $1 trillion
annual sales focusing on performance-based products designed to address the
health care needs of the world’s population. Currently, the pharmaceutical industry
is experiencing a number of significant changes in its business and regulatory
environments. Especially, the pharmaceutical industry is under pressure to mod-
ernize its manufacturing process and to deliver its end products with minimum
time, space, cost, and resources while guaranteeing desirable quality of the prod-
ucts. The pharmaceutical companies are therefore going through a paradigm shift
from traditional manufacturing mode to modernized mode built on cutting-edge
technology and computer-aided methods and tools. Apparently, such shift can
benefit tremendously from the application of methods and tools of process systems
engineering (PSE). Therefore, systematic process and system engineering methods
and tools are needed that can solve the problems related to pharmaceutical industry
more efficiently.
This book elucidates how the PSE methods and tools help and promote the dis-
covery, development, deployment of pharmaceutical products, and the relevant
manufacturing processes. The state-of-the-art computer-aided methods and tools
in PSE field have been described in different chapters that will help to modernize
the pharmaceutical industry and can solve its problems more efficiently. The four
interesting areas where PSE methods and tools can significantly contribute have
been included. These areas are pharmaceutical product and process synthesis and
design; pharmaceutical production process modeling, simulation, analysis, and
optimization; pharmaceutical production process dynamics, control, monitoring,
and operations; and enterprise-wide optimization and supply chain management
for pharmaceutical-manufacturing processes.
Continuous manufacturing (CM) is evolving as a preferred platform for pharma-
ceutical products. One advantage of CM among others is that the product quality can
be controlled in real time and thereby it opens the possibilities of achieving Quality
by Design (QbD), Quality by Control (QbC), and real-time release (RTR) paradigms.
The different types of continuous pharmaceutical manufacturing processes such as
powder to tablet, drop on demand, and end-to-end continuous pharmaceutical
manufacturing processes have been included. The application of PSE for continuous
pharmaceutical manufacturing such as modeling, optimization, automation, sensing,
and control has been systematically illustrated.
This book includes 24 chapters. The first chapter describes the new product
development and supply chains in the pharmaceutical industry. The development
of a pharmaceutical oral solid-dosage form has been described in Chapter 2.
Chapter 3 explains the innovative process development and production concepts
for small-molecule API manufacturing. Plant-wide technoeconomic analysis and
separation solvent selection for continuous active pharmaceutical ingredients
manufacturing has been described in Chapter 4.
xxiii
xxiv Preface
Chapter 5 describes the flowsheet modeling of a continuous direct-compression

pharmaceutical tablet-manufacturing process. A plant-wide dynamic model for the
integrated continuous pharmaceutical manufacturing process including recycle has
been described in Chapter 6. An advanced multiphase hybrid model of fluidized bed
wet granulation processes has been given in Chapter 7. Global sensitivity, feasibility,
and flexibility analysis of continuous pharmaceutical manufacturing processes has
been performed in Chapter 8.
Crystallization process monitoring and control using process analytical tech-
nology has been described in Chapter 9. Bioprocess performance monitoring using
multiway interval partial least squares is given in Chapter 10. Chapter 11 reviews the
process dynamics and control of API manufacturing and purification processes.
PAT for pharmaceutical manufacturing process involving solid dosages forms
is described in Chapter 12. Model-based control system design and evaluation for
continuous pharmaceutical tablet manufacturing via direct compaction, roller com-
paction, and wet granulation routes is given in Chapter 13. Fast stochastic model pre-
dictive control of end-to-end continuous pharmaceutical manufacturing is described
in Chapter 14. Advanced control for the continuous dropwise additive manufacturing
of pharmaceutical products is given in Chapter 15. Control system implementation
and plant-wide control of continuous pharmaceutical manufacturing pilot plant (end-
to-end manufacturing process) is illustrated in Chapter 16. Automation of continuous
pharmaceutical manufacturing process is described in Chapter 17. Implementation of
control system into continuous pharmaceutical manufacturing pilot plant (powder to
tablet) is demonstrated in Chapter 18. Monitoring and control of a continuous tumble
mixer is described in Chapter 19. The applications of S88 batch standards and object-
oriented design for continuous pharmaceutical tablet manufacturing is given in
Chapter 20.
Chapter 21 introduces the optimal planning and scheduling of pharmaceutical
clinical trials. Integrated production planning and inventory management in a mul-
tinational pharmaceutical supply chain is given in Chapter 22. Optimal production of
biopharmaceutical manufacturing is described in Chapter 23. Finally, the perspective
on PSE in pharmaceutical process development and innovation is given in
Chapter 24.
These chapters systematically introduce the use of PSE methods and tools for
discovering, developing, deploying greener, safer, cost-effective, and efficient phar-
maceutical production processes. A wide spectrum of case studies has been described
where different PSE tools and methods have been used to improve various pharma-
ceutical production processes with distinct final products. This book will promote the
applications of process system engineering for pharmaceutical manufacturing and
will serve as a foundation for future research and development of this area.
Ravendra Singh
Rutgers, The State University of New Jersey, Piscataway, NJ, United States of America
CHAPTER
New Product Development

and Supply Chains in the
Pharmaceutical Industry
1
Laboratoire de G
enie Chimique, Universit
e de Toulouse, CNRS, Toulouse, France
1 INTRODUCTION
The dynamics of innovation of a company can be assessed through the life cycle of its
products. Classically, the life cycle of a product includes the phases of development,
launch, growth, maturity, and ends with a stage of decline. The typical features of
these stages depend on the scope of application in which the company is competing.
Whatever the domain, the steps are carried out by a number of functional groups
within the company, including R&D, manufacturing and distribution networks, in
compliance with environmental, safety, and environmental standards as well as
the quality of products developed. In that context, a supply chain has a pivotal role
including all the organizational, operational, and value-adding activities needed to
manufacture products from development to the marketplace and get them to the cus-
tomer. So, a pharmaceutical supply chain covers every activity from new product
development (NPD) through to delivery to the hospital, retail pharmacy, or patient.
The choices of these entities are guided, among others, by strategic decisions
involving the allocation of capital expenditures, economic profitability, marketing
strategies, product and technology portfolio management, supply chain design deci-
sions, including the manufacturing and structure of the distribution network as well
as the selection of strategic partners. The complexity of this environment stems from
the multiple stakeholders and strategic decisions must involve multiple functional
units and integrate the tactical and operational levels of the entire product portfolio.
In the pharmaceutical context, the problem is made difficult by the presence of
several key stakeholders, such as drug manufacturers, wholesale distributors, retail
pharmacies, hospitals, managed care organizations, and insurance companies.
The decisions must be taken in an environment in which both external and inter-
nal uncertainties are encountered: external pressures and uncertainties include, for
example, product demand, price setting, entry of some competitors into the market,
suppliers and buyers, overall economic dynamics, whereas internal uncertainties
result in particular from unexpected technical problems, production deviation due
to the variation in the quality of raw materials, the risks of failure of R&D
activities, etc.
Computer Aided Chemical Engineering, Volume 41, ISSN 1570-7946, https://doi.org/10.1016/B978-0-444-63963-9.00001-4
© 2018 Elsevier B.V. All rights reserved.
1
2 CHAPTER 1 New product discovery and development
This chapter presents the main characteristics of the life cycle of a drug and the
decision-making problems faced by a pharmaceutical company. It discusses some
relevant solution methods of new product portfolio management and pharmaceutical
supply chain design and operation. It identifies the challenges that must be addressed
for the integration of the different levels.
2 TYPICAL FEATURES OF PHARMACEUTICAL INDUSTRY

2.1 ANALYSIS OF THE PRODUCT DEVELOPMENT PROCESS
Within the scope of research and development pipeline management problem, sev-
eral NPD projects compete for a limited pool of various resource types. The discov-
ery and the development of new medicine indeed involve a very long, complex, and
expensive process (Lebret et al., 2010). An average duration of 12 years is required
for the development of a new drug (Torjesen, 2015). The research and development
of molecules in the pharmaceutical industry has thus a central place. The research
and development journey of a new drug that make it to market costs around
US$2.6 Billion according to a study carried out by the Tufts Center for the Study
of Drug Development (Mullard, 2014). These costs particularly increased these last
years with the explosion of the costs of clinical trials (60% increase between 2000
and 2005). Every stage of the process requires a series of tasks before product com-
mercialization. The interconnection of these stages leads to a supply chain by which a
company transfers its products from development to market with the objective to
generate a profit. It includes all the activities of organization, operation, and added
value steps that are necessary for product manufacturing and supply to the customer.
For a pharmaceutical company, these activities can include the development of
the product until the delivery to the hospital, the pharmacy, or to the patient. If a
task leads to a failure, the development of the product is stopped, which can entail
consequent financial losses. A generic sequence of the various tasks is proposed
in Fig. 1.
Preclinical
Exploratory Preclinical
trials: Registration Commercialization
research trials
Phases I, II, and III
10,000 targeted 100 tested

10 drug candidates 1 drug
molecules molecules
5 years
10 R&D years
20 years
Patent Patent
deposit expiration
FIG. 1
Drug development process.
2 Typical features of pharmaceutical industry 3
2.2 LIFE CYCLE OF A DRUG

From an even more macroscopic point of view, three major stages are involved in the
life cycle of a medicine, i.e., discovery, development, and marketing.
First of all, the therapeutic targets related to a pathology must be identified.
Among the families of targets, there are membrane receptors (with two big families,
G protein-coupled receptors (GPCRs) and ionotropic receptors), nuclear receptors,
enzymes, pumps, and the ionic channels. There are at present 330 targets among
which 270 are coded by the genome and 60 stemming from pathogenic bodies for
6500 potential targets: 3500 enzymes (among which 4% are investigated), 1000
channels (2.5% investigated), and 2000 GPCRs (10% investigated). The exploration
of the human genome allowed to increase enormously the potential of new targets
these last years, which will contribute to more specific treatments. Once the target
is validated, it is necessary to elucidate its biological function. The defined target is
then submitted to the action of various substances to isolate the most promising com-
ponent, according to a “screening” stage. The selected molecule can result from a
database, a biomedical research, or from a modification of the structure of a preex-
istent active ingredient. Then, the chemical and biological assay run follows to dem-
onstrate the selectivity, the safety, and the efficiency of the studied molecule.
The tests are practiced at first in vitro, then studies to the animal (pharmacolog-
ical, pharmacokinetic, pharmacodynamical, toxicological) are led to investigate the
behavior and confirm the harmlessness of the candidate drug.
If all the obtained results are positive, the clinical tests can thus be conducted on
healthy volunteers then on first patients. This phase of development involves very
important material resources.
Phase I. In this stage, first clinical trials are carried out and drugs are administered
to healthy volunteers. At the same time, acute/chronic and reproductive studies
are also conducted in animals (mice/rats). Positive results will allow to the drug to
go on the process, whereas an unacceptable behavior in human and animal studies
can terminate the study.
Phase II. The Drug is administered to unhealthy human patients with the disease
by using the results of dosing studies from Phase I. Coincident with these
studies are long-term oncogenic toxicological studies in animals and market
research to obtain sales estimates. If the compound fails to treat the disease or is
inferior to competitive products, it is destaged or returned to the discovery phase
for modification.
Phase III. Large-scale clinical studies are carried out on unhealthy human
patients. The FDA (Food and Drug Administration) is involved and indicates
benchmarks for giving their approval. In addition to confirming the efficiency,
these studies identify drug-drug interactions, human demographics, etc. This
most expensive phase of the development process requires extensive global
coordination and cooperation. The results should confirm what was learned in
Phase II but on a much larger scale; otherwise, the compound may be terminated.
4 CHAPTER 1 New product discovery and development
First submission for approval. All information (efficacy, toxicology, process,

drug-drug interactions, side effects, etc.) obtained is gathered and submitted to
the FDA. In the United States, drugs are approved by the FDA, in Europe by the
European Medicines Agency (EMA). The approval through these central
authorities is recognized by numerous countries.
Simultaneously, the marketing strategy is evolving, price negotiations are being con-
ducted with suppliers/distributors, and promotional materials are being developed.
The building of a commercial plant is in progress. Approval for selling the new drug
is the anticipated outcome.
Prelaunch activities. This is the final stage before launch-approval has been
received from FDA; a global penetration strategy has been completed; the
commercial plant has been built and started up; the promotional campaign
launched. This phase ends when the new drug is distributed.
Launch activities. The product is launched over a period of years in various global
markets until mature sales levels are reached the ramp-up period. Mature sales are
maintained until patents expire or competition is carried out either from
competitors or planned cannibalization.
Product supply chain activities. Sample preparation, process research, process
development, process design, and plant construction occur simultaneously with
other development activities (see Fig. 2). Initial focus is on preparing sufficient
sample material for various animal/human studies. Once the launch prospects
Capital and operational expenditures (CAPEX, OPEX)

Development activity
Supply chain deploymen
activity
Prelaunch activity
First FP1 FP2 FP3
Clinical trials Clinical trials Clinical trials
Launch activity human dose
preparation Phase I Phase II Phase III
Discovery of a
? ? ?
drug candidate
Sample Process Process

Plant design
preparation development I development II
Total duration:
Plant
10–18 years
building
Sale Sale
Mature sales Sale ramp up I
ramp up III ramp up II
First
Prelaunch I submission
for approval
Profits Capital and operational expenditures (CAPEX, OPEX)
Falilure probability Falilure probability Falilure probability

FP1 FP2 FP3
Phase I of clinical trials Phase II of clinical trials Phase III of clinical trials
FIG. 2
Drug life cycle.
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7.
Who tooke to wife as yee shall vnderstand

A mayden of a noble house and olde,
Raulfe Neuil’s daughter, earle of Westmerland,
Whose sonne earle Richard, was a baron bolde,
And had the right of Salisbury in holde,
Through mariage made with good earle Thomas heyre,
Whose earned prayses neuer shall appayre.
8.
The duke my father had by this his wife

Four sonnes, of whom the eldest Edward hight,
The second Eadmund, who [in youth] did loose his life,
[1174]
At Wakefielde slayne by Clyfford cruell knight:
I George am third, of Clarence duke by right:
The fourth, borne to the mischiefe of vs all,
Was duke of Glocester,[1175] whom men did[1176]
Richard call.
9.
Whan as our sire in sute of right was slaine,

(Whose life and death himselfe declared earst)
My brother Edward plyed his cause amayne,[1177]
And got[1178] the crowne, as Warwicke hath rehearst:
The pride whereof so deepe his stomacke pearst
That hee forgot his friendes, dispisde his kin,
Of oth or office passing not a pyn.[1179]
10.
Which made the earle of Warwicke to maligne

My brother’s state,[1180] and to attempt a way
To bring from prison Henry, seely king,
To helpe him to the kingdome[1181] if hee may,
And knowing mee to bee the chiefest stay
My brother had, hee did mee vndermine
To cause mee to his treasons to encline.[1182]
11.
Whereto I was prepared long before,

My brother had beene to mee so vnkinde:
For sure no cankar fretteth flesh so sore,[1183]
As vnkinde dealing doth a louing minde:
Loue’s strongest bandes vnkindnes doth vnbinde,
It moueth loue to malice, zeale to hate,
Chiefe friendes to foes, and brethren to debate.
12.
And though the earle of Warwicke, subtile sire

Perceiude I bare a grudge against my brother,
Yet toward his feate to set mee more on fire,
Hee kindled vp one firebrand with another:
For knowing fancy was the forcing rother
Which stirreth youth to any kinde of strife,
Hee offered mee his daughter to my wife.
13.
Where through, and with his crafty filed tongue,

Hee stale my heart that earst vnsteady was,
For I was witlesse, wanton, fond and yong,
Whole bent to pleasure, brittle as the glasse,
I can not lye, In vino veritas:
I did esteeme the bewty of my bryde
Aboue my selfe, and all the world beside.
14.
These fond affections ioynd with lacke of skill,

(Which trap the heart, and blind the eyes of youth,
And pricke the minde to practise any ill)
So tickled mee, that voyde of kindly truth,
(Which if it want all wretchednes[1184] ensueth)
I stinted not to persecute my brother,
Til time hee left his kingdom to another.
15.
Thus carnall loue did quench the loue of kinde,

Till lust were lost through fancy fully fed:
But whan at length I came vnto my minde,
I saw how lewdly lightnes had mee led,
To seeke with payne the perill of my heade:
For had king Henry once beene setled sure,
I was assurde my dayes could not endure.
16.
And therefore, though I bound my selfe with[1185] oth

To help king Henry all that euer[1186] I might,
Yet at the treaty of my brethren both,
Which reason graunted to require but right:
I left his part, whereby hee perisht quite:
And reconcilde mee to my brethren twayne,
And so came Edward to the crowne agayne.
17.
This made my father[1187] in law to fret and fume,

To stamp and stare, and call mee false forsworne,
And at the length with all his power, presume
To help king Henry, vtterly forlorne:
Our friendly proffers still hee tooke in scorne,
Refused peace, and came to Barnet fielde,
And there was kild, because hee would not yeelde.
18.
His brother also there with him was slayne,

Whereby decayed the keyes of chiualrye:
For neuer liu’d the matches of them twayne,
In manhood, power, and martiall pollecy,
In vertuous thewes, and friendly constancy,
That would to God, if it had bene his will,
They might haue tournde to vs and liued still.
19.
But what shalbe, shall bee: there is no choyse,

Thinges needes must driue as desteny decreeth,
For which wee[1188] ought in all our haps reioyce,
Because the eye eterne all things foreseeth
Which to no ill at any tyme agreeth,
For ills, to ill to vs, be good to it,
So far his skill’s exceede our reach of wit.
20.
The wounded man which must abyde the smart

Of stitching vp, or searing of his sore,
As thing to bad, reproues the surgeon’s art
Which not withstanding doth his health restore.
The childe likewise to science plied sore,
Counts knowledge ill, his teacher to be wood,
Yet surgery and sciences be good.
21.
But as the pacient’s griefe and scholer’s payne,

Cause them deme bad such things as sure be best,
So want of wisdome causeth vs complaine
Of euery hap, wherby we seme opprest:
The poore doe pine for pelfe, the rich for rest,
And when as losse or sicknesse vs assayle
We curse our fate, our fortune we bewayle.
22.
Yet for our good, God worketh euery thing:

For, through the death of these two noble peres,
My brother liu’d and raynde a quiet king,
Who, had they liued, perchaunce in course of years
Would haue deliuered Henry fro the breres,
Or holpe his sonne t’[1189]enioy the carefull crowne,
Wherby our line should haue bene quite put downe.
23.
A carefull crowne it may be iustly named,

Not onely for the cares thereto annext,[1190]
To see the subiect well and duly framed,
With which good care few kings are greatly vext,
But for the dred wherwith they are perplext,
Of losing lordship, liberty, or life:
Which wofull wracks in kingdoms happen ryfe.
24.
The which to shun while some to sore haue sought,

They haue not sparde all persons to suspect:
And to destroy such as they gilty thought,
Though no apparaunce proued them infect.
Take me for one of this wrong punisht sect,
Imprisonde first, accused without cause,
And done to death, no processe had by lawes.
25.
Wherin I note how vengeaunce doth acquite

Like yll for yll, how vices vertue quell:
For as my mariage loue did me excite
Agaynst the king my brother to rebell,
So loue to haue his children prosper well,
Prouoked him, agaynst both law and right,
To murder me, his brother, and his knight.
26.
For by his queene two princelyke sonnes he had,

Borne to be punisht for their parent’s synne:
Whose fortunes kalked made the father sad,
Such wofull haps were found to be therin:
Which to auouch, writ in a rotten skin,
A prophesie was found, which sayd, a G
Of Edward’s children should destruction bee.
27.
Mee to bee G, because my name was George,

My brother thought, and therefore did mee hate,
But woe be to the[1191] wicked heads that forge
Such doubtfull dreames to breede vnkinde debate:
For God, a gleue, a gibbet, grate, or gate,
A Gray, a Griffeth, or a Gregory,
As well as George, are written with a G.
28.
Such doubtfull riddles are no prophesies:

For prophesies, in writing though obscure,
Are playne in sence, the darke be very lies:
What God foresheweth is euident and pure,
Truth is no harold nor noe sophist sure:
She noteth not men’s names, their shieldes, nor
creasts,
Though she compare them vnto byrds and beasts.
29.
But whom she doth forshewe shall rayne by force,

She tearms a wolfe, a dragon, or a beare:
A wilfull prince, a raynlesse ranging[1192] horse:
A bold, a lion: a cowarde much in feare,
A hare or harte: a crafty, pricked eare:
A leacherous, a bull, a goate, a foale:
An vndermyner, a moldwarpe, or a mole.
30.
By knowen beastes thus truth doth playne declare

What men they be of whom shee speakes before:
And who so can men’s properties compare
And marke what beast they doe resemble more:
Shall soone discerne who is the griesly bore:
For God by beastes expresseth men’s condicions,
And not theyr badges, haroldes supersticions.
31.
And learned Merlyne, whom God gaue[1193] the sprite

To know and vtter princes actes to come,
Like to the Iewish prophets, did recite
In shade of beastes, theyr doings all and some,
Expressing plaine by maners of the dome,
That kinges and lordes such propertyes should haue
As haue the beastes whose name he to them gaue.
32.
Which while the foolish did not well consider,

And seeing princes gaue, for difference
And knowledge of theyr issues mixt together,
All maner beastes for badges of pretence,
There tooke those badges to expresse the sence
Of Merlyne’s minde, and those that gaue the same,
To bee the princes noted by theyr name.
33.
And hereof sprang the false namde prophesies,
That goe by letters, siphers, armes, or sines:
Which all bee foolish, false, and crafty lyes,
Deuisde by gesse, or guiles vntrue deuines:
For whan they saw that many[1194] of many lynes
Gaue[1195] armes alyke, they wist not which was hee
Whom Merlyne ment the noted beast to bee.
34.
For all the broode of Warwicke’s gaue the beare,

The Buckinghams doe likewise gieue the swan:
But which beare bearer should the lyon teare
They were as wise as Goose the fery man:
Yet in theyr skill they ceased not to scan,
And to bee deemed of the people wise,
Set forth theyr gloses vpon[1196] prophesies.
35.
And whome they douted openly to name

They darkely tearmed or by some letter ment,
For so they thought, how euer the world did frame,
Preserue themselues from shame, or being shent:
For, howsoeuer contrary it went,
They might expound their meaning otherwise,
As haps in things should newely still arise.
36.
And thus there grewe of a mistaken truth,

An art so false as made the true suspect:
Whereof hath come much mischiefe, more the ruth
That errours should our mindes so much infect,
True prophets[1197] haue fowly beene reiect:
The false, which breede both murder, warre, and strife,
Beleeued to the losse[1198] of many a good man’s life.
37.
And therefore, Baldwine, teach men to discerne,

Which prophecies be false and which bee true:
And for a ground this lesson let them learne,
That all bee false which are deuised newe:
The age of thinges are iudged by the hue:
All riddels made by letters, names or armes,
Are yong and false, far worse then witche’s charmes.
38.
I knowe thou musest at this lore of mine,

How I, no studient, should haue learned it:
And dost impute it to the fume of wine
That stirs the tongue, and sharpneth vp the wit:
But harke, a friend did teach mee euery whit,
A man of mine, in all good knowledge rife,
For which hee guiltlesse lost his learned life.
39.
This man abode my seruaunt many a day,

And still in study set his whole delight:
Which taught mee more then I could beare away
Of euery arte: and by his searching sight
Of thinges to come hee would foreshew as right,
As I rehearse the pageants that were past:
Such perfectnes God gaue him at the last.
40.
He knew my brother Richard was the bore,

Whose tuskes should teare my brother’s boyes and me,
And gaue me warning therof long before:
But wyt nor warning can in no degree
Let thinges to hap, which are ordainde to bee:
Witnesse the painted lionesse, which slue
A prince imprisoned, lyons to eschewe.
41.
He told me eke[1199] my yoke fellow should dy,

(Wherin would God he had bene no deuyne)
And after her death I[1200] should woo earnestly
A spouse, wherat my brother would repine,
And finde the meanes she should be none of[1201] mine:
For which such malice should among vs ryse,
As saue my death no treaty should decise.
42.
And as he sayd, so all things came to passe:

For whan king Henry and his sonne were slaine,
And euery broyle so throughly quenched was
That the king my[1202] brother quietly did raygne,
I, reconciled to his loue agayne,
In prosperous health did leade a quiet lyfe,
For fiue yeares space with honours laden rife.
43.
And to augment the fulnesse of my blisse,

Two louely children by my wife I had:
But froward hap, whose maner euer is
In chiefest ioy to make the happy sad,
Bemixt my sweete with bitternes too bad:
For while I swam in ioyes on euery side,
My louing wife, my cheifest iewell dyed.
44.
Whose lacke whan sole I had bewaylde a yeare,

The duke of Burgoine’s wife, dame Margarete,
My louing sister willing me to chere,
To mary[1203] agayne did kindely me intreate:
And wisht me matched with a mayden nete,
A step daughter of her’s, duke Charles’ hayre,[1204]
A noble damsell, yong, discrete and fayre.
45.
To whose desire because I did enclyne,

The king my brother douting my degree
Through prophesies, against vs did repyne,
And at no hand would to our wills agree:
For which such rancoure pearst both him and mee,
That face to face we fell at flat defiaunce,
But were appeased by frends of our aliaunce.
46.
Howbeit my mariage vtterly was dasht:

Wherin because my seruant sayd his minde,
A meane was sought wherby he mought[1205] be lasht:
And, for they could no crime agaynst him fynd,
They forgde a fault the people’s eyes to blinde,
And told he should by sorceries pretend
To bring the king vnto a spedy ende.
47.
Of all which poynts he was as innocent

As is the babe that lacketh kindely breth:
And yet condemned by the king’s assent,
Most cruelly put to a shamefull death:
This fierd my hart, as foulder doth the heath:
So that I could not but exclame and cry,
Agaynst so great and open iniury.
48.
For this I was commaunded to the tower,

The king my brother was so cruel harted,
And when my brother Richard saw the hower
Was come, for which his hart so sore had smarted,
He thought it best take time before it parted:
For he endeuoured to attayne the crowne,
From which my life must nedes haue held him downe.
49.
For though the king within a while had died,

As nedes he must, he surfayted so oft,
I must haue had his children in my guyde,
So Richard should besyde the crowne haue coft:
This made him ply the while the wax was soft,
To finde a meane to bring me to an ende,
For realm-rape spareth neyther kin nor frend.
50.
And whan hee sawe how reason can asswage

Through length of time my brother Edward’s ire,
With forged tales hee set him newe in rage,
Till at the last they did my death conspire:
And though my truth sore troubled their desire,
For all the world did knowe mine innocence,
Yet they agreede to charge mee with offence.
51.
And, couertly, within the tower they calde

A quest, to geue such verdite as they should:
Who what with feare and what with fauour thralde,
Durst not pronounce but as my brethren would:
And though my false accusers neuer could
Proue ought they sayd, I guiltlesse was condemned:
Such verdites passe where iustice is contemned.
52.
This feate atchiued, yet could they not for shame
Cause mee bee kild by any[1206] common way,
But like a wolfe the tyrant Richard came,
(My brother, nay my butcher I may say)[1207]
Unto the tower when all men were away,[1208]
Saue such as were prouided for the feate:
Who in this wise did straungely mee entreate.
53.
His purpose was with a prepared string

To strangle mee: but I bestird mee so,
That by no force they could mee therto bring,
Which caused him that purpose to forgo:
Howbeit they bound mee, whether I would or no,
And in a but of malmesey standing by,
Newe christned mee, because I should not cry.[1209]
54.
Thus drownde I was, yet for no due desert,

Except the zeale of justice bee a crime:
False prophecies bewitcht king Edward’s hart,
My brother Richard to the crowne would clime:
Note these three causes in thy rufull rime,
And boldly say they did procure my fall,
And death of deaths most straunge and hard of all.
55.
And warne all[1210] princes prophecyes to eschue,

That are to darke and doubtfull to be knowen:
What God hath sayd, that cannot but ensue,
Though all the worlde would haue it ouerthrowne:
When men suppose by fetches of theyr owne
To fly[1211] theyr fate, they furder on the same,
Like quenching blastes which[1212] oft reuiue the flame.
56.
Will princes therefore, not to thinke by murder

They may auoyde what prophecyes behight,
But by theyr meanes, theyr mischiefes they may furder,
And cause God’s vengeaunce heauier to alight:
Woe worth the wretch that striues with God’s foresight:
They are not wise, but wickedly do arre,
Which thinke yll deedes due destenies may barre.
57.
For if wee thinke that prophecyes be true,

We must beleue it cannot but betyde,
Which God in them foresheweth shall ensue,
For his decrees vnchaunged doe abide:
Which to be true my brethren both haue tryed,
Whose wicked warkes warne princes to detest,
That other’s harmes may keepe them better blest.[1213]
[By that this tragedy was ended, night was so nere come that
wee could not conueniently tary together any longer: and therefore
sayd maister Ferrers: “It is best my maisters to stay here. For wee be
come now[1214] to the end of Edward the fourth’s raigne.[1215] For
the last whom wee finde vnfortunate therein, was the duke of
Clarence: in whose behalfe I commend much that which hath bene
noted. Let vs therefore for this time leaue with him, and this day
seauen nights hence, if your busines will so suffer, let vs all meete
here together[1216] agayne. And you shall see that in the meane
season I will not only deuise vpon this my selfe, but cause diuers
other of my acquayntance, which can doe very well, to helpe vs
forwarde with the rest.” To this euery man gladly agreed. “Howbeit,”
sayd[1217] another, “seing we shall end at Edward the fourth’s end,
let himselfe make an ende of our daye’s labour, with the same
oration which maister Skelton made in his name, the tenour whereof,
so far as I remember, is as foloweth.”][1218]
Howe King Edward the fourth[1219]
through his surfeting and
vntemperate life, sodaynly dyed in the
middest of his prosperity, the nynth of
Aprill, Anno 1483.
1.
Miseremini mei yee that bee my frendes,

This world hath formed mee downe to fall:
How may I endure whan that euery thing ends?
What creature is borne to be eternall?
Now there is no more but pray for mee all,
Thus say I, Edward, that late was your king,
And twenty-two[1220] yeares ruled this imperiall,[1221]
Some vnto pleasure and some to no lyking:
Mercy I aske of my misdoyng,
What avayleth it frendes to bee my foe?
Sith I cannot resist, nor amend your complayning,
Quia ecce[1222] nunc in puluere dormio.
2.
I sleepe now in mould as it is naturall,

As earth vnto earth hath his reuerture:
What ordayned God to bee terrestriall,[1223]
Without recourse to the earth by nature?
Who to liue euer may himselfe assure?
What is it to trust to mutability?
Sith that in this worlde nothing may endure:
(For now am I gone that was late in prosperity)
To presume thereuppon it is but[1224] vanity:
Not certayne, but as a chery fayre full of wo:
Raigned not I of late in great prosperity?[1225]
Et ecce in nunc puluere dormio.
3.
Where was in my life such an one as I,

While lady fortune had with me[1226] continuaunce:
Graunted not shee mee to haue victory,
In England to raigne and to contribute Fraunce?
Shee tooke mee by the hand and led me a daunce,
And with her sugred lips on mee shee smyled,
But what for dissembled countenaunce,
I could not beware till I was beguyled:
Now from this world shee hath mee exiled,
Whan I was lothest hence for to goe,
And am in age as[1227] (who sayth) but a childe,
Et ecce nunc in puluere dormio.
4.
I had enough, I held mee not content,

Without remembraunce that I should dye:
And moreouer to encroch redy was I bent,
I knew not how long I should it occupye,
I made the towre strong, I wist not why:
I knew not to whom I purchased Tartersall:
I mended Douer on the mountayne hye:
And London I prouoked to fortify the wall:
I made Notingham a place full royall:
Windsore, Eltam, and many other mo,
Yet at the last I went from them all,
5.
Where is now my conquest and victory?
Where is my riches and royall array?
Where be my coursers and my horses hye,
Where is my myrth, my solace, and my play?
As vanity to nought all[1228] is wythered away:
O lady Bes long for mee may you call,
For I am departed vntill dome’s day:
But loue you that lord that is soueraine of all:
Where bee my castles and buildings royall?
But Windsore alone now haue I no moe,
And of Eton the prayers perpetuall,
6.
Why should a man bee prowde or presume hye?

Saint Bernard thereof nobly doth treate,
Saying a man is but a sacke of stercory,
And shall retourne vnto wormes meate:
Why, what became of Alexander the great?
Or else of strong Sampson, who can tell?
Were not wormes ordaynde theyr flesh to freate?
And of Salomon that was of wit the well,
Absolon preferred his hayre for to sell,
Yet for his bewty wormes eate him also,
And I but late in honoures did excell,
7.
I haue played my pageant, now am I past,

Yee wot well all I was of no great elde:
Thus all thing concluded shalbe at the last,
When death approcheth then lost is the fielde:
Then seing this world me no longer vpheld,
(For nought would conserue mee here in this place)
In manus tuas Domine my spirit vp I yeelde,
Humbly beseeching thee, O God, of thy grace,
O you courteous commons your heartes embrace,
Beningly now to pray for mee also,
For right well you[1229] know your king I was:
Et ecce nunc in puluere dormio.[1230]
[Whan this was sayd, euery man for that[1231] time tooke his
leaue of other, and departed (for then it waxed darke) appointing a
new day of meeting, which being come, we met all together againe.
And whan we had saluted one another, then one tooke the booke,
and began to read the story of king Edward the fifte: (for there wee
left) and when hee came to the apprehending of the lord Riuers:
“Stay there I pray you,” sayd I, “for here is his complaint. For the
better vnderstanding whereof, you must imagine that he was
accompanied with the lord Richard Gray, Hawt, and Clappam,
whose infortunes hee bewaileth after this maner.”]

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Process Systems Engineering for

Pharmaceutical Manufacturing 1st

For information on all Elsevier publications

Publisher: Susan Dennis

CHAPTER 1 New Product Development and Supply Chains

CHAPTER 2 The development of a pharmaceutical oral

3.3. Disintegrating Agents ...........................................................41

CHAPTER 3 Innovative process development and

CHAPTER 4 Plantwide technoeconomic analysis and

CHAPTER 5 Flowsheet modeling of a continuous direct

CHAPTER 6 Applications of a plant-wide dynamic model of

CHAPTER 7 Advanced multiphase hybrid model development

CHAPTER 8 Global sensitivity, feasibility, and flexibility

CHAPTER 9 Crystallization process monitoring and control

CHAPTER 10 BioProcess performance monitoring using

4. Prediction and Monitoring Results.............................................252

CHAPTER 11 Process dynamics and control of API

CHAPTER 12 PAT for pharmaceutical manufacturing process

3. Chemometrics in NIR Monitoring Methods ..............................297

CHAPTER 13 Model-based control system design and

9. Control of Continuous Tablet Manufacturing Process

CHAPTER 14 Fast stochastic model predictive control of

CHAPTER 15 Advanced control for the continuous dropwise

CHAPTER 16 Control system implementation and plant-wide

CHAPTER 17 Automation of continuous pharmaceutical

CHAPTER 18 Implementation of control system into

6. Nonspectroscopic Sensor-Based Control System:

CHAPTER 19 Monitoring and control of a continuous

CHAPTER 20 Flexible continuous manufacturing—based

2.3. Fixed Continuous Process Drawbacks ...............................491

CHAPTER 21 Planning pharmaceutical clinical trials under

9. A Parallel Branch-and-Bound Algorithm for Solving

CHAPTER 22 Integrated production planning and inventory

CHAPTER 23 Optimal production of biopharmaceutical

Chapter 5 describes the flowsheet modeling of a continuous direct-compression

New Product Development

2 TYPICAL FEATURES OF PHARMACEUTICAL INDUSTRY

10,000 targeted 100 tested

2.2 LIFE CYCLE OF A DRUG

First submission for approval. All information (efficacy, toxicology, process,

Capital and operational expenditures (CAPEX, OPEX)

Sample Process Process

Profits Capital and operational expenditures (CAPEX, OPEX)

Falilure probability Falilure probability Falilure probability

Who tooke to wife as yee shall vnderstand

The duke my father had by this his wife

Whan as our sire in sute of right was slaine,

Which made the earle of Warwicke to maligne

Whereto I was prepared long before,

And though the earle of Warwicke, subtile sire

Where through, and with his crafty filed tongue,

These fond affections ioynd with lacke of skill,

Thus carnall loue did quench the loue of kinde,

And therefore, though I bound my selfe with[1185] oth

This made my father[1187] in law to fret and fume,

His brother also there with him was slayne,

But what shalbe, shall bee: there is no choyse,

The wounded man which must abyde the smart

But as the pacient’s griefe and scholer’s payne,

Yet for our good, God worketh euery thing:

A carefull crowne it may be iustly named,

The which to shun while some to sore haue sought,

Wherin I note how vengeaunce doth acquite