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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
Acknowledgments ........................................................................... 210
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
Acknowledgments ........................................................................... 290
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
Acknowledgments ........................................................................... 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
Acknowledgments ........................................................................... 348
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
2.1. Process Description ............................................................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
Acknowledgments ........................................................................... 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
4.1. Process Description ............................................................411
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
8. Results and Discussion ...............................................................441
9. Conclusions .................................................................................444
Acknowledgments ........................................................................... 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
7. Results and Discussion ...............................................................465
8. Conclusions .................................................................................467
Acknowledgments ........................................................................... 468
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
Acknowledgments ........................................................................... 487
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
Acknowledgments ........................................................................... 548
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
Acknowledgments ........................................................................... 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
Acknowledgments ........................................................................... 587
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
Catherine Azzaro-Pantel
Laboratoire de G

enie Chimique, Universit
e 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
University of Puerto Rico, Mayaguez, PR, United States
Shaun Galbraith
The University of Massachusetts Lowel, Lowell, MA, United States
Rafiqul Gani
Technical University of Denmark, Kgs. Lyngby, Denmark
Dimitrios I. Gerogiorgis
University of Edinburgh, Edinburgh, United Kingdom
Elçin Içten
Amgen Inc., Cambridge, MA, United States

xix
Another random document with
no related content on Scribd:
You will not easily make me credit that.

Phœbe.

Ask her.

Enter Camma as Priestess (in front of the curtains).

Priestess.

You will not marry Synorix?

Camma.

My girl, I am the bride of Death, and only

Marry the dead.

Priestess.

Not Synorix then?

Camma.

My girl,
At times this oracle of great Artemis
Has no more power than other oracles
To speak directly.

Phœbe.

Will you speak to him,

The messenger from Synorix who waits
Before the Temple?

Camma.

Why not? Let him enter.

[Comes forward on to step by tripod.

 Enter a Messenger.

Messenger (kneels).

Greeting and health from Synorix! More than once

You have refused his hand. When last I saw you,
You all but yielded. He entreats you now
For your last answer. When he struck at Sinnatus—
As I have many a time declared to you—
He knew not at the moment who had fasten’d
About his throat—he begs you to forget it
As scarce his act:—a random stroke: all else
Was love for you: he prays you to believe him.

Camma.

I pray him to believe—that I believe him.

Messenger.

Why that is well. You mean to marry him?

Camma.

I mean to marry him—if that be well.

Messenger.

This very day the Romans crown him king

For all his faithful services to Rome.
He wills you then this day to marry him,
And so be throned together in the sight
Of all the people, that the world may know
You twain are reconciled, and no more feuds
Disturb our peaceful vassalage to Rome.

Camma.

To-day? Too sudden. I will brood upon it.

When do they crown him?

Messenger.

Even now.

Camma.

And where?

Messenger.

Here by your temple.

Camma.

Come once more to me

Before the crowning,—I will answer you.

[Exit Messenger.

Phœbe.

Great Artemis! O Camma, can it be well,

Or good, or wise, that you should clasp a hand
Red with the sacred blood of Sinnatus?

Camma.

Good! mine own dagger driven by Synorix found

All good in the true heart of Sinnatus,
And quench’d it there for ever. Wise!
Life yields to death and wisdom bows to Fate,
Is wisest, doing so. Did not this man
Speak well? We cannot fight imperial Rome,
But he and I are both Galatian-born,
And tributary sovereigns, he and I
Might teach this Rome—from knowledge of our people—
Where to lay on her tribute—heavily here
And lightly there. Might I not live for that,
And drown all poor self-passion in the sense
Of public good?

Phœbe.

I am sure you will not marry him.

Camma.

Are you so sure? I pray you wait and see.

[Shouts (from the distance), “Synorix!

Synorix!”

Camma.

Synorix, Synorix! So they cried Sinnatus

Not so long since—they sicken me. The One
Who shifts his policy suffers something, must
Accuse himself, excuse himself; the Many
Will feel no shame to give themselves the lie.

Phœbe.

Most like it was the Roman soldier shouted.

Camma.

Their shield-borne patriot of the morning star

Hang’d at mid-day, their traitor of the dawn
The clamour’d darling of their afternoon!
And that same head they would have play’d at ball with,
And kick’d it featureless—they now would crown.

[Flourish of trumpets.

Enter a Galatian Nobleman with crown on a cushion.

 Noble (kneels).

Greeting and health from Synorix. He sends you

This diadem of the first Galatian Queen,
That you may feed your fancy on the glory of it,
And join your life this day with his, and wear it
Beside him on his throne. He waits your answer.

Camma.

Tell him there is one shadow among the shadows,

One ghost of all the ghosts—as yet so new,
So strange among them—such an alien there,
So much of husband in it still—that if
The shout of Synorix and Camma sitting
Upon one throne, should reach it, it would rise
He!... He, with that red star between the ribs,
And my knife there—and blast the king and me,
And blanch the crowd with horror. I dare not, sir!
Throne him—and then the marriage—ay and tell him
That I accept the diadem of Galatia—

[All are amazed.

Yea, that ye saw me crown myself withal.

[Puts on the crown.

I wait him his crown’d queen.

Noble.

So will I tell him.

[Exit.

Music. Two Priestesses go up the steps before the shrine,

draw the curtains on either side (discovering the Goddess), then
open the gates and remain on steps, one on either side, and
kneel. A Priestess goes off and returns with a veil of marriage,
then assists Phœbe to veil Camma. At the same time
Priestesses enter and stand on either side of the Temple.
Camma and all the Priestesses kneel, raise their hands to the
Goddess, and bow down.

[Shouts, “Synorix! Synorix!” All rise.

Camma.

Fling wide the doors, and let the new-made children

Of our imperial mother see the show.

[Sunlight pours through the doors.

I have no heart to do it. (To Phœbe). Look for me!

[Crouches. Phœbe looks out.

[Shouts, “Synorix! Synorix!”

Phœbe.

He climbs the throne. Hot blood, ambition, pride

So bloat and redden his face—O would it were
His third last apoplexy! O bestial!
O how unlike our goodly Sinnatus.

Camma (on the ground).

You wrong him surely; far as the face goes

A goodlier-looking man than Sinnatus.

Phœbe (aside).

How dare she say it? I could hate her for it

But that she is distracted.

[A flourish of trumpets.
 Camma.

Is he crown’d?

Phœbe.

Ay, there they crown him.

[Crowd without shout, “Synorix!

Synorix!”

Camma (rises).

[A Priestess brings a box of spices to

Camma, who throws them on the
altar flame.

Rouse the dead altar-flame, fling in the spices,

Nard, cinnamon, amomum, benzoin.
Let all the air reel into a mist of odour,
As in the midmost heart of Paradise.
Lay down the Lydian carpets for the king.
The king should pace on purple to his bride,
And music there to greet my lord the king.

[Music.

(To Phœbe.) Dost thou remember when I wedded Sinnatus?

Ay, thou wast there—whether from maiden fears
Or reverential love for him I loved,
Or some strange second-sight, the marriage-cup
Wherefrom we make libation to the Goddess
So shook within my hand, that the red wine
Ran down the marble and lookt like blood, like blood.

Phœbe.

I do remember your first-marriage fears.

 Camma.

I have no fears at this my second marriage.

See here—I stretch my hand out—hold it there.
How steady it is!

Phœbe.

Steady enough to stab him!

Camma.

O hush! O peace! This violence ill becomes

The silence of our Temple. Gentleness,
Low words best chime with this solemnity.

Enter a procession of Priestesses and Children bearing

garlands and golden goblets, and strewing flowers.

Enter Synorix (as King, with gold laurel-wreath crown and

purple robes), followed by Antonius, Publius, Noblemen,
Guards, and the Populace.

Camma.

Hail, King!

Synorix.

Hail, Queen!
The wheel of Fate has roll’d me to the top.
I would that happiness were gold, that I
Might cast my largess of it to the crowd!
I would that every man made feast to-day
Beneath the shadow of our pines and planes!
For all my truer life begins to-day.
The past is like a travell’d land now sunk
Below the horizon—like a barren shore
That grew salt weeds, but now all drown’d in love
And glittering at full tide—the bounteous bays
And havens filling with a blissful sea.
Nor speak I now too mightily, being King
And happy! happiest, Lady, in my power
To make you happy.

Camma.

Yes, sir.

Synorix.

Our Antonius,
Our faithful friend of Rome, tho’ Rome may set
A free foot where she will, yet of his courtesy
Entreats he may be present at our marriage.

Camma.

Let him come—a legion with him, if he will.

(To Antonius.) Welcome, my lord Antonius, to our Temple.
(To Synorix.) You on this side the altar. (To Antonius.) You on
that.
Call first upon the Goddess, Synorix.

[All face the Goddess. Priestesses,

Children, Populace, and Guards
kneel—the others remain
standing.

Synorix.

O Thou, that dost inspire the germ with life,

The child, a thread within the house of birth,
And give him limbs, then air, and send him forth
The glory of his father—Thou whose breath
Is balmy wind to robe our hills with grass,
And kindle all our vales with myrtle-blossom,
And roll the golden oceans of our grain,
And sway the long grape-bunches of our vines,
And fill all hearts with fatness and the lust
Of plenty—make me happy in my marriage!

Chorus (chanting).

Artemis, Artemis, hear him, Ionian Artemis!

Camma.

O Thou that slayest the babe within the womb

Or in the being born, or after slayest him
As boy or man, great Goddess, whose storm-voice
Unsockets the strong oak, and rears his root
Beyond his head, and strows our fruits, and lays
Our golden grain, and runs to sea and makes it
Foam over all the fleeted wealth of kings
And peoples, hear.
Whose arrow is the plague—whose quick flash splits
The mid-sea mast, and rifts the tower to the rock,
And hurls the victor’s column down with him
That crowns it, hear.
Who causest the safe earth to shudder and gape,
And gulf and flatten in her closing chasm
Domed cities, hear.
Whose lava-torrents blast and blacken a province
To a cinder, hear.
Whose winter-cataracts find a realm and leave it
A waste of rock and ruin, hear. I call thee
To make my marriage prosper to my wish!

Chorus.

Artemis, Artemis, hear her, Ephesian Artemis!

Camma.
Artemis, Artemis, hear me, Galatian Artemis!
I call on our own Goddess in our own Temple.

Chorus.

Artemis, Artemis, hear her, Galatian Artemis!

[Thunder. All rise.

Synorix (aside).

Thunder! Ay, ay, the storm was drawing hither

Across the hills when I was being crown’d.
I wonder if I look as pale as she?

Camma.

Art thou—still bent—on marrying?

Synorix.

Surely—yet
These are strange words to speak to Artemis.

Camma.

Words are not always what they seem, my King.

I will be faithful to thee till thou die.

Synorix.

I thank thee, Camma,—I thank thee.

Camma (turning to Antonius).

Antonius,
Much graced are we that our Queen Rome in you
Deigns to look in upon our barbarisms.
 [Turns, goes up steps to altar before
the Goddess. Takes a cup from
off the altar. Holds it towards
Antonius. Antonius goes up to
the foot of the steps, opposite to
Synorix.

You see this cup, my lord.

[Gives it to him.

Antonius.

Most curious!
The many-breasted mother Artemis
Emboss’d upon it.

Camma.

It is old, I know not

How many hundred years. Give it me again.
It is the cup belonging our own Temple.

[Puts it back on altar, and takes up the

cup of Act I. Showing it to
Antonius.

Here is another sacred to the Goddess,

The gift of Synorix; and the Goddess, being
For this most grateful, wills, thro’ me her Priestess,
In honour of his gift and of our marriage,
That Synorix should drink from his own cup.

Synorix.

I thank thee, Camma,—I thank thee.

Camma.
 For—my lord—
It is our ancient custom in Galatia
That ere two souls be knit for life and death,
They two should drink together from one cup,
In symbol of their married unity,
Making libation to the Goddess. Bring me
The costly wines we use in marriages.

[They bring in a large jar of wine.

Camma pours wine into cup.

(To Synorix.) See here, I fill it. (To Antonius.)

Will you drink, my lord?

Antonius.

I? Why should I? I am not to be married.

Camma.

But that might bring a Roman blessing on us.

Antonius (refusing cup).

Thy pardon, Priestess!

Camma.

Thou art in the right.

This blessing is for Synorix and for me.
See first I make libation to the Goddess,

[Makes libation.

And now I drink.

[Drinks and fills the cup again.

Thy turn, Galatian King.

Drink and drink deep—our marriage will be fruitful.
Drink and drink deep, and thou wilt make me happy.

[Synorix goes up to her. She hands

him the cup. He drinks.

Synorix.

There, Camma! I have almost drain’d the cup—

A few drops left.

Camma.

Libation to the Goddess.

[He throws the remaining drops on the

altar and gives Camma the cup.

Camma (placing the cup on the altar).

Why then the Goddess hears.

[Comes down and forward to tripod.

Antonius follows.

Antonius,
Where wast thou on that morning when I came
To plead to thee for Sinnatus’s life,
Beside this temple half a year ago?

Antonius.

I never heard of this request of thine.

Synorix (coming forward hastily to foot of tripod steps).

I sought him and I could not find him. Pray you,

Go on with the marriage rites.
 Camma.

Antonius——
“Camma!” who spake?

Antonius.

Not I.

Phœbe.

Nor any here.

Camma.

I am all but sure that some one spake. Antonius,

If you had found him plotting against Rome,
Would you have tortured Sinnatus to death?

Antonius.

No thought was mine of torture or of death,

But had I found him plotting, I had counsell’d him
To rest from vain resistance. Rome is fated
To rule the world. Then, if he had not listen’d,
I might have sent him prisoner to Rome.

Synorix.

Why do you palter with the ceremony?

Go on with the marriage rites.

Camma.

They are finish’d.

Synorix.

How!
 Camma.

Thou hast drunk deep enough to make me happy.

Dost thou not feel the love I bear to thee
Glow thro’ thy veins?

Synorix.

The love I bear to thee

Glows thro’ my veins since first I look’d on thee.
But wherefore slur the perfect ceremony?
The sovereign of Galatia weds his Queen.
Let all be done to the fullest in the sight
Of all the Gods. (Starts.) This pain—what is it?—again?
I had a touch of this last year—in—Rome.
Yes, yes. (To Antonius.) Your arm—a moment—It will pass.
I reel beneath the weight of utter joy—
This all too happy day, crown—queen at once.

[Staggers.

O all ye Gods—Jupiter!—Jupiter!

[Falls backward.

Camma.

Dost thou cry out upon the Gods of Rome?

Thou art Galatian-born. Our Artemis
Has vanquish’d their Diana.

Synorix (on the ground).

I am poison’d.
She—close the Temple doors. Let her not fly.

Camma (leaning on tripod).

Have I not drunk of the same cup with thee?

 Synorix.

Ay, by the Gods of Rome and all the world,

She too—she too—the bride! the Queen! and I—
Monstrous! I that loved her.

Camma.

I loved him.

Synorix.

O murderous mad-woman! I pray you lift me

And make me walk awhile. I have heard these poisons
May be walk’d down.

[Antonius and Publius raise him up.

My feet are tons of lead,

They will break in the earth—I am sinking—hold me—
Let me alone.

[They leave him; he sinks down on

ground.

Too late—thought myself wise—

A woman’s dupe. Antonius, tell the Senate
I have been most true to Rome—would have been true
To her—if—if——

[Falls as if dead.

Camma (coming and leaning over him).

So falls the throne of an hour.

Synorix (half rising).

Throne? is it thou? the Fates are throned, not we—

Not guilty of ourselves—thy doom and mine—
Thou—coming my way too—Camma—good-night.

[Dies.

Camma (upheld by weeping Priestesses).

Thy way? poor worm, crawl down thine own black hole
To the lowest Hell. Antonius, is he there?
I meant thee to have follow’d—better thus.
Nay, if my people must be thralls of Rome,
He is gentle, tho’ a Roman.

[Sinks back into the arms of the

Priestesses.

Antonius.

Thou art one

With thine own people, and tho’ a Roman I
Forgive thee, Camma.

Camma (raising herself).

“Camma!”—why there again

I am most sure that some one call’d. O women,
Ye will have Roman masters. I am glad
I shall not see it. Did not some old Greek
Say death was the chief good? He had my fate for it,
Poison’d. (Sinks back again). Have I the crown on? I will go
To meet him, crown’d! crown’d victor of my will—
On my last voyage—but the wind has fail’d—
Growing dark too—but light enough to row.
Row to the blessed Isles! the blessed Isles!—
Sinnatus!
Why comes he not to meet me? It is the crown
Offends him—and my hands are too sleepy
To lift it off.
 [Phœbe takes the crown off.

Who touch’d me then? I thank you.

[Rises, with outspread arms.

There—league on league of ever-shining shore

Beneath an ever-rising sun—I see him—
“Camma, Camma!” Sinnatus, Sinnatus!

[Dies.

THE END.
 THE FALCON
“The Falcon” was produced at the St. James’s Theatre,
under the management of Messrs. Hare and Kendal, in
December 1879, with the following cast:—

The Count Federigo degli Alberighi Mr. Kendal.

Filippo, Count’s foster-brother Mr. Denny.
The Lady Giovanna Mrs. Kendal.
Elisabetta, the Count’s nurse Mrs. Gaston Murray.