Going Green Using Combined Real-Time
   Analytics and Process Automation


                              Dominique Hebraul...
The Paradigm of Faster and Better…




         Source: Chemistry Today, 2008, Copyright Teknoscienze Publications
How Can Process Analytical Technology Help?




“Greener Processes: PAT & QbD take root” Pharmaceutical Manufacturing at w...
Presentation Outline


Introduction

 Case Studies

    - PAT for Continuous Processing and Micro-Reaction Technology
   ...
On Adopting New Technologies…




         Source: Chemistry Today, 2009, Copyright Teknoscienze Publications
Where is Continuous Flow Chemistry Used?

                                          Drug discovery
                      ...
Mid-IR In-Line Reaction Analysis for Flow Chemistry

                                    3-D Spectra




                 ...
In-Line FTIR in Continuous Manufacturing of API
Development and Scale-up of Three
Consecutive Continuous Reactions for
Pro...
In-Line FTIR in Continuous Manufacturing of API
 Challenge                                                               ...
In-Line FTIR in Continuous Manufacturing of API
                                                                          ...
In-Line FTIR in Continuous Manufacturing of API
 Outcome
  - Ensure product quality via real-time
    adjustment of base ...
In-Line FTIR Micro Flow Cell in the Laboratory

ReactIRTM Micro Flow Cell
A New Analytical Tool for Continuous Flow
Chemic...
In-Line FTIR Micro Flow Cell in the Laboratory

 Heterocycle saturation




Carter, C. F.; Lange, H.; Ley, S. V.; Baxenda...
In-Line FTIR Micro Flow Cell in the Laboratory

 BDA protection of halopropane diols




IR flow cell used for screening
...
In-Line FTIR Micro Flow Cell in the Laboratory

 Peptide coupling in batch mode




IR      monitoring             of    ...
In-Line FTIR Micro Flow Cell in the Laboratory

 Conclusions

Faster screening of process variables

PAT for continuous o...
No More Batch Processing?

 Use of existing equipment, no capital
  investment

 More concise measurements
 Better suit...
Presentation Outline


Introduction

 Case Studies

    - PAT for Continuous Processing and Micro-Reaction Technology
   ...
Reaction Calorimetry: Process Safety and PAT
Execution of a Performic Acid Oxidation on Multikilogram Scale

     Introdu...
Reaction Calorimetry: Process Safety and PAT
 Challenges

Key process safety questions

    How much energy does the reac...
Reaction Calorimetry: Process Safety and PAT
 Conclusions

Highly exothermic performic acid
oxidation

Fast reaction, no ...
In-Situ FTIR Helps Green (Batch) Processing

 Real time monitoring of toxic compounds to reduce personnel’s exposure
  Ly...
Presentation Outline


Introduction

 Case Studies

    - PAT for Continuous Processing and Micro-Reaction Technology
   ...
Green Crystallization and Downstream Processing

 How much product is wasted during your crystallization and downstream
 ...
PAT in Crystallization: Reduce Waste, Improve Throughput

Crystallization Improvements   of    a
Diastereomeric    Kinetic...
PAT in Crystallization: Reduce Waste, Improve Throughput

    Conditions

Lab scale-down (L) with real time FBRM         ...
PAT in Crystallization: Reduce Waste, Improve Throughput

    Results

Mixing:         TN       (higher         purity,  ...
PAT in Crystallization: Reduce Waste, Improve Throughput




                                   Different seeding and agit...
PAT in Crystallization: Reduce Waste, Improve Throughput

Scale-up         at     50      and       400       L,     and
i...
PAT to Enhance Crystallization Processes

 Process analytics to ensure quality consistency and reliability at scale
  M.D...
Presentation Outline


Introduction

 Case Studies

    - PAT for Continuous Processing and Micro-Reaction Technology
   ...
Beyond Today’s PAT
Reaction Progress Kinetic Analysis - RPKA
  Continuous real time reaction                                                 ...
Acknowledgements
 University of Cambridge, UK
    - Catherine F. Carter, Heiko Lange, and Pr. Steven V. Ley*

 Bristol-M...
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3rd International Symposium On Green Processing

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3rd International Symposium On Green Processing

  1. 1. Going Green Using Combined Real-Time Analytics and Process Automation Dominique Hebrault Sr. Technology & Application Consultant Boston, October 1, 2010
  2. 2. The Paradigm of Faster and Better… Source: Chemistry Today, 2008, Copyright Teknoscienze Publications
  3. 3. How Can Process Analytical Technology Help? “Greener Processes: PAT & QbD take root” Pharmaceutical Manufacturing at www.pharmamanufacturing.doc, May 2010, 9, (5), 18-24; “Building Green Pharmaceutical Manufacturing on a Foundation of PAT and QbD” Paul Thomas, Sr Editor Pharmaceutical Manufacturing magazine, webinar Nov. 3rd 2010
  4. 4. Presentation Outline Introduction  Case Studies - PAT for Continuous Processing and Micro-Reaction Technology - PAT for the Greening of Batch Processing - Applying the Principles of Green Chemistry to Crystallization and Downstream Processing  Beyond Today’s PAT
  5. 5. On Adopting New Technologies… Source: Chemistry Today, 2009, Copyright Teknoscienze Publications
  6. 6. Where is Continuous Flow Chemistry Used?  Drug discovery - Microflow and small scale flow reactors - Safer and more space efficient than RBF - Used to prepare g to kg material - Used for highly energetic transformation: nitration, diazotation, hydrogenation, high temperatures (> 200 ºC).  Chemical development - Avoid scale-up issues, improves safety profile and yield at production scale - Kinetics and thermodynamics properties studied in a batch mode Special Feature Section: Process Intensification/Continuous Processing, Org. Process Res. Dev., 2001, 5 (6), 612-664, Chemical & Engineering News, 2006, 84, 10, p17; Katsunori Tanaka and Koichi Fukase, Org. Process Res. Dev., 2009, 13, 983-990
  7. 7. Mid-IR In-Line Reaction Analysis for Flow Chemistry 3-D Spectra Absorbance Flow cells ATR-FTIR Time  In-line, real time, faster turnover rate  Structural specificity  Software designed for reaction monitoring Intermediates, component spectra Steady state, component profiles Relative concentration Absorbance or Time
  8. 8. In-Line FTIR in Continuous Manufacturing of API Development and Scale-up of Three Consecutive Continuous Reactions for Production of 6-Hydroxybuspirone  Introduction Active metabolite of Buspirone, manufactured and marketed as Buspar, employed for the treatment of anxiety disorders and depression Multi Kg amount needed for clinical development, initially made in batch Process lack of ruggedness and unreliable product quality Thomas L. LaPorte,* Mourad Hamedi, Jeffrey S. DePue, Lifen Shen, Daniel Watson, and Daniel Hsieh, Bristol-Myers Squibb Pharmaceutical Research Institute, NJ, USA, Organic Process Research and Development, 2008, 12, 956-966; Mettler Toledo Real Time Analytics Users’ Forum 2005 - New York
  9. 9. In-Line FTIR in Continuous Manufacturing of API  Challenge KHMDS Control base / buspirone stoichiometry is critical to product quality Undercharged of base → unreacted 1 Overcharge of base → dihydroxy 8 1627cm-1 1677cm-1 Base feed adjusted in real time based on inline FTIR data Thomas L. LaPorte,* Mourad Hamedi, Jeffrey S. DePue, Lifen Shen, Daniel Watson, and Daniel Hsieh, Bristol-Myers Squibb Pharmaceutical Research Institute, NJ, USA, Organic Process Research and Development, 2008, 12, 956-966; Mettler Toledo Real Time Analytics Users’ Forum 2005 - New York
  10. 10. In-Line FTIR in Continuous Manufacturing of API Buspirone 1 signal 1. Pump solvent and 1 through the column 2. Solvent replace by KHMDS feed, slight undercharge of base 3. Flow rate increased at 1% increments until no decrease of buspirone 1 signal is observed 4. Base feed rate was reduced 1-3% 5. The base is slightly undercharged, diol 8 impurity minimized Thomas L. LaPorte,* Mourad Hamedi, Jeffrey S. DePue, Lifen Shen, Daniel Watson, and Daniel Hsieh, Bristol-Myers Squibb Pharmaceutical Research Institute, NJ, USA, Organic Process Research and Development, 2008, 12, 956-966; Mettler Toledo Real Time Analytics Users’ Forum 2005 - New York
  11. 11. In-Line FTIR in Continuous Manufacturing of API  Outcome - Ensure product quality via real-time adjustment of base feed rate - Prevent time and resource consuming final purification stages - Faster and more accurate reach of steady state via real-time detection of phase transitions - Minimize waste of starting material  Scale-up - Lab reactor: Over 40 hours at steady state - Pilot-plant reactor: Successful implementation (3-batch, 47kg/batch) Thomas L. LaPorte,* Mourad Hamedi, Jeffrey S. DePue, Lifen Shen, Daniel Watson, and Daniel Hsieh, Bristol-Myers Squibb Pharmaceutical Research Institute, NJ, USA, Organic Process Research and Development, 2008, 12, 956-966; Mettler Toledo Real Time Analytics Users’ Forum 2005 - New York
  12. 12. In-Line FTIR Micro Flow Cell in the Laboratory ReactIRTM Micro Flow Cell A New Analytical Tool for Continuous Flow Chemical Processing Internal volume: 10 & 50 ml ATR-FTIR Up to 30 bar (435 psi) Up to 60ºC Spectral range 600-4000 cm-1 Carter, C. F.; Lange, H.; Ley, S. V.; Baxendale, I. R.; Goode, J. G.; Gaunt, N. L.; Wittkamp, B. Org. Res. Proc. Dev. 2010, 14, 393-404
  13. 13. In-Line FTIR Micro Flow Cell in the Laboratory  Heterocycle saturation Carter, C. F.; Lange, H.; Ley, S. V.; Baxendale, I. R.; Goode, J. G.; Gaunt, N. L.; Wittkamp, B. Org. Res. Proc. Dev. 2010, 14, 393-404
  14. 14. In-Line FTIR Micro Flow Cell in the Laboratory  BDA protection of halopropane diols IR flow cell used for screening Screening results consistent with batch screening (required five separate experiments!) Used to make a large sample over almost 24 h Carter, C. F.; Lange, H.; Ley, S. V.; Baxendale, I. R.; Goode, J. G.; Gaunt, N. L.; Wittkamp, B. Org. Res. Proc. Dev. 2010, 14, 393-404
  15. 15. In-Line FTIR Micro Flow Cell in the Laboratory  Peptide coupling in batch mode IR monitoring of batch processes: Withdrawing/returning 200 µL from reaction mixture (5 mL) through the cell Flow cell more convenient than probe for mL scale experiments Carter, C. F.; Lange, H.; Ley, S. V.; Baxendale, I. R.; Goode, J. G.; Gaunt, N. L.; Wittkamp, B. Org. Res. Proc. Dev. 2010, 14, 393-404
  16. 16. In-Line FTIR Micro Flow Cell in the Laboratory  Conclusions Faster screening of process variables PAT for continuous or batch processes on a small volume (< 1ml) , less solvent and reagent waste Gain information about reactive intermediates Monitoring of hazardous substances (azide derivatives) Carter, C. F.; Lange, H.; Ley, S. V.; Baxendale, I. R.; Goode, J. G.; Gaunt, N. L.; Wittkamp, B. Org. Res. Proc. Dev. 2010, 14, 393-404
  17. 17. No More Batch Processing?  Use of existing equipment, no capital investment  More concise measurements  Better suited, more flexible, for small batches in the pharma and fine chemicals industries  Heat transfer limitations, process safety  Mass transfer issues  Solvent extraction problems  Crystallization and polymorphism Dr. Trevor Laird; Chemical Industry Digest July 2010, 51-56
  18. 18. Presentation Outline Introduction  Case Studies - PAT for Continuous Processing and Micro-Reaction Technology - PAT for the Greening of Batch Processing - Applying the Principles of Green Chemistry to Crystallization and Downstream Processing  Beyond Today’s PAT
  19. 19. Reaction Calorimetry: Process Safety and PAT Execution of a Performic Acid Oxidation on Multikilogram Scale  Introduction En route toward CP-865,569 8, a CCR1 antagonist Selection of a greener oxidation pathway Performic acid David H. Brown Ripin, Gerald A. Weisenburger, David J. am Ende, David R. Bill, Pamela J. Clifford, Clifford N. Meltz, and Jam es E. Phillips; Pfizer Global Research; Organic Process Research & Development 2007, 11, 762-765
  20. 20. Reaction Calorimetry: Process Safety and PAT  Challenges Key process safety questions How much energy does the reaction release? What is the instantaneous heat output? How much thermal accumulation? Reaction heat: - 975 kJ/mol ( ) DTadbatch 172 ºC DSC ARC Maximum heat output 44 W/Kg Thermal accumulation: 9% ( / ) RC1e David H. Brown Ripin, Gerald A. Weisenburger, David J. am Ende, David R. Bill, Pamela J. Clifford, Clifford N. Meltz, and Jam es E. Phillips; Pfizer Global Research; Organic Process Research & Development 2007, 11, 762-765
  21. 21. Reaction Calorimetry: Process Safety and PAT  Conclusions Highly exothermic performic acid oxidation Fast reaction, no delayed onset Fed-controlled process will be safe Dosing time will be adjusted based on the cooling capacity of plant equipment Five 30-35 kg batches CP-865,569 prepared in 300-gal pilot plant vessel Real time monitoring using MonARC and sampling for offline HPLC assay David H. Brown Ripin, Gerald A. Weisenburger, David J. am Ende, David R. Bill, Pamela J. Clifford, Clifford N. Meltz, and Jam es E. Phillips; Pfizer Global Research; Organic Process Research & Development 2007, 11, 762-765
  22. 22. In-Situ FTIR Helps Green (Batch) Processing  Real time monitoring of toxic compounds to reduce personnel’s exposure Lynette M. Oh, Huan Wang, Susan C. Shilcrat, Robert E. Herrmann, Daniel B. Patience, P. Grant Spoors, and Joseph Sisko GlaxoSmithKline, Organic Process Research & Development 2007, 11, 1032–1042 Jacques Wiss, Arne Zilian, Novartis, Organic Process Research & Development 2003, 7, 1059-1066  Real time process control for improved safety and efficiency Terrence J. Connolly, John L. Considine, Zhixian Ding, Brian Forsatz, Mellard N. Jennings, Michael F. MacEwan, Kevin M. McCoy, David W. Place, Archana Sharma, and Karen Sutherland; Wyeth Research; Organic Process Research & Development 2010, 14, 459–465 Holger Kryk, Günther Hessel, and Wilfried Schmitt, Institute of Safety Research Germany, Organic Process Research & Development 2007, 11, 1135–1140 Atsushi Akao, Nobuaki Nonoyama, Toshiaki Mase, Nobuyoshi Yasuda, Merck, Organic Process Research & Development 2006, 10, 1178-1183  Large scale use of in-situ real time FTIR Lynette M. Oh et al, GlaxoSmithKline, Organic Process Research & Development, 2009, 13, 729-738 Jaan Pesti, Chien-Kuang Chen et al, Organic Process Research & Development, 2009, 13, 716-728 David H. Brown Ripin, Gerald A. Weisenburger, David J. am Ende, David R. Bill, Pamela J. Clifford, Clifford N. Meltz, and James E. Phillips; Pfizer Global Research; Organic Process Research & Development 2007, 11, 762-765
  23. 23. Presentation Outline Introduction  Case Studies - PAT for Continuous Processing and Micro-Reaction Technology - PAT for the Greening of Batch Processing - Applying the Principles of Green Chemistry to Crystallization and Downstream Processing  Beyond Today’s PAT
  24. 24. Green Crystallization and Downstream Processing  How much product is wasted during your crystallization and downstream processing steps? • Dry milling can cause 10+% loss due to hold up in the milling equipment • Also, generation of fine particles during milling results in potential exposure and explosion hazard • Crystals are easy to get but crystallization processes difficult to optimize Holistic approach to achieving energy and material efficiency gain
  25. 25. PAT in Crystallization: Reduce Waste, Improve Throughput Crystallization Improvements of a Diastereomeric Kinetic Resolution through Understanding of Secondary Nucleation  Introduction Target product fails optical purity specs at contract manufacturing site Failed batches exhibit longer filtration and drying times Significance of secondary nucleation: Induction temperature, stirring speed, seed surface area Patrick Mousaw, Kostas Saranteas, and Bob Prytko, Sepracor Inc.; Organic Process Research and Development, 2008, 12, 243-248
  26. 26. PAT in Crystallization: Reduce Waste, Improve Throughput  Conditions Lab scale-down (L) with real time FBRM 46ºC Seeded (46ºC) cooling crystallization Seeding process not immediately followed by significant growth Rate of particle formation versus time TN: temperature of nucleation High TN: Low supersaturation, higher purity, better separation How can nucleation be forced earlier, at higher temperature? Patrick Mousaw, Kostas Saranteas, and Bob Prytko, Organic Process Research and Development, 2008, 12, 243-248
  27. 27. PAT in Crystallization: Reduce Waste, Improve Throughput  Results Mixing: TN (higher purity, better separation) correlated to shear rate Seeding: Surface area, not amount, increases TN Patrick Mousaw, Kostas Saranteas, and Bob Prytko, Organic Process Research and Development, 2008, 12, 243-248
  28. 28. PAT in Crystallization: Reduce Waste, Improve Throughput Different seeding and agitation condition  Faster filtration rate  Shorter cycle time  Improved optical purity Patrick Mousaw, Kostas Saranteas, and Bob Prytko, Organic Process Research and Development, 2008, 12, 243-248
  29. 29. PAT in Crystallization: Reduce Waste, Improve Throughput Scale-up at 50 and 400 L, and implemented at contract manufacturing site Centrifugation time divided by 3 No need to scrape the product out Higher optical purity, above specs Results consistency Increased time and energy efficiency Safer working conditions Improved quality and process reliability Patrick Mousaw, Kostas Saranteas, and Bob Prytko, Organic Process Research and Development, 2008, 12, 243-248
  30. 30. PAT to Enhance Crystallization Processes  Process analytics to ensure quality consistency and reliability at scale M.D. Argentine, T.M. Braden, J. Czarnik, E.W. Conder, S.E. Dunlap, J.W. Fennell, M.A. LaPack, R.R. Rothhaar, R.B. Scherer, C.R. Schmid, J.T. Vicenzi, J.G. Wei, J.A. Werner*, and R.T. Roginski, Org. Process Res. Dev., 2009, 13, 131– 143. Vincenzo Liotta, Vijay Sabesan, Org. Process Res. Dev., 2004, 8, 488-494  Particle Engineering: Design the crystal product to avoid unnecessary processing S. Kim, B. Lotz, M. Lindrud, K. Girard, T. Moore, K. Nagarajan, M. Alvarez, T. Lee, F. Nikfar, M. Davidovich, S. Srivastava, and S. Kiang, Org. Process Res. Dev., 2005, 9, 894-901 Sridhar Desikan, Rodney L. Parsons, Jr.,, Wayne P. Davis,, James E. Ward,, Will J. Marshall, and, Pascal H. Toma., Org. Process Res. Dev., 2005, 9, 933-942  Automating Metastable Zone Width Determination and Supersaturation Control Barrett, P. and B. Glennon, Chem. Eng. Res. Des. 2002, 80, 799-805 Mark Barrett, Mairtin McNamara, HongXun Hao, Paul Barrett, Brian Glennon, Chem. Eng. Res. & Des., 2010, 88, 8, 1108- 1119 Cote, A., G. Zhou, M. Stanik, Org. Process Res. Dev., 2009,13, 1276-1283
  31. 31. Presentation Outline Introduction  Case Studies - PAT for Continuous Processing and Micro-Reaction Technology - PAT for the Greening of Batch Processing - Applying the Principles of Green Chemistry to Crystallization and Downstream Processing  Beyond Today’s PAT
  32. 32. Beyond Today’s PAT
  33. 33. Reaction Progress Kinetic Analysis - RPKA Continuous real time reaction Graphical, intuitive data monitoring (calorimetry, FTIR…) manipulation • Less experiments, more knowledge • Catalyst performance • Process robustness • Driving force analysis Early-on kinetic simulation RPKA provides a full kinetic analysis from 3+ experiments Blackmond, D. G. Angew. Chemie Int. Ed. 2005, 44, 4302; Blackmond, D. G. et al., J. Org. Chem. 2006, 71, 4711
  34. 34. Acknowledgements  University of Cambridge, UK - Catherine F. Carter, Heiko Lange, and Pr. Steven V. Ley*  Bristol-Myers Squibb Pharmaceutical Research, New Brunswick, NJ, USA - Thomas L. LaPorte, Mourad Hamedi, Jeffrey S. DePue, Lifen Shen, Daniel Watson, and Daniel Hsieh  Pfizer Global Research, Groton, CT, USA - David H. Brown Ripin, Gerald A. Weisenburger, David J. am Ende, David R. Bill, Pamela J. Clifford, Clifford N. Meltz, and James E. Phillips  Sepracor Inc., Marlborough, MA, USA - Patrick Mousaw, Kostas Saranteas, Bob Prytko  Mettler Toledo Autochem - Jon G. Goode, Nigel L. Gaunt, Brian Wittkamp, and Jian Wang

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