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GlaxoSmithKline Jim Ward, Bob Herrmann, Teo Ching-Lay and Ann Diederich Sequential Design – the challenge of multiphase systems
Outline ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Conventional Modeling Approaches (1) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],A blended approach may provide benefits of both statistical and mechanistic modeling Motivation and the Challenge of Various Approaches
Conventional Modeling Approaches (2) Fractional screening and robustness are resource consuming.  May have to do at a reasonable scale if equipment sensitive.  Without mechanistic knowledge, number of factors is large. Route Selection Scoping Study (Scoping studies are used to narrow into the experimental region of interest) (4 Experiments) Fractional/ Screening   (These designs are utilized to identify factors that affect the process) (16 Experiments) Foldover (Once the factors of interest are identified the foldover removes aliasing from the fractional design) (8 Experiments) RSM or Composite Design (utilized to determine curvature and to hone into an optimized process) Robustness Study (utilized to narrow or widen process parameters) (8 Experiments)
Conventional Approach: Factorial Burden ,[object Object],[object Object],[object Object],[object Object],[object Object],Even Optimized – Experimental Design can be Costly 2 http://en.wikipedia.org/wiki/Pareto_principle Realistically, we can only do about 20 pilot/kilo scale experiments for scale sensitive reactions, so factor selection is essential
Selected Process Isolate Hydrate via Filtration at 25 °C Agitate until  Conversion Complete  Charge 6 volumes Acetonitrile Heat to at least 60 C Charge Isolate Form A Anhydrate Vessel One Filter Drier Our process involves the formation of a hydrate and its subsequent desolvation to form an anhydrate (product) Greater than 20 unit operations- which factors to study?
Our Approach: Dehydration Mechanism ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],S. R. Byrn;  Solid State Chemistry of Drugs, 2 nd  Ed., Chapter 14 – Loss of Solvent of Crystallization   Know the mechanism – Narrow the factor list
Our Approach (1): Dehydration Mechanism ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],S. R. Byrn;  Solid State Chemistry of Drugs, 2 nd  Ed., Chapter 14 – Loss of Solvent of Crystallization   Know the mechanism – Narrow the factor list
Our Approach: Dehydration Mechanism – Experimental  ReactIR Filtered Saturated Solution Unstable  Form charged Anhydrate Hydrate Solvate Seeded With Stable form Monitor  Conversion PAT/Mechanism - ReactIR
Our Approach: Dehydration Mechanism – Results Theoretical Actual PAT/Mechanism - ReactIR The conversion is solvent mediated.  Key factors are temperature and composition of the solvent    affect solubility Hydrate Charged Concentration Time
Detailed Solubility Data ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Our Approach: Desaturation Mechanism Determination Dissolution Growth Nucleation B    Surface Area *  Δ Cb G     Δ Ca   From solution to Solid  A. G. Jones;  Crystallization Process Systems, Pg 204 Eqs 7.36 & 7.38 simplified
Desaturation Mechanism - Experimental PAT / Mechanism – RC1 Monitor  Thermal Conversion by  RC1 Filtered Saturated Solution Unstable  Form charged Unstable form charged while Seeded with Stable form Monitor  Conversion Monitor  Conversion
Our Approach: Desaturation Mechanism - Results ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],2 Minutes RC1 – Thermal Conversion
Desaturation Mechanism - Results ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Unseeded X 90  - 34 Seeded X 90  - 20 Both the conversion rate and particle size supports a nucleation dominated mechanism, with minor crystal growth also occurs Important factors:  amount of supersaturation (temperature, solvent comp., agitation rate)
Factor Selection ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Dissolution Nucleation B ∽ Surface Area *  Δ Cb
Parameter Investigation - Results ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Figure : D90 LOD/Temp Contour Plot Figure : D90 Agitation Contour Plot
Scale-Up of Selected Process DoE Robustness Kilo Pilot Plant Campaign I/II 1000x Scale Manufacturing Campaigns I/II 2000x Scale Results: Model worked well throguh kilo lab, 1000x DOE scale. Particle size changed when going to 2000x scale.  Numbers acceptable, but unexplained variance
Process surprises- a new chance to optimize ,[object Object],[object Object]
New Process Design: Using solubility data to determine solvate stability regions
Detailed Thermo ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],4 Hours
New Process Design: DOE Results
Selected Route Isolate Hydrate via Filtration at 25 °C Agitate until  Conversion Complete  Charge 6 volumes Acetonitrile Heat to at least 60 C Charge Isolate Form A Anhydrate Vessel One Filter Drier
Selected Route Isolate Hydrate via Filtration at 25 °C Agitate until  Conversion Complete  Charge 6 volumes Acetonitrile Heat to at least 60 C Charge Isolate Form A Anhydrate Vessel One Filter Drier
Selected Route Isolate Hydrate via Filtration at 25 °C Agitate until  Conversion Complete  Charge 6 volumes Acetonitrile Heat to at least 65 C Charge Isolate Form A Vessel One Filter Drier
Selected Route Isolate Hydrate via Filtration at 25 °C Agitate until  Conversion Complete  Charge 6 volumes Acetonitrile Heat to at least 65 C Charge Isolate Form A Vessel One Filter Drier Charge Water Charge Seeds Heat above  Conversion Temp
Scale-up of modified process Unmodified Modified Variability Source Both variance in particle size and form issue mitigated through guided experimental design
Alternative Workflow Route Selection Thermodynamics (ensure the process  is on stable  thermodynamic  footing)  PAT guided mechanistic studies (kinetic model not required)   Factor selection and scoping (using small scale results select factors and design space) 4 Experiments Factor investigation (DoE) 14 Experiments Robustness Study
 
Alternative Workflow ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
FDA Guidance A process is generally considered well understood when (1) all critical sources of variability are  identified  and explained; (2) variability is managed by the process; and,  (3) product quality attributes can be  accurately and reliably predicted  over the design space established for materials used, process parameters, manufacturing, environmental, and other conditions. PAT – A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance 1 1 www.fda.gov/cder/guidance/6419fnl.pdf
Modeling – Statistical or Mechanistic 3 http://www.scale-up.com/usersarea/FDA/FDA_notes_28Feb08.pdf Question to the FDA “ the agency at the moment is much more tuned in to statistical models, in part due to the fact that drug product often requires statistical models in the absence of mechanistic detail” FDA Response Agreed.  Statistics and DOEs should be integrated with mechanistic modeling. We do not want to see so many experiments  “in the dark”  as we are seeing now.  Do fewer experiments.  Show us that you have identified all the really critical parameters and understand the effects of all the CPPs . Notes of DynoChem presentation to FDA CDER, 28 February 2008 3
Mechanism – A word of caution We need a word of caution at this point.  Just because the mechanism and the rate-limiting step may fit the rate data does not imply that the mechanism is correct.   H. Scott Fogler Elements of Chemical Reaction Engineering, 3 RD  Ed. Page 614
Robustness Study ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
The Scoping Study - Experimental ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Robustness Study ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

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Sequential Design – The Challenge Of Multiphase Systems Pd

  • 1. GlaxoSmithKline Jim Ward, Bob Herrmann, Teo Ching-Lay and Ann Diederich Sequential Design – the challenge of multiphase systems
  • 2.
  • 3.
  • 4. Conventional Modeling Approaches (2) Fractional screening and robustness are resource consuming. May have to do at a reasonable scale if equipment sensitive. Without mechanistic knowledge, number of factors is large. Route Selection Scoping Study (Scoping studies are used to narrow into the experimental region of interest) (4 Experiments) Fractional/ Screening (These designs are utilized to identify factors that affect the process) (16 Experiments) Foldover (Once the factors of interest are identified the foldover removes aliasing from the fractional design) (8 Experiments) RSM or Composite Design (utilized to determine curvature and to hone into an optimized process) Robustness Study (utilized to narrow or widen process parameters) (8 Experiments)
  • 5.
  • 6. Selected Process Isolate Hydrate via Filtration at 25 °C Agitate until Conversion Complete Charge 6 volumes Acetonitrile Heat to at least 60 C Charge Isolate Form A Anhydrate Vessel One Filter Drier Our process involves the formation of a hydrate and its subsequent desolvation to form an anhydrate (product) Greater than 20 unit operations- which factors to study?
  • 7.
  • 8.
  • 9. Our Approach: Dehydration Mechanism – Experimental ReactIR Filtered Saturated Solution Unstable Form charged Anhydrate Hydrate Solvate Seeded With Stable form Monitor Conversion PAT/Mechanism - ReactIR
  • 10. Our Approach: Dehydration Mechanism – Results Theoretical Actual PAT/Mechanism - ReactIR The conversion is solvent mediated. Key factors are temperature and composition of the solvent  affect solubility Hydrate Charged Concentration Time
  • 11.
  • 12. Our Approach: Desaturation Mechanism Determination Dissolution Growth Nucleation B  Surface Area * Δ Cb G  Δ Ca From solution to Solid A. G. Jones; Crystallization Process Systems, Pg 204 Eqs 7.36 & 7.38 simplified
  • 13. Desaturation Mechanism - Experimental PAT / Mechanism – RC1 Monitor Thermal Conversion by RC1 Filtered Saturated Solution Unstable Form charged Unstable form charged while Seeded with Stable form Monitor Conversion Monitor Conversion
  • 14.
  • 15.
  • 16.
  • 17.
  • 18. Scale-Up of Selected Process DoE Robustness Kilo Pilot Plant Campaign I/II 1000x Scale Manufacturing Campaigns I/II 2000x Scale Results: Model worked well throguh kilo lab, 1000x DOE scale. Particle size changed when going to 2000x scale. Numbers acceptable, but unexplained variance
  • 19.
  • 20. New Process Design: Using solubility data to determine solvate stability regions
  • 21.
  • 22. New Process Design: DOE Results
  • 23. Selected Route Isolate Hydrate via Filtration at 25 °C Agitate until Conversion Complete Charge 6 volumes Acetonitrile Heat to at least 60 C Charge Isolate Form A Anhydrate Vessel One Filter Drier
  • 24. Selected Route Isolate Hydrate via Filtration at 25 °C Agitate until Conversion Complete Charge 6 volumes Acetonitrile Heat to at least 60 C Charge Isolate Form A Anhydrate Vessel One Filter Drier
  • 25. Selected Route Isolate Hydrate via Filtration at 25 °C Agitate until Conversion Complete Charge 6 volumes Acetonitrile Heat to at least 65 C Charge Isolate Form A Vessel One Filter Drier
  • 26. Selected Route Isolate Hydrate via Filtration at 25 °C Agitate until Conversion Complete Charge 6 volumes Acetonitrile Heat to at least 65 C Charge Isolate Form A Vessel One Filter Drier Charge Water Charge Seeds Heat above Conversion Temp
  • 27. Scale-up of modified process Unmodified Modified Variability Source Both variance in particle size and form issue mitigated through guided experimental design
  • 28. Alternative Workflow Route Selection Thermodynamics (ensure the process is on stable thermodynamic footing) PAT guided mechanistic studies (kinetic model not required) Factor selection and scoping (using small scale results select factors and design space) 4 Experiments Factor investigation (DoE) 14 Experiments Robustness Study
  • 29.  
  • 30.
  • 31. FDA Guidance A process is generally considered well understood when (1) all critical sources of variability are identified and explained; (2) variability is managed by the process; and, (3) product quality attributes can be accurately and reliably predicted over the design space established for materials used, process parameters, manufacturing, environmental, and other conditions. PAT – A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance 1 1 www.fda.gov/cder/guidance/6419fnl.pdf
  • 32. Modeling – Statistical or Mechanistic 3 http://www.scale-up.com/usersarea/FDA/FDA_notes_28Feb08.pdf Question to the FDA “ the agency at the moment is much more tuned in to statistical models, in part due to the fact that drug product often requires statistical models in the absence of mechanistic detail” FDA Response Agreed. Statistics and DOEs should be integrated with mechanistic modeling. We do not want to see so many experiments “in the dark” as we are seeing now. Do fewer experiments. Show us that you have identified all the really critical parameters and understand the effects of all the CPPs . Notes of DynoChem presentation to FDA CDER, 28 February 2008 3
  • 33. Mechanism – A word of caution We need a word of caution at this point. Just because the mechanism and the rate-limiting step may fit the rate data does not imply that the mechanism is correct. H. Scott Fogler Elements of Chemical Reaction Engineering, 3 RD Ed. Page 614
  • 34.
  • 35.
  • 36.