Pharma Product Portfolio 2011 210211

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Pharma Product Portfolio 2011 210211

  1. 1. Pharma Twin Screw Extruders 2011Kurt KortokraxSales Account ManagerKurt.Kortokrax@Thermofisher.com
  2. 2. Thermo Fisher Scientific – a strong brand Thermo’s world-class New capabilities Famous catalogs and analytical technologies acquired from Fisher supply-chain services + • New brand stands for innovation and quality • Mark of choice and • Thermo instruments plus new reagents, convenience consumables and equipment • Complete product portfolio • Even better laboratory workflow solutions of equipment & supplies • One-stop, total lab supplier All from Thermo Fisher Scientific2
  3. 3. Pharma Twin Screw Extruders 2011 Hot Melt Extrusion Twin Screw Granulation Information HME Information TSG Product Portfolio HME Product Portfolio TSG Customized Solutions3
  4. 4. Introduction Hot Melt Extrusion Introduction HME4
  5. 5. HMI – What„s your challenge today? Taste masking Limited by your API New capsule New dosage materials New delivery concepts methods5
  6. 6. Where is pharmaceutical Hot Melt Extrusion? “For both the pharmaceutical industry and the academic community HME became an innovative drug delivery technology that is receiving increased attention. HME turned now into highly dynamic, interdisciplinary topics that provide a creative link between engineering and pharmaceutical sciences for the purposes of drug delivery. Research in these vibrant research areas is making significant advances resulting in innovative, engineered drug delivery systems.” Source: G. P. Andrews, Phil. Trans. R. Soc. A (2007) 365, 2935–29496
  7. 7. What is Hot Melt Extrusion? Processing of polymeric materials above their glass transition temperature (Tg) in order to effect molecular level mixing of thermoplastic binders and/or polymers and active compounds Melt extrusion is a combination of melting and mechanical energy with advantages like: • Continuous • Reproducible • Fairly high throughput • Dust reduction • On-line-monitoring7
  8. 8. Biopharmaceutics Classification Scheme Class II Class I Low Solubility High Solubility High Permeability High Permeability Permeability 90% Class IV Class III Low Solubility High Solubility Low Permeability Low Permeability 0.1 mg/ml Solubility8
  9. 9. Why Hot Melt Extrusion9
  10. 10. Different Types of Solid Dispersions/SolutionsPolymer: amorphous amorphous amorphousDrug: crystalline amorphous molecularly dissolvedThermo-dynamic almost stable unstable stable (drug belowStability (kinetically controlled) saturation solubility)10
  11. 11. Pharmaceutical Development Needs • Consistent, small scale production. • Low consumption of expensive materials • Easy cleaning with simple verification. • Flexibility for new product development. • Reliable and repeatable operating conditions. • Accurate process data for product audit.11
  12. 12. How Extrusion Technology can support you…  Hot melt extrusion supports you by establishing stable solid solutions which increase the availability of poorly soluble ingredients,  A continuous steady state process monitored by process control allows you to minimize failed batches  Extrusion technology allows you to produce new drug dosage forms e.g. mini implants  Melt extrusion allows you to reduce the consumption of solvents - for instance in comparison with the wet granulation process  and many other good reasons … Extrusion technology is a mature process used in the polymer industry for more than 40 years and in the pharmaceutical for approx. >20 years known.12
  13. 13. Validation Aspects Regulatory aspects of melt extrusion: Hot melt extrusion has a comprehensive documentation, which satisfy regulatory authorities Melt extrusion is a mature technology Measurable parameters such as feeding rate, equipment temperatures, discharge pressure, vacuum control, etc. can be monitored on-line with local sensors. Data logging provides supporting documentation to ensure the quality of production lots and simplify quality control. Use of in-line sensors PAT provide a good basis for the FDA – QbD initiative13
  14. 14. Product Portfolio Hot Melt Extrusion Product Portfolio HME14
  15. 15. Twin Screw Solutions for HME Mini MiniLab Pharma mini HME 16 mm EuroLab EuroLab Pharma Pharma 16 HME 24 mm Pharma 24 HME15
  16. 16. Phases of Pharmaceutical Development Constraints o Quantity of API o Quality of API o Consistent quality of Drug product o Time Phase 0 Regulatory Preclinical Phase 1 Phase 2 Phase 3 Approval Launch Chemistry Medicinal Kilogramme Process Chemistry Production Site Production Site Lab API Batch mg - g 0.2 -10 kg 10 – 100 kg 1,000 kg 1,000 kg Size Process 10 g 0.2 - 5 kg 5 – 50 kg 100 – 500 kg 500 kg Batch Testing In Vitro & Safety in Safety and Efficacy Market Market Animal Human16
  17. 17. The Solution for your Phase Phase 0 Regulatory Preclinical Phase 1 Phase 2 Phase 3 Approval Launch Chemistry Medicinal Kilogramme Lab Process Chemistry Production Site Production Site API Batch mg - g 0.2-10 kg 10 – 100 kg 1,000 kg 1,000 kg Size Process 10 g 0.2-5 kg 5 – 50 kg 100 – 500 kg 500 kg Batch Twin Screw Pharma Pharma 16 Pharma 24 Granulator Pharma 16 Pharma 24 mini HME Pharma 24 scale out Process 10 g 0.2-5 kg/h 0.2 – 5 kg/h Output 1 – 50 kg/h 1 – 50 kg/h 1 – 50 kg/h 25 – 100 kg/h17
  18. 18. The MiniLab HAAKE MiniLab – suitable e.g. for  Proof of concept studies  Creating specimen for drug delivery systems  Your advantages of a Micro Compounders  Substantial cost savings for proof of concept studies due to compounding of small quantities of ingredients (5g)  Understanding of material characteristics by documenting structural changes via integrated viscosity measurement  Flexible process conditions for different materials by  Using conical co- or counter-rotating screws  Automatic bypass operation for extrusion/recirculation  Force Feeder especially for continuous powder feeding18
  19. 19. Pharma mini HME for Micro Scale Production Pharma mini HME  Allows the preparation of small sample batches for clinical trials (e.g. phase 1) when only a few grams of material is needed (minimum 4 grams)  Continuous micro scale production (up to 100 grams per hour) for dedicated Pharma applications (e.g. implants)  Feasibility trials in a very early stage with high potent materials in a Glove Box / Isolator environment (small footprint, easy handling).19
  20. 20. Pharma mini HME Features Pharma mini HME  The characteristics of our GMP Version are  All product contact parts made from pharma grade stainless steel  Horizontally split barrel with top and bottom half lifting upwards, with barrel clamps for easy removing, exchanging and cleaning  Cooling block for cooling of feed port with air or water  Minimization of screw threads and focus on easy-to-clean components  Optional available manual feeder and Force Feeder  Replacement barrels available as option (to avoid contamination between different materials and save time because of cleaning between several material runs)20
  21. 21. Pharma mini HME Features Pharma mini HME  Additional Features  Without backflow channel (available as option)  Straight, easy to clean split extrusion channel  Touch screen control with user levels and password protection, quick data trending (data logging software as option)  Can be used as co- and counter- rotating setup21
  22. 22. EuroLabEuroLab Ideal for material and process studies at Universities and R&D centers Continuous runs with 200 g/hr up to 5 kg/hr Modular tool to understand and improve process and get knowledge about material behavior and material composition22
  23. 23. EuroLab FeaturesEuroLab The characteristics of our Eurolab are  Horizontally split barrel with top half lifting upwards for better access to the screws and better process understanding  Modularity: 25:1 extruder with 15:1 extension offers flexibility for several applications  Optional available volumetric and gravimetric single and twin screw feeding systems for solids and liquids with full integration into extruder touch screen (as option)  Segmented upper barrel allows flexibility in feeding and venting  Bench mounted system, small footprint23
  24. 24. EuroLab Features EuroLab  Additional Features  Touch screen control with quick data trending (data logging software as option)  Wide range of up- and downstream equipment (e.g. strand line, face cut pelletiser etc. Available)  Scales to EuroLab Pharma, Pharma 16 and Pharma 2424
  25. 25. EuroLab Pharma Eurolab Pharma  Allows the preparation of small sample batches  For material and process studies in Pharma R&D environments  Continuous runs with 200 g/hr up to 5 kg/hr25
  26. 26. EuroLab Pharma FeaturesEuroLab Pharma Additional Features  All product contact parts made from Pharma grade stainless steel, material certs and surface roughness measurements avaialable  Stainless steel cover for barrel and bench  Small feeder platform included  Optional barrel cooling  Conversion kit HME -> TSG available  Touch screen control with user levels and password protection, quick data trending (data logging software as option) 26
  27. 27. Pharma 16 Hot Melt Extruder Pharma 16 HME Process development studies Producing samples for Clinical Trials Advantages of a Pharma HME Substantial cost savings for process development from compounding of samples (from 200g) Significant time savings from ability to process multiple samples in succession. Flexible process configurations for different materials from segmented screws and barrels. Opportunities for multiple feed streams to minimise use of expensive API. Special feeding accessories for difficult to handle ingredients.27
  28. 28. Pharma 16 HME Features • Product contact parts made from pharmagrade steel • Stainless steel housing • Material cerificates available • Full validation documentation available • Removable and segmented top and bottom barrel • Touchscreen control • Integrated feeding solutions • Automated start-up procedure available • Integration of PAT (e.g. NIR) possible • Based on casters, movable28
  29. 29. Pharma 16 HME – Barrel and Screws Removal Barrel clamps Barrel clamps removed Upper barrel removed Lower liner and screws removed29
  30. 30. Pharma 16 HME – Barrel and Screws Removal30
  31. 31. Pharma 16 HME – Design Features Design features Stainless steel GMP construction. No external painted parts. Sheet metal base is made of stainless steel. Process contact parts from pharma- grade through-hardened surgical stainless steel Easily removable screws and barrels for cleaning or reconfiguration. Adjustment of effective process length to minimise residence time.31
  32. 32. Pharma 16 HME – Segmented Barrel32
  33. 33. Pharma 16 HME – Flexible Screw Design Distributive Element (narrow) Dispersive Element (wide)33
  34. 34. Pharma 16 HME – Flexible Screw Design34
  35. 35. Pharma 16 Air Cooled Conveyor Belt35
  36. 36. Pharma 16 – Varicut and Twin Servo Pelletiser36
  37. 37. Pharma 16 – Strand Pelletising Line Pharma 16 Feeding Systems PharmaLab16 HME Pharma 16 Twin Screw Extruder Air Cooled Conveyor Pharma 16 Varicut Pelletiser37
  38. 38. Pharma 24 Hot Melt Extruder38
  39. 39. Pharma 24 HME – Barrel Liners and Screws Removal Barrel close-up Barrel open Barrel liners and plugs removed All contact parts removed39
  40. 40. Pharma 24 Chill Roll – The Compact Cooling Solution Flaker parts removed Belt cartridge removed40
  41. 41. Pharma 24 Chill Roll Interlocked roll guard Flaker removed Nip gap adjustment Roll opening handles41
  42. 42. Pharma 24 Chill Roll Belt Cartridge Belt Cartridge removed Pharma 24 Chill Roll Removing the Belt Cartridge.42
  43. 43. Pharma 24 Chill Roll Flaker Cleaning Flaker parts removed Pharma 24 Chill Roll (Opening Flaker)43
  44. 44. Pharma 24 Hot Melt Discharge Die Nozzle Long Reach Die Pressure Probe Vacuum Vent StackDie Temperature Probe Discharge Nozzle44
  45. 45. Pharma 24 Vacuum Venting Vacuum Gauge Air Bleed Control Blocked Vent Indicator Vacuum Vent Stack45
  46. 46. Pharma 24 Feeding Solutions Hopper ExtensionDischarge Tube, Fitted withFlexible Bellows Load Cell Feeder Controller Extruder Touch Screen 46
  47. 47. Pharma 16 and 24 Feeder Plattforms47
  48. 48. Pharma 16 and 24 Feeder Arrangement48
  49. 49. Pharma 24 HME with Chill Roll Gravimetric Screw FeederPressure Probe Vacuum VentPharma 24 PharmaLab 24 HMEChill Roll/Flaker Twin Screw Extruder 49
  50. 50. Twin Screw Granulation Introduction TSG50
  51. 51. Reasons for Granulation • To prevent segregation of the constituents of the powder mix • Aid downstream processing by improving the physical characteristics of the mix in terms of: • Flow • Density • Dustiness • Compressibility • Etc.51
  52. 52. Granulation • Wet granulation involves the agglomeration of a mix of dry primary powder particles using a granulating fluid. • The fluid, which is added during the granulation step, must be pharmaceutically safe and volatile enough so that it can be evaporated by a subsequent drying step. • In Melt granulation the binding fluid is created by heating the formulation and causing one or more of the dry ingredients to become molten. Cooling the mix at the end of the granulation step solidifies the molten binder.52
  53. 53. Pharmaceutical Batch Granulation • Traditional batch processes • High speed wet granulation (like APV, GEA, Fielder.) • Roll Compaction • Fluidised bed granulation • Risks of Batch to batch variation require careful and complex procedures and controls. • Method and order of charging ingredients • Time and technique for introduction of binders • Definition of end point • Large scale equipment needed in development to reduce risk of scale- up. • Large quantities of expensive API (Active Pharmaceutical Ingredient) required • Difficulty to produce small samples on production scale equipment.53
  54. 54. Continuous Granulation • Controlled continuous process • Suitable for PAT • No batch to batch variation • Small inventory of in-process materials • Reduced risk of product loss • Reduced Powder risks • On demand production • Reduced scale-up risk54
  55. 55. The Clinical Trials Development Cycle STUDY PHASE Number of Patients Duration Primary Purpose Phase 1 20 – 100 normal, Up to one year Safety healthy patients Phase 2 Up to several One to two years Safety and hundred patients efficacy Phase 3 Several hundred to Two to four years Efficacy and cost several thousand benefits patients Phase 4 Several hundred to Two to ten years Cost benefits (Post Launch) several thousand and outcomes patients55
  56. 56. Batch vs. Continuous Granulation 3-10 litre Phase 1 65-150 litre Phase 2 Phase 3 300-600 litre Pharmalab 16mm Phase 1 Phase 2 and Pharmalab 24mm Phase 356
  57. 57. Equivalent Production Capacities Batch Granulating Daily output of Continuous Granulating Equipment Granulate Equipment 65 Litre Batch Mixer 60 kg Pharma 16 TSG 15 kg batch Based on 4 batches per 0.2 – 6 kg/h 12h day 300 Litre Batch Mixer 225 kg Pharma 24 TSG 75 kg batch Based on 3 batches per 1 – 60 kg/h 12h day 600 Litre Batch Mixer 300 kg Pharma 24 TSG 150 kg batch Based on 2 batches per 1 – 60 kg/h 12h day57
  58. 58. Equivalent Production Capacities Equipment Volume Process Evaluation Samples Daily Production Rates Batch Mixer Number of Typical Total Batch Minimum process Continuous Tank Working Batch Materials Sample samples per Sample Batches Daily (24h) Volume Volume Size Cost Size Batch Materials Cost per day Output Mixer Size Litre Litre Kg Kg Kg 3 Litre 3 1.5 0.75 $750 0.750 1 $750 5 3.75 10 Litre 10 5 2.5 $2,500 2.500 1 $2,500 5 12.5 65 Litre 65 32.5 16.25 $16,250 16.250 1 $16,250 4 65 150 Litre 150 75 37.5 $37,500 37.500 1 $37,500 4 150 300 Litre 300 150 75 $75,000 75.000 1 $75,000 3 225 600 Litre 600 300 150 $150,000 150.000 1 $150,000 3 450 Number of Continuous process Typical Mixer Extruder Minimum Batch Minimum samples per Continuous Free Maximum Batch Materials Sample Minimum Single Sample Output Kg Daily (24h) Volume Inventory Size Cost Size Batch Materials Cost per Hour Output Screw Diameter Litre Grammes Grammes Kg Kg Kg Minilab 0.007 3.5 5 $5 0.005 1 $5 0.1 2.4 Pharmalab 16 25:1 0.068 34 500 $500 0.170 3 $170 4 96 Pharmalab 16 40:1 0.109 54.5 900 $900 0.273 2 $273 4 96 Pharmalab 24 25:1 0.228 114 2000 $2,000 0.570 5 $570 20 480 Pharmalab 24 40:1 0.365 182.5 3000 $3,000 0.913 4 $913 20 480 Based on:- Formulation Density g/ml 0.50 Formulation Cost per Kg $1,00058
  59. 59. Batch Granulation Population Balance59
  60. 60. Comparison of materials – example of batch mixed granules 50 45 40 characteristic peak @ 90-150 microns Wt % on sieve 35 30 Fines variable 25 2-18% 20 Variable quantities of coarse material 15 Between 2-14% @ 500 micron 10 5 0 0 53 75 90 150 250 355 500 710 850 1000 Sieve size (microns) Source ISPE Conference John Robertson GlaxoSmithkline60
  61. 61. Comparison of materials – example of batch mixed granules 35 30 25 20 Lower variability in fines 15 Much lower variability at coarse end 10 5 0 0 53 75 90 150 250 355 500 710 850 1000 Potential for more consistent process ! Source ISPE Conference John Robertson GlaxoSmithkline61
  62. 62. Motivation for adopting continuous granulation • Financial and business drivers • Reduced footprint • facilities cost • No or little scale up from development to commercial • reduced tech transfer costs and risks • reduced FTE requirements • reduction in API requirements through development • Potential for common platform throughout development and commercial network • Reduced capital and OPEX costs • Lights out operation • Containment of high actives • Potential for modular construction approach • Reduced inventory – scope for just in time delivery • Technical Drivers • Implementation of PAT • Scope for improved control and consistency Source ISPE Conference John Robertson GlaxoSmithKline62
  63. 63. Product Portfolio Twin Screw Granulation Product Portfolio TSG63
  64. 64. Twin Screw Solutions for TSG 16 mm EuroLab EuroLab Pharma Pharma 16 TSG 24 mm Pharma 24 TSG64
  65. 65. Pharma 16 Twin Screw Granulator Gravimetric Liquid Feeding Screw Feeder PumpPharma16 TSGTwin Screw Granulator65
  66. 66. Pharma 16 TSG with powder bridge braker66
  67. 67. Pharma 16 TSG showing discharge area67
  68. 68. Pharma 16 TSG dismantled for cleaning68
  69. 69. Pharma 24 Twin Screw GranulatorGravimetricScrew Feeder Gravimetric Liquid Feeding PumpCrammer FeederPharma 24 TSGTwin Screw Granulator69
  70. 70. Pharma 24 TSG with feeder platforms70
  71. 71. Pharma 24 TSG showing barrel clamps71
  72. 72. Pharma 16 and 24 Feeder Platforms72
  73. 73. Customized Solutions Examples of Customized Solutions73
  74. 74. EuroLab in Isolator EuroLab extruder and spheronizer in Isolator (Glove-Box) Motor EuroLab and Feeder outside Touchscreen outside Modified extruder base, splash-proof Electronics integrated in isolator-base74
  75. 75. Customized Pharma 24 mm Chill Roll Clear protection coverModified belttake-offDischarge valve Electronic modification to allow control via 3rd party Collection bins extruder control75
  76. 76. Special Sheet Layering Application Twin bore ram feeder to feed sticky or pasty materialsSheetlayering withrelease tape 76

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