Emerging Technologies in Freeze Drying                                                      Stirling Innovation Park - 3rd...
The Freezing Drying Process                                                                      General Introduction Fre...
Primary Drying                                                           The Concept of MTM and SMART Freeze Dryer, 1 Th...
Primary Drying                                                The Concept of MTM and SMART Freeze Dryer, 2 The SMART  F...
Primary Drying                                       SMART Freeze Drying Cycle, Example         75 mg/mL sucrose, uncontr...
Primary Drying                                                                                                            ...
The Freezing Phase                                                                                               Nucleatio...
The Freezing Phase                                      Impact on Product Morphology and Cake Appearance  Super-Cooling  ...
The Freezing Phase                                           Controlling Nucleation - ControLyo, Praxair, 1 Concept 11,1...
The Freezing Phase          Controlling Nucleation - ControLyo, Praxair, 2Page 10
The Freezing Phase                                                                       Controlling Nucleation - ControLy...
SMART and ControLyo                                                                             Study Design SMART Cyc...
SMART and ControLyo                                            Obtained Primary Drying Recipes          Phase           ...
SMART and ControLyo                                                                                                     ...
SMART and ControLyo                                                            Process / Primary Drying Time, 2         ...
SMART and ControLyo                                                                                                     ...
SMART and ControLyo                                                                                  Product Appearance ...
SMART and ControLyo                                                                              Water Content[Staertzel...
SMART and ControLyo                                                         Summary and Conclusion The freezing phase i...
Literature (1)      Wang DQ. 2000. Lyophilization and development of solid protein pharmaceuticals. Int. J. of Pharmaceuti...
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Enhanced Process / Product Understanding and Control in Freeze Drying by using Manometric Temperature Measurement (MTM) and Nucleation Control

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This presentation gives an overview into how advanced techniques such as manometric temperature measurement (MTM) and ice nucleation control can be used to enhance understanding of the freeze drying of your product, and provide additional control of its behaviour throughout the freeze drying cycle. This presentation was originally presented at Emerging Technologies in Freeze Drying, Stirling, 3rd April 2012.

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Enhanced Process / Product Understanding and Control in Freeze Drying by using Manometric Temperature Measurement (MTM) and Nucleation Control

  1. 1. Emerging Technologies in Freeze Drying Stirling Innovation Park - 3rd April 2012 Enhanced Process / Product Understanding and Control in Freeze Drying by using Manometric Temperature Measurement (MTM) and Nucleation ControlDr. Margit GieselerFriedrich-Bergius-Ring 15 E-Mail: info@gilyos.comD-97076 Würzburg Web: www.gilyos.com
  2. 2. The Freezing Drying Process General Introduction Freeze Drying Phases - Overview  Freezing phase: • Principal dehydration step 3 - 6 hrs • Separation of most of the solvent hrs - days (typically water) from the solutes to form ice  Primary drying phase: 3 - 10 hrs • Ice sublimation • Longest phase  optimization of great economical impact!  Secondary drying phase: • Removal of unfrozen water by diffusion and desorption Optimization  Over the last years/decades: optimization efforts focused on primary drying phase.  A truly optimized cycle includes all phases of the freeze drying process!  Primary drying: run process close to / at / above critical formulation temperature, tool: Manometric Temperature Measurement (MTM), Lyostar (SMART) freeze dryer.  Freezing phase: nucleation control, tool: ControLyo.Page 2
  3. 3. Primary Drying The Concept of MTM and SMART Freeze Dryer, 1 The “MTM Procedure”: 3-7  Isolate chamber from condenser for a short period of time (25 sec).  Monitor pressure rise, collect pressure rise data (10 points/sec).  Fit raw data to a pressure rise model function derived from heat and mass transfer theory (MTM equation) by non-linear regression analysis.  Calculate data for the vapor pressure of ice at the sublimation interface (Pice) and dry product layer and stopper resistance (Rp+Rs).  Use fundamental steady state heat and mass transfer equations to calculate (from Pice and Rp data) additional parameters required to optimize the process.   3.461 N  Ap  Ts     0.114  P(t)  Pice  (Pice  P0)  exp   V  Rp  Rs    t  0.0465 Pice  T  1 0.811 exp   t   X  t       Lice  T  24.7  Lice  Pice  P0 /Rp  Rs  0.0102 Lice  Ts  Tp 1  0.0102 Lice Pice: pressure of ice, Torr (fit) Po: chamber pressure, Torr (set) Rp+Rs: product resistance, cm² Torr h / g (fit) Ap: inner area of vials, cm² (known) TS: shelf temperature, K (set) V: chamber volume, L (known) N: number of vials (known) X: parameter for linear increase (fit) Lice: ice thickness, cm (calculated) t: time of pressure rise (known) ∆T: product temperature difference, sublimation surface ↔ bottom of the vial (calc.)Page 3
  4. 4. Primary Drying The Concept of MTM and SMART Freeze Dryer, 2 The SMART  Freeze Dryer  LyoStar platform (SP Scientific).  Expert system: • Selection of optimum freezing procedure (crystalline / amorphous material) • Automatic determination of target product temperature • Selection of optimum chamber pressure (based on target product temperature) • Dynamic adjustment of shelf temperature in primary drying based on MTM feedback loop  Input Parameters (among others): • Number and type of product vials • Inner vial cross-sectional area • Fill weight / fill volume / density of solute • Concentration of solution • Nature of drug product • Critical formulation temperature (Tc, Teu, Tg′)  Auto-MTM: user pre-defined recipe, conduction and recording of MTM measurements, no automatic adjustment.Page 4
  5. 5. Primary Drying SMART Freeze Drying Cycle, Example 75 mg/mL sucrose, uncontrolled nucleation, 5 cc tubing vials, 2.5 mL fill volume [Staertzel P, Gieseler M, Gieseler H, unpublished data , 2012]Page 5
  6. 6. Primary Drying Product Resistance 12 TYPE 4 Product Resistance, Rp (cm Torr hr / g) 11 10 92 8 TYPE 3 7 l = dry layer thickness 6 5 RP (0) = resistance at l = 0 4 TYPE 2 A1, A2 = constants 3 TYPE 1 2 1 0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 (13) Dry Layer Thickness, l (cm)Page 6
  7. 7. The Freezing Phase Nucleation and Freezing  Nucleation  Nucleation = start of ice crystal formation.  Nucleation does not start at the thermodynamic freezing point (Tf) but at a temperature Tn , lower than Tf.  RANDOM event!! freezing point Tf  Freezing  Freezing of pure ice.  Concentration of all dissolved Temperature [°C] Components ↑. Tn nucleation temp. Tn  Crystallization at Teu (crystalline systems). shelf temperature shelf temperature  Solidification at Tg′ (amorphous systems). Time [min] (9), modifiedPage 7
  8. 8. The Freezing Phase Impact on Product Morphology and Cake Appearance  Super-Cooling  Degree of super-cooling (Tn - Tf) determines ice crystal size: Low Tn High Tn • High Rp • Low Rp • Long primary drying time • Short primary drying time • Short secondary drying • Long secondary drying time time (10)  Biggest obstacle in scale-up!Page 8
  9. 9. The Freezing Phase Controlling Nucleation - ControLyo, Praxair, 1 Concept 11,12  Cool product vials to desired nucleation temperature below the equilibrium freezing point (e.g. -5°C); equilibrate product.  Pressurize product chamber with argon (or nitrogen) gas to approximately 26 - 28 psig (ca. 1340 - 1450 Torr); equilibrate product.  Depressurize the chamber to approximately 2 psig (ca. 100 Torr) in less than 3 sec to induce nucleation.Page 9
  10. 10. The Freezing Phase Controlling Nucleation - ControLyo, Praxair, 2Page 10
  11. 11. The Freezing Phase Controlling Nucleation - ControLyo, Praxair, 3 Controlled vs. Uncontrolled Nucleation 75 mg/mL sucrose, 5 mL vials, 2.5 mL fill, uncontrolled nucleation 75 mg/mL sucrose, 5 mL vials, 2.5 mL fill, controlled nucleation @ -3°C [Staertzel P, Gieseler M, Gieseler H, unpublished data , 2012]Page 11
  12. 12. SMART and ControLyo Study Design SMART Cycle Uncontrolled  Freezing / Thermal Treatment: 0.5°C/min to -40°C  Primary Drying: SMART Annealing  Freezing / Thermal Treatment: 0.5°C/min to -40°C + 6 h annealing @ -15°C  Primary Drying: Auto-MTM, same settings as in SMART cycle uncontrolled ControLyo @ -8°C and @ -3°C  Freezing / Thermal Treatment: nucleation at -8°C or -3°C, respectively, 0.5°C/min to -40°C after nucleation  Primary Drying: Auto-MTM, same settings as in SMART cycle uncontrolled SMART Cycle Controlled @ -3°C  Freezing / Thermal Treatment: nucleation at -3°C, 0.5°C/min to -40°C after nucleation  Primary Drying: SMART Secondary Drying Conditions  ALL cycles: 0.1°C/min to 40°C, hold 360 minPage 12
  13. 13. SMART and ControLyo Obtained Primary Drying Recipes Phase Step Primary Secondary Drying Step 1 2 3 17 Shelf Temperature SP [°C] uncontrolled -37.0 -20.9 -24.4 40.0 controlled -37.0 -20.7 -17.1 40.0 Ramp Time [min] uncontrolled 6 32 7 644 controlled 6 33 7 571 Hold Time [min] uncontrolled 90 391 2497 360 controlled 90 90 1775 360 Vacuum SP [mTorr] 57 57 57 57 [Staertzel P, Gieseler M, Gieseler H, unpublished data , 2012]Page 13
  14. 14. SMART and ControLyo Process / Primary Drying Time, 1 Pirani/CM Differential [mTorr] 40 20 SMART, Uncontr. Annealing ControLyo@-3°C ControLyo@-8°C SMART+ControLyo@-3°C 2 mTorr 0 0 5 10 15 20 25 30 35 40 45 50 55 60 [Staertzel P, Gieseler M, Gieseler H, unpublished data , 2012] 1°Drying Time [hrs]Page 14
  15. 15. SMART and ControLyo Process / Primary Drying Time, 2 Primary Total Process Saving Saving Total Drying Time Time Primary Process [hrs] [hrs ] Drying Time* Time* [%] [%]SMART uncontrolled 49.5 72.7 0 0Auto-MTM ControLyo @ -3°C 41.9 68.1 15.3 6.3Auto-MTM ControLyo @ -8°C 44.6 70.2 10.0 3.5Annealing 44.7 81.2 9.7 -11.7SMART ControLyo @ -3°C 33.1 56.8 33.2 21.8* compared to SMART uncontrolled [Staertzel P, Gieseler M, Gieseler H, unpublished data , 2012]Page 15
  16. 16. SMART and ControLyo TP-MTM / Rp 6 -35 -36 5 -37 -38 Rp [cm2*Torr*hr/g] 4 Temperature [°C] -39 3 -40 SMART, Uncontr._Rp Annealing_Rp ControLyo@-3°C_Rp -41 2 ControLyo@-8°C_Rp ControLyo+SMART_Rp SMART, Uncontr._Tp-MTM -42 Annealing_Tp-MTM ControLyo@-3°C_Tp-MTM -43 1 ControLyo@-8°C_Tp-MTM ControLyo+SMART_Tp-MTM -44 0 10 20 30 Primary Drying Time [hrs] [Staertzel P, Gieseler M, Gieseler H, unpublished data , 2012]Page 16
  17. 17. SMART and ControLyo Product Appearance and Morphology Uncontrolled nucleationUncontrolled nucleation ControLyo @ -3°C ControLyo @ -8°C + Annealing 200 µm 200 µm 200 µm 200 µm [Staertzel P, Gieseler M, Gieseler H, unpublished data , 2012] Page 17
  18. 18. SMART and ControLyo Water Content[Staertzel P, Gieseler M, Gieseler H, unpublished data , 2012] Karl Fischer Titration, oven method, n=4Page 18
  19. 19. SMART and ControLyo Summary and Conclusion The freezing phase is an important part of the freeze drying cycle. The degree of super-cooling determines ice crystal size and hence cake morphology and drying performance (primary and secondary drying). Nucleation is a random process which can now be controlled, facilitating batch homogeneity and easier scale-up. ControLyo in combination with MTM technology (SMART), an established tool to optimize freeze drying cycles during the first run, can provide useful information about the correlation of freezing regimen / pore size and drying performance. A 33% saving of primary drying time could be achieved for 75 mg/mL sucrose by combination of ControLyo and SMART.Page 19
  20. 20. Literature (1) Wang DQ. 2000. Lyophilization and development of solid protein pharmaceuticals. Int. J. of Pharmaceutics 203 (2000). (2) Pikal MJ. 2002. „ Freeze Drying”. In: Encyclopedia of Pharmaceutical Technology, Marcel Dekker, New York. (3) Milton N, Pikal MJ, Roy ML, Nail SL. 1997. Evaluation of Manometric Temperature Measurement as a Method of Monitoring Product Temperature During Lyophilization. PDA J. Pharm. Sci. Technol. 51(1), 7-16. (4) Tang X, Nail SL, Pikal MJ. 2005. Freeze-Drying Process Design by Manometric Temperature Measurement: Design of a Smart Freeze-Dryer. Pharm. Res. 22(4), 685-700. (5) Tang X, Nail SL, Pikal MJ. 2006. Evaluation of Manometric Temperature Measurement, a Process Analytical Technology Tool for Freeze-Drying: Part I, Product Temperature Measurement. Pharm Sci Tech, 7 (1) Art. 14. (6) Tang XC, Nail SL, Pikal MJ. 2006. Evaluation of Manometric Temperature Measurement, a Process Analytical Technology Tool for Freeze-drying: Part II Measurement of Dry-layer Resistance. AAPS PharmSci-Tech, 7 (4) Art. 93. (7) Tang XC, Nail SL, Pikal MJ. 2006. Evaluation of Manometric Temperature Measurement (MTM), a Process Analytical Technology Tool in Freeze-Drying, Part III: Heat and Mass Transfer Measurement. AAPS Pharm SciTech, 7 (4) Art. 97. (8) Tang X, Pikal MJ. 2004. Design of Freeze-Drying Processes for Pharmaceuticals: Practical Advice. Pharm. Res. 21(2):191-200. (9) Searles et al. The Ice Nucleation Temperature Determines the Primary Drying Rate of Lyophilization for Samples Frozen on a Temperature-controlled Shelf. J. Pharm. Sci., 90:860-871, 2001. (10) Shon, M., The Importance of Controlling Nucleation Temperature During the Freeze Step, Introduction of ControLyo™ Nucleation on Demand Technology on the New FTS/SP Scientific™ LyoStar™3 Freeze Dryer, SP Scientific 2011 (11) Konstantinidis A, Kuu W, Otten L, Nail SL, Siever RR. 2011. Controlled Nucleation in Freeze-Drying: Effects on Pore Size in Dried Product Layer, Mass Transfer Resistance, and Primary Drying Rate. J. Pharm. Sci., early view. (12) Sever, R. 2010. Controlling Nucleation in Lyophilization: Effects on Process and Product. Proc. CPPR Freeze-Drying of Pharma- ceuticals and Biologicals Conference. Garmisch-Partenkirchen, October 2010. (13) Pikal, MJ. 1985. Use of Laboratory Data in Freeze Drying Process Design: Heat and Mass Transfer Coefficients and the Computer Simulation of Freeze Drying. J. Parenter. Sci. Technol.: 33 (3) May-June, 115-138.Page 20

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