enhanced process / product understanding and control in freeze drying by using manometric...
DESCRIPTION
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.TRANSCRIPT
E-Mail: [email protected]: www.gilyos.com
Friedrich-Bergius-Ring 15D-97076 Würzburg
Emerging Technologies in Freeze DryingStirling Innovation Park - 3rd April 2012
Enhanced Process / Product Understanding and Control in Freeze Drying by using Manometric
Temperature Measurement (MTM) and Nucleation Control
Dr. Margit Gieseler
Page 2
Freeze Drying Phases - Overview Freezing phase:
• Principal dehydration step• Separation of most of the solvent
(typically water) from the solutes to form ice Primary drying phase:
• 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.
The Freezing Drying ProcessGeneral Introduction
3 - 6 hrs
hrs - days
3 - 10 hrs
Page 3
Primary DryingThe 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.
tXtL
TPtRRV
TANPPPtPice
icesp
spiceice
114.0 exp811.010465.0461.3 exp)()( 0
ice
psicespiceice
L.TTL.RR/PPL.T
010201
01020724 0
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 4
Primary DryingThe 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 5
Primary DryingSMART 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 6
Primary DryingProduct Resistance
0.0 0.1 0.2 0.3 0.4 0.5 0.60
1
2
3
4
5
6
7
8
9
10
11
12TYPE 4
TYPE 3
TYPE 2
Prod
uct R
esis
tanc
e, R
p (c
m2 T
orr h
r / g
)
Dry Layer Thickness, l (cm)
TYPE 1
l = dry layer thickness
RP (0) = resistance at l = 0
A1, A2 = constants
(13)
Page 7
shelf temperature
nucleation temp. Tn
Time [min]
Tem
pera
ture
[°C
]
freezing point Tf
(9), modified
Tn
shelf temperature
The Freezing PhaseNucleation 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 Freezing of pure ice. Concentration of all dissolved
Components ↑. Crystallization at Teu (crystalline
systems). Solidification at Tg′ (amorphous
systems).
Page 8
Super-Cooling Degree of super-cooling (Tn - Tf) determines ice crystal size:
Biggest obstacle in scale-up!
The Freezing PhaseImpact on Product Morphology and Cake Appearance
(10)
Low Tn High Tn
• High Rp• Long primary drying time• Short secondary drying
time
• Low Rp• Short primary drying time• Long secondary drying
time
Page 9
The Freezing PhaseControlling 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 10
The Freezing PhaseControlling Nucleation - ControLyo, Praxair, 2
Page 11
The Freezing PhaseControlling 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 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 min
Page 13
SMART and ControLyo
Obtained Primary Drying Recipes
Phase StepPrimary Secondary
Drying Step 1 2 3 17Shelf Temperature SP [°C] uncontrolledcontrolled
-37.0-37.0
-20.9-20.7
-24.4-17.1
40.040.0
Ramp Time [min] uncontrolledcontrolled
66
3233
77
644571
Hold Time [min] uncontrolledcontrolled
9090
39190
24971775
360360
Vacuum SP [mTorr] 57 57 57 57[Staertzel P, Gieseler M, Gieseler H, unpublished data , 2012]
Page 14
SMART and ControLyo
0 5 10 15 20 25 30 35 40 45 50 55 600
20
40
SMART, Uncontr. Annealing ControLyo@-3°C ControLyo@-8°C SMART+ControLyo@-3°C
2 mTorrPira
ni/C
M D
iffer
entia
l [m
Torr
]
1°Drying Time [hrs]
Process / Primary Drying Time, 1
[Staertzel P, Gieseler M, Gieseler H, unpublished data , 2012]
Page 15
SMART and ControLyo
Process / Primary Drying Time, 2
Primary Drying Time
[hrs]
Total ProcessTime[hrs ]
SavingPrimary
Drying Time* [%]
Saving Total Process
Time* [%]
SMART uncontrolled 49.5 72.7 0 0
Auto-MTM ControLyo @ -3°C 41.9 68.1 15.3 6.3
Auto-MTM ControLyo @ -8°C 44.6 70.2 10.0 3.5
Annealing 44.7 81.2 9.7 -11.7
SMART 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 16
0 10 20 30
1
2
3
4
5
6
SMART, Uncontr._Rp Annealing_Rp ControLyo@-3°C_Rp ControLyo@-8°C_Rp ControLyo+SMART_Rp SMART, Uncontr._Tp-MTM Annealing_Tp-MTM ControLyo@-3°C_Tp-MTM ControLyo@-8°C_Tp-MTM ControLyo+SMART_Tp-MTM
Primary Drying Time [hrs]
Rp
[cm
2*To
rr*h
r/g]
-44
-43
-42
-41
-40
-39
-38
-37
-36
-35
Tem
pera
ture
[°C
]
SMART and ControLyo
TP-MTM / Rp
[Staertzel P, Gieseler M, Gieseler H, unpublished data , 2012]
Page 17
SMART and ControLyo
Product Appearance and Morphology
Uncontrolled nucleation Uncontrolled nucleation+ Annealing ControLyo @ -3°C ControLyo @ -8°C
200 µm 200 µm 200 µm 200 µm
[Staertzel P, Gieseler M, Gieseler H, unpublished data , 2012]
Page 18
SMART and ControLyo
Water Content
Karl Fischer Titration, oven method, n=4
[Staertzel P, Gieseler M, Gieseler H, unpublished data , 2012]
Page 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 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.