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Quality / Compliance
Supply Reliability
Cost / Cash /Value
Compromise to quality and compliance is not an option
Effect of Pressure upon Secondary Drying
Jim Searles, Ph.D. Technical FellowPfizer Global Supply, Global Technical Services
Pfizer Inc., McPherson, KS
SMI Lyophilization USA 27April2016 Iselin, NJ
Get a CMO’s Perspective onContracts, Risk and Metrics for Success
Brad BergPfizer CentreOne
6th CMO Quality Oversight& Risk Management Summit
April 20-21, 2016, Boston
Introducing
Lab WorkSridhar Aravapalli, Ph.D., Contract Scientist
SponsorshipCentreOne (previously One 2 One)Tom TemplemanAlex Tracy
3
Acknowledgements
4
• We are implementing significant lyophilization cycle optimization projects– Optimized primary drying steps are sometimes as
high as 600 mTorr (900 µBar)– Published work on effect of pressure during
secondary drying goes up to 200 mTorr• Scale-up within a production dryer can lead to
higher final moisture content– Suggests an effect of water vapor– Some older lyophilizers do not control pressure by
nitrogen injection, but by throttling the vacuum pump
Background
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Pressure Control
55
Connecting Duct
T
Vacuum Pump
DoorGasFlow
T P
Product Chamber
Condenser Chamber
Valve(open position)
Condenser CoilsP
Shelf heat
transfer fluid
Condenser heat
transfer fluid
Product vials on shelves
N2 gas bleed for P control
Older design
has vacuum throttling
valve
6
• The only paper addressing the effect of pressure upon secondary drying
• Formulations tested:– 5% Povidone (PVP, polyvinylpyrrolidone)– 18% Moxalactam di-sodium + 12% mannitol
• Pressure range 50 – 200 mTorr (67 – 267 µBar) with N2
• Samples were re-hydrated following complete lyophilization, then put through secondary drying
• Used a sample thief to stopper and remove samples• About 6% water vapor in the product chamber at 200
mTorr
Pikal, M.J. et al. (1990) “The secondary drying stage of freeze drying: drying kinetics as a function of temperature and chamber pressure.” International Journal of Pharmaceutics, 60: p.203-217
7
0 1 2 3 4 5 60
1
2
3
4
5
6
Pikal 2C 200mT
Pikal 18 C, 200 mT
Pikal 36 C, 200 mT
Pikal 36 C, 50 mTorr
Time (hours)
Moi
stur
e (%
)Pikal et al. 1990 Results for PVP
•Water content decreases rapidly initially and approaches equilibrium
•Equilibrium level decreases with increase in temperature
•No dependence upon chamber pressure
8
Pikal et al. 1990 Results for Moxalactam
PVP (on prev slide)
9
Pikal et al. 1990 This Work
Formulation(s)5% PVP (Povidone)
18% Moxalactam di-sodium + 12% mannitol
5% PVP (Povidone)
Vials 10 mL vials with 4 mL solution 10 mL vials with 4 mL solution
Samples PVP samples pre-equilibrated to 5.1% H2O
Proceeded directly from primary to secondary drying w/ sampling
Gas for sec dry N2 N2 or H2O
Shelf T and Chamber P
Chamber P (mT) Shelf T 50 200 600 2 ºC 18 ºC 36 ºC
Chamber P (mT) Shelf T 50 200 600 2 ºC 18 ºC 36 ºC
Work Comparison
10
• One full shelf of 176 sample vials• Lyophilization cycle:
– Freeze to 0 oC for 0.5 hours– Ramp to -40 oC at 1 oC/min, hold for 4 hours– Establish vacuum at 200 mTorr– Ramp shelf temperature to -10 oC, hold for 44 hours– Continue into secondary drying conditions specific for each experiment
• Secondary drying pressure achieved in one of two ways:– Normal operation of lyophilizer using N2 injection, or– “Water vapor” method described in following slides
• Three sample vials removed at each time point using sample extractor. Only non-edge vials were sampled.
• Gas <30% H2O (estimated using Pirani data)
Experiments
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Sample Extractor
12
-1 0 1 2 3 4 5 6 7 8 9 100
1
2
3
4
5
6
Pikal 2C 200mT2C, 50mTLogarithmic (2C, 50mT)2C, 200mT2C, 600mTPower (2C, 600mT)
Time (hours)
Moi
stur
e (%
)2 ºC Results
13
-2 -1 0 1 2 3 4 5 6 7 8 9 100
1
2
3
4
5
6
Pikal 36 C, 200 mT
Pikal 36 C, 50 mTorr
36C, 50mT
36C, 200mT
36C, 600mT
Time (hours)
Moi
stur
e (%
)36 ºC Results
14
Water Vapor Studies
Adjustable gate valve between chamber and
condenser
Ballast vials on shelf zero
Use sample thief to adjust gate valve to
achieve desired pressure
High fill of sucrose + mannitol formulation
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• Primary drying carried out as before• The ballast vials provide H2O vapor throughout
secondary drying of the sample vials– Pirani gauge does not drop
• At end of primary drying, pressure set to 0– No nitrogen injection
• Gate valve adjusted to achieve desired pressure– Only water vapor in chamber
• Sample throughout secondary drying
• >90% H2O as estimated with Pirani gauge
Water Vapor Studies
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-1 0 1 2 3 4 5 6 7 8 9 100
1
2
3
4
5
6
7
8
9
10
2C, 600mT
Power (2C, 600mT)
36C, 600mT
2C, 600mT water vapor
18C, 600mT water vapor
36C, 600mT water vapor
Time (hours)
Moi
stur
e (%
)Water Vapor in Chamber
17
PVP Equilibrium Sorption IsothermsA.P. Mackenzie and D.H.
Rasmussen in "Water Structure at the Water-
Polymer Interface," (H.H.G. Jellineck ed.),
Plenum Publishing Co., New York (1972).
*Additional PVP Equilibrium Sorption
Data in this Presentation is from:
"The Interaction of Water with Amorphous
Solids," Cynthia A. Oksanen, Master's
Thesis, University of Wisconsin, 1989
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Many ways to express. Most common is the partial pressure of water divided by saturation pressure:
, “relative humidity”, “aw”
Saturation pressure Po is a strong function of temperature
Saturation Pressure of H2O
https://commons.wikimedia.org/wiki/File:Dewpoint.jpg
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1 10 100 1,000 10,000 100,0000%
10%
20%
30%
40%
50%
60%
70%
-40-30-20-1022230405060
Partial Pressure of Water Vapor (mTorr)
Equi
libriu
m P
VP M
oist
ure
Cont
ent (
%) Sample
Temp (°C)
PVP H2O per Pw at Sample Temperature
20
1 10 100 1,000 10,0000%
1%
2%
3%
4%
5%
6%
7%
8%
9%
10%
-40-30-20-1022230405060
Partial Pressure of Water Vapor (mTorr)
Equi
libriu
m P
VP M
oist
ure
Cont
ent (
%)
Results with N2 gas P control
2 C, 600 mT water
vapor
18 C, 600 mT water
vapor
36 C, 600 mT water
vapor
Results Using Water Vapor
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1 10 100 1,000 10,0000%
1%
2%
3%
4%
5%
6%
7%
8%
9%
10%
-40-30-20-1022230405060
Pressure (mTorr)
Wat
er C
onte
nt a
t Equ
ilibr
ium
(%)
Design Space Concept
“Safe Zone”
22
• Pressure can have a profound effect upon secondary drying in the range 50 – 600 mTorr, but only if water vapor content is high– Water vapor content will be high in any lyophilizer that
does not control pressure using dry gas injection (e.g. throttling valve on vacuum line)
• Sorption data can be used to guide lyophilization secondary drying process development
• The “old” way of setting chamber pressure as low as possible for secondary drying makes sense in light of the “old” way of controlling chamber pressure- vacuum line throttling
Conclusions
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• Know how your lyophilizers control chamber pressure (N2 gas injection or vacuum line throttling)
• Secondary drying pressure:– N2 gas injection: Pressure in the range 50-600 is not a factor
Most lab lyos use N2 gas injection, but a smaller percentage of production lyos do!
– Vacuum pump throttling: Very low pressures recommended in order to assure low partial pressure of water vapor
Prevent scale-up surprises, improve lot-to-lot consistency
• Understand moisture sorption behavior of your product• Understand water vapor levels in laboratory and
production lyophilizers
Recommendations
24
Thank You