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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

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Introducing

Lab WorkSridhar Aravapalli, Ph.D., Contract Scientist

SponsorshipCentreOne (previously One 2 One)Tom TemplemanAlex Tracy

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Acknowledgements

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• 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

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• 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

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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

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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

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• 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

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-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

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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

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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

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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

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”

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• 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

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Thank You