040607 aaps pharmaceutics devel and implement lyo cycles

Critical Considerations in the Development and Implementation

of a Lyophilization Cycle

Jim SearlesJune 7, 2004

AAPS Pharmaceutics and Drug DeliveryPhiladelphia, PA

Jim Searles, Eli Lilly Inc., 7June04 2

Outline

1. Parametrically-sequenced cycles vs proven acceptable ranges

2. Freezing3. Shelf heat transfer4. Sonic water vapor flow


1. Parametrically sequenced cycles vs proven acceptable ranges • Parametric sequencing

– Steps of predetermined duration as long as process parameters are within range

– Product temperature or pressure rise measurements only used for confirmation

• Proven acceptable range– Acceptable range for each process parameter

(chamber pressure, shelf fluid inlet T, ramp rates, product T, pressure-rise)


Implementation of Parametric Cycle Control

Lower PAR

Upper PAR

Lower Alert

Upper Alert

don’t accrue elapsed step

time

“at setpoint”

deviation- evaluate for product quality impacts

deviation- evaluate for product quality impacts

Shelf T or Chamber P

Time

check equipment

check equipment

•Need wide PARs for shelf T and chamber P•Do not want to always run for drying time sufficient for minimum PARs•Therefore implement ALERT limits within control capability•STOP step timer when below ALERT, Deviation when outside of PAR•Allows ALERT limits to ensure good control WITHIN PAR range


2. Freezing


Freezing can affect process and product quality parameters

•Primary and secondary drying rates•Surface area•Solute crystallization•Product aggregation and denaturation•Storage stability•Reconstitution•Inter- and intra-batch consistency


Freezing Recommendations

Care must be taken through the process development and technology transfer sequence to avert unintended modifications to the lyophilized product attributes due to unintended effects on the freezing step.

For example, lyophilization development runs may be conducted in environments higher in environmental particulate burdens than production scale cGMP vial washing, depyrogenation, filling, loading, freezing, and lyophilization facilities, or may be conducted with discarded lots of product.


3. Shelf Heat Transfer

Heat Transfer Fluid in Shelf

IcePlastic Film

Sublimation Interface

Heat Transfer

Mass Transfer

Shelf Wall

Thermocouples


Shelf Heat Transfer• Ice slab sublimation• Ice interface at equilibrium with

chamber pressure• Fluid inlet T unchanged between

the two cases• Turbulent convection (blue)

results in more efficient heat transfer to the shelf surface and therefore a higher shelf temperature under load and higher drying rate

• Efficiency depends upon viscosity, temperature, and flow rate

TTurbulent

Laminar


Shelf Heat Transfer Coefficient

)(

)(

)(

)(

1

12

−

−−

−∆

=

−=∆=

skgm

KmWh

TTAHm

h

TTAhQHmQ

subl

shelf

surfacefluidshelf

sublsublshelf

surfacefluidshelfshelfsubl

sublsublsubl

&

&

&


Effects of Temperature and ScaleNote: shelf fluid flow ratealso changing with temperature

Overall heat transfer coefficient for ice slab on plastic film

Predicted Overall Heat Transfer Coefficient

02468

1012141618

-50 -30 -10 10 30 50 70Shelf T (C)

h (W

/m2K

)

LabProduction AProduction BProduction C

Shelf Heat Transfer Coefficient

0

50

100

150

200

250

-50 -30 -10 10 30 50 70Shelf T (C)

h (W

/m2 K

)

Jim Searles, Eli Lilly Inc., 7Jun04


Shelf Heat Transfer Recommendations

• Measure the heat transfer coefficients of your freeze-dryers

• Beware of the fact that they are affected by fluid flow rate and temperature (do you monitor flow rate?)

• Beware of associated scale-up issues


4. Sonic Water Vapor FlowThe objective of lyophilization process development

is to deliver a cycle that achieves the following:1. Acceptable product quality, consistent within a batch and

from batch to batch2. Operation within the capabilities of the equipment with

appropriate safety margins to ensure robustness3. Efficient plant utilization via the shortest possible cycle

time and full loading of the lyophilizerThis section is motivated by the second and third of these

objectives: We should design lyophilization cycles so that the drying rate is as high as possible with the freeze-dryer fully loaded with vials, while remaining safely within the capabilities of the equipment.

J. Searles, American Pharmaceutical Review, Spring 2004


Water Vapor Flow PathT

Connecting Duct

Shelves with Vials

Vacuum Pump

Door

Water Vapor Flow

P

Product Chamber Condenser

Chamber

Mushroom Valve(open position)

Condenser Coils


Compressible Fluid Flow• At steady state, conservation of mass calls for the mass flow rate to be constant

through the length of the duct. Because gas is compressible and the pressure is decreasing from left to right, the velocity of the gas increases from left to right, with it reaching its maximum value at the duct exit where the pressure is lowest.

• Thermodynamic theory shows that for ducts of constant cross-section the maximum possible velocity that can be achieved is Mach 1

• For a fixed upstream pressure (Pu), as the downstream pressure (Pd) is gradually reduced, the flow rate will increase but can continue to do so only until the flow velocity reaches Mach 1 at the duct exit. At this point he flow is said to be “choked” and further reduction in the downstream pressure will have no effect on the rate of mass flow.

FlowPu Pd

Pu > Pd


ChokingUpstream P = 0.1 Torr (100 mT)

0

2

4

6

8

10

12

14

16

0 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 0.1 0.11

Downstream P (Torr)

Flo

w (

kg/h

r)


Speed of Sound

vS = speed of sound (m s-1), γ = ratio of specific heats (CP/CV) for the gas (1.3 for water vapor in the vicinity of 0 ºC)R, T, and M = ideal gas constant, temperature, and molecular weight, respectively. The speed of sound is independent of pressure and weakly dependent upon temperature. The speed of sound in water vapor at 0 ºC is approximately 400 m/s.

MRT

vSγ

=


Problematic Freeze-Drying Runs

-80

-60

-40

-20

0

20

40

0 2 4 6 8 10 12 14

Time (hr)

T (°

C)

0

20

40

60

80

100

120

140P

ress

ure

(mT)

Shelf Inlet

Product 1

Product 2

Product 3

Product 4

Product 5

Product 6

Condenser

Chamber P

Condenser P

-80

-60

-40

-20

0

20

40

0

20

40

60

80

100

120

140A

B

Step Operating Parameters Hold Freezing Freeze to –45 ºC at 30 ºC/hr Hold 3 hours Primary Drying 30 ºC shelf fluid inlet T

100 mT chamber pressure Hold for at least 22.5 hours, advance once all product thermocouples are 26 °C or above

Secondary Drying 50 °C shelf fluid inlet T 100 mT chamber pressure

Hold for at least 11.0 hours, advance once all product thermocouples are 46 °C or above



StrategyDetermine the maximum product loading: I. Water sublimation tests in lyophilizers A and B to

determine the maximum sublimation rate (kg/hr) that each could support while maintaining a chamber pressure of 100 mT

II. Gas flow modeling to understand the mechanism limiting the achievable sublimation rate, and to confirm the results from the above sublimation tests

III. Small-scale tests to measure the maximum product sublimation rate (kg/hr/vial)(not shown)


Ice Slab Sublimation Testing

-40

-30

-20

-10

0

10

20

30

40

50

60

5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0

Tem

pera

ture

(C)

0

20

40

60

80

100

120

140

160

180

Pre

ssur

e (m

T)

Failure Point

Product ChamberPressure

CondenserPressure

Shelf Fluid Inlet Temperature

A

-40

-30

-20

-10

0

10

20

8 9 10 11 12 13 14Time (hrs)

Tem

pera

ture

(C)

0

20

40

60

80

100

120

Pre

ssur

e (m

T)

Product ChamberPressure

CondenserPressure

Shelf Fluid Inlet Temperature

B



Ice Test Results

Lyophilizer Lyo A Lyo B Connecting duct dimensions (diameter, length)(m)

0.57, 0.81 0.80, 1.22

Connecting duct nominal cross-sectional area (m2)

0.26 0.50

Connecting duct valve Mushroom (14 cm stroke)

Butterfly

Gas flow obstructions None Connecting duct partially obstructed by thermal radiation shield

Usable shelf area for product 20.1 m2 22.3 m2 Space capacity (product vials) 34,400 38,280 Maximum Supportable Sublimation Rate at 100 mT (from water sublimation tests)

15.8 kg hr-1 0.79 kg hr-1·m-2

19.7 kg hr-1 0.88 kg hr-1·m-2


ModelingAdiabatic Flow Equation

γ = ratio of specific heats for the gas/vapor (1.3 for water vapor in the vicinity of 0 ºC)

Mn = Mach number of the flow at the duct entranceMx = Mach number of the flow at the duct exitfD = Darcy friction factorL = length of ductD = diameter of duct

DLf

MM

MM

MMD

x

n

n

x

xn

=

+−+−

+−−

2)1(2)1(

ln2

)1(1112

22

22 γγγ

γ

Gordon Livesey, BOC Edwards


Modeling

The throughput (referenced to the initial stagnant temperature) is related to the inlet Mach number by

where we write

A = cross section area of ductT = initial temperature of gas/vaporM = molecular weight of gas/vapor (0.018 for water vapor)Pu = upstream pressure

Gordon Livesey, BOC Edwards

)1(21

2

2/10

)1(211

−+

−+

=γ

γ

γ

γ

n

nuz

M

MPCQ

MTR

ACz0=


Modeling Results

0

5

10

15

20

25Orifice0 Bends1 Bend2 Bends3 Bends4 BendsDATA

0

5

10

15

20

25

0 20 40 60 80 100Condenser Pressure (mT)

-40 C Gas-20 C Gas0 C GasDATA

Wat

er V

apo

r R

ate

(kg

/hr)

A

B


FD Capacity vs PressureMaximum Sublimation Rate

0.0

0.5

1.0

1.5

2.0

2.5

0 50 100 150 200 250Chamber P (mT)

Gas

Flo

w R

ate

(kg/

hr/m

2 ) LabProduction AProduction BProduction CLinear (Lab)

unpublished data Jim Searles, Eli Lilly Inc., 7Jun04


Choked Pressure Ratio

Choked flow can be diagnosed by the ratio of the product chamber to condenser pressures. One will not have choked flow if the ratio is less than that for a perfect orifice (1.83). For most lyophilizer duct configurations a ratio of greater than 3 will confirm choked flow. However a ratio between these values will require more detailed investigation.

1.83 1.9

2.44

2.813.11

3.38

1.5

2.0

2.5

3.0

3.5

4.0

Orifice 0 Bends 1 Bend 2 Bends 3 Bends 4 BendsMin

imu

m C

ho

ked

Pre

ssu

re

Rat

io (

Ch

amb

er/C

on

den

ser)


Optimal Capacity Utilization

While the maximum sublimation rate for a given product temperature can be found at the lowest feasible operating pressure, use of lower pressure increases the risk of encountering equipment limitations imposed by choked flow.

B. S. Chang and N. L. Fischer, Pharm. Res, 12:831-837 (1995).


Choked Flow Conclusions and Recommendations

• Lyophilizers should be specified, designed, and tested with specific capabilities in mind. One of these capabilities should be the minimum required drying rate (kg/hr) supportable by the system while maintaining a specific product chamber pressure.

• Conduct drying rate tests at a range of operating pressures to learn if their lyophilizer meets design specifications and to know their true capacity

• Pay close attention to design of the flow path, including valves and radiation shields

• Lyophilizers should have well calibrated capacitance manometers on both the product and condenser chambers

• Pursue Process Analytical Technologies (PAT) that measure the current sublimation rate

• Understand how much of your available drying rate capacity is being used

040607 aaps pharmaceutics devel and implement lyo cycles

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