040607 aaps pharmaceutics devel and implement lyo cycles
TRANSCRIPT
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
Jim Searles, Eli Lilly Inc., 7June04 3
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)
Jim Searles, Eli Lilly Inc., 7June04 4
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
Jim Searles, Eli Lilly Inc., 7June04 5
2. Freezing
Jim Searles, Eli Lilly Inc., 7June04 6
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
Jim Searles, Eli Lilly Inc., 7June04 7
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.
Jim Searles, Eli Lilly Inc., 7June04 8
3. Shelf Heat Transfer
Heat Transfer Fluid in Shelf
IcePlastic Film
Sublimation Interface
Heat Transfer
Mass Transfer
Shelf Wall
Thermocouples
Jim Searles, Eli Lilly Inc., 7June04 9
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
Jim Searles, Eli Lilly Inc., 7June04 10
Shelf Heat Transfer Coefficient
)(
)(
)(
)(
1
12
−
−−
−∆
=
−=∆=
skgm
KmWh
TTAHm
h
TTAhQHmQ
subl
shelf
surfacefluidshelf
sublsublshelf
surfacefluidshelfshelfsubl
sublsublsubl
&
&
&
Jim Searles, Eli Lilly Inc., 7June04 11
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
Jim Searles, Eli Lilly Inc., 7June04 12
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
Jim Searles, Eli Lilly Inc., 7June04 13
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
Jim Searles, Eli Lilly Inc., 7June04 14
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
Jim Searles, Eli Lilly Inc., 7June04 15
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
Jim Searles, Eli Lilly Inc., 7June04 16
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)
Jim Searles, Eli Lilly Inc., 7June04 17
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
=
Jim Searles, Eli Lilly Inc., 7June04 18
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
Jim Searles, Eli Lilly Inc., 7Jun04
Jim Searles, Eli Lilly Inc., 7June04 19
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)
Jim Searles, Eli Lilly Inc., 7June04 20
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
Jim Searles, Eli Lilly Inc., 7Jun04
Jim Searles, Eli Lilly Inc., 7June04 21
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
Jim Searles, Eli Lilly Inc., 7June04 22
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
Jim Searles, Eli Lilly Inc., 7June04 23
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=
Jim Searles, Eli Lilly Inc., 7June04 24
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
Jim Searles, Eli Lilly Inc., 7June04 25
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
Jim Searles, Eli Lilly Inc., 7June04 26
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)
Jim Searles, Eli Lilly Inc., 7June04 27
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).
Jim Searles, Eli Lilly Inc., 7June04 28
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