- Freeze Drying
Midwest Chapter Annual Meeting
Contemporary Approaches to
Lyophilization Process Validation
(in the Product Lifecycle)
Edward Trappler, Lyophilization Technology, Inc.
Early Development
Pre-formulation
API Characterization
Formulation
Presentation
Phase I Clinical
Short term stability
Product characterization
Phase II Clinical
Long term stability
Product specifications
Processing experience
Phase III Clinical
Development report
Technology transfer
Large scale batches
Bench scale Bench scale
Lab scale Lab scale
Pilot scale Pilot scale
Manufacturing Manufacturing
Development Pathway
Development Pathway
Governing Factors
Governing Factors
Product Quality
Economics
Compliance
Product Life Cycle
Product Life Cycle
Development:
Appropriate / reproducible process parameters
Consistent finished product quality attributes
Adequate long term stability
Product Life Cycle
Product Life Cycle
Tech Transfer / Scale-up to Manufacturing:
Qualified Equipment
Confirmed process design/reproducible parameters
Batch uniformity
Consistent product qualities
Product Life Cycle
Product Life Cycle
Routine Manufacturing:
Operate within an established envelope
Collect and analyze product and process data
Routine review and statistical analysis
State of control for process
Consistent critical quality attributes
Development Objectives
Address and Document
Clear intended outcome of process
Established critical independent processing parameters (CPP)
Assigned key dependent processing parameters (KPP)
Well defined critical quality attributes (CQA)
Appropriate in-process and finished product testing
Supporting stability data
Development Objectives
Development Objectives
Product and Process
Product and Process
Knowledge and Understanding
Knowledge and Understanding
Product Development
Dosage Form
Dosage Form
Demonstrates reproducibility
Demonstrates reproducibility
C
)
0
100
200
300
400
500
600
700
800
900
1000
Setpoint
Shelf I nlet
Shelf Temperature
Cooling Control and Uniformity
Control at loading temperatures
Cooling rate determination
Control at low temperatures
Shelf Temperature
Heating Control and Uniformity
Heating rate determination
Control at high temperatures
Control at intermediate temperatures
Shelf Cooling/Heating/Control Test
Shelf Cooling/Heating/Control Test
-60
-40
-20
0
20
40
60
80
0 500 1000 1500 2000 2500
Time (Minut es)
T
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Condenser Cooling
Cooling Rate
Rate of chilling to process limit
Blank-Off Temperature
Ultimate temperature achieved
FD7 Condenser Cool i ng
Study X60301
-80
-70
-60
-50
-40
-30
-20
-10
0
10
0 10 20 30 40 50 60 70 80
Time (Minut es)
T
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(
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COND 1 COND 2
Condenser Cooling Test
Condenser Cooling Test
Vacuum Pumping
Pull-Down Rate
Rate of evacuation to process limit
Blank-Off Pressure
Ultimate pressure achieved
FD-7 Chamber Evacuat ion Test ing
St udy X41201
-2000
0
2000
4000
6000
8000
10000
12000
14000
0 5 10 15 20 25 30 35 40
Time (min)
T
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(
C
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CH VAC
Chamber Evacuation Rate
Chamber Evacuation Rate
Pressure Control
Set Point Control During Drying
Minimum, maximum and selected
intermediate set points
Pressure Control During Stoppering
Setpoint control for vial headspace pressure
0
200
400
600
800
1000
1200
1400
0 20 40 60 80 100 120 140
Time (Minut es)
P
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PRESSURE
Pressure Control Test
Pressure Control Test
Pressure Control Test
Pressure Control Test
90
92
94
96
98
100
102
104
106
108
110
20 25 30 35 40 45 50 55 60
Time (Minut es)
P
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s
s
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(
M
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PRESSURE
Pressure Control Test
Pressure Control Test
490
492
494
496
498
500
502
504
506
508
510
60 65 70 75 80 85 90 95
Time (Minut es)
P
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s
s
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(
M
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)
PRESSURE
Pressure Control Test
Pressure Control Test
990
992
994
996
998
1000
1002
1004
1006
1008
1010
86 91 96 101 106 111 116 121
Time (Minut es)
P
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PRESSURE
Sublimation - Condensation
Sublimation / Condensation Rates
Produce maximum sublimation rate achievable
Condenser Capacity
Sublime quantity of water equal to total condenser
capacity at the maximum sublimation rate
Process Control
Activities
Computer validation
Input and output checks
Software development
documentation
Verification of programs
Verification of alarms
hierarchy and response
failure challenges
Data Acquisition
Data Acquisition Systems
Prove that the system is capable of the resolution,
accuracy and precision necessary for adequate
control and documentation of the process
Lyophilizer Uniformity Studies
Objective
Demonstrate uniformity of conditions and product
attributes unique to lyophiles throughout batch,
independent of location within the lyophilizer.
Goal
Assurance of reproducible processing conditions and
consistent dried product characteristics with desirable
attributes throughout a batch and for every batch,
independent of location.
Lyophilizer Uniformity Studies
Benefits
Allows correlation of sample temperature during
processing to dried product attributes.
Opportunity for statistical analysis.
Identify location within lyophilizer as points for
future monitoring and finished product
sampling.
Lyophilizer Uniformity Studies
Lyophilizer Uniformity Studies
Location in lyophilizer
Includes product temperature range at
critical times during process.
Correlate to dried product attributes.
Most representative and extreme location
in the lyophilizer.
Lyophilizer Uniformity
Monitoring & Sampling Locations
Five locations
on each shelf
(filled with product)
Monitor for product temperature
and evaluate dried product attributes
Lyophilizer Uniformity
Monitoring & Sampling Locations
Five locations
on each of
the shelves
Product Temperature Uniformity
Product Temperature Uniformity
-50
-40
-30
-20
-10
0
10
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30
40
T
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Left Location A Shelf 02 Location E Shelf 11 Location A Shelf 12 Centre Shelf 07 Location E Shelf 08
Centre Shelf 10 Location A Shelf 06 Location A Shelf 09 Location E Left Shelf 05 Location E Right Shelf 03
Centre Shelf 13 Centre Shelf 04 Centre Outlet Shelf 01 Centre Inlet Shelf 01 Centre Shelf 01
Centre Inlet Shelf 13 Centre Outlet Shelf 13 Centre Inlet Shelf 07 Centre Outlet Shelf 07
End of Freezing
End of Primary Drying
End of Secondary Drying
Lyophilizer Uniformity Studies
Use of model or actual product
Actual product formulation
Placebo vials spiked with active product vials
Use of a Surrogate
Surrogate Product Attributes
Surrogate Product Attributes
Presentation
Sufficient size (fill volume)
Ease of inspection
Ease of inspection
Model formulation
Discernable melt back or collapse
Distinguishable residual moisture
Representative
May emulate actual product
Similar to range of products
Critical Dried Product Qualities
Critical Dried Product Qualities
Dried cake appearance
Expected appearance