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International Society of Lyophilization

- 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

Critical Quality Attributes (CQA)


Critical Quality Attributes (CQA)
Process Design

Define Critical Process Parameters (CPP)


Identify Key Process Parameters (KPP)
Product Characteristics
Compounding Procedures
Compounding Procedures
Order of addition
Mixing
pH adjustment
Physico-chemical aspects
Product Characteristics
Bulk Solution Storage
Bulk Solution Storage
Storage conditions
Expiration
Product Characteristics
Low Temperature Analysis
Low Temperature Analysis
Phase Transition
Eutectic, glass transition (T
g
), collapse
Morphology
Amorphous or crystalline
Product Characteristics
Finished Product Qualities
Finished Product Qualities
Morphology / Thermal Properties
Dried Cake Appearance
Residual Moisture Range
Constituted Solution Attributes
Product Characteristics
Finished Product Qualities
Finished Product Qualities
Morphology
Amorphous or crystalline
Phase Transition Temperature
Crystalline melt, glass transition (T
g
)
Product Characteristics
Finished Product Qualities
Finished Product Qualities
Dry Cake Appearance
Color, density, uniformity, shrinkage,
collapse, meltback
Moisture Content
Average and range
Product Characteristics
Finished Product Qualities
Finished Product Qualities
Reconstitution
Technique
Complete dissolution
Constituted Solution Appearance
Clarity
Color
Product Characteristics
Finished Product Qualities
Finished Product Qualities
Product Assay
Initial
Constituted solution (after storage)
pH
Target and Range
Process Parameters
Establish critical independent parameters
Shelf (inlet) temperature
Chamber pressure
Time
Identify key dependent parameters
Product temperature
Condenser temperature
Target Lyophilization Parameters
Target Lyophilization Parameters
-50
-40
-30
-20
-10
0
10
20
30
40
0 200 400 600 800 1000 1200 1400 1600 1800
Ti me (mi nutes)
T
e
m
p
e
r
a
t
u
r
e

(
o
C
)
0
200
400
600
800
1000
1200
1400
1600
1800
2000
M
i
c
r
o
n
s
Chamber Pressure
Shelf Temperature
Product Temperature
Threshold Temperature
Proven Acceptable Range
Proven Acceptable Range
Boundary Parameters
Boundary Parameters
Define acceptable critical
parameter range
Proven Acceptable Range (PAR)
Boundary Conditions
Lyophilization Parameter PAR
Lyophilization Parameter PAR
-20
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
400 420 440 460 480 500
Ti me (mi nutes)
T
e
m
p
e
r
a
t
u
r
e

(
o
C
)
PAR: 5
o
< Target
PAR: 5
o
> Target
Target Lyophilization Parameters
Target Lyophilization Parameters
-20
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
400 420 440 460 480 500
Ti me (mi nutes)
T
e
m
p
e
r
a
t
u
r
e

(
o
C
)
40
50
60
70
80
90
100
110
120
M
i
c
r
o
n
s
PAR: 20 Hg < Target
PAR: 20 Hg> Target
Proven Acceptable Range
Proven Acceptable Range
Boundary
Boundary
Studies
Studies
Three batches at target conditions

Process conducted at ideal parameters


Process conducted at ideal parameters
Four batches at boundary conditions

High and low shelf temperatures


High and low shelf temperatures

High and low chamber pressures


High and low chamber pressures
Proven Acceptable Range
Proven Acceptable Range
Boundary Studies
Boundary Studies
Three batches at target conditions

Demonstrates reproducibility
Demonstrates reproducibility

Confirms consistent product qualities


Confirms consistent product qualities
Four batches at boundary conditions

Envelopes processing conditions


Envelopes processing conditions

Establishes proven acceptable range


Establishes proven acceptable range
-80
-60
-40
-20
0
20
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0 200 400 600 800 1000 1200 1400 1600 1800
Ti me (Mi nutes)
T
e
m
p
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a
t
u
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(
o
C
)
0
100
200
300
400
500
600
700
800
900
1000
Shelf Temperature
Chamber Pressure
Proven Acceptable Range
Proven Acceptable Range
-
-
Acceptable Boundary Conditions
Acceptable Boundary Conditions
Proven Acceptable Range
Proven Acceptable Range
Boundary Parameters
Boundary Parameters
Define acceptable critical
process parameter range (CPP)
Verify with product analysis and
stability (CQA)
Target Lyophilization Parameters
Target Lyophilization Parameters
-20
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
400 420 440 460 480 500
Ti me (mi nutes)
T
e
m
p
e
r
a
t
u
r
e

(
o
C
)
PAR: 5
o
< Target
PAR: 5
o
> Target
Action Level: 4
o
> Target
Action Level: 4
o
< Target
Alert Level: 2
o
< Target
Alert Level: 2
o
> Target
Target Lyophilization Parameters
Target Lyophilization Parameters
-20
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
400 420 440 460 480 500
Ti me (mi nutes)
T
e
m
p
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a
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e

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o
C
)
40
50
60
70
80
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100
110
120
M
i
c
r
o
n
s
PAR: 20 Hg < Target
Action Level: 15 Hg< Target
Action Level: 15 Hg> Target
Alert Level: 10 Hg> Target
Alert Level: 10 Hg< Target
PAR: 20 Hg> Target
Proven Acceptable Range
Boundary Conditions
Alert Level: If these conditions continue
the process will approach an Action
Level.
Action Level: If these conditions continue
the process will approach a Boundary
Condition.
Process Qualification
Demonstrate and document
capability of reproducible
commercial manufacture
Qualification of unit operation
Performance Qualification
Process Qualification
Capability of reproducible
commercial manufacture
CGMP compliant procedures
Successful completion prior to
commercial distribution
Process Qualification
Capability of reproducible
commercial manufacture
CGMP compliant procedures
Successful completion prior to
commercial distribution
Laboratory and pilot studies
can provide additional
assurance
Process Qualification
Address and Document
Intended outcome of process
Critical Processing Parameters (CPP)
Key Processing Parameters (KPP)
Critical Quality Attributes (CQA)
In-process and finished product testing
Extensive sampling and stability data
Additional analysis may be appropriate
Equipment Qualification
Goals
Verify that the equipment is adequate and appropriate.
Document the design, construction and installation.
Demonstrate the proper functions and performance
Prove that the equipment does what it is intended to do
Equipment Qualification
Scope and Objectives
Evaluation of each system function required for
processing, including verifying reproducibility
and consistency (uniformity) of conditions and
outcome.
Assure that the system performance is adequate
to support the process intended.
Benefits
Effective project management
Successful integration
Economics
Compliance
Equipment Qualification
Maximum Cooling and Heating Rate
Shelf Temperature Control
Shelf Temperature Uniformity
Condenser Cooling Rate
Condenser Capacity
Equipment Qualification
System Evacuation Rate
Pressure Control
Sublimation / Condensation Rate
Process Control / Data Acquisition
Lyophilization Cycle Run
Shelf Temperature
Maximum Cooling and Heating
Heat Transfer Fluid System
Refrigeration for Cooling
Heaters for Warming
Shelf Temperature Uniformity
Monitoring Locations
Five locations
on each shelf
Each corner and
geometric center
Shelf Temperature Uniformity
Monitoring Locations
Five locations
on each of the
shelves
Maximum Shelf Cooling / Heating Test
Maximum Shelf Cooling / Heating Test
Shelf I nlet
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-40
-20
0
20
40
60
80
0 50 100 150 200 250 300 350 400 450 500
Time (Minut es)
T
e
m
p
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a
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e
(

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
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-40
-20
0
20
40
60
80
0 500 1000 1500 2000 2500
Time (Minut es)
T
e
m
p
e
r
a
t
u
r
e
(

C
)
Condenser Cooling
Cooling Rate
Rate of chilling to process limit
Blank-Off Temperature
Ultimate temperature achieved
FD7 Condenser Cool i ng
Study X60301
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-70
-60
-50
-40
-30
-20
-10
0
10
0 10 20 30 40 50 60 70 80
Time (Minut es)
T
e
m
p
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a
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e

(

C
)
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
e
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(
C
)
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
r
e
s
s
u
r
e

(
M
i
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o
n
s
)
PRESSURE
Pressure Control Test
Pressure Control Test
Pressure Control Test
Pressure Control Test
90
92
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96
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100
102
104
106
108
110
20 25 30 35 40 45 50 55 60
Time (Minut es)
P
r
e
s
s
u
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e

(
M
i
c
r
o
n
s
)
PRESSURE
Pressure Control Test
Pressure Control Test
490
492
494
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500
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508
510
60 65 70 75 80 85 90 95
Time (Minut es)
P
r
e
s
s
u
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e

(
M
i
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s
)
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
r
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s
s
u
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e

(
M
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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
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10
20
30
40
T
i
m
e
1
4
:
3
6
:
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0
1
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:
5
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:
0
0
1
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:
1
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:
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0
1
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3
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:
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0
2
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:
0
0
:
0
0
2
1
:
2
1
:
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0
2
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:
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:
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0
0
:
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:
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0
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0
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:
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0
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:
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:
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0
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2
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:
0
0
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:
4
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:
0
0
8
:
0
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:
0
0
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:
3
0
:
0
0
1
0
:
5
1
:
0
0
1
2
:
1
2
:
0
0
1
3
:
3
3
:
0
0
1
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:
5
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:
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0
1
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:
1
5
:
0
0
1
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:
3
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:
0
0
1
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:
5
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:
0
0
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0
:
1
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:
0
0
2
1
:
3
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:
0
0
2
3
:
0
0
:
0
0
0
:
2
1
:
0
0
1
:
4
2
:
0
0
3
:
0
3
:
0
0
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:
2
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:
0
0
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:
4
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:
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:
0
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2
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:
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0
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

Absence of melt back or collapse


Absence of melt back or collapse
Acceptable Residual Moisture
Average
Range
Reconstitution
Time
Solution appearance
Lyophilizer Uniformity
Results of Monitoring & Sampling
Five locations
on each of
the shelves
Most Extreme
Most Representative
S
h
e
l
f
1
S
h
e
l
f
3
Lyophilizer Uniformity Studies
Lyophilizer Uniformity Studies
Locations in lyophilizer
Most representative reflects
the majority of the batch.
Most extreme is the outlier
that envelopes the entire batch.
FDA Definition:
Expectation for Validation
Establishing documented evidence which
provides a high degree of assurance that a
specific process will consistently produce
a product meeting its predetermined
specifications and quality attributes.
Validation for Compliance
Example of an Objective
The objective of validation for (product XYZ) is to show
that product manufactured and tested in accordance
with Master Batch Record ABC and Validation Protocol
123 will consistently meet its predetermined
specifications and quality attributes. This will be done
using 3 consecutively manufactured batches of product.
Heather Pederson, former Pre-Approval Inspection Program Manager, USFDA (Newark District)
Manufacturing Process Control
PROCESSES TO I NCLUDE
Formulation
Filling
Vial Transfer
Lyophilization
Sealing / Capping
Visual Inspection
Development to Manufacturing
Development to Manufacturing
SHOULD BE:
BIO-BATCHES
(PRODUCT SPECIFICATIONS)
SCALE UP BATCHES
(PROCESS PARAMETERS)
DEVELOPMENT REPORT
VALIDATION PROTOCOL
VALIDATION BATCHES
VALIDATION REPORT
OFTEN IS:
BIO-BATCHES
SCALE UP BATCHES
DEVELOPMENT BATCHES
DEVELOPMENT BATCHES
DEVELOPMENT BATCHES
VALIDATION REPORT
Heather Pederson, former Pre-Approval Inspection
Program Manager, USFDA (Newark District)
Performance Qualification
Performance Qualification
Address and Document
Intended outcome of process
Critical processing parameters (CPP)
Key processing parameters (KPP)
Critical quality attributes (CQA)
In-process and finished product testing
Stability data
Performance Qualification Studies
Performance Qualification Studies
Sequence in processing
Location in lyophilizer
Consistent Product Attributes
Performance Qualification Studies
Performance Qualification Studies
Sequence in processing
Consistent quality attributes throughout batch
Sample beginning, middle, and end of fill
Evaluate dispensed liquid and lyophilized samples.
Potency and Purity Attributes
Potency and Purity Attributes
Liquid Preparation
Liquid Preparation
Evaluate starting bulk liquid attributes
Monitor stability of starting liquid product to
quantify attributes from beginning to end of
batch.
Analysis demonstrates achievement of
predicted level of quality, purity, efficacy and
bulk liquid stability.
Lyophilization as a Unit Operation
Lyophilization as a Unit Operation
Loading
Freezing
Primary Drying
Secondary Drying
Stoppering
Process Parameters
Established critical independent
parameters (CPP)
Shelf (inlet) temperature
Chamber pressure
Time
Identified key dependent
parameters (KPP)
Product temperature
Condenser temperature
Lyophilization Process
Lyophilization Process
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2000
M
i
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n
s
Chamber Pressure
Shelf Temperature
Product Temperature
Threshold Temperature
Potency and Purity Attributes
Potency and Purity Attributes
Lyophilized Product
Lyophilized Product
Assess stability of lyophilized attributes
Verify lyophilization process does not alter
attributes or magnify any differences for the
dried product upon long term storage.
Analysis demonstrates achievement of
predicted level of quality, purity, efficacy and
solid state stability.
Performance Qualification Studies
Performance Qualification Studies
Consistent Product Attributes
Characteristics unique to
lyophilized preparations with
potency and purity attributes
Correlate initial quality attributes
with results upon storage.
Performance Qualification
Loading
Trays
Loading order & pattern
Shelf temperature
Holding time
Product temperature &
thermocouple placement
Performance Qualification
Loading
Final shelf temperature and range
Time
Product temperature
Performance Qualificaiton
Freezing
Ramps: Average Controlled Rates of Change
Final shelf temperature and range
Time
Product temperature threshold
Performance Qualification
Primary Drying
Shelf temperature
(soaks and ramps)
Chamber pressure
Product temperature
(Phase transition temperature)
Condenser temperature
Performance Qualification
Secondary Drying
Shelf temperature
(soaks and ramps)
Chamber pressure
Product temperature
(Phase transition temperature)
Condenser temperature
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TIME (Mi nutes)
T
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)
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M
I
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O
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S
SHELF TEMPERATURE
THRESHOLD PRODUCT TEMPERATURE
MAXIMUM CONDENSER TEMPERATURE
CONDENSER TEMPERATURE
PRODUCT TEMPERATURES
CHAMBER PRESSURE
Demonstrated Process Control
Demonstrated Process Control
Performance Qualification Objectives
Summary
Summary
Process Parameters
Controlling independent and monitoring dependent
process variables assures maintenance within a
proven acceptable range.
Product Characteristics
Verifying consistent achievement of predicted level
of quality, purity, efficacy and stability.
Development for Quality
Example of an Objective
Design Excellence (DEX) / Design for Six Sigma (DFSS)
Achieving Design Excellence using a set of design tools
and methodologies for improving product and process
development to consistently provide reliable and
manufacturable products that consistently meet
customer requirements.
Denise Hudson, VP Worldwide Process Excellence, J &J Pharmaceutical Group
Opportunity
Validation for Quality
Design for Six Sigma
Define
Measure
Analyze
Design
Verify/Validate
Transfer
Define
Develop Scope and Charter the Project
Measure
Gather & Quantify Design Inputs
Analyze
Develop and Investigate Conceptual Designs
Design
Develop Detailed Product Design &
Production Process
Verify/Validate
Confirm design outputs meet design input
requirements and ensure specifications
conform with Intended Uses and Users
Summary
Summary
Achieving Design Excellence
Achieving Design Excellence
Product design and processing conditions
are identified during development.
Reproducible process parameters and
consistent product quality attributes are
verified during scale-up and technology
transfer.
Control and reproducibility of the process to
consistently yield product of acceptable
quality, purity, efficacy and stability are
validated in manufacturing.
Thank you for participating!
References
References
Guidelines
Guidelines
Guide to Inspection of Lyophilization of
Parenterals (7/93)
Formulation of products
Aseptic FiIling
Cycle, Controls, Validation
Sterilization and Aseptic Processing
Finished Product Inspection and Testing
References
References
Inspection Documents
Inspection Documents
Compliance Program Guidance Manual, 7356.002A
- Sterile Drug Inspections (9/93)
Identify when using CMO
When manufacturing in house
Manufacturer of lyophilizer
Percentage of products lyophilized
Equipment general description
Processing procedures
References
References
Inspection Documents
Inspection Documents
Compliance Program Guidance Manual, 7356.002A
- Sterile Drug Inspections (9/93)
Equipment general description
Heating and cooling systems
Vacuum system
Gas used to break vacuum (sterile)
Temperature controlling system
References
References
Inspection Documents
Inspection Documents
Compliance Program Guidance Manual, 7356.002A
- Sterile Drug Inspections (9/93)
Processing procedures
Preparation of the sterile product for drying
Procedures for protecting product from
contamination while loading into lyophilizer
How are stoppers seating in vials
Conditions during stoppering under vacuum, what
gas is used and how sterilized
References
References
Inspection Documents
Inspection Documents
Compliance Program Guidance Manual, 7356.002A
- Sterile Drug Inspections (9/93)
Review of production records
Review at least three production records
Verify cycle parameters and observed results are
within scope of validation studies
Identify criteria for acceptable vs unacceptable runs:
general appearance, moisture, etc
References
References
Guidance for Industry
Guidance for Industry
Contents & Format of Chemistry, Manufacturing & Controls
Information and Establishment Description Information for
a Vaccine or Related Product, Section G (1/99)
A validation summary for lyophilization
Narrative description of the validation
Certification of completed IQ and OQ
Validation data summary
Explanation of all excursions or failures
Deviation reports and results of investigation
References
References
Guidance for Industry
Guidance for Industry
Submission of Chemistry, Manufacturingfor Human
Plasma Derived Biological Products, Animal or
Serum-Derived Products, Part 2, Section III, D (2/99)
A validation summary for lyophilization
Narrative description of the validation
Certification of completed IQ and OQ
Validation data summary
Explanation of all excursions or failures
Deviation reports and results of investigation
References
References
Guidance for Industry
Guidance for Industry
Content and Format of Chemistry, Manufacturing
for a Biological InVitro Diagnostic Product,
Section II, C, Methods of Manufacturing and
Packaging (3/99)
A complete description of the manufacturing
process flowshould be provided. This discussion
should include a description of:
Vialing / filling
lyophilization
labeling
packaging
References
References
Guidance for Industry
Guidance for Industry
Content and Format of Chemistry, Manufacturing
for a Biological InVitro Diagnostic Product,
Section II, C, Stability (3/99)
Stability data supporting the proposed shelf life of
the reconstituted in vitro product for all labeled
dilutions
References
References
Regulations
Regulations
Title 21 CFR, Section 211: GMP
Title 21 CFR Sections 600
(applicable to product category)
601.12: Changes to an Approved Application
610.13 Purity (a)(1) Test for Residual Moisture
References
References
Regulations
Regulations
211.137 (g) Expiration dating information of
reconstituted drugs for investigational use.
211.166 (a) (5) Stability Testing. Perform
stability testing of drug after reconstitution.