Module 9:
Validation - OQ
© Institute for International Research, Inc. 2006. All rights reserved.
Module 9 Purpose and Objectives
 Module Purpose:
 Process optimization requires understanding
the process. The student will review the detail
for a Validation.
 Module Objectives:
 After this module, you will be able to
 Write an Operational Qualification for a
Lyophilizer
 Think through a Performance Qualification
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Overview
 Computer & Software Validation
 Equipment Systems Validation
 Cycles Validation
 “Document the Result” vs “Meet a
Specification”
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Software Validation
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Security
Screen Content
Buttons & Lights
Alarms
Power Failure
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Software Recovery
Radio Freq. Interfer.
System Stability
Network Connection
Paper Charts
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Software Validation
Security:
•Verify that the access is password
protected for each level and
screen.
•Opportunity to define all
screens if not previously done.
•Often necessary to implement
password security for a system
that already has the
passwords code.
•Document specific personnel
and their password
authorization levels.
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Software Validation 2
 Screen Content: Verify that the
information displayed on each screen
is correct.
Schematic diagrams must reflect the “as
built” equipment.
Look carefully at the labels and content for
tables.
Confirm that trend data is accurate for its
labels, dates, and data.
Later – test that cycle input data is
correctly implemented.
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Software Validation 3
 Lights/Switches/Buttons/Devices:
Confirm for each screen that all blingbling does as it had ought to!
Often the same menu is displayed from every
screen. Assure that every button on every
screen works.
Since every combination is impossible, lay
out a scheme for the combinations tested.
Also verify controls on any ancillary panel
other than the HMI
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Software Validation 4
 Alarms: Tediously test each alarm and
document the result.
Where possible simulate an actual failure
to cause each tested alarm.
Assure the presence of critical alarms for
pressure/time/temperature.
This may take several days
Make note of software alarms that could
exist and do not.
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Software Validation 5
 Power Failure: Document the result of a
power failure.
Check against expectation from an
existing SOP, or
Create an equipment specific SOP entry
for power failure.
“If there is anything to be done, the person
available doesn’t know how to do it!”
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Software Validation 6
 Software Recovery: Verify that the
software can be restored according to a
written procedure.
Can the system be re-installed onto a new
computer?
Verify how historical data is backed up.
Verify some of the backed-up data.
Document what was done.
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Software Validation 7
 System stability: Verify how difficult or
easy it is to hack or “bring down” the
system.
Assure that an operator cannot
accidentally crash the system.
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Software Validation 8
 Network: If data is sent over a network,
verify that the data sent is accurate and
that the network connection is
functional.
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Software Validation 9
 RFI: Verify that local RFI doesn’t
interfere with data reception. This
doesn’t have to be sophisticated.
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Software Validation 10
 Paper Charts: Verify that any charts are
calibrated, that the pens work, and that
an SOP exists to assure their operation
over a cycle that is multiple days in
duration.
Verify that the recorded data can be
identified by color or dot pattern and time.
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Systems Summary
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Vacuum System
Refrigeration and Heat Transfer
Air/Nitrogen/Gas Filtration
Stoppering
Chamber
Condenser
Isolation Valve
Door(s)
Instrument Calibrations
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Systems Validation 1
 Vacuum System
Pump Down Rate
Leak Rate <0.02 mbar-liter/sec
Blank Off Vacuum
Ultimate Low Pressure
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Pump Down Rate
The pipe section
with the smallest
conductance will
determine the
maximum
conductance.
A pipe is a
resistor in a
linear circuit.
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Leak Rate
mbar  L
mTorr  L
.02
 15.001
s
s
Volume
Liters
50
250
500
1000
2000
3000
4000
5000
6000
7000
8000
Specification
mTorr/min
18.001
3.600
1.800
0.900
0.450
0.300
0.225
0.180
0.150
0.129
0.113
Volume
Liters
9000
10000
11000
12000
13000
14000
15000
16000
17000
18000
19000
Parenteral Drug
Association Spec.
Specification
mTorr/min
0.100
0.090
0.082
0.075
0.069
0.064
0.060
0.056
0.053
0.050
0.047
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Lyo Volume Measurement
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Lyo Volume Measurement
 Volume of Atmospheric Air (23C) Needed to Raise the
Pressure from 100mT to 500mT
Moles of Gas at 100 mT
0.1torr  LyoV
n1 
RT
0.5torr  LyoV
n2 
RT
n1  0.016 mol
Moles of Gas at 500 mT
n2  0.081 mol
n2  n1
BottleVolume 
RT
760torr
(ignores bottle volume)
torr  L
R  62.3636686
mol  K
Approximate Bottle Volume Needed in order to
obtain an “on scale” measurement.
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Lyo Volume Measurement
LyoV
VolBottle 760000 mTorr
P  mTorr
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Systems Validation 2
 Refrigeration and Heat Transfer
Record Suction/Head Pressure
Note Oil Level
Verify operation with only 1 compressor
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Systems Validation 3
Air/Nitrogen/Gas
Filtration
 Verify gas pressures
 Assure filter integrity
after a fast vacuum
break
 Assure adequate
Nitrogen.
 This check is
probably not
provided by the
Lyo Manufacturer
and may be part of
an SOP rather
than a mechanical
alarm.
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Systems Validation 4
 Stoppering: Calculate the stoppering pressure
per vial for the largest and smallest vial.
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Stoppering - continued
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Ram Pressure x Cylinder Area = Force
Force/(Vials on Shelf) = Force/Vial
Force/(Shelf Area) = Shelf Pressure
Vials begin to break at about 25 lbf (111 N)
Vials fail to stopper with less than 4 lbf (17.8 N)
For most vials a setting of 10 psig is acceptable.
Shelf Pressure = 10 psi (69 kPa)
Verify the SOP for Stoppering – especially if it is
manual.
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Systems Validation 5
 Chamber/Shelves
 Determine shelf flatness
o Important for stoppering
 Determine shelf temperature uniformity
o Many thermocouples
o Measure during temperature ramps as well as
steady state.
o Specification can be + 1C
 Drain
o Can broken glass get trapped in the diaphragm
valve seal below the chamber? If YES, then verify a
procedure to assure that the valve will hold vacuum
for every run.
 Chilling Rate
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o Measure shelf chilling rate under full load from 0 to 50C
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Systems Validation 6
 Condenser
 Maximum Condenser Capacity
o Test, but don’t exceed mnfg’s stated capacity.
o Record whether condenser T varies with load.
 Minimum Condenser Temperature
o At three different shelf temperatures.
– Shelf set point = -50C
– Shelf set point = -20C
– Shelf set point = +30C
o For each shelf set point determine condenser T when
there are 2 condensers.
 Condenser Chilling Rate
o Monitor condenser coils during chilling from 0 to -60C.
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Systems Validation 7
 Isolation Valve
Gas Leakage:
o Evacuate Chamber & Condenser
o Close Valve
o Raise chamber pressure to ~½ atmosphere.
o Compare Condenser pressure to “normal”
leak rate.
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Systems Validation 8
 Door(s)
Verify the door closing procedure.
Does it require a slight chamber
vacuum?
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Systems Validation 9
 Instrument Calibrations
Do these UP FRONT
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Cycle Validation 1
 Sterilization: A Lyo is not an autoclave.
Map the autoclave with thermocouples to
find the 8 coldest points.
Temperatures > 121°C during the SIP hold
for all times.
Saturated Steam conditions exist.
All temperatures in the chamber are within
2C of each other.
Use biological indicators and verify a 12
log reduction.
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Cycle Validation 2
 Lyophilization:
Demonstrate an acceptable full scale run
with a simulant such as 2% Mannitol.
Perform a choked flow analysis according
to the procedure of
 James Searles, Observation and Implications of Sonic
Water Vapor Flow During Freeze-Drying AMERICAN
PHARMACEUTICAL REVIEW 2004, VOL 7; ISSU 2, pages
58-69
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Cycle Validation 3
 Filter Integrity
Verify the automatic cycle.
Or Verify the SOP.
Integrity testing should be performed
between every cycle.
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Cycle Validation 4
 Stoppering
Verify the automatic cycle
Or Verify the SOP
Assure and verify a loading pattern for
partial loads.
Verify that all vials are stoppered in a full
load.
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Cycle Validation 5
 Clean in Place
Verify the automatic cycle
Use riboflavin and a black light to assure
coverage during CIP.
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Time to Validate
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8 to 12 Weeks.
1 or 2 Personnel
Calibration of gauges in advance
Adequate temperature logging devices.
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Summary
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Security
Screen Content
Buttons & Lights
Alarms
Power Failure
Software Recovery
Radio Freq. Interfer.
System Stability
Network Connection
Paper Charts
•Sterilization
•Lyophilization
•Filter Integrity
•Stoppering
•Clean in Place
•Vacuum System
•Refrigeration and Heat Transfer
•Air/Nitrogen/Gas Filtration
•Stoppering
•Chamber
•Condenser
•Isolation Valve
•Door(s)
•Instrument Calibrations
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Exercise 9.1:
Flowchart the PQ for a real phase III product expecting a
PAI*.
•Does the lyo have to be run at the real lot size?
•How many runs have to be done?
•What cycle conditions should be used?
•Should the target parameters be set to operate at the
edges of temperature or pressure ranges?
•Can the product used for validation be sold?
*PAI = Pre Approval Inspection from FDA happens 60 or more days prior
to approval for sales.
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