module 9: validation - oq

© Institute for International Research, Inc. 2006. All rights reserved.

Module 9:Validation - OQ

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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

Security Screen Content Buttons & Lights Alarms Power Failure

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 bling-bling 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 daysMake 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, orCreate 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

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 SystemPump Down RateLeak Rate <0.02 mbar-liter/secBlank Off VacuumUltimate 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

.02mbar Ls

15.001mTorr L

s Parenteral Drug

Association Spec.

Volume Liters

Specification mTorr/min

Volume Liters

Specification mTorr/min

50 18.001 9000 0.100250 3.600 10000 0.090500 1.800 11000 0.082

1000 0.900 12000 0.0752000 0.450 13000 0.0693000 0.300 14000 0.0644000 0.225 15000 0.0605000 0.180 16000 0.0566000 0.150 17000 0.0537000 0.129 18000 0.0508000 0.113 19000 0.047

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Lyo Volume Measurement

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Lyo Volume Measurement

Volume of Atmospheric Air (23C) Needed to Raise the Pressure from 100mT to 500mT

Moles of Gas at 100 mT

Moles of Gas at 500 mT

(ignores bottle volume)

BottleVolumen2 n1760torr

R T R 62.3636686torr Lmol K

n10.1torr LyoV

R T n1 0.016 mol

n20.5torr LyoV

R T n2 0.081 mol

Approximate Bottle Volume Needed in order to obtain an “on scale” measurement.

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Lyo Volume Measurement

LyoVVolBottle 760000 mTorr

P mTorr

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Systems Validation 2

Refrigeration and Heat TransferRecord Suction/Head Pressure Note Oil LevelVerify 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

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/ShelvesDetermine shelf flatness

o Important for stopperingDetermine shelf temperature uniformity

o Many thermocoupleso Measure during temperature ramps as well as

steady state.o Specification can be + 1C

Draino 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 Rateo Measure shelf chilling rate under full load from 0 to -

50C

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Systems Validation 6

CondenserMaximum Condenser Capacity

o Test, but don’t exceed mnfg’s stated capacity.o Record whether condenser T varies with load.

Minimum Condenser Temperatureo At three different shelf temperatures.

– Shelf set point = -50C– Shelf set point = -20C– Shelf set point = +30C

o For each shelf set point determine condenser T when there are 2 condensers.

Condenser Chilling Rateo Monitor condenser coils during chilling from 0 to -60C.

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Systems Validation 7

Isolation ValveGas Leakage:

o Evacuate Chamber & Condensero Close Valveo 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 CalibrationsDo 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

2C 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 IntegrityVerify the automatic cycle. Or Verify the SOP. Integrity testing should be performed

between every cycle.

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Cycle Validation 4

StopperingVerify the automatic cycleOr Verify the SOPAssure 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 PlaceVerify the automatic cycleUse riboflavin and a black light to assure

coverage during CIP.

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Time to Validate

8 to 12 Weeks. 1 or 2 Personnel Calibration of gauges in advance Adequate temperature logging devices.

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Summary

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.