1. © Institute for International Research, Inc. 2006. All rights reserved. Module 9: Validation - OQ

2. 2 international 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

3. 3 international Overview  Computer & Software Validation  Equipment Systems Validation  Cycles Validation  “Document the Result” vs “Meet a Specification”

4. 4 international Software Validation  Security  Screen Content  Buttons & Lights  Alarms  Power Failure  Software Recovery  Radio Freq. Interfer.  System Stability  Network Connection  Paper Charts

5. 5 international 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.

6. 6 international 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.

7. 7 international 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

8. 8 international 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.

9. 9 international 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!”

10. 10 international 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.

11. 11 international 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.

12. 12 international 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.

13. 13 international Software Validation 9  RFI: Verify that local RFI doesn’t interfere with data reception. This doesn’t have to be sophisticated.

14. 14 international 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.

15. 15 international Systems Summary  Vacuum System  Refrigeration and Heat Transfer  Air/Nitrogen/Gas Filtration  Stoppering  Chamber  Condenser  Isolation Valve  Door(s)  Instrument Calibrations

16. 16 international Systems Validation 1  Vacuum System  Pump Down Rate  Leak Rate <0.02 mbar-liter/sec  Blank Off Vacuum  Ultimate Low Pressure

17. 17 international Pump Down Rate The pipe section with the smallest conductance will determine the maximum conductance. A pipe is a resistor in a linear circuit.

18. 18 international Leak Rate Parenteral Drug Association Spec.

19. 19 international Lyo Volume Measurement

20. 20 international Lyo Volume Measurement  Volume of Atmospheric Air (23  C) Needed to Raise the Pressure from 100mT to 500mT Moles of Gas at 100 mT Moles of Gas at 500 mT (ignores bottle volume) Approximate Bottle Volume Needed in order to obtain an “on scale” measurement.

21. 21 international Lyo Volume Measurement

22. 22 international Systems Validation 2  Refrigeration and Heat Transfer  Record Suction/Head Pressure  Note Oil Level  Verify operation with only 1 compressor

23. 23 international 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.

24. 24 international Systems Validation 4  Stoppering: Calculate the stoppering pressure per vial for the largest and smallest vial.

25. 25 international 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.

26. 26 international Systems Validation 5  Chamber/Shelves  Determine shelf flatness oImportant for stoppering  Determine shelf temperature uniformity oMany thermocouples oMeasure during temperature ramps as well as steady state. oSpecification can be + 1  C  Drain oCan 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 oMeasure shelf chilling rate under full load from 0  to - 50  C

27. 27 international Systems Validation 6  Condenser  Maximum Condenser Capacity oTest, but don’t exceed mnfg’s stated capacity. oRecord whether condenser T varies with load.  Minimum Condenser Temperature oAt three different shelf temperatures. –Shelf set point = -50  C –Shelf set point = -20  C –Shelf set point = +30  C oFor each shelf set point determine condenser  T when there are 2 condensers.  Condenser Chilling Rate oMonitor condenser coils during chilling from 0 to -60  C.

28. 28 international Systems Validation 7  Isolation Valve  Gas Leakage: oEvacuate Chamber & Condenser oClose Valve oRaise chamber pressure to ~½ atmosphere. oCompare Condenser pressure to “normal” leak rate.

29. 29 international Systems Validation 8  Door(s)  Verify the door closing procedure.  Does it require a slight chamber vacuum?

30. 30 international Systems Validation 9  Instrument Calibrations  Do these UP FRONT

31. 31 international 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.

32. 32 international 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

33. 33 international Cycle Validation 3  Filter Integrity  Verify the automatic cycle.  Or Verify the SOP.  Integrity testing should be performed between every cycle.

34. 34 international 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.

35. 35 international Cycle Validation 5  Clean in Place  Verify the automatic cycle  Use riboflavin and a black light to assure coverage during CIP.

36. 36 international Time to Validate  8 to 12 Weeks.  1 or 2 Personnel  Calibration of gauges in advance  Adequate temperature logging devices.

37. 37 international 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

38. 38 international 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.