Validation & Post Validation Monitoring

1. Validation & Post Validation Monitoring Reefer Validation Done Right David Ulrich Abbott Laboratories, QA Distribution Manager

2. What is Validation? • According to the Food and Drug Administration (FDA), the goal of validation is to: “[Establish] documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes.” - FDA, Guideline on General Principles of Process Validation

3. How do we Validate? • FDA’s Center for Drug Evaluation & Research (CDER) General Principles of Process Validation: • Installation Qualification (IQ) • Insures that the system/equipment and its components are installed correctly and to the original manufacturer’s specifications. • Operational Qualification (OQ) • The OQ, tests are performed on the critical parameters of the system/process. These are usually the independent and/or manipulated variables associated with the system/equipment • Performance Qualification (PQ) • This phase tests the ability of the process to perform over long periods of time within tolerance deemed acceptable.

4. Validation is NOT new for Pharma Mfg’ers (nor the FDA) • We currently execute validations on: • Methods, Assays, cleaning, recovery, E/U/F, computers, water systems (PW, DW, PO, WFI, etc), Lab instruments, etc • Processes (process validation); fill/finish mfg’ing, RO units, steam sterilization, EtOH sterilization, endotoxin removal, viral clearance, model virus studies, etc

5. Good Distribution Practices (GDP) Good Cold Chain Practices (GCCPs) Three main components of GDPs Good Import Practices (GIPs) Distribution Control Systems (DCS) GDP

6. Good Distribution Practices (GDP) RF TT, ISS Qualification, “import/Export ” Issues, returns, restock, Reverse Logistics Complaint mgt, Quality Agreements Good Cold Chain Practices (GCCPs) C-TPAT, TSA (CCFS/CCSP) Rules of Origin (COO), 10+2 (ocean transport), Trusted importer program GTIN, TnT, ePedigree (RFID), Lot number vs. 1-6-3-3, Serialization Mfg’ing/MA vs. Dist Control Good Import Practices (GIPs) Distribution Control Systems (DCS) GDP FEI rule changes Beyond Our Boarders, FDA Green lane, Import optimization (AOCC), RF enabled info Flow and “supplier supplier” information, Lacey Amendment, etc Congress (Dingle amendment, Kennedy Amendment, etc) And Other Gov’t initiatives

7. GDP – Program Overview  AQ16-00-GN-001

8. What do we Validate? • Mixers, granulators, mills, grinders, etc • Fluid Bed Dryers (FBDers), RO units, UF units, etc • Sterilizers, Ovens • Software (SQA, SIQ, SOQ, etc) • Manufacturing process of bulk APIs • Manufacturing process of finished goods • Shipment process of finished goods • HVAC units, clean rooms (class 100 hoods), etc • Controlled temperature warehouses • Refrigerated trucks (as part of the E/U/F validation program)

9. So how do we (should we) “validate” a reefer truck? • Big “V” and little “v”

10. What do we Validate? Refrigerated trucks are nomore complex • Insulated Trailer • Insulating capacity • Refrigeration unit • Cooling / Heating efficiently • Air flow efficiency All trailers (Class A, B, C) are all validated the same

11. Requirements - CFR Trailer Qualification Title 7: Agriculture – Can be used for your DQ, IQ, OQ • Chapter XXXIII—Office of Transportation, Department of Agriculture • PART 3300_ATP means the Agreement on the International Carriage of Perishable Foodstuffs and on the Special Equipment to be Used for Such Carriage (ATP), • Sec. 3300.61 Testing and verification requirements. • Sec. 3300.64 “the effective refrigerating capacity, W, in watts, of the appliance at an outside temperature of +30°C and the inside temperature for the class of equipment for which certification is sought”

12. Requirements – Industry Standards Industrial Standardization… • is the process of establishing agreement on uniform identifications for definite characteristics of quality, design, performance, quantity, service, etc. • sets acceptance criteria to meet requirements • maintains process controls and establishes testing methods • For reefer trucks  the standard is already in place • So no need to repeat the DQ, IQ, OQ • As part of your quality agreement – make sure your TSP know this AND has acceptable maintaiance

13. Validation – The Steps • FDA’s Center for Drug Evaluation & Research (CDER) General Principles of Process Validation (big “V”): • The little “v” componensts of the big “V” • Design Qualification (DQ) • Installation Qualification (IQ) • Operational Qualification (OQ) • Performance Qualification (PQ) • Process Validation (PV) for the “process”

14. Validation – Installation Qualification (IQ) Insures that the system/equipment and its components are installed correctly and to the original manufacturer’s specifications • Vendor’s Data Sheet or Specification required: • Insulating specification or data sheet for the trailer • Refrigeration and heating system specification or data sheet for the trailer HVAC on wheels

15. Validation – Operational Qualification (OQ) Tests are performed on the critical parameters of the system/process. These are usually the independent and/or manipulated variables associated with the system/equipment • ATP testing meets OQ requirements: • A trailer’s insulating capacity • A trailer refrigeration / heating system must have sufficient capacity to remove and add heat generated by: • Residual heat from the air inside the trailer • Exterior heat conducted through the floor, walls and ceiling • Infiltration heat from outside air through small holes, cracks and seals • A trailer air circulation system must have sufficient air flow (VOLUME AND VELOCITY) to carry the heat of the trailer to the refrigeration unit where it can be removed.

16. Validation – Performance Qualification (PQ) This phase tests the ability of the process to perform over long periods of time within tolerance deemed acceptable. • Testing Actual shipments • Run in triplicate • Next steps Post PQ: Periodic Monitoring

17. Reefer Validation – History • What’s been done: • It was suggested that a staggered (wall loading) loading pattern was safer AND would adequately cool • That’s was wrong • Why? Blocked airflow

18. Data Review • Actual PQ data review

19. Ambient Temps Week of 7-9-07 Chicago Ambient Temperatures Somerset Ambient Temperatures Air temperature

20. All Monitors 7-9-07 Shipment Truck surface temperature Next to wall Next to ice bricks • Maximum load of 4 ½ product pallets plus Commodities • Loaded with the Off-set Wall loading pattern

21. Current Monitor Locations – based off previous Reefer truck mapping Long “cool down” time Next to wall, first pallet in Blue Line – Pallet A driver side Green Line – Pallet B facing back doors Red Line – Pallet V, last pallet facing doors

22. Monitors on outsides of pallets Long “cool down” Wide “profile” Monitor next to ice bricks, Walls, and on the top of commodity pallets not included. Warmest location – Pallet D up against the wall Coldest location – Last pallet facing the back doors

23. External Monitors – Stationary Truck ExternalSurface temp > Ambient air temp 115 °F 40 °C Air cooling effect Maximum air temperature was 92 °F (33 °C) Blue Line – Back door of trailer Green Line – Driver side Trailer wall Red Line – Passenger side Trailer wall

24. Monitors on Product Pallets – Wall Loading Pallet D – Passenger side (against the wall) Pallet E – next to the ice bricks Wall loading “blocks” airflow causing long cool down times and variable profile. Not a flat line.

25. Monitors on Commodity Pallets No heat load/sink, therefore, does not effect temperature, BUT loading pattern is still critical Ambient corrugate doesn’t effect profile

26. Internal on the product pallets – Wall loading Wide “Product” temperature profile and long cool down Pallet A took 6.5 hours to get within spec. Blue Line – Pallet A Green Line – Pallet B Red Line – Pallet C Yellow Line – Pallet D

27. Pallet A Monitors – Next to driver side wall Bad airflow, therefore, > 8 °C Per ASHRAE – airflow is more critical than temperature Blue Line – Driver side(against the wall) Red Line – internal to the pallet Green Line – Middle between rows of pallets Yellow Line – Top of pallet

28. Monitors on the inside of the trailer walls (6 ft high) Pallet height was variable from 5 Ft to 7 Ft Above 8 °C for 3.5 hours. Longer to achieve acceptable temperature – not optimal

29. Monitors on pallets up against the walls – Wall Loading Wall Loading blocks airflow Highest to Lowest Temperature (Maximum Delta of 8.5 °C) Green Line – Pallet D Blue Line – Pallet A Red Line – Pallet E Yellow Line – Pallet L Light Blue Line – Pallet U

30. TempTales on pallets away from the walls Still a long time to cool vs centerline loading (and not a flat line) Highest to Lowest Temperature (Maximum Delta of 2.2 °C) Green Line – Pallet C Red Line – Pallet K Blue Line – Pallet B Yellow Line – Pallet V

31. Middle Monitors between Pallets – stayed above temp as long as wall pallets 6 hours above 8 °C Next to ice bricks Highest to Lowest Temperature (Maximum Delta of 21°C) Red Line – Pallet U Green Line - Pallet E (next to icebricks)

32. What Should be Done • Centerline Loading • Shows that loading pattern is most critical and that set point can be maintained with proper loading pattern

33. Ambient Temps Week of 7-16-07 Chicago Ambient Temperatures Somerset Ambient Temperatures

34. All internal monitors - Centerline Quick cool down and excellent control (low variability) Looks like a cold room

35. External Monitors – Truck surface Blue Line – Back door of trailer Green Line – Driver side Trailer wall Red Line – Passenger side Trailer wall

36. Monitors on Product Pallets Good airflow – based off loading pattern, no hot/cold spots, therefore, monitor location not critical

37. Internal on the product pallet Monitor location not critical Blue Line – Pallet A Green Line – Pallet B

38. Monitors on the inside of the trailer walls External wall temp ~ 100 °F, R value is adequate to insulate vs. conduction

39. Middle Monitor between Pallets Flat line

40. Ambient Temps Week of 7-23-07 Chicago Ambient Temperatures Somerset Ambient Temperatures

41. All Monitors 7-23-07 Shipment – Centerline Loading • Maximum load of 4 ½ product pallets plus Commodities • Loaded with the Centerline loading pattern

42. Current Monitor Locations (3 per shipment) Blue line – Pallet A driver side Red Line – Pallet N, last pallet facing back doors Green Line – Pallet B, facing back doors

43. All possible monitoring locations Nice and tight Warmest location – Pallet M, middle between pallets Coldest location – Pallet D, top

44. External Monitors – truck surface Blue Line – Back door of trailer Green Line – Driver side Trailer wall Red Line – Passenger side Trailer wall

45. Monitors on Product Pallets Tight

46. Monitors on Commodity Pallets No heat load

47. Internal on the product pallet Product was at 2-8 °C and stayed at 2-8 °C Blue Line – Pallet A Green Line – Pallet B Red Line – Pallet C Yellow Line – Pallet D Lt Blue Line – Pallet E

48. Monitors on the inside of the trailer walls Airflow and wall R value keeps inside wall temperatures acceptable

49. Monitors placed towards the walls Monitor facing the wall – potential heat source 4-6 °C = beautiful Highest to Lowest Temperature (Maximum Delta of 2°C) Orange Line – Pallet F Aqua Green Line – Pallet M

50. Middle Monitors between Pallets 4-6 °C = beautiful Highest to Lowest Temperature (Maximum Delta of 4°C) Light Blue Line – Pallet M Dark Blue Line - Pallet A