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
HPCLC - Validation
March 2009

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.
HPCLC - Validation
March 2009

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
HPCLC - Validation
March 2009

5. GDP Good Distribution Practices (GDP) Three main components of GDPs
Good Cold Chain Practices (GCCPs)
Three main
components of GDPs
Good Import Practices (GIPs)
Distribution Control Systems (DCS)
GDP
HPCLC - Validation
March 2009

6. GDP Good Distribution Practices (GDP)
Good Cold Chain Practices (GCCPs)
RF TT, ISS Qualification, “import/Export ”
Issues, returns, restock, Reverse Logistics
Complaint mgt, Quality Agreements
C-TPAT, TSA (CCFS/CCSP)
Rules of Origin (COO),
10+2 (ocean transport),
Trusted importer program
GTIN, TnT, ePedigree (RFID),
Lot number vs ,
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
HPCLC - Validation
March 2009

7. GDP – Program Overview  AQ16-00-GN-001
GDPs are Similar to the other GXPs
Maintain product quality and ensure compliance with global regulations and industry standards for the storage, handling and distribution of temperature-sensitive products
Qualification / Validation
LSP Management
Product Stability Studies
Performance Measurement and Reporting
Communication and Education
Continuous Improvement
Ambient Temperature Profiles
Shipping Systems / Shipping Lanes
Shipping Lane Temperature Monitoring
Facilities / Equipment
Validation Master Plans
Ambient Temperature Profiles
MKT &PDA TR 39
Shipping Systems / Shipping Lanes
Shipping Lane Temperature Monitoring
Facilities / Equipment
Supply Lane VMP: DQ, OQ, PQ & Supply lane qualification
LSP Mgt
TSP Mgt
Quality Questionnaires
Quality Agreements
Quarterly Business Review (QBR) Meetings
Set and communicate expectations
LSP List
Quality Questionnaires
Quality Agreements
Quarterly Business Review Meetings
Stability Studies
Temperature Cycle Studies
“Typical” Supply Chain Excursions
Distribution Stability Website
How to handle cumulative supply chain excursions
Stability Studies
Distribution Website
Exception Management (RCA/CAPA)
Performance Measurement and Reporting
Root-Cause Analysis and Trend Analysis
Global CAPA effectivity
Quarantine
Returns & restocks
Exception Management (RCA/CAPA)
Performance Measurement and Reporting
Root-Cause Analysis and Trend Analysis
Policies / Procedures
Training Modules
Website
Newsletter
Quarterly Management Update Meetings
Benchmarking & Reaching out to other divisions
Policies / Procedures
Training Modules
Website
Newsletter
Quarterly Management Update Meetings
GTIN, TnT & Serialization
RF enabled temp monitoring
Unit level cumulative temp indicating
Shipping Systems
Regulatory and Industry Trends Monitoring
Benchmarking
HPCLC - Validation
March 2009

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)
HPCLC - Validation
March 2009

9. So how do we (should we) “validate” a reefer truck?
Big “V” and little “v”
HPCLC - Validation
March 2009

10. What do we Validate? Refrigerated trucks are no more complex
Insulated Trailer
Insulating capacity
Refrigeration unit
Cooling / Heating efficiently
Air flow efficiency
All trailers (Class A, B, C) are all validated the same
HPCLC - Validation
March 2009

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 Testing and verification requirements.
Sec “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”
HPCLC - Validation
March 2009

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
HPCLC - Validation
March 2009

13. Validation – The Steps Design Qualification (DQ)
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”
HPCLC - Validation
March 2009

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
HPCLC - Validation
March 2009

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.
HPCLC - Validation
March 2009

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
HPCLC - Validation
March 2009

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
HPCLC - Validation
March 2009

18. Data Review
Actual PQ data review
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March 2009

19. Ambient Temps Week of 7-9-07
Chicago Ambient Temperatures
Somerset Ambient Temperatures
Air temperature
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March 2009

20. All Monitors 7-9-07 Shipment
4/5/2017
All Monitors 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
HPCLC - Validation
March 2009

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
HPCLC - Validation
March 2009

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
HPCLC - Validation
March 2009

23. Maximum air temperature was 92 °F (33 °C)
External Monitors – Stationary Truck External Surface 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
HPCLC - Validation
March 2009

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.
HPCLC - Validation
March 2009

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
HPCLC - Validation
March 2009

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
HPCLC - Validation
March 2009

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
HPCLC - Validation
March 2009

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
HPCLC - Validation
March 2009

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
HPCLC - Validation
March 2009

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
HPCLC - Validation
March 2009

31. Highest to Lowest Temperature (Maximum Delta of 21°C)
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)
HPCLC - Validation
March 2009

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
HPCLC - Validation
March 2009

33. Ambient Temps Week of 7-16-07
Chicago Ambient Temperatures
Somerset Ambient Temperatures
HPCLC - Validation
March 2009

34. All internal monitors - Centerline
Quick cool down and excellent control (low variability)
Looks like a cold room
HPCLC - Validation
March 2009

35. External Monitors – Truck surface
Blue Line – Back door of trailer Green Line – Driver side Trailer wall Red Line – Passenger side Trailer wall
HPCLC - Validation
March 2009

36. Monitors on Product Pallets
Good airflow –
based off loading pattern, no hot/cold spots, therefore, monitor location not critical
HPCLC - Validation
March 2009

37. Internal on the product pallet
Monitor location not critical
Blue Line – Pallet A Green Line – Pallet B
HPCLC - Validation
March 2009

38. Monitors on the inside of the trailer walls
External wall temp ~ 100 °F, R value is adequate to insulate vs. conduction
HPCLC - Validation
March 2009

39. Middle Monitor between Pallets
Flat line
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March 2009

40. Ambient Temps Week of 7-23-07
Chicago Ambient Temperatures
Somerset Ambient Temperatures
HPCLC - Validation
March 2009

41. All Monitors 7-23-07 Shipment – Centerline Loading
Maximum load of 4 ½ product pallets plus Commodities
Loaded with the Centerline loading pattern
HPCLC - Validation
March 2009

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
HPCLC - Validation
March 2009

43. All possible monitoring locations
Nice and tight
Warmest location – Pallet M, middle between pallets Coldest location – Pallet D, top
HPCLC - Validation
March 2009

44. External Monitors – truck surface
Blue Line – Back door of trailer Green Line – Driver side Trailer wall Red Line – Passenger side Trailer wall
HPCLC - Validation
March 2009

45. Monitors on Product Pallets
Tight
HPCLC - Validation
March 2009

46. Monitors on Commodity Pallets
No heat load
HPCLC - Validation
March 2009

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
HPCLC - Validation
March 2009

48. Monitors on the inside of the trailer walls
Airflow and wall R value keeps inside wall temperatures acceptable
HPCLC - Validation
March 2009

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
HPCLC - Validation
March 2009

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
HPCLC - Validation
March 2009

51. Loading Pattern Criteria Wall Loading Centerline Loading
Impact of Load
High
Minimal
Hot/cold spots
Yes No
Cool down times
Lengthy – up to 8 hours
Less than 2 hours
Temperature
Profile
Wide and Varied
Tight and within specifications
Airflow
Reduced, making walls heat up and product temperatures rise
Optimal
Monitor
location/quantity
Monitor the hot and cold spots / need 3+ monitors
Location and quantity not critical
HPCLC - Validation
March 2009

52. Transport Equipment Guidelines
These documents provide definitions, requirements, test methods, and conformance
conditions for the
trucking industry.
HPCLC - Validation
March 2009

53. Conclusion Loading pattern is critical (airflow is most important)
Set point has to be correct
DQ, IQ, OQ has already been done per the stds
PQ – do this to understand your equipment and loading/transportation process
Equipment maintenance is critical
Post validation monitoring
0-1 point based of PQ
We did not see a hot or cold spot with proper loading
Program and any justification should be part of the VMP
HPCLC - Validation
March 2009

54. Questions?
HPCLC - Validation
March 2009