Validation

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Validation Post Validation Monitoring

• Reefer Validation Done Right
• David Ulrich
• Abbott Laboratories, QA Distribution Manager

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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

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How do we Validate?

• FDAs 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 manufacturers 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.

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Validation is NOT new for Pharma Mfgers (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
  mfging, RO units, steam sterilization, EtOH
  sterilization, endotoxin removal, viral
  clearance, model virus studies, etc

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Good Distribution Practices (GDP)
Good Cold Chain Practices (GCCPs)
Three main components of GDPs
Good Import Practices (GIPs)
Distribution Control Systems (DCS)
GDP
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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), 102 (ocean transport), Trusted importer
program
GTIN, TnT, ePedigree (RFID), Lot number vs.
1-6-3-3, Serialization Mfging/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 Govt initiatives
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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
LSP List Quality Questionnaires Quality Agreements Quarterly Business Review Meetings
Stability Studies Distribution Website
Exception Management (RCA/CAPA) Performance Measurement and Reporting Root-Cause Analysis and Trend Analysis
GTIN, TnT Serialization RF enabled temp monitoring Unit level cumulative temp indicating Shipping Systems Regulatory and Industry Trends Monitoring Benchmarking
Policies / Procedures Training Modules Website Newsletter Quarterly Management Update Meetings
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
Stability Studies Temperature Cycle Studies Typical Supply Chain Excursions Distribution Stability Website How to handle cumulative supply chain excursions
Exception Management (RCA/CAPA) Performance Measurement and Reporting Root-Cause Analysis and Trend Analysis Global CAPA effectivity Quarantine Returns restocks
Policies / Procedures Training Modules Website Newsletter Quarterly Management Update Meetings Benchmarking Reaching out to other divisions
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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)

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

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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
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Requirements - CFR Trailer Qualification

• Title 7 Agriculture Can be used for your DQ,
  IQ, OQ
• Chapter XXXIIIOffice 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 30C and the inside
  temperature for the class of equipment for which
  certification is sought

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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

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Validation The Steps

• FDAs 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

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Validation Installation Qualification (IQ)
Insures that the system/equipment and its
components are installed correctly and to the
original manufacturers specifications

• Vendors 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
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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 trailers 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.

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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

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Reefer Validation History

• Whats been done
• It was suggested that a staggered (wall loading)
  loading pattern was safer AND would adequately
  cool
• Thats was wrong
• Why? Blocked airflow

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Data Review

• Actual PQ data review

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

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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
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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
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External Monitors Stationary Truck
ExternalSurface temp gt 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
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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.
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Monitors on Commodity Pallets
No heat load/sink, therefore, does not effect
temperature, BUT loading pattern is still critical
Ambient corrugate doesnt effect profile
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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
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Pallet A Monitors Next to driver side wall
Bad airflow, therefore, gt 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
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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
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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
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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
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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
21C) Red Line Pallet U Green Line -
Pallet E (next to icebricks)
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What Should be Done

• Centerline Loading
• Shows that loading pattern is most critical and
  that set point can be maintained with proper
  loading pattern

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Ambient Temps Week of 7-16-07
Chicago Ambient Temperatures
Somerset Ambient Temperatures
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All internal monitors - Centerline
Quick cool down and excellent control (low
variability)
Looks like a cold room
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External Monitors Truck surface
Blue Line Back door of trailer Green Line
Driver side Trailer wall
Red Line Passenger side Trailer wall
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Monitors on Product Pallets
Good airflow based off loading pattern, no
hot/cold spots, therefore, monitor location not
critical
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Internal on the product pallet
Monitor location not critical
Blue Line Pallet A Green Line Pallet B
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Monitors on the inside of the trailer walls
External wall temp 100 F, R value is adequate
to insulate vs. conduction
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Middle Monitor between Pallets
Flat line
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Ambient Temps Week of 7-23-07
Chicago Ambient Temperatures
Somerset Ambient Temperatures
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All Monitors 7-23-07 Shipment Centerline Loading

• Maximum load of 4 ½ product pallets plus
  Commodities
• Loaded with the Centerline loading pattern

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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
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All possible monitoring locations
Nice and tight
Warmest location Pallet M, middle between
pallets Coldest location Pallet D, top
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External Monitors truck surface
Blue Line Back door of trailer Green Line
Driver side Trailer wall
Red Line Passenger side Trailer wall
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Monitors on Product Pallets
Tight
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Monitors on Commodity Pallets
No heat load
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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
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Monitors on the inside of the trailer walls
Airflow and wall R value keeps inside wall
temperatures acceptable
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Monitors placed towards the walls
Monitor facing the wall potential heat source
4-6 C beautiful
Highest to Lowest Temperature (Maximum Delta of
2C) Orange Line Pallet F Aqua
Green Line Pallet M
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Middle Monitors between Pallets
4-6 C beautiful
Highest to Lowest Temperature (Maximum Delta of
4C) Light Blue Line Pallet M Dark
Blue Line - Pallet A
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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
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Transport Equipment Guidelines
These documents provide definitions,
requirements, test methods, and conformance
conditions for the trucking industry.
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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

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• Questions?