Validation & Post Validation Monitoring

Validation & Post Validation MonitoringReefer Validation Done Right

David UlrichAbbott Laboratories, QA Distribution Manager

HPCLC - ValidationMarch 2009

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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?

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.


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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


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Good Distribution Practices (GDP)

Good Import Practices (GIPs)

Good Cold Chain Practices (GCCPs)

Distribution Control Systems

(DCS)

GDP

Three maincomponents of GDPs


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Good Distribution Practices (GDP)

Good Import Practices (GIPs)

Good Cold Chain Practices (GCCPs)

Distribution Control Systems

(DCS)

GDP

RF TT, ISS Qualification, “import/Export ”Issues, returns, restock, Reverse Logistics

Complaint mgt, Quality Agreements

GTIN, TnT, ePedigree (RFID),Lot number vs. 1-6-3-3,

Serialization Mfg’ing/MA vs.Dist Control

Beyond Our Boarders,FDA Green lane, Import

optimization (AOCC), RF enabled infoFlow and “supplier supplier” information,

Lacey Amendment, etc

C-TPAT, TSA (CCFS/CCSP)Rules of Origin (COO),10+2 (ocean transport),

Trusted importer program

Congress (Dingle amendment,Kennedy Amendment, etc)And Other Gov’t initiatives

FEI rulechanges


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GDP – Program Overview AQ16-00-GN-001

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

Qualification / Validation

LSP ManagementProduct Stability

Studies

Performance Measurement and

Reporting

Communication and Education

Continuous Improvement

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

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 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”


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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

FDA’s Center for Drug Evaluation & Research (CDER) General Principles of Process Validation (big “V”):

The little “v” componensts of the big “V”

1. Design Qualification (DQ)

2. Installation Qualification (IQ)

3. Operational Qualification (OQ)

4. Performance Qualification (PQ)

5. Process Validation (PV) for the “process”


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Validation – Installation Qualification (IQ)

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

Insures that the system/equipment and its components are installed correctly and to the original manufacturer’s specifications

HVAC on wheels


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Validation – Operational Qualification (OQ)

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.

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


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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

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


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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 TemperaturesAir temperature


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All Monitors 7-9-07 Shipment

•Maximum load of 4 ½ product pallets plus Commodities•Loaded with the Off-set Wall loading pattern

Truck surface temperature

Next to wall

Next to ice bricks


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Current Monitor Locations – based off previous Reefer truck mapping

Blue Line – Pallet A driver side Green Line – Pallet B facing back doors Red Line – Pallet V, last pallet facing doors

Next to wall, first pallet inLong “cool down” time


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Monitors on outsides of pallets

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

Long “cool down”Wide “profile”


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External Monitors – Stationary Truck ExternalSurface temp > Ambient air temp

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

115 °F

Air cooling effect

40 °C


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Monitors on Product Pallets – Wall Loading

Pallet E – next to the ice bricks

Pallet D – Passenger side (against the wall)

Wall loading “blocks” airflow causing long cool down times and variable profile. Not a flat line.


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Monitors on Commodity Pallets

Ambient corrugate doesn’t effect profile

No heat load/sink, therefore, does not effect temperature, BUT loading pattern is still

critical


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Internal on the product pallets – Wall loading

Blue Line – Pallet A Green Line – Pallet B Red Line – Pallet C Yellow Line – Pallet D

Pallet A took 6.5 hours to get within spec.

Wide “Product” temperature profile and long cool down


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Pallet A Monitors – Next to driver side wall

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

Bad airflow, therefore, > 8 °CPer ASHRAE – airflow is more critical than

temperature


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Monitors on the inside of the trailer walls (6 ft high)

Above 8 °C for 3.5 hours.Longer to achieve acceptable temperature – not optimal

Pallet height was variable from 5 Ft to 7 Ft


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Monitors on pallets up against the walls – Wall Loading

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

Wall Loading blocks airflow


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TempTales on pallets away from the walls

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

Still a long time to cool vs centerline loading (and not a flat line)


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Middle Monitors between Pallets – stayed above temp as long as wall pallets

6 hours above 8 °C

Highest to Lowest Temperature (Maximum Delta of 21°C) Red Line – Pallet U Green Line - Pallet E (next to icebricks)

Next to ice bricks


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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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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



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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

Blue Line – Pallet A Green Line – Pallet B

Monitor location not critical


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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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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

Warmest location – Pallet M, middle between pallets Coldest location – Pallet D, top

Nice and tight


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External Monitors – truck surface



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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

Blue Line – Pallet A Green Line – Pallet B Red Line – Pallet C Yellow Line – Pallet D Lt Blue Line – Pallet E

Product was at 2-8 °C and stayed at 2-8 °C


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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

Highest to Lowest Temperature (Maximum Delta of 2°C)Orange Line – Pallet F Aqua Green Line – Pallet M

Monitor facing the wall – potential heat source

4-6 °C = beautiful


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Middle Monitors between Pallets

Highest to Lowest Temperature (Maximum Delta of 4°C) Light Blue Line – Pallet M Dark Blue Line - Pallet A

4-6 °C = beautiful


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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

1. Loading pattern is critical (airflow is most important)

2. Set point has to be correct

3. DQ, IQ, OQ has already been done per the stds

4. PQ – do this to understand your equipment and loading/transportation process

• Equipment maintenance is critical

5. Post validation monitoring

• 0-1 point based of PQ

6. We did not see a hot or cold spot with proper loading

7. Program and any justification should be part of the VMP


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Questions?

Documents

Validation & Post Validation Monitoring