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Product temperature requirements
Any product can have a ‘fatal threshold’, that temperature in which it is effectively not usable. Failure to maintain a product with-in its specified temperature range could not only affect its quality but it could be lethal if consumed.

In the event of a temperature deviation outside the specified limits, a pharmaceutical product can be released from quarantine only if product stability data is available to support both the range and duration of the excursions. It is typically the QA Department that establishes the product’s temperature storage conditions based on the product specific performance criteria.

Vaccines and insulin must be protected from freezing. Even a brief period at sub-zero temperatures may irreversibly denature protein and lead to a loss of efficacy. Products based on emulsion systems and solutions of sparingly soluble components may become physically unstable at sub-zero temperatures. High ttemperatures can also cause product decomposition and an increased rate of degradation due to:
~ Separation of emulsion systems
~ Sedimentation of active ingredient(s) in suspensions and semi-solids
~ Changes in crystalline structure in fatty bases and active ingredients resulting in changes in melting time and bioavailability respectively

The increased expectations from regulatory bodies are requiring pharmaceutical companies to perform more extensive product stability studies to support both the shelf life documentation used during filing and to define the potential impact of any temperature excursion that may occur during product transportation.

Regulatory agencies require the product label to “numerically define” the product storage temperature requirements. As an example, the product label must be labeled “2°C to 8°C” as opposed to “Refrigerated”. This is to prevent different interpretations and, because the temperature ranges defined by various sources is not always consistent.

Source Room temperature
(controlled) Cool Cold Refrigerated Frozen Deep-frozen
Pharmaceutical
Quality Group 15 to 30°C No higher
than 15°C Does not exceed 8°C 2 to 8°C Below
-10°C
Health Sciences Authority 15 to 30°C 8 to 15°C Does not exceed 8°C 2 to 8°C -20 to
-10°C
European
Pharmacopoeia 15 to 25°C 8 to 15°C 8 to 15°C 2 to 8°C Below
-15°C
US
Pharmacopoeia ‘Controlled room
temperature’ or
‘up to 25°C’ 8 to 15°C Does not exceed 8°C 2 to 8°C -25 to
-10°C


Regardless of those differing temperature definitions, the most common product temperature ranges shipped in Envirotainer container is noted below. However, since the required temperature depends on the product requirements so one should always follow the documentation provided by the shipper or consignee:

• Deep frozen- Maintain products at -18°C or colder
• Refrigerated- Maintain products at 2°C to 8°C
• Do not freeze- Typically have a range of 2°C to 25°C (or 2°C to 30°C)
• Controlled room temperature (CRT)- Maintain product at 15°C to 25°C (or 30°C)


Container types
The RKN, RAP and CLD containers are thermostat controlled air cargo containers designed to transport temperature sensitive cargo in the refrigerated, controlled room temperature and deep frozen product temperature ranges as noted in the table below.

There are two types of technology in use:
• The “e1” type container is an electric “heating / cooling” technology and uses rechargeable batteries.
• The “t2” type container is “cooling only” technology and uses dry ice as a refrigerant. Because the “t2” container cannot heat, the container must be stored indoors and away from cold ambient temperatures.

Both the RKN and CLD containers are fork liftable when loaded with cargo. The RAP container can be moved with a fork lift when empty but must be moved with a roller bed system when it is loaded.


Container Container temperature range Description Product temperature types

CLD
-20°C to +20°C

*Provided the ambient temperature is 5°C to 25°C above the container set point
“Cooling only” unit using dry ice
(up to 35Kg)
• Refrigerated
• Do not freeze
• Deep frozen

RKNt2
-20°C to +20°C

*Provided the ambient temperature is 5°C to 25°C above the container set point
“Cooling only” unit using dry ice
(up to 1805Kg)
• Refrigerated
• Do not freeze
• Deep frozen

RAPt2 -20°C to +20°C

*Provided the ambient temperature is 5°C to 25°C above the container set point
“Cooling only” unit using dry ice
(up to 300Kg)
• Refrigerated
• Do not freeze
• Deep frozen


RKNe1 0°C to +20°C

*38 hours at the temperature extreme of either -10°C or +30°C

Electric heating & cooling using rechargeable batteries

• Refrigerated
• Do not freeze
• Controlled room Temperature


It is very important to use the correct container type and follow proper procedures to maintain the product temperature:


Refrigerated products- Both the RKNe1 and “t2” type containers are designed for this type of product. To maintain a 2°C to 8°C product temperature range in a “t2” type container, limit exposure to ambient temperatures below 10°C to 2 hours. Also, do not over-ice the container when the container may be exposed to cold ambient temperatures and this will increase the chance of overcooling the product.

Controlled room temperature products- The RKNe1 container is designed to both heat or cool as required to maintain product temperature is it the best solution for shipping CRT products as the container can be exposed to ambient temperature below the container set point.

If using a “t2” type container to ship CRT products, the challenge is to limit exposure to ambient temperatures below the product lower temperature limit (15°C) to 2 hours. This is because the container does not heat. While this is possible in Summer conditions (when the ambient temperatures are higher than 15°C), Envirotainer does not recommend using the t2 container for shipping CRT products in the Winter unless certain practices are followed (the more implemented, the less risk). Even then, the solution should be qualified for the trade lane before starting live shipments.
1) No dry ice is used in the container
2) The product is preconditioned to a least 20°C (the higher the better)
3) An overpack use used. In order of most to least effective overpacks, is
to load the product:
• In insulated boxes with gel-packs surrounding the goods (this reduces the volume for shipping goods).
• In insulated boxes before loading in the container
• On a pallet and all six sides are covered with foam insulation (with the edges sealed with tape)
• On a pallet and wrapped in several layers of bubble wrap
4) The temperature monitor is placed at inside the overpack at least one layer deep in the load, to protect it from measuring air temperature.
5) Thermal trucks (set at 20°C) are used for all ground transportation
6) Warehouse temperature are confirmed to be above 15°C
7) Tarmac time is strictly controlled to 2 hours or less
8) Aircraft temperatures can be maintained above 15°C
9) The container set temperature is 12°C. This will ensure the fan stays on and reduces temperature gradients in the container, however since dry ice is not used, the container will not maintain the set point. As the fan will run continuously, the battery consumption will be relatively high. We therefore recommend to change batteries every 24 hours.

Do not freeze products- These product types are easily shipped in the container since it has a broader temperature range than refrigerated product. However, the container’s exposure to ambient temperatures below 10°C must be limited to 2 hours.

Deep frozen products- Envirotainer containers are designed to maintain product temperature provided the ambient temperature does not exceed 25°C above the set point.

So how are deep frozen products shipped when ambient temperatures are above this limit? Given the fact that deep frozen is defined as -18°C or colder, up to 80% of the total amount of dry ice is added to the cargo area (the remaining 20% is placed in the bunker).

With dry ice is loaded in the cargo area, the container active cooling system has been “by passed” and, while the container can maintain -18°C or colder, the container can not regulate the lower temperature since the temperature of the dry ice is 78°C.


“t2” theory of operation
While the theory of operation of all “t2” containers is the same, there are two control unit types, so there are some differences in the user interface (buttons and display).

The container uses dry ice as refrigerant and 16 D-Cell alkaline batteries to power the control unit and fan(s). The RKN has one fan while the RAP has two fans. The CLD container differs in the fact that is uses one cooling fan and has a second circulation fan that comes on when the cooling fan turns off.

Envirotainer containers maintain product temperature by circulating air around the product. A temperature sensor in the container sends a signal to the control unit which turns the fan on or off to maintain the set temperature. The fan draws warm air from the container where it is cooled as it circulates around the outside of the dry ice bunker. The cooled air return to the cargo area through the air guides where it then flows around the cargo as a result of the convection process.

Air must flow around the cargo in order to maintain temperatures so the container has spacers along the walls to help ensure adequate airflow even when the cargo has shifted against the wall. To allow airflow underneath the cargo, it must be placed on a pallet or placed on spacers that are at least 2 cm high. It is also important to keep the area in front of the fan clear to allow airflow.

RKNe1 theory of operation
The RKNe1 container also maintains product temperature by circulating air around the product. However, unlike the “t2” type container, the fans remain on all the time and the exit air temperature is very close to the set temperature. The fan draws air from the container where it is circulates around the container’s heating/cooling unit. The temperature sensor in the container sends a signal to the control unit which turns on the heater(s) or cooling compressor(s) as heating or cooling is required. The cooled air return to the cargo area through the air guides where it then flows around the cargo as a result of the convection process.

“t2” container battery installation
This first step in operating the container is installing the batteries which provide power to the fan motor, control unit and display To mount the batteries, open the control unit door and place the 16 “D-Cell” alkaline batteries in the holder while ensuring the battery polarity is positioned as shown on the inside of the control unit door.


“t2” container battery life
The “t2” containers use 16 “D-Cell” alkaline batteries. Alkaline batteries must be used since other battery types discharge much quicker. Under typical conditions the container will operate for a maximum of 72hrs (82hrs for the CLD) before the batteries must be replaced.

However, there are conditions (high ambient / deep frozen cargo) when the fan(s) stays on longer and the battery life is reduced. Because of this, it is important to periodically check and, if the voltage falls below 9V, replace the batteries during transport.


“t2” battery voltage check
There are two batteries circuits for redundancy, so two different battery voltages are displayed. The batteries must be changed if they read below 11V when new or are below 9V anytime during transit.
The procedure for checking the battery voltage differs depending on the control unit type. Refer to the container operations manual for details.

Checking the container temperature
On both types of control units, the default display indicates the container temperature. Refer to the container operations manual for details.

Setting the temperature scale (Celsius or Fahrenheit)
The procedure for setting the container for Celsius or Fahrenheit depends on the control unit type. Refer to the container operations manual for details.

Changing the container temperature
The procedure for changing the container temperature, follow these steps depending on the control unit type. Refer to the container operations manual for details.


Container physical inspection
Envirotainer performs an inspection prior to releasing the container in accordance with the inspection criteria set forth in Envirotainer Customer Inspection Handbook Version 1.0.
However, this inspection is also performed by the service provider. This “double inspection” ensures the container function before the loading process.

While the service provider’s inspection may not be as detailed as that noted in the Customer Inspection Handbook, it does involve checking for obvious physical damage:
 No foreign material in or on the container (labels, batteries, trash or bags)
 All panels and roof are washed and the container is dry
 There is no panel separation of the aluminum and insulation (delamination)
 No holes or cracks that puncture the container panel (dent or deep scratch is OK)
 No hardware damage that affects its function or extends beyond the container profile
 Door and cover gaskets are in place and able to maintain door profile
 No bad battery box connections or oxidation

If there are issues with the container, action should be taken in accordance with the service provider’s standard operating procedure.


Container functional test
After the physical inspection, a functional test ensures the container operates. The test steps and purpose is noted below:

Step Purpose
1. Install the batteries and check the voltage (should read at least 11V) Confirms the batteries are installed correctly and are at the proper voltage

Confirms the control unit display is functioning

Confirms the battery connections are good

1. Set the temperature 3°C lower than the temperature in the container

2. Confirm fan is on by noting airflow from the air guide

3. Set temperature 3°C higher than temperature in the container

4. Confirm fan has shut off Confirms operation of the buttons and control unit

Confirms fan and thermostat is functioning



If there are no problems noted during the functional test, the container is ready for use.


Product preconditioning
Preconditioning is a term used to describe the temperature of the container or product prior to loading. The container must also be pre-cooled before loading to ensure an unbroken cold chain. Also, since the container is designed to maintain product temperatures (and not cool the product down), unless the product is properly preconditioned, it will cause the problems noted below:

Product temperature too warm: Dry ice will be used to cool the product causing it to be depleted before the scheduled time. This will cause a “high temperature deviation” (above the 8°C limit in the case of a refrigerated product).

Product temperature too cold: This will contribute to “low temperature deviation” much quicker than normal if the container is exposed to cold ambient temperatures.


Container preconditioning
The container is preconditioned using either a cold room or dry ice with a different procedure for each method.

Cold room preconditioning: After the functional test, the batteries are removed and the container placed in the cold room with the product. The doors are opened and the container allowed to cool down for at least one hour. This also applies to preconditioning a container in a temperature controlled truck.

Dry ice preconditioning: The amount of dry ice required to both precondition the container and maintain product temperature during the shipment is loaded in the bunker. Batteries are placed in the container and it is set to the product temperature. The container is then left to cool down for at least one hour.

When preconditioning for a deep frozen shipment, 20% of the dry ice is placed in the bunker and 50Kg (5Kg for a CLD) is placed on a pallet inside the container. The dry ice bunker and container doors are closed, batteries placed in the container and it is set to the desired temperature. The container is then left to cool down for at least two hour.


Container preconditioning in high ambient temperatures
In extremely high ambient temperatures (and depending on the amount of dry ice loaded in the container), an empty container may not reach the desired temperature range. This is because the container requires the thermal mass of the product to stabilize internal air temperatures under high ambient conditions.

Even if the container does not reach the desired temperature range, the product should be loaded after the allotted time; container temperature will drop into the desired range shortly thereafter or there is a problem with the container or dry ice load.


Dry ice
Dry ice is used as a refrigerant in Envirotainer containers because:
 It is readily available and relatively inexpensive
 It absorbs more heat than conventional ice
 Its temperature (-78°C) allows for good heat transfer

Dry ice is actually frozen carbon dioxide gas. While carbon dioxide gas is not toxic, it is heavier than air and, as a result, it displaces air in closed spaces and could cause asphyxiation if inhaled. Dry ice is a Class 9 Dangerous Good and should be noted in the Air Way Bill according to IATA DG Regulations.
When handling dry ice, use gloves to prevent frostbite.

Dry ice comes in varying forms; blocks, slices and pellets. Dry ice can also be either wrapped or unwrapped. Wrapping (in paper and plastic) insulates the dry ice to reduce the heat transfer rate and is typically used for refrigerated shipments. Unwrapped dry ice is always used for deep frozen shipments.

Envirotainer recommends using sliced dry ice (in 2 to 7Kg pieces) to allow even distribution in the bunker and ease of handling.


Dry ice amounts
Even though the container bunkers can hold a considerable amount of dry ice (30Kg for the CLD, 180Kg for the RKN and 300Kg for the RAP), it is not recommended to simply fully load the bunker. Rather, the dry ice load should be calculated based on the transportation schedule’s time and temperature profile.

This is especially true if there is a chance that the container will be exposed to ambient temperatures with-in 5°C of the set point. Under those conditions there is less heat being absorbed by the container than being removed by the dry ice and ambient conditions.




Dry ice calculation
Because it is important to have the correct amount of dry ice in the container, it must be calculated based on the expected transportation schedule’s time and temperature profile.

 The dry ice amount can be calculated using the container Operation Manual or Envirotainer can provide this service. Complete the Transportation Schedule form which is located on the dry ice page of www.envirotainer.com, Email to:
 Europe, Middle-East and Africa emeadryicerequest@envirotainer.com
 Rest of the world dryicerequest@envirotainer.com
 Allow 24 hour response time


Dry ice loading
Small blocks or slices weighing between 2 and 7kg are recommended for use since they last longer than pellets and can be evenly distributed in the container bunker. If pellets must be used, 2 to 7Kg should be placed in a closed bag before distributing in the bunker.
For refrigerated products, , wrapped dry ice is typically used. However, if the average ambient temperature is greater than +25°C, unwrapped dry ice is recommended and frozen products (-18°C or below) should always use unwrapped dry ice.


Monitoring product temperature
For most shipments, a temperature monitor is included with the cargo to record the product temperature. This data is used by the shipper or consignee’s quality department as evidence that the product was maintained within the prescribed range.

Referring to PDA Technical Report #39, “Calibrated temperature monitors should be placed directly in contact with the product or representative product, if possible, to collect temperature data.”

While following this guidance may not be feasible, the temperature monitor should at least be placed down between the product boxes and not on the outside of the box where it will measure temperatures more indicative of the product temperature and not the air temperature in the container.

The Envirotainer container is designed to maintain product temperature not container air temperature. Because of this, it cannot be expected that the air temperature in the container will always stay within the specified product temperature range during shipment. This is especially true when the container is exposed to ambient temperatures outside the specified limits.

Due to the insulation properties of the product package, excursions in the container air temperature outside the specified product temperature range for a short period of time will not affect the product.

This is illustrated below; while the container air temperature is outside the acceptable product temperature range, the product is not. Measuring air temperature in this case would record a “false deviation”.


Product loading
Container loading takes place indoors or in a shaded area taking care to minimize the container door opening and product exposure to ambient temperatures.

For the RKN and RAP containers, the cargo is typically loaded on a pallet, however, if loading the product by hand, the product boxes must be placed on at least 2cm high spacers to allow airflow. For the CLD, there are spacers on the bottom of the container, so the boxes can be loaded directly in the container.

After securing the cargo using the container’s tie-down brackets (RKN /RAP only), close the doors.


Product loading (deep frozen)
Recall Envirotainer containers are designed to maintain product temperature provided the ambient temperature does not exceed 25°C above the set point.

So how are deep frozen products shipped when ambient temperatures are above this limit? Given the fact that deep frozen is defined as -18°C or colder, up to 80% of the total amount of dry ice is added to the cargo area (the remaining 20% is placed in the bunker).

With dry ice is loaded in the cargo area, the container active cooling system has been “by passed” and the temperature range cannot be controlled.

Dry ice is placed in boxes, distributed on top of the cargo and secured into position. Any remaining dry ice is placed on spacers on the floor of the cargo area. Refer to the RKN/RAP Container Checklist for Deep Frozen Products in the Container Operations manual for more information.


After loading
After loading, it is important to allow the container to stabilize within the desired product temperature range before shipment. The container is designed to maintain the set point with a +/-3°C temperature range so if the container does not reach this range, the most probable causes are:

 Container exposed to high/low ambient temperatures
 Cargo not preconditioned to the set temperature
 Incorrect amount of dry ice / wrong type / not distributed evenly
 Problem with the container (chances are slight if a functional test was done!)

If there are problems, action must be taken at the shipper so that, if required, the product can be placed back in the cold room.

Handling the container
The CLD and RKN containers can be moved with a forklift. The RAP can also be moved with a forklift when empty, but when full, it must be moved with a roller bed.

If a roller bed is not available, the RAP can be placed on two heavy beams running the full length of the container. The container is then picked up from the side using a lift with extended forks. It should be noted that the container was designed for use with a roller bed and any alternative means to handle the container may result in damage. Any container damage is responsibility of the Lessee.


Container transport
Here are a few points to consider when transporting the container:

• When planning the route, keep the transportation time to a minimum.
• If transporting the container by truck for more than 2 hours when the ambient temperature is with-in 5°C of the set point, use a temperature controlled truck set at 15°C (not required for deep frozen shipments).
• The most critical time during transportation is when the container is on the tarmac and exposed to ambient temperatures and the sun; limit tarmac time to 1 hour.
• On the aircraft, ensure the container is loaded in a heated cargo hold. If possible, position the container away from the cargo door where temperatures can low.
• Arrange to check the battery voltage and temperature at transit points. Plan ahead in case re-icing or batteries need changing.
• Arrange for customs pre-clearance to minimize the time at destination.

Deep frozen cargo
The container will maintain -20oC temperatures provided the ambient temperature is no more than 25oC above the set temperature. However, ambient temperatures typically exceed this limit, so dry ice must also be loaded in with the cargo to maintain a deep frozen state. Note that by loading dry ice in with the cargo, the container can no longer maintain a temperature range.

To expedite the preconditioning process, dry ice is placed in the cargo area in addition to the dry ice bunker. The procedure for container preconditioning is:
 Calculate the total amount of dry ice required
 Insert batteries, check fan operation and set the temperature
 Place 25 to 50 kg of unwrapped dry ice on a pallet in the cargo area
 Load 20% of the dry ice in the bunker. Hold remaining amount to load with cargo
 Close the container doors and allow at least one hour before loading the cargo
 Remove pallet and dry ice from the cargo area before loading

Typically 80% of the required amount of dry ice is distributed on top of the cargo. Any remaining dry ice should be put on spacers on the container floor. Unwrapped dry ice should be used and secured using plastic wrap or placed in boxes.
 Remove the batteries from the container and open the container doors
 Load the cargo on a pallet or spacers placed on the container floor
 Place 80% of the dry ice on top of cargo in boxes and secure into position
 Put and remaining dry ice in boxes and load around the cargo on spacers
 Close & secure the container doors
 Reinstall the batteries and set the container temperature

Re-icing the container
In the event of delays, long transit times or extreme ambient temperatures, it may be required to add dry ice to the container. To "re-ice" the container:
 Unlatch and open the dry ice bunker lid
 Discard remaining dry ice remove empty wrappings and redistribute the remaining dry ice
 Put the correct amount of fresh dry ice in the bunker
 Close and secure the dry ice bunker lid


Handling & transportation guidelines
Observe the following basic guidelines when handling the container:
 Ensure all doors and covers are secured before moving the container
 RKN containers can be fork lifted when empty or loaded
 Use slave pallets or roller bed to move a loaded RAP container.
 Use the container straps to handle the container on roller beds

If transporting a container in cold temperatures for a period of time that exceeds the specified limits, use a temperature controlled truck set at +15°C. Also take care not to leave a container on a non-temperature controlled truck in hot weather.

When transporting a loaded container by air, limit time on the tarmac during aircraft loading (to avoid temperature extremes and direct sunlight). Maintain a 15°C aircraft cargo hold setting and do not position the container near the cargo door where temperatures are much colder. Finally, always comply with airline regulations for the carriage of dry ice.