The 'Cold Chain'

It is expected that storage facilities will comply with the requirements of Part 4 of the Blood Safety and Quality Regulations, e.g. 2-6 ^oC for red cell storage. Calibration limits applied to monitoring devices should also be appropriate to meet these requirements. If alarm settings or storage specifications are outside these limits, a scientifically-based justification should be provided.

This article seeks to raise awareness with Hospital Transfusion Laboratories the areas which they will need to consider under the Blood Safety and Quality Regulations 2005.

• The cold chain for the hospital transfusion laboratory starts from the receipt of the blood from the blood centre to the time the unit is transfused or otherwise disposed of.
• GDP (Good Distribution Practice) requires us to – “ensure that storage conditions are observed at all times, including during transportation”
• Cold storage
  • Temperatures should be measured continually
  • Continuous 24 hour, 365 day monitoring for temperature alarm conditions
  • Defined procedure for responding to alarms, and contingency arrangements for dealing with stock in prolonged alarm situations
  • Maximum and minimum recorded daily
  • Accuracy of ± 0.5 ^oC
  • Consider the location of the equipment
  • Red cell components must be stored within the temperature range
    • 2 - 6 ^oC core temperature
  • Chart recorder, digital readout, max/min thermometer, central monitoring system, BUT whichever you choose will need to be calibrated annually and you will need an in date certificate for the calibration equipment, traceable to National Standards.
  • Paperwork/electronic storage records kept for 15 years

• Maintained electrical supply for unit / alarm
• Alarm testing – SOP determining
  • How often
  • By whom
  • When, including weekends and out of hours?
  • Local and remote
  • Evidence kept
• SOP for alarm incidents/ failure
  • At testing
  • Fridge or unit failure
  • Instruction for contact procedure, criteria for corrective action and contingency arrangements for stock transfer
• SOP for cleaning fridges etc.
• Fridge maintenance
  • Performed by whom
  • Current Certificate of calibration
  • Responsibility for satellite fridges, and if applicable clearly defined acceptance criteria and returns procedure Where lab not responsible for satellite fridge, any returns policy will require justification by strict lab audit of control/ monitoring procedures and records.
  • Review the need (written report) for each satellite fridge on an annual basis

Transportation

It is expected that storage facilities will comply with the requirements of Part 4 of the Blood Safety and Quality Regulations, e.g. 2-6 ^oC for red cell storage. Calibration limits applied to monitoring devices should also be appropriate to meet these requirements. If alarm settings or storage specifications are outside these limits, a scientifically-based justification should be provided.

• Cold chain goods – things to consider
  • Route and time
  • Seasonal variations
  • Nature of the load – red cells, platelets, other – how many as minimum and maximum loads?
  • Labelling
  • Clearly defined and documented instruction on procedure to be followed, with guidelines on ‘do’s and don’ts’.
• Transport - Guidelines for the Blood Transfusion Services in the UK
  • For red cell components, transit containers, packing materials and procedures should have been validated to ensure the component surface temperature can be maintained between 2 ^oC and 10 ^oC during transportation.
  • Additionally: The validation exercise should be repeated periodically
  • As far as practicable, transit containers should be equilibrated to their storage temperature prior to filling with components
  • If melting ice is used, it should not come into direct contact with the components
  • Dead air space in packaging containers should be minimised
  • Transport time normally should not exceed 12 hours
• Validation
  • As defined in BSQR 2005 – “validation is the establishment of documented and objective evidence that the particular requirements for a specific intended use can be consistently fulfilled”
  • Validation is performed in advance to ensure that transport of components provides the right storage conditions
  Consider:-
• What is the intended use
• What are the requirements
• How to get the objective evidence
• Documented evidence

1. Select the appropriate container
2. Prepare protocol for validation trial (i.e. describing plan and defining acceptance criteria) The plan should include the following points.
3. Take number of blood components packs considered to be maximum for the box
4. If time expired components not available, Fill empty packs with water to the nominal volume of component.
5. “Set up” temperature logger between units
6. Cover with packing material, including ‘wet ice’ packs where applicable.
7. Close box and secure
8. Store filled container/s in area/s representative of worst case transit conditions (i.e. high and low temperature challenges)and “log” area temperature
9. Leave for maximum journey storage time
10. Remove units and logger
11. interrogate both loggers
12. note period units remained between 2 ^oC and 6 ^oC core temperature
13. Note environments temperature range
14. If unable to obtain suitable storage time repeat using alternative container and/or packaging procedure
15. Repeat whole procedure with minimum load (e.g.1 unit)
16. On completion write report, including procedure, results, conclusions and recommendations
17. Ensure report is authorised for introduction of procedure into routine, that defined procedure is available to all groups of staff involved, and that report is accessible for audit

- transport validation
- monitoring deliveries
- fridge/freezer mapping
- storage at room temperature mapping

- write a specification
- calibrated
- have dedicated software
- battery shelf life and ease of replacement
- interface to connect to PC
- ensure no hidden costs
- robust and waterproof
- ease of use

- Performance

- hard/soft probes
- Temperature range
- Accuracy
- memory/frequency
- Manual/programmable
- temperature response time
- graphical/tabular reports

- CE marked
- Clear instructions for use
- Training provided by company
- Delivery time
- Proven record of reliability
- Mechanism for problem solving

Cold Chain clarification

A meeting with a professional panel was convened to discuss some of the confusion regarding the requirements of GMP.

The panel members where:

Stephen Bates, Cheltenham & Gloucester Hospital: Chair
Dr Ian Stewart, MHRA
Joan Jones, Chair of the OIG
Martin Slatford, Labcold Ltd
Latif Alayoub, Trackflow Ltd

The minutes of that meeting can be downloaded here (pdf).

Issued April 2007

(See initial "Understanding the 'Cold Chain' requirements")

There have been several "cold chain" issues raised at hospital blood bank inspections. This is an area where there appears to be some lack of understanding, despite previous information being provided. It is hoped that this further clarification will unravel some of the areas where compliance as required by the MHRA, is currently not being met.

The current air temperature alarm set at 2 and 8 °C is an ALERT alarm to warn of possible problems. It is allowable for this alarm to have a reasonable time delay built in (e.g. 10 minutes).

A buffered load alarm is required to work on the core temperature of the blood. This alarm must have trigger points of 2 and 6 °C (with acceptable probe calibration tolerances of ± 0.5 °C). This is an ACTION ALARM and must not have a time delay. The thermal mass and position of this probe should be at a position defined by suitable temperature mapping and scientific considerations, as defined in BS 4376 e.g. equivalent temperature capacity to 200 ml water. The time between sampling should be no more than 5 minutes which in real terms equates to the ACTION alarm sounding as soon as the trigger points are reached. This alarm should require a manual acknowledgement and not reset automatically if the temperature returns to within tolerance.

Temperatures recorded from the ACTION ALARM may be chosen as the PRIMARY SYSTEM to replace the temperature records provided by the paper chart recorder.

Temperature mapping

All equipment controlling temperature must be temperature mapped once a year.

The test must have a duration of at least 24 hours and should, for the smallest of storage equipment, include a minimum of 3 points which will normally be at least the centre chamber, top and bottom. The number of probes must be sufficient to comprehensively cover the area being mapped, therefore for equipment such as larger fridges, dual chamber fridges and walk-in cold rooms the number of probes should be increased based on a documented scientific justification. In the case of larger equipment, it is expected that mapping locations will normally be at least the centre chamber, and the 4 corners top and bottom of the parts of the cabinet used for storage. Mapping exercises should include correlation between the routine probe readings and the mapping probes to demonstrate that any condition shown by the routine probes will be representative of any extremes seen i.e. the routine probes must be demonstrated as being in the hot and cold spots of the bank.

The cabinet can be used during the test. The amount and type of product in the cabinet during the test must be recorded with the test results.

The minimum mapping probe calibration tolerance is ± 0.5 °C and the frequency of temperature logging to be no longer than 5 minutes.

Issued August 2007

Further clarification in respect of the 'cold chain'

It would appear from the various comments, emails and phone calls regarding the clarification on the cold chain, posted on the OIG website in April 2007 (see 'Cold Chain' clarification 1) that the issues raised are still causing some problems in understanding.

The aim was not to be prescriptive but to raise awareness and allow hospital transfusion laboratories to determine, through some scientific evaluation of their own systems how to implement the key issue of:

Objective, documented evidence that red cells are stored at a core temperature of 2-6°C ±0.5°C

This could be achieved in several ways e.g.:

If your current system has an alert alarm (air temperature alarm, 2-8°C, with a built in delay) you could:

1. Add a separate action alarm, buffered load, set at of 2-6°C ±0.5°C
2. Review over a predetermined period of time (this should be based on an assessment to ensure that all extremes of use e.g. heavy usage periods, are covered ) the correlation between the air temperature alarms and the buffered load temperature readings. To do this, monitor all the air temperature alarms and the core temperature recordings and document that the core temperature never goes outside the 2-6°C requirement with your current delay that is set on your air temperature alarm.
3. Use calibrated (±0.5°C) min/max thermometers, there is an expectation for a buffered probes and record the readings at regular (twice a day) intervals. The equivalent of a buffered load temperature

Your laboratory protocols should identify how to deal with temperature failures and when and how you would determine whether red cells are 'fit for purpose'

Some other areas, which have been identified, are:

• Not all alarms are documented with the corresponding corrective or preventative action appended. The benefits of this are the identification of trends such as:

  • Compressor about to fail
  • Training issues
  • Inappropriate delay i.e. too short giving regular 'false' alarms

• Temperature records kept , signed and dated to show that they have been examined.

• 'out of temperature' deviations occurring with no explanation should be recorded

All of the above points are for consideration by each hospital transfusion laboratory manager in conjunction with the Quality Manager to determine whether the scientific evaluation of their systems meets the GMP requirements for cold chain storage as determined by the Regulations. If you are going to make any changes remember to complete any change control documentation and document any validation performed.

Q. When performing mapping on a new fridge the information states empty and full. How is “full” best achieved?

The user should specify what ‘full’ means, and then in routine operation, ensure that the contents of the fridge do not exceed this level (without performing a new map).

While it is often stated that validation should be risk-based etc, lab managers should also be cautious not to ‘risk assess’ bad practice. In this example, risk assessment and science-based justification could be used for the number of monitoring probes, duration of study, and the opening/closing of the fridge doors during the mapping exercise. The known use of an unvalidated fridge to store blood components for patient use would not be acceptable – if the blood components are being issued during the course of the mapping study, and subsequently it is found that the temperature profile was non-compliant, the patients have already received blood which has not been stored at the correct temperature. (Note that this is different to the periodic re-mapping ‘in use’, as the repeat maps are to verify that the fridge is still operating in the same manner).

August 2009