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Requirements

Due to the severity of damage resulting from insufficient temperature control for certain types of goods, strict temperature monitoring requirements are set by the government and federal agencies to standardise a high level of safety throughout the pharmaceutical industry.

The required temperature is based on the biological activity level of the sample and the expected storage period. The following guidelines are used in the pharmaceutical industry:

  • Short storage period (weeks): can be done at -18 to -30°C using mechanical freezers.
  • Medium storage period (1-3 months): can be done at -30 to -50°C using mechanical freezers.
  • Long storage period (6-12 months): can be done at -50 to -80°C using ultra low mechanical freezers.
  • Extended storage period (years) can be done at -131°C or lower using special cryogenic freezers or liquid nitrogen.

The process of freezing down and storing samples is done by using mechanical freezers or special storage tanks using LN2 (liquid nitrogen).  This is typically used within the following medical/pharma applications:

  • Stem cell storage
  • Cord blood storage
  • Cell line storage
  • Other biological material storage

Dry Storage

Although temperature is usually the most critical measuring parameter, in situations where bulk powders are stored, relative humidity is equally as important. High levels of humidity will cause powders to congeal, which can affect product quality or deem ingredients unusable.

Validation & Monitoring Requirements

Validation must be conducted regularly to ensure that a low temperature cabinet or cryogenic freezer is capable of accurate and repeatable performance. Ellab has a variety of wireless loggers that are capable of monitoring down to -80°C. Well-designed wireless loggers with an efficient  battery management system are required for cold storage applications.

At every point in the cold storage and supply chain, precautions can be taken to minimise the effect of external conditions on the quality and stability of the products, for both internal QA and external audits by regulatory bodies.

Environmental monitoring software is required to record data in a consistent manner that meets strict regulatory requirements. A centralised monitoring system allows data to be collected from all cold storage areas, so that users benefit from gap-free data throughout the entire cold chain, whilst also maintaining a clear record of data for auditing purposes.

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Process

Cold storage systems vary in design based on storage volume and temperature range. The only parameters of interest are temperature and humidity. Samples are often placed in closed containers so that no cross contamination is possible.

Qualification, Validation and Monitoring of cold storage freezers/tanks generally fall into three main categories.

 

Standard laboratory freezers/cabinets

Standard laboratory freezers/cabinets with a temperature range of -10 to -30°C do not usually pose any special challenges as the required parameters are simple to maintain.

 

Low temperature freezers

Low temperature freezers that operate between -30 to -80°C require special low temperature loggers.

 

Ultra-low temperature freezers

Ultra-Low temperature freezers (or Cryogenics) as well as LN2 tanks require special equipment as temperature exposure will make most materials very fragile thus breakage by mechanical stress can happen. When using cable based equipment metal sheeted SSU-MM sensors are ideal. It is recommended that the logger body is kept outside of extreme conditions.

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Validation Challenges

Depending on the length of the validation process, the sample rate for data collection may need to be adjusted to match the logger memory capacity.

 

The FDA regards Mean Kinetic Temperature (MKT) as a calculation that will show if a product has exceeded storage conditions. MKT can also be used to determine if storage, handling, or shipment, etc. has affected the shelf life of the product. MKT is a calculated fixed temperature that replicates the effects of temperature variations on a product over a period of time. It expresses the cumulative thermal stress experienced by a product at varying temperatures during storage. In addition to MKT it is recommended that min and max values are calculated including a description of the time and place of occurrence.

 

Potential challenges when validating a cold storage system are:

  • To determine the cold and warm zones of the cold storage system
  • To confirm pre-defined temperature / humidity ranges
  • To identify and improve temperature / humidity equilibration
  • To determine the highest temperature / humidity fluctuations within the cold storage chamber
  • To calculate and document the Mean Kinetic Temperature

 

Solutions

Wireless solutions solve many of the challenges presented during each stage of the cold storage process. A centralised monitoring system allows data to be collected from all cold storage areas, so that users benefit from gap-free data throughout the entire cold chain, whilst also maintaining a clear record of data for auditing purposes.

 

However for validation and qualification of very small and low volume freezers/chambers using thermocouples could be advantageous to reduce impact on chamber volume (if access port(s) available).

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On-site Service

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Guidelines

There are no specific standards covering cold storage validation but Ellab’s ValSuite Pro software calculates MKT according to these standards:

  • USP chapter no. 1151:”Pharmaceutical Dosage Forms in chapter Stability”.
  • ICH norm no. Q1A (R2) page 15.

Validation of a cold storage system consists of various steps regarding Installation Qualification (IQ), Operational Qualifications (OQ) and Performance Qualifications (PQ).
The IQ is conducted to demonstrate that the cold storage system is inspected and contains all the required parts for its proper functioning.

In the OQ, the performance of the cold storage system and its operational procedure is verified. The OQ portion consists of temperature mapping of the empty chamber over several hours to confirm that the empty chamber works within the specified limits throughout the chamber. The OQ also contains information about the calibration of the measuring equipment and defines the location of the thermocouples and /or data loggers in the chamber. Finally, checking of the warning and alarm limits adds to the test.

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Cold Storage – PQ

The PQ verifies that the loaded cold storage chamber is capable of reaching and maintaining the target temperature range and works (while loaded) within the specified limits of temperature. The specified limits of temperature throughout the chamber are typically measured for up to 30 days to verify that the environment is stable over time.

The effect of opening doors for two different lengths of time and the effect of a power failure on the cold storage is also tested.

Ambient temperature during test shall be 22 +/-3°C.

Method

A specified number of loggers are placed in the cold storage system in the pre-determined critical mapping points while taking into account the expected gradient throughout the chamber. The temperature mapping is typically performed over a minimum period of 48 hours.

Generally, the temperature mapping grid should have all temperature recording devices and loggers positioned at distances following the sensor’s capacity to efficiently measure the temperature changes across the entire volume. The mapping grid should allow the thermal mapping activity to capture both the hot and the cold zones.
The frequency of the temperature mapping is done at least once a year. Additional temperature mapping may be required for changes such as conditions mentioned below:

Temperature settings change
Changes made to the storage capacity
Replacement of critical components e.g. valves or compressors
New accessory is installed that may impact the temperature and relative humidity
Any other changes made that could affect temperature/humidity
For pharmaceutical clients, most applications will require the use of advanced software such as ValSuite™ Pro with its 21 CFR Part 11 compliance and sophisticated reports/features. For validation purposes creating a Unit with the exact position of each measuring point is advantageous when handling many sample points. Further, adding it all up in a Profile including a Limit Report as well as Statistical Report is useful and time saving.

 

At the end of each study report(s) can be signed by Electronic Signature(s), stored, printed, and distributed in a secure and locked PDF format. For other clients that do not need the electronic records, ValSuite Basic is the right choice. This software version provides the same Statistical and Limit report options but without the Part 11 compliance.

Using the built-in calibration functionality, users can calibrate the Ellab sensors at regular intervals. The ValSuite™ Pro software generates an easy to read calibration report that includes all measurements and tolerances that are defined by the user. It is recommended that Ellab sensors and probes are sent in at least once a year for factory calibration (which includes a traceable calibration certificate).

 

Cold Storage Method

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ValSuite® Software Reports

Cold Storage

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Process Graph
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Limit Report
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Statistics
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Unit Report
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