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Introduction to cold chain validation procedures.

This graphic is of a cold chain validated delivery van.

Cold Chain Validation suddenly became a hot topic when the results of a government investigation into Cold Chain distribution compliance were published.
The facts release indicated that nearly a quarter (23%) of all drugs distributed in the USA, are of unknown efficacy. The distribution of these temperature sensitive products in vehicle containers that lacked validated methods of maintaining the correct internal temperature or even the ability to produce a validated history of what the actual conditions were; has rendered these products 'adultered', i.e. of unknown efficacy or safety. Vehicle body internal temperatures; with seasonal variations, can range from a high of 50 to a low of -40 (degrees centigrade). In contrast the mandated internal temperature for distribution containers for standard drugs and medical products is 2 to 8 (degrees centigrade), with much lower temperatures specified for some drugs.

This shocking news has certainly guaranteed that Cold Chain Validation compliance will be top of everyone's audit list, specifically when drug interactions with the end user are considered as critical. The implications of products being damaged and out of specification may induce many companies to replace doubtful goods or even trigger the regulators into initiating product recalls. This problem is expected to create a veritable stampede as distributors scramble to ensure that all the vehicles and containers they used in this essential everyday service, are rendered Cold Chain compliant, as soon as is possible.

Those who are not familiar with the requirement can find it all here - Cold Chain Legislation. There are now clearly defined requirements for the verification of all elements and aspects of the product temperature while in transit. It is essential to realize that temperature mapping of temperature controlled containers, trailers and or other containment devices used in transporting temperature sensitive controlled substances may only be one aspect of your overall validation requirements.

cGMP procedures mandates that pharmaceutical produce in transit or storage must not be subjected to temperatures that can induce unwanted changes to their efficacy, quality or purity.
21 CFR part 211.142 refers.

Auditors and the Idiosyncrasies of Compliance.

This graphic represents the ealy days of the cold chain validation requirement.

There is now legislation in nearly all countries to ensure that all regulatory controlled drugs are protected from exposure to out of specification climatic conditions by rigid adherence to cold chain compliance practices and procedures. It is now commonly accepted that there are many instances where the efficacy of drugs has been directly impaired because their stored climatic conditions were not strictly monitored and temperatures were allowed to exceed specified safe maximums and at times minimums. So care must be taken to ensure that the procurement process for all such climatic equipment is comprehensive enough to specify which parameters are critical and require constant monitoring and management. An analysis of these requirements User Requirements Specification (URS) should be developed to ensure that the storage conditions are correctly specified and safely engineered.

Lack of continuous monitoring has allowed drugs to be permanently damaged due to poor handling procedures i.e. cabinets doors left open, cabinets switched off inadvertently or even cabinets accessed to frequently. These errant conditions would have been observed had continuous monitoring systems been in use. However with properly engineered alarm systems they can be immediately identified and prevented from causing product damage. This is where the emphasis is now being applied - Cold Chain Validation verification will ensure that all temperature controlled transportation and or holding areas, such as; rooms, fridges, freezers, trailers, delivery vans and haulage lorries, are cGMP compliant.

In a recent project where the product went through a six stage production process. From start to finish the product had to be maintained sub minus 20ºC. At times there were several days between processes, also some processes were much faster than others, inevitably product queues developed as product waited between process stages. During this processing and in between stages, the product was held in 3cumt mobile freezers (122 of them) running at minus 25ºC.

On a regulatory visit the regulators decided to investigate this process. They were very persistent and thorough. All the freezer cabinets and all temperature controlled transport containers and trailers were run through the full range of functional tests. They all failed their defrost cycle and subsequently required extensive reworking. The failures were in large down to the cabinet control systems. However there were fundamental design requirements that the company did not have in their URS.

The under listed requirements were agreed with the regulators as FDA minimums for holding controlled product in an engineered climatically (hot or cold) controlled environment./div>

  • An external indication of internal temperature.
  • A door not closed alarm.
  • A power cord electric power on or off alarm.
  • A temperature out of specification alarm.
  • A Controlled entry system.

The Urgency for Compliant Cold Chain Transportation.

This graphic represents picture of the vans that was subjected to the full cold chain validation procedure.

According to a recent study conducted by the U.K. based Medicines and Healthcare Products Regulatory Agency (MHRA), a staggering 43% of critical and major product deficiencies are related to ineffective temperature control and monitoring during storage and transportation.

Similarly the World Health Organization (WHO) recently maintained that 25% of all vaccine products arrive at their final destination in a degraded state. Given the high cost of conducting global clinical trials and the even higher cost of failure, regulatory agencies and pharmaceutical companies alike now demand that every party involved in the pharmaceutical supply chain - transportation and logistics providers included − conform to GxP guidelines and immediately activate procedures to attain Cold Chain Validation compliance.

  1. WHO’s “Good distribution practices for pharmaceutical products” and “Guide to good storage practices for pharmaceuticals”

  1. FDA’s “cGMP / 21 CFR 211”
  1. U.S. Pharmacopeia (USP) <1079> “Good Storage and Shipping Practices”
  1. Canada’s “Guidelines for Temperature Control of Drug Products during Storage and Transportation”
  1. Ireland’s “Guide to control and monitoring of storage and transportation temperature conditions for medicinal products and active substances”
  1. EU’s “Guidelines on Good Distribution Practice of Medicinal Products for Human Use” (94/C 63/03)

It is anticipated that these finding will move all things to do with - product quality in transit - to the top of visiting regulators inspection lists. The obvious priority being the thermal validation of transit containers - be they demountable or integral to a motor vehicle.

Validation of these containers and or vehicles is not difficult and can be tackled (using our fully detailed documents) by most technicians and or laboratory assistants.



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21 Years of retailing cGMP - 35k templates supplied to the industry.

Interactive Intuitive templates easy to edit and simple to execute at new prices
Single Documents from $20.00
Complete validation Equip/HVAC/Com/soft/Util/Steam Packages VMP/VRA/URS/DQ/IQ/OQ/PQ from $199.00
The ever popular Combination IQ/OQ/PQ FOR $199.00
Only one on the net Steam Qualification pack $199.00
These templates cut costs - Author 50/75% Execution 20/40%.

Validation Risk Assessment (Issue 11) $125.00

Risk Mitigation in Validation template (Issue 11) $125.00 The Risk and Part 11 Validation Risk Assessment(VRA) protocol is becoming the most important document in the validation online train. The VRA reassures the regulators that you have looked at specific equipment functionality and considered the appropriate level of validation that is required. You have also considered various aspects of its use and the implications of any malfunctions. From the results of this exercise the scope of all validation activity can and must be justified. This is a robust and simple to execute document, one that will lead you through the process and deliver a result that can be used as the foundation for your Risk Mitigation in Validation template.

This VRA now includes the assessment table for categorizing and documenting the new 21 CFR Part 11 guidance ruling on what predicate data must be stored in a Part compliant system, along with the new broadsheet to establish your new database of part 11 records. (now mandatory).

Combined IQ-OQ-PQ Computer (Issue-4) $159.00

This Pharmaceutical Validation combination protocol has been produced in response to several hundred reader suggestions we received in our ‘Suggestions Section’. It has been carefully designed to make it the preferred choice for Process and Laboratory stand alone equipment and associated standard operating procedure TEMPLATE. The associated medical device validation  Master Plan template is interactive, easy to use and suitable for all mixes of equipment with and without software. Where temperature mapping is required it will included in this section. This of course may well be a Risk Mitigation in Validation risk Assessment template. As per 21 CFR Part 11.

The Installation Qualification Template or IQ section establishes documented verification that all medical device validation template online executables are catered for and that key aspects of the equipment Qualification adhere to approved design Qualification template and the recommendations of the manufacturer have been suitably considered. The Operational Qualification Template section establishes that there is documented verification that the installed system functions as specified and that there is sufficient documented process validation A executables to demonstrate this. The PQ section develops documented evidence that all the requirements specified in your corporate validation 4U manual have been verified as operating consistently and exactly as specified in the medical device validation template; The User Requirements Specification template 

Installation Qualification. SOP & Protocol (Issue 9.) $115.00 10000020

The Standard Operating Procedure template (SOP) used to generate this installation Qualification template (IQ), takes you through the process line by line, chapter by chapter. It really is unique to find a SOP document so easy to use, all the work is done for you. All the documents are detailed, all the drawings listed and all the checks and tests detailed. The final product is a professional and comprehensive Installation Qualification template. One that you can produce in less than 60 minutes. Yes, think about it, we all know how long producing IQ documents has taken in the past, whether for current Good Manufacturing Practice use medical device use or a simple installation qualification template. 

Operational Qualification, SOP & Protocol (Issue 10.) $115.00 

You will find this validation online intuitive Operational Qualification template (OQ) delightfully simple and straightforward to use, as it takes you through the process of customization of your Operational Qualification Protocol template. Following the attached SOP will quickly and smoothly convert your template into an equipment specific 21 CFR Part 11 compliant Installation  Qualification Template. The OQ template comes complete with all the standard test scripts, more specialist test scripts can be found listed below. These can easily be pasted into the standard OQ, allowing you to quickly build your own fully detailed and referenced company bespoke Operational Qualification Protocol, along with the installation qualification template.

Cold Chain Validation Package level-1 (Issue 3) $575.00

This is the common document package that is sent out with all our Cold Chain Validation Packages. It contains five documents that make up the advertised document package. No matter what your validation requirements are these documents will guide you through the task. No matter whether you are to validate a cold container or a mobile cold cabinet or a vehicle integral container or smaller service van. In all these cases you require the Validation Plan (VP) to detail the what, where, how and who of your task. Then the Validation Risk Assessment (VRA) to define your task. After this, the standard flow of documents is required - Installation Qualification (IQ), the Operational Qualification (OQ) and finally the Performance Qualification (PQ). All of these documents are mandated by cGMP's. There are no short cuts to compliance.


This package contains one of each of these documents, but no data loggers. The end user has to supply a means of capturing all the transient temperature data.


Cold Chain Validation Package Level-2

The content of this package includes the document pack as detailed in Level 1 above. Plus quantity 10 off, single channel data loggers. Simple and robust to use. This is now the simplest, most expedient and cost effective method of validating the climatic condition within any mobile container or vehicle body.


This package contains one of each of these documents. Plus 10 off single channel data loggers and is sufficient to validate a volume of 8 (cubic metres).


Cold Chain Validation Package Level-3

The content of this package includes the document pack as detailed in Level 1 above. Plus quantity 20 off, single channel data loggers. Simple and robust to use. This is now the simplest, most expedient and cost effective method of validating the climatic condition within any mobile container or vehicle body.


This package contains one of each of these documents. Plus 20 off single channel data recorder and is sufficient to validate the volume in a standard 20 foot (38 cubic metres) container.


Cold Chain Validation Package Level-4

The content of this package includes the document pack as detailed in Level 1 above. Plus quantity 30 off, single channel data loggers. Simple and robust to use. This is now the simplest, most expedient and cost effective method of validating the climatic condition within any mobile container or vehicle body.


This package contains one of each of these documents. Plus 30 off single channel data loggers and is sufficient to validate the volume in a standard 40 foot (77 cubic metres) container.