There are many different regulations with sometimes contradicting content – but in one topic, they are all the same: If you work with pharmaceutical products and want to comply with GMP and GDP guidelines, you must produce, handle, store and transport your products in qualified facilities.
A Validation is according to GMP/GDP to check if a process or activity has the expected result. Validation is therefore about taking a closer look at a complete process. The GxP rules define that all quality relevant processes must be validated. The first part of the validation is to define the expected results; the second part is to verify and document that the process delivers the expected result. For example, to store products in a warehouse, you need the warehouse itself of course, but you also need employees, which are qualified to do their job, systems to support the process and you might need other equipment to ensure the product is stored according to its needs. In a validation all of the mentioned things are being validated.
Validation is only possible if all used elements are qualified upfront. Quality-relevant elements of the supply chain which need qualification are e.g.: storage facilities, cold rooms, containers, insulated boxes, reefer trucks, vans, data loggers, software for evaluation and archiving, etc. If all of these elements are qualified according to EU-GMP Guideline, Annex 15, one can start the validation of the process using all those elements.
Qualification is the process of proving that a room, system, facility, transport box, truck or supplier fulfills the intended purpose. In other words, a piece of equipment is used in some way to produce, handle, store or transport pharmaceutical products. Therefore, a qualification must demonstrate that the equipment is fit for purpose. For example, a warehouse must to maintain 2 to 8°C in every area. The qualification certifies that the warehouse is fit for purpose and that the temperature range from 2 to 8°C is maintained.
As a result, the qualification therefore always starts with the definition of the intended purpose and then continues with an evaluation and documentation of whether the equipment is suitable to fulfill the intended purpose.
A simple rule to remember: whatever you can touch, you can qualify - the rest is validated.
There are no detailed formal requirements to a Qualification. So whoever performs a qualification is free to decide in what form and document structure the qualification is performed. However, regulation gives some hints and there is plenty of industry best practice:
In every GxP-Qualification the so called V-Model is applied. There are four phases: Plan, Build, Test and Use. It is easiest explained by a simple example of a Refrigerator.
The same V-shaped principle works for any piece of equipment.
The process of establishing documentary evidence demonstrating that a process carried out maintains the desired level of compliance at all stages.
An action of proving that equipment which is part of a validation is properly installed, works correctly and actually leads to the expected results.
An activity which is part of a Qualification which measures and documents the temperature distribution within a room by locating the hottest and coldest spot.
A Mapping Study is the activity to measure and document the temperature distribution within a room by locating the hottest and coldest spot. According to WHO, "mapping may also be used to identify zones where remedial action needs to be taken; for example by altering existing air distribution to eliminate hot and cold spots". A mapping study takes place for a defined time period, typically a few days or weeks, and monitors temperature in various defined locations inside the room (e.g. refrigerator, warehouse, box or container) forming the mapping grid. The mapping grid follows two principles:
Following the mapping plan (floor plan), the calibrated mapping loggers are configured, clearly labeled and placed at the defined mapping points. After the defined time period, all mapping loggers are collected, the measurement curves are overlaid and the hottest and coldest spot in the room are evaluated. The mapping is successful if no temperature outside the required temperature range has been found. The hottest and coldest spots are obvious places to install sensors of the monitoring solution, since a temperature excursion at those spots would be most critical first and therefore measured first.
A Mapping is always just the testing and proofing part of a Qualification, so it is a sub-set of activities and documents. You could also say that the first part of the Qualification is the theoretical part and the second part of the Qualification is the Mapping part, which is the testing part. The theoretical part of the Qualification has its focus on describing requirements, evaluating risks and defining specifications, the testing part (mapping) is very practical with distributing mapping data loggers and analyzing measurement rows.
Qualifying a refrigerator, freezer or ULT-freezer is a rather simple type of qualification:
Companies usually operate many refrigerators, freezers, ULT-freezers or incubators. Therefore, Qualifications are typically done as a so called fleet or farm qualification, which is performed as follows:
Qualifying and Mapping warehouses, cold rooms and storage facilities is much more complex than refrigerators, because they are not off-the-shelf products. Although built with standard components, they are engineered facilities with individual designs, layouts, air flows, doors and control systems. There are many different types of Warehouses, Cold Rooms or Storage Facilities with different temperature ranges and applications which have a major implication on the Qualification and Mapping strategy.
Taking this into consideration leads us to the question how to structure the Qualification. In most cases, the planning and building phase is thereby delegated to specialized engineering firms. Still the documentation of the qualification and mapping must be consistent in following these steps:
Companies typically operate many trucks or vans in one fleet. Therefore, truck and van qualifications are typically done as fleet Qualification, which is performed as follows:
Qualifying a transport box or container is much more complex than qualifying a refrigerator. Since the object to be qualified moves around in uncontrolled environments, we first need clarity on the planned purpose of the box and container by answering the following two questions: is it a road, air or ocean shipment? How long will the shipment take? The following picture shows an overview of different transport modes:
Furthermore, when performing a qualification of a transport box or container, another challenge is to come up with a realistic temperature profile to test against. How long will the shipment take? What temperatures will be expected at origin, on the way and at destination? Are there seasonal changes? There are two approaches to define the right ambient temperature profile:
Last but not least, there is a significant difference between passive insulated boxes using phase change materials (PCM) with insulation and active heating/cooling containers. From a qualification side, the difference of the two technologies is not so much performance but rather the involved risks which need to be considered. The following explains the difference between the two technologies incl. a high-level risk appraisal.
High-level-risk appraisal: The highest risk is a packaging error (e.g. wrong conditioning of PCM). As soon as a shipment is on its way, the solution is very stable and there are only minimal risks.
High-level-risk appraisal: While active containers are very easy to load, there are significant risks during shipment involving human error (e.g. no re-charging) and mechanical failure (heating and cooling containers consists of hundreds of mechanical and electronic components which can fail).
As soon as the box or container has been chosen and the intended purpose is defined, qualification can start applying the steps of the V-Model:
Validating a transport route or an entire network starts with qualifying all used equipment elements (warehouses, transport boxes or containers, trucks or vans). But in order to be able to find the right subjects for qualification inside a network, a clustering of equipment (e.g. fleet, boxes and container) must be performed. Clustering criteria of the transport elements can be:
After clustering the network into homogeneous groups, a high-level risk analysis can be performed. Cluster-specific risks are described and evaluated. The higher the risk rating, the more focus must be given when defining mitigation measures. After performing the clustering and risk analysis, each “cluster element” must now be qualified. The following table shows an overview of potential clusters, risks and mitigation strategies:
Get more insights with our experts about temperature monitoring of pharmaceutical products.
Find all elements and features of a GxP-compliant temperature monitoring solution on this page.
Find out more about the process of a calibration and why it is even necessary to calibrate a sensor.