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All you need to know
about Qualification, Validation & Mapping

If you want to comply with GMP and GDP guidelines, you need to produce, handle, store and transport your products in qualified facilities. Read more about the formal requirements and industry best practices and become Qualification Champion.

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All you need to know
about Qualification, Validation & Mapping

If you want to comply with GMP and GDP guidelines, you need to produce, handle, store and transport your products in qualified facilities. Read more about the formal requirements and industry best practices and become Qualification Champion.

Introduction to Qualification, Validation and Mapping 

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.

What is a Validation?

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.

What is a Qualification?

Qualification, Mapping, Calibration - The Difference

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.

Warehouse Validation Qualification

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What is Temperature Mapping?

Mapping of a Warehouse aligned with GxP guidelines

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:

  • A 3-dimensional network of mapping points with consistent intervals in the x, y and z axes. WHO defines the expected distance between the mapping points.
  • Additional mapping points being the expected hot and cold spot (which could be near the air outlet, door, seal or wall)

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.

What is the Difference between
Qualification and Mapping

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.

Qualification vs. Mapping - the difference

Validation

The process of establishing documentary evidence demonstrating that a process carried out maintains the desired level of compliance at all stages.

 

Qualification

An action of proving that equipment which is part of a validation is properly installed, works correctly and actually leads to the expected results.

Mapping

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.

What are formal Requirements for a Qualification?

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:

  • Documented proof: A Qualification should follow the good documentation practice and therefore include clear document naming, versioning, change history and document ownership. Furthermore, a proof is only possible with evidence – which means that a test plan and clearly identifiable and reproducible test results must exist.
  • Intended purpose stated: Clear requirements must be documented: What is the equipment, which is in the qualification process, supposed to do? By defining the intention one automatically excludes all other non-intended purposes and effects and minimizes risks.

What is the Industry Best Practice for a Qualification?

Qualification - Industry Best Practice using the V-Modell

 

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.

  1. User Requirement Specification (URS): The first document needed is a so called URS. For a fridge, this could be really simple and only contain a handful of points, for example: “Must maintain 2 to 8°C” and “must fit under a counter”.
  2. Risk Analysis: As a next step one conducts a risk analysis. In the risk analysis you think about everything that could go wrong and decrease the patient's safety. In our fridge case it could be “door open” and “power outage”. Each risk is now evaluated and rated in probability, severity and detectability.
  3. Design Specification: Since a power outage is a critical risk you may define an uninterrupted power supply in your Design Specification for the fridge. Of course you also define what type of fridge (model, manufacturer, etc.) you want to buy.
  4. Design Qualification: After the installation of the fridge, the Design Qualification checks if the right fridge has been purchased and if the uninterrupted power supply is actually installed.
  5. Operational Qualification (Mapping): Now you can perform the first mappings. By conducting the Operational Qualification Mapping, you test the functionality of the regulations and the ability to maintain 2 to 8°C temperature range in the fridge. It is the dry run before you put the fridge into service.
  6. Performance Qualification (Mapping): Finally, in the Performance Qualification Mapping, the regulations are tested to work in real operation, meaning with full load.

The same V-shaped principle works for any piece of equipment.

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Why and what to qualify

GDP regulations define that all equipment used, which has a relevant influence on patient safety, must be qualified and processes validated. In a cold chain, many pieces of equipment are relevant to patient safety:

experience

Warehouses

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Fleets of Trucks & Vans

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Containers & Transport Boxes

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Networks

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Temperature monitoring solutions

Examples on how to conduct a Qualification & Mapping

 

How to qualify and map a Refrigerator

Qualification of a Fridge - V-Modell

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Qualifying a refrigerator, freezer or ULT-freezer is a rather simple type of qualification:

  • Refrigerators are standard equipments purchased as stand-alone devices. Compared to other more complex and customized pieces of equipment (like warehouses, transport boxes), the risks are limited.
  • Refrigerators are operated in a controlled room temperature environment. The risks are limited to the following four risks: air outlet blockage, power outage, wrong loading and door opening.

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:

  1. Cluster the fleet of refrigerators into homogeneous groups, for example clustered by same supplier, same model and same size.
  2. For each group apply the V-Model and work out:
    • User Requirement Specification: document temperature range and description of application.
    • Risk Analysis: evaluate placement, power supply and operational aspects like frequency and lengths of door opening, loading and cleaning patterns.
    • Design Specification: For each cluster of refrigerators, define exact purchased model and installation instructions (avoid blockage of air flow compressor, power supply).
    • Operational Qualification: One fridge from each cluster is mapped in detail following WHO guidelines in an empty status.
      Mapping of a Fridge aligned with GxP Guidelines
  3. We can now perform the design qualification for one refrigerator per cluster group by simply checking: is it the right model and does the air flow and power supply comply with the specifications?
  4. Since one refrigerator per cluster group has already been mapped, it is now possible for the remaining refrigerators of the same group to leave out the dry run Qualification and to directly perform a Performance Qualification (mapping of the full refrigerator) during normal operation. Of course the mapping should be performed with data loggers which are calibrated and compliant.

How to qualify a Warehouse, Cold Room or Storage Facility

Mapping of a Warehouse aligned with GxP guidelines

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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.

Warehouse 

  • Type: Large room/hall with open space or high racks 
  • Typical temperature range: 2-8°C or 15-25°C.
  • Implications on Qualification & Mapping: Warehouses typically have outer walls directly exposed to ambient conditions and seasonal effects. Insulation of the building and the absence of windows and other openings are vital. Since there is influence from ambient conditions, a winter and summer mapping will be necessary. Same applies for the loading dock.

Cold Room 

  • Type: Smaller room/hall with open space or racks.
  • Typical temperature range: 2-8°C or -20°C
  • Implications on Qualification & Mapping: Cold rooms are typically rooms inside a building and the walls have no direct exposure to ambient conditions and seasonal effects. Often there is no need for performing a separate winter and summer mapping.

Other facilities and loading docks

  • Type: Small room with racks
  • Typical temperature range: 15-25°C or 2-30°C or <40°C
  • Implications on Qualification & Mapping: The framework and complexity of the qualification and mapping of other facilities will be defined by the stored/handled products, their required label condition and their length of stay within the facility.

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:

  1. Define User Requirement Specifications describing the purpose of the warehouse, cold room or storage facility.
  2. Perform detailed Risk Analysis describing all structural and operational risks
  3. Define high-level design requirements (floor plan, equipment for temperature control, power supply)
  4. Perform a simple design qualification: Has the facility been built as planned?
  5. Perform an operational qualification: Mapping of the empty facility in winter and summer condition (perform only one mapping if seasonal effects can be fully excluded per above table).
  6. Perform the performance qualification: Mapping with full load during normal operation.

How to qualify and map a Truck or Van

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:

  1. Cluster the fleet of trucks or vans into homogeneous groups. Example criteria can be: same brand, same model, same layout, same type and version.
  2. For each group apply the V-Model and work out:
    • User Requirement Specification: Temperature range and description of application (lengths of trip, expected extreme ambient conditions, winter/summer profiles)
    • Risk Analysis: Power supply and operational aspects like loading/unloading, frequency and lengths of door opening.
    • Design Specification: For each type, definition of exact purchased model and set-up.
  3. We can now perform the Design qualification for one truck/van per cluster group by simply checking the few points defined: Is it the right model with the exact same configuration and application range?
  4. Since one truck or van per cluster group has already been mapped, it is now possible for the remaining trucks/vans of the same group to leave out the dry run Qualification and to directly perform a Performance Qualification (Mapping of the full truck) during normal operation. Of course the mapping should be performed with data loggers which are calibrated and compliant.

How to qualify a Transport Box or Container

Mapping of a Transport Box aligned with GxP guidelines

 

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:

Qualification of a Transport Box - 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:

  1. Use empirical data: An often seen approach is to classify the shipment into shipment sections (origin to hub, hub to hub, hub to destination) or to cluster them by assigning climatic zones to the sections (e.g. cold, moderate, warm, hot) and to define extreme seasonal weather changes (e.g. cold to hot, hot to cold). The difficulty with this approach is to define the specific length of each shipment section (how many hours the product has in each section) and estimate a realistic average temperature within each climate zone.
  2. Map the ambient temperature: The best way is to measure the temperature of the specific route in reality. This is done for example by performing several seasonal shipments and collecting the temperature data from each of the shipments. Afterwards, the average temperatures from each shipment section are calculated and used. This is the most elaborated method.

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.

Passive Insulated Box

  • Technology used: Thermal Packs filled with Phase Change Material (PCM) having a defined melting point (5°C melting point for 2-8°C shipments) and insulation materials such as Vacuum Panels.
  • Process at origin: Phase Change Material (PCM) must be pre-conditioned and must have the right temperature when loaded. To ensure the promised performance, the box must be built-up exactly as designed: product surrounded by minimum one layer of PCM, surrounded by minimum one layer of Vacuum Panels, held together by a cardboard box.
  • Process during Shipment: Ensure the shipment is not exceeding the defined shipment lengths (e.g. the box is built to keep temperature for 72 hours; a longer shipment time could thus damage the goods).
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.

 

Active Container

  • Technology used: Insulated container with air ventilation, heating and cooling unit (typically compressor cooling and electrical heating) and  battery incl. charging unit.
  • Process at origin:The battery must be charged before loading and the right set temperature must be defined.
  • Process during Shipment: Re-charge the unit at hubs and airports. Prevent manipulation of the set temperature or door openings.
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:

  1. Define Specifications of the transport box or container describing the type transport box, loading volume, set temperature, shipment lengths of the transport box or container and specific temperature profiles.
  2. Risk Analysis describing all operational and technical risks of the transport box or container.
  3. Operational Qualification by testing the box in a Climate Chamber (Mapping) running through all defined temperature profiles.
  4. Performance Qualification by performing test shipments (Mapping) on a specified route (e.g. shipment from an extreme cold environment to an extreme hot environment).

How to validate a Transport Route or Network

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:

  • Transport mode (e.g. truck, van, rail, air, ocean)
  • Secondary packaging (e.g. no secondary packaging needed, thermal cover, insulated box or active container)
  • Truck or van type
  • Trip lengths
  • Trade-lane (Origin/Destination)
  • Climate zones and seasons

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:

Validation of a Transport Route - Risk Analysis and Mitigation

 

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