EU GMP Annex 15 Revisions: Improving Qualification and Validation

Published: 7-Apr-2014

Validation and qualification form an important part of the quality system in the pharmaceutical sector and can be defined in different ways. Tim Sandle, Head of Microbiology, BPL, UK discusses some standard definitions from a Good Manufacturing Practice (GMP) perspective

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There are subtle differences between the terms ‘validation’ and ‘qualification’. Validation is establishing documented evidence to provide a high degree of assurance that a specific system, process or facility will consistently produce a product meeting its predetermined specifications and quality attributes. Qualification is a process of assurance that the specific system, premises or equipment is able to achieve the predetermined acceptance criteria to confirm the attributes of what it purports to do.

Qualification is about documented evidence that a specific equipment, facility or system is fit/ready for intended use and validation is documenting that the way the equipment, facility or system is used will result in a system meeting its predetermined specifications and quality attributes. To put it simply, things are qualified – equipment, systems and so forth – and process and procedures (the way we use things) are validated.

Examples of things that are qualified include HVAC, pharmaceutical grade water, compressed air lines and so on. Calibration is also a part of qualification. Qualification would also apply to the training of a laboratory technician to run an assay. Examples of validation include manufacturing processes, cleaning processes, or an analytical method.

Formal validation and qualification are both requirements of GMP. Within Europe, the accepted regulatory approach is set out in Annex 15 of the EU GMP Guide. The European Commission has recently published a draft version of Annex 15.1 The consultation document is available on the Commission’s website, where the draft takes the form of a concept paper. The draft is currently available for public comment and a final version is expected during 2014. This article discusses some of the main changes that are being proposed for the Annex.

GMP Annex 15

Annex 15 of the EU GMP guide is concerned with the ‘Qualification and Validation’ of pharmaceutical facilities, addressing requirements for equipment, utilities and processes that are used for the manufacture of medicinal products. The broad requirement of Annex 15 is that a pharma manufacturer needs to identify what qualification and validation work is required; next, the manufacturer must prove that critical aspects of work are controlled; and finally, the key elements of qualification and validation need to be defined and documented.

Arguably the most important addition to the draft Annex is the inclusion of a section relating to change control

Given that the Annex was last updated in 2001,2 the 2013–2014 revision process has, unsurprisingly, led to some significant changes. Arguably the most important addition to the draft Annex is the inclusion of a section relating to change control. Change control is an established part of GMP and with respect to this any planned changes to the facilities, equipment, utilities and processes that may affect the quality of the product should be formally documented.

With change controls, as the draft guidance indicates, written procedures should be in place to describe the actions to be taken if a planned change is proposed. The change process must assess whether the change during the lifecycle of the equipment or utility could affect product quality or reproducibility. From this assessment, certain changes may trigger a re-validation exercise. An example would be an update to computer software.

As part of the validation of an item of equipment or a utility, the performance needs to be assessed. In the past, and as indicated in the current version of the Annex, the equipment should be qualified with three batches of product (or three process runs). With the revised version there is no longer any mention of three batches. This has been replaced by the requirement that: ‘The number of batches manufactured and the number of samples taken should be based on quality risk management principles…’ This implies that a risk assessment is required.

Before a validation is conducted on a process, it is also important to ensure that the equipment has passed its qualification.

The validation process is no longer a series of exercises undertaken when the equipment is installed. Here the revised Annex embraces regulatory thinking in relation to the ‘life cycle’ approach. Behind this philosophy is the concept that the qualification should extend through the life span of the item of equipment. For this, organisations should monitor equipment or utility status and product quality to ensure that a state of control is maintained throughout the lifecycle.

Another important change is that all reference to ‘retrospective validation’ has been removed

For this assessment trends must be evaluated using performance metrics (such as Statistical Process Control) and a summary made to annual Product Quality Reviews. Further to this, the Annex discusses the implication on the validation status of equipment where adjustments are made to process parameters. Where equipment requires adjustment outside the range assessed during the initial qualification, then an assessment is needed to determine if these adjustments affect the validation status of the equipment. This also requires a risk assessment.

Another important change to the Annex is that all reference to ‘retrospective validation’ has been removed. This was an approach where pieces of equipment that were installed prior to 2001 could be examined according to current Annex and assessed as acceptable or otherwise by carrying out a retrospective review. With the removal of this section the assumption is now that any equipment installed prior to 2001 will either have been validated or replaced. As it stands, retrospective validation is no longer an acceptable practice.

New additions

There are some new sections within the Annex pertaining to transportation verification, packaging validation, validation of utilities and validation of analytical methods. The transport section refers to the distribution of pharmaceutical products. This has been added because variable conditions can occur during the transport of medicinal products, such as delays at airports. The recommendation here is for continuous monitoring of all critical environmental conditions to which the product may be subjected.

The text relating to utilities will be of interest to readers of Cleanroom Technology. For this the quality of steam, water, air, other inert gases, coolants and so forth needs to be confirmed following their installation. The draft guidance makes a recommendation that the period and extent of qualification should also reflect any seasonal variations and the intended use of the utility.

Another aspect referred to is, again, risk assessment. The draft recommends that a risk assessment should be carried out for any utility where there may be direct contact with the product. This would include, for example, HVAC systems and barrier devices used for aseptic filling.

Cleaning validation has received increasing attention from the GMP inspectors in recent inspections

Another area of interest will be cleaning validation, which has received increasing attention from the GMP inspectors in recent inspections. Cleaning validation is the activity of ensuring that residues are removed from equipment as part of the cleaning (and sometimes disinfection or sanitisation procedure). All residues are removed to predetermined levels to ensure the quality of the next product manufactured is not compromised by waste from the previous product and the quality of future products using the equipment, to prevent cross-contamination and as a GMP requirement.

The validation process here involves ‘soiling’ and measuring any chemical and microbiological residues. For this, pharmaceutical manufacturers must have written general procedures on how cleaning processes will be validated. The procedures should dictate who is responsible for performing and approving the validation study, sampling methods, analytical methods, physical parameters, the acceptance criteria, and when revalidation will be required.

The guidance addresses the sometimes thorny issue of re-validation. This causes some debate within the industry in relation to when to re-validate and, some-times, if re-validation is required at all. The revised guidance is unambiguous: facilities, utilities, systems, equipment should be evaluated at an appropriate frequency to confirm that they remain in a state of control.

Other reasons for the revision are procedural. The changes here take into account updates to other sections of the EU GMP Guide, including Annex 1 ‘Computerised Systems’ (which was published in January 2011). An important part of validation procedure is the Validation Master Plan. This overarching document sets out the requirements of a validation exercise. The Annex provides useful guidance on putting the plan together.

Master Plan

A Master Plan should contain the following elements:

  • Validation policy
  • The organisational structure for validation activities
  • Summary of the facilities, systems, equipment, processes on site and the current validation status
  • Template formats to be used for protocols and reports
  • Planning and scheduling
  • Change control and deviation management for validation
  • Handling of acceptance criteria
  • References to existing documents
  • An assessment of the resources required
  • The on-going validation strategy, including revalidation and/or requalification, where applicable
  • Confirmation that the materials used for validation are of the required quality and suppliers are qualified to the appropriate level

Other aspects of validation documentation remain unaltered (including the standard Installation, Operational and Performance Qualification approaches). There are, however, some additions that bring the Annex in-line with other validation approaches. For this, the URS (User Requirement Specification) has been added to the section on Qualification for Facilities and Equipment, as has the Factory Acceptance Testing (FAT)/Site Acceptance Testing (SAT).

The best documentation practices outlined in the Annex emphasise that the responsibility of performing validation must be clearly identified; that validation is conducted in accordance with predefined, approved validation protocols; and that recorded results and conclusions are presented in written validation reports. From the results of validation activities, Standard Operating Procedures (SOPs) should be generated.

The final part of the Annex contains a revised and expanded glossary.

Best practice

In conclusion, the changes outlined in Annex 15 draw together examples of industry best practice under the GMP umbrella. Overall the draft Annex is an improvement upon the current version. The only criticism is that some parts remain open to interpretation (such as the scale of the activities required for re-validation) and with other aspects of the GMP guide there are no case studies. The inclusion of examples of best practice would have helped those tasked with assessing new equipment and utilities. The final version of the Annex is scheduled to be published in quarter four of 2014.


1. EudraLex. The Rules Governing Medicinal Products in the European Union, Volume 4: EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 15: Qualification and Validation. See:

2. Eudralex. The Rules Governing Medicinal Products in the European Community (Directive 2003/94/EC), Volume 4, Annex 15, published by the European Commission, Brussels, Belgium, 2001

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