EU releases Annex 15 validation and qualification

On the 30th of March, the EU released its updated version of Annex 15 Qualification and Validation which will be effective on 01 October 2015. When the draft was publicised back in February 2014, we at PharmOut scrutinised the document and produced a White Paper detailing the proposed changes.

In this article, I will discuss the changes between the draft version and the revised Annex 15 version. When the draft was released, there was a lot of industry discussion on the main changes which included :

  • Cross-references to Annex 11 Computerised systems
  • Changes to planning and documentation for Qualification and Validation
  • Added information on the qualification stages for equipment, facilities and utilities
  • Major revision of the Process and Cleaning Validation sections
  • New sections added for Ongoing Process Verification during Lifecycle, Verification of Transportation, Validation of Packaging, Qualification of Utilities and Validation of Test Methods

Industry was concerned about the section on Cleaning Validation, including the definition which stated that it “will remove all traces of the previous product used in the equipment”, and that the number of cleaning validation runs was no longer three, but should be justified. The section also indicated that “visually clean” was not acceptable on its own. The shift towards cleaning limits being based on a toxicological evaluation to determine the product specific permitted daily exposure (PDE) value has been a hot topic over the last few months, and led to some great discussions, which are available in Trevor’s blogs Dedicated facilities or not? and Update from the PIC/S Seminar on Dedicated Facilities.

The new and improved Annex validation and qualification

The new version now may also be used as supplementary optional guidance for active substances without introduction of additional requirements to EudraLex, Volume 4, Part II. The Principle section now clearly states that retrospective validation is no longer an acceptable approach and in several instances, the term “validation” has been replaced with “qualification and validation” to reflect the true intent of the Annex 15.

An “equivalent document” to a VMP may be used for qualification and validation planning, but a VMP no longer needs to include protocol and report templates, scheduling and planning information or confirmation of materials and suppliers used. This section does instead state that “for large and complex projects, planning takes on added importance and separate validation plans may enhance clarity“.

The importance of Quality Risk Management is still evident, but if further knowledge and understanding is gained from any changes during the project phase or during commercial production, “the risk assessments should be repeated, as required.” Data integrity is also mentioned were “appropriate checks” needs to be built into qualification and validation tasks “to ensure the integrity of all data obtained“. Several regulators (such as the MHRA) are now paying particular attention to data integrity, and this increased scrutiny will be discussed as part of our PharmOut Dinner Updates / Breakfasts in the coming weeks.

The section on qualification stages mentions User Requirement Specification (URS). The definition has been added to the Glossary and is defined as “The set of owner, user and engineering requirements necessary and sufficient to create a feasible design meeting the intended purpose of the system“. These specifications “should be a point of reference throughout the validation life cycle“. Design Qualification (DQ) is defined as “where the compliance of the design with GMP should be demonstrated and documented“. Minor updates now state that IQ’s should also involve the “verification of the correct installation of components, instrumentation” and OQ’s should “ensure the system is operating as designed“.


A new section on requalification states that equipment, facilities, utilities and systems should be evaluated at an appropriate frequency to confirm that they remain in a state of control. In instances where re-qualification is necessary and performed at a specific time period, the period should be justified and the criteria for evaluation defined. Also, Annex 15 now states that the possibility of small changes over time should be assessed.

Process Validation

Within the General description for Process Validation (PV), Annex 15 now states that it is implicit in that a “robust product development process is in place to enable successful process validation” and that GMP requirements for PV should continue through the product lifecycle. This reflects the intent of the ICH Q8-Q11 documents and part of the reason for the revision. The section also discusses the approaches of continuous verification and hybrid approaches as well as the use of bracketing for new products where extensive process and product knowledge exists. Also of note is that the PV protocol should now reference the respective Master Batch Record. The section also cross-references Annex 13 for the PV of investigational medicinal products (IMP).

And so to Cleaning Validation…

In the Glossary section, the definition of Cleaning Validation has thankfully been modified to state:

Cleaning validation is documented evidence that an approved cleaning procedure will reproducibly remove the previous product or cleaning agents used in the equipment below the scientifically set maximum allowable carryover level“.

When performing CV in order to confirm the effectiveness of a cleaning procedure, now it is indicated that “simulating agents may be used with appropriate scientific justification“. The reference to permitted daily exposure (PDE) for calculating limits of product residues has been removed but the EMA Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities has been referenced instead. This document will come into effect on 01 June 2015.

It is good to see that common sense prevailed for products that would not require toxicological evaluation:

“Therapeutic macromolecules and peptides are known to degrade and denature when exposed to pH extremes and/or heat, and may become pharmacologically inactive. A toxicological evaluation may therefore not be applicable in these circumstances. If it is not feasible to test for specific product residues, other representative parameters may be selected, e.g. total organic carbon (TOC) and conductivity”.

Also where a cleaning process is ineffective or is not appropriate for some equipment, “dedicated equipment or other appropriate measures should be used for each product as indicated in Chapters 3 and Chapter 5 of EudraLex, Volume 4, Part I“. Note that these chapters were recently revised and effective since the 1st of March and the changes discussed in a previous blog.

What next for Annex 15 validation and qualification?

As stated above, this new version of Annex 15 will become effective in the EU on October 1st of this year. Watch this space for potential PIC/S adoption in the coming year.

Tell us what you think of the changes.