Detailed Analysis of Annex 15 Draft

In our News EMA published a concept paper on the revision of the Annex 15 we reported about the planned revision of Annex 15. The draft EU GMP Annex 15 is now available. Compared to the original 11 pages of Annex 15 the draft has now 17 pages. The above-mentioned EMA Concept Paper is mentioned as a reason for the revision, i.e. adjustments to:

  • Changes in Part 1 of the EU GMP Guide
  • Changes in Annex 11
  • ICH documents Q8-11
  • The EMA draft on Process Validation
  • Changes in manufacturing technologies

New points have been added to the table of contents like subparts of the Process Validation Chapter, topics on transport verification, packaging validation, qualification of utilities, and validation of test methods.  The issue revalidation has been replaced by requalification.

Principles: The root principles address a product / process lifecycle which should be accompanied by qualification and validation activities. In addition, it is now highlighted that changes should also assess the influence on "control strategy". Furthermore, references have been made to validate computerised systems according to Annex 11 and to consider the requirements of ICH Q8-11.

There is a brand new section ("General") in which a "justified and documented" risk analysis (as part of the quality risk management approach) should be the basis for decision making regarding the scope and depth of the qualification/ validation activities. In this chapter too, the principles of ICH Q8-11 (or others if comparable or better) are mentioned as support for qualification/ validation activities. According to the last section of this chapter "data supporting qualification and/or validation studies which were obtained from sources outside of the manufacturers own validation programme may be used provided that this approach has been justified and that there is adequate assurance that controls were in place throughout the acquisition of such data".

The name of the original first chapter "Validation planning" is now named "Organisation and Planning for Qualification and Validation". There, importance is attached to the analysis of the life cycles of equipment, processes and products, and to the respective training of validation employees according to approved validation SOPs. Report structures of the validation personnel should be based on the internal quality system of the company; not necessary given to a QM or QS function. But an appropriate "oversight" over the whole validation life cycle should be available. Later in the text, the validation master plan is addressed. The requirements are very similar to the previous version of Annex 15. Nevertheless, the current validation status of facilities, systems and processes, and that of the location has to be indicated now. Moreover, the description of deviation management in the validation master plan, the handling of acceptance criteria, die evaluation of necessary resources and the "ongoing validation strategy" is now required. With regard to the "ongoing validation strategy", the term "revalidation" (as well as "requalification") appears once more. In addition, a confirmation should be provided "that the materials used for validation are of the required quality and suppliers are qualified to the appropriate level". There is also an additional new requirement which refers to quality risk management. The "approach should be used for validation activities with risk assessments repeated, as required, in light of increased knowledge and understanding from any changes during the project phase or during commercial production. The way in which risk assessments are used to support validation activity should be clearly documented".

The second chapter "Documentation" starts with the requirement with regard to the use of "good documentation practices" to support "knowledge management" during the validation life cycle. All the validation documents have to be approved and authorised according to the determinations of the quality system. In case of complex validation projects, there should be clear references between the documents. Important and critical systems, attributes and parameters, as well as their acceptance criteria should be listed in a validation protocol. If validation protocols are delivered by third parties, the manufacturer has to confirm their suitability and compliance with the internal procedure before any approval. Each change to approved protocols should be documented as deviation and be scientifically evaluated. Results outside the acceptance criteria should also be treated as deviation and investigated. Besides, the influences on validation should be discussed in the report. Regarding the content, the requirements on reporting haven't changed. A cross reference to the protocol isn't required any longer but the results should be opposed to the acceptance criteria. The draft reveals to be flexible with regard to the releases of validation steps which can be part of the release of the validation report, or can be summarised on a document. Mentioning conditional approval to proceed to the next stage is something new: this approval can be "given where certain acceptance criteria or deviations have not been fully addressed and there is a documented assessment that there is no significant impact on the next activity."

Chapter 3 "Qualification stages for equipment, facilities and utilities"  starts with underlining the fact that all stages from initial development of the user requirements should be considered. Specifications for new facilities, systems or equipment should be defined in a user requirements specification (URS) and/or a functional specification. This should help building in quality at this stage and minimising GMP risks. The URS should be "a point of reference" throughout the validation life cycle. 

The design qualification (DQ) is now the second step of qualification. There haven't been many changes with regard to the content; only the obligation to verify the user requirements during the design qualification has been added.

Factory acceptance tests (FAT) are new, and site acceptance tests (SAT) have been included in the draft. For equipment with novel or complex technology, the FAT is  binding ("should be evaluated at the vendor prior delivery"). Documentation review and some tests could be performed at the FAT stage where appropriate and justified, but only when transport has no influence on these functions. On the contrary, the use of SAT is mentioned as "may be" option.

The requirements on installation qualification (IQ) have remained almost unchanged; but the listing is made of a "could" wording. There is a new sub item regarding the verification of the correct installation against pre-defined acceptance criteria.

Regarding operational qualification (OQ) there is now the possibility to perform this task together with IQ and IOQ depending on the complexity of the equipment.  The formal release required after OQ has slipped.

It is now explicitly mentioned that it is possible (in some cases) to perform performance qualification (PQ) in conjunction with process validation. The use of "worst case batch sizes" has been newly added. In addition the frequency of sampling in the PQ should be justified. The activities for IQ, OQ and PQ are "could" provisions according to the new draft Annex 15.

Generally, the section on the qualification of established (in-use) facilities, systems and equipment has disappeared.

The complete detailed analysis of the new draft is avialable in the ECA´s members area.

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