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The new EU GMP Annex 15 in practice

Evolution of the regulatory environment.
Evolution of the regulatory environment.

Since the publication of the current Annex 15 in September 2001, a number of developments have occurred in the GMP environment. The new Annex 15 takes the changed regulatory landscape, including changes in other sections of EudraLex Volume 4, and reflects the effects of technological advances. This article provides an overview of the most important changes to the latest version of Annex 15, which takes effect this October.


Planning, organization and life cycle approach
The contents of the validation master plan (VMP) have now been specified in greater detail. Among other things, it should describe the qualification/validation strategy, the current validation status and the acceptance criteria.

New: an integrated life cycle approach
Quality risk management (QRM) continues throughout the entire life cycle of a product. That means that risk assessments can change during the product life cycle and must be adapted accordingly. They must always be traceable to the original requirements. Annex 15 is still based on the classic V model. The specification page is supplemented by a user requirements specification (URS) as a central reference point in the product life cycle. The URS should include quality components applicable to the product in order to minimize GMP risks at
an early stage, as well as the classic components DQ, FAT/SAT, IQ, OQ, PQ. However, it is explicitly permitted to combine verification phases appropriately, e.g. IQ/OQ or OQ/PQ. A factory acceptance test (FAT) on the premises of the system manufacturer is required for equipment that incorporates «new» or «complex» technology. If a FAT was carried out, certain IQ/OQ tests do not need to be repeated if it can be shown that function was not impaired during transport or installation. In general, compliance with good documentation practice is emphasized.

Process validation
One thing is clear: Companies that have already qualified in compliance with EU GMP will not have to change anything.chosen. Retrospective approaches are no longer acceptable.Those who wish to use quality by design (QbD), design space or PAT approaches to process validation in the future will find the corresponding requirements in the new version of Annex 15. Data from process and product development form the basis for informative process validation (PV). Should research and development data be used in the process validation, these must be prepared so that they are GMP-compliant.

Suppliers of starting materials and primary packaging materials must be qualified before the production of the validation batches.

The classic three-batch approach is still accepted, but this is only a minimum requirement. It must be shown that the process consistently delivers the defined quality. This must subsequently be documented with informative data (representative number of batches, standard range, batch size as in routine production).

Concurrent validation is now permissible only in special cases. The prerequisite for this procedure is a deep understanding of the process and complete mastery of the process based on an adequate supply of data.

The number of validation batches required can be reduced by using the «bracketing» approach, in which batches with identical or very similar design factors can be handled together.

The approach known as «continuous process verification (CPV)» is brand new. However, it can be used only for processes already developed in accordance with QbD. The specific implementation of this approach is not described in detail.

Revalidation is no longer mentioned. Instead, the term «ongoing process verification» (OPV) has been introduced. Together with the product quality review (PQR), OPV will replace revalidation.


Cleaning validation
The section on cleaning validation is now significantly more detailed and includes further aspects such as the use of quality risk assessment, toxicological evaluation and automated cleaning processes. The visual check for cleanliness is now explicitly named as an important criterion for acceptance, but exclusively visual monitoring is not acceptable. The earlier requirement of three consecutive cleaning procedures for cleaning validation has been replaced by a risk-based assessment for the specification of the necessary number of validation runs.


New sections
The new sections listed below have been added.

Transport verification
This is intended to ensure that products are transported in compliance with the approval dossier and specification. Transport routes must be clearly specified. For example, seasonal fluctuations, delays, data logger malfunctions, etc. must
 e included and their influence on product quality analyzed.

Packaging validation
This applies to the critical process parameters (e.g. temperature, speed, sealing pressure) in primary packaging that potentially have a direct influence on the product. Validation should encompass the entire range of operations.

Qualification of the utilities
This includes water, steam, air and gases, for example. Direct (e.g. heating, ventilation, air-conditioning) or indirect (e.g. heat exchanger) product contact must be subjected to risk assessment in order to keep control over the effects in the event of faults.

Validation of the test methods
The analytical methods used for qualification, validation and cleaning must be validated. Here reference is made to EU GMP Part 1. For microbial testing, the validation should confirm that the product itself does not promote bacterial growth. Likewise, the validation of wipe tests in cleanrooms should show that the cleaning agents used do not influence the result.

Change control
The «Change Control» section has been expanded to include new content. The change process is now to be handled as an important part of knowledge management within the framework of the pharmaceutical quality system.


Overall, this reform is a big step toward standardization. The concepts described in ICH Q8, Q9, Q10 and Q11 must be explicitly taken into account. With an integrated life cycle concept, QRM and contemporary PV approaches, Annex 15 has responded to practical experience and harmonization goals, including those of the FDA.

The Business Designers support pharmaceutical manufacturers and suppliers in the implementation of the regulatory requirements. Take advantage of the experience of our highly qualified experts to implement the new regulatory specifications pragmatically, safely and reliably.


Dr. Peter Schober|Senior Consultant Efficient IT|Chemgineering|The Business Designers


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