What triggers the recent Changes in EU GMP?

Nitrosamines, the implementation of ICH Q9, data governance, and artificial intelligence are the main drivers of the current changes to the EU GMP Guidelines. Let us take a closer look at the details.

Chapter 1 - Pharmaceutical Quality System

The revised Chapter 1 aims to strengthen Risk Management but also Knowledge Management and to clarify the requirements for the Product Quality Review (PQR).

It primarily reflects the updated ICH guideline on Quality Risk Management, ICH Q9(R1). Seven new paragraphs/sections are to be added, incorporating key QRM principles.

In a new paragraph 1.4(xviii), it is emphasised that Knowledge Management should be applied together with QRM "to provide an early warning system that supports effective oversight and response to evolving quality/manufacturing risks." In addition, a new paragraph 1.13 specifies that "knowledge should be used to make informed decisions, trigger re-evaluations, and stimulate continual improvement."

The revised chapter also clarifies requirements for the Product Quality Review (PQR), particularly with regard to product grouping and situations where only a limited number of batches are manufactured during the review period. Review timeframes may be adjusted as appropriate, provided adequate justification is documented.

Chapter 4 - Documentation

The revised Chapter 4 introduces changes supporting the use of new technologies, hybrid solutions, and emerging services in document management. Risk management principles are now central and integrated into the data governance system to ensure the accuracy, integrity, availability, and legibility of documents across all formats-paper, digital, or hybrid.

All documentation, whether in text, image, video, or audio format, must remain complete and readable throughout its lifecycle. The guideline also clarifies requirements for the management of electronic records and signatures, as well as data integrity, while ensuring alignment with the concurrent revision of Annex 11.

Annex 6 - Manufacture of Medicinal Gases

According to the introduction of the concept paper, an update is necessary to reflect changes in current practice and stakeholder recommendations submitted to the Agency following the COVID-19 pandemic. Only a "limited review and update of the guideline" is planned.

Of particular interest are the considerations regarding batch certification in a more practical manner, taking into account process risks and the availability of the Qualified Person (QP), for example with respect to remote and/or retrospective certification.

Annex 11 - Computerised Systems

The revised Annex 11 establishes enhanced requirements for the lifecycle management of computerised systems, mandating that Quality Risk Management principles be comprehensively applied at all stages. The updated provisions reinforce obligations concerning the definition and ongoing maintenance of system requirements, as well as the oversight of suppliers and external service providers.

Furthermore, the Annex strengthens controls related to data integrity, audit trails, electronic signatures, and system security.

Annex 15 - Qualification and Validation

In the introduction to the concept paper, it is stated that N-nitrosamine impurities in sartan medicines triggered the revision of Annex 15. It highlights the lack of sufficient process and product knowledge during the development stage, as well as GMP deficiencies among active substance manufacturers.

The document therefore recommends making Annex 15 mandatory for active substance manufacturers. Until now, its application has been optional for this group. This change would affect manufacturers of both chemical and biological active substances. In addition, the changes in Quality Risk Management introduced in ICH Q9 (R1) are to be incorporated.

In this context, the concept paper further emphasises the need for thorough investigations in cases where deviations from predefined acceptance criteria occur. This is intended to promote a deeper understanding of manufacturing processes among API manufacturers.

Annex 22 - Artificial Intelligence

The new Annex 22 on Artificial Intelligence (draft) establishes requirements for the use of AI and machine learning in the manufacture of active substances and medicinal products. It sets out requirements for the selection, training, and validation of AI models.

Emphasis is placed on clearly defining the intended use of the model, establishing appropriate performance metrics, ensuring the quality of training data, and managing and processing test data. Annex 22 also foresees continuous oversight of AI systems, including change control, performance monitoring, and procedures for human review where necessary.