As agreed during the 115th meeting of EMA’s GMP/GDP Inspectors Working Group (GMDP IWG) in September 2024, the European Medicines Agency has launched a targeted revision of Annex 15 of the Good Manufacturing Practices (GMPs). The consultation period on the Concept Paper, jointly published by EMA and PIC/S in February 2026, will remain open until 9 April 2026. This initial phase will be followed by the publication of a revised draft guideline and a second round of consultation, with the final text expected to be published by the end of 2026.
The initiative to revise Annex 15 stems from lessons learned since 2020 regarding the presence of N-nitrosamine impurities in medicines containing sartans as active ingredients. The report published on the case highlighted, among other aspects, an insufficient level of knowledge and understanding of the manufacturing processes of active substances by their producers. This lack of process understanding contributed to quality issues affecting active pharmaceutical ingredients (APIs) and to inadequate measures to control contamination by impurities. The report on the nitrosamine case ultimately recommended making the application of Annex 15 mandatory also for API manufacturers.
This recommendation was taken up in 2024 during the 115th meeting of the GMDP IWG and has now led to the publication of the new Concept Paper by EMA and PIC/S, the international scheme for cooperation in pharmaceutical inspections.
Objectives of the revision
According to the document, the revision aims to extend the scope of Annex 15 to manufacturers of active substances, both chemical and biological. The update will also introduce selected modifications to the current text and strengthen the link with the provisions set out in Part II of the EU GMP guidelines, which specifically address active substances. Another key objective is to align the Annex more closely with the ICH Q9 (R1) guideline on Quality Risk Management, in order to ensure greater consistency between the two frameworks when making decisions related to qualification and validation activities.
The Concept Paper indicates that greater emphasis should be placed on the validation documentation for active substances, including the Validation Master File, as well as on the definition of a clearer qualification and validation policy. Such a policy should specify roles and responsibilities, the criteria used, including acceptance criteria, and the monitoring strategies adopted during the lifecycle of the manufacturing process.
A lifecycle-based approach to validation
At the core of the proposed revision is the introduction of a lifecycle-based approach to validation. This approach would cover the entire process lifecycle, from process design and qualification to ongoing performance monitoring and final evaluation, based on data and metrics collected throughout the manufacturing lifecycle.
The Concept Paper also highlights the need for robust procedures to investigate non-conforming results, supported by appropriate corrective and preventive actions (CAPA). In the area of qualification, the revision is expected to strengthen several key concepts, including the definition of User Requirements Specifications (URS) and the role of Factory Acceptance Testing and Site Acceptance Testing (FAT/SAT).