Expert comment: Revision of GMP Annex 15 – What does it mean for manufacturers?

The European Medicines Agency has released a concept paper for revision of GMP Annex 15. Annex 15 is currently intended for used by active substance manufacturers as an optional supplementary guidance to the requirements set out in EudraLex, Volume 4, Part II. However, in June 2020 the report “Lessons learnt from presence of N-nitrosamine impurities in sartan medicines” was published, recommending that Annex 15 be made mandatory for all active substance manufacturers.

This recommendation has been endorsed by the GMP/GDP Inspectors Working Group, which agreed that it should be implemented through a targeted revision of Annex 15. The proposal aims to extend the scope of the annex to include active substance manufacturers and to amend selected sections to supplement and align with guidance provided in EudraLex, Volume 4, Part II, as well as other guidance related to active substances.

Impact on active substance manufacturers

The proposed changes that are most relevant to active substance manufacturers include requirements and guidance on:

• Validation activities performed by third party contractors
• Thorough investigations of results that fail to meet predefined acceptance criteria.
• User Requirements Specifications, Factory Acceptance Testing / Site Acceptance Testing
• Supplier qualification, extension of process validation to include material and solvent recovery, emphasis on identifying and controlling variables that impact critical quality attributes and addressing them appropriately in process validation protocols and guidance on continuous process verification and hybrid approach
• Guidance on the verification of transportation processes

In addition, the proposal includes targeted revisions to incorporate considerations from the ICH Q9 (R1) on Quality Risk Management.

Next steps

If Annex 15 becomes mandatory for active substances manufacturers, it will have an impact on drug product manufacturers and QPs as well. This would lead to increased oversight responsibilities to ensure that active substances manufacturers comply with the revised guideline and may affect quality agreements, QP declarations for active substances, and the need for additional audits.

The deadline for submitting comments is April 2026, and a draft of Annex 15 is expected shortly thereafter, with final adoption of the updated guideline planned for December 2026. This period will allow manufacturers to assess the impact of the proposed changes and implement updates in line with the new requirements.