Recently, the EMA (European Medicines Agency) and PIC/S (Pharmaceutical Inspection Convention) have published a concept paper on the revision of Eudralex Vol.4 Annex 15, following the recommendations of the report “Lessons learnt from presence of N-nitrosamine impurities in sartan medicines”. This report highlighted nitrosamine contaminations in sartan medicine products and key insights from GMP inspections of active pharmaceutical ingredient (API) manufacturers, revealing critical gaps such as insufficient process and product knowledge during development or weaknesses in contamination controls, emphasizing the need to reinforce qualification, validation, and risk management requirements.

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All of this helped trigger the decision to make Annex 15 mandatory for API manufacturers and to align it with ICH Q9 (R1) on quality risk management.

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This revision highlights several key areas, including:

• Extend the scope of Annex 15 to explicitly include chemical and biological API manufacturers.

• Extend the concepts of Validation Master File, Qualification and Validation Policy.

• Stronger requirements for investigation of results outside predefined acceptance criteria.

• Expand qualification stages, including URS (User Requirements Specifications), DQ (Design Qualification), IQ (Installation Qualification), OQ (Operational Qualification), and PQ (Performance Qualification).

• Reinforce robust process development by monitoring variables that impact Critical Quality Attributes (CQAs) and strengthening existing In-Process Controls (IPCs).

• Emphasize process validation for the recovery of materials and solvents.

• Improve transportation verifications to better safeguard the quality of APIs.

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For a full overview of all proposed changes, please refer to the official EMA concept paper.

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With this shift, the regulators are expecting to further enhance public health safety by promoting manufacturers to have more oversight and understanding about their processes and products.

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The concept paper entered public consultation in February 2026, comments can be submitted until 09 April 2026 and a final version is expected to be available by the end of 2026.

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Proactive planning will help API manufacturers quickly align with the future updated Annex 15 requirements.