The European Medicines Agency (EMA), in collaboration with the Pharmaceutical Inspection Co-operation Scheme (PIC/S), has announced a major revision of qualification and validation rules in pharmaceutical manufacturing. According to the published concept paper, the requirements of Annex 15 to the GMP guidelines will become mandatory for manufacturers of active pharmaceutical ingredients (APIs).
The full text of the conceptual document is available on the official EMA website. Public consultations on the draft started on February 9, 2026, and will run until April 9, 2026.
Response to the “Nitrosamine Crisis”
The key driver for these changes was the findings made after the discovery of N-nitrosamine impurities in sartan-type medicines. In a “lessons learnt” report published by regulators, it was acknowledged that one of the causes of the crisis was a lack of process and product knowledge during development, as well as systemic deficiencies in quality assurance among substance manufacturers.
“Inspections identified inadequate investigation of quality problems and insufficient measures for contamination control”.
— From the EMA and PIC/S concept paper
To bridge these gaps, the status of Annex 15 is changing: while it previously served only as supplementary non-binding guidance for API manufacturers, its compliance will now become a strict requirement.
What Will Change for Manufacturers?
The proposed revision covers a wide range of processes aimed at strengthening control and production transparency:
- Qualification and External Management: Requirements for the Validation Master Plan (VMP) and change control are being expanded. Particular emphasis is placed on processes transferred to third-party contractors to ensure the customer maintains full control over all stages of work.
- Failure Investigation: A mandatory requirement is introduced to conduct deep investigations into any Out-of-Specification (OOS) results. This is intended to increase manufacturers’ understanding of their own technological processes.
- Equipment Lifecycle: User Requirement Specifications (URS), as well as Factory and Site Acceptance Testing (FAT/SAT), are officially extended to substance production and linked to all qualification stages (DQ, IQ, OQ, PQ).
- Material Recovery: Solvent and material regeneration stages will be included in process validation protocols—a critical area that is often a source of undesirable impurities.
- Transportation: The document adds strengthened requirements for transportation verification, linking Good Manufacturing Practice (GMP) with Good Distribution Practice (GDP) principles.
A New Approach to Risk Management
A second important goal of the revision is to synchronize European rules with the updated international ICH Q9 (R1) guideline on Quality Risk Management. The new version of Annex 15 will require a risk-based approach not only during qualification but also in the design of monitoring systems and the implementation of regular risk review procedures.
Timelines and Forecasts
The final version of the updated guideline is expected to be published by the European Commission and adopted by PIC/S by December 2026.
Regulators believe that while the transition from “recommendatory” to “mandatory” status will require effort, it will not deal a critical blow to the industry, as Annex 15 principles are already de facto recognized in the sector. Nevertheless, EMA encourages stakeholders to actively participate in the discussion to assess the real impact of the new norms on business.
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