The European Medicines Agency (EMA) and the Pharmaceutical Inspection Co-operation Scheme (PIC/S) have proposed a targeted revision of Annex 15 of the Good Manufacturing Practice guidelines. The concept paper proposes the transition of Annex 15 from its current status as optional supplementary guidance for active substance (AS) manufacturers to a mandatory requirement. This new scope will encompass manufacturers of both chemical and biological active substances.
The proposal stems from lessons learnt from the presence of N-nitrosamine impurities in sartan medicines, which was made public in June 2020. Investigations into these cases revealed that the contamination was often due to gaps in knowledge of processes and products, as well as GMP deficiencies among active pharmaceutical ingredient manufacturers. By making Annex 15 mandatory, regulatory authorities aim to ensure better contamination control and a more robust investigation of quality issues.
The revision intends to align validation practices with quality standards and includes several critical updates:
- Quality Risk Management (QRM): validation and qualification activities will be updated to align with the revised ICH Q9 (R1) guideline, emphasizing the use of QRM throughout the product lifecycle, including the design of monitoring systems.
- Enhanced Documentation: AS manufacturers will be expected to adopt the concepts of the “Validation Master File” and “Qualification and Validation policy” to improve how activities are defined and documented.
- Process Oversight: the new guidelines will focus on sound process development, stricter change control as part of knowledge management, and more rigorous supplier qualification.
- Qualification Stages: concepts such as User Requirements Specifications (URS) and Factory/Site Acceptance Testing (FAT/SAT) will be formally extended to AS manufacturing.
- Transport and Distribution: in line with Good Distribution Practices (GDP), the revision will provide guidance on verifying transportation to ensure that the quality of active substances is not compromised during transit.
Implementation Timeline
The revision process is already underway. A public consultation period is scheduled from February 9 to April 9, 2026. Following the review of comments and final endorsements, the European Commission is expected to publish the finalized guideline by December 2026.
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