A joint EMA–PIC/S concept paper proposes extending Annex 15 to active substance manufacturers and aligning it with ICH Q9(R1). The current Annex 15 stays in force, and the earliest a revised text could be published is 2028.
A joint EMA–PIC/S concept paper proposes extending Annex 15 to active substance manufacturers and aligning it with ICH Q9(R1). The current Annex 15 remains in force — the earliest a revised text could be published is 2028.
What happened
On 10 February 2026, PIC/S announced that the joint EMA–PIC/S drafting group had developed a concept paper on the revision of Annex 15 (Qualification and validation) of the EU–PIC/S GMP Guide. The paper itself, published by the EMA on 19 January 2026 under reference EMA/INS/GMP/20217/2026 (the July 2026 reissue carries the updated reference EMA/INS/GMP/163466/2026), was agreed by the EMA GMP/GDP Inspectors Working Group on 30 November 2025 and by PIC/S on 14 January 2026. Joint consultation opened on 9 February 2026, with comments due by 9 April 2026.
This is a concept paper — a statement of intent and rationale — not a revised guideline. Annex 15 as it stands continues to apply as written. Its stated aim is to extend the annex's scope to active substances manufacturers and to account for ICH Q9(R1) on quality risk management.
Why it matters
Annex 15 is at present described in the concept paper as guidance that active substance manufacturers "may also [use] as supplementary optional guidance … without introduction of additional requirements to EudraLex, Volume 4, Part II." The revision stems from the June 2020 report on lessons learnt from N-nitrosamine impurities in sartan medicines. Chapter 4 identifies insufficient process and product knowledge during development and GMP deficiencies at active substance manufacturers — including inadequate investigation of quality issues and insufficient contamination control — and recommends making Annex 15 mandatory for those manufacturers.
The paper states the revised annex "will be applicable to manufacturers of chemical and biological active substances," with EU and PIC/S inspectorates ensuring compliance during inspections. For teams buying or auditing APIs, that is the direction of travel. The paper's own impact assessment notes the shift from optional to mandatory "is not expected to have a critical impact on companies," since the principles are already generally recognised in the sector.
What is particularly interesting
Several proposed amendments touch directly on cleaning and cross-contamination work. The paper proposes extending the "Validation Master File", the notion of a qualification and validation policy, and change control — the latter framed as part of knowledge management. It also proposes investigating results failing pre-defined acceptance criteria and extending validation expectations to third-party contractors, giving API manufacturers more control over outsourced work.
Qualification is to be broadened: user requirements specifications and factory/site acceptance testing are to be extended to active substance manufacturing and linked to DQ, IQ, OQ and PQ. Process validation expectations would emphasise robust development, clarify concurrent validation, strengthen supplier qualification, address recovery of materials and solvents, and support continuous process verification and periodic review. QRM is to be woven into monitoring-system design and qualification, supported by risk review activities.
What could we learn
The consultation questions name cleaning validation alongside process validation, transport validation, investigations, qualification and change control. The drafting group is asking, in effect, how consistently Annex 15 principles are already used in API manufacturing and what mandatory status would change. For cleaning validation professionals the signal is the direction rather than any specific limit: risk-based justification, documented acceptance-criteria investigation, periodic review and change control as connected lifecycle activities. "Optional supplementary guidance" carries less inspection weight than a directly applicable expectation.
Questions worth asking in our own programme
- If Annex 15 principles became directly applicable to our API suppliers, how would we evidence their qualification and validation practices today?
- Do we investigate results failing pre-defined acceptance criteria as thoroughly as out-of-specification results — and document the root cause?
- Is our validation master file and change control framework genuinely used to manage knowledge, or does it record decisions after the fact?
- How do our outsourced validation and cleaning activities at contractors show we retain control?
- Where do we rely on periodic review to justify continued validation status, and is it risk-based and current?
- How do our cleaning validation acceptance criteria connect to the process knowledge that the sartans lessons-learnt exercise found lacking?
Wider context
The paper traces the revision to the 115th meeting of the GMDP IWG in September 2024, where a targeted revision of Annex 15 was agreed and a drafting group formed, and where alignment with ICH Q9(R1) was also agreed. A comprehensive review is intended later, once this targeted revision is complete. The proposed timetable puts the draft guideline out for consultation in April 2026, with comments due June 2026, EMA GMP/GDP IWG endorsement in July 2026, and publication by the European Commission and adoption by PIC/S by December 2026. Until then, the obligation is to the current text. (The July 2026 reissue of the concept paper revised this timetable; we cover that update separately.)
Sources
- PIC/S — Concept paper on the revision of EU-PIC/S GMP Annex 15 (Qualification and validation), Geneva, 10 February 2026.
- European Medicines Agency — Concept paper on the revision of the guidelines on Good Manufacturing Practice for medicinal products – Annex 15 – Qualification and Validation, EMA/INS/GMP/20217/2026, 19 January 2026 (reissued July 2026 as EMA/INS/GMP/163466/2026).
- PIC/S — Concept paper document (full text): https://picscheme.org/docview/11269
Validation takeaway
Nothing changes yet — the current Annex 15 remains in force and the revised text is not foreseen before 2028. But the concept paper confirms a clear direction: mandatory scope for chemical and biological active substance manufacturers, explicit ICH Q9(R1) risk-management integration, and lifecycle expectations (change control, acceptance-criteria investigation, periodic review, contractor oversight) that cleaning validation programmes already sit inside. Treat this as a reason to review how well your current qualification, validation and cleaning documentation would withstand that standard, not as a trigger for immediate remediation.
Questions worth asking in our own programme
- If Annex 15 principles became directly applicable to our API suppliers, how would we evidence their qualification and validation practices today?
- Do we investigate results that fail pre-defined acceptance criteria as thoroughly as out-of-specification results — and do we document the root cause?
- Is our validation master file and change control framework genuinely used to manage knowledge, or does it record decisions after the fact?
- How do our outsourced validation and cleaning activities at contractors demonstrate that we retain control?
- Where do we rely on periodic review to justify continued validation status, and is that review risk-based and current?
- How do our cleaning validation acceptance criteria connect to the process knowledge that the sartans lessons-learnt exercise found lacking?
