The EMA GMP/GDP Inspectors Working Group (GMP/GDP IWG), together with PIC/S, has launched a public consultation on a concept paper to revise EU GMP Annex 15 (Qualification and Validation).
The targeted revision would extend the scope of Annex 15 to include manufacturers of chemical and biological active substances (AS) and, critically, move it from “optional supplementary guidance” to a formally applicable expectation for AS manufacturers, with implementation verified through EU and PIC/S inspections.
The public consultation opened on 9 February 2026 and closes on 9 April 2026.
30 Seconds Takeaway
Why Is This Revision Happening Now?
Annex 15 already influences expectations across the industry, but for active substancesit is still considered supplementary, optional guidance that should not introduce additional requirements beyond EudraLex Volume 4, Part II.
The concept paper ties the revision to the June 2020 “lessons learnt” report following N-nitrosamine impurities in sartan medicines.
In the paper’s rationale, inspections of active substance manufacturers during that period highlighted recurring weaknesses that are validation-adjacent, but ultimately process understanding and control problems, specifically:
- insufficient process and product knowledge during development,
- inadequate investigation of quality issues, and
- insufficient contamination control measures, among other GMP deficiencies.
The lessons learnt report recommendation referenced in the concept paper is straightforward: make Annex 15 mandatory for active substance manufacturers to address the shortcomings and strengthen assurance of quality and patient safety.
Two additional drivers are explicitly stated:
- The revision should be targeted first (with a broader, comprehensive review later), and
- The update should reflect ICH Q9(R1) Quality Risk Management expectations.
What Is Proposed to Change
The drafting group proposes to extend the scope to AS manufacturers and amend Annex 15 in selected areas, supplementing and linking with Part II and other relevant guidance for active substances (including GDP aspects).
| Proposed change | Concept Paper Changes | Practical impact for AS manufacturers |
|---|---|---|
| Scope | Extend Annex 15 to chemical and biological active substances (AS); compliance checked in EU/PIC/S inspections. | Annex 15 becomes a direct inspection reference for API qualification and validation. |
| VMF / Q&V policy + Change control | Extend the Validation Master File and Q&V policy; emphasize change control as knowledge management (linked to Part II §12.20). | Stronger lifecycle governance and traceable change impact logic. |
| Third-party validation | Strengthen expectations for validation activities performed by contractors; increased oversight of outsourced work. | Clear ownership and accountability for outsourced validation activities. |
| Investigations vs acceptance criteria | Extend the requirement to investigate results failing predefined acceptance criteria. | Fewer “close-it” justifications; deeper process understanding expected. |
| Qualification stages | Extend URS and FAT/SAT concepts to AS; formally link to DQ, IQ, OQ, and PQ. | Stronger design intent and acceptance testing narrative for equipment and utility qualification. |
| Process validation lifecycle | Emphasize robust development; clarify concurrent validation; reinforce supplier qualification; include recovery; focus on variables impacting CQAs; add CPV, hybrid approaches, and periodic review. | Broader, lifecycle-based process validation expectations for APIs. |
| Transport verification (GDP interface) | Provide more guidance on transport verification (extending Part II Chapter 10) and include transport impact in AS product knowledge. | Transport becomes an integral part of the API quality and knowledge narrative. |
| ICH Q9(R1) QRM integration | Targeted revisions to incorporate ICH Q9(R1): QRM in monitoring system design and qualification, risk review activities; reinforced QRM expectations even for traditional processes. | More explicit risk-based justification and review for qualification and validation decisions. |
1) Scope: Annex 15 Explicitly Covers Active Substances
This is the headline change: Annex 15 would apply to manufacturers of chemical and biological active substances, and EU and PIC/S inspectorates would verify compliance during inspections.
What this changes in practice: the “optional guidance” argument largely disappears. EU and PIC/S inspectorates will ensure implementation and compliance during inspections.
2) Extended Validation Governance: Validation Master File / Q&V Policy + Change Control
The concept paper proposes extending the Validation Master File concept, the Qualification & Validation policy, and change control to support knowledge management.
Why it matters: Many sites have protocols and reports, but the lifecycle logic is fragile. Inspectors usually probe how:
- your Q&V programme is defined and prioritised
- acceptance criteria were set (and justified)
- changes trigger Q&V actions (or re-qualification)
- you demonstrate “state of control” beyond a one-time study
This proposal further positions Annex 15 as a governance framework rather than a protocol template.
Related Article: Qualification vs Validation in GMP
3) Outsourced Validation by Third-Party Contractors
Annex 15 revisions are proposed to strengthen expectations for validation performed by third-party contractors, ensuring AS manufacturers retain control over outsourced activities.
What this looks like in inspections: “contractor executed” is acceptable; “contractor owned” is where findings appear. Expect investigation focused on:
- who designed the approach (scientific rationale)
- how deviations/raw data were handled and reviewed
- how conclusions were approved and integrated into the QMS
4) Investigations When Acceptance Criteria Are Not Met
The concept paper explicitly proposes extending the need to investigate results that fail predefined acceptance criteria to promote deeper process knowledge.
Practical implication: a missed criterion in qualification or validation can’t be treated as a paperwork inconvenience. The expectation moves toward:
- defensible root cause paths
- linkage to process understanding (variables/CQAs)
- decisions on failures vs. acceptance criteria will require investigation to build deeper process knowledge.
This aligns tightly with the nitrosamine “lessons learnt” theme: weak investigations = weak knowledge.
5) Qualification Lifecycle: URS + FAT/SAT Linked to DQ/IQ/OQ/PQ
Annex 15 would emphasise URS and FAT/SAT for AS manufacturing and link them with expectations for DQ/IQ/OQ/PQ.
Why this matters for AS sites: API operations often have equipment that evolves through upgrades, retrofits, and “like-for-like” replacements. Strengthening URS/FAT/SAT supports an inspection narrative that design intent was defined up front and verified before routine use.
See Also: IQ vs OQ vs PQ: Key Differences in GMP
6) Concurrent Process Validation Approach
The concept paper signals several additions/strengthening points:
- emphasis on robust process development
- clearer expectations around concurrent validation
- greater emphasis on supplier qualification
- explicit consideration of process recovery of materials and solvents
- focus on variables impacting critical quality attributes (CQAs) when drafting validation protocols
- guidance on continuous process verification (CPV) and hybrid approaches
- emphasis on periodic review
Why recovery is called out: recovery/recycling can be a quiet pathway for impurity build-up or variability. The concept paper is signalling that “validation thinking” should cover these operations as part of the process control strategy.
See Also: Process Validation in Pharmaceutical Industry
7) Transport Verification: Stronger API GDP Interface
The proposal includes additional guidance on verifying transportation, extends Part II, chapter 10, and emphasizes that transport impact should be part of product knowledge for the active substance.
Interpretation: for APIs sensitive to temperature/humidity, handling stress, or long transport lanes, transport verification becomes a stronger expectation within the Q&V/knowledge narrative, not an isolated logistics document.
8) ICH Q9(R1): Explicit QRM Built Into Qualification/Validation Decisions
Targeted revisions are planned to reflect ICH Q9(R1). The concept paper calls out:
- use of QRM in the design and validation/qualification of monitoring systems
- provisions for risk review activities supporting Q&V (linked to Part II chapter 2)
- emphasis on QRM even in “traditional process” contexts
What this means in real terms: decisions on study scope, sampling plans, monitoring design, and requalification frequency will increasingly require documented risk logic and periodic review using performance data.
Timeline: What to Expect Through 2026
The concept paper provides a clear timetable:
- Draft concept paper preparation: from Nov 2024
- Approval of draft concept paper by EMA GMP/GDP IWG: Nov 2025
- Public consultation on the concept paper (2 months): Feb–Apr 2026
- Discussion in drafting group: from Apr 2026
- Consultation on draft guideline (3 months): Apr–Jun 2026
- Endorsement by EMA GMP/GDP IWG: Jul 2026
- Publication by European Commission: by Dec 2026
- Adoption by PIC/S GMDP Harmonisation sub-committee: by Dec 2026
Practical Readiness Checklist for Active Substance Manufacturers
Even at the concept stage, you can still run a quick reality check aligned to the proposed revision:
A) Governance and Lifecycle Control
- Do you have a clear Validation Master File (VMF) or Q&V policy that defines the scope, priorities, lifecycle, and documentation structure?
- Can you show a tight linkage between change control and Q&V impact assessment decisions?
B) Investigations and Knowledge Depth
- When Q&V acceptance criteria are missed, do investigations demonstrate a defensible path to cause, impact, and decision?
- Are process knowledge gaps logged and tracked as risks (not just closed as deviations)? (This is the direction implied by the concept paper’s “knowledge management” angle.)
C) Qualification Execution
- Are URS and FAT/SAT consistently used and connected to DQ/IQ/OQ/PQ decisions?
- Can you justify qualification depth using QRM and show periodic reassessment?
D) Process Validation Lifecycle
- Is your approach to concurrent validation clearly justified and controlled?
- Are recovery operations within the validation/control strategy (materials/solvents) not treated as “utilities”?
- Do you have a defined approach to CPV/ hybrid verification and periodic review?
E) Outsourcing and GDP Interfaces
- Do you retain documented oversight for contractor-executed Q&V work?
- Where transport can affect API quality, is transport verification linked back to product knowledge and Part II expectations?
Final Thoughts
This concept paper clearly signals that Annex 15 is being repositioned as a practical inspection benchmark for active substance manufacturers, with the scope explicitly extended to chemical and biological AS, and implementation verified through EU and PIC/S inspections.
The proposed edits are targeted, but they touch the areas that decide whether an API site can tell a defensible lifecycle control story on how:
- qualification/validation is governed (VMF/Q&V policy + change control)
- failures against acceptance criteria are investigated
- outsourced validation is overseen,
- process validation incorporates development knowledge (including recovery operations),
- CPV/hybrid approaches and periodic review are used, and
- transport verification is integrated into product knowledge under the GDP interface.
The consultation is open until 9 April 2026. If you operate or audit API manufacturing, this is a useful window to comment on what will be practical, what needs clearer wording, and where guidance should stay risk-based rather than prescriptive.
