In the previous article we analyzed What changes does Annex 15 bring and what key message are inspectors sending?, as well as a brief comparison between the current one and the changes that are coming.

In this installment, we will focus on How the revision of Annex 15 affects manufacturers, especially in those of APIs.

1. Annex 15 – GMP Qualification and Validation is currently under review.

He Annex 15 – Qualification and Validation is under review as part of the new work plan of the EMA GMP/GDP Inspectors Working Group (GMDP IWG) for the period 2026–2028.

This Annex, one of the classic pillars of the European GMP, will have a change of focus que conllevará un impacto real en cómo se planifican, ejecutan y defienden las actividades de validación durante una inspección.

2. ¿Por qué se revisa el Anexo 15?

Se trata de una revisión motivada por deficiencias detectadas, riesgos emergentes y la necesidad de modernizar la regulación.

La revisión del Anexo 15 no es un simple ajuste, sino una respuesta estratégica a problemas reales identificados en los últimos años. A continuación, las razones de fondo más relevantes.

3. Lecciones aprendidas por el caso de las impurezas nitrosaminas en sartanes

Este es el detonante principal de la revisión.

En 2018 se descubrieron impurezas carcinogénicas N‑nitrosaminas en medicamentos tipo sartan. La EMA identificó systematic problems in API manufacturers:

• Lack of knowledge of the process and the product during development.
• Significant GMP deficiencies.
• Insufficient pollution controls.
• Inadequate quality research.

He Lessons Learnt Report of 2020 explicitly recommended make Annex 15 mandatory for API manufacturers, as a structural measure to prevent this situation from occurring again.

Conclusion: The review is a global corrective action to raise the level of control and qualification required of API manufacturers, which proved insufficient in a case of international health impact.

4. Schedule 15 was optional for API manufacturers — and this left a regulatory gap

Historically, Schedule 15 was considered optional orientation for manufacturers of active ingredients (APIs), a situation that left a gap in regulatory supervision.

He concept paper explicitly proposes:

• Convert Annex 15 into a mandatory requirement.
• Extend your application to manufacturers of chemical and biological APIs.
• Make your compliance verifiable in inspections both EMA and PIC/S.

Conclusion: The review is necessary to close this gap and align standards between finished product manufacturers and active substance manufacturers.

5. Alignment with ICH Q9 (R1): risk management update

The revision explicitly incorporates document updates I Q9 (R1) on Quality Risk Management (Quality Risk Management, QRM).

Regulators seek:

• Integrate QRM into qualification and validation activities.
• Ensure a risk-based approach throughout the process lifecycle.

Conclusion: European regulation needs to be modernized to align with recently revised international standards.

6. Reinforcement of expectations in investigation of deviations

Another critical finding in recent quality cases was the insufficient investigation of deviations by several API manufacturers.

The concept paper highlights:

• The need for deeper investigations into deviations.
• The obligation to reinforce root cause analysis and impact evaluation.

Conclusion: The review seeks to increase rigor in the investigation of deviations and strengthen understanding of the process.

7. Technological and industrial evolution (processes, digitalization, automation)

The current version of Annex 15 dates from 2015, but:

• Production technology has changed.
• Computerized and automated systems are much more implemented.
• The complexity of biotechnological processes has increased.

Conclusion: The industrial environment is not the same, and Annex 15 needs to be updated to reflect this technological transformation.

8. Better harmonization between Part I, Part II and other annexes

The review also seeks to align Annex 15 with:

• Part I of EudraLex Volume 4
• Part II (equivalent to ICH Q7)
• Annex 11 (Computerized systems)
• ICH Guides Q8, Q9, Q10 and Q11.

Conclusion: The review provides regulatory cohesion and prevents inconsistent interpretations between different manufacturers and authorities.

9. Need to increase market surveillance

The EMA identified that the lack of robust controls and knowledge of the process is a systemic risk with a direct impact on patient safety.

He Lessons Learnt recommended strengthening surveillance by adopting structural preventive measures.

Conclusion: The review of Annex 15 is a tool to improve regulatory oversight and prevent future quality incidents.

10. Mandato del GMDP Inspectors Working Group (IWG)

In 2024, the GMDP IWG agreed that:

• It was necessary a targeted review, based on lessons learned.
• A writing group to prepare the draft.

There is an explicit mandate from the European inspectors themselves to strengthen this regulatory area.

For all these reasons, the EMA GMP/GDP inspector group, along with PIC/S, published a concept paper proposing a directed review of Annex 15.

• The public consultation is open from February 9, 2026 to April 9, 2026.
• The review proposes extend the scope of Annex 15 to manufacturers of chemical and biological active substances, going from being an optional guide to an applicable and verifiable requirement during inspections.
• The update will also integrate elements of I Q9 (R1) on quality risk management.
• It is expected a final draft towards the end of 2026.

11. Impact of the revision of Annex 15 on manufacturers

The ongoing revision of Annex 15 represents a significant change for the pharmaceutical industry, especially for manufacturers of active substances (APIs). These are the main effects:

Area	What changes with the revision of Annex 15	Practical impact for manufacturers
Applicability to APIs	Annex 15 is no longer an optional guide and becomes mandatory for manufacturers of APIs (chemical and biological).	Formal implementation of qualification and validation systems aligned with GMP Part I, verifiable in EU/PIC/S inspection.
Validation approach	Explicit reinforcement of the risk- and lifecycle-based approach (aligned with ICH Q9 R1 and ICH Q12).	Technical justification of the validation scope; less “validate by default” and more explaining why and to what extent it is validated.
Process and product knowledge	Greater emphasis on demonstrating process understanding and real control.	Need to demonstrate CPPs, CQAs and control logic; Validation becomes a test of knowledge, not just execution.
Deviation management	Higher expectations in investigation of deviations related to qualification and validation.	Deeper investigations, better root cause analysis, and clear impact assessment on validated status.
Risk Management (QRM)	Mandatory and demonstrable integration of Quality Risk Management in C&V.	Live risk assessments, used for real decisions (scope, revalidations, changes), not just as supporting documentation.
Using validation data	Greater demands on the robustness and traceability of data, including historical or external data.	Better reasoned validations, with clear criteria for the use of previous data and consistent evidence throughout the life cycle.
Relationship with the PQS	Validation is fully integrated into the Pharmaceutical Quality System (Chap. 1).	Mayor conexión entre validación, gestión de cambios, desviaciones, CAPAs y trending; la validación deja de ser un silo técnico.
Cadena de suministro	Refuerzo del control sobre proveedores y actividades subcontratadas.	Revisión de acuerdos técnicos, ampliación de auditorías y mayor alineación entre fabricantes de APIs y de producto terminado.
Expectativa en inspección	Los inspectores pasan de preguntar “¿está validado?” a “¿por qué lo validó así?”.	Mayor presión sobre la capacidad de explicar decisiones técnicas con criterio científico y enfoque basado en riesgo.
Preparación regulatoria	Calendario regulatorio claro con impacto a corto plazo (2026–2027).	Necesidad de realizar gap assessments early and review validation strategies before the next inspection.

Taken together, the revision of Annex 15 raises the expected level of technical and regulatory maturity of manufacturers, especially of APIs, and makes validation a central element of the GMP strategy, not just compliance.

Conclusion

The revision of Annex 15 represents a clear elevation of the expected level of control, validation and knowledge of the process, especially for API manufacturers. The industry must prepare to:

• More formal requirements.
• More scientific evidence.
• More scrutiny in inspections.
• Greater integration of risk management.
• Review of relationships with suppliers.

Inspections no longer evaluate just compliance, but understanding and control of the process.

If you want to review whether your current qualification and validation approach is aligned with the new EMA inspection framework, our team can accompany you in the evaluation, definition and implementation of a robust, risk-based strategy. Put you in contact with us to analyze your specific case.