The EMA concept paper on revising Annex 15 sends a clear signal: qualification and validation for active substance (API) manufacturers are moving from supplementary guidance toward a mandatory, risk-based expectation. For many API sites, this will require rethinking how process knowledge, validation strategy, and change control integrate across the lifecycle.
Today, Annex 15 is optional supplementary guidance for active substance manufacturers alongside EudraLex Volume 4 Part II. The concept paper proposes making it formally mandatory for chemical and biological APIs. This shift is largely driven by the nitrosamine crisis in sartans, where investigations revealed insufficient process and product understanding, weak contamination control, and GMP deficiencies at API manufacturers.
The revised Annex 15 is expected to strengthen expectations for process development, clarify concurrent validation, extend third-party validation oversight, and emphasise robust failure investigations and transport validation under a stronger quality risk management (QRM) framework aligned with ICH Q9(R1).
This article outlines what API manufacturers should prepare now to align qualification and validation practices with the forthcoming Annex 15 expectations.
From Guidance to Compliance Anchor
For API manufacturers, the impact is twofold. Regulators will expect a more structured, documented approach to qualification and validation, and they will verify it during inspections of API facilities under EU and PIC/S inspectorates.
Topics such as User Requirement Specifications (URS), FAT/SAT, full qualification stages (DQ/IQ/OQ/PQ), process validation (including solvent recovery), transport verification, and periodic review will become explicit compliance anchors rather than optional good practice. This also implies stronger control over outsourced validation work and clearer, data-driven investigations when acceptance criteria are not met.
Preparing a Risk-Based Validation Lifecycle
QbD Group supports API manufacturers in translating these evolving Annex 15 expectations into a pragmatic, lifecycle-based validation roadmap rather than a last-minute compliance scramble.
Building on experience in Annex 15 and risk-based validation, QbD performs structured gap assessments against the evolving Annex 15 text and Part II, identifying where current qualification, validation, and change control practices fall short. Using QRM tools aligned with ICH Q9(R1), QbD supports redesign of validation master plans, process validation strategies (including continuous process verification or hybrid models), and supplier or third-party validation oversight.
Consultants also help define or refine URS, FAT/SAT, and lifecycle qualification strategies for equipment and systems critical to API quality, embedding risk review and periodic requalification within the Pharmaceutical Quality System.
Building an Inspection-Ready Validation Story
QbD also coaches API manufacturers in building an inspection-ready validation story: how development data, risk assessments, validation protocols, deviation investigations, and transport studies collectively demonstrate control of critical quality attributes and prevention of unexpected impurities such as nitrosamines.
Acting now, during the concept and draft guideline phase, allows API companies to spread workload, pilot updated approaches on selected processes, and enter the final Annex 15 implementation phase with a mature, defensible validation framework rather than reacting to corrective actions after inspections.
Preparing API validation systems for the Annex 15 revision?
QbD Group helps API manufacturers assess gaps, redesign lifecycle validation strategies, and build inspection-ready qualification frameworks aligned with Annex 15 and ICH Q9(R1).
About the Author
Global Head Qualification & Validation
Jo Doucet is an expert in qualification and validation with over 20 years of experience in the pharmaceutical industry. He leads the Qualification/Validation division at QbD Group, supporting teams and clients in GxP compliance projects across manufacturing, IT, QC, and medical devices.
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