Practical Guide to Annex 15: The Step-by-Step Qualification and Validation Process

Beyond IQ/OQ/PQ, the Lifecycle Approach of Annex 15

In the GMP world, "validation" has for decades been synonymous with the "3-batch rule." A fixed ritual: a system was installed, IQ (Installation Qualification), OQ (Operational Qualification), and PQ (Performance Qualification) were performed, three compliant batches were produced, and the report was filed.

Annex 15 of the EU GMP (2015 revision) has swept away this static approach.

Aligning with international guidelines (ICH Q8, Q9, Q10) and the FDA's "Process Validation Guidance" (2011), Annex 15 formally introduced the life cycle approach and Quality Risk Management (QRM) .

This means that validation is no longer an event, but a continuous process that begins before design and ends only with the decommissioning of the plant. For validation and QA professionals, this requires a shift in mindset and a structured working method.

Let's see how to implement Annex 15 in a practical, step-by-step process.

🗺️ Phase 1 (Planning): The Validation Master Plan (VMP)

Before writing any protocol, a strategy is needed. The Validation Master Plan (VMP) is the planning document required by Annex 15 that defines what, how, and why validation is performed.

A robust VMP, as required by Section 4.3 of the Annex, shall include:

1. The Validation Policy: The company philosophy (e.g. risk-based approach, use of C&Q data, etc.).
2. Organization and Responsibilities: Who does what (Validation, QA, Engineering, Production).
3. Systems List: An inventory of facilities, processes, utilities, and computerized systems, with their current validation status.
4. Risk Management (QRM): How the QRM (Annex 20) will be used to determine the extent and priority of validations.
5. Re-qualification Strategy: No longer "every 5 years", but a risk-based and data-driven approach based on "Continued Verification".
6. Document Management: How protocols, reports, deviations, and change control will be managed in the context of validation.

GMP Best Practice: The VMP should not be a "dead" document. It should be updated regularly (at least annually or following major changes) and used to plan validation resources.

🏗️ Phase 2 (Specification & Design): DQ and the Importance of "Risk-Based"

Validation begins before you purchase the system.

• URS (User Requirements Specification): The user (Production, QC) defines what the facility must do. QA adds GMP requirements (e.g., sanitization, data integrity, suitable materials).
• DQ (Design Qualification): Annex 15 defines it as "documented verification that the proposed design [...] is fit for its intended use." At this stage, the validation team and QA must challenge the engineering design to ensure it is "validable."

Be careful... Leverage FAT (Factory Acceptance Testing) and SAT (Site Acceptance Testing) . Annex 15 encourages the use of these tests, provided they are documented and supervised (including by QA), to "lighten" subsequent IQ/OQ tests, avoiding unnecessary duplication. This is an efficient, risk-based approach, in line with ISPE guidelines (e.g., Baseline Guide 5).

⚙️ Phase 3 (Execution): Qualification (IQ, OQ, PQ)

This is the classic operational phase, but Annex 15 calls for a risk-focused approach.

1. Installation Qualification (IQ):
• Objective: Is the system installed as designed?
• What to check: Check P&IDs, wetted materials, calibrations, utility connections, supplier documentation.
2. Operational Qualification (OQ):
• Objective: Is the system performing as per operating specifications?
• What to check: Test operating ranges (min/max), alarms, automatic sequences, safety interlocks, operating procedures (SOPs).
3. Performance Qualification (PQ):
• Objective: Does the plant consistently produce a quality product under real-world conditions?
• What to check: Worst-case testing, process simulations (e.g., Media Fill for Annex 1), robustness, product uniformity.

🔄 Phase 4 (Lifecycle): Process Validation and CPV

Here Annex 15 introduced the most radical changes (Section 5).

Stop Retrospective Validation

Annex 15 is categorical: retrospective validation (based only on historical data from batches already produced) "is no longer considered an acceptable approach." If you have unvalidated legacy processes, you must plan for prospective validation.

The Three Approaches to Process Validation (PV)

Annex 15, aligning with FDA, offers flexibility:

1. Traditional Approach: The classic validation on a defined number of batches (e.g., 3 batches). It is still valid, especially for simple and well-understood processes.
2. Continuous Process Verification (CPV): For processes developed through Quality by Design (QbD), continuous monitoring can be used instead of batch monitoring. This requires a high level of process maturity and robust statistical control (SPC) systems.
3. Hybrid Approach: This is the most common. One to three PQ/PV batches are run and then a "Continued Process Verification" (or Ongoing Process Verification - OPV) phase is entered.

The never-ending "Phase 5": Continued Process Verification (CPV/OPV)

Annex 15 requires that, after PQ, the process be maintained in a controlled state through continuous monitoring.

• What to do in practice?
• Identify CPPs (Critical Process Parameters) and CQAs (Critical Quality Attributes).
• Collect this data for each trading lot.
• Analyze them statistically (e.g. control charts, Cpk) during the annual Product Quality Review (PQR).
• Objective: Identify process drifts before they generate an OOS (Out of Specification).

🧼 Phase 6 (Special Areas): Cleaning & Transport

Annex 15 has elevated the importance of two often overlooked areas:

• Cleaning Validation:
• What's changing: You can no longer use arbitrary limits (e.g., "10 ppm" or "1/1000 of the dose").
• What to do: Residue limits must be based on scientific toxicological data (PDE - Permitted Daily Exposure), as required by EMA guidelines. This requires close collaboration between QA, Validation, and toxicologists.
• Transport Validation:
• What's changing: Transport is formally included in Annex 15.
• What to do: Shipping routes, containers and data loggers need to be qualified, simulating worst-case conditions (e.g. summer/winter).

🚫 Common Errors and Inspection Findings (from Section 6.5)

• Error: Having processes in commercial use without any validation (as highlighted in a 2025 FDA Warning Letter).
• Error: Implementing a Change Control (e.g., batch scale-up, sieve change) without re-evaluating the impact on the validation state.
• Error: Still using obsolete (10 ppm) and non-PDE based cleanup limits.
• Error: Neglecting Data Integrity (e.g., raw qualification files not saved or reviewed).

✅ Summary Operational Checklist for Annex 15 (from Section 6.6)

Use this mini-checklist for a quick self-assessment:

1. VMP: Do we have an updated VMP that reflects the risk-based strategy?
2. Retrospective Validation: Have we eliminated all processes based on retrospective validation?
3. QRM: Do we use QRM to determine the extent of qualification testing?
4. Cleaning Validation: Are our cleaning limits based on toxicological data (PDE)?
5. CPV: Do we have a Continued Process Verification system to monitor processes after PQ (and do we use it in PQR)?
6. Change Control: Does our Change Control system automatically trigger a validation status impact assessment?

✅ Conclusion: Validation as a Driver of Quality

Annex 15 has transformed validation from a bureaucratic "cost" to a strategic investment. A robust validation program, based on lifecycle and QRM, not only ensures compliance but also reduces waste, deviations, and OOS, improving production efficiency.

Implementing this approach requires expertise, planning, and rigorous documentation.

Our comprehensive operational guide explores each section of Annex 15, providing detailed checklists, ISPE best practices, and sample protocols to help you build a robust, audit-proof validation system.

Learn more with the complete guide on GuideGxP.com