Validation has always been a cornerstone of GMP compliance. However, the recently published EMA/PIC/S Concept Paper on the revision of Annex 15 suggests that regulators are now looking beyond the successful execution of qualification and validation activities.
The focus is increasingly shifting towards three key elements:
- Stronger process knowledge
- Better use of Quality Risk Management
- Greater control throughout the product lifecycle
Although the revision was triggered by the lessons learned from the nitrosamine contamination cases, its impact is expected to extend far beyond that specific issue. The proposal addresses how manufacturers develop, qualify, validate, monitor and continuously improve their processes over time.
Why is Annex 15 being revised?
According to the Concept Paper, inspections and regulatory assessments performed after the nitrosamine events identified recurring weaknesses in areas such as process understanding, investigation of quality issues and contamination control. These findings led regulators to conclude that additional guidance and greater consistency are needed across the industry.
The objective is not to create a completely new framework. Instead, the revision aims to reinforce existing GMP principles while aligning Annex 15 with the latest expectations from ICH Q9(R1) on Quality Risk Management.
A major driver of this revision is also the proposed extension of Annex 15 from optional supplementary guidance to a mandatory expectation for manufacturers of chemical and biological active substances.
Validation is a lifecycle activity
One of the clearest messages emerging from the Concept Paper is that validation should not be treated as a one-time exercise.
Regulators are placing increasing emphasis on maintaining a validated state throughout the lifecycle of a process. This includes not only the initial qualification and validation activities, but also ongoing monitoring, periodic review and continuous process understanding.
The draft revision is expected to reinforce concepts such as:
- Robust process development
- Understanding critical process parameters
- Continuous Process Verification (CPV)
- Periodic review of validated systems and processes
In other words, demonstrating that a process worked during validation may no longer be enough. Companies will also need to demonstrate how they continue to understand and control that process over time.
A stronger role for Quality Risk Management
Risk-based thinking is already embedded in GMP, but the revised Annex 15 is expected to further integrate Quality Risk Management into qualification and validation activities.
The Concept Paper specifically refers to the application of ICH Q9(R1) principles and the use of risk reviews to support lifecycle management decisions. This reflects a broader industry trend towards making quality decisions based on science, knowledge and data rather than relying solely on procedural compliance.
For many organisations, the challenge will not be conducting risk assessments. The challenge will be demonstrating how those assessments influence real decisions throughout the lifecycle of equipment, systems and processes.
Looking beyond process validation
Annex 15 is not only about validating manufacturing processes. The revision is expected to reinforce how companies define, purchase, qualify and control equipment, systems, suppliers and outsourced services that may impact product quality.
It also reflects a broader view of validation, covering activities that have traditionally received less attention, such as recovery processes, transportation verification and the investigation of results that fail predefined acceptance criteria.
The message is clear: manufacturers are expected to understand and control not only the production process itself, but also the wider activities that may affect product quality.
What happens next?
At this stage, only the Concept Paper has been published and drafting activities are ongoing. While the original timeline was ambitious, the industry does not expect the draft guideline to be available before late 2026, with the final version likely to follow thereafter.
This means there is still time for companies to prepare.
Rather than waiting for the final text, manufacturers can already start reviewing whether their current systems adequately support:
- Process knowledge management
- Validation lifecycle management
- Change control effectiveness
- Supplier and contractor oversight
- Quality Risk Management integration
These topics are already closely aligned with current inspection expectations and are unlikely to disappear from the final revision.
Final thoughts
The proposed revision of Annex 15 is about much more than making the guideline mandatory for certain manufacturers.
It is another step towards a lifecycle-based approach where validation, qualification, risk management and process knowledge are tightly connected.
The companies that will navigate this transition most successfully are unlikely to be those with the largest number of protocols. They will be the ones that can clearly demonstrate understanding, control and continuous oversight of their processes.
How Qualipharma can help
Many of the themes highlighted in the Concept Paper are already common topics during GMP inspections.
At Qualipharma, we support manufacturers in:
- Gap assessments against evolving GMP expectations
- Validation and qualification strategy reviews
- Validation Master Plan development and remediation
- Risk management integration in validation activities
- Supplier and contractor qualification programmes
- Inspection readiness and response to regulatory findings
The final text may still be some time away. However, strengthening validation and lifecycle management systems now can reduce future compliance risks and help organisations approach upcoming inspections with greater confidence.
